LACTATION SECTION.


8.2 Lactation Risk Summary. Amlodipine and atorvastatin tablets are contraindicated during breastfeeding.. Atorvastatin Atorvastatin use is contraindicated during breastfeeding [see Contraindications (4)]. There is no available information on the effects of the drug on the breastfed infant or the effects of the drug on milk production. It is not known whether atorvastatin is present in human milk, but it has been shown that another drug in this class passes into human milk and atorvastatin is present in rat milk. Because of the potential for serious adverse reactions in breastfed infant, advise women that breastfeeding is not recommended during treatment with amlodipine and atorvastatin tablets.. Amlodipine Limited available data from published clinical lactation study reports that amlodipine is present in human milk at an estimated median relative infant dose of 4.2%. No adverse effects of amlodipine on the breastfed infant have been observed. There is no available information on the effects of amlodipine on milk production.

RECENT MAJOR CHANGES SECTION.


Dosage and Administration (2) 12/2019Warnings and Precautions, Myopathy and Rhabdomyolysis (5.1) 12/2019.

RENULLL IMPAIRMENT SUBSECTION.


Renal Impairment Amlodipine. The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial amlodipine dose.. Atorvastatin. Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin; thus, dose adjustment of atorvastatin in patients with renal dysfunction is not necessary [see Dosage and Administration (2) and Warnings and Precautions (5.1)].

RISKS.


Risk Summary. Amlodipine and atorvastatin tablets are contraindicated in women who are pregnant.. Atorvastatin Atorvastatin is contraindicated for use in pregnant women since safety in pregnant women has not been established and there is no apparent benefit of lipid-lowering drugs during pregnancy. Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, atorvastatin may cause fetal harm when administered to pregnant woman. Amlodipine and atorvastatin tablets should be discontinued as soon as pregnancy is recognized [see Contraindications (4)]. Limited published data on the use of atorvastatin are insufficient to determine drug-associated risk of major congenital malformations or miscarriage. In animal reproduction studies in rats and rabbits there was no evidence of embryo-fetal toxicity or congenital malformations at doses up to 30 and 20 times, respectively, the human exposure at the MRHD of 80 mg, based on body surface area (mg/m2). In rats administered atorvastatin during gestation and lactation, decreased postnatal growth and development was observed at doses >= times the MRHD (see Data ).. Amlodipine The limited available data based on post-marketing reports with amlodipine use in pregnant women are not sufficient to inform drug-associated risk for major birth defects and miscarriage. There are risks to the mother and fetus associated with poorly controlled hypertension in pregnancy (see Clinical Considerations ). In animal reproduction studies, there was no evidence of adverse developmental effects when pregnant rats and rabbits were treated orally with amlodipine maleate during organogenesis at doses approximately 10 and 20-times MRHD, respectively. However for rats, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold). Amlodipine has been shown to prolong both the gestation period and the duration of labor in rats at this dose (see Data ).The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.. Clinical Considerations Disease-associated Maternal and/or Embryo/Fetal Risk. Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly.. Data Human Data. Atorvastatin: Limited published data on atorvastatin calcium from observational studies, meta-analyses and case reports have not shown an increased risk of major congenital malformations or miscarriage. Rare reports of congenital anomalies have been received following intrauterine exposure to other HMG-CoA reductase inhibitors. In review of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or lovastatin, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed what would be expected in the general population. The number of cases is adequate to exclude >= to 4-fold increase in congenital anomalies over the background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified.. Animal Data. Atorvastatin: Atorvastatin crosses the rat placenta and reaches level in fetal liver equivalent to that of maternal plasma. When administered to pregnant rats and rabbits during organogenesis at oral doses up to 300 mg/kg/day and 100 mg/kg/day, respectively, atorvastatin was not teratogenic in rats at doses up to 300 mg/kg/day or in rabbits at doses up to 100 mg/kg/day. These doses resulted in multiples of about 30 times (rat) or 20 times (rabbit) the human exposure at the MRHD based on surface area (mg/m2). In rats, the maternally toxic dose of 300 mg/kg resulted in increased post-implantation loss and decreased fetal body weight. At the maternally toxic doses of 50 and 100 mg/kg/day in rabbits, there was increased post-implantation loss, and at 100 mg/kg/day fetal body weights were decreased.In study in pregnant rats administered atorvastatin calcium at doses equivalent to 20, 100, or 225 mg/kg/day, from gestation day through to lactation day 20 (weaning), there was decreased survival at birth, postnatal day 4, weaning, and post-weaning in pups of mothers dosed with 225 mg/kg/day, dose at which maternal toxicity was observed. Pup body weight was decreased through postnatal day 21 at 100 mg/kg/day, and through postnatal day 91 at 225 mg/kg/day. Pup development was delayed (rotorod performance at 100 mg/kg/day and acoustic startle at 225 mg/kg/day; pinnae detachment and eye-opening at 225 mg/kg/day). These doses of atorvastatin correspond to times (100 mg/kg) and 22 times (225 mg/kg) the human exposure at the MRHD, based on AUC.AmlodipineNo evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine maleate at doses up to 10 mg amlodipine/kg/day (approximately 10 and 20 times the MRHD based on body surface area, respectively) during their respective periods of major organogenesis. However, for rats, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold) in rats receiving amlodipine maleate at dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating and gestation. Amlodipine maleate has been shown to prolong both the gestation period and the duration of labor in rats at this dose.

SPL PATIENT PACKAGE INSERT SECTION.


Patient Information Amlodipine and Atorvastatin Tablets, USP(am loe di peen tor va stat in)Read the patient information that comes with amlodipine and atorvastatin tablets before you start taking them, and each time you get refill. There may be new information. This information does not replace talking with your doctor about your condition or treatment. If you have any questions about amlodipine and atorvastatin tablets, ask your doctor or pharmacist.What are amlodipine and atorvastatin tabletsAmlodipine and atorvastatin tablets are prescription drug that combines Norvasc(R) (amlodipine besylate) and Lipitor(R) (atorvastatin calcium) in one pill.Amlodipine and atorvastatin tablets are used in adults who need both Norvasc and Lipitor.Norvasc is used to treat: ohigh blood pressure (hypertension) and ochest pain (angina) and oblocked arteries of the heart (coronary artery disease)Lipitor is used to lower the levels of bad cholesterol and triglycerides in your blood. It can also raise the levels of good cholesterol.Lipitor is also used to lower the risk for heart attack, stroke, certain types of heart surgery, and chest pain in patients who have heart disease or risk factors for heart disease such as:oage, smoking, high blood pressure, low levels of good cholesterol, heart disease in the family.Lipitor can lower the risk for heart attack or stroke in patients with diabetes and risk factors such as:odiabetic eye or kidney problems, smoking, or high blood pressure.Amlodipine and atorvastatin tablets have not been studied in children.Who should not use amlodipine and atorvastatin tabletsDo not use amlodipine and atorvastatin tablets if you:oAre pregnant or think you may be pregnant, or are planning to become pregnant. Amlodipine and atorvastatin tablets may harm your unborn baby. If you get pregnant, stop taking amlodipine and atorvastatin tablets and call your doctor right away.oAre breastfeeding. Amlodipine and atorvastatin can pass into your breast milk and may harm your baby. Do not breastfeed if you take amlodipine and atorvastatin tablets. oHave liver problems. oAre allergic to anything in amlodipine and atorvastatin tablets. The active ingredients are atorvastatin calcium and amlodipine besylate. See the end of this leaflet for complete list of ingredients.What should tell my doctor before taking amlodipine and atorvastatin tabletsTell your doctor about all of your health conditions, including, if you have:oheart diseaseomuscle aches or weaknessodiabetesothyroid problemsokidney problemsoor drink more than glasses of alcohol dailyTell your doctor about all the medicines you take including prescription and nonprescription medicines, vitamins, and herbal supplements. Amlodipine and atorvastatin tablets and some other medicines can interact, causing serious side effects. Especially tell your doctor if you take medicines for:oyour immune system oinfectionsocholesterolohepatitis virusobirth controloheart failureoHIV (AIDS)oanti-viralsYou can use nitroglycerin and amlodipine and atorvastatin tablets together. If you take nitroglycerin for chest pain (angina), do not stop taking it while taking amlodipine and atorvastatin tablets.Know all the medicines you take. Keep list of them with you to show your doctor and pharmacist.How should take amlodipine and atorvastatin tabletsoTake amlodipine and atorvastatin tablets once day, exactly as your doctor tells you. Do not change your dose or stop amlodipine and atorvastatin tablets without talking to your doctor.oTake amlodipine and atorvastatin tablets each day at any time of day, at about the same time each day. Amlodipine and atorvastatin tablets can be taken with or without food.oDo not break the tablets before taking them. Talk to your doctor if you have problem swallowing pills.oYour doctor should start you on low-fat diet before giving you amlodipine and atorvastatin tablets. Stay on this low-fat diet when you take amlodipine and atorvastatin tablets.oIf you miss dose, take it as soon as you remember. Do not take amlodipine and atorvastatin tablets if it has been more than 12 hours since your missed dose. Just take the next dose at your regular time. Do not take doses of amlodipine and atorvastatin tablets at the same time.oIf too many amlodipine and atorvastatin tablets are taken by accident, call your doctor or poison control center, or go to the nearest emergency room.What should avoid while taking amlodipine and atorvastatin tabletsoAvoid getting pregnant. If you get pregnant, stop taking amlodipine and atorvastatin tablets right away and call your doctor.oDo not breastfeed. Amlodipine and atorvastatin can pass into your breast milk and may harm your baby.What are possible side effects of amlodipine and atorvastatin tabletsAmlodipine and atorvastatin tablets can cause serious side effects. These side effects happen only to small number of people. Your doctor can monitor you for them. These side effects usually go away if your dose is lowered or amlodipine and atorvastatin tablets are stopped. These serious side effects include:oMuscle problems. Amlodipine and atorvastatin tablets can cause serious muscle problems that can lead to kidney problems, including kidney failure. You have higher chance for muscle problems if you are taking certain other medicines with amlodipine and atorvastatin tablets.oLiver problems. Your doctor should do blood tests to check your liver before you start taking amlodipine and atorvastatin tablets and if you have symptoms of liver problems while you take amlodipine and atorvastatin tablets. Call your doctor right away if you have the following symptoms of liver problems:ofeel tired or weakoloss of appetiteoupper belly painodark amber colored urineoyellowing of your skin or the whites of your eyes oLow blood pressure or dizzinessoMuscle rigidity, tremor and/or abnormal muscle movementCall your doctor right away if:oyou have muscle problems like weakness, tenderness, or pain that happen without good reason, especially if you also have fever or feel more tired than usual. This may be an early sign of rare muscle problem.omuscle problems that do not go away even after your doctor has advised you to stop taking amlodipine and atorvastatin tablets. Your doctor may do further tests to diagnose the cause of your muscle problems.oallergic reactions including swelling of the face, lips, tongue, and/or throat that may cause difficulty in breathing or swallowing which may require treatment right awayoyou have nausea and vomiting, stomach painoyou are passing brown or dark-colored urineoyou feel more tired than usualoyour skin and white of your eyes get yellowoyou have allergic skin reactionsoChest pain that does not go away or gets worse. Sometimes when you start amlodipine and atorvastatin tablets or increase your dose, chest pain can get worse or heart attack can happen. If this happens, call your doctor or go to the emergency room right away.Common side effects of amlodipine and atorvastatin tablets include:odiarrheaoswelling of your legs or anklesonauseaoupset stomachomuscle and joint painoalterations in some laboratory blood testsAdditional side effects have been reported: tiredness, tendon problems, memory loss, and confusion.Talk to your doctor or pharmacist about side effects that bother you or do not go away. There are other side effects of amlodipine and atorvastatin tablets. Ask your doctor or pharmacist for complete list.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How do store amlodipine and atorvastatin tabletsoStore amlodipine and atorvastatin tablets at room temperature, 20 to 25C (68 to 77F).oDo not keep medicine that is out-of-date or that you no longer need.oKeep amlodipine and atorvastatin tablets and all medicines out of the reach of children. Keep medicines in places where children cannot get them.General information about amlodipine and atorvastatin tabletsMedicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use amlodipine and atorvastatin tablets for condition for which they were not prescribed. Do not give amlodipine and atorvastatin tablets to other people, even if they have the same problem you have. They may harm them. This leaflet summarizes the most important information about amlodipine and atorvastatin tablets. If you want more information, talk with your doctor. Ask your doctor or pharmacist for information about amlodipine and atorvastatin tablets written for health professionals. You can also call Mylan at 1-877-446-3679 (1-877-4-INFO-RX).What is high blood pressure (hypertension)You have high blood pressure when the force of blood against the walls of your arteries stays high. This can damage your heart and other parts of your body. Drugs that lower blood pressure lower your risk of having stroke or heart attack.What is angina (chest pain)Angina is pain that keeps coming back when part of your heart does not get enough blood. It feels like something is pressing or squeezing your chest under the breastbone. Sometimes you can feel it in your shoulders, arms, neck, jaw, or back.What is cholesterolCholesterol is fat-like substance made in your body. It is also found in foods. You need some cholesterol for good health, but too much is not good for you. Cholesterol can clog your blood vessels.What is heart attackA heart attack occurs when heart muscle does not get enough blood. Symptoms include chest pain, trouble breathing, nausea, and weakness. Heart muscle cells may be damaged or die. The heart cannot pump well or may stop beating.What is strokeA stroke occurs when nerve cells in the brain do not get enough blood. The cells may be damaged or die. The damaged cells may cause weakness or problems speaking or thinking.What are the ingredients in amlodipine and atorvastatin tabletsActive ingredients: amlodipine besylate, atorvastatin calciumInactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hydroxypropyl cellulose, L-arginine, lecithin, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, pregelatinized starch (corn), sodium carbonate anhydrous, talc, titanium dioxide and xanthan gum. The 10 mg/10 mg, 10 mg/20 mg, 10 mg/40 mg and 10 mg/80 mg tablets also contain FD&C Blue No. Aluminum Lake.The brands listed are trademarks of their respective owners.Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.Manufactured by: Mylan Laboratories Limited Hyderabad -- 500 096, India750XXXXXRevised: 2/2020MX:AMAT:R7. ohigh blood pressure (hypertension) and ochest pain (angina) and oblocked arteries of the heart (coronary artery disease). oage, smoking, high blood pressure, low levels of good cholesterol, heart disease in the family.. odiabetic eye or kidney problems, smoking, or high blood pressure.. oAre pregnant or think you may be pregnant, or are planning to become pregnant. Amlodipine and atorvastatin tablets may harm your unborn baby. If you get pregnant, stop taking amlodipine and atorvastatin tablets and call your doctor right away.. oAre breastfeeding. Amlodipine and atorvastatin can pass into your breast milk and may harm your baby. Do not breastfeed if you take amlodipine and atorvastatin tablets. oHave liver problems. oAre allergic to anything in amlodipine and atorvastatin tablets. The active ingredients are atorvastatin calcium and amlodipine besylate. See the end of this leaflet for complete list of ingredients.. oheart disease. omuscle aches or weakness. odiabetes. othyroid problems. okidney problems. oor drink more than glasses of alcohol daily. oyour immune system oinfections. ocholesterol. ohepatitis virus. obirth control. oheart failure. oHIV (AIDS). oanti-virals. oTake amlodipine and atorvastatin tablets once day, exactly as your doctor tells you. Do not change your dose or stop amlodipine and atorvastatin tablets without talking to your doctor.. oTake amlodipine and atorvastatin tablets each day at any time of day, at about the same time each day. Amlodipine and atorvastatin tablets can be taken with or without food.. oDo not break the tablets before taking them. Talk to your doctor if you have problem swallowing pills.. oYour doctor should start you on low-fat diet before giving you amlodipine and atorvastatin tablets. Stay on this low-fat diet when you take amlodipine and atorvastatin tablets.. oIf you miss dose, take it as soon as you remember. Do not take amlodipine and atorvastatin tablets if it has been more than 12 hours since your missed dose. Just take the next dose at your regular time. Do not take doses of amlodipine and atorvastatin tablets at the same time.. oIf too many amlodipine and atorvastatin tablets are taken by accident, call your doctor or poison control center, or go to the nearest emergency room.. oAvoid getting pregnant. If you get pregnant, stop taking amlodipine and atorvastatin tablets right away and call your doctor.. oDo not breastfeed. Amlodipine and atorvastatin can pass into your breast milk and may harm your baby.. oMuscle problems. Amlodipine and atorvastatin tablets can cause serious muscle problems that can lead to kidney problems, including kidney failure. You have higher chance for muscle problems if you are taking certain other medicines with amlodipine and atorvastatin tablets.. oLiver problems. Your doctor should do blood tests to check your liver before you start taking amlodipine and atorvastatin tablets and if you have symptoms of liver problems while you take amlodipine and atorvastatin tablets. Call your doctor right away if you have the following symptoms of liver problems:ofeel tired or weakoloss of appetiteoupper belly painodark amber colored urineoyellowing of your skin or the whites of your eyes ofeel tired or weak. oloss of appetite. oupper belly pain. odark amber colored urine. oyellowing of your skin or the whites of your eyes. oLow blood pressure or dizziness. oMuscle rigidity, tremor and/or abnormal muscle movement. oyou have muscle problems like weakness, tenderness, or pain that happen without good reason, especially if you also have fever or feel more tired than usual. This may be an early sign of rare muscle problem.. omuscle problems that do not go away even after your doctor has advised you to stop taking amlodipine and atorvastatin tablets. Your doctor may do further tests to diagnose the cause of your muscle problems.. oallergic reactions including swelling of the face, lips, tongue, and/or throat that may cause difficulty in breathing or swallowing which may require treatment right away. oyou have nausea and vomiting, stomach pain. oyou are passing brown or dark-colored urine. oyou feel more tired than usual. oyour skin and white of your eyes get yellow. oyou have allergic skin reactions. oChest pain that does not go away or gets worse. Sometimes when you start amlodipine and atorvastatin tablets or increase your dose, chest pain can get worse or heart attack can happen. If this happens, call your doctor or go to the emergency room right away.. odiarrhea. oswelling of your legs or ankles. onausea. oupset stomach. omuscle and joint pain. oalterations in some laboratory blood tests. oStore amlodipine and atorvastatin tablets at room temperature, 20 to 25C (68 to 77F).. oDo not keep medicine that is out-of-date or that you no longer need.. oKeep amlodipine and atorvastatin tablets and all medicines out of the reach of children. Keep medicines in places where children cannot get them.

ADVERSE REACTIONS SECTION.


