SPL UNCLASSIFIED SECTION.

2.2 Administering Oral Solution by Feeding Tube. Because NORVIR oral solution contains ethanol and propylene glycol, it is not recommended for use with polyurethane feeding tubes due to potential incompatibility. Feeding tubes that are compatible with ethanol and propylene glycol, such as silicone and polyvinyl chloride (PVC) feeding tubes, can be used for administration of NORVIR oral solution. Follow instructions for use of the feeding tube to administer the medicine.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. When co-administering NORVIR with other protease inhibitors, see the full prescribing information for the co-administered protease inhibitor including important information for use in special populations.. Lactation: Women infected with HIV should be instructed not to breastfeed due to the potential for HIV transmission (8.2). Lactation: Women infected with HIV should be instructed not to breastfeed due to the potential for HIV transmission (8.2). 8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to NORVIR during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.Risk SummaryProspective pregnancy data from the Antiretroviral Pregnancy Registry (APR) are not sufficient to adequately assess the risk of birth defects or miscarriage. Available data from the APR show no difference in the rate of overall birth defects for ritonavir compared to the background rate for major birth defects of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) [see Data]. In animal reproduction studies, no evidence of adverse developmental outcomes was observed with oral administration of ritonavir to pregnant rats and rabbits. During organogenesis in the rat and rabbit, systemic exposure (AUC) was approximately 1/3 lower than human exposure at the recommended daily dose. In the rat pre- and post-natal developmental study, maternal systemic exposure to ritonavir was approximately 1/2 of the exposure in humans at the recommended daily dose, based on body surface area conversion factor [see Data]. NORVIR oral solution is not recommended during pregnancy because there is no known safe level of ethanol exposure during pregnancy [see Clinical Considerations, Dosage and Administration (2.3) and Warnings and Precautions (5.2)].The 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 2-4% and 15-20%, respectively.Clinical ConsiderationsDose Adjustments During Pregnancy and the Postpartum PeriodNORVIR oral solution contains approx. 43% ethanol (v/v) and approx. 27% (w/v) propylene glycol and is not recommended during pregnancy because there is no known safe level of ethanol exposure during pregnancy [see Dosage and Administration (2.3) and Warnings and Precautions (5.2)]. DataHuman DataBased on prospective reports to the APR of approximately 6100 live births following exposure to ritonavir-containing regimens (including over 2800 live births exposed in the first trimester and over 3200 live births exposed in the second and third trimesters), there was no difference in the rate of overall birth defects for ritonavir compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 2.3% (95% CI: 1.7%-2.9%) following first-trimester exposure to ritonavir-containing regimens and 2.9% (95% CI: 2.3%-3.5%) following second and third trimester exposure to ritonavir-containing regimens.While placental transfer of ritonavir and fetal ritonavir concentrations are generally low, detectable levels have been observed in cord blood samples and neonate hair.Animal DataRitonavir was administered orally to pregnant rats (at 0, 15, 35, and 75 mg/kg/day) and rabbits (at 0, 25, 50, and 110 mg/kg/day) during organogenesis (on gestation days through 17 and through 19, respectively). No evidence of teratogenicity due to ritonavir was observed in rats and rabbits at doses producing systemic exposures (AUC) equivalent to approximately 1/3 lower than human exposure at the recommended daily dose. Developmental toxicity observed in rats (early resorptions, decreased fetal body weight and ossification delays and developmental variations) occurred at maternally toxic dose, at an exposure equivalent to approximately 1/3 lower than human exposure at the recommended daily dose. slight increase in the incidence of cryptorchidism was also noted in rats (at maternally toxic dose) at an exposure approximately 1/5 lower than human exposure at the recommended daily dose. Developmental toxicity was observed in rabbits (resorptions, decreased litter size and decreased fetal weights) at maternally toxic doses approximately 1.8 times higher than the recommended daily dose, based on body surface area conversion factor. In pre-and postnatal development study in rats, ritonavir was administered at doses of 0, 15, 35, and 60 mg/kg/day from gestation day through postnatal day 20. At doses of 60 mg/kg/day, no developmental toxicity was noted with ritonavir dosage equivalent to 1/2 of the recommended daily dose, based on body surface area conversion factor.. 8.2 Lactation. Risk SummaryThe Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV.Limited published data reports that ritonavir is present in human milk. There is no information on the effects of ritonavir on the breastfed infant or the effects of the drug on milk production. Because of the potential for (1) HIV transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants) and (3) serious adverse reactions in breastfed infant, instruct mothers not to breastfeed if they are receiving NORVIR. 8.3 Females and Males of Reproductive Potential. ContraceptionUse of NORVIR may reduce the efficacy of combined hormonal contraceptives. Advise patients using combined hormonal contraceptives to use an effective alternative contraceptive method or an additional barrier method of contraception [see Drug Interactions (7.2)]. 8.4 Pediatric Use. In HIV-infected patients age greater than month to 21 years, the antiviral activity and adverse event profile seen during clinical trials and through postmarketing experience were similar to that for adult patients.. 8.5 Geriatric Use. Clinical studies of NORVIR did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 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.. 8.6 Hepatic Impairment. No dose adjustment of ritonavir is necessary for patients with either mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. No pharmacokinetic or safety data are available regarding the use of ritonavir in subjects with severe hepatic impairment (Child-Pugh Class C), therefore, ritonavir is not recommended for use in patients with severe hepatic impairment [see Warnings and Precautions (5.3), Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. The following have been observed in patients receiving NORVIR:The concomitant use of NORVIR and certain other drugs may result in known or potentially significant drug interactions. Consult the full prescribing information prior to and during treatment for potential drug interactions. (5.1, 7.2) Toxicity in preterm neonates: NORVIR oral solution should not be used in preterm neonates in the immediate postnatal period because of possible toxicities. safe and effective dose of NORVIR oral solution in this patient population has not been established (2.4, 5.2) Hepatotoxicity: Fatalities have occurred. Monitor liver function before and during therapy, especially in patients with underlying hepatic disease, including hepatitis and hepatitis C, or marked transaminase elevations (5.3, 8.6) Pancreatitis: Fatalities have occurred; suspend therapy as clinically appropriate (5.4) Allergic Reactions/Hypersensitivity: Allergic reactions have been reported and include anaphylaxis, toxic epidermal necrolysis, Stevens-Johnson syndrome, bronchospasm and angioedema. Discontinue treatment if severe reactions develop (5.5, 6.2) PR interval prolongation may occur in some patients. Cases of second and third degree heart block have been reported. Use with caution with patients with preexisting conduction system disease, ischemic heart disease, cardiomyopathy, underlying structural heart disease or when administering with other drugs that may prolong the PR interval (5.6, 12.3) Total cholesterol and triglycerides elevations: Monitor prior to therapy and periodically thereafter (5.7) Patients may develop new onset or exacerbations of diabetes mellitus, hyperglycemia (5.8) Patients may develop immune reconstitution syndrome (5.9) Patients may develop redistribution/accumulation of body fat (5.10) Hemophilia: Spontaneous bleeding may occur, and additional factor VIII may be required (5.11) The concomitant use of NORVIR and certain other drugs may result in known or potentially significant drug interactions. Consult the full prescribing information prior to and during treatment for potential drug interactions. (5.1, 7.2) Toxicity in preterm neonates: NORVIR oral solution should not be used in preterm neonates in the immediate postnatal period because of possible toxicities. safe and effective dose of NORVIR oral solution in this patient population has not been established (2.4, 5.2) Hepatotoxicity: Fatalities have occurred. Monitor liver function before and during therapy, especially in patients with underlying hepatic disease, including hepatitis and hepatitis C, or marked transaminase elevations (5.3, 8.6) Pancreatitis: Fatalities have occurred; suspend therapy as clinically appropriate (5.4) Allergic Reactions/Hypersensitivity: Allergic reactions have been reported and include anaphylaxis, toxic epidermal necrolysis, Stevens-Johnson syndrome, bronchospasm and angioedema. Discontinue treatment if severe reactions develop (5.5, 6.2) PR interval prolongation may occur in some patients. Cases of second and third degree heart block have been reported. Use with caution with patients with preexisting conduction system disease, ischemic heart disease, cardiomyopathy, underlying structural heart disease or when administering with other drugs that may prolong the PR interval (5.6, 12.3) Total cholesterol and triglycerides elevations: Monitor prior to therapy and periodically thereafter (5.7) Patients may develop new onset or exacerbations of diabetes mellitus, hyperglycemia (5.8) Patients may develop immune reconstitution syndrome (5.9) Patients may develop redistribution/accumulation of body fat (5.10) Hemophilia: Spontaneous bleeding may occur, and additional factor VIII may be required (5.11) 5.1 Risk of Serious Adverse Reactions Due to Drug Interactions. Initiation of NORVIR, CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving NORVIR, may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of NORVIR, respectively. These interactions may lead to:Clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications.Clinically significant adverse reactions from greater exposures of NORVIR.Loss of therapeutic effect of NORVIR and possible development of resistance.When co-administering NORVIR with other protease inhibitors, see the full prescribing information for that protease inhibitor including important Warnings and Precautions.See Table for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Drug Interactions (7)]. Consider the potential for drug interactions prior to and during NORVIR therapy; review concomitant medications during NORVIR therapy, and monitor for the adverse reactions associated with the concomitant medications [see Contraindications (4) and Drug Interactions (7)].. Clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications.. Clinically significant adverse reactions from greater exposures of NORVIR.. Loss of therapeutic effect of NORVIR and possible development of resistance.. 5.2 Toxicity in Preterm Neonates. NORVIR oral solution contains the excipients ethanol (approx. 43% v/v) and propylene glycol (approx. 27% w/v). When administered concomitantly with propylene glycol, ethanol competitively inhibits the metabolism of propylene glycol, which may lead to elevated concentrations. Preterm neonates may be at an increased risk of propylene glycol-associated adverse events due to diminished ability to metabolize propylene glycol, thereby leading to accumulation and potential adverse events. Postmarketing life-threatening cases of cardiac toxicity (including complete AV block, bradycardia, and cardiomyopathy), lactic acidosis, acute renal failure, CNS depression and respiratory complications leading to death have been reported, predominantly in preterm neonates receiving lopinavir/ritonavir oral solution which also contains the excipients ethanol and propylene glycol. NORVIR oral solution should not be used in preterm neonates in the immediate postnatal period because of possible toxicities. However, if the benefit of using NORVIR oral solution to treat HIV infection in infants immediately after birth outweighs the potential risks, infants should be monitored closely for increases in serum osmolality and serum creatinine, and for toxicity related to NORVIR oral solution including: hyperosmolality, with or without lactic acidosis, renal toxicity, CNS depression (including stupor, coma, and apnea), seizures, hypotonia, cardiac arrhythmias and ECG changes, and hemolysis. Total amounts of ethanol and propylene glycol from all medicines that are to be given to infants should be taken into account in order to avoid toxicity from these excipients [see Dosage and Administration (2.4) and Overdosage (10)].. 5.3 Hepatotoxicity. Hepatic transaminase elevations exceeding times the upper limit of normal, clinical hepatitis, and jaundice have occurred in patients receiving NORVIR alone or in combination with other antiretroviral drugs (see Table 3). There may be an increased risk for transaminase elevations in patients with underlying hepatitis or C. Therefore, caution should be exercised when administering NORVIR to patients with pre-existing liver diseases, liver enzyme abnormalities, or hepatitis. Increased AST/ALT monitoring should be considered in these patients, especially during the first three months of NORVIR treatment [see Use in Specific Populations (8.6)].There have been postmarketing reports of hepatic dysfunction, including some fatalities. These have generally occurred in patients taking multiple concomitant medications and/or with advanced AIDS.. 5.4 Pancreatitis. Pancreatitis has been observed in patients receiving NORVIR therapy, including those who developed hypertriglyceridemia. In some cases fatalities have been observed. Patients with advanced HIV disease may be at increased risk of elevated triglycerides and pancreatitis [see Warnings and Precautions (5.7)]. Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory values (such as increased serum lipase or amylase values) suggestive of pancreatitis should occur. Patients who exhibit these signs or symptoms should be evaluated and NORVIR therapy should be discontinued if diagnosis of pancreatitis is made. 5.5 Allergic Reactions/Hypersensitivity. Allergic reactions including urticaria, mild skin eruptions, bronchospasm, and angioedema have been reported. Cases of anaphylaxis, toxic epidermal necrolysis (TEN), and Stevens-Johnson syndrome have also been reported. Discontinue treatment if severe reactions develop.. 5.6 PR Interval Prolongation Ritonavir prolongs the PR interval in some patients. Post marketing cases of second or third degree atrioventricular block have been reported in patients.NORVIR should be used with caution in patients with underlying structural heart disease, preexisting conduction system abnormalities, ischemic heart disease, cardiomyopathies, as these patients may be at increased risk for developing cardiac conduction abnormalities. The impact on the PR interval of co-administration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers, beta-adrenergic blockers, digoxin and atazanavir) has not been evaluated. As result, co-administration of ritonavir with these drugs should be undertaken with caution, particularly with those drugs metabolized by CYP3A. Clinical monitoring is recommended [see Drug Interactions (7) and Clinical Pharmacology (12.3)]. 5.7 Lipid Disorders. Treatment with NORVIR therapy alone or in combination with saquinavir has resulted in substantial increases in the concentration of total cholesterol and triglycerides [see Adverse Reactions (6.1)]. Triglyceride and cholesterol testing should be performed prior to initiating NORVIR therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate, taking into account any potential drug-drug interactions with NORVIR and HMG CoA reductase inhibitors [see Contraindications (4) and Drug Interactions (7)]. 5.8 Diabetes Mellitus/Hyperglycemia. New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and causal relationship between protease inhibitor therapy and these events has not been established. Consider monitoring for hyperglycemia, new onset diabetes mellitus, or an exacerbation of diabetes mellitus in patients treated with NORVIR.. 5.9 Immune Reconstitution Syndrome. Immune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including NORVIR. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia, or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves disease, polymyositis, and Guillain-Barre syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.. 5.10 Fat Redistribution. Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. causal relationship has not been established. 5.11 Patients with Hemophilia. There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type and treated with protease inhibitors. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced. causal relationship between protease inhibitor therapy and these events has not been established. 5.12 Resistance/Cross-resistance. Varying degrees of cross-resistance among protease inhibitors have been observed. Continued administration of ritonavir 600 mg twice daily following loss of viral suppression may increase the likelihood of cross-resistance to other protease inhibitors [see Microbiology (12.4)].. 5.13 Laboratory Tests. Ritonavir has been shown to increase triglycerides, cholesterol, SGOT (AST), SGPT (ALT), GGT, CPK, and uric acid. Appropriate laboratory testing should be performed prior to initiating NORVIR therapy and at periodic intervals or if any clinical signs or symptoms occur during therapy.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are discussed in greater detail in other sections of the labeling.Drug Interactions [see Warnings and Precautions (5.1)] Hepatotoxicity [see Warnings and Precautions (5.3)] Pancreatitis [see Warnings and Precautions (5.4)] Allergic Reactions/Hypersensitivity [see Warnings and Precautions (5.5)] When co-administering NORVIR with other protease inhibitors, see the full prescribing information for that protease inhibitor including adverse reactions.. Drug Interactions [see Warnings and Precautions (5.1)] Hepatotoxicity [see Warnings and Precautions (5.3)] Pancreatitis [see Warnings and Precautions (5.4)] Allergic Reactions/Hypersensitivity [see Warnings and Precautions (5.5)] The most frequently reported adverse drug reactions among patients receiving NORVIR alone or in combination with other antiretroviral drugs were gastrointestinal (including diarrhea, nausea, vomiting, abdominal pain (upper and lower), neurological disturbances (including paresthesia and oral paresthesia), rash, and fatigue/asthenia (6.1) To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trial Experience. Because clinical trials are conducted under widely varying conditions, adverse reactions 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.Adverse Reactions in AdultsThe safety of NORVIR alone and in combination with other antiretroviral agents was studied in 1,755 adult patients. Table lists treatment-emergent Adverse Reactions (with possible or probable relationship to study drug) occurring in greater than or equal to 1% of adult patients receiving NORVIR in combined Phase II/IV studies. The most frequently reported adverse drug reactions among patients receiving NORVIR alone or in combination with other antiretroviral drugs were gastrointestinal (including diarrhea, nausea, vomiting, abdominal pain (upper and lower)), neurological disturbances (including paresthesia and oral paresthesia), rash, and fatigue/asthenia. Table 2. Treatment-Emergent Adverse Reactions (With Possible or Probable Relationship to Study Drug) Occurring in greater than or equal to 1% of Adult Patients Receiving NORVIR in Combined Phase II/IV Studies (N 1,755)Adverse Reactionsn%Eye disorders Blurred vision1136.4Gastrointestinal disorders Abdominal Pain (upper and lower)46426.4 Diarrhea including severe with electrolyte imbalance1,19267.9 Dyspepsia20111.5 Flatulence1428.1 Gastrointestinal hemorrhage412.3 Gastroesophageal reflux disease (GERD)191.1 Nausea1,00757.4 Vomiting55931.9General disorders and administration site conditions Fatigue including asthenia81146.2Hepatobiliary disorders Blood bilirubin increased (including jaundice)251.4 Hepatitis (including increased AST, ALT, GGT)1538.7Immune system disorders Hypersensitivity including urticaria and face edema1148.2Metabolism and nutrition disorders Edema and peripheral edema1106.3 Gout241.4 Hypercholesterolemia523.0 Hypertriglyceridemia1589.0 Lipodystrophy acquired512.9Musculoskeletal and connective tissue disorders Arthralgia and back pain32618.6 Myopathy/creatine phosphokinase increased663.8 Myalgia1568.9Nervous system disorders Dizziness27415.6 Dysgeusia28516.2 Paresthesia (including oral paresthesia)88950.7 Peripheral neuropathy17810.1 Syncope583.3Psychiatric disorders Confusion523.0 Disturbance in attention442.5Renal and urinary disorders Increased urination744.2Respiratory, thoracic and mediastinal disorders Coughing38021.7 Oropharyngeal Pain27915.9Skin and subcutaneous tissue disorders Acne673.8 Pruritus21412.2 Rash (includes erythematous and maculopapular) 47527.1Vascular disorders Flushing, feeling hot23213.2 Hypertension583.3 Hypotension including orthostatic hypotension301.7 Peripheral coldness211.2 Represents medical concept including several similar MedDRA PTsLaboratory Abnormalities in AdultsTable shows the percentage of adult patients who developed marked laboratory abnormalities.Table 3. Percentage of Adult Patients, by Study and Treatment Group, with Chemistry and Hematology Abnormalities Occurring in greater than 3% of Patients Receiving NORVIR Study 245Naive PatientsStudy 247Advanced PatientsStudy 462 PI-Naive PatientsVariableLimitNORVIR plus ZDVNORVIR ZDV NORVIR Placebo NORVIR plus SaquinavirChemistryHigh Cholesterol> 240 mg/dL30.744.89.336.58.065.2CPK> 1000 IU/L9.612.111.09.16.39.9GGT> 300 IU/L1.85.21.719.611.39.2SGOT (AST)> 180 IU/L5.39.52.56.47.07.8SGPT (ALT)> 215 IU/L5.37.83.48.54.49.2Triglycerides> 800 mg/dL9.617.23.433.69.423.4Triglycerides> 1500 mg/dL1.82.6-12.60.411.3Triglycerides Fasting> 1500 mg/dL1.51.3-9.90.3-Uric Acid> 12 mg/dL---3.80.21.4HematologyLow Hematocrit< 30%2.6-0.817.322.00.7Hemoglobin< 8.0 g/dL0.9--3.83.9-Neutrophils<= 0.5 109/L---6.08.3-RBC< 3.0 1012/L1.8-5.918.624.4-WBC< 2.5 109/L-0.96.836.959.43.5- Indicates no events reported.Adverse Reactions in Pediatric PatientsNORVIR has been studied in 265 pediatric patients greater than month to 21 years of age. The adverse event profile observed during pediatric clinical trials was similar to that for adult patients.Vomiting, diarrhea, and skin rash/allergy were the only drug-related clinical adverse events of moderate to severe intensity observed in greater than or equal to 2% of pediatric patients enrolled in NORVIR clinical trials.Laboratory Abnormalities in Pediatric PatientsThe following Grade 3-4 laboratory abnormalities occurred in greater than 3% of pediatric patients who received treatment with NORVIR either alone or in combination with reverse transcriptase inhibitors: neutropenia (9%), hyperamylasemia (7%), thrombocytopenia (5%), anemia (4%), and elevated AST (3%).. 6.2 Postmarketing Experience. The following adverse events (not previously mentioned in the labeling) have been reported during post-marketing use of NORVIR. Because these reactions are reported voluntarily from population of unknown size, it is not possible to reliably estimate their frequency or establish causal relationship to NORVIR exposure.Body as WholeDehydration, usually associated with gastrointestinal symptoms, and sometimes resulting in hypotension, syncope, or renal insufficiency has been reported. Syncope, orthostatic hypotension, and renal insufficiency have also been reported without known dehydration.Co-administration of ritonavir with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system.Cardiovascular SystemFirst-degree AV block, second-degree AV block, third-degree AV block, right bundle branch block have been reported [see Warnings and Precautions (5.6)].Cardiac and neurologic events have been reported when ritonavir has been co-administered with disopyramide, mexiletine, nefazodone, fluoxetine, and beta blockers. The possibility of drug interaction cannot be excluded.Endocrine SystemCushings syndrome and adrenal suppression have been reported when ritonavir has been co-administered with fluticasone propionate or budesonide.Nervous SystemThere have been postmarketing reports of seizure. Also, see Cardiovascular System.Renal and Urinary DisordersNephrolithiasisSkin and subcutaneous tissue disordersToxic epidermal necrolysis (TEN) has been reported.