6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label:oRhabdomyolysis and myopathy [see Warnings and Precautions (5.1)]oLiver enzyme abnormalities [see Warnings and Precautions (5.2)]. oRhabdomyolysis and myopathy [see Warnings and Precautions (5.1)]. oLiver enzyme abnormalities [see Warnings and Precautions (5.2)]. Most common adverse reaction (3% greater than placebo) to amlodipine is edema (6.1).Most common adverse reactions leading to atorvastatin discontinuation were myalgia and diarrhea (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.. Amlodipine and Atorvastatin Tablets. Amlodipine and atorvastatin tablets (amlodipine besylate/atorvastatin calcium) have been evaluated for safety in 1,092 patients in double-blind placebo-controlled studies treated for co-morbid hypertension and dyslipidemia. In general, treatment with amlodipine and atorvastatin tablets was well tolerated. For the most part, adverse reactions have been mild or moderate in severity. In clinical trials with amlodipine and atorvastatin tablets, no adverse reactions peculiar to this combination have been observed. Adverse reactions are similar in terms of nature, severity, and frequency to those reported previously with amlodipine and atorvastatin.The following information is based on the clinical experience with amlodipine and atorvastatin.. Amlodipine. Amlodipine has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials. In general, treatment with amlodipine was well tolerated at doses up to 10 mg daily. Most adverse reactions reported during therapy with amlodipine were of mild or moderate severity. In controlled clinical trials directly comparing amlodipine (N 1,730) at doses up to 10 mg to placebo (N 1,250), discontinuation of amlodipine because of adverse reactions was required in only about 1.5% of patients and was not significantly different from placebo (about 1%). The most commonly reported side effects more frequent than placebo are dizziness and edema. The incidence (%) of side effects that occurred in dose-related manner are as follows:AmlodipinePlaceboN 5202.5 mgN 2755 mgN 29610 mgN 268Edema1.83.010.80.6Dizziness1.13.43.41.5Flushing0.71.42.60.0Palpitations0.71.44.50.6Other adverse reactions that were not clearly dose related but were reported at an incidence greater than 1.0% in placebo-controlled clinical trials include the following:Amlodipine (%)(N 1,730)Placebo (%)(N 1,250)Fatigue4.52.8Nausea2.91.9Abdominal Pain1.60.3Somnolence1.40.6Edema, flushing, palpitations, and somnolence appear to be more common in women than in men.The following events occurred in 1% but 0.1% of patients treated with amlodipine in controlled clinical trials or under conditions of open trials or marketing experience where causal relationship is uncertain; they are listed to alert the physician to possible relationship:Cardiovascular: arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, peripheral ischemia, syncope, tachycardia, vasculitis.Central and Peripheral Nervous System: hypoesthesia, neuropathy peripheral, paresthesia, tremor, vertigo.Gastrointestinal: anorexia, constipation, dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia.General: allergic reaction, asthenia,1 back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease.Musculoskeletal System: arthralgia, arthrosis, muscle cramps,1 myalgia.Psychiatric: sexual dysfunction (male1 and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization.Respiratory System: dyspnea,1 epistaxis.Skin and Appendages: angioedema, erythema multiforme, pruritus,1 rash,1 rash erythematous, rash maculopapular.Special Senses: abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus.Urinary System: micturition frequency, micturition disorder, nocturia.Autonomic Nervous System: dry mouth, sweating increased.Metabolic and Nutritional: hyperglycemia, thirst.Hemopoietic: leukopenia, purpura, thrombocytopenia.1 These events occurred in less than 1% in placebo-controlled trials, but the incidence of these side effects was between 1% and 2% in all multiple dose studies.Amlodipine therapy has not been associated with clinically significant changes in routine laboratory tests. No clinically relevant changes were noted in serum potassium, serum glucose, total TG, TC, HDL-C, uric acid, blood urea nitrogen, or creatinine.. Atorvastatin. In the atorvastatin placebo-controlled clinical trial database of 16,066 patients (8,755 atorvastatin vs. 7,311 placebo; age range 10-93 years, 39% women; 91% Caucasians, 3% Blacks, 2% Asians, 4% other) with median treatment duration of 53 weeks, 9.7% of patients on atorvastatin and 9.5% of the patients on placebo discontinued because of adverse reactions regardless of causality. The five most common adverse reactions in patients treated with atorvastatin that led to treatment discontinuation and occurred at rate greater than placebo were: myalgia (0.7%), diarrhea (0.5%), nausea (0.4%), alanine aminotransferase increase (0.4%), and hepatic enzyme increase (0.4%).The most commonly reported adverse reactions (incidence >= 2% and greater than placebo) regardless of causality, in patients treated with atorvastatin in placebo-controlled trials (n 8,755) were: nasopharyngitis (8.3%), arthralgia (6.9%), diarrhea (6.8%), pain in extremity (6.0%), and urinary tract infection (5.7%).Table summarizes the frequency of clinical adverse reactions, regardless of causality, reported in >= 2% and at rate greater than placebo in patients treated with atorvastatin (n 8,755), from seventeen placebo-controlled trials.Table 3. Clinical Adverse Reactions Occurring in >= 2% in Patients Treated with Any Dose of Atorvastatin and at an Incidence Greater than Placebo Regardless of Causality (% of Patients)Adverse ReactionAdverse Reaction >= 2% in any dose greater than placebo.Any DoseN 8,75510 mgN 3,90820 mgN 18840 mgN 60480 mgN 4,055PlaceboN 7,311Nasopharyngitis8.312.95.37.04.28.2Arthralgia6.98.911.710.64.36.5Diarrhea6.87.36.414.15.26.3Pain in extremity6.08.53.79.33.15.9Urinary tract infection5.76.96.48.04.15.6Dyspepsia4.75.93.26.03.34.3Nausea4.03.73.77.13.83.5Musculoskeletal pain3.85.23.25.12.33.6Muscle spasms3.64.64.85.12.43.0Myalgia3.53.65.98.42.73.1Insomnia3.02.81.15.32.82.9Pharyngolaryngeal pain2.33.91.62.80.72.1Other adverse reactions reported in placebo-controlled studies include:Body as Whole: malaise, pyrexia; Digestive System: abdominal discomfort, eructation, flatulence, hepatitis, cholestasis;Musculoskeletal System: musculoskeletal pain, muscle fatigue, neck pain, joint swelling; Metabolic and Nutritional System: transaminases increase, liver function test abnormal, blood alkaline phosphatase increase, creatine phosphokinase increase, hyperglycemia; Nervous System: nightmare; Respiratory System: epistaxis; Skin and Appendages: urticaria; Special Senses: vision blurred, tinnitus; Urogenital System: white blood cells urine positive.. Treating to New Targets Study (TNT) In TNT [see Clinical Studies (14.6)] involving 10,001 subjects (age range 29-78 years, 19% women; 94.1% Caucasians, 2.9% Blacks, 1.0% Asians, 2.0% other) with clinically evident CHD treated with atorvastatin 10 mg daily (n 5,006) or atorvastatin 80 mg daily (n 4,995), serious adverse reactions and discontinuations because of adverse reactions increased with dose. Persistent transaminase elevations (>= x ULN twice within 4-10 days) occurred in 62 (1.3%) individuals with atorvastatin 80 mg and in nine (0.2%) individuals with atorvastatin 10 mg. Elevations of CK (>= 10 ULN) were low overall, but were higher in the high-dose atorvastatin treatment group (13, 0.3%) compared to the low-dose atorvastatin group (6, 0.1%).. Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) In SPARCL involving 4,731 subjects (age range 21-92 years, 40% women; 93.3% Caucasians, 3.0% Blacks, 0.6% Asians, 3.1% other) without clinically evident CHD but with stroke or transient ischemic attack (TIA) within the previous months treated with atorvastatin 80 mg (n 2,365) or placebo (n 2,366) for median follow-up of 4.9 years, there was higher incidence of persistent hepatic transaminase elevations (>= x ULN twice within 4-10 days) in the atorvastatin group (0.9%) compared to placebo (0.1%). Elevations of CK (> 10 ULN) were rare, but were higher in the atorvastatin group (0.1%) compared to placebo (0.0%). Diabetes was reported as an adverse reaction in 144 subjects (6.1%) in the atorvastatin group and 89 subjects (3.8%) in the placebo group [see Warnings and Precautions (5.5)].In post-hoc analysis, atorvastatin 80 mg reduced the incidence of ischemic stroke (218/2,365, 9.2% vs. 274/2,366, 11.6%) and increased the incidence of hemorrhagic stroke (55/2,365, 2.3% vs. 33/2,366, 1.4%) compared to placebo. The incidence of fatal hemorrhagic stroke was similar between groups (17 atorvastatin vs. 18 placebo). The incidence of non-fatal hemorrhagic strokes was significantly greater in the atorvastatin group (38 non-fatal hemorrhagic strokes) as compared to the placebo group (16 non-fatal hemorrhagic strokes). Subjects who entered the study with hemorrhagic stroke appeared to be at increased risk for hemorrhagic stroke [7 (16%) atorvastatin vs. (4%) placebo].There were no significant differences between the treatment groups for all-cause mortality: 216 (9.1%) in the atorvastatin 80 mg/day group vs. 211 (8.9%) in the placebo group. The proportions of subjects who experienced cardiovascular death were numerically smaller in the atorvastatin 80 mg group (3.3%) than in the placebo group (4.1%). The proportions of subjects who experienced non-cardiovascular death were numerically larger in the atorvastatin 80 mg group (5.0%) than in the placebo group (4.0%).. Adverse Reactions from Clinical Studies of Atorvastatin in Pediatric Patients In 26-week controlled study in boys and postmenarchal girls with HeFH (ages 10 years to 17 years) (n 140, 31% female; 92% Caucasians, 1.6% Blacks, 1.6% Asians, 4.8% other), the safety and tolerability profile of atorvastatin 10 to 20 mg daily, as an adjunct to diet to reduce TC, LDL-C, and apo levels, was generally similar to that of placebo [see Use in Specific Populations (8.4) and Clinical Studies (14.11)].. 6.2Postmarketing Experience The following adverse reactions have been identified during post-approval of amlodipine and atorvastatin. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.. Amlodipine. The following postmarketing event has been reported infrequently where causal relationship is uncertain: gynecomastia. In postmarketing experience, jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), in some cases severe enough to require hospitalization, have been reported in association with use of amlodipine.Postmarketing reporting has also revealed possible association between extrapyramidal disorder and amlodipine.Amlodipine has been used safely in patients with chronic obstructive pulmonary disease, well-compensated congestive heart failure, coronary artery disease, peripheral vascular disease, diabetes mellitus, and abnormal lipid profiles.. Atorvastatin. Adverse reactions associated with atorvastatin therapy reported since market introduction that are not listed above, regardless of causality assessment, include the following: anaphylaxis, angioneurotic edema, bullous rashes (including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis), rhabdomyolysis, myositis, fatigue, tendon rupture, fatal and non-fatal hepatic failure, dizziness, depression, peripheral neuropathy, pancreatitis and interstitial lung disease.There have been rare reports of immune-mediated necrotizing myopathy associated with statin use [see Warnings and Precautions (5.1)].There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of weeks).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Amlodipine. Rats and mice treated with amlodipine maleate in the diet for up to years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 mg amlodipine/kg/day, showed no evidence of carcinogenic effect of the drug. For the mouse, the highest dose was, on mg/m2 basis, similar to the MRHD of 10 mg amlodipine/day.2 For the rat, the highest dose level was, on mg/m2 basis, about twice the MRHD.2 Mutagenicity studies conducted with amlodipine maleate revealed no drug related effects at either the gene or chromosome levels.There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days and females for 14 days prior to mating) at doses up to 10 mg amlodipine/kg/day (8 times the MRHD2 of 10 mg/day on mg/m2 basis).2 Based on patient weight of 50 kg.. Atorvastatin. In 2-year carcinogenicity study with atorvastatin calcium in rats at dose levels equivalent to 10, 30, and 100 mg atorvastatin/kg/day, rare tumors were found in muscle in high-dose females: in one, there was rhabdomyosarcoma and, in another, there was fibrosarcoma. This dose represents plasma AUC (0-24) value of approximately 16 times the mean human plasma drug exposure after an 80 mg oral dose.A 2-year carcinogenicity study in mice given atorvastatin calcium at dose levels equivalent to 100, 200, or 400 mg atorvastatin/kg/day resulted in significant increase in liver adenomas in high-dose males and liver carcinomas in high-dose females. These findings occurred at plasma AUC (0-24) values of approximately times the mean human plasma drug exposure after an 80 mg oral dose.In vitro, atorvastatin was not mutagenic or clastogenic in the following tests with and without metabolic activation: the Ames test with Salmonella typhimurium and Escherichia coli, the HGPRT forward mutation assay in Chinese hamster lung cells, and the chromosomal aberration assay in Chinese hamster lung cells. Atorvastatin was negative in the in vivo mouse micronucleus test.In female rats, atorvastatin at doses up to 225 mg/kg (56 times the human exposure) did not cause adverse effects on fertility. Studies in male rats performed at doses up to 175 mg/kg (15 times the human exposure) produced no changes in fertility. There was aplasia and aspermia in the epididymides of of 10 rats treated with atorvastatin calcium at dose equivalent to 100 mg atorvastatin/kg/day for months (16 times the human AUC at the 80 mg dose); testis weights were significantly lower at 30 and 100 mg/kg/day and epididymal weight was lower at 100 mg/kg/day. Male rats given the equivalent of 100 mg atorvastatin/kg/day for 11 weeks prior to mating had decreased sperm motility, spermatid head concentration, and increased abnormal sperm. Atorvastatin caused no adverse effects on semen parameters, or reproductive organ histopathology in dogs given doses of atorvastatin calcium equivalent to 10, 40, or 120 mg atorvastatin/kg/day for years.