BOXED WARNING SECTION.

WARNING: DRUG-DRUG INTERACTIONS LEADING TO POTENTIALLY SERIOUS AND/OR LIFE THREATENING REACTIONS. Co-administration of NORVIR with several classes of drugs including sedative hypnotics, antiarrhythmics, or ergot alkaloid preparations may result in potentially serious and/or life-threatening adverse events due to possible effects of NORVIR on the hepatic metabolism of certain drugs. Review medications taken by patients prior to prescribing NORVIR or when prescribing other medications to patients already taking NORVIR [see Contraindications (4), Warnings and Precautions (5.1)].. WARNING: DRUG-DRUG INTERACTIONS LEADING TO POTENTIALLY SERIOUS AND/OR LIFE THREATENING REACTIONSSee full prescribing information for complete boxed warningCo-administration of NORVIR with several classes of drugs including sedative hypnotics, antiarrhythmics, or ergot alkaloid preparations may result in potentially serious and/or life-threatening adverse events due to possible effects of NORVIR on the hepatic metabolism of certain drugs. Review medications taken by patients prior to prescribing NORVIR or when prescribing other medications to patients already taking NORVIR. (4, 5.1).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Ritonavir is an antiretroviral drug [see Microbiology (12.4)].. 12.2 Pharmacodynamics. Cardiac ElectrophysiologyQTcF interval was evaluated in randomized, placebo and active (moxifloxacin 400 mg once-daily) controlled crossover study in 45 healthy adults, with 10 measurements over 12 hours on Day 3. The maximum mean (95% upper confidence bound) time-matched difference in QTcF from placebo after baseline correction was 5.5 (7.6) milliseconds (msec) for 400 mg twice-daily ritonavir. Ritonavir 400 mg twice daily resulted in Day ritonavir exposure that was approximately 1.5 fold higher than observed with ritonavir 600 mg twice-daily dose at steady state.PR interval prolongation was also noted in subjects receiving ritonavir in the same study on Day 3. The maximum mean (95% confidence interval) difference from placebo in the PR interval after baseline correction was 22 (25) msec for 400 mg twice-daily ritonavir [see Warnings and Precautions (5.6)].. 12.3 Pharmacokinetics. The pharmacokinetics of ritonavir have been studied in healthy volunteers and HIV-infected patients (CD4 greater than or equal to 50 cells per uL). See Table for ritonavir pharmacokinetic characteristics.AbsorptionThe absolute bioavailability of ritonavir has not been determined. After 600 mg dose of oral solution, peak concentrations of ritonavir were achieved approximately hours and hours after dosing under fasting and non-fasting (514 KCal; 9% fat, 12% protein, and 79% carbohydrate) conditions, respectively.NORVIR tablets are not bioequivalent to NORVIR capsules. Under moderate fat conditions (857 kcal; 31% fat, 13% protein, 56% carbohydrates), when single 100 mg NORVIR dose was administered as tablet compared with capsule, AUC(0- met equivalence criteria but mean Cmax was increased by 26% (92.8% confidence intervals: 15 -39%). No information is available comparing NORVIR tablets to NORVIR capsules under fasting conditions.After administration of single 100 mg dose under fed conditions (617 Kcal, 29% calories from fat), NORVIR oral powder demonstrated comparable bioavailability to the oral solution. Effect of Food on Oral AbsorptionThe bioavailability of NORVIR tablet, oral solution, and oral powder is decreased under fed conditions as compared to fasted conditions.Following the administration of 100 mg tablet dose of NORVIR, Cmax and AUCinf of ritonavir were decreased by 21-23% under moderate fat (857 Kcal, 30% from fat) or high fat conditions (917 Kcal, 60% calories from fat) relative to fasting conditions.Following the administration of 600 mg dose NORVIR oral solution, Cmax and AUCinf of ritonavir were decreased by 23% and 7%, respectively, under nonfasting conditions (514 Kcal, 10% from fat) relative to fasting conditions. Dilution of the oral solution, within one hour of administration, with 240 mL of chocolate milk, Advera(R) or Ensure(R) did not significantly affect the extent and rate of ritonavir absorption.Following the administration of 100 mg dose of NORVIR oral powder, Cmax and AUCinf of ritonavir were decreased by 23-49% under moderate fat (617 Kcal, 29% calories from fat) or high fat conditions (917 Kcal, 60% calories from fat) relative to fasting conditions. MetabolismNearly all of the plasma radioactivity after single oral 600 mg dose of 14C-ritonavir oral solution (n 5) was attributed to unchanged ritonavir. Five ritonavir metabolites have been identified in human urine and feces. The isopropylthiazole oxidation metabolite (M-2) is the major metabolite and has antiviral activity similar to that of parent drug; however, the concentrations of this metabolite in plasma are low. In vitro studies utilizing human liver microsomes have demonstrated that cytochrome P450 3A (CYP3A) is the major isoform involved in ritonavir metabolism, although CYP2D6 also contributes to the formation of M-2.EliminationIn study of five subjects receiving 600 mg dose of 14C-ritonavir oral solution, 11.3 +- 2.8% of the dose was excreted into the urine, with 3.5 +- 1.8% of the dose excreted as unchanged parent drug. In that study, 86.4 +- 2.9% of the dose was excreted in the feces with 33.8 +- 10.8% of the dose excreted as unchanged parent drug. Upon multiple dosing, ritonavir accumulation is less than predicted from single dose possibly due to time and dose-related increase in clearance.Table 5. Ritonavir Pharmacokinetic CharacteristicsParameterNValues (Mean +- SD)V/F 910.41 +- 0.25 L/kgt 1/2 - hCL/F SS+ 108.8 +- 3.2 L/hCL/F 914.6 +- 1.6 L/hCLR 62< 0.1 L/hRBC/Plasma Ratio 0.14Percent Bound 98 to 99%+ SS steady state; patients taking ritonavir 600 mg q12h. Single ritonavir 600 mg dose. Primarily bound to human serum albumin and alpha-1 acid glycoprotein over the ritonavir concentration range of 0.01 to 30 ug/mL.Special PopulationsGender, Race and AgeNo age-related pharmacokinetic differences have been observed in adult patients (18 to 63 years). Ritonavir pharmacokinetics have not been studied in older patients.A study of ritonavir pharmacokinetics in healthy males and females showed no statistically significant differences in the pharmacokinetics of ritonavir. Pharmacokinetic differences due to race have not been identified.Pediatric PatientsSteady-state pharmacokinetics were evaluated in 37 HIV-infected patients ages to 14 years receiving doses ranging from 250 mg per m2 twice-daily to 400 mg per m2 twice-daily in PACTG Study 310, and in 41 HIV-infected patients ages month to years at doses of 350 and 450 mg per m2 twice-daily in PACTG Study 345. Across dose groups, ritonavir steady-state oral clearance (CL/F/m2) was approximately 1.5 to 1.7 times faster in pediatric patients than in adult subjects. Ritonavir concentrations obtained after 350 to 400 mg per m2 twice-daily in pediatric patients greater than years were comparable to those obtained in adults receiving 600 mg (approximately 330 mg per m2) twice-daily. The following observations were seen regarding ritonavir concentrations after administration with 350 or 450 mg per m2 twice-daily in children less than years of age. Higher ritonavir exposures were not evident with 450 mg per m2 twice-daily compared to the 350 mg per m2 twice-daily. Ritonavir trough concentrations were somewhat lower than those obtained in adults receiving 600 mg twice-daily. The area under the ritonavir plasma concentration time curve and trough concentrations obtained after administration with 350 or 450 mg per m2 twice-daily in children less than years were approximately 16% and 60% lower, respectively, than that obtained in adults receiving 600 mg twice daily.Renal ImpairmentRitonavir pharmacokinetics have not been studied in patients with renal impairment, however, since renal clearance is negligible, decrease in total body clearance is not expected in patients with renal impairment.Hepatic ImpairmentDose-normalized steady-state ritonavir concentrations in subjects with mild hepatic impairment (400 mg twice-daily, = 6) were similar to those in control subjects dosed with 500 mg twice-daily. Dose-normalized steady-state ritonavir exposures in subjects with moderate hepatic impairment (400 mg twice-daily, n= 6) were about 40% lower than those in subjects with normal hepatic function (500 mg twice-daily, = 6). Protein binding of ritonavir was not statistically significantly affected by mild or moderately impaired hepatic function. No dose adjustment is recommended in patients with mild or moderate hepatic impairment. However, health care providers should be aware of the potential for lower ritonavir concentrations in patients with moderate hepatic impairment and should monitor patient response carefully. Ritonavir has not been studied in patients with severe hepatic impairment.PregnancyBased on evaluation of the published literature, ritonavir exposures are reduced during pregnancy relative to postpartum.Drug Interactions[see also Contraindications (4), Warnings and Precautions (5.1), and Drug Interactions (7)]Table and Table summarize the effects on AUC and Cmax, with 95% confidence intervals (95% CI), of co-administration of ritonavir with variety of drugs. For information about clinical recommendations see Table in Drug Interactions (7) .Table 6. Drug Interactions Pharmacokinetic Parameters for Ritonavir in the Presence of the Co-administered DrugCo-administeredDrugDose of Co-administeredDrug (mg)Dose ofNORVIR (mg)NAUC (95% CI)Cmax (95% CI)Cmin (95% CI)Clarithromycin500 q12h, d200 q8h, d22 12%(2, 23%) 15%(2, 28%) 14%(-3, 36%)Didanosine200 q12h, d600 q12h, d12<-><-><->Fluconazole400 single dose, day 1;200 daily, d200 q6h, d8 12%(5, 20%) 15%(7, 22%) 14%(0, 26%)Fluoxetine30 q12h, d600 single dose, d16 19%(7, 34%)<->NDKetoconazole200 daily, d500 q12h, 10 d12 18%(-3, 52%) 10%(-11, 36%)NDRifampin600 or300 daily, 10 d500 q12h, 20 d7, 35%(7, 55%) 25%(-5, 46%) 49%(-14, 91%)Voriconazole400 q12h, d;then 200 q12h, d400 q12h, d <-><->NDZidovudine200 q8h, d300 q6h, d10<-><-><->ND=not determinedTable 7. Drug Interactions Pharmacokinetic Parameters for Co-administered Drug in the Presence of NORVIRCo-administered DrugDose of Co-administered Drug (mg)Dose of NORVIR (mg)NAUC (95% CI)Cmax (95% CI)Cmin (95% CI)Alprazolam1, single dose500 q12h, 10 d12 12% (-5, 30%) 16% (5, 27%)NDAvanafil50, single dose600 q12h146 13-fold 2.4-foldNDClarithromycin 14-OH clarithromycin metabolite500 q12h, d200 q8h, d22 77% (56, 103%) 100% 31% (15, 51%) 99% 2.8-fold (2.4, 3.3X) 100%Desipramine 2-OH desipraminemetabolite100, single dose500 q12h, 12 d14 145% (103, 211%) 15% (3, 26%) 22% (12, 35%) 67% (62, 72%)ND NDDidanosine200 q12h, d600 q12h, d12 13% (0, 23%) 16% (5, 26%)<->Ethinyl estradiol50 ug single dose500 q12h, 16 d23 40% (31, 49%) 32% (24, 39%)NDFluticasonepropionate aqueousnasal spray200 mcg qd, d100 mg q12h, d18 approximately 350-fold5 approximately 25-fold5 Indinavir1 Day 14 Day 15400 q12h, 15 d400 q12h, 15 d10 6% (-14, 29%) 7% (-22, 28%) 51% (40, 61%) 62% (52, 70%) 4-fold (2.8, 6.8X) 4-fold (2.5, 6.5X)Ketoconazole200 daily, d500 q12h, 10 d12 3.4-fold (2.8, 4.3X) 55% (40, 72%)NDMeperidine Normeperidinemetabolite50 oral single dose500 q12h, 10 d8 62% (59, 65%) 47% (-24, 345%) 59% (42, 72%) 87% (42, 147%)ND NDMethadone2 5, single dose500 q12h, 15 d11 36% (16, 52%) 38% (28, 46%)NDRaltegravir400, single dose100 q12h, 16 d10 16% (-30, 1%) 24% (-45, 4%) 1% (-30, 40%)Rivaroxaban10, single dose (days and 7)600 q12h(days to 7)12 150% (130-170%)7 60% (40-70%)7 NDRifabutin25-O-desacetylrifabutinmetabolite150 daily, 16 d500 q12h, 10 d5, 11 4-fold (2.8, 6.1X) 38-fold (28, 56X) 2.5-fold (1.9, 3.4X) 16-fold (13, 20X) 6-fold (3.5, 18.3X) 181-fold (ND)Sildenafil100, single dose500 twice daily, d28 11-fold 4-foldNDSimeprevir200 mg qd, d100 mg bid,15 d12 618% (463%-815%)8 370% (284%-476%)8 1335% (929%-1901%)8 Sulfamethoxazole3 800, single dose500 q12h, 12 d15 20% (16, 23%)<->NDTadalafil20 mg, single dose200 mg q12h 124%<->NDTheophylline3 mg/kg q8h, 15 d500 q12h, 10 d13, 11 43% (42, 45%) 32% (29, 34%) 57% (55, 59%)Trazodone50 mg, single dose200 mg q12h, doses10 2.4-fold 34% Trimethoprim3 160, single dose500 q12h, 12 d15 20% (3, 43%)<->NDVardenafil5 mg600 q12h 49-fold 13-foldNDVoriconazole400 q12h, d; then 200 q12h, d400 q12h, d 82% 66% 400 q12h, d; then 200 q12h, d100 q12h, d 39% 24% Warfarin S-Warfarin R-Warfarin5, single dose400 q12h, 12d12 9% (-17, 44%)4 33% (-38, -27%)4 9% (-16, -2%)4 <->ND NDZidovudine200 q8h, d300 q6h, d9 25% (15, 34%) 27% (4, 45%)NDND=not determined1 Ritonavir and indinavir were co-administered for 15 days; Day 14 doses were administered after 15%-fat breakfast (757 Kcal) and 9%-fat evening snack (236 Kcal), and Day 15 doses were administered after 15%-fat breakfast (757 Kcal) and 32%-fat dinner (815 Kcal). Indinavir Cmin was also increased 4-fold. Effects were assessed relative to an indinavir 800 mg q8h regimen under fasting conditions.2 Effects were assessed on dose-normalized comparison to methadone 20 mg single dose.3 Sulfamethoxazole and trimethoprim taken as single combination tablet.4 90% CI presented for R- and S-warfarin AUC and Cmax ratios.5 This significant increase in plasma fluticasone propionate exposure resulted in significant decrease (86%) in plasma cortisol AUC.6 For the reference arm: N=14 for Cmax and AUC(0-inf), and for the test arm: N=13 for Cmax and N=4 for AUC(0-inf).7 90% CI presented for rivaroxaban8 90% CI presented for simeprevir (change in exposure presented as percentage increase) Indicates increase, indicates decrease, <-> indicates no change. Parallel group design; entries are subjects receiving combination and control regimens, respectively.. 12.4 Microbiology. Mechanism of ActionRitonavir is peptidomimetic inhibitor of the HIV-1 protease. Inhibition of HIV protease renders the enzyme incapable of processing the Gag-Pol polyprotein precursor which leads to production of non-infectious immature HIV particles.Antiviral Activity in Cell CultureThe activity of ritonavir was assessed in acutely infected lymphoblastoid cell lines and in peripheral blood lymphocytes. The concentration of drug that inhibits 50% (EC50) value of viral replication ranged from 3.8 to 153 nM depending upon the HIV-1 isolate and the cells employed. The average EC50 value for low passage clinical isolates was 22 nM (n 13). In MT4 cells, ritonavir demonstrated additive effects against HIV-1 in combination with either didanosine (ddI) or zidovudine (ZDV). Studies which measured cytotoxicity of ritonavir on several cell lines showed that greater than 20 microM was required to inhibit cellular growth by 50% resulting in cell culture therapeutic index of at least 1000.ResistanceHIV-1 isolates with reduced susceptibility to ritonavir have been selected in cell culture. Genotypic analysis of these isolates showed mutations in the HIV-1 protease gene leading to amino acid substitutions I84V, V82F, A71V, and M46I. Phenotypic (n 18) and genotypic (n 48) changes in HIV-1 isolates from selected patients treated with ritonavir were monitored in phase I/II trials over period of to 32 weeks. Substitutions associated with the HIV-1 viral protease in isolates obtained from 43 patients appeared to occur in stepwise and ordered fashion at positions V82A/F/T/S, I54V, A71V/T, and I36L, followed by combinations of substitutions at an additional specific amino acid positions (M46I/L, K20R, I84V, L33F and L90M). Of 18 patients for whom both phenotypic and genotypic analysis were performed on free virus isolated from plasma, 12 showed reduced susceptibility to ritonavir in cell culture. All 18 patients possessed one or more substitutions in the viral protease gene. The V82A/F substitution appeared to be necessary but not sufficient to confer phenotypic resistance. Phenotypic resistance was defined as greater than or equal to 5-fold decrease in viral sensitivity in cell culture from baseline.Cross-Resistance to Other AntiretroviralsAmong protease inhibitors variable cross-resistance has been recognized. Serial HIV-1 isolates obtained from six patients during ritonavir therapy showed decrease in ritonavir susceptibility in cell culture but did not demonstrate concordant decrease in susceptibility to saquinavir in cell culture when compared to matched baseline isolates. However, isolates from two of these patients demonstrated decreased susceptibility to indinavir in cell culture (8-fold). Isolates from patients were also tested for cross-resistance to amprenavir and nelfinavir; isolates from patients had decrease in susceptibility to nelfinavir (6- to 14-fold), and none to amprenavir. Cross-resistance between ritonavir and reverse transcriptase inhibitors is unlikely because of the different enzyme targets involved. One ZDV-resistant HIV-1 isolate tested in cell culture retained full susceptibility to ritonavir.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The activity of NORVIR as monotherapy or in combination with nucleoside reverse transcriptase inhibitors has been evaluated in 1446 patients enrolled in two double-blind, randomized trials.. 14.1 Advanced Patients with Prior Antiretroviral Therapy. Study 247 was randomized, double-blind trial (with open-label follow-up) conducted in HIV-infected patients with at least nine months of prior antiretroviral therapy and baseline CD4 cell counts less than or equal to 100 cells per uL. NORVIR 600 mg twice-daily or placebo was added to each patients baseline antiretroviral therapy regimen, which could have consisted of up to two approved antiretroviral agents. The study accrued 1,090 patients, with mean baseline CD4 cell count at study entry of 32 cells per uL. After the clinical benefit of NORVIR therapy was demonstrated, all patients were eligible to switch to open-label NORVIR for the duration of the follow-up period. Median duration of double-blind therapy with NORVIR and placebo was months. The median duration of follow-up through the end of the open-label phase was 13.5 months for patients randomized to NORVIR and 14 months for patients randomized to placebo.The cumulative incidence of clinical disease progression or death during the double-blind phase of Study 247 was 26% for patients initially randomized to NORVIR compared to 42% for patients initially randomized to placebo. This difference in rates was statistically significant.Cumulative mortality through the end of the open-label follow-up phase for patients enrolled in Study 247 was 18% (99/543) for patients initially randomized to NORVIR compared to 26% (142/547) for patients initially randomized to placebo. This difference in rates was statistically significant. However, since the analysis at the end of the open-label phase includes patients in the placebo arm who were switched from placebo to NORVIR therapy, the survival benefit of NORVIR cannot be precisely estimated. During the double-blind phase of Study 247, CD4 cell counts increases from baseline for patients randomized to NORVIR at Week and Week were observed. From Week and through Week 24, mean CD4 cell counts for patients randomized to NORVIR appeared to plateau. In contrast, there was no apparent change in mean CD4 cell counts for patients randomized to placebo at any visit between baseline and Week 24 of the double-blind phase of Study 247.. 14.2 Patients without Prior Antiretroviral Therapy. In Study 245, 356 antiretroviral-naive HIV-infected patients (mean baseline CD4 364 cells per uL) were randomized to receive either NORVIR 600 mg twice-daily, zidovudine 200 mg three-times-daily, or combination of these drugs.During the double-blind phase of study 245, greater mean CD4 cell count increases were observed from baseline to Week 12 in the NORVIR-containing arms compared to the zidovudine arms. Mean CD4 cell count changes subsequently appeared to plateau through Week 24 in the NORVIR arm, whereas mean CD4 cell counts gradually diminished through Week 24 in the zidovudine and NORVIR plus zidovudine arms. Greater mean reductions in plasma HIV-1 RNA levels were observed from baseline to Week for the NORVIR-containing arms compared to the zidovudine arm. After Week and through Week 24, mean plasma HIV-1 RNA levels either remained stable in the NORVIR and zidovudine arms or gradually rebounded toward baseline in the NORVIR plus zidovudine arm.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. When co-administering NORVIR with other protease inhibitors, see the full prescribing information for that protease inhibitor including contraindication information.NORVIR is contraindicated in patients with known hypersensitivity (e.g., toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome) to ritonavir or any of its ingredients.NORVIR is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening reactions [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].Alpha 1- Adrenoreceptor Antagonist alfuzosinAntianginal: ranolazineAntiarrhythmics: amiodarone, dronedarone, flecainide, propafenone, quinidineAntifungal: voriconazoleAnti-gout: colchicineAntipsychotics: lurasidone, pimozideErgot Derivatives: dihydroergotamine, ergotamine, methylergonovineGI Motility Agent: cisaprideHMG-CoA Reductase Inhibitors: lovastatin, simvastatinMicrosomal triglyceride transfer protein (MTTP) Inhibitor: lomitapidePDE5 Inhibitor: sildenafil (Revatio(R)) when used for the treatment of pulmonary arterial hypertensionSedative/Hypnotics: triazolam, orally administered midazolam NORVIR is contraindicated with drugs that are potent CYP3A inducers where significantly reduced ritonavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance and cross-resistance [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)].Anticancer Agents: apalutamideHerbal Products: St. Johns Wort (hypericum perforatum) When co-administering NORVIR with other protease inhibitors, see the full prescribing information for that protease inhibitor including contraindication information.. NORVIR is contraindicated in patients with known hypersensitivity (e.g., toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome) to ritonavir or any of its ingredients.. NORVIR is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening reactions [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].Alpha 1- Adrenoreceptor Antagonist alfuzosinAntianginal: ranolazineAntiarrhythmics: amiodarone, dronedarone, flecainide, propafenone, quinidineAntifungal: voriconazoleAnti-gout: colchicineAntipsychotics: lurasidone, pimozideErgot Derivatives: dihydroergotamine, ergotamine, methylergonovineGI Motility Agent: cisaprideHMG-CoA Reductase Inhibitors: lovastatin, simvastatinMicrosomal triglyceride transfer protein (MTTP) Inhibitor: lomitapidePDE5 Inhibitor: sildenafil (Revatio(R)) when used for the treatment of pulmonary arterial hypertensionSedative/Hypnotics: triazolam, orally administered midazolam Alpha 1- Adrenoreceptor Antagonist alfuzosin. Antianginal: ranolazine. Antiarrhythmics: amiodarone, dronedarone, flecainide, propafenone, quinidine. Antifungal: voriconazole. Anti-gout: colchicine. Antipsychotics: lurasidone, pimozide. Ergot Derivatives: dihydroergotamine, ergotamine, methylergonovine. GI Motility Agent: cisapride. HMG-CoA Reductase Inhibitors: lovastatin, simvastatin. Microsomal triglyceride transfer protein (MTTP) Inhibitor: lomitapide. PDE5 Inhibitor: sildenafil (Revatio(R)) when used for the treatment of pulmonary arterial hypertension. Sedative/Hypnotics: triazolam, orally administered midazolam. NORVIR is contraindicated with drugs that are potent CYP3A inducers where significantly reduced ritonavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance and cross-resistance [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)].Anticancer Agents: apalutamideHerbal Products: St. Johns Wort (hypericum perforatum) Anticancer Agents: apalutamide. Herbal Products: St. Johns Wort (hypericum perforatum). NORVIR is contraindicated in patients with known hypersensitivity to ritonavir (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome) or any of its ingredients (4) Co-administration with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations may be associated with serious and/or life-threatening events (4) Co-administration with drugs that significantly reduce ritonavir (4) NORVIR is contraindicated in patients with known hypersensitivity to ritonavir (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome) or any of its ingredients (4) Co-administration with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations may be associated with serious and/or life-threatening events (4) Co-administration with drugs that significantly reduce ritonavir (4).