CLINICAL PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Amlodipine and atorvastatin tablets are combination of two drugs, dihydropyridine calcium channel blocker (amlodipine) and an HMG-CoA reductase inhibitor (atorvastatin). The amlodipine component of amlodipine and atorvastatin tablets inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. The atorvastatin component of amlodipine and atorvastatin tablets is selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme to mevalonate, precursor of sterols, including cholesterol.. Amlodipine. Amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine.Amlodipine is peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause reduction in peripheral vascular resistance and reduction in blood pressure.The precise mechanisms by which amlodipine relieves angina have not been fully delineated, but are thought to include the following:. Exertional Angina In patients with exertional angina, amlodipine reduces the total peripheral resistance (afterload) against which the heart works and reduces the rate pressure product, and thus myocardial oxygen demand, at any given level of exercise.. Vasospastic Angina Amlodipine has been demonstrated to block constriction and restore blood flow in coronary arteries and arterioles in response to calcium, potassium epinephrine, serotonin, and thromboxane A2 analog in experimental animal models and in human coronary vessels in vitro. This inhibition of coronary spasm is responsible for the effectiveness of amlodipine in vasospastic (Prinzmetals or variant) angina.. Atorvastatin. Atorvastatin is selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme to mevalonate, precursor of sterols, including cholesterol. In animal models, atorvastatin lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by increasing the number of hepatic LDL receptors on the cell surface to enhance uptake and catabolism of LDL; atorvastatin also reduces LDL production and the number of LDL particles. 12.2 Pharmacodynamics Amlodipine. Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation resulting in reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by significant change in heart rate or plasma catecholamine levels with chronic dosing. Although the acute intravenous administration of amlodipine decreases arterial blood pressure and increases heart rate in hemodynamic studies of patients with chronic stable angina, chronic oral administration of amlodipine in clinical trials did not lead to clinically significant changes in heart rate or blood pressures in normotensive patients with angina.With chronic once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients. The magnitude of reduction in blood pressure with amlodipine is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105-114 mmHg) had about 50% greater response than patients with mild hypertension (diastolic pressure 90-104 mmHg). Normotensive subjects experienced no clinically significant change in blood pressures (+1/-2 mmHg).In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic studies, amlodipine has not been associated with negative inotropic effect when administered in the therapeutic dose range to intact animals and man, even when co-administered with beta-blockers to man. Similar findings, however, have been observed in normal or well-compensated patients with heart failure with agents possessing significant negative inotropic effects.Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or man. In patients with chronic stable angina, intravenous administration of 10 mg did not significantly alter A-H and H-V conduction and sinus node recovery time after pacing. Similar results were obtained in patients receiving amlodipine and concomitant beta-blockers. In clinical studies in which amlodipine was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed. In clinical trials with angina patients alone, amlodipine therapy did not alter electrocardiographic intervals or produce higher degrees of AV blocks.. Atorvastatin. Atorvastatin, as well as some of its metabolites, are pharmacologically active in humans. The liver is the primary site of action and the principal site of cholesterol synthesis and LDL clearance. Drug dosage, rather than systemic drug concentration, correlates better with LDL-C reduction. Individualization of drug dosage should be based on therapeutic response [see Dosage and Administration (2)].. Drug Interactions. Sildenafil When amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect [see Drug Interactions (7.1)]. 12.3 Pharmacokinetics Absorption. Amlodipine After oral administration of therapeutic doses of amlodipine alone, absorption produces peak plasma concentrations between and 12 hours. Absolute bioavailability has been estimated to be between 64% and 90%.. Atorvastatin After oral administration alone, atorvastatin is rapidly absorbed; maximum plasma concentrations occur within to hours. Extent of absorption increases in proportion to atorvastatin dose. The absolute bioavailability of atorvastatin (parent drug) is approximately 14% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism. Plasma atorvastatin concentrations are lower (approximately 30% for Cmax and AUC) following evening drug administration compared with morning. However, LDL-C reduction is the same regardless of the time of day of drug administration [see Dosage and Administration (2)].. Amlodipine and Atorvastatin Tablets Following oral administration of amlodipine and atorvastatin tablets, peak plasma concentrations of amlodipine and atorvastatin are seen at to 12 hours and to hours post dosing, respectively. The rate and extent of absorption (bioavailability) of amlodipine and atorvastatin from amlodipine and atorvastatin tablets are not significantly different from the bioavailability of amlodipine and atorvastatin administered separately (see above).The bioavailability of amlodipine from amlodipine and atorvastatin tablets was not affected by food. Food decreases the rate and extent of absorption of atorvastatin from amlodipine and atorvastatin tablets by approximately 32% and 11%, respectively, as it does with atorvastatin when given alone. LDL-C reduction is similar whether atorvastatin is given with or without food.. Distribution. Amlodipine Ex vivo studies have shown that approximately 93% of the circulating amlodipine drug is bound to plasma proteins in hypertensive patients. Steady-state plasma levels of amlodipine are reached after to days of consecutive daily dosing.. Atorvastatin Mean volume of distribution of atorvastatin is approximately 381 liters. Atorvastatin is >= 98% bound to plasma proteins. blood/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells. Based on observations in rats, atorvastatin calcium is likely to be secreted in human milk [see Contraindications (4) and Use in Specific Populations (8.3)].. Metabolism. Amlodipine Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism.. Atorvastatin Atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In vitro studies suggest the importance of atorvastatin metabolism by cytochrome P4503A4, consistent with increased plasma concentrations of atorvastatin in humans following co-administration with erythromycin, known inhibitor of this isozyme [see Drug Interactions (7)]. In animals, the ortho-hydroxy metabolite undergoes further glucuronidation.. Excretion. Amlodipine Elimination from the plasma is biphasic with terminal elimination half-life of about 30-50 hours. Ten percent of the parent amlodipine compound and 60% of the metabolites of amlodipine are excreted in the urine.. Atorvastatin Atorvastatin and its metabolites are eliminated primarily in bile following hepatic and/or extra-hepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin in humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours because of the contribution of active metabolites. Less than 2% of dose of atorvastatin is recovered in urine following oral administration.. Specific Populations. Geriatric Amlodipine. Elderly patients have decreased clearance of amlodipine with resulting increase in AUC of approximately 40-60%, and lower initial dose of amlodipine may be required.. Atorvastatin. Plasma concentrations of atorvastatin are higher (approximately 40% for Cmax and 30% for AUC) in healthy elderly subjects (age >= 65 years) than in young adults. Clinical data suggest greater degree of LDL-lowering at any dose of atorvastatin in the elderly population compared to younger adults [see Use in Specific Populations (8.5)].. Pediatric Amlodipine. Sixty-two hypertensive patients aged to 17 years received doses of amlodipine between 1.25 mg and 20 mg. Weight-adjusted clearance and volume of distribution were similar to values in adults.. Atorvastatin. Apparent oral clearance of atorvastatin in pediatric subjects appeared similar to that of adults when scaled allometrically by body weight as the body weight was the only significant covariate in atorvastatin population pharmacokinetics model with data including pediatric HeFH patients (ages 10 years to 17 years of age, = 29) in an open-label, 8-week study.. Gender Atorvastatin. Plasma concentrations of atorvastatin in women differ from those in men (approximately 20% higher for Cmax and 10% lower for AUC); however, there is no clinically significant difference in LDL-C reduction with atorvastatin between men and women.. Renal Impairment Amlodipine. The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial amlodipine dose.. Atorvastatin. Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin; thus, dose adjustment of atorvastatin in patients with renal dysfunction is not necessary [see Dosage and Administration (2) and Warnings and Precautions (5.1)].. Hemodialysis While studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to clear atorvastatin or amlodipine since both drugs are extensively bound to plasma proteins.. Hepatic Impairment Amlodipine. Elderly patients and patients with hepatic insufficiency have decreased clearance of amlodipine with resulting increase in AUC of approximately 40-60%.. Atorvastatin. In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin are markedly increased. Cmax and AUC are each 4-fold greater in patients with Childs-Pugh disease. Cmax and AUC of atorvastatin are approximately 16-fold and 11-fold increased, respectively, in patients with Childs-Pugh disease [see Contraindications (4)].Atorvastatin is contraindicated in patients with active liver disease.. Heart Failure Amlodipine. In patients with moderate to severe heart failure, the increase in AUC for amlodipine was similar to that seen in the elderly and in patients with hepatic insufficiency.. Effects of Other Drugs on Amlodipine and Atorvastatin Tablets. Amlodipine Co-administered cimetidine, magnesium- and aluminum hydroxide antacids, sildenafil, and grapefruit juice have no impact on the exposure to amlodipine.. CYP3A Inhibitors Co-administration of 180 mg daily dose of diltiazem with mg amlodipine in elderly hypertensive patients resulted in 60% increase in amlodipine systemic exposure. Erythromycin co-administration in healthy volunteers did not significantly change amlodipine systemic exposure. However, strong inhibitors of CYP3A (e.g., itraconazole, clarithromycin) may increase the plasma concentrations of amlodipine to greater extent [see Drug Interactions (7.1)].. Atorvastatin Atorvastatin is substrate of the hepatic transporters, OATP1B1 and OATP1B3 transporter. Metabolites of atorvastatin are substrates of OATP1B1. Atorvastatin is also identified as substrate of the efflux transporter BCRP, which may limit the intestinal absorption and biliary clearance of atorvastatin.Table shows effects of other drugs on the pharmacokinetics of atorvastatin.Table 4. Effect of Co-administered Drugs on the Pharmacokinetics of AtorvastatinCo-administered Drug and Dosing RegimenAtorvastatinDose (mg) Ratio of AUCRepresents ratio of treatments (co-administered drug plus atorvastatin vs. atorvastatin alone).Ratio of CmaxSee Sections 5.1 and for clinical significance.Cyclosporine 5.2 mg/kg/day, stable dose 10 mg QDOnce daily for 28 days8.69 10.66Tipranavir 500 mg BIDb/ritonavir 200 mg BIDTwice daily, days10 mg SDSingle dose 9.368.58Glecaprevir 400 mg QD/pibrentasvir 120 mg QD, days10 mg QD for days8.2822.00Telaprevir 750 mg q8hEvery hours, 10 days20 mg SDc 7.8810.60, The dose of saquinavir plus ritonavir in this study is not the clinically used dose. The increase in atorvastatin exposure when used clinically is likely to be higher than what was observed in this study. Therefore, caution should be applied and the lowest dose necessary should be used.Saquinavir 400 mg BID/ritonavir 400 mg BIDb, 15 days40 mg QD for days3.934.31Elbasvir 50 mg QD/grazoprevir 200 mg QD, 13 days10 mg SD 1.954.34Simeprevir 150 mg QD, 10 days40 mg SD 2.121.70Clarithromycin 500 mg BID, days80 mg QD for days4.545.38Darunavir 300 mg BID/ritonavir 100 mg BID, days10 mg QD for days3.452.25Itraconazole 200 mg QD, days40 mg SD 3.321.20 Letermovir 480 mg QD, 10 days20 mg SD 3.292.17Fosamprenavir 700 mg BID/ritonavir 100 mg BID, 14 days10 mg QD for days2.532.84 Fosamprenavir 1400 mg BID, 14 days10 mg QD for days2.304.04 Nelfinavir 1250 mg BID, 14 days10 mg QD for 28 days1.742.22Grapefruit Juice, 240 mL QD,Greater increases in AUC (ratio of AUC up to 2.5) and/or Cmax (ratio of Cmax up to 1.71) have been reported with excessive grapefruit consumption (>= 750 mL-1.2 liters per day).40 mg SD 1.37 1.16 Diltiazem 240 mg QD, 28 days40 mg SD 1.511.00Erythromycin 500 mg QIDFour times daily, days10 mg SD 1.33 1.38 Amlodipine 10 mg, single dose80 mg SD 1.18 0.91 Cimetidine 300 mg QID, weeks10 mg QD for weeks 1.000.89 Colestipol 10 BID, 24 weeks40 mg QD for weeks NULL 0.74Ratio based on single sample taken 8-16 post dose. Maalox TC(R) 30 mL QID, 17 days10 mg QD for 15 days 0.66 0.67 Efavirenz 600 mg QD, 14 days10 mg for days 0.59 1.01 Rifampin 600 mg QD, days (co-administered)Due to the dual interaction mechanism of rifampin, simultaneous co-administration of atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with significant reduction in atorvastatin plasma concentrations.40 mg SD 1.12 2.90Rifampin 600 mg QD, days (doses separated)40 mg SD 0.20 0.60 Gemfibrozil 600 mg BID, days40 mg SD 1.35 1.00Fenofibrate 160 mg QD, days40 mg SD 1.03 1.02 Boceprevir 800 mg TIDThree times daily, days40 mg SD 2.322.66. Effects of Amlodipine and Atorvastatin Tablets on Other Drugs. Amlodipine Amlodipine is weak inhibitor of CYP3A and may increase exposure to CYP3A substrates.In vitro data indicate that amlodipine has no effect on the human plasma protein binding of digoxin, phenytoin, warfarin, and indomethacin.Co-administered amlodipine does not affect the exposure to atorvastatin, digoxin, ethanol and the warfarin prothrombin response time.. Cyclosporine A prospective study in renal transplant patients (N 11) showed on an average of 40% increase in trough cyclosporine levels when concomitantly treated with amlodipine [see Drug Interactions (7.2)].. Tacrolimus A prospective study in healthy Chinese volunteers (N 9) with CYP3A5 expressers showed 2.5- to 4-fold increase in tacrolimus exposure when concomitantly administered with amlodipine compared to tacrolimus alone. This finding was not observed in CYP3A5 non-expressers (N 6). However, 3-fold increase in plasma exposure to tacrolimus in renal transplant patient (CYP3A5 non-expresser) upon initiation of amlodipine for the treatment of post-transplant hypertension resulting in reduction of tacrolimus dose has been reported. Irrespective of the CYP3A5 genotype status, the possibility of an interaction cannot be excluded with these drugs [see Drug Interactions (7.2)].. Atorvastatin Table shows the effects of atorvastatin on the pharmacokinetics of other drugs. Table 5. Effect of Atorvastatin on the Pharmacokinetics of Co-administered DrugsAtorvastatinCo-administered Drug and Dosing RegimenDrug/Dose (mg)Ratio of AUCRatio of Cmax80 mg QDOnce daily for 15 daysAntipyrine, 600 mg SDSingle dose 1.030.8980 mg QD for 10 daysSee Section for clinical significance.Digoxin 0.25 mg QD, 20 days1.151.2040 mg QD for 22 daysOral contraceptive QD, months- norethindrone mg ethinyl estradiol 35 ug1.281.191.231.3010 mg SD Tipranavir 500 mg BIDTwice daily/ritonavir 200 mg BID, days1.080.9610 mg QD for daysFosamprenavir 1400 mg BID, 14 days0.730.8210 mg QD for daysFosamprenavir 700 mg BID/ritonavir 100 mg BID, 14 days0.990.94.

CLINICAL STUDIES SECTION.