DESCRIPTION SECTION.

11 DESCRIPTION. NORVIR (ritonavir) is an inhibitor of HIV protease with activity against the Human Immunodeficiency Virus (HIV).Ritonavir is chemically designated as 10-Hydroxy-2-methyl-5-(1-methylethyl)-1- [2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12- tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester, [5S-(5R,8R,10R,11R)]. Its molecular formula is C37H48N6O5S2, and its molecular weight is 720.95. Ritonavir has the following structural formula:Ritonavir is white-to-light-tan powder. Ritonavir has bitter metallic taste. It is freely soluble in methanol and ethanol, soluble in isopropanol and practically insoluble in water.NORVIR tablets are available for oral administration in strength of 100 mg ritonavir with the following inactive ingredients: copovidone, anhydrous dibasic calcium phosphate, sorbitan monolaurate, colloidal silicon dioxide, and sodium stearyl fumarate. The following are the ingredients in the film coating: hypromellose, titanium dioxide, polyethylene glycol 400, hydroxypropyl cellulose, talc, polyethylene glycol 3350, colloidal silicon dioxide, and polysorbate 80.NORVIR oral solution is available for oral administration as 80 mg per mL of ritonavir in peppermint and caramel flavored vehicle. Each 8-ounce bottle contains 19.2 grams of ritonavir. NORVIR oral solution also contains ethanol, water, polyoxyl 35 castor oil, propylene glycol, anhydrous citric acid to adjust pH, saccharin sodium, peppermint oil, creamy caramel flavoring, and FD&C Yellow No. 6. NORVIR oral solution contains approximately 43% (v/v) ethanol and approximately 27% (w/v) propylene glycol. NORVIR oral powder is beige/pale yellow to yellow and is available for oral administration as packet containing 100 mg of ritonavir with the following inactive ingredients: copovidone, sorbitan monolaurate, and colloidal silicon dioxide.. norvir chem structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. NORVIR oral solution is not recommended for use with polyurethane feeding tubes due to potential incompatibility. Feeding tubes composed of silicone or polyvinyl chloride (PVC) can be used. (2.2) Adult patients: 600 mg twice-day with meals (2.3) Pediatrics patients: The recommended twice daily dose for children greater than one month of age is based on body surface area and should not exceed 600 mg twice daily with meals (2.4) NORVIR oral solution should not be administered to neonates before postmenstrual age (first day of the mothers last menstrual period to birth plus the time elapsed after birth) of 44 weeks has been attained (2.4, 5.2) NORVIR oral powder can only be used for dosing increments of 100 mg (2.4) Instructions for Use should be followed for preparation and administration of NORVIR oral powder (2.5) Dose modification for NORVIR is necessary when used with other protease inhibitors (2.6) NORVIR oral solution is not recommended for use with polyurethane feeding tubes due to potential incompatibility. Feeding tubes composed of silicone or polyvinyl chloride (PVC) can be used. (2.2) Adult patients: 600 mg twice-day with meals (2.3) Pediatrics patients: The recommended twice daily dose for children greater than one month of age is based on body surface area and should not exceed 600 mg twice daily with meals (2.4) NORVIR oral solution should not be administered to neonates before postmenstrual age (first day of the mothers last menstrual period to birth plus the time elapsed after birth) of 44 weeks has been attained (2.4, 5.2) NORVIR oral powder can only be used for dosing increments of 100 mg (2.4) Instructions for Use should be followed for preparation and administration of NORVIR oral powder (2.5) Dose modification for NORVIR is necessary when used with other protease inhibitors (2.6) 2.1 General Administration Recommendations. NORVIR must be used in combination with other antiretroviral agents.NORVIR is administered orally. NORVIR tablets should be swallowed whole, and not chewed, broken or crushed. Take NORVIR with meals.Patients may improve the taste of NORVIR oral solution by mixing with chocolate milk, Ensure(R), or Advera(R) within one hour of dosing.NORVIR oral powder should be mixed with soft food such as apple sauce or vanilla pudding, or mixed with liquid such as water, chocolate milk, or infant formula [see Dosage and Administration (2.5) and Instructions for Use]. The bitter aftertaste of NORVIR oral powder may be lessened if administered with food.General Dosing GuidelinesPatients who take the 600 mg twice daily soft gel capsule NORVIR dose may experience more gastrointestinal side effects such as nausea, vomiting, abdominal pain or diarrhea when switching from the soft gel capsule to the tablet formulation because of greater maximum plasma concentration (Cmax) achieved with the tablet formulation relative to the soft gel capsule [see Clinical Pharmacology (12.3)]. Patients should also be aware that these adverse events (gastrointestinal or paresthesias) may diminish as therapy is continued.. NORVIR must be used in combination with other antiretroviral agents.. NORVIR is administered orally. NORVIR tablets should be swallowed whole, and not chewed, broken or crushed. Take NORVIR with meals.. Patients may improve the taste of NORVIR oral solution by mixing with chocolate milk, Ensure(R), or Advera(R) within one hour of dosing.. NORVIR oral powder should be mixed with soft food such as apple sauce or vanilla pudding, or mixed with liquid such as water, chocolate milk, or infant formula [see Dosage and Administration (2.5) and Instructions for Use]. The bitter aftertaste of NORVIR oral powder may be lessened if administered with food.. 2.2 Administering Oral Solution by Feeding Tube. Because NORVIR oral solution contains ethanol and propylene glycol, it is not recommended for use with polyurethane feeding tubes due to potential incompatibility. Feeding tubes that are compatible with ethanol and propylene glycol, such as silicone and polyvinyl chloride (PVC) feeding tubes, can be used for administration of NORVIR oral solution. Follow instructions for use of the feeding tube to administer the medicine.. 2.3 Dosage Recommendations in Adults. Recommended Dosage for Treatment of HIV-1:The recommended dosage of NORVIR is 600 mg twice daily by mouth to be taken with meals. Use of dose titration schedule may help to reduce treatment-emergent adverse events while maintaining appropriate ritonavir plasma levels. NORVIR should be started at no less than 300 mg twice daily and increased at to day intervals by 100 mg twice daily. The maximum dose of 600 mg twice daily should not be exceeded upon completion of the titration [see Dosage and Administration (2.6)].Pregnant WomenNORVIR oral solution is not recommended during pregnancy due to its ethanol content. NORVIR oral solution contains the excipients ethanol (approx. 43% v/v) and propylene glycol (approx. 27% w/v) [see Use in Specific Populations (8.1)]. 2.4 Dosage Recommendations in Pediatric Patients. NORVIR must be used in combination with other antiretroviral agents [see Dosage and Administration (2)]. The recommended dosage of NORVIR in pediatric patients older than month is 350 to 400 mg per m2 twice daily by mouth to be taken with meals and should not exceed 600 mg twice daily. NORVIR should be started at 250 mg per m2 twice daily and increased at to day intervals by 50 mg per m2 twice daily. If patients do not tolerate 400 mg per m2 twice daily due to adverse events, the highest tolerated dose may be used for maintenance therapy in combination with other antiretroviral agents, however, alternative therapy should be considered [see Dosage and Administration (2.6)]. Pediatric Dosage Guidelines for Oral SolutionNORVIR oral solution should not be administered to neonates before postmenstrual age (first day of the mothers last menstrual period to birth plus the time elapsed after birth) of 44 weeks has been attained [see Warnings and Precautions (5.2)]. NORVIR oral solution contains the excipients ethanol (approx. 43% v/v) and propylene glycol (approx. 27% w/v). Special attention should be given to accurate calculation of the dose of NORVIR, transcription of the medication order, dispensing information and dosing instructions to minimize the risk for medication errors, and overdose. This is especially important for young children. Total amounts of ethanol and propylene glycol from all medicines that are to be given to pediatric patients to months of age should be taken into account in order to avoid toxicity from these excipients [see Warnings and Precautions (5.2) and Overdosage (10)]. When possible, dose should be administered using calibrated dosing syringe.Table 1. Pediatric Dosage Guidelines for Oral SolutionBody Surface Area (m2)Twice Daily Dose250 mg per m2 Twice Daily Dose300 mg per m2 Twice Daily Dose350 mg per m2 Twice Daily Dose400 mg per m2 0.200.6 mL (50 mg)0.75 mL (60 mg)0.9 mL (70 mg)1.0 mL (80 mg)0.250.8 mL (62.5 mg)0.9 mL (75 mg)1.1 mL (87.5 mg)1.25 mL (100 mg)0.501.6 mL (125 mg)1.9 mL (150 mg)2.2 mL (175 mg)2.5 mL (200 mg)0.752.3 mL (187.5 mg)2.8 mL (225 mg)3.3 mL (262.5 mg)3.75 mL (300 mg)1.003.1 mL (250 mg)3.75 mL (300 mg)4.4 mL (350 mg)5 mL (400 mg)1.253.9 mL (312.5 mg)4.7 mL (375 mg)5.5 mL (437.5 mg)6.25 mL (500 mg)1.504.7 mL (375 mg)5.6 mL (450 mg)6.6 mL (525 mg)7.5 mL (600 mg)The concentration of the oral solution is 80 mg per mL.Body surface area (BSA) can be calculated as follows1:Pediatric Dosage Guidelines for Oral PowderNORVIR oral powder should be used only for dosing increments of 100 mg. NORVIR powder should not be used for doses less than 100 mg or for incremental doses between 100 mg intervals. NORVIR oral solution is the preferred formulation for patients requiring doses less than 100 mg or incremental doses between 100 mg intervals.. norvir equation. 2.5 Preparation of Norvir Oral Powder. For details on the preparation and administration of NORVIR oral powder (see Instructions for Use). NORVIR oral powder should only be used for dosing increments of 100 mg.Prepare the dose using the required number of packets. For example, use one packet for doses of 100 mg and two packets for doses of 200 mg. Pour and mix the entire contents of each packet over soft food or liquid. All of the powder mixed with soft food or liquid should be administered within hours of preparation. If not administered within hours of preparation, the mixture should be discarded and new dose prepared.The prescribed dose of NORVIR oral powder can be administered via feeding tube after being mixed with water (see Instructions for Use). Follow the instructions for the feeding tube to administer the medicine.. 2.6 Dose Modification due to Drug Interaction. Dose reduction of NORVIR is necessary when used with other protease inhibitors: atazanavir, darunavir, fosamprenavir, saquinavir, and tipranavir.Prescribers should consult the full prescribing information and clinical study information of these protease inhibitors if they are co-administered with reduced dose of ritonavir [see Warnings and Precautions (5.1) and Drug Interactions (7)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. NORVIR TabletsWhite film-coated ovaloid tablets debossed with the a logo and the code NK providing 100 mg ritonavir.NORVIR Oral Solution Orange-colored liquid containing 600 mg ritonavir per 7.5 mL marked dosage cup (80 mg per mL).NORVIR Oral PowderBeige/pale yellow to yellow powder in child-resistant packet. Each packet contains 100 mg of ritonavir.. NORVIR Tablets. NORVIR Oral Solution NORVIR Oral Powder. Tablet: 100 mg (3) Oral Solution: 80 mg per milliliter (3) Oral Powder: 100 mg per packet (3) Tablet: 100 mg (3) Oral Solution: 80 mg per milliliter (3) Oral Powder: 100 mg per packet (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. When co-administering NORVIR with other protease inhibitors (atazanavir, darunavir, fosamprenavir, saquinavir, and tipranavir), see the full prescribing information for that protease inhibitor including important information for drug interactions.. Co-administration of NORVIR can alter the concentrations of other drugs. The potential for drug-drug interactions must be considered prior to and during therapy (4, 5.1, 7, 12.3) Co-administration of NORVIR can alter the concentrations of other drugs. The potential for drug-drug interactions must be considered prior to and during therapy (4, 5.1, 7, 12.3) 7.1 Potential for NORVIR to Affect Other Drugs. Ritonavir is an inhibitor of cytochrome P450 3A (CYP3A) and may increase plasma concentrations of agents that are primarily metabolized by CYP3A. Agents that are extensively metabolized by CYP3A and have high first pass metabolism appear to be the most susceptible to large increases in AUC (greater than 3-fold) when co-administered with ritonavir. Thus, co-administration of NORVIR with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. Co-administration with other CYP3A substrates may require dose adjustment or additional monitoring as shown in Table 4.Ritonavir also inhibits CYP2D6 to lesser extent. Co-administration of substrates of CYP2D6 with ritonavir could result in increases (up to 2-fold) in the AUC of the other agent, possibly requiring proportional dosage reduction. Ritonavir also appears to induce CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2B6 as well as other enzymes, including glucuronosyl transferase.These examples are guide and not considered comprehensive list of all possible drugs that may interact with ritonavir. The healthcare provider should consult appropriate references for comprehensive information.. 7.2 Established and Other Potentially Significant Drug Interactions. Table provides list of established or potentially clinically significant drug interactions. Alteration in dose or regimen may be recommended based on drug interaction studies or predicted interaction [see Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)] for magnitude of interaction.Table 4. Established and Other Potentially Significant Drug InteractionsConcomitant Drug Class:Drug NameEffect on Concentration of Ritonavir or Concomitant DrugClinical Comment HIV-Antiviral Agents HIV-1 Protease Inhibitor:atazanavirdarunavirfosamprenavir amprenavir atazanavir darunavirSee the complete prescribing information for fosamprenavir, atazanavir, darunavir for details on co-administration with ritonavir. HIV-1 Protease Inhibitor:indinavir indinavirAppropriate doses for this combination, with respect to efficacy and safety, have not been established.HIV-1 Protease Inhibitor:saquinavir saquinavirSee the complete prescribing information for saquinavir for details on co-administration of saquinavir and ritonavir.Saquinavir/ritonavir in combination with rifampin is not recommended due to the risk of severe hepatotoxicity (presenting as increased hepatic transaminases) if the three drugs are given together.HIV-1 Protease Inhibitor:tipranavir tipranavirSee the complete prescribing information for tipranavir for details on co-administration of tipranavir and ritonavir. Non-Nucleoside Reverse Transcriptase Inhibitor:delavirdine ritonavirAppropriate doses of this combination with respect to safety and efficacy have not been established.HIV-1 CCR5 antagonist: maraviroc maravirocSee the complete prescribing information for maraviroc for details on co-administration of maraviroc and ritonavir-containing protease inhibitors.Integrase Inhibitor: raltegravir raltegravirThe effects of ritonavir on raltegravir with ritonavir dosage regimens greater than 100 mg twice daily have not been evaluated, however raltegravir concentrations may be decreased with ritonavir coadministration.Other AgentsAlpha 1- AdrenoreceptorAntagonist:alfuzosin alfuzosinContraindicated due to potential hypotension [see Contraindications (4)].Antianginal:ranolazine ranolazineContraindicated due to potential for serious and/or life-threatening reactions [see Contraindications (4)].Analgesics, Narcotic:tramadol, propoxyphene,methadone,fentanyl analgesics methadone fentanylA dose decrease may be needed for these drugs when co-administered with ritonavir. Dosage increase of methadone may be considered. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with NORVIR.Anesthetic:meperidine meperidine/ normeperidine (metabolite)Dosage increase and long-term use of meperidine with ritonavir are not recommended due to the increased concentrations of the metabolite normeperidine which has both analgesic activity and CNS stimulant activity (e.g., seizures).Antialcoholics:disulfiram/ metronidazole Ritonavir formulations contain ethanol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).Antiarrhythmics:amiodarone,dronedarone,flecainide,propafenone, quinidine antiarrhythmicsContraindicated due to potential for cardiac arrhythmias [see Contraindications (4)].Antiarrhythmics:disopyramide, lidocaine, mexiletine antiarrhythmicsCaution is warranted and therapeutic concentration monitoring is recommended for antiarrhythmics when co-administered with ritonavir, if available.Anticancer Agents: abemaciclib,apalutamide,dasatinib, encorafenib,ibrutinib,ivosidenib,neratinib,nilotinib,venetoclax,vinblastine,vincristine anticancer agents ritonavir Apalutamide is contraindicated due to potential for loss of virologic response and possible resistance to NORVIR or to the class of protease inhibitors [see Contraindications (4)]. Avoid co-administration of encorafenib or ivosidenib with NORVIR due to potential risk of serious adverse events such as QT interval prolongation. If co-administration of encorafenib with NORVIR cannot be avoided, modify dose as recommended in encorafenib USPI. If co-administration of ivosidenib with NORVIR cannot be avoided, reduce ivosidenib dose to 250 mg once daily.Avoid use of neratinib, venetoclax or ibrutinib with NORVIR.For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when ritonavir is administered concurrently with vincristine or vinblastine.Clinicians should be aware that if the ritonavir containing regimen is withheld for prolonged period, consideration should be given to altering the regimen to not include CYP3A or P-gp inhibitor in order to control HIV-1 viral load.A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as NORVIR. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.Anticoagulant: warfarin warfarinInitial frequent monitoring of the INR during ritonavir and warfarin co-administration is recommended.Anticoagulant: rivaroxaban rivaroxabanAvoid concomitant use of rivaroxaban and ritonavir. Co-administration of ritonavir and rivaroxaban may lead to risk of increased bleeding.Anticonvulsants:carbamazepine, clonazepam, ethosuximide anticonvulsantsA dose decrease may be needed for these drugs when co-administered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available.Anticonvulsants:divalproex, lamotrigine, phenytoin anticonvulsantsA dose increase may be needed for these drugs when co-administered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available.Antidepressants:nefazodone, selective serotonin reuptake inhibitors (SSRIs): e.g.fluoxetine,paroxetine,tricyclics: e.g.amitriptyline,nortriptyline antidepressantsA dose decrease may be needed for these drugs when co-administered with ritonavir.Antidepressant:bupropion bupropion active metabolite, hydroxybupropionPatients receiving ritonavir and bupropion concurrently should be monitored for an adequate clinical response to bupropion. Antidepressant:desipramine desipramineDosage reduction and concentration monitoring of desipramine is recommended.Antidepressant:trazodone trazodoneAdverse events of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and NORVIR. lower dose of trazodone should be considered.Antiemetic:dronabinol dronabinolA dose decrease of dronabinol may be needed when co-administered with ritonavir.Antifungals:ketoconazoleitraconazolevoriconazole ketoconazole itraconazole voriconazoleHigh doses of ketoconazole or itraconazole (greater than 200 mg per day) are not recommended. Co-administration of voriconazole and ritonavir doses of 400 mg every 12 hours or greater is contraindicated due to the potential for loss of antifungal response [see Contraindications (4)]. Co-administration of voriconazole and ritonavir 100 mg should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.Anti-gout: colchicine colchicineContraindicated due to potential for serious and/or life-threatening reactions in patients with renal and/or hepatic impairment [see Contraindications (4)]. For patients with normal renal or hepatic function: Treatment of gout flares-co-administration of colchicine in patients on ritonavir:0.6 mg (one tablet) for one dose, followed by 0.3 mg (half tablet) one hour later. Dose to be repeated no earlier than three days. Prophylaxis of gout flares-co-administration of colchicine in patients on ritonavir: If the original colchicine regimen was 0.6 mg twice day, the regimen should be adjusted to 0.3 mg once day.If the original colchicine regimen was 0.6 mg once day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on ritonavir: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice day).Anti-infective:clarithromycin clarithromycinFor patients with renal impairment, adjust clarithromycin dose as follows: For patients with CLCR 30 to 60 mL per min the dose of clarithromycin should be reduced by 50%.For patients with CLCR less than 30 mL per min the dose of clarithromycin should be decreased by 75%.No dose adjustment for patients with normal renal function is necessary.Antimycobacterial:bedaquiline bedaquilineBedaquiline should only be used with ritonavir if the benefit of co-administration outweighs the risk.Antimycobacterial:rifabutin rifabutin and rifabutin metaboliteDosage reduction of rifabutin by at least three-quarters of the usual dose of 300 mg per day is recommended (e.g., 150 mg every other day or three times week). Further dosage reduction may be necessary.Antimycobacterial:rifampin ritonavirMay lead to loss of virologic response. Alternate antimycobacterial agents such as rifabutin should be considered.Antiparasitic:atovaquone atovaquoneClinical significance is unknown; however, increase in atovaquone dose may be needed.Antiparasitic:quinine quinineA dose decrease of quinine may be needed when co-administered with ritonavir.Antipsychotics:lurasidone pimozide lurasidone pimozideContraindicated due to potential for serious and/or life-threatening reactions [see Contraindications (4)]. Contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4)].Antipsychotics: perphenazine, risperidone, thioridazine antipsychoticsA dose decrease may be needed for these drugs when co-administered with ritonavir.Antipsychotics:quetiapine quetiapineInitiation of NORVIR in patients taking quetiapine:Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking NORVIR:Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.-Blockers:metoprolol, timolol beta-blockersCaution is warranted and clinical monitoring of patients is recommended. dose decrease may be needed for these drugs when co-administered with ritonavir.Bronchodilator:theophylline theophyllineIncreased dosage of theophylline may be required; therapeutic monitoring should be considered.Calcium channel blockers:diltiazem, nifedipine, verapamil calcium channel blockersCaution is warranted and clinical monitoring of patients is recommended. dose decrease may be needed for these drugs when co-administered with ritonavir.Digoxin digoxinConcomitant administration of ritonavir with digoxin may increase digoxin levels. Caution should be exercised when co-administering ritonavir with digoxin, with appropriate monitoring of serum digoxin levels.Endothelin receptor antagonists: bosentan bosentanCo-administration of bosentan in patients on ritonavir:In patients who have been receiving ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Co-administration of ritonavir in patients on bosentan:Discontinue use of bosentan at least 36 hours prior to initiation of ritonavir. After at least 10 days following the initiation of ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.GnRH Receptor Antagonists:elagolix elagolix ritonavirConcomitant use of elagolix 200 mg twice daily and NORVIR for more than month is not recommended due to potential risk of adverse events such as bone loss and hepatic transaminase elevations. Limit concomitant use of elagolix 150 mg once daily and NORVIR to months.Ergot Derivatives:dihydroergotamine,ergotamine,methylergonovine ergot derivativesContraindicated due to potential for acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system [see Contraindications (4)].GI Motility Agent:cisapride cisaprideContraindicated due to potential for cardiac arrhythmias [see Contraindications (4)].Hepatitis direct acting antiviral:glecaprevir/pibrentasvir simeprevir glecaprevir pibrentasvir simeprevirIt is not recommended to co-administer ritonavir with glecaprevir/pibrentasvir, or simeprevir.Herbal Products: St. Johns Wort(hypericum perforatum) ritonavirContraindicated due to potential for loss of virologic response and possible resistance to NORVIR or to the class of protease inhibitors [see Contraindications (4)].Lipid-modifying agentsHMG-CoA Reductase Inhibitor:lovastatinsimvastatin atorvastatinrosuvastatin Microsomal triglyceridetransfer protein (MTTP)Inhibitor:lomitapide lovastatin simvastatin atorvastatin rosuvastatin lomitapideContraindicated due to potential for myopathy including rhabdomyolysis [see Contraindications (4)].Titrate atorvastatin and rosuvastatin dose carefully and use the lowest necessary dose.If NORVIR is used with another protease inhibitor, see the complete prescribing information for the concomitant protease inhibitor for details on co-administration with atorvastatin and rosuvastatin.Lomitapide is sensitive substrate for CYP3A4 metabolism. CYP3A4 inhibitors increase the exposure of lomitapide, with strong inhibitors increasing exposure approximately 27-fold. Concomitant use of moderate or strong CYP3A4 inhibitors with lomitapide is contraindicated due to potential for hepatotoxicity [see Contraindications (4)].Immunosuppressants:cyclosporine,tacrolimus,sirolimus(rapamycin) immunosuppressantsTherapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with ritonavir.Kinase Inhibitors:fostamatinib (also see anticancer agents above) fostamatinib metabolite R406Monitor for toxicities of R406 exposure resulting in dose-related adverse events such as hepatotoxicity and neutropenia. Fostamatinib dose reduction may be required.Long-acting beta-adrenoceptor agonist: salmeterol salmeterolConcurrent administration of salmeterol and ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.Oral Contraceptives or Patch Contraceptives: ethinyl estradiol ethinyl estradiolAlternate methods of contraception should be considered.PDE5 Inhibitors:avanafil sildenafil, tadalafil,vardenafil avanafil sildenafil tadalafil vardenafilSildenafil when used for the treatment of pulmonary arterial hypertension (Revatio(R)) is contraindicated due to the potential for sildenafil-associated adverse events, including visual abnormalities, hypotension, prolonged erection, and syncope [see Contraindications (4)].Do not use ritonavir with avanafil because safe and effective avanafil dosage regimen has not been established. Particular caution should be used when prescribing sildenafil, tadalafil or vardenafil in patients receiving ritonavir. Coadministration of ritonavir with these drugs may result in an increase in PDE5 inhibitor associated adverse events, including hypotension, syncope, visual changes, and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio(R)) is contraindicated [see Contraindications (4)]. The following dose adjustments are recommended for use of tadalafil (Adcirca(R)) with ritonavir: Co-administration of ADCIRCA in patients on ritonavir: In patients receiving ritonavir for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Co-administration of ritonavir in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of ritonavir. Stop ADCIRCA at least 24 hours prior to starting ritonavir. After at least one week following the initiation of ritonavir, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for the treatment of erectile dysfunction: It is recommended not to exceed the following doses: Sildenafil: 25 mg every 48 hoursTadalafil: 10 mg every 72 hoursVardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events. Sedative/hypnotics:buspirone, clorazepate, diazepam, estazolam, flurazepam, zolpidem sedative/hypnotics dose decrease may be needed for these drugs when co-administered with ritonavir.Sedative/Hypnotics:triazolam,orally administered midazolam triazolam midazolamContraindicated due to potential for prolonged or increased sedation or respiratory depression [see Contraindications (4)].Sedative/hypnotics: Parenteral midazolam midazolamCo-administration should be done in setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than single dose of midazolam is administered. Stimulant:methamphetamine methamphetamineUse with caution. dose decrease of methamphetamine may be needed when co-administered with ritonavir.Systemic/Inhaled/Nasal/OphthalmicCorticosteroids:e.g., betamethasonebudesonideciclesonidedexamethasonefluticasonemethylprednisolonemometasoneprednisonetriamcinolone glucocorticoidsCoadministration with corticosteroids whose exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushings syndrome and adrenal suppression.Alternative corticosteroids including beclomethasone and prednisolone (whose PK and/or PD are less affected by strong CYP3A inhibitors relative to other studied steroids) should be considered, particularly for long-term use.refers to interaction with apalutamide.. For patients with CLCR 30 to 60 mL per min the dose of clarithromycin should be reduced by 50%.. For patients with CLCR less than 30 mL per min the dose of clarithromycin should be decreased by 75%.. Sildenafil: 25 mg every 48 hours. Tadalafil: 10 mg every 72 hours. Vardenafil: 2.5 mg every 72 hours.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Clinical studies of NORVIR did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. The package sizes, strengths, and storage and handling recommendations for NORVIR (ritonavir) tablets, oral solution and oral powder are shown in the table below. NORVIR Tablets,100 mg RitonavirNORVIR Oral Solution,80 mg per mL RitonavirNORVIR Oral Powder, 100 mgPacketPresentationWhite film-coated ovaloid tabletsdebossed with the a logo andthe code NKorange-colored liquid,in amber-colored, multi-dose bottles containing 600 mg ritonavir per 7.5 mLmarked dosage cupbeige/pale yellow to yellow powder,in packetscontaining 100mg of ritonavirPackagingSizeBottles containing 30 tablets240 mL bottles30 foil/laminate,child-resistantpackets per cartonNDC Number0074-3333-300074-1940-63 0074-3399-30RecommendedStorageStore at or below30C (86F). Exposureto temperaturesup to 50C (122F)for seven dayspermitted.Dispense in originalcontainer or USPequivalent tightcontainer (60 mL or less). For patient use:exposure of this product to high humidity outside theoriginal or USPequivalent tightcontainer (60 mL orless) for longerthan weeksis not recommended.Store at room temperature 20-25C (68-77F).Do not refrigerate.Shake wellbefore each use. Product should be storedand dispensed in theoriginal container. Avoid exposure toexcessive heat. Keep captightly closed.Store at or below 30C (86F).