14 CLINICAL STUDIES 14.1Amlodipine for Hypertension Adult Patients. The antihypertensive efficacy of amlodipine has been demonstrated in total of 15 double-blind, placebo-controlled, randomized studies involving 800 patients on amlodipine and 538 on placebo. Once daily administration produced statistically significant placebo-corrected reductions in supine and standing blood pressures at 24 hours post dose, averaging about 12/6 mmHg in the standing position and 13/7 mmHg in the supine position in patients with mild to moderate hypertension. Maintenance of the blood pressure effect over the 24-hour dosing interval was observed, with little difference in peak and trough effect. Tolerance was not demonstrated in patients studied for up to year. The parallel, fixed dose, dose-response studies showed that the reduction in supine and standing blood pressures was dose related within the recommended dosing range. Effects on diastolic pressure were similar in young and older patients. The effect on systolic pressure was greater in older patients, perhaps because of greater baseline systolic pressure. Effects were similar in black patients and in white patients.. Pediatric Patients. Two hundred sixty-eight hypertensive patients aged to 17 years were randomized first to amlodipine 2.5 or mg once daily for weeks and then randomized again to the same dose or to placebo for another weeks. Patients receiving 2.5 mg or mg at the end of weeks had significantly lower systolic blood pressure than those secondarily randomized to placebo. The magnitude of the treatment effect is difficult to interpret, but it is probably less than mmHg systolic on the mg dose and 3.3 mmHg systolic on the 2.5 mg dose. Adverse events were similar to those seen in adults.. 14.2Amlodipine for Chronic Stable Angina The effectiveness of 5-10 mg/day of amlodipine in exercise-induced angina has been evaluated in placebo-controlled, double-blind clinical trials of up to weeks duration involving 1,038 patients (684 amlodipine, 354 placebo) with chronic stable angina. In of the studies, significant increases in exercise time (bicycle or treadmill) were seen with the 10 mg dose. Increases in symptom-limited exercise time averaged 12.8% (63 sec) for amlodipine 10 mg, and averaged 7.9% (38 sec) for amlodipine mg. Amlodipine 10 mg also increased time to mm ST segment deviation in several studies and decreased angina attack rate. The sustained efficacy of amlodipine in angina patients has been demonstrated over long-term dosing. In patients with angina, there were no clinically significant reductions in blood pressures (4/1 mmHg) or changes in heart rate (+0.3 bpm). 14.3Amlodipine for Vasospastic Angina In double-blind, placebo-controlled clinical trial of weeks duration in 50 patients, amlodipine therapy decreased attacks by approximately 4/week compared with placebo decrease of approximately 1/week (p 0.01). Two of 23 amlodipine and of 27 placebo patients discontinued from the study for lack of clinical improvement.. 14.4Amlodipine for Coronary Artery Disease In PREVENT, 825 patients with angiographically documented CAD were randomized to amlodipine (5-10 mg once daily) or placebo and followed for years. Although the study did not show significance on the primary objective of change in coronary luminal diameter as assessed by quantitative coronary angiography, the data suggested favorable outcome with respect to fewer hospitalizations for angina and revascularization procedures in patients with CAD.CAMELOT enrolled 1,318 patients with CAD recently documented by angiography, without left main coronary disease and without heart failure or an ejection fraction 40%. Patients (76% males, 89% Caucasian, 93% enrolled at U.S. sites, 89% with history of angina, 52% without PCI, 4% with PCI and no stent, and 44% with stent) were randomized to double-blind treatment with either amlodipine (5-10 mg once daily) or placebo in addition to standard care that included aspirin (89%), statins (83%), beta-blockers (74%), nitroglycerin (50%), anticoagulants (40%), and diuretics (32%), but excluded other calcium channel blockers. The mean duration of follow-up was 19 months. The primary endpoint was the time to first occurrence of one of the following events: hospitalization for angina pectoris, coronary revascularization, myocardial infarction, cardiovascular death, resuscitated cardiac arrest, hospitalization for heart failure, stroke/TIA, or peripheral vascular disease. total of 110 (16.6%) and 151 (23.1%) first events occurred in the amlodipine and placebo groups, respectively, for hazard ratio of 0.691 (95% CI: 0.540-0.884, = 0.003). The primary endpoint is summarized in Figure below. The outcome of this study was largely derived from the prevention of hospitalizations for angina and the prevention of revascularization procedures (see Table 6). Effects in various subgroups are shown in Figure 2.In an angiographic substudy (n 274) conducted within CAMELOT, there was no significant difference between amlodipine and placebo on the change of atheroma volume in the coronary artery as assessed by intravascular ultrasound.Figure 1. Kaplan-Meier Analysis of Composite Clinical Outcomes for Amlodipine Versus Placebo Figure 2. Effects on Primary Endpoint of Amlodipine Versus Placebo Across Sub-GroupsTable below summarizes the significant composite endpoint and clinical outcomes from the composites of the primary endpoint. The other components of the primary endpoint including cardiovascular death, resuscitated cardiac arrest, myocardial infarction, hospitalization for heart failure, stroke/TIA, or peripheral vascular disease did not demonstrate significant difference between amlodipine and placebo.Table 6. Incidence of Significant Clinical Outcomes for CAMELOTClinical OutcomesN (%)Amlodipine(N 663)Placebo(N 655)Risk Reduction(p-value)Composite CVEndpoint110(16.6)151(23.1)31%(0.003)Hospitalization for AnginaTotal patients with these events. 51(7.7)84(12.8)42%(0.002)Coronary Revascularization 78(11.8)103(15.7)27%(0.033). Figure 1. Kaplan-Meier Analysis of Composite Clinical Outcomes for Amlodipine Versus Placebo. Figure 2. Effects on Primary Endpoint of Amlodipine Versus Placebo Across Sub-Groups. 14.5Amlodipine for Heart Failure Amlodipine has been compared to placebo in four 8-12 week studies of patients with NYHA Class II/III heart failure, involving total of 697 patients. In these studies, there was no evidence of worsened heart failure based on measures of exercise tolerance, NYHA classification, symptoms, or left ventricular ejection fraction. In long-term (follow-up at least months, mean 13.8 months) placebo-controlled mortality/morbidity study of amlodipine 5-10 mg in 1,153 patients with NYHA Classes III (n 931) or IV (n 222) heart failure on stable doses of diuretics, digoxin, and ACE inhibitors, amlodipine had no effect on the primary endpoint of the study which was the combined endpoint of all-cause mortality and cardiac morbidity (as defined by life-threatening arrhythmia, acute myocardial infarction, or hospitalization for worsened heart failure), or on NYHA classification, or symptoms of heart failure. Total combined all-cause mortality and cardiac morbidity events were 222/571 (39%) for patients on amlodipine and 246/583 (42%) for patients on placebo; the cardiac morbid events represented about 25% of the endpoints in the study.Another study (PRAISE-2) randomized patients with NYHA Class III (80%) or IV (20%) heart failure without clinical symptoms or objective evidence of underlying ischemic disease, on stable doses of ACE inhibitors (99%), digitalis (99%), and diuretics (99%), to placebo (n 827) or amlodipine (n 827) and followed them for mean of 33 months. There was no statistically significant difference between amlodipine and placebo in the primary endpoint of all-cause mortality (95% confidence limits from 8% reduction to 29% increase on amlodipine). With amlodipine there were more reports of pulmonary edema.. 14.6Atorvastatin for Prevention of Cardiovascular Disease In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), the effect of atorvastatin on fatal and non-fatal coronary heart disease was assessed in 10,305 hypertensive patients 40-80 years of age (mean of 63 years), without previous myocardial infarction and with total-C levels <= 251 mg/dL (6.5 mmol/L). Additionally, all patients had at least of the following cardiovascular risk factors: male gender (81.1%), age 55 years (84.5%), smoking (33.2%), diabetes (24.3%), history of CHD in first-degree relative (26%), TC:HDL 6 (14.3%), peripheral vascular disease (5.1%), left ventricular hypertrophy (14.4%), prior cerebrovascular event (9.8%), specific ECG abnormality (14.3%), proteinuria/albuminuria (62.4%). In this double-blind, placebo-controlled study, patients were treated with anti-hypertensive therapy (Goal BP 140/90 mmHg for non-diabetic patients; 130/80 mmHg for diabetic patients) and allocated to either atorvastatin 10 mg daily (n 5,168) or placebo (n 5,137), using covariate adaptive method that took into account the distribution of nine baseline characteristics of patients already enrolled and minimized the imbalance of those characteristics across the groups. Patients were followed for median duration of 3.3 years.The effect of 10 mg/day of atorvastatin on lipid levels was similar to that seen in previous clinical trials.Atorvastatin significantly reduced the rate of coronary events [either fatal coronary heart disease (46 events in the placebo group vs. 40 events in the atorvastatin group) or non-fatal MI (108 events in the placebo group vs. 60 events in the atorvastatin group)] with relative risk reduction of 36% [(based on incidences of 1.9% for atorvastatin vs. 3.0% for placebo), = 0.0005 (see Figure 3)]. The risk reduction was consistent regardless of age, smoking status, obesity, or presence of renal dysfunction. The effect of atorvastatin was seen regardless of baseline LDL levels. Because of the small number of events, results for women were inconclusive.Figure 3. Effect of Atorvastatin 10 mg/day on Cumulative Incidence of Non-Fatal Myocardial Infarction or Coronary Heart Disease Death (in ASCOT-LLA)Atorvastatin also significantly decreased the relative risk for revascularization procedures by 42% (incidences of 1.4% for atorvastatin and 2.5% for placebo). Although the reduction of fatal and non-fatal strokes did not reach pre-defined significance level (p 0.01), favorable trend was observed with 26% relative risk reduction (incidences of 1.7% for atorvastatin and 2.3% for placebo). There was no significant difference between the treatment groups for death from cardiovascular causes (p 0.51) or noncardiovascular causes (p 0.17).In the Collaborative Atorvastatin Diabetes Study (CARDS), the effect of atorvastatin on cardiovascular disease endpoints was assessed in 2,838 subjects (94% white, 68% male), ages 40-75 with type diabetes based on WHO criteria, without prior history of cardiovascular disease, and with LDL <= 160 mg/dL and TG <= 600 mg/dL. In addition to diabetes, subjects had or more of the following risk factors: current smoking (23%), hypertension (80%), retinopathy (30%), or microalbuminuria (9%) or macroalbuminuria (3%). No subjects on hemodialysis were enrolled in the study. In this multicenter, placebo-controlled, double-blind clinical trial, subjects were randomly allocated to either atorvastatin 10 mg daily (1,429) or placebo (1,411) in 1:1 ratio and were followed for median duration of 3.9 years. The primary endpoint was the occurrence of any of the major cardiovascular events: myocardial infarction, acute CHD death, unstable angina, coronary revascularization, or stroke. The primary analysis was the time to first occurrence of the primary endpoint.Baseline characteristics of subjects were: mean age of 62 years; mean HbA1c 7.7%; median LDL-C 120 mg/dL; median total-C 207 mg/dL; median TG 151 mg/dL; median HDL-C 52 mg/dL.The effect of atorvastatin 10 mg/day on lipid levels was similar to that seen in previous clinical trials.Atorvastatin significantly reduced the rate of major cardiovascular events (primary endpoint events) (83 events in the atorvastatin group vs. 127 events in the placebo group) with relative risk reduction of 37%, HR 0.63, 95% CI (0.48, 0.83) (p 0.001) (see Figure 4). An effect of atorvastatin was seen regardless of age, sex, or baseline lipid levels.Atorvastatin significantly reduced the risk of stroke by 48% (21 events in the atorvastatin group vs. 39 events in the placebo group), HR 0.52, 95% CI (0.31, 0.89) (p 0.016) and reduced the risk of MI by 42% (38 events in the atorvastatin group vs. 64 events in the placebo group), HR 0.58, 95.1% CI (0.39, 0.86) (p 0.007). There was no significant difference between the treatment groups for angina, revascularization procedures, and acute CHD death.There were 61 deaths in the atorvastatin group vs. 82 deaths in the placebo group (HR 0.73, = 0.059).Figure 4. Effect of Atorvastatin 10 mg/day on Time to Occurrence of Major Cardiovascular Events (Myocardial Infarction, Acute CHD Death, Unstable Angina, Coronary Revascularization, or Stroke) in CARDSIn the Treating to New Targets Study (TNT), the effect of atorvastatin 80 mg/day vs. atorvastatin 10 mg/day on the reduction in cardiovascular events was assessed in 10,001 subjects (94% white, 81% male, 38% >= 65 years) with clinically evident coronary heart disease who had achieved target LDL-C level 130 mg/dL after completing an 8-week, open-label, run-in period with atorvastatin 10 mg/day. Subjects were randomly assigned to either 10 mg/day or 80 mg/day of atorvastatin and followed for median duration of 4.9 years. The primary endpoint was the time to first occurrence of any of the following major cardiovascular events (MCVE): death from CHD, non-fatal myocardial infarction, resuscitated cardiac arrest, and fatal and non-fatal stroke. The mean LDL-C, TC, TG, non-HDL, and HDL-C levels at 12 weeks were 73, 145, 128, 98, and 47 mg/dL during treatment with 80 mg of atorvastatin and 99, 177, 152, 129, and 48 mg/dL during treatment with 10 mg of atorvastatin.Treatment with atorvastatin 80 mg/day significantly reduced the rate of MCVE (434 events in the 80 mg/day group vs. 548 events in the 10 mg/day group) with relative risk reduction of 22%, HR 0.78, 95% CI (0.69, 0.89), = 0.0002 (see Figure and Table 7). The overall risk reduction was consistent regardless of age (< 65, >= 65) or gender.Figure 5. Effect of Atorvastatin 80 mg/day vs. 10 mg/day on Time to Occurrence of Major Cardiovascular Events (TNT) Table 7. Overview of Efficacy Results in TNTHR hazard ratio; CHD coronary heart disease; CI confidence interval; MI myocardial infarction; CHF congestive heart failure; CV cardiovascular; PVD peripheral vascular disease; CABG coronary artery bypass graftConfidence intervals for the Secondary Endpoints were not adjusted for multiple comparisons.EndpointAtorvastatin10 mg(N 5,006)Atorvastatin80 mg(N 4,995)HRAtorvastatin 80 mg: atorvastatin 10 mg (95% CI)PRIMARY ENDPOINTn(%)n(%)First major cardiovascular endpoint548(10.9)434(8.7)0.78 (0.69, 0.89)Components of the Primary EndpointCHD death127(2.5)101(2.0)0.80 (0.61, 1.03)Non-fatal, non-procedure related MI308(6.2)243(4.9)0.78 (0.66, 0.93)Resuscitated cardiac arrest26(0.5)25(0.5)0.96 (0.56, 1.67)Stroke (fatal and non-fatal)155(3.1)117(2.3)0.75 (0.59, 0.96)SECONDARY ENDPOINTSSecondary endpoints not included in primary endpointFirst CHF with hospitalization164(3.3)122(2.4)0.74 (0.59, 0.94)First PVD endpoint282(5.6)275(5.5)0.97 (0.83, 1.15)First CABG or other coronary revascularization procedureComponent of other secondary endpoints 904(18.1)667(13.4)0.72 (0.65, 0.80)First documented angina endpoint 615(12.3)545(10.9)0.88 (0.79, 0.99)All-cause mortality282(5.6)284(5.7)1.01 (0.85, 1.19)Components of All-Cause MortalityCardiovascular death155(3.1)126(2.5)0.81 (0.64, 1.03)Noncardiovascular death127(2.5)158(3.2)1.25 (0.99, 1.57)Cancer death75(1.5)85(1.7)1.13 (0.83, 1.55)Other non-CV death43(0.9)58(1.2)1.35 (0.91, 2.00)Suicide, homicide, and other traumatic non-CV death9(0.2)15(0.3)1.67 (0.73, 3.82)Of the events that comprised the primary efficacy endpoint, treatment with atorvastatin 80 mg/day significantly reduced the rate of non-fatal, non-procedure related MI and fatal and non-fatal stroke, but not CHD death or resuscitated cardiac arrest (Table 7). Of the predefined secondary endpoints, treatment with atorvastatin 80 mg/day significantly reduced the rate of coronary revascularization, angina, and hospitalization for heart failure, but not peripheral vascular disease. The reduction in the rate of CHF with hospitalization was only observed in the 8% of patients with prior history of CHF.There was no significant difference between the treatment groups for all-cause mortality (Table 7). The proportions of subjects who experienced cardiovascular death, including the components of CHD death and fatal stroke, were numerically smaller in the atorvastatin 80 mg group than in the atorvastatin 10 mg treatment group. The proportions of subjects who experienced noncardiovascular death were numerically larger in the atorvastatin 80 mg group than in the atorvastatin 10 mg treatment group.In the Incremental Decrease in Endpoints Through Aggressive Lipid Lowering Study (IDEAL), treatment with atorvastatin 80 mg/day was compared to treatment with simvastatin 20-40 mg/day in 8,888 subjects up to 80 years of age with history of CHD to assess whether reduction in CV risk could be achieved. Patients were mainly male (81%), white (99%) with an average age of 61.7 years, and an average LDL-C of 121.5 mg/dL at randomization; 76% were on statin therapy. In this prospective, randomized, open-label, blinded endpoint (PROBE) trial with no run-in period, subjects were followed for median duration of 4.8 years. The mean LDL-C, TC, TG, HDL, and non-HDL-C levels at Week 12 were 78, 145, 115, 45, and 100 mg/dL during treatment with 80 mg of atorvastatin and 105, 179, 142, 47, and 132 mg/dL during treatment with 20-40 mg of simvastatin.There was no significant difference between the treatment groups for the primary endpoint, the rate of first major coronary event (fatal CHD, non-fatal MI, and resuscitated cardiac arrest): 411 (9.3%) in the atorvastatin 80 mg/day group vs. 463 (10.4%) in the simvastatin 20-40 mg/day group, HR 0.89, 95% CI (0.78, 1.01), = 0.07.There were no significant differences between the treatment groups for all-cause mortality: 366 (8.2%) in the atorvastatin 80 mg/day group vs. 374 (8.4%) in the simvastatin 20-40 mg/day group. The proportions of subjects who experienced CV or non-CV death were similar for the atorvastatin 80 mg group and the simvastatin 20-40 mg group.. Figure 3. Effect of Atorvastatin 10 mg/day on Cumulative Incidence of Non-Fatal Myocardial Infarction or Coronary Heart Disease Death (in ASCOT-LLA). Figure 4. Effect of Atorvastatin 10 mg/day on Time to Occurrence of Major Cardiovascular Events (Myocardial Infarction, Acute CHD Death, Unstable Angina, Coronary Revascularization, or Stroke) in CARDS. Figure 5. Effect of Atorvastatin 80 mg/day vs. 10 mg/day on Time to Occurrence of Major Cardiovascular Events (TNT). 14.7Atorvastatin for Hyperlipidemia and Mixed Dyslipidemia Atorvastatin reduces total-C, LDL-C, very-low density lipoprotein cholesterol (VLDL-C), apo B, and TG, and increases HDL-C in patients with hyperlipidemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson Types IIa and IIb). Therapeutic response is seen within weeks, and maximum response is usually achieved within weeks and maintained during chronic therapy.Atorvastatin is effective in wide variety of patient populations with hyperlipidemia, with and without hypertriglyceridemia, in men and women, and in the elderly.In two multicenter, placebo-controlled, dose-response studies in patients with hyperlipidemia, atorvastatin given as single dose over weeks significantly reduced total-C, LDL-C, apo B, and TG. (Pooled results are provided in Table 8.)Table 8. Dose Response in Patients with Primary Hyperlipidemia (Adjusted Mean Change From Baseline)Results are pooled from dose-response studies. DoseNTCLDL-CApo BTGHDL-CNon-HDL-C/HDL-CPlacebo2144310-371022-29-39-32-196-342020-33-43-35-269-414021-37-50-42-296-458023-45-60-50-375-53In patients with Fredrickson Types IIa and IIb hyperlipoproteinemia pooled from 24 controlled trials, the median (25th and 75th percentile) percent changes from baseline in HDL-C for atorvastatin 10, 20, 40, and 80 mg were 6.4 (-1.4, 14), 8.7 (0, 17), 7.8 (0, 16), and 5.1 (-2.7, 15), respectively. Additionally, analysis of the pooled data demonstrated consistent and significant decreases in total-C, LDL-C, TG, total-C/HDL-C, and LDL-C/HDL-C.In three multicenter, double-blind studies in patients with hyperlipidemia, atorvastatin was compared to other statins. After randomization, patients were treated for 16 weeks with either atorvastatin 10 mg per day or fixed dose of the comparative agent (Table 9).Table 9. Mean Percentage Change from Baseline at Endpoint (Double-Blind, Randomized, Active-Controlled Trials)Treatment(Daily Dose)NTotal-CLDL-CApo BTGHDL-CNon-HDL-C/HDL-CStudy 1Atorvastatin 10 mg707-27Significantly different from lovastatin, ANCOVA, <= 0.05 -36 -28 -17 +7-37 Lovastatin 20 mg 191-19-27-20-6+7-2895% CI for DiffA negative value for the 95% CI for the difference between treatments favors atorvastatin for all except HDL-C, for which positive value favors atorvastatin. If the range does not include 0, this indicates statistically significant difference.-9.2, -6.5-10.7, -7.1-10.0, -6.5-15.2, -7.1-1.7, 2.0-11.1, -7.1Study 2Atorvastatin 10 mg222-25Significantly different from pravastatin, ANCOVA, <= 0.05 -35 -27 -17 +6-36 Pravastatin 20 mg 77-17-23-17-9+8-2895% CI for Diff-10.8, -6.1-14.5, -8.2-13.4, -7.4-14.1, -0.7-4.9, 1.6-11.5, -4.1Study 3Atorvastatin 10 mg132-29Significantly different from simvastatin, ANCOVA, <= 0.05 -37 -34 -23 +7-39 Simvastatin 10 mg 45-24-30-30-15+7-3395% CI for Diff-8.7, -2.7-10.1, -2.6-8.0, -1.1-15.1, -0.7-4.3, 3.9-9.6, -1.9The impact on clinical outcomes of the differences in lipid-altering effects between treatments shown in Table is not known. Table does not contain data comparing the effects of atorvastatin 10 mg and higher doses of lovastatin, pravastatin, and simvastatin. The drugs compared in the studies summarized in the table are not necessarily interchangeable.. 14.8Atorvastatin for Hypertriglyceridemia The response to atorvastatin in 64 patients with isolated hypertriglyceridemia (Fredrickson Type IV) treated across several clinical trials is shown in the table below (Table 10). For the atorvastatin-treated patients, median (min, max) baseline TG level was 565 (267-1502).Table 10. Combined Patients with Isolated Elevated TG: Median (min, max) Percentage Change From BaselinePlacebo(N 12)Atorvastatin10 mg(N 37)Atorvastatin20 mg(N 13)Atorvastatin80 mg(N 14)TG-12.4 (-36.6, 82.7)-41.0 (-76.2, 49.4)-38.7 (-62.7, 29.5)-51.8 (-82.8, 41.3)Total-C-2.3 (-15.5, 24.4)-28.2 (-44.9, -6.8)-34.9 (-49.6, -15.2)-44.4 (-63.5, -3.8)LDL-C3.6 (-31.3, 31.6)-26.5 (-57.7, 9.8)-30.4 (-53.9, 0.3)-40.5 (-60.6, -13.8)HDL-C3.8 (-18.6, 13.4)13.8 (-9.7, 61.5)11.0 (-3.2, 25.2)7.5 (-10.8, 37.2)VLDL-C-1.0 (-31.9, 53.2)-48.8 (-85.8, 57.3)-44.6 (-62.2, -10.8)-62.0 (-88.2, 37.6)non-HDL-C-2.8 (-17.6, 30.0)-33.0 (-52.1, -13.3)-42.7 (-53.7, -17.4)-51.5 (-72.9, -4.3). 14.9Atorvastatin for Dysbetalipoproteinemia The results of an open-label crossover study of 16 patients (genotypes: 14 apo E2/E2 and apo E3/E2) with dysbetalipoproteinemia (Fredrickson Type III) are shown in the table below (Table 11).Table 11. Open-Label Crossover Study of 16 Patients with Dysbetalipoproteinemia (Fredrickson Type III)Median Change (min, max)Median (min, max) at Baseline (mg/dL)Atorvastatin 10 mgAtorvastatin 80 mgTotal-C442 (225, 1,320)-37 (-85, 17)-58 (-90, -31)TG678 (273, 5,990)-39 (-92, -8)-53 (-95, -30)Intermediate-density lipoprotein cholesterol (IDL-C) VLDL-C215 (111, 613)-32 (-76, 9)-63 (-90, -8)non-HDL-C411 (218, 1,272)-43 (-87, -19)-64 (-92, -36). 14.10Atorvastatin for Homozygous Familial Hypercholesterolemia In study without concurrent control group, 29 patients ages years to 37 years with HoFH received maximum daily doses of 20 to 80 mg of atorvastatin. The mean LDL-C reduction in this study was 18%. Twenty-five patients with reduction in LDL-C had mean response of 20% (range of 7% to 53%, median of 24%); the remaining patients had 7% to 24% increases in LDL-C. Five of the 29 patients had absent LDL-receptor function. Of these, patients also had portacaval shunt and had no significant reduction in LDL-C. The remaining receptor-negative patients had mean LDL-C reduction of 22%.. 14.11Atorvastatin for Heterozygous Familial Hypercholesterolemia in Pediatric Patients In double-blind, placebo-controlled study followed by an open-label phase, 187 boys and postmenarchal girls 10 years to 17 years of age (mean age 14.1 years) with HeFH or severe hypercholesterolemia, were randomized to atorvastatin (n 140) or placebo (n 47) for 26 weeks and then all received atorvastatin for 26 weeks. Inclusion in the study required 1) baseline LDL-C level >= 190 mg/dL or 2) baseline LDL-C level >= 160 mg/dL and positive family history of FH or documented premature cardiovascular disease in first or second-degree relative. The mean baseline LDL-C value was 218.6 mg/dL (range: 138.5-385.0 mg/dL) in the atorvastatin group compared to 230.0 mg/dL (range: 160.0-324.5 mg/dL) in the placebo group. The dosage of atorvastatin (once daily) was 10 mg for the first weeks and uptitrated to 20 mg if the LDL-C level was 130 mg/dL. The number of atorvastatin-treated patients who required uptitration to 20 mg after Week during the double-blind phase was 78 (55.7%).Atorvastatin significantly decreased plasma levels of total-C, LDL-C, TG, and apolipoprotein during the 26-week double-blind phase (see Table 12).Table 12. Lipid-Altering Effects of Atorvastatin in Adolescent Boys and Girls with Heterozygous Familial Hypercholesterolemia or Severe Hypercholesterolemia (Mean Percentage Change from Baseline at Endpoint in Intention-to-Treat Population)DOSAGENTotal-CLDL-CHDL-CTGApo BPlacebo47-1.5-0.4-1.91.00.7Atorvastatin140-31.4-39.62.8-12.0-34.0The mean achieved LDL-C value was 130.7 mg/dL (range: 70.0-242.0 mg/dL) in the atorvastatin group compared to 228.5 mg/dL (range: 152.0-385.0 mg/dL) in the placebo group during the 26-week double-blind phase.Atorvastatin was also studied in 3-year open-label, uncontrolled trial that included 163 patients with HeFH who were 10 years to 15 years old (82 boys and 81 girls). All patients had clinical diagnosis of HeFH confirmed by genetic analysis (if not already confirmed by family history). Approximately 98% were Caucasian, and less than 1% were Black or Asian. Mean LDL-C at baseline was 232 mg/dL. The starting atorvastatin dosage was 10 mg once daily and doses were adjusted to achieve target of 130 mg/dL LDL-C. The reductions in LDL-C from baseline were generally consistent across age groups within the trial as well as with previous clinical studies in both adult and pediatric placebo-controlled trials.. 14.12Amlodipine and Atorvastatin Tablets for Hypertension and Dyslipidemia In double-blind, placebo-controlled study, total of 1,660 patients with co-morbid hypertension and dyslipidemia received once daily treatment with eight dose combinations of amlodipine and atorvastatin (5/10, 10/10, 5/20, 10/20, 5/40, 10/40, 5/80, or 10/80 mg), amlodipine alone (5 mg or 10 mg), atorvastatin alone (10 mg, 20 mg, 40 mg, or 80 mg), or placebo. In addition to concomitant hypertension and dyslipidemia, 15% of the patients had diabetes mellitus, 22% were smokers, and 14% had positive family history of cardiovascular disease. At weeks, all eight combination-treatment groups of amlodipine and atorvastatin demonstrated statistically significant dose-related reductions in systolic blood pressure (SBP), diastolic blood pressure (DBP), and LDL-C compared to placebo, with no overall modification of effect of either component on SBP, DBP, and LDL-C (Table 13). Table 13. Effects of Amlodipine and Atorvastatin on Blood Pressure and LDL-CBP (mmHg)AtorvastatinAmlodipine0 mg10 mg20 mg40 mg80 mg0 mg---1.5/-0.8-3.2/-0.6-3.2/-1.8-3.4/-0.85 mg-9.8/-4.3-10.7/-4.9-12.3/-6.1-9.7/-4.0-9.2/-5.110 mg-13.2/-7.1-12.9/-5.8-13.1/-7.3-13.3/-6.5-14.6/-7.8LDL-C (% change)AtorvastatinAmlodipine0 mg10 mg20 mg40 mg80 mg0 mg---32.3-38.4-42.0-46.15 mg1.0-37.6-41.2-43.8-47.310 mg-1.4-35.5-37.5-42.1-48.0.

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS oActive Liver Disease, Which May Include Unexplained Persistent Elevations in Hepatic Transaminase LevelsoPregnancy [see Use in Specific Populations (8.1)]oLactation [see Use in Specific Populations (8.2)] oActive Liver Disease, Which May Include Unexplained Persistent Elevations in Hepatic Transaminase Levels. oPregnancy [see Use in Specific Populations (8.1)]. oLactation [see Use in Specific Populations (8.2)] oActive liver disease (4)oPregnancy (4)oLactation (4) oActive liver disease (4). oPregnancy (4). oLactation (4).

DESCRIPTION SECTION.


11 DESCRIPTION Amlodipine and atorvastatin tablets, USP combine the calcium channel blocker amlodipine besylate with the HMG CoA-reductase inhibitor atorvastatin calcium.Amlodipine besylate is chemically described as 3-ethyl 5-methyl (4RS)-2-[(2-aminoethoxy) methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate benzenesulfonate. Its molecular formula is C20H25ClN2O5oC6H6O3S.Atorvastatin calcium is chemically described as Calcium (R,R)-2-(p-fluorophenyl)-,-dihydroxy-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)pyrrole-1-heptanoate (1:2), trihydrate. Its molecular formula is C66H68CaF2N4O10o3H2O.The structural formulae for amlodipine besylate and atorvastatin calcium are shown below.Amlodipine and atorvastatin tablets contain amlodipine besylate USP, white or almost white powder, and atorvastatin calcium USP, white to off-white crystalline powder. Amlodipine besylate has molecular weight of 567.1 and atorvastatin calcium has molecular weight of 1209.42. Amlodipine besylate is slightly soluble in water and sparingly soluble in ethanol. Atorvastatin calcium is insoluble in aqueous solutions of pH and below. Atorvastatin calcium is very slightly soluble in distilled water, pH 7.4 phosphate buffer, and acetonitrile; slightly soluble in ethanol; and freely soluble in methanol.Each film-coated tablet also contains colloidal silicon dioxide, croscarmellose sodium, hydroxypropyl cellulose, L-arginine, lecithin, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, pregelatinized starch (corn), sodium carbonate anhydrous, talc, titanium dioxide and xanthan gum. The 10 mg/10 mg, 10 mg/20 mg, 10 mg/40 mg and 10 mg/80 mg tablets also contain FD&C Blue No. Aluminum Lake. Amlodipine Besylatea and Atorvastatin Calcium Structural Formulae.

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION Amlodipine and Atorvastatin Tablets: Dosage of amlodipine and atorvastatin tablets must be individualized on the basis of both effectiveness and tolerance for each individual component in the treatment of hypertension/angina and hyperlipidemia. Select doses of amlodipine and atorvastatin independently.Amlodipine and atorvastatin tablets may be substituted for their individually titrated components. Patients may be given the equivalent dose of amlodipine and atorvastatin tablets or dose of amlodipine and atorvastatin tablets with increased amounts of amlodipine, atorvastatin, or both for additional antianginal effects, blood pressure lowering, or lipid-lowering effect.Amlodipine and atorvastatin tablets may be used to provide additional therapy for patients already on one of their components. Amlodipine and atorvastatin tablets may be used to initiate treatment in patients with hyperlipidemia and either hypertension or angina.Amlodipine: The usual initial antihypertensive oral dose of amlodipine is mg once daily, and the maximum dose is 10 mg once daily.Pediatric (age 6 years), small adult, fragile, or elderly patients, or patients with hepatic insufficiency may be started on 2.5 mg once daily and this dose may be used when adding amlodipine to other antihypertensive therapy.Adjust dosage according to blood pressure goals. In general, wait to 14 days between titration steps. Titration may proceed more rapidly, however, if clinically warranted, provided the patient is assessed frequently.Angina: The recommended dose of amlodipine for chronic stable or vasospastic angina is 5-10 mg, with the lower dose suggested in the elderly and in patients with hepatic insufficiency. Most patients will require 10 mg for adequate effect.Coronary Artery Disease: The recommended dose range of amlodipine for patients with CAD is 5-10 mg once daily. In clinical studies, the majority of patients required 10 mg [see Clinical Studies (14.4)].Pediatrics: The effective antihypertensive oral dose of amlodipine in pediatric patients ages 6-17 years is 2.5 mg to mg once daily. Doses in excess of mg daily have not been studied in pediatric patients [see Clinical Pharmacology (12.3), Clinical Studies (14.1)].Atorvastatin (Hyperlipidemia): Hyperlipidemia and Mixed Dyslipidemia: The recommended starting dose of atorvastatin is 10 or 20 mg once daily. Patients who require large reduction in LDL-C (more than 45%) may be started at 40 mg once daily. The dosage range of atorvastatin is 10 to 80 mg once daily. Atorvastatin can be administered as single dose at any time of the day, with or without food. The starting dose and maintenance doses of atorvastatin should be individualized according to patient characteristics such as goal of therapy and response. After initiation and/or upon titration of atorvastatin, lipid levels should be analyzed within to weeks and dosage adjusted accordingly.Homozygous Familial Hypercholesterolemia: The dosage range of atorvastatin in patients with HoFH is 10 to 80 mg daily. Atorvastatin should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.Concomitant Lipid-Lowering Therapy: Atorvastatin may be used with bile acid resins. Monitor for signs of myopathy in patients receiving the combination of HMG-CoA reductase inhibitors (statins) and fibrates [see Warnings and Precautions (5.1), Drug Interactions (7)].Patients with Renal Impairment: Renal disease does not affect the plasma concentrations nor LDL-C reduction of atorvastatin; thus, dosage adjustment in patients with renal dysfunction is not necessary [see Warnings and Precautions (5.1), Clinical Pharmacology (12.3)].Use with Cyclosporine, Clarithromycin, Itraconazole, Letermovir, or Certain Protease Inhibitors: In patients taking cyclosporine or the human immunodeficiency virus (HIV) protease inhibitor tipranavir plus ritonavir or the hepatitis virus (HCV) protease inhibitor glecaprevir plus pibrentasvir, or letermovir when co-administered with cyclosporine, therapy with atorvastatin should be avoided. In patients with HIV taking lopinavir plus ritonavir, use the lowest dose necessary of atorvastatin. In patients taking clarithromycin, itraconazole, elbasvir plus grazoprevir, or in patients with HIV taking combination of saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, or letermovir, therapy with atorvastatin should be limited to 20 mg, and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of atorvastatin is used. In patients taking the HIV protease inhibitor nelfinavir therapy with atorvastatin should be limited to 40 mg. When co-prescribing atorvastatin with other protease inhibitors, appropriate clinical assessment is recommended to ensure that the lowest dose necessary of atorvastatin is used [see Warnings and Precautions (5.1), Drug Interactions (7)].Heterozygous Familial Hypercholesterolemia in Pediatric Patients (10 Years to 17 Years of Age): The recommended starting dose of atorvastatin is 10 mg/day; the usual dose range is 10 to 20 mg orally once daily [see Clinical Studies (14.11)]. Doses should be individualized according to the recommended goal of therapy [see Indications and Usage (1.4) and Clinical Pharmacology (12)]. Adjustments should be made at intervals of weeks or more.. Usual Starting Dose(mg daily)Maximum Dose(mg daily)Amlodipine5Start small adults or children, fragile, or elderly patients, or patients with hepatic insufficiency on 2.5 mg once daily (2) 10Atorvastatin10-20Start patients requiring large LDL-C reduction (> 45%) at 40 mg once daily (2) 80.

DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS Amlodipine and Atorvastatin Tablets, USP are available containing amlodipine besylate, USP equivalent to 2.5 mg, mg or 10 mg amlodipine and atorvastatin calcium, USP equivalent to 10 mg, 20 mg, 40 mg or 80 mg atorvastatin. Amlodipine and Atorvastatin Tablets, USP are formulated for oral administration in the following strength combinations:Table 1. Atorvastatin (mg)10204080Amlodipine(mg)2.5XXX--5XXXX10XXXXCombinations of atorvastatin with 2.5 mg and mg amlodipine are film-coated white to off-white, and combinations of atorvastatin with 10 mg amlodipine are film-coated blue.oThe 2.5 mg/10 mg tablets are white to off-white, film-coated, round, unscored tablets debossed with on one side of the tablet and AA1 on the other side.oThe 2.5 mg/20 mg tablets are white to off-white, film-coated, capsule shaped, unscored tablets debossed with on one side of the tablet and AA2 on the other side. oThe 2.5 mg/40 mg tablets are white to off-white, film-coated, oval, unscored tablets debossed with on one side of the tablet and AA3 on the other side. oThe mg/10 mg tablets are white to off-white, film-coated, oval, unscored tablets debossed with on one side of the tablet and AA4 on the other side. oThe mg/20 mg tablets are white to off-white, film-coated, round, unscored tablets debossed with on one side of the tablet and AA5 on the other side. oThe mg/40 mg tablets are white to off-white, film-coated, capsule shaped, unscored tablets debossed with on one side of the tablet and AA6 on the other side. oThe mg/80 mg tablets are white to off-white, film-coated, oval, unscored tablets debossed with on one side of the tablet and AA7 on the other side. oThe 10 mg/10 mg tablets are blue, film-coated, barrel shaped, unscored tablets debossed with on one side of the tablet and AA8 on the other side. oThe 10 mg/20 mg tablets are blue, film-coated, oval, unscored tablets debossed with on one side of the tablet and AA9 on the other side.oThe 10 mg/40 mg tablets are blue, film-coated, round, unscored tablets debossed with on one side of the tablet and AA10 on the other side.oThe 10 mg/80 mg tablets are blue, film-coated, capsule shaped, unscored tablets debossed with on one side of the tablet and AA11 on the other side. oThe 2.5 mg/10 mg tablets are white to off-white, film-coated, round, unscored tablets debossed with on one side of the tablet and AA1 on the other side.. oThe 2.5 mg/20 mg tablets are white to off-white, film-coated, capsule shaped, unscored tablets debossed with on one side of the tablet and AA2 on the other side. oThe 2.5 mg/40 mg tablets are white to off-white, film-coated, oval, unscored tablets debossed with on one side of the tablet and AA3 on the other side. oThe mg/10 mg tablets are white to off-white, film-coated, oval, unscored tablets debossed with on one side of the tablet and AA4 on the other side. oThe mg/20 mg tablets are white to off-white, film-coated, round, unscored tablets debossed with on one side of the tablet and AA5 on the other side. oThe mg/40 mg tablets are white to off-white, film-coated, capsule shaped, unscored tablets debossed with on one side of the tablet and AA6 on the other side. oThe mg/80 mg tablets are white to off-white, film-coated, oval, unscored tablets debossed with on one side of the tablet and AA7 on the other side. oThe 10 mg/10 mg tablets are blue, film-coated, barrel shaped, unscored tablets debossed with on one side of the tablet and AA8 on the other side. oThe 10 mg/20 mg tablets are blue, film-coated, oval, unscored tablets debossed with on one side of the tablet and AA9 on the other side.. oThe 10 mg/40 mg tablets are blue, film-coated, round, unscored tablets debossed with on one side of the tablet and AA10 on the other side.. oThe 10 mg/80 mg tablets are blue, film-coated, capsule shaped, unscored tablets debossed with on one side of the tablet and AA11 on the other side. Tablets contain amlodipine besylate equivalent to amlodipine 2.5, 5, or 10 mg and atorvastatin calcium equivalent to atorvastatin 10, 20, 40, or 80 mg (3).

DRUG INTERACTIONS SECTION.


7 DRUG INTERACTIONS Data from drug-drug interaction study involving 10 mg of amlodipine and 80 mg of atorvastatin in healthy subjects indicate that the pharmacokinetics of amlodipine are not altered when the drugs are co-administered. The effect of amlodipine on the pharmacokinetics of atorvastatin showed no effect on the Cmax: 91% (90% confidence interval: 80 to 103%), but the AUC of atorvastatin increased by 18% (90% confidence interval: 109 to 127%) in the presence of amlodipine, which is not clinically meaningful.No drug interaction studies have been conducted with amlodipine and atorvastatin tablets and other drugs, although studies have been conducted in the individual amlodipine and atorvastatin components, as described below:Amlodipine:. Increased Risk of Myopathy/Rhabdomyolysis (2, 5.1, 7, 12.3)Cyclosporine, tipranavir plus ritonavir, glecaprevir plus pibrentasvir, letermovir when co-administered with cyclosporineAvoid atorvastatinClarithromycin, itraconazole, saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir, letermovirDo not exceed 20 mg atorvastatin dailyNelfinavirDo not exceed 40 mg atorvastatin dailyLopinavir plus ritonavir, simeprevir, fibric acid derivatives, erythromycin, azole antifungals, lipid-modifying doses of niacin, colchicineUse with caution and lowest dose necessaryoOther Lipid-Lowering Medications: Increased risk of myopathy (7).oRifampin: Take at same time as amlodipine and atorvastatin tablets (7.9).oDigoxin: Monitor digoxin levels (7.10).oOral Contraceptives: Norethindrone and ethinyl estradiol may be increased (7.11).. oOther Lipid-Lowering Medications: Increased risk of myopathy (7).. oRifampin: Take at same time as amlodipine and atorvastatin tablets (7.9).. oDigoxin: Monitor digoxin levels (7.10).. oOral Contraceptives: Norethindrone and ethinyl estradiol may be increased (7.11).. 7.1Impact of Other Drugs on Amlodipine CYP3A Inhibitors. Co-administration with CYP3A inhibitors (moderate and strong) results in increased systemic exposure to amlodipine and may require dose reduction. Monitor for symptoms of hypotension and edema when amlodipine is co-administered with CYP3A inhibitors to determine the need for dose adjustment [see Clinical Pharmacology (12.3)].. CYP3A Inducers. No information is available on the quantitative effects of CYP3A inducers on amlodipine. Blood pressure should be closely monitored when amlodipine is co-administered with CYP3A inducers.. Sildenafil. Monitor for hypotension when sildenafil is co-administered with amlodipine [see Clinical Pharmacology (12.2)].. 7.2Impact of Amlodipine on Other Drugs Immunosuppressants. Amlodipine may increase the systemic exposure of cyclosporine or tacrolimus when co-administered. Frequent monitoring of trough blood levels of cyclosporine and tacrolimus is recommended and adjust the dose when appropriate [see Clinical Pharmacology (12.3)].AtorvastatinThe risk of myopathy during treatment with statins is increased with concurrent administration of fibric acid derivatives, lipid-modifying doses of niacin, cyclosporine, or strong CYP3A4 inhibitors (e.g., clarithromycin, HIV and HCV protease inhibitors, and itraconazole) [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].. 7.3Strong Inhibitors of CYP3A4 Atorvastatin is metabolized by CYP3A4. Concomitant administration of atorvastatin with strong inhibitors of CYP3A4 can lead to increases in plasma concentrations of atorvastatin. The extent of interaction and potentiation of effects depend on the variability of effect on CYP3A4.. Clarithromycin. Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin 80 mg with clarithromycin (500 mg twice daily) compared to that of atorvastatin alone [see Clinical Pharmacology (12.3)]. Therefore, in patients taking clarithromycin, avoid atorvastatin doses 20 mg [see Dosage and Administration (2) and Warnings and Precautions (5.1)].. Combination of Protease Inhibitors. Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin with several combinations of protease inhibitors [see Clinical Pharmacology (12.3)]. In patients taking tipranavir plus ritonavir or glecaprevir plus pibrentasvir, concomitant use of atorvastatin should be avoided. In patients taking lopinavir plus ritonavir or simeprevir, use the lowest necessary atorvastatin dose. In patients taking saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, or elbasvir plus grazoprevir, the dose of atorvastatin should not exceed 20 mg. In patients taking nelfinavir, the dose of atorvastatin should not exceed 40 mg and close clinical monitoring is recommended [see Dosage and Administration (2) and Warnings and Precautions (5.1)].. Itraconazole. Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin 40 mg and itraconazole 200 mg [see Clinical Pharmacology (12.3)]. Therefore, in patients taking itraconazole, avoid atorvastatin doses 20 mg [see Dosage and Administration (2) and Warnings and Precautions (5.1)].. 7.4Grapefruit Juice Contains one or more components that inhibit CYP3A4 and can increase plasma concentrations of atorvastatin, especially with excessive grapefruit juice consumption (> 1.2 liters per day).. 7.5Transporter Inhibitors Atorvastatin is substrate of the hepatic transporters. Atorvastatin-metabolites are substrates of the OATP1B1 transporter [see Clinical Pharmacology (12.3)].. Cyclosporine. Inhibitors of the OATP1B1 (e.g., cyclosporine) can increase the bioavailability of atorvastatin. Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin 10 mg and cyclosporine 5.2 mg/kg/day compared to that of atorvastatin alone [see Clinical Pharmacology (12.3)]. The co-administration of atorvastatin with cyclosporine should be avoided [see Warnings and Precautions (5.1)].Concomitant administration of atorvastatin 20 mg and letermovir 480 mg daily resulted in an increase in exposure to atorvastatin (ratio of AUC: 3.29) [see Clinical Pharmacology (12.3)]. Letermovir inhibits efflux transporters P-gp, BCRP, MRP2, OAT2 and hepatic transporter OATP1B1/1B3, thus it increases exposure to atorvastatin. Do not exceed 20 mg atorvastatin daily [see Dosage and Administration (2)].The magnitude of CYP3A- and OATP1B1/1B3-mediated drug interactions on co-administered drugs may be different when letermovir is co-administered with cyclosporine. Use of atorvastatin is not recommended in patients taking letermovir co-administered with cyclosporine.Concomitant administration of glecaprevir and pibrentasvir or elbasvir and grazoprevir may lead to increased plasma concentrations of atorvastatin and an increased risk of myopathy.Coadministration of glecaprevir and pibrentasvir with atorvastatin increase plasma concentrations of atorvastatin by 8.3-fold due in part to BCRP, OATP1B1/1B3, and CYP3A inhibition; therefore, coadministration of atorvastatin in patients receiving concomitant medications with products containing glecaprevir and pibrentasvir is not recommended.Coadministration of elbasvir and grazoprevir with atorvastatin increase plasma concentrations of atorvastatin by 1.9-fold due in part to BCRP, OATP1B1/1B3, and CYP3A inhibition; therefore, the dose of atorvastatin should not exceed 20 mg daily in patients receiving concomitant medications with products containing elbasvir and grazoprevir [see Dosage and Administration (2), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].. 7.6Gemfibrozil Because of an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are co-administered with gemfibrozil, avoid concomitant administration of atorvastatin with gemfibrozil [see Warnings and Precautions (5.1)].. 7.7Other Fibrates The risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of other fibrates [see Warnings and Precautions (5.1)].. 7.8Niacin The risk of skeletal muscle effects may be enhanced when atorvastatin is used in combination with niacin; consider reduction in atorvastatin dosage in this setting [see Warnings and Precautions (5.1)].. 7.9Rifampin or Other Inducers of CYP3A4 Concomitant administration of atorvastatin with inducers of CYP3A4 (e.g., efavirenz, rifampin) can lead to variable reductions in plasma concentrations of atorvastatin. Because of the dual interaction mechanism of rifampin, simultaneous co-administration of atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with significant reduction in atorvastatin plasma concentrations.. 7.10Digoxin When multiple doses of atorvastatin and digoxin were co-administered, steady-state plasma digoxin concentrations increased [see Clinical Pharmacology (12.3)]. Monitor digoxin levels.. 7.11Oral Contraceptives Co-administration of atorvastatin and an oral contraceptive increased AUC values for norethindrone and ethinyl estradiol [see Clinical Pharmacology (12.3)]. Consider these increases when selecting an oral contraceptive for woman taking amlodipine and atorvastatin tablets.. 7.12Warfarin Atorvastatin had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment.. 7.13Colchicine Cases of myopathy, including rhabdomyolysis, have been reported with atorvastatin co-administered with colchicine.