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. NORVIR tablets and oral solution are indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.NORVIR oral powder is indicated in combination with other antiretroviral agents for the treatment of pediatric patients with HIV-1 infection.. NORVIR tablets and oral solution are HIV protease inhibitors indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection (1) NORVIR oral powder is indicated in combination with other antiretroviral agents for the treatment of pediatric patients with HIV-1 infection (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use)General Administration Information [see Dosage and Administration (2)] :Advise patients and caregivers to pay special attention to accurate preparation and administration of their dose to minimize the risk of accidental overdose or underdose of NORVIR.For Norvir oral powder, advise patients or caregivers to read and follow the Instructions for Use for preparing the correct dose. Advise caregivers to inform their healthcare provider if their childs weight changes in order to make sure that the childs NORVIR dose is adjusted as needed. Advise patients to take NORVIR with meals.For adult patients taking NORVIR tablets, the maximum dose of 600 mg twice daily by mouth with meals should not be exceeded.Advise patients to remain under the care of physician while using NORVIR and to take NORVIR and other concomitant antiretroviral therapy every day as prescribed. NORVIR must always be used in combination with other antiretroviral drugs. Advise patients not to alter the dose or discontinue therapy without consulting with their healthcare provider. If dose of NORVIR is missed patients should take the dose as soon as possible and then return to their normal schedule. However, if dose is skipped the patient should not double the next dose.Continued NORVIR therapy at dose of 600 mg twice daily following loss of viral suppression may increase the likelihood of cross-resistance to other protease inhibitors.NORVIR is not cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should remain under the care of physician when using NORVIR.Drug InteractionsNORVIR may interact with some drugs; therefore, patients should be advised to report to their doctor the use of any other prescription, non-prescription medication or herbal products, particularly St. Johns Wort.Instruct patients receiving combined hormonal contraception to use an effective alternative contraceptive method or an additional barrier method during therapy with NORVIR because hormonal levels may decrease [see Drug Interactions (7.2), Use in Specific Populations (8.3)]. HepatotoxicityPre-existing liver disease including Hepatitis or can worsen with use of NORVIR. This can be seen as worsening of transaminase elevations or hepatic decompensation. Advise patients that their liver function tests will need to be monitored closely especially during the first several months of NORVIR treatment and that they should notify their healthcare provider if they develop the signs and symptoms of worsening liver disease including loss of appetite, abdominal pain, jaundice, and itchy skin [see Warnings and Precautions (5.3)].PancreatitisPancreatitis, including some fatalities, has been observed in patients receiving NORVIR therapy. Advise patients to notify their healthcare provider of signs and symptoms (nausea, vomiting, and abdominal pain) that might be suggestive of pancreatitis [see Warnings and Precautions (5.4)]. Allergic Reactions/HypersensitivitySkin rashes ranging in severity from mild to Stevens-Johnson syndrome have been reported in patients receiving NORVIR. Advise patients to contact their healthcare provider if they develop rash while taking NORVIR [see Warnings and Precautions (5.5)]. PR Interval ProlongationNORVIR may produce changes in the electrocardiogram (e.g., PR prolongation). Advise patients to consult their healthcare provider if they experience symptoms such as dizziness, lightheadedness, abnormal heart rhythm or loss of consciousness [see Warnings and Precautions (5.6)].Lipid DisordersAdvise patients that treatment with NORVIR therapy can result in substantial increases in the concentration of total cholesterol and triglycerides [see Warnings and Precautions (5.7)]. Diabetes Mellitus/HyperglycemiaAdvise patients that new onset of diabetes or exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported and to notify their healthcare provider if they develop the signs and symptoms of diabetes mellitus including frequent urination, excessive thirst, extreme hunger or unusual weight loss and/or an increased blood sugar while on NORVIR as they may require change in their diabetes treatment or new treatment [see Warnings and Precautions (5.8)]. Immune Reconstitution SyndromeAdvise patients that immune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including NORVIR [see Warnings and Precautions (5.9)].Fat RedistributionAdvise patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long term health effects of these conditions are not known at this time [see Warnings and Precautions (5.10)].Patients with HemophiliaAdvise patients with hemophilia that they may experience increased bleeding when treated with protease inhibitors such as NORVIR [see Warnings and Precautions (5.11)].NORVIR Oral Solution Not Recommended During PregnancyAdvise pregnant women that use of NORVIR oral solution during pregnancy is not recommended due to its ethanol content [see Dosage and Administration (2.3) and Use in Specific Population (8.1)].Pregnancy Exposure Registry Inform patients that there is an antiretroviral pregnancy registry that monitors fetal outcomes of pregnant women exposed to NORVIR [see Use in Specific Populations (8.1)]. LactationInstruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk [see Use in Specific Populations (8.2)].NORVIR tablets and oral solution are manufactured by:AbbVie Inc. North Chicago, IL 60064 USANORVIR oral powder is manufactured for:AbbVie Inc. North Chicago, IL 60064 USA (C) 2020 AbbVie Inc. All rights reserved.20065432. Advise patients and caregivers to pay special attention to accurate preparation and administration of their dose to minimize the risk of accidental overdose or underdose of NORVIR.. For Norvir oral powder, advise patients or caregivers to read and follow the Instructions for Use for preparing the correct dose. Advise caregivers to inform their healthcare provider if their childs weight changes in order to make sure that the childs NORVIR dose is adjusted as needed. Advise patients to take NORVIR with meals.. For adult patients taking NORVIR tablets, the maximum dose of 600 mg twice daily by mouth with meals should not be exceeded.. Advise patients to remain under the care of physician while using NORVIR and to take NORVIR and other concomitant antiretroviral therapy every day as prescribed. NORVIR must always be used in combination with other antiretroviral drugs. Advise patients not to alter the dose or discontinue therapy without consulting with their healthcare provider. If dose of NORVIR is missed patients should take the dose as soon as possible and then return to their normal schedule. However, if dose is skipped the patient should not double the next dose.. Continued NORVIR therapy at dose of 600 mg twice daily following loss of viral suppression may increase the likelihood of cross-resistance to other protease inhibitors.. NORVIR is not cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should remain under the care of physician when using NORVIR.. NORVIR may interact with some drugs; therefore, patients should be advised to report to their doctor the use of any other prescription, non-prescription medication or herbal products, particularly St. Johns Wort.. Instruct patients receiving combined hormonal contraception to use an effective alternative contraceptive method or an additional barrier method during therapy with NORVIR because hormonal levels may decrease [see Drug Interactions (7.2), Use in Specific Populations (8.3)].