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.


8.3 Females and Males of Reproductive Potential Contraception. Atorvastatin may cause fetal harm when administered to pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with amlodipine and atorvastatin tablets [see Use in Specific Populations (8.1)].

GERIATRIC USE SECTION.


8.5 Geriatric Use Safety and effectiveness of amlodipine and atorvastatin tablets have not been established in geriatric populations.. Amlodipine. Clinical studies of amlodipine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Elderly patients have decreased clearance of amlodipine with resulting increase of AUC of approximately 40-60%, and lower initial dose may be required [see Dosage and Administration (2)].. Atorvastatin. Of the 39,828 patients who received atorvastatin in clinical studies, 15,813 (40%) were >= 65 years old and 2,800 (7%) were >= 75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older adults cannot be ruled out. Advanced age (>= 65 years) is predisposing factor for myopathy.

HEPATIC IMPAIRMENT SUBSECTION.


Hepatic Impairment Amlodipine. Elderly patients and patients with hepatic insufficiency have decreased clearance of amlodipine with resulting increase in AUC of approximately 40-60%.. Atorvastatin. In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin are markedly increased. Cmax and AUC are each 4-fold greater in patients with Childs-Pugh disease. Cmax and AUC of atorvastatin are approximately 16-fold and 11-fold increased, respectively, in patients with Childs-Pugh disease [see Contraindications (4)].Atorvastatin is contraindicated in patients with active liver disease.

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING Amlodipine and Atorvastatin Tablets, USP are available containing amlodipine besylate, USP equivalent to 2.5 mg, mg or 10 mg amlodipine and atorvastatin calcium, USP equivalent to 10 mg, 20 mg, 40 mg or 80 mg atorvastatin, providing for the following combinations: 2.5 mg/10 mg, 2.5 mg/20 mg, 2.5 mg/40 mg, mg/10 mg, mg/20 mg, mg/40 mg, mg/80 mg, 10 mg/10 mg, 10 mg/20 mg, 10 mg/40 mg and 10 mg/80 mg. The 2.5 mg/10 mg tablets are white to off-white, film-coated, round, unscored tablets debossed with on one side of the tablet and AA1 on the other side. They are available as follows:NDC 0378-4510-93bottles of 30 tabletsThe 2.5 mg/20 mg tablets are white to off-white, film-coated, capsule shaped, unscored tablets debossed with on one side of the tablet and AA2 on the other side. They are available as follows:NDC 0378-4511-93bottles of 30 tabletsThe 2.5 mg/40 mg tablets are white to off-white, film-coated, oval, unscored tablets debossed with on one side of the tablet and AA3 on the other side. They are available as follows:NDC 0378-4512-93bottles of 30 tabletsThe mg/10 mg tablets are white to off-white, film-coated, oval, unscored tablets debossed with on one side of the tablet and AA4 on the other side. They are available as follows:NDC 0378-4513-93bottles of 30 tabletsThe mg/20 mg tablets are white to off-white, film-coated, round, unscored tablets debossed with on one side of the tablet and AA5 on the other side. They are available as follows:NDC 0378-4514-93bottles of 30 tabletsThe mg/40 mg tablets are white to off-white, film-coated, capsule shaped, unscored tablets debossed with on one side of the tablet and AA6 on the other side. They are available as follows:NDC 0378-4515-93bottles of 30 tabletsThe mg/80 mg tablets are white to off-white, film-coated, oval, unscored tablets debossed with on one side of the tablet and AA7 on the other side. They are available as follows:NDC 0378-4516-93bottles of 30 tabletsThe 10 mg/10 mg tablets are blue, film-coated, barrel shaped, unscored tablets debossed with on one side of the tablet and AA8 on the other side. They are available as follows:NDC 0378-4517-93bottles of 30 tabletsThe 10 mg/20 mg tablets are blue, film-coated, oval, unscored tablets debossed with on one side of the tablet and AA9 on the other side. They are available as follows:NDC 0378-4518-93bottles of 30 tabletsThe 10 mg/40 mg tablets are blue, film-coated, round, unscored tablets debossed with on one side of the tablet and AA10 on the other side. They are available as follows:NDC 0378-4519-93bottles of 30 tabletsThe 10 mg/80 mg tablets are blue, film-coated, capsule shaped, unscored tablets debossed with on one side of the tablet and AA11 on the other side. They are available as follows:NDC 0378-4520-93bottles of 30 tabletsStore at 20 to 25C (68 to 77F). [See USP Controlled Room Temperature.]Dispense in tight, light-resistant container as defined in the USP using child-resistant closure.

INDICATIONS & USAGE SECTION.


1 INDICATIONS AND USAGE Amlodipine and atorvastatin tablets are indicated in patients for whom treatment with both amlodipine and atorvastatin is appropriate.Amlodipine. Amlodipine and atorvastatin tablets are combination of amlodipine besylate, calcium channel blocker, and atorvastatin calcium, HMG CoA-reductase inhibitor, indicated in patients for whom treatment with both amlodipine and atorvastatin is appropriate.Amlodipine is indicated for the treatment of hypertension, to lower blood pressure (1.1). Lowering blood pressure reduces the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. Amlodipine is indicated for the treatment of Coronary Artery Disease (1.2).Atorvastatin is indicated as an adjunct therapy to diet for prevention of cardiovascular disease (1.3) and hyperlipidemia (1.4).. 1.1Hypertension Amlodipine is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from wide variety of pharmacologic classes including amlodipine.Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Programs Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).Numerous antihypertensive drugs, from variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to lower blood pressure goal.Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.Amlodipine may be used alone or in combination with other antihypertensive agents.. 1.2Coronary Artery Disease (CAD) Chronic Stable Angina. Amlodipine is indicated for the symptomatic treatment of chronic stable angina. Amlodipine may be used alone or in combination with other antianginal agents.. Vasospastic Angina (Prinzmetals or Variant Angina). Amlodipine is indicated for the treatment of confirmed or suspected vasospastic angina. Amlodipine may be used as monotherapy or in combination with other antianginal agents.. Angiographically Documented CAD. In patients with recently documented CAD by angiography and without heart failure or an ejection fraction 40%, amlodipine is indicated to reduce the risk of hospitalization for angina and to reduce the risk of coronary revascularization procedure.Atorvastatin Therapy with HMG CoA-reductase inhibitors (lipid-altering agents) should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease from hypercholesterolemia. Drug therapy is recommended as an adjunct to diet when the response to diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate. In patients with coronary heart disease (CHD) or multiple risk factors for CHD, atorvastatin can be started simultaneously with diet restriction.. 1.3Prevention of Cardiovascular Disease (CVD) in Adults In adult patients without clinically evident coronary heart disease, but with multiple risk factors for coronary heart disease such as age, smoking, hypertension, low high-density lipoprotein cholesterol (HDL-C), or family history of early coronary heart disease, atorvastatin is indicated to: oReduce the risk of myocardial infarction (MI)oReduce the risk of stroke oReduce the risk for revascularization procedures and anginaIn adult patients with type diabetes, and without clinically evident coronary heart disease, but with multiple risk factors for coronary heart disease such as retinopathy, albuminuria, smoking, or hypertension, atorvastatin is indicated to: oReduce the risk of myocardial infarction oReduce the risk of strokeIn adult patients with clinically evident coronary heart disease, atorvastatin is indicated to:oReduce the risk of non-fatal myocardial infarctionoReduce the risk of fatal and non-fatal strokeoReduce the risk for revascularization proceduresoReduce the risk of hospitalization for congestive heart failure (CHF)oReduce the risk of angina. oReduce the risk of myocardial infarction (MI). oReduce the risk of stroke oReduce the risk for revascularization procedures and angina. oReduce the risk of myocardial infarction oReduce the risk of stroke. oReduce the risk of non-fatal myocardial infarction. oReduce the risk of fatal and non-fatal stroke. oReduce the risk for revascularization procedures. oReduce the risk of hospitalization for congestive heart failure (CHF). oReduce the risk of angina. 1.4Hyperlipidemia Atorvastatin is indicated:oAs an adjunct to diet to reduce elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein (apo B), and triglycerides (TG) levels and to increase HDL-C in adult patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson Types IIa and IIb) oAs an adjunct to diet for the treatment of adult patients with elevated serum TG levels (Fredrickson Type IV) oFor the treatment of adult patients with primary dysbetalipoproteinemia (Fredrickson Type III) who do not respond adequately to diet oTo reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH) as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable oAs an adjunct to diet to reduce total-C, LDL-C, and apo levels in pediatric patients, 10 years to 17 years of age, with heterozygous familial hypercholesterolemia (HeFH) if after an adequate trial of diet therapy the following findings are present:a.LDL-C remains >= 190 mg/dL orb.LDL-C remains >= 160 mg/dL and:othere is positive family history of premature CVD orotwo or more other CVD risk factors are present in the pediatric patient oAs an adjunct to diet to reduce elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein (apo B), and triglycerides (TG) levels and to increase HDL-C in adult patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson Types IIa and IIb) oAs an adjunct to diet for the treatment of adult patients with elevated serum TG levels (Fredrickson Type IV) oFor the treatment of adult patients with primary dysbetalipoproteinemia (Fredrickson Type III) who do not respond adequately to diet oTo reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH) as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable oAs an adjunct to diet to reduce total-C, LDL-C, and apo levels in pediatric patients, 10 years to 17 years of age, with heterozygous familial hypercholesterolemia (HeFH) if after an adequate trial of diet therapy the following findings are present:a.LDL-C remains >= 190 mg/dL orb.LDL-C remains >= 160 mg/dL and:othere is positive family history of premature CVD orotwo or more other CVD risk factors are present in the pediatric patient a.LDL-C remains >= 190 mg/dL or. b.LDL-C remains >= 160 mg/dL and:othere is positive family history of premature CVD orotwo or more other CVD risk factors are present in the pediatric patient othere is positive family history of premature CVD or. otwo or more other CVD risk factors are present in the pediatric patient. 1.5Limitations of Use Atorvastatin has not been studied in conditions where the major lipoprotein abnormality is elevation of chylomicrons (Fredrickson Types and V).

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information).Information for Patients: Because of the risk of myopathy with statins, the drug class to which atorvastatin belongs, advise patients to report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever.Advise patients taking atorvastatin that cholesterol is chronic condition and they should adhere to their medication along with their National Cholesterol Education Program (NCEP)-recommended diet, regular exercise program as appropriate, and periodic testing of fasting lipid panel to determine goal attainment.Advise patients about substances they should not take concomitantly with atorvastatin [see Warnings and Precautions (5.1)]. Patients should inform other healthcare professionals prescribing new medication that they are taking amlodipine and atorvastatin tablets.Muscle Pain: Advise patients starting therapy with amlodipine and atorvastatin tablets of the risk of myopathy and to report promptly any unexplained muscle pain, tenderness, or weakness particularly if accompanied by malaise or fever or if these muscle signs or symptoms persist after discontinuing amlodipine and atorvastatin tablets. The risk of this occurring is increased when taking certain types of medication or consuming larger quantities (> liter) of grapefruit juice. They should discuss all medication, both prescription and over the counter, with their healthcare professional.Liver Enzymes: Advise patients treated with amlodipine and atorvastatin tablets to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice.Embryofetal Toxicity: Advise females of reproductive potential of the risk to fetus, to use effective contraception during treatment and to inform their healthcare provider of known or suspected pregnancy while using amlodipine and atorvastatin tablets [see Contraindications (4) and Use in Specific Populations (8.1, 8.3)].Lactation: Advise women not to breastfeed during treatment with amlodipine and atorvastatin tablets [see Contraindications (4) and Use in Specific Populations (8.2)].

MECHANISM OF ACTION SECTION.


12.1 Mechanism of Action Amlodipine and atorvastatin tablets are combination of two drugs, dihydropyridine calcium channel blocker (amlodipine) and an HMG-CoA reductase inhibitor (atorvastatin). The amlodipine component of amlodipine and atorvastatin tablets inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. The atorvastatin component of amlodipine and atorvastatin tablets is selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme to mevalonate, precursor of sterols, including cholesterol.. Amlodipine. Amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine.Amlodipine is peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause reduction in peripheral vascular resistance and reduction in blood pressure.The precise mechanisms by which amlodipine relieves angina have not been fully delineated, but are thought to include the following:. Exertional Angina In patients with exertional angina, amlodipine reduces the total peripheral resistance (afterload) against which the heart works and reduces the rate pressure product, and thus myocardial oxygen demand, at any given level of exercise.. Vasospastic Angina Amlodipine has been demonstrated to block constriction and restore blood flow in coronary arteries and arterioles in response to calcium, potassium epinephrine, serotonin, and thromboxane A2 analog in experimental animal models and in human coronary vessels in vitro. This inhibition of coronary spasm is responsible for the effectiveness of amlodipine in vasospastic (Prinzmetals or variant) angina.. Atorvastatin. Atorvastatin is selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme to mevalonate, precursor of sterols, including cholesterol. In animal models, atorvastatin lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by increasing the number of hepatic LDL receptors on the cell surface to enhance uptake and catabolism of LDL; atorvastatin also reduces LDL production and the number of LDL particles.

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Amlodipine. Rats and mice treated with amlodipine maleate in the diet for up to years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 mg amlodipine/kg/day, showed no evidence of carcinogenic effect of the drug. For the mouse, the highest dose was, on mg/m2 basis, similar to the MRHD of 10 mg amlodipine/day.2 For the rat, the highest dose level was, on mg/m2 basis, about twice the MRHD.2 Mutagenicity studies conducted with amlodipine maleate revealed no drug related effects at either the gene or chromosome levels.There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days and females for 14 days prior to mating) at doses up to 10 mg amlodipine/kg/day (8 times the MRHD2 of 10 mg/day on mg/m2 basis).2 Based on patient weight of 50 kg.. Atorvastatin. In 2-year carcinogenicity study with atorvastatin calcium in rats at dose levels equivalent to 10, 30, and 100 mg atorvastatin/kg/day, rare tumors were found in muscle in high-dose females: in one, there was rhabdomyosarcoma and, in another, there was fibrosarcoma. This dose represents plasma AUC (0-24) value of approximately 16 times the mean human plasma drug exposure after an 80 mg oral dose.A 2-year carcinogenicity study in mice given atorvastatin calcium at dose levels equivalent to 100, 200, or 400 mg atorvastatin/kg/day resulted in significant increase in liver adenomas in high-dose males and liver carcinomas in high-dose females. These findings occurred at plasma AUC (0-24) values of approximately times the mean human plasma drug exposure after an 80 mg oral dose.In vitro, atorvastatin was not mutagenic or clastogenic in the following tests with and without metabolic activation: the Ames test with Salmonella typhimurium and Escherichia coli, the HGPRT forward mutation assay in Chinese hamster lung cells, and the chromosomal aberration assay in Chinese hamster lung cells. Atorvastatin was negative in the in vivo mouse micronucleus test.In female rats, atorvastatin at doses up to 225 mg/kg (56 times the human exposure) did not cause adverse effects on fertility. Studies in male rats performed at doses up to 175 mg/kg (15 times the human exposure) produced no changes in fertility. There was aplasia and aspermia in the epididymides of of 10 rats treated with atorvastatin calcium at dose equivalent to 100 mg atorvastatin/kg/day for months (16 times the human AUC at the 80 mg dose); testis weights were significantly lower at 30 and 100 mg/kg/day and epididymal weight was lower at 100 mg/kg/day. Male rats given the equivalent of 100 mg atorvastatin/kg/day for 11 weeks prior to mating had decreased sperm motility, spermatid head concentration, and increased abnormal sperm. Atorvastatin caused no adverse effects on semen parameters, or reproductive organ histopathology in dogs given doses of atorvastatin calcium equivalent to 10, 40, or 120 mg atorvastatin/kg/day for years.

OVERDOSAGE SECTION.


10 OVERDOSAGE There is no information on overdosage with amlodipine and atorvastatin tablets in humans.Amlodipine: Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly reflex tachycardia. In humans, experience with intentional overdosage of amlodipine is limited.Single oral doses of amlodipine maleate equivalent to 40 mg amlodipine/kg and 100 mg amlodipine/kg in mice and rats, respectively, caused deaths. Single oral amlodipine maleate doses equivalent to or more mg amlodipine/kg or higher in dogs (11 or more times the MRHD on mg/m2 basis) caused marked peripheral vasodilation and hypotension.If overdose should occur with amlodipine, initiate active cardiac and respiratory monitoring. Perform frequent blood pressure measurements. Should hypotension occur, provide cardiovascular support including elevation of the extremities and administration of fluids. If hypotension remains unresponsive to these conservative measures, consider administration of vasopressors (such as phenylephrine) with specific attention to circulating volume and urine output. As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.Atorvastatin: There is no specific treatment for atorvastatin overdosage. In the event of an overdose, the patient should be treated symptomatically, and supportive measures instituted as required. Because of extensive drug binding to plasma proteins, hemodialysis is not expected to significantly enhance atorvastatin clearance.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PRINCIPAL DISPLAY PANEL 2.5 mg/10 mg NDC 0378-4510-93Amlodipine andAtorvastatinTablets, USP2.5 mg/10 mgRx only 30 TabletsEach film-coated tablet containsamlodipine besylate, USP equivalent to 2.5 mgamlodipine and atorvastatin calcium, USPequivalent to 10 mg atorvastatin.Usual Dosage: See accompanyingprescribing information.Store at 20 to 25C (68 to 77F). [See USP Controlled RoomTemperature.]Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.Made in IndiaMylan.comRMX4510H3Dispense in tight,light-resistant container asdefined in the USP using achild-resistant closure.Keep container tightly closed.Keep this and all medication out of the reach of children.Code No.: MH/DRUGS/25/NKD/89. Amlodipine and Atorvastatin Tablets 2.5 mg/10 mg Bottle Label.

PEDIATRIC USE SECTION.


8.4 Pediatric Use The safety and effectiveness of amlodipine and atorvastatin tablets have not been established in pediatric populations.. Amlodipine. Amlodipine (2.5 to mg daily) is effective in lowering blood pressure in patients to 17 years [see Clinical Studies (14.1)]. The effect of amlodipine on blood pressure in patients less than years of age is not known.. Atorvastatin. Heterozygous Familial Hypercholesterolemia (HeFH) Safety and effectiveness of atorvastatin have been established in patients 10 years to 17 years of age with HeFH as an adjunct to diet to reduce total cholesterol, LDL-C, and apo levels when, after an adequate trial of diet therapy, the following are present:oLDL-C >= 190 mg/dL, oroLDL-C >= 160 mg/dL andoa positive family history of FH, or premature CVD in first, or second-degree relative, orotwo or more other CVD risk factors are present. Use of atorvastatin for this indication is supported by evidence from [see Dosage and Administration (2), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.11)]:oA placebo-controlled clinical trial of months duration in 187 boys and postmenarchal girls, 10 years to 17 years of age. Patients treated with 10 mg or 20 mg daily atorvastatin had an adverse reaction profile generally similar to that of patients treated with placebo. In this limited controlled study, there was no significant effect on growth or sexual maturation in boys or on menstrual cycle length in girls.oA 3-year open-label uncontrolled trial that included 163 pediatric patients 10 to 15 years of age with HeFH who were titrated to achieve target LDL-C 130 mg/dL. The safety and efficacy of atorvastatin in lowering LDL-C appeared generally consistent with that observed for adult patients, despite limitations of the uncontrolled study design.Advise postmenarchal girls of contraception recommendations, if appropriate for the patient [see Use in Specific Populations (8.1)].The long-term efficacy of atorvastatin therapy initiated in childhood to reduce morbidity and mortality in adulthood has not been established.The safety and efficacy of atorvastatin have not been established in pediatric patients younger than 10 years of age with HeFH.. oLDL-C >= 190 mg/dL, or. oLDL-C >= 160 mg/dL andoa positive family history of FH, or premature CVD in first, or second-degree relative, orotwo or more other CVD risk factors are present. oa positive family history of FH, or premature CVD in first, or second-degree relative, or. otwo or more other CVD risk factors are present.. oA placebo-controlled clinical trial of months duration in 187 boys and postmenarchal girls, 10 years to 17 years of age. Patients treated with 10 mg or 20 mg daily atorvastatin had an adverse reaction profile generally similar to that of patients treated with placebo. In this limited controlled study, there was no significant effect on growth or sexual maturation in boys or on menstrual cycle length in girls.. oA 3-year open-label uncontrolled trial that included 163 pediatric patients 10 to 15 years of age with HeFH who were titrated to achieve target LDL-C 130 mg/dL. The safety and efficacy of atorvastatin in lowering LDL-C appeared generally consistent with that observed for adult patients, despite limitations of the uncontrolled study design.. Homozygous Familial Hypercholesterolemia (HoFH) Clinical efficacy of atorvastatin with dosages up to 80 mg/day for year was evaluated in an uncontrolled study of patients with HoFH including pediatric patients [see Clinical Studies (14.10)].

PHARMACODYNULLMICS SECTION.


12.2 Pharmacodynamics Amlodipine. Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation resulting in reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by significant change in heart rate or plasma catecholamine levels with chronic dosing. Although the acute intravenous administration of amlodipine decreases arterial blood pressure and increases heart rate in hemodynamic studies of patients with chronic stable angina, chronic oral administration of amlodipine in clinical trials did not lead to clinically significant changes in heart rate or blood pressures in normotensive patients with angina.With chronic once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients. The magnitude of reduction in blood pressure with amlodipine is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105-114 mmHg) had about 50% greater response than patients with mild hypertension (diastolic pressure 90-104 mmHg). Normotensive subjects experienced no clinically significant change in blood pressures (+1/-2 mmHg).In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic studies, amlodipine has not been associated with negative inotropic effect when administered in the therapeutic dose range to intact animals and man, even when co-administered with beta-blockers to man. Similar findings, however, have been observed in normal or well-compensated patients with heart failure with agents possessing significant negative inotropic effects.Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or man. In patients with chronic stable angina, intravenous administration of 10 mg did not significantly alter A-H and H-V conduction and sinus node recovery time after pacing. Similar results were obtained in patients receiving amlodipine and concomitant beta-blockers. In clinical studies in which amlodipine was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed. In clinical trials with angina patients alone, amlodipine therapy did not alter electrocardiographic intervals or produce higher degrees of AV blocks.. Atorvastatin. Atorvastatin, as well as some of its metabolites, are pharmacologically active in humans. The liver is the primary site of action and the principal site of cholesterol synthesis and LDL clearance. Drug dosage, rather than systemic drug concentration, correlates better with LDL-C reduction. Individualization of drug dosage should be based on therapeutic response [see Dosage and Administration (2)].. Drug Interactions. Sildenafil When amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect [see Drug Interactions (7.1)].

PHARMACOKINETICS SECTION.


12.3 Pharmacokinetics Absorption. Amlodipine After oral administration of therapeutic doses of amlodipine alone, absorption produces peak plasma concentrations between and 12 hours. Absolute bioavailability has been estimated to be between 64% and 90%.. Atorvastatin After oral administration alone, atorvastatin is rapidly absorbed; maximum plasma concentrations occur within to hours. Extent of absorption increases in proportion to atorvastatin dose. The absolute bioavailability of atorvastatin (parent drug) is approximately 14% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism. Plasma atorvastatin concentrations are lower (approximately 30% for Cmax and AUC) following evening drug administration compared with morning. However, LDL-C reduction is the same regardless of the time of day of drug administration [see Dosage and Administration (2)].. Amlodipine and Atorvastatin Tablets Following oral administration of amlodipine and atorvastatin tablets, peak plasma concentrations of amlodipine and atorvastatin are seen at to 12 hours and to hours post dosing, respectively. The rate and extent of absorption (bioavailability) of amlodipine and atorvastatin from amlodipine and atorvastatin tablets are not significantly different from the bioavailability of amlodipine and atorvastatin administered separately (see above).The bioavailability of amlodipine from amlodipine and atorvastatin tablets was not affected by food. Food decreases the rate and extent of absorption of atorvastatin from amlodipine and atorvastatin tablets by approximately 32% and 11%, respectively, as it does with atorvastatin when given alone. LDL-C reduction is similar whether atorvastatin is given with or without food.. Distribution. Amlodipine Ex vivo studies have shown that approximately 93% of the circulating amlodipine drug is bound to plasma proteins in hypertensive patients. Steady-state plasma levels of amlodipine are reached after to days of consecutive daily dosing.. Atorvastatin Mean volume of distribution of atorvastatin is approximately 381 liters. Atorvastatin is >= 98% bound to plasma proteins. blood/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells. Based on observations in rats, atorvastatin calcium is likely to be secreted in human milk [see Contraindications (4) and Use in Specific Populations (8.3)].. Metabolism. Amlodipine Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism.. Atorvastatin Atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In vitro studies suggest the importance of atorvastatin metabolism by cytochrome P4503A4, consistent with increased plasma concentrations of atorvastatin in humans following co-administration with erythromycin, known inhibitor of this isozyme [see Drug Interactions (7)]. In animals, the ortho-hydroxy metabolite undergoes further glucuronidation.. Excretion. Amlodipine Elimination from the plasma is biphasic with terminal elimination half-life of about 30-50 hours. Ten percent of the parent amlodipine compound and 60% of the metabolites of amlodipine are excreted in the urine.. Atorvastatin Atorvastatin and its metabolites are eliminated primarily in bile following hepatic and/or extra-hepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin in humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours because of the contribution of active metabolites. Less than 2% of dose of atorvastatin is recovered in urine following oral administration.. Specific Populations. Geriatric Amlodipine. Elderly patients have decreased clearance of amlodipine with resulting increase in AUC of approximately 40-60%, and lower initial dose of amlodipine may be required.. Atorvastatin. Plasma concentrations of atorvastatin are higher (approximately 40% for Cmax and 30% for AUC) in healthy elderly subjects (age >= 65 years) than in young adults. Clinical data suggest greater degree of LDL-lowering at any dose of atorvastatin in the elderly population compared to younger adults [see Use in Specific Populations (8.5)].. Pediatric Amlodipine. Sixty-two hypertensive patients aged to 17 years received doses of amlodipine between 1.25 mg and 20 mg. Weight-adjusted clearance and volume of distribution were similar to values in adults.. Atorvastatin. Apparent oral clearance of atorvastatin in pediatric subjects appeared similar to that of adults when scaled allometrically by body weight as the body weight was the only significant covariate in atorvastatin population pharmacokinetics model with data including pediatric HeFH patients (ages 10 years to 17 years of age, = 29) in an open-label, 8-week study.. Gender Atorvastatin. Plasma concentrations of atorvastatin in women differ from those in men (approximately 20% higher for Cmax and 10% lower for AUC); however, there is no clinically significant difference in LDL-C reduction with atorvastatin between men and women.. Renal Impairment Amlodipine. The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial amlodipine dose.. Atorvastatin. Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin; thus, dose adjustment of atorvastatin in patients with renal dysfunction is not necessary [see Dosage and Administration (2) and Warnings and Precautions (5.1)].. Hemodialysis While studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to clear atorvastatin or amlodipine since both drugs are extensively bound to plasma proteins.. Hepatic Impairment Amlodipine. Elderly patients and patients with hepatic insufficiency have decreased clearance of amlodipine with resulting increase in AUC of approximately 40-60%.. Atorvastatin. In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin are markedly increased. Cmax and AUC are each 4-fold greater in patients with Childs-Pugh disease. Cmax and AUC of atorvastatin are approximately 16-fold and 11-fold increased, respectively, in patients with Childs-Pugh disease [see Contraindications (4)].Atorvastatin is contraindicated in patients with active liver disease.. Heart Failure Amlodipine. In patients with moderate to severe heart failure, the increase in AUC for amlodipine was similar to that seen in the elderly and in patients with hepatic insufficiency.. Effects of Other Drugs on Amlodipine and Atorvastatin Tablets. Amlodipine Co-administered cimetidine, magnesium- and aluminum hydroxide antacids, sildenafil, and grapefruit juice have no impact on the exposure to amlodipine.. CYP3A Inhibitors Co-administration of 180 mg daily dose of diltiazem with mg amlodipine in elderly hypertensive patients resulted in 60% increase in amlodipine systemic exposure. Erythromycin co-administration in healthy volunteers did not significantly change amlodipine systemic exposure. However, strong inhibitors of CYP3A (e.g., itraconazole, clarithromycin) may increase the plasma concentrations of amlodipine to greater extent [see Drug Interactions (7.1)].. Atorvastatin Atorvastatin is substrate of the hepatic transporters, OATP1B1 and OATP1B3 transporter. Metabolites of atorvastatin are substrates of OATP1B1. Atorvastatin is also identified as substrate of the efflux transporter BCRP, which may limit the intestinal absorption and biliary clearance of atorvastatin.Table shows effects of other drugs on the pharmacokinetics of atorvastatin.Table 4. Effect of Co-administered Drugs on the Pharmacokinetics of AtorvastatinCo-administered Drug and Dosing RegimenAtorvastatinDose (mg) Ratio of AUCRepresents ratio of treatments (co-administered drug plus atorvastatin vs. atorvastatin alone).Ratio of CmaxSee Sections 5.1 and for clinical significance.Cyclosporine 5.2 mg/kg/day, stable dose 10 mg QDOnce daily for 28 days8.69 10.66Tipranavir 500 mg BIDb/ritonavir 200 mg BIDTwice daily, days10 mg SDSingle dose 9.368.58Glecaprevir 400 mg QD/pibrentasvir 120 mg QD, days10 mg QD for days8.2822.00Telaprevir 750 mg q8hEvery hours, 10 days20 mg SDc 7.8810.60, The dose of saquinavir plus ritonavir in this study is not the clinically used dose. The increase in atorvastatin exposure when used clinically is likely to be higher than what was observed in this study. Therefore, caution should be applied and the lowest dose necessary should be used.Saquinavir 400 mg BID/ritonavir 400 mg BIDb, 15 days40 mg QD for days3.934.31Elbasvir 50 mg QD/grazoprevir 200 mg QD, 13 days10 mg SD 1.954.34Simeprevir 150 mg QD, 10 days40 mg SD 2.121.70Clarithromycin 500 mg BID, days80 mg QD for days4.545.38Darunavir 300 mg BID/ritonavir 100 mg BID, days10 mg QD for days3.452.25Itraconazole 200 mg QD, days40 mg SD 3.321.20 Letermovir 480 mg QD, 10 days20 mg SD 3.292.17Fosamprenavir 700 mg BID/ritonavir 100 mg BID, 14 days10 mg QD for days2.532.84 Fosamprenavir 1400 mg BID, 14 days10 mg QD for days2.304.04 Nelfinavir 1250 mg BID, 14 days10 mg QD for 28 days1.742.22Grapefruit Juice, 240 mL QD,Greater increases in AUC (ratio of AUC up to 2.5) and/or Cmax (ratio of Cmax up to 1.71) have been reported with excessive grapefruit consumption (>= 750 mL-1.2 liters per day).40 mg SD 1.37 1.16 Diltiazem 240 mg QD, 28 days40 mg SD 1.511.00Erythromycin 500 mg QIDFour times daily, days10 mg SD 1.33 1.38 Amlodipine 10 mg, single dose80 mg SD 1.18 0.91 Cimetidine 300 mg QID, weeks10 mg QD for weeks 1.000.89 Colestipol 10 BID, 24 weeks40 mg QD for weeks NULL 0.74Ratio based on single sample taken 8-16 post dose. Maalox TC(R) 30 mL QID, 17 days10 mg QD for 15 days 0.66 0.67 Efavirenz 600 mg QD, 14 days10 mg for days 0.59 1.01 Rifampin 600 mg QD, days (co-administered)Due to the dual interaction mechanism of rifampin, simultaneous co-administration of atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with significant reduction in atorvastatin plasma concentrations.40 mg SD 1.12 2.90Rifampin 600 mg QD, days (doses separated)40 mg SD 0.20 0.60 Gemfibrozil 600 mg BID, days40 mg SD 1.35 1.00Fenofibrate 160 mg QD, days40 mg SD 1.03 1.02 Boceprevir 800 mg TIDThree times daily, days40 mg SD 2.322.66. Effects of Amlodipine and Atorvastatin Tablets on Other Drugs. Amlodipine Amlodipine is weak inhibitor of CYP3A and may increase exposure to CYP3A substrates.In vitro data indicate that amlodipine has no effect on the human plasma protein binding of digoxin, phenytoin, warfarin, and indomethacin.Co-administered amlodipine does not affect the exposure to atorvastatin, digoxin, ethanol and the warfarin prothrombin response time.. Cyclosporine A prospective study in renal transplant patients (N 11) showed on an average of 40% increase in trough cyclosporine levels when concomitantly treated with amlodipine [see Drug Interactions (7.2)].. Tacrolimus A prospective study in healthy Chinese volunteers (N 9) with CYP3A5 expressers showed 2.5- to 4-fold increase in tacrolimus exposure when concomitantly administered with amlodipine compared to tacrolimus alone. This finding was not observed in CYP3A5 non-expressers (N 6). However, 3-fold increase in plasma exposure to tacrolimus in renal transplant patient (CYP3A5 non-expresser) upon initiation of amlodipine for the treatment of post-transplant hypertension resulting in reduction of tacrolimus dose has been reported. Irrespective of the CYP3A5 genotype status, the possibility of an interaction cannot be excluded with these drugs [see Drug Interactions (7.2)].. Atorvastatin Table shows the effects of atorvastatin on the pharmacokinetics of other drugs. Table 5. Effect of Atorvastatin on the Pharmacokinetics of Co-administered DrugsAtorvastatinCo-administered Drug and Dosing RegimenDrug/Dose (mg)Ratio of AUCRatio of Cmax80 mg QDOnce daily for 15 daysAntipyrine, 600 mg SDSingle dose 1.030.8980 mg QD for 10 daysSee Section for clinical significance.Digoxin 0.25 mg QD, 20 days1.151.2040 mg QD for 22 daysOral contraceptive QD, months- norethindrone mg ethinyl estradiol 35 ug1.281.191.231.3010 mg SD Tipranavir 500 mg BIDTwice daily/ritonavir 200 mg BID, days1.080.9610 mg QD for daysFosamprenavir 1400 mg BID, 14 days0.730.8210 mg QD for daysFosamprenavir 700 mg BID/ritonavir 100 mg BID, 14 days0.990.94.

PREGNULLNCY SECTION.