INSTRUCTIONS FOR USE SECTION.

Instructions for UseNORVIR(R) (ritonavir)oral powderRead these Instructions for Use before you give or take dose of NORVIR oral powder for the first time and every time you get new prescription. There may be new information. Talk to your healthcare provider if you have any questions. Important informationYour healthcare provider will tell you your dose of NORVIR oral powder and how many packets you will need.Each packet contains 100 mg of NORVIR oral powder. When you receive your NORVIR oral powder prescription at the pharmacy, check to make sure that the carton is not damaged and that the packets are not opened.Check that the expiration date on the carton and packet has not passed.Make sure you have enough packets of NORVIR oral powder to give full dose. Call your healthcare provider if you need more NORVIR oral powder. Do not run out of your medicine. NORVIR oral powder can be prepared with either food or liquid. This Instructions for Use is for preparing the dose with food. The food can be replaced with liquid and the same steps can be followed for preparing dose. If your healthcare provider tells you to give NORVIR oral powder through feeding tube, use water to mix NORVIR oral powder. Follow your healthcare providers instructions to give the mixture through feeding tube.Be sure to give or take the entire prepared dose of NORVIR oral powder within hours of preparing the dose.For more information about NORVIR oral powder see the Patient Information section of the Prescribing Information.Items included in the NORVIR oral powder cartonFigure AGather texts to prepare your doseIf your dose is 100 mg or 200 mg: You will need packet of NORVIR oral powder for 100 mg and packets of NORVIR oral powder for 200 mg.Note: If your healthcare provider prescribes dose of NORVIR oral powder that is not 100 mg or 200 mg, your healthcare provider should tell you how to prepare your dose. Be sure to prepare your dose exactly as your healthcare provider tells you.You will also need the following texts to prepare your dose of NORVIR oral powder with food (not included in the NORVIR oral powder carton): Soft food such as applesauce or vanilla puddingSpoonSmall cup or bowlFigure BIf you are preparing dose of NORVIR oral powder in liquid, you will also need the following texts (not included in your NORVIR oral powder carton): Drinking glass with oz. of drinking water, infant formula or chocolate milk Spoon (teaspoon or larger)Figure CThe instructions below show the dose being prepared with food, but if you are using liquid you can swap the food for liquid.Prepare your doseStep 1: Place your supplies on clean, flat surface, like table.Check to make sure your small cup or bowl and spoon are clean and dry.Step 2: Check the prescription label on the carton for the number of packets you need to prepare dose. Take the prescribed number of packets out of the carton. For example, remove packet if your dose is 100 mg or packets if your dose is 200 mg.Figure DStep 3: Put spoonful or more of soft food into the small cup or bowl.Figure EStep 4: Tap the packet(s) to move all the powder to the bottom of the packet. Completely tear or cut off the top of the packet and make sure the packet is fully open.Figure FStep 5: Pour all of the powder from the packet(s) onto the soft food. Look inside the packet(s) to make sure there is no powder left inside. If there is powder left inside, hold the open end of the packet over your small cup or bowl and tap the packet(s) again to get all of the powder out. Note: To make sure full dose of NORVIR is given, it is important not to spill any powder and that there is no powder left in the packet(s).Figure GStep 6: Use the spoon to mix the powder and soft food well. Note: If mixing NORVIR oral powder with liquid, the mixture may look cloudy. This is okay.Figure HStep 7: Give or take the mixture.Be sure that all of the mixture is taken.If there is any powder left in the small cup, bowl, or spoon, add more soft food to the powder and mix. Then give or take the mixture.If there is any powder left in the drinking glass, add more liquid to the powder and mix. Then give or take the mixture.Note: The mixture must be given within hours of mixing with food or liquid. If not given within hours of mixing, discard (throw away) the mixture and prepare new dose. If only part of the dose has been taken or given within the hours, follow up with your healthcare provider.Figure IStep 8: Put the empty packet(s) in the trash. Hand wash the spoon, small cup or bowl, or drinking glass in warm water and soap. Rinse the spoon, small cup or bowl, or drinking glass with warm water and allow to air dry. Wash and dry the area used to prepare the NORVIR mixture. Wash and dry your hands.This Instructions for Use has been approved by the U.S. Food and Drug Administration.Manufactured by: NORVIR Oral Powder is manufactured for: AbbVie Inc., North Chicago, IL 60064 USA.Issued: September 2017430135. Your healthcare provider will tell you your dose of NORVIR oral powder and how many packets you will need.. Each packet contains 100 mg of NORVIR oral powder. When you receive your NORVIR oral powder prescription at the pharmacy, check to make sure that the carton is not damaged and that the packets are not opened.. Check that the expiration date on the carton and packet has not passed.. Make sure you have enough packets of NORVIR oral powder to give full dose. Call your healthcare provider if you need more NORVIR oral powder. Do not run out of your medicine. NORVIR oral powder can be prepared with either food or liquid. This Instructions for Use is for preparing the dose with food. The food can be replaced with liquid and the same steps can be followed for preparing dose.. If your healthcare provider tells you to give NORVIR oral powder through feeding tube, use water to mix NORVIR oral powder. Follow your healthcare providers instructions to give the mixture through feeding tube.. Be sure to give or take the entire prepared dose of NORVIR oral powder within hours of preparing the dose.. Soft food such as applesauce or vanilla pudding. Spoon. Small cup or bowl. Drinking glass with oz. of drinking water, infant formula or chocolate milk Spoon (teaspoon or larger). 30-packet-100mg. food-spoon-cup. glass-spoon. 100mg-packet. food-step3. tap-tear-packet. mix-with-food. food-step6. food-step7.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Ritonavir is an antiretroviral drug [see Microbiology (12.4)].

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisCarcinogenicity studies in mice and rats have been carried out on ritonavir. In male mice, at levels of 50, 100 or 200 mg per kg per day, there was dose dependent increase in the incidence of both adenomas and combined adenomas and carcinomas in the liver. Based on AUC measurements, the exposure at the high dose was approximately 0.3-fold for males that of the exposure in humans with the recommended therapeutic dose (600 mg twice-daily). There were no carcinogenic effects seen in females at the dosages tested. The exposure at the high dose was approximately 0.6-fold for the females that of the exposure in humans. In rats dosed at levels of 7, 15 or 30 mg per kg per day there were no carcinogenic effects. In this study, the exposure at the high dose was approximately 6% that of the exposure in humans with the recommended therapeutic dose. Based on the exposures achieved in the animal studies, the significance of the observed effects is not known. MutagenesisHowever, ritonavir was found to be negative for mutagenic or clastogenic activity in battery of in vitro and in vivo assays including the Ames bacterial reverse mutation assay using S. typhimurium and E. coli, the mouse lymphoma assay, the mouse micronucleus test and chromosomal aberration assays in human lymphocytes.Impairment of FertilityRitonavir produced no effects on fertility in rats at drug exposures approximately 40% (male) and 60% (female) of that achieved with the proposed therapeutic dose. Higher dosages were not feasible due to hepatic toxicity.

NURSING MOTHERS SECTION.

8.2 Lactation. Risk SummaryThe Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV.Limited published data reports that ritonavir is present in human milk. There is no information on the effects of ritonavir on the breastfed infant or the effects of the drug on milk production. Because of the potential for (1) HIV transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants) and (3) serious adverse reactions in breastfed infant, instruct mothers not to breastfeed if they are receiving NORVIR.

OTHER SAFETY INFORMATION.

8.3 Females and Males of Reproductive Potential. ContraceptionUse of NORVIR may reduce the efficacy of combined hormonal contraceptives. Advise patients using combined hormonal contraceptives to use an effective alternative contraceptive method or an additional barrier method of contraception [see Drug Interactions (7.2)].

OVERDOSAGE SECTION.

10 OVERDOSAGE. Acute Overdosage Human Overdose ExperienceHuman experience of acute overdose with NORVIR is limited. One patient in clinical trials took NORVIR 1500 mg per day for two days. The patient reported paresthesias which resolved after the dose was decreased. post-marketing case of renal failure with eosinophilia has been reported with ritonavir overdose.The approximate lethal dose was found to be greater than 20 times the related human dose in rats and 10 times the related human dose in mice.Management of OverdosageNORVIR oral solution contains approx. 43% ethanol (v/v) and approx. 27% (w/v) propylene glycol. Ingestion of the product over the recommended dose by young child could result in significant toxicity and could potentially be lethal. Treatment of overdose with NORVIR consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. There is no specific antidote for overdose with NORVIR. If indicated, elimination of unabsorbed drug should be achieved by gastric lavage; usual precautions should be observed to maintain the airway. Administration of activated charcoal may also be used to aid in removal of unabsorbed drug. Since ritonavir is extensively metabolized by the liver and is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the drug. However, dialysis can remove both ethanol and propylene glycol in the case of overdose with ritonavir oral solution. Certified Poison Control Center should be consulted for up-to-date information on the management of overdose with NORVIR.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