8.1 Pregnancy Risk Summary. Amlodipine and atorvastatin tablets are contraindicated in women who are pregnant.. Atorvastatin Atorvastatin is contraindicated for use in pregnant women since safety in pregnant women has not been established and there is no apparent benefit of lipid-lowering drugs during pregnancy. Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, atorvastatin may cause fetal harm when administered to pregnant woman. Amlodipine and atorvastatin tablets should be discontinued as soon as pregnancy is recognized [see Contraindications (4)]. Limited published data on the use of atorvastatin are insufficient to determine drug-associated risk of major congenital malformations or miscarriage. In animal reproduction studies in rats and rabbits there was no evidence of embryo-fetal toxicity or congenital malformations at doses up to 30 and 20 times, respectively, the human exposure at the MRHD of 80 mg, based on body surface area (mg/m2). In rats administered atorvastatin during gestation and lactation, decreased postnatal growth and development was observed at doses >= times the MRHD (see Data ).. Amlodipine The limited available data based on post-marketing reports with amlodipine use in pregnant women are not sufficient to inform drug-associated risk for major birth defects and miscarriage. There are risks to the mother and fetus associated with poorly controlled hypertension in pregnancy (see Clinical Considerations ). In animal reproduction studies, there was no evidence of adverse developmental effects when pregnant rats and rabbits were treated orally with amlodipine maleate during organogenesis at doses approximately 10 and 20-times MRHD, respectively. However for rats, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold). Amlodipine has been shown to prolong both the gestation period and the duration of labor in rats at this dose (see Data ).The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.. Clinical Considerations Disease-associated Maternal and/or Embryo/Fetal Risk. Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly.. Data Human Data. Atorvastatin: Limited published data on atorvastatin calcium from observational studies, meta-analyses and case reports have not shown an increased risk of major congenital malformations or miscarriage. Rare reports of congenital anomalies have been received following intrauterine exposure to other HMG-CoA reductase inhibitors. In review of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or lovastatin, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed what would be expected in the general population. The number of cases is adequate to exclude >= to 4-fold increase in congenital anomalies over the background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified.. Animal Data. Atorvastatin: Atorvastatin crosses the rat placenta and reaches level in fetal liver equivalent to that of maternal plasma. When administered to pregnant rats and rabbits during organogenesis at oral doses up to 300 mg/kg/day and 100 mg/kg/day, respectively, atorvastatin was not teratogenic in rats at doses up to 300 mg/kg/day or in rabbits at doses up to 100 mg/kg/day. These doses resulted in multiples of about 30 times (rat) or 20 times (rabbit) the human exposure at the MRHD based on surface area (mg/m2). In rats, the maternally toxic dose of 300 mg/kg resulted in increased post-implantation loss and decreased fetal body weight. At the maternally toxic doses of 50 and 100 mg/kg/day in rabbits, there was increased post-implantation loss, and at 100 mg/kg/day fetal body weights were decreased.In study in pregnant rats administered atorvastatin calcium at doses equivalent to 20, 100, or 225 mg/kg/day, from gestation day through to lactation day 20 (weaning), there was decreased survival at birth, postnatal day 4, weaning, and post-weaning in pups of mothers dosed with 225 mg/kg/day, dose at which maternal toxicity was observed. Pup body weight was decreased through postnatal day 21 at 100 mg/kg/day, and through postnatal day 91 at 225 mg/kg/day. Pup development was delayed (rotorod performance at 100 mg/kg/day and acoustic startle at 225 mg/kg/day; pinnae detachment and eye-opening at 225 mg/kg/day). These doses of atorvastatin correspond to times (100 mg/kg) and 22 times (225 mg/kg) the human exposure at the MRHD, based on AUC.AmlodipineNo evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine maleate at doses up to 10 mg amlodipine/kg/day (approximately 10 and 20 times the MRHD based on body surface area, respectively) during their respective periods of major organogenesis. However, for rats, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold) in rats receiving amlodipine maleate at dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating and gestation. Amlodipine maleate has been shown to prolong both the gestation period and the duration of labor in rats at this dose.

SPL UNCLASSIFIED SECTION.


1.1Hypertension Amlodipine is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from wide variety of pharmacologic classes including amlodipine.Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Programs Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).Numerous antihypertensive drugs, from variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to lower blood pressure goal.Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.Amlodipine may be used alone or in combination with other antihypertensive agents.

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS oHepatic Impairment: Plasma concentrations of atorvastatin markedly increased in patients with active liver disease (8.6, 12.3).oFemales of reproductive potential: Advise females of reproductive potential to use effective contraception during treatment with amlodipine and atorvastatin tablets (8.3).. oHepatic Impairment: Plasma concentrations of atorvastatin markedly increased in patients with active liver disease (8.6, 12.3).. oFemales of reproductive potential: Advise females of reproductive potential to use effective contraception during treatment with amlodipine and atorvastatin tablets (8.3).. 8.1 Pregnancy Risk Summary. Amlodipine and atorvastatin tablets are contraindicated in women who are pregnant.. Atorvastatin Atorvastatin is contraindicated for use in pregnant women since safety in pregnant women has not been established and there is no apparent benefit of lipid-lowering drugs during pregnancy. Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, atorvastatin may cause fetal harm when administered to pregnant woman. Amlodipine and atorvastatin tablets should be discontinued as soon as pregnancy is recognized [see Contraindications (4)]. Limited published data on the use of atorvastatin are insufficient to determine drug-associated risk of major congenital malformations or miscarriage. In animal reproduction studies in rats and rabbits there was no evidence of embryo-fetal toxicity or congenital malformations at doses up to 30 and 20 times, respectively, the human exposure at the MRHD of 80 mg, based on body surface area (mg/m2). In rats administered atorvastatin during gestation and lactation, decreased postnatal growth and development was observed at doses >= times the MRHD (see Data ).. Amlodipine The limited available data based on post-marketing reports with amlodipine use in pregnant women are not sufficient to inform drug-associated risk for major birth defects and miscarriage. There are risks to the mother and fetus associated with poorly controlled hypertension in pregnancy (see Clinical Considerations ). In animal reproduction studies, there was no evidence of adverse developmental effects when pregnant rats and rabbits were treated orally with amlodipine maleate during organogenesis at doses approximately 10 and 20-times MRHD, respectively. However for rats, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold). Amlodipine has been shown to prolong both the gestation period and the duration of labor in rats at this dose (see Data ).The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.. Clinical Considerations Disease-associated Maternal and/or Embryo/Fetal Risk. Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly.. Data Human Data. Atorvastatin: Limited published data on atorvastatin calcium from observational studies, meta-analyses and case reports have not shown an increased risk of major congenital malformations or miscarriage. Rare reports of congenital anomalies have been received following intrauterine exposure to other HMG-CoA reductase inhibitors. In review of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or lovastatin, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed what would be expected in the general population. The number of cases is adequate to exclude >= to 4-fold increase in congenital anomalies over the background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified.. Animal Data. Atorvastatin: Atorvastatin crosses the rat placenta and reaches level in fetal liver equivalent to that of maternal plasma. When administered to pregnant rats and rabbits during organogenesis at oral doses up to 300 mg/kg/day and 100 mg/kg/day, respectively, atorvastatin was not teratogenic in rats at doses up to 300 mg/kg/day or in rabbits at doses up to 100 mg/kg/day. These doses resulted in multiples of about 30 times (rat) or 20 times (rabbit) the human exposure at the MRHD based on surface area (mg/m2). In rats, the maternally toxic dose of 300 mg/kg resulted in increased post-implantation loss and decreased fetal body weight. At the maternally toxic doses of 50 and 100 mg/kg/day in rabbits, there was increased post-implantation loss, and at 100 mg/kg/day fetal body weights were decreased.In study in pregnant rats administered atorvastatin calcium at doses equivalent to 20, 100, or 225 mg/kg/day, from gestation day through to lactation day 20 (weaning), there was decreased survival at birth, postnatal day 4, weaning, and post-weaning in pups of mothers dosed with 225 mg/kg/day, dose at which maternal toxicity was observed. Pup body weight was decreased through postnatal day 21 at 100 mg/kg/day, and through postnatal day 91 at 225 mg/kg/day. Pup development was delayed (rotorod performance at 100 mg/kg/day and acoustic startle at 225 mg/kg/day; pinnae detachment and eye-opening at 225 mg/kg/day). These doses of atorvastatin correspond to times (100 mg/kg) and 22 times (225 mg/kg) the human exposure at the MRHD, based on AUC.AmlodipineNo evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine maleate at doses up to 10 mg amlodipine/kg/day (approximately 10 and 20 times the MRHD based on body surface area, respectively) during their respective periods of major organogenesis. However, for rats, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold) in rats receiving amlodipine maleate at dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating and gestation. Amlodipine maleate has been shown to prolong both the gestation period and the duration of labor in rats at this dose. 8.2 Lactation Risk Summary. Amlodipine and atorvastatin tablets are contraindicated during breastfeeding.. Atorvastatin Atorvastatin use is contraindicated during breastfeeding [see Contraindications (4)]. There is no available information on the effects of the drug on the breastfed infant or the effects of the drug on milk production. It is not known whether atorvastatin is present in human milk, but it has been shown that another drug in this class passes into human milk and atorvastatin is present in rat milk. Because of the potential for serious adverse reactions in breastfed infant, advise women that breastfeeding is not recommended during treatment with amlodipine and atorvastatin tablets.. Amlodipine Limited available data from published clinical lactation study reports that amlodipine is present in human milk at an estimated median relative infant dose of 4.2%. No adverse effects of amlodipine on the breastfed infant have been observed. There is no available information on the effects of amlodipine on milk production. 8.3 Females and Males of Reproductive Potential Contraception. Atorvastatin may cause fetal harm when administered to pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with amlodipine and atorvastatin tablets [see Use in Specific Populations (8.1)]. 8.4 Pediatric Use The safety and effectiveness of amlodipine and atorvastatin tablets have not been established in pediatric populations.. Amlodipine. Amlodipine (2.5 to mg daily) is effective in lowering blood pressure in patients to 17 years [see Clinical Studies (14.1)]. The effect of amlodipine on blood pressure in patients less than years of age is not known.. Atorvastatin. Heterozygous Familial Hypercholesterolemia (HeFH) Safety and effectiveness of atorvastatin have been established in patients 10 years to 17 years of age with HeFH as an adjunct to diet to reduce total cholesterol, LDL-C, and apo levels when, after an adequate trial of diet therapy, the following are present:oLDL-C >= 190 mg/dL, oroLDL-C >= 160 mg/dL andoa positive family history of FH, or premature CVD in first, or second-degree relative, orotwo or more other CVD risk factors are present. Use of atorvastatin for this indication is supported by evidence from [see Dosage and Administration (2), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.11)]:oA placebo-controlled clinical trial of months duration in 187 boys and postmenarchal girls, 10 years to 17 years of age. Patients treated with 10 mg or 20 mg daily atorvastatin had an adverse reaction profile generally similar to that of patients treated with placebo. In this limited controlled study, there was no significant effect on growth or sexual maturation in boys or on menstrual cycle length in girls.oA 3-year open-label uncontrolled trial that included 163 pediatric patients 10 to 15 years of age with HeFH who were titrated to achieve target LDL-C 130 mg/dL. The safety and efficacy of atorvastatin in lowering LDL-C appeared generally consistent with that observed for adult patients, despite limitations of the uncontrolled study design.Advise postmenarchal girls of contraception recommendations, if appropriate for the patient [see Use in Specific Populations (8.1)].The long-term efficacy of atorvastatin therapy initiated in childhood to reduce morbidity and mortality in adulthood has not been established.The safety and efficacy of atorvastatin have not been established in pediatric patients younger than 10 years of age with HeFH.. oLDL-C >= 190 mg/dL, or. oLDL-C >= 160 mg/dL andoa positive family history of FH, or premature CVD in first, or second-degree relative, orotwo or more other CVD risk factors are present. oa positive family history of FH, or premature CVD in first, or second-degree relative, or. otwo or more other CVD risk factors are present.. oA placebo-controlled clinical trial of months duration in 187 boys and postmenarchal girls, 10 years to 17 years of age. Patients treated with 10 mg or 20 mg daily atorvastatin had an adverse reaction profile generally similar to that of patients treated with placebo. In this limited controlled study, there was no significant effect on growth or sexual maturation in boys or on menstrual cycle length in girls.. oA 3-year open-label uncontrolled trial that included 163 pediatric patients 10 to 15 years of age with HeFH who were titrated to achieve target LDL-C 130 mg/dL. The safety and efficacy of atorvastatin in lowering LDL-C appeared generally consistent with that observed for adult patients, despite limitations of the uncontrolled study design.. Homozygous Familial Hypercholesterolemia (HoFH) Clinical efficacy of atorvastatin with dosages up to 80 mg/day for year was evaluated in an uncontrolled study of patients with HoFH including pediatric patients [see Clinical Studies (14.10)]. 8.5 Geriatric Use Safety and effectiveness of amlodipine and atorvastatin tablets have not been established in geriatric populations.. Amlodipine. Clinical studies of amlodipine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Elderly patients have decreased clearance of amlodipine with resulting increase of AUC of approximately 40-60%, and lower initial dose may be required [see Dosage and Administration (2)].. Atorvastatin. Of the 39,828 patients who received atorvastatin in clinical studies, 15,813 (40%) were >= 65 years old and 2,800 (7%) were >= 75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older adults cannot be ruled out. Advanced age (>= 65 years) is predisposing factor for myopathy.. 8.6Hepatic Impairment Amlodipine and atorvastatin tablets are contraindicated in patients with active liver disease which may include unexplained persistent elevations in hepatic transaminase levels [see Contraindications (4) and Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS oMyopathy and Rhabdomyolysis: Advise patients to promptly report to their physician unexplained and/or persistent muscle pain, tenderness, or weakness. Amlodipine and atorvastatin tablet therapy should be discontinued if myopathy is diagnosed or suspected (2, 5.1, 8.5).oHepatic Transaminitis: Monitor liver enzymes before and during treatment (5.2).oSymptomatic hypotension is possible, particularly in patients with severe aortic stenosis. However, acute hypotension is unlikely (5.4).oAngina or myocardial infarction may occur with initiation or dose increase (5.3).. oMyopathy and Rhabdomyolysis: Advise patients to promptly report to their physician unexplained and/or persistent muscle pain, tenderness, or weakness. Amlodipine and atorvastatin tablet therapy should be discontinued if myopathy is diagnosed or suspected (2, 5.1, 8.5).. oHepatic Transaminitis: Monitor liver enzymes before and during treatment (5.2).. oSymptomatic hypotension is possible, particularly in patients with severe aortic stenosis. However, acute hypotension is unlikely (5.4).. oAngina or myocardial infarction may occur with initiation or dose increase (5.3).. 5.1Myopathy and Rhabdomyolysis Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with atorvastatin and with other drugs in this class. history of renal impairment may be risk factor for the development of rhabdomyolysis. Such patients merit closer monitoring for skeletal muscle effects.Atorvastatin, like other statins, occasionally causes myopathy, defined as muscle aches or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values 10 times upper limit of normal [ULN]. The concomitant use of higher doses of atorvastatin with certain drugs such as cyclosporine and strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., clarithromycin, itraconazole, and HIV and HCV protease inhibitors) increases the risk of myopathy/rhabdomyolysis.There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents.Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, or marked elevation of CPK. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing amlodipine and atorvastatin tablets. Amlodipine and atorvastatin tablet therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected.The risk of myopathy during treatment with statins is increased with concurrent administration of the drugs listed in Table 2. Physicians considering combined therapy of amlodipine and atorvastatin tablets with any of these drugs should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Lower starting and maintenance doses of atorvastatin should be considered when taken concomitantly with the aforementioned drugs [see Drug Interactions (7)]. Periodic creatine phosphokinase (CPK) determinations may be considered in such situations, but there is no assurance that such monitoring will prevent the occurrence of severe myopathy.Prescribing recommendations for interacting agents are summarized in Table [see Dosage and Administration (2), Drug Interactions (7), and Clinical Pharmacology (12.3)].Table 2. Atorvastatin Drug Interactions Associated with Increased Risk of Myopathy/RhabdomyolysisCyclosporine, tipranavir plus ritonavir, glecaprevir plus pibrentasvir, letermovir when co-administered with cyclosporineAvoid atorvastatinClarithromycin, itraconazole, saquinavir plus ritonavirUse the lowest dose necessary (12.3), darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir, letermovirDo not exceed 20 mg atorvastatin dailyNelfinavirDo not exceed 40 mg atorvastatin dailyLopinavir plus ritonavir, simeprevir, fibric acid derivatives, erythromycin, azole antifungals, lipid-modifying doses of niacin, colchicineUse with caution and lowest dose necessaryWithhold or discontinue in any patient with an acute, serious condition suggestive of myopathy or having risk factor predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., severe acute infection; hypotension; major surgery; trauma; severe metabolic, endocrine, and electrolyte disorders; and uncontrolled seizures).. 5.2Liver Dysfunction Statins, like atorvastatin, and some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. Persistent elevations (> times the upper limit of normal [ULN] occurring on or more occasions) in serum transaminases occurred in 0.7% of patients who received atorvastatin in clinical trials. The incidence of these abnormalities was 0.2%, 0.2%, 0.6%, and 2.3% for 10, 20, 40, and 80 mg, respectively.One patient in clinical trials with atorvastatin developed jaundice. Increases in liver function tests (LFT) in other patients were not associated with jaundice or other clinical signs or symptoms. Upon dose reduction, drug interruption, or discontinuation, transaminase levels returned to or near pretreatment levels without sequelae. Eighteen of 30 patients with persistent LFT elevations continued treatment with reduced dose of atorvastatin.It is recommended that liver enzyme tests be obtained prior to initiating therapy with atorvastatin and repeated as clinically indicated. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including atorvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with amlodipine and atorvastatin tablets, promptly interrupt therapy. If an alternate etiology is not found, do not restart amlodipine and atorvastatin tablets.Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of amlodipine and atorvastatin tablets [see Contraindications (4)].. 5.3Increased Angina and Myocardial Infarction Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of amlodipine, particularly in patients with severe obstructive coronary artery disease.. 5.4Hypotension Symptomatic hypotension is possible with use of amlodipine, particularly in patients with severe aortic stenosis. Because of the gradual onset of action, acute hypotension is unlikely.. 5.5Endocrine Function Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including atorvastatin.Statins interfere with cholesterol synthesis and theoretically might blunt adrenal and/or gonadal steroid production. Clinical studies have shown that atorvastatin does not reduce basal plasma cortisol concentration or impair adrenal reserve. The effects of statins on male fertility have not been studied in adequate numbers of patients. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown. Avoid statin with drugs that may decrease the levels or activity of endogenous steroid hormones such as ketoconazole, spironolactone, and cimetidine.. 5.6CNS Toxicity Brain hemorrhage was seen in female dog treated with atorvastatin for months at 120 mg/kg/day. Brain hemorrhage and optic nerve vacuolation were seen in another female dog that was sacrificed in moribund condition after 11 weeks of escalating doses up to 280 mg/kg/day. The 120 mg/kg dose resulted in systemic exposure approximately 16 times the human plasma area-under-the-curve (AUC, 0-24 hours) based on the maximum human dose of 80 mg/day. single tonic convulsion was seen in each of male dogs (one treated at 10 mg/kg/day and one at 120 mg/kg/day) in 2-year study. No CNS lesions have been observed in mice after chronic treatment for up to years at doses up to 400 mg/kg/day or in rats at doses up to 100 mg/kg/day. These doses were to 11 times (mouse) and to 16 times (rat) the human AUC (0-24) based on the maximum recommended human dose (MRHD) of 80 mg/day.CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with other statins. chemically similar drug in this class produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in dose-dependent fashion at dose that produced plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose.. 5.7Hemorrhagic Stroke In post-hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study where atorvastatin 80 mg vs. placebo was administered in 4,731 subjects without CHD who had stroke or TIA within the preceding months, higher incidence of hemorrhagic stroke was seen in the atorvastatin 80 mg group compared to placebo (55, 2.3% atorvastatin vs. 33, 1.4% placebo; HR: 1.68, 95% CI: 1.09, 2.59; = 0.0168). The incidence of fatal hemorrhagic stroke was similar across treatment groups (17 vs. 18 for the atorvastatin and placebo groups, respectively). The incidence of non-fatal hemorrhagic stroke was significantly higher in the atorvastatin group (38, 1.6%) as compared to the placebo group (16, 0.7%). Some baseline characteristics, including hemorrhagic and lacunar stroke on study entry, were associated with higher incidence of hemorrhagic stroke in the atorvastatin group [see Adverse Reactions (6.1)].