NDC 0074-3333-30Norvir(R) Ritonavir Tablets 100 mg 30 TabletsAttention Pharmacists and Patients: Tablet formulation. Store at room temperature (see side panel). Take NORVIR with meals.ALERT: Find out about medicines that should NOT be taken with NORVIR.Note to Pharmacist: Do not cover ALERT box with pharmacy label.Package insert is provided with tear-off patient information.Rx only abbvieNDC 0074-1940-63Norvir(R) Ritonavir Oral Solution 80 mg per mL 240 mLDo Not RefrigerateALERT: Find out about medicines that should NOT be taken with NORVIR.Note to Pharmacist: Do not cover ALERT box with pharmacy label. Store and dispense in original container. Do not cover expiration date on bottle.Package insert is provided with tear-off patient information.Rx onlyabbvieNDC 0074-3399-30Norvir(R) (ritonavir) Oral Powder 100 mgFor Oral UseALERT: Find out about medicines that should NOT be taken with Norvir.Note to Pharmacist: Do not cover ALERT box with pharmacy label.Package insert is provided with tear-off patient information.30 single-use foil packetsRx only abbvie. label-norvir-tablets-100mg-30ct. carton-norvir-oral-solution-240ml. label-norvir-oral-powder-100mg-30ct.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. In HIV-infected patients age greater than month to 21 years, the antiviral activity and adverse event profile seen during clinical trials and through postmarketing experience were similar to that for adult patients.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Cardiac ElectrophysiologyQTcF interval was evaluated in randomized, placebo and active (moxifloxacin 400 mg once-daily) controlled crossover study in 45 healthy adults, with 10 measurements over 12 hours on Day 3. The maximum mean (95% upper confidence bound) time-matched difference in QTcF from placebo after baseline correction was 5.5 (7.6) milliseconds (msec) for 400 mg twice-daily ritonavir. Ritonavir 400 mg twice daily resulted in Day ritonavir exposure that was approximately 1.5 fold higher than observed with ritonavir 600 mg twice-daily dose at steady state.PR interval prolongation was also noted in subjects receiving ritonavir in the same study on Day 3. The maximum mean (95% confidence interval) difference from placebo in the PR interval after baseline correction was 22 (25) msec for 400 mg twice-daily ritonavir [see Warnings and Precautions (5.6)].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics of ritonavir have been studied in healthy volunteers and HIV-infected patients (CD4 greater than or equal to 50 cells per uL). See Table for ritonavir pharmacokinetic characteristics.AbsorptionThe absolute bioavailability of ritonavir has not been determined. After 600 mg dose of oral solution, peak concentrations of ritonavir were achieved approximately hours and hours after dosing under fasting and non-fasting (514 KCal; 9% fat, 12% protein, and 79% carbohydrate) conditions, respectively.NORVIR tablets are not bioequivalent to NORVIR capsules. Under moderate fat conditions (857 kcal; 31% fat, 13% protein, 56% carbohydrates), when single 100 mg NORVIR dose was administered as tablet compared with capsule, AUC(0- met equivalence criteria but mean Cmax was increased by 26% (92.8% confidence intervals: 15 -39%). No information is available comparing NORVIR tablets to NORVIR capsules under fasting conditions.After administration of single 100 mg dose under fed conditions (617 Kcal, 29% calories from fat), NORVIR oral powder demonstrated comparable bioavailability to the oral solution. Effect of Food on Oral AbsorptionThe bioavailability of NORVIR tablet, oral solution, and oral powder is decreased under fed conditions as compared to fasted conditions.Following the administration of 100 mg tablet dose of NORVIR, Cmax and AUCinf of ritonavir were decreased by 21-23% under moderate fat (857 Kcal, 30% from fat) or high fat conditions (917 Kcal, 60% calories from fat) relative to fasting conditions.Following the administration of 600 mg dose NORVIR oral solution, Cmax and AUCinf of ritonavir were decreased by 23% and 7%, respectively, under nonfasting conditions (514 Kcal, 10% from fat) relative to fasting conditions. Dilution of the oral solution, within one hour of administration, with 240 mL of chocolate milk, Advera(R) or Ensure(R) did not significantly affect the extent and rate of ritonavir absorption.Following the administration of 100 mg dose of NORVIR oral powder, Cmax and AUCinf of ritonavir were decreased by 23-49% under moderate fat (617 Kcal, 29% calories from fat) or high fat conditions (917 Kcal, 60% calories from fat) relative to fasting conditions. MetabolismNearly all of the plasma radioactivity after single oral 600 mg dose of 14C-ritonavir oral solution (n 5) was attributed to unchanged ritonavir. Five ritonavir metabolites have been identified in human urine and feces. The isopropylthiazole oxidation metabolite (M-2) is the major metabolite and has antiviral activity similar to that of parent drug; however, the concentrations of this metabolite in plasma are low. In vitro studies utilizing human liver microsomes have demonstrated that cytochrome P450 3A (CYP3A) is the major isoform involved in ritonavir metabolism, although CYP2D6 also contributes to the formation of M-2.EliminationIn study of five subjects receiving 600 mg dose of 14C-ritonavir oral solution, 11.3 +- 2.8% of the dose was excreted into the urine, with 3.5 +- 1.8% of the dose excreted as unchanged parent drug. In that study, 86.4 +- 2.9% of the dose was excreted in the feces with 33.8 +- 10.8% of the dose excreted as unchanged parent drug. Upon multiple dosing, ritonavir accumulation is less than predicted from single dose possibly due to time and dose-related increase in clearance.Table 5. Ritonavir Pharmacokinetic CharacteristicsParameterNValues (Mean +- SD)V/F 910.41 +- 0.25 L/kgt 1/2 - hCL/F SS+ 108.8 +- 3.2 L/hCL/F 914.6 +- 1.6 L/hCLR 62< 0.1 L/hRBC/Plasma Ratio 0.14Percent Bound 98 to 99%+ SS steady state; patients taking ritonavir 600 mg q12h. Single ritonavir 600 mg dose. Primarily bound to human serum albumin and alpha-1 acid glycoprotein over the ritonavir concentration range of 0.01 to 30 ug/mL.Special PopulationsGender, Race and AgeNo age-related pharmacokinetic differences have been observed in adult patients (18 to 63 years). Ritonavir pharmacokinetics have not been studied in older patients.A study of ritonavir pharmacokinetics in healthy males and females showed no statistically significant differences in the pharmacokinetics of ritonavir. Pharmacokinetic differences due to race have not been identified.Pediatric PatientsSteady-state pharmacokinetics were evaluated in 37 HIV-infected patients ages to 14 years receiving doses ranging from 250 mg per m2 twice-daily to 400 mg per m2 twice-daily in PACTG Study 310, and in 41 HIV-infected patients ages month to years at doses of 350 and 450 mg per m2 twice-daily in PACTG Study 345. Across dose groups, ritonavir steady-state oral clearance (CL/F/m2) was approximately 1.5 to 1.7 times faster in pediatric patients than in adult subjects. Ritonavir concentrations obtained after 350 to 400 mg per m2 twice-daily in pediatric patients greater than years were comparable to those obtained in adults receiving 600 mg (approximately 330 mg per m2) twice-daily. The following observations were seen regarding ritonavir concentrations after administration with 350 or 450 mg per m2 twice-daily in children less than years of age. Higher ritonavir exposures were not evident with 450 mg per m2 twice-daily compared to the 350 mg per m2 twice-daily. Ritonavir trough concentrations were somewhat lower than those obtained in adults receiving 600 mg twice-daily. The area under the ritonavir plasma concentration time curve and trough concentrations obtained after administration with 350 or 450 mg per m2 twice-daily in children less than years were approximately 16% and 60% lower, respectively, than that obtained in adults receiving 600 mg twice daily.Renal ImpairmentRitonavir pharmacokinetics have not been studied in patients with renal impairment, however, since renal clearance is negligible, decrease in total body clearance is not expected in patients with renal impairment.Hepatic ImpairmentDose-normalized steady-state ritonavir concentrations in subjects with mild hepatic impairment (400 mg twice-daily, = 6) were similar to those in control subjects dosed with 500 mg twice-daily. Dose-normalized steady-state ritonavir exposures in subjects with moderate hepatic impairment (400 mg twice-daily, n= 6) were about 40% lower than those in subjects with normal hepatic function (500 mg twice-daily, = 6). Protein binding of ritonavir was not statistically significantly affected by mild or moderately impaired hepatic function. No dose adjustment is recommended in patients with mild or moderate hepatic impairment. However, health care providers should be aware of the potential for lower ritonavir concentrations in patients with moderate hepatic impairment and should monitor patient response carefully. Ritonavir has not been studied in patients with severe hepatic impairment.PregnancyBased on evaluation of the published literature, ritonavir exposures are reduced during pregnancy relative to postpartum.Drug Interactions[see also Contraindications (4), Warnings and Precautions (5.1), and Drug Interactions (7)]Table and Table summarize the effects on AUC and Cmax, with 95% confidence intervals (95% CI), of co-administration of ritonavir with variety of drugs. For information about clinical recommendations see Table in Drug Interactions (7) .Table 6. Drug Interactions Pharmacokinetic Parameters for Ritonavir in the Presence of the Co-administered DrugCo-administeredDrugDose of Co-administeredDrug (mg)Dose ofNORVIR (mg)NAUC (95% CI)Cmax (95% CI)Cmin (95% CI)Clarithromycin500 q12h, d200 q8h, d22 12%(2, 23%) 15%(2, 28%) 14%(-3, 36%)Didanosine200 q12h, d600 q12h, d12<-><-><->Fluconazole400 single dose, day 1;200 daily, d200 q6h, d8 12%(5, 20%) 15%(7, 22%) 14%(0, 26%)Fluoxetine30 q12h, d600 single dose, d16 19%(7, 34%)<->NDKetoconazole200 daily, d500 q12h, 10 d12 18%(-3, 52%) 10%(-11, 36%)NDRifampin600 or300 daily, 10 d500 q12h, 20 d7, 35%(7, 55%) 25%(-5, 46%) 49%(-14, 91%)Voriconazole400 q12h, d;then 200 q12h, d400 q12h, d <-><->NDZidovudine200 q8h, d300 q6h, d10<-><-><->ND=not determinedTable 7. Drug Interactions Pharmacokinetic Parameters for Co-administered Drug in the Presence of NORVIRCo-administered DrugDose of Co-administered Drug (mg)Dose of NORVIR (mg)NAUC (95% CI)Cmax (95% CI)Cmin (95% CI)Alprazolam1, single dose500 q12h, 10 d12 12% (-5, 30%) 16% (5, 27%)NDAvanafil50, single dose600 q12h146 13-fold 2.4-foldNDClarithromycin 14-OH clarithromycin metabolite500 q12h, d200 q8h, d22 77% (56, 103%) 100% 31% (15, 51%) 99% 2.8-fold (2.4, 3.3X) 100%Desipramine 2-OH desipraminemetabolite100, single dose500 q12h, 12 d14 145% (103, 211%) 15% (3, 26%) 22% (12, 35%) 67% (62, 72%)ND NDDidanosine200 q12h, d600 q12h, d12 13% (0, 23%) 16% (5, 26%)<->Ethinyl estradiol50 ug single dose500 q12h, 16 d23 40% (31, 49%) 32% (24, 39%)NDFluticasonepropionate aqueousnasal spray200 mcg qd, d100 mg q12h, d18 approximately 350-fold5 approximately 25-fold5 Indinavir1 Day 14 Day 15400 q12h, 15 d400 q12h, 15 d10 6% (-14, 29%) 7% (-22, 28%) 51% (40, 61%) 62% (52, 70%) 4-fold (2.8, 6.8X) 4-fold (2.5, 6.5X)Ketoconazole200 daily, d500 q12h, 10 d12 3.4-fold (2.8, 4.3X) 55% (40, 72%)NDMeperidine Normeperidinemetabolite50 oral single dose500 q12h, 10 d8 62% (59, 65%) 47% (-24, 345%) 59% (42, 72%) 87% (42, 147%)ND NDMethadone2 5, single dose500 q12h, 15 d11 36% (16, 52%) 38% (28, 46%)NDRaltegravir400, single dose100 q12h, 16 d10 16% (-30, 1%) 24% (-45, 4%) 1% (-30, 40%)Rivaroxaban10, single dose (days and 7)600 q12h(days to 7)12 150% (130-170%)7 60% (40-70%)7 NDRifabutin25-O-desacetylrifabutinmetabolite150 daily, 16 d500 q12h, 10 d5, 11 4-fold (2.8, 6.1X) 38-fold (28, 56X) 2.5-fold (1.9, 3.4X) 16-fold (13, 20X) 6-fold (3.5, 18.3X) 181-fold (ND)Sildenafil100, single dose500 twice daily, d28 11-fold 4-foldNDSimeprevir200 mg qd, d100 mg bid,15 d12 618% (463%-815%)8 370% (284%-476%)8 1335% (929%-1901%)8 Sulfamethoxazole3 800, single dose500 q12h, 12 d15 20% (16, 23%)<->NDTadalafil20 mg, single dose200 mg q12h 124%<->NDTheophylline3 mg/kg q8h, 15 d500 q12h, 10 d13, 11 43% (42, 45%) 32% (29, 34%) 57% (55, 59%)Trazodone50 mg, single dose200 mg q12h, doses10 2.4-fold 34% Trimethoprim3 160, single dose500 q12h, 12 d15 20% (3, 43%)<->NDVardenafil5 mg600 q12h 49-fold 13-foldNDVoriconazole400 q12h, d; then 200 q12h, d400 q12h, d 82% 66% 400 q12h, d; then 200 q12h, d100 q12h, d 39% 24% Warfarin S-Warfarin R-Warfarin5, single dose400 q12h, 12d12 9% (-17, 44%)4 33% (-38, -27%)4 9% (-16, -2%)4 <->ND NDZidovudine200 q8h, d300 q6h, d9 25% (15, 34%) 27% (4, 45%)NDND=not determined1 Ritonavir and indinavir were co-administered for 15 days; Day 14 doses were administered after 15%-fat breakfast (757 Kcal) and 9%-fat evening snack (236 Kcal), and Day 15 doses were administered after 15%-fat breakfast (757 Kcal) and 32%-fat dinner (815 Kcal). Indinavir Cmin was also increased 4-fold. Effects were assessed relative to an indinavir 800 mg q8h regimen under fasting conditions.2 Effects were assessed on dose-normalized comparison to methadone 20 mg single dose.3 Sulfamethoxazole and trimethoprim taken as single combination tablet.4 90% CI presented for R- and S-warfarin AUC and Cmax ratios.5 This significant increase in plasma fluticasone propionate exposure resulted in significant decrease (86%) in plasma cortisol AUC.6 For the reference arm: N=14 for Cmax and AUC(0-inf), and for the test arm: N=13 for Cmax and N=4 for AUC(0-inf).7 90% CI presented for rivaroxaban8 90% CI presented for simeprevir (change in exposure presented as percentage increase) Indicates increase, indicates decrease, <-> indicates no change. Parallel group design; entries are subjects receiving combination and control regimens, respectively.

RECENT MAJOR CHANGES SECTION.

Contraindications (4)12/2019.

REFERENCES SECTION.

15 REFERENCES. Sewester CS. Calculations. In: Drug Facts and Comparisons. St. Louis, MO: J.B. Lippincott Co; January, 1997:xix.. Sewester CS. Calculations. In: Drug Facts and Comparisons. St. Louis, MO: J.B. Lippincott Co; January, 1997:xix.

SPL PATIENT PACKAGE INSERT SECTION.

NORVIR(R) (NOR-VEER)(ritonavir)TabletsPatient InformationNORVIR(R) (NOR-VEER)(ritonavir)Oral SolutionNORVIR(R) (NOR-VEER)(ritonavir)Oral PowderWhat is the most important information should know about NORVIRNORVIR can interact with other medicines and cause serious side effects. It is important to know the medicines that should not be taken with NORVIR. See the section Who should not take NORVIR What is NORVIRNORVIR tablets and oral solution are prescription medicines that are used with other antiviral medicines to treat people with human immunodeficiency virus (HIV-1) infection. NORVIR oral powder is prescription medicine that is used with other antiviral medicines to treat children with HIV-1 infection.HIV-1 is the virus that causes AIDS (Acquired Immune Deficiency Syndrome). Do not take NORVIR if you or your child:are allergic to ritonavir or any of the ingredients in NORVIR. See the end of this leaflet for complete list of ingredients in NORVIR.If you take any of the following medicines: alfuzosinapalutamideranolazinedronedaronecolchicine, if you have kidney or liver problems.lurasidone pimozide amiodaroneergot-containing medicines including:dihydroergotamine mesylateergotamine tartratemethylergonovine maleatecisaprideflecainidelovastatinsimvastatinlomitapidesildenafil (REVATIO(R)) only when used for treating the lung problem, pulmonary arterial hypertension (PAH) triazolam midazolam when taken by mouthpropafenonequinidine St. Johns Wort (Hypericum perforatum) or product that contains St. Johns wortvoriconazole if your NORVIR dose is 400 mg every 12 hours or greaterSerious problems can happen if you or your child takes any of these medicines with NORVIR.Before taking NORVIR, tell your healthcare provider about all of your medical conditions, including if you or your child:have liver problems, including Hepatitis or Hepatitis Chave heart problems have high blood sugar (diabetes)have bleeding problems or hemophilia are pregnant or plan to become pregnant.NORVIR oral solution contains alcohol. You should not take NORVIR oral solution during pregnancy because there is no known safe level of alcohol exposure during pregnancy. Tell your healthcare provider if you become pregnant during treatment with NORVIR. NORVIR may reduce how well hormonal birth control works. Females who may become pregnant should use another effective form of birth control or an additional barrier method of birth control during treatment with NORVIR.Pregnancy Registry: There is pregnancy registry for women who take antiviral medicines during pregnancy. The purpose of the registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry. are breastfeeding or plan to breastfeed. Do not breastfeed if you take NORVIR. You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.NORVIR may pass into your breastmilk.Talk to your healthcare provider about the best way to feed your baby. Tell your healthcare provider about all the medicines you take including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medicines interact with NORVIR. Keep list of your medicines to show our healthcare provider and pharmacist. You can ask your healthcare provider or pharmacist for list of medicines that interact with NORVIR.Do not start taking new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take NORVIR with other medicines. How should take NORVIRSee the detailed Instructions for Use for information about how to give or take dose of NORVIR oral powder.Take NORVIR exactly as your healthcare provider tells you to take it. You should stay under healthcare providers care during treatment with NORVIR. Do not change your dose of NORVIR or stop your treatment without talking with your healthcare provider first.If your child is taking NORVIR, your childs healthcare provider will decide the right dose based on your childs height and weight. Tell your healthcare provider if your childs weight changes. If your child does not tolerate NORVIR oral solution or NORVIR oral powder, ask your childs healthcare provider for advice.Swallow NORVIR tablets whole. Do not chew, break, or crush tablets before swallowing. If you cannot swallow NORVIR tablets whole, tell your healthcare provider. You may need different medicine. Take NORVIR with meals.NORVIR oral solution is peppermint or caramel flavored.You can take it alone, or may improve the taste by mixing it with ounces of chocolate milk, Ensure(R), or Advera(R).NORVIR oral solution should be taken within hour after mixing with these fluids.Ask your healthcare provider, nurse or pharmacist about other ways to improve the taste of NORVIR oral solution.Do not run out of NORVIR. Get your NORVIR prescription refilled from your healthcare provider or pharmacy before you run out. If you miss dose of NORVIR, take it as soon as possible and then take your next scheduled dose at its regular time. If it is almost time for your next dose, wait and take the next dose at the regular time. Do not double the next dose.If you take too much NORVIR, call your local poison control center or go to the nearest hospital emergency room right away.Contact your doctor if you are planning to take Norvir Oral Solution through feeding tube because some feeding tubes are not recommended for use with ethanol and/or propylene glycol-containing products like NORVIR. What are the possible side effects of NORVIRNORVIR can cause serious side effects including:See What is the most important information should know about NORVIRLiver problems. Some people taking NORVIR in combination with other antiviral medicines have developed liver problems which may be life-threatening. Your healthcare provider should do regular blood tests during your combination treatment with NORVIR. If you have chronic hepatitis or infection, your healthcare provider should check your blood tests more often because you have an increased chance of developing liver problems. Tell your healthcare provider right away if you get any of the following signs and symptoms of liver problems:loss of appetite pain or tenderness on your right side below your ribsyellowing of your skin or whites of your eyesitchy skinInflammation of your pancreas (pancreatitis). NORVIR can cause serious pancreas problems, which may lead to death. Tell your healthcare provider right away if you have signs or symptoms of pancreatitis such as:nausea stomach (abdomen) pain vomitingAllergic reactions. Sometimes these allergic reactions can become severe and require treatment in hospital. Call your healthcare provider right away if you develop rash. Stop taking NORVIR and get medical help right away if you have any of the following symptoms of severe allergic reaction:trouble breathing wheezingdizziness or faintingthroat tightness or hoarsenessfast heartbeat or pounding in your chest (tachycardia)sweatingswelling of your face, lips or tonguemuscle or joint pain blisters or skin lesionsmouth sores or ulcersChanges in the electrical activity of your heart called PR prolongation. PR prolongation can cause irregular heartbeats. Tell your healthcare provider right away if you have symptoms such as:dizziness lightheadednessfeel faint or pass outabnormal heart beatIncrease in cholesterol and triglyceride levels. Treatment with NORVIR may increase your blood levels of cholesterol and triglycerides. Your healthcare provider should do blood tests before you start your treatment with NORVIR and regularly to check for an increase in your cholesterol and triglycerides levels.Diabetes and high blood sugar (hyperglycemia). Some people who take protease inhibitors including NORVIR can get high blood sugar, develop diabetes, or your diabetes can get worse. Tell your healthcare provider if you notice an increase in thirst or urinate often during treatment with NORVIR.Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for long time. Call your healthcare provider right away if you start having new symptoms after starting your HIV-1 medicine.Change in body fat can happen in some people who taking HIV-1 medicines. These changes may include an increased amount of fat in the upper back and neck (buffalo hump), breast, and around the middle part of your body (trunk). Loss of fat from the legs, arms, and face may also happen. The exact cause and long-term health effects of these conditions are not known.Increased bleeding for hemophiliacs. Some people with hemophilia have increased bleeding with protease inhibitors including NORVIR.Kidney stonesThe most common side effects of NORVIR include:diarrheanauseavomitingupper and lower stomach (abdominal) paintingling feeling or numbness in hands or feet or around the lipsrashfeeling weak or tired NORVIR oral solution contains large amount of alcohol. If toddler or young child accidentally drinks more than the recommended dose of NORVIR, it could make him/her sick from too much alcohol. Go to the nearest emergency room right away if this happens. These are not all of the possible side effects of NORVIR. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should store NORVIRStore NORVIR tablets and NORVIR oral solution in the original container given to you by the pharmacist.Use NORVIR tablets, NORVIR oral solution, and NORVIR oral powder by the expiration date.Store NORVIR tablets:Store below 30C (86F). Exposure to temperatures up to 50C (122F) for seven days permitted.Exposure to high humidity outside the original container for longer than weeks is not recommended.Store NORVIR oral solution:At room temperature between 20C to 25C (68F to 77F).Do not refrigerate.Shake well before each use.Keep away from heat.Keep bottle cap tightly closed.Store NORVIR oral powder:At or below 30C (86F).Keep NORVIR and all medicines out of the reach of children.General information about the safe and effective use of NORVIRMedicines are sometimes prescribed for purposes other than those listed in Patient Information Leaflet. Do not use NORVIR for condition for which it was not prescribed. Do not give NORVIR to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about NORVIR that is written for healthcare professionals. What are the ingredients in NORVIRActive ingredient: ritonavirInactive ingredients: NORVIR tablet: copovidone, anhydrous dibasic calcium phosphate, sorbitan monolaurate, colloidal silicon dioxide, and sodium stearyl fumarate. The film coating contains: hypromellose, titanium dioxide, polyethylene glycol 400, hydroxypropyl cellulose, talc, polyethylene glycol 3350, colloidal silicon dioxide, and polysorbate 80.NORVIR oral solution: ethanol, water, polyoxyl 35 castor oil, propylene glycol, anhydrous citric acid to adjust pH, saccharin sodium, peppermint oil, creamy caramel flavoring, and FD&C Yellow No. 6.NORVIR oral powder: copovidone, sorbitan monolaurate, and colloidal silicon dioxide.NORVIR tablets and NORVIR oral solution are manufactured by: AbbVie Inc., North Chicago, IL 60064 USA. NORVIR oral powder is manufactured for: AbbVie Inc., North Chicago, IL 60064 USA. For more information, call 1-800-633-9110. The brands listed are trademarks of their respective owners and are not trademarks of AbbVie Inc. The makers of these brands are not affiliated with and do not endorse AbbVie Inc. or its products. (C) 2020 AbbVie Inc. All rights reserved.This Patient Information has been approved by the U.S. Food and Drug Administration.20065432Revised: October 2020. NORVIR can interact with other medicines and cause serious side effects. It is important to know the medicines that should not be taken with NORVIR. See the section Who should not take NORVIR NORVIR tablets and oral solution are prescription medicines that are used with other antiviral medicines to treat people with human immunodeficiency virus (HIV-1) infection. NORVIR oral powder is prescription medicine that is used with other antiviral medicines to treat children with HIV-1 infection.. are allergic to ritonavir or any of the ingredients in NORVIR. See the end of this leaflet for complete list of ingredients in NORVIR.. If you take any of the following medicines: alfuzosin. apalutamide. ranolazine. dronedarone. colchicine, if you have kidney or liver problems.. lurasidone pimozide amiodarone. ergot-containing medicines including:. dihydroergotamine mesylate. ergotamine tartrate. methylergonovine maleate. cisapride. flecainide. lovastatin. simvastatin. lomitapide. sildenafil (REVATIO(R)) only when used for treating the lung problem, pulmonary arterial hypertension (PAH) triazolam midazolam when taken by mouth. propafenone. quinidine St. Johns Wort (Hypericum perforatum) or product that contains St. Johns wort. voriconazole if your NORVIR dose is 400 mg every 12 hours or greater. have liver problems, including Hepatitis or Hepatitis C. have heart problems have high blood sugar (diabetes). have bleeding problems or hemophilia are pregnant or plan to become pregnant.NORVIR oral solution contains alcohol. You should not take NORVIR oral solution during pregnancy because there is no known safe level of alcohol exposure during pregnancy. Tell your healthcare provider if you become pregnant during treatment with NORVIR. NORVIR may reduce how well hormonal birth control works. Females who may become pregnant should use another effective form of birth control or an additional barrier method of birth control during treatment with NORVIR.Pregnancy Registry: There is pregnancy registry for women who take antiviral medicines during pregnancy. The purpose of the registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry. NORVIR oral solution contains alcohol. You should not take NORVIR oral solution during pregnancy because there is no known safe level of alcohol exposure during pregnancy. Tell your healthcare provider if you become pregnant during treatment with NORVIR. NORVIR may reduce how well hormonal birth control works. Females who may become pregnant should use another effective form of birth control or an additional barrier method of birth control during treatment with NORVIR.. Pregnancy Registry: There is pregnancy registry for women who take antiviral medicines during pregnancy. The purpose of the registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry.. are breastfeeding or plan to breastfeed. Do not breastfeed if you take NORVIR. You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.NORVIR may pass into your breastmilk.Talk to your healthcare provider about the best way to feed your baby. You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.. NORVIR may pass into your breastmilk.. Talk to your healthcare provider about the best way to feed your baby.. You can ask your healthcare provider or pharmacist for list of medicines that interact with NORVIR.. Do not start taking new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take NORVIR with other medicines.. Take NORVIR exactly as your healthcare provider tells you to take it. You should stay under healthcare providers care during treatment with NORVIR. Do not change your dose of NORVIR or stop your treatment without talking with your healthcare provider first.. If your child is taking NORVIR, your childs healthcare provider will decide the right dose based on your childs height and weight. Tell your healthcare provider if your childs weight changes. If your child does not tolerate NORVIR oral solution or NORVIR oral powder, ask your childs healthcare provider for advice.. Swallow NORVIR tablets whole. Do not chew, break, or crush tablets before swallowing. If you cannot swallow NORVIR tablets whole, tell your healthcare provider. You may need different medicine. Take NORVIR with meals.. NORVIR oral solution is peppermint or caramel flavored.You can take it alone, or may improve the taste by mixing it with ounces of chocolate milk, Ensure(R), or Advera(R).NORVIR oral solution should be taken within hour after mixing with these fluids.Ask your healthcare provider, nurse or pharmacist about other ways to improve the taste of NORVIR oral solution.. You can take it alone, or may improve the taste by mixing it with ounces of chocolate milk, Ensure(R), or Advera(R).. NORVIR oral solution should be taken within hour after mixing with these fluids.. Ask your healthcare provider, nurse or pharmacist about other ways to improve the taste of NORVIR oral solution.. Do not run out of NORVIR. Get your NORVIR prescription refilled from your healthcare provider or pharmacy before you run out. If you miss dose of NORVIR, take it as soon as possible and then take your next scheduled dose at its regular time. If it is almost time for your next dose, wait and take the next dose at the regular time. Do not double the next dose.. If you take too much NORVIR, call your local poison control center or go to the nearest hospital emergency room right away.. Contact your doctor if you are planning to take Norvir Oral Solution through feeding tube because some feeding tubes are not recommended for use with ethanol and/or propylene glycol-containing products like NORVIR. See What is the most important information should know about NORVIR. Liver problems. Some people taking NORVIR in combination with other antiviral medicines have developed liver problems which may be life-threatening. Your healthcare provider should do regular blood tests during your combination treatment with NORVIR. If you have chronic hepatitis or infection, your healthcare provider should check your blood tests more often because you have an increased chance of developing liver problems. Tell your healthcare provider right away if you get any of the following signs and symptoms of liver problems:. loss of appetite pain or tenderness on your right side below your ribs. yellowing of your skin or whites of your eyes. itchy skin. Inflammation of your pancreas (pancreatitis). NORVIR can cause serious pancreas problems, which may lead to death. Tell your healthcare provider right away if you have signs or symptoms of pancreatitis such as:. nausea stomach (abdomen) pain vomiting. Allergic reactions. Sometimes these allergic reactions can become severe and require treatment in hospital. Call your healthcare provider right away if you develop rash. Stop taking NORVIR and get medical help right away if you have any of the following symptoms of severe allergic reaction:. trouble breathing wheezing. dizziness or fainting. throat tightness or hoarseness. fast heartbeat or pounding in your chest (tachycardia). sweating. swelling of your face, lips or tongue. muscle or joint pain blisters or skin lesions. mouth sores or ulcers. dizziness lightheadedness. feel faint or pass out. abnormal heart beat. Increase in cholesterol and triglyceride levels. Treatment with NORVIR may increase your blood levels of cholesterol and triglycerides. Your healthcare provider should do blood tests before you start your treatment with NORVIR and regularly to check for an increase in your cholesterol and triglycerides levels.. Diabetes and high blood sugar (hyperglycemia). Some people who take protease inhibitors including NORVIR can get high blood sugar, develop diabetes, or your diabetes can get worse. Tell your healthcare provider if you notice an increase in thirst or urinate often during treatment with NORVIR.. Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for long time. Call your healthcare provider right away if you start having new symptoms after starting your HIV-1 medicine.. Change in body fat can happen in some people who taking HIV-1 medicines. These changes may include an increased amount of fat in the upper back and neck (buffalo hump), breast, and around the middle part of your body (trunk). Loss of fat from the legs, arms, and face may also happen. The exact cause and long-term health effects of these conditions are not known.. Increased bleeding for hemophiliacs. Some people with hemophilia have increased bleeding with protease inhibitors including NORVIR.. Kidney stones. diarrhea. nausea. vomiting. upper and lower stomach (abdominal) pain. tingling feeling or numbness in hands or feet or around the lips. rash. feeling weak or tired Store NORVIR tablets and NORVIR oral solution in the original container given to you by the pharmacist.. Use NORVIR tablets, NORVIR oral solution, and NORVIR oral powder by the expiration date.. Store below 30C (86F). Exposure to temperatures up to 50C (122F) for seven days permitted.. Exposure to high humidity outside the original container for longer than weeks is not recommended.. At room temperature between 20C to 25C (68F to 77F).. Do not refrigerate.. Shake well before each use.. Keep away from heat.. Keep bottle cap tightly closed.. At or below 30C (86F).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisCarcinogenicity studies in mice and rats have been carried out on ritonavir. In male mice, at levels of 50, 100 or 200 mg per kg per day, there was dose dependent increase in the incidence of both adenomas and combined adenomas and carcinomas in the liver. Based on AUC measurements, the exposure at the high dose was approximately 0.3-fold for males that of the exposure in humans with the recommended therapeutic dose (600 mg twice-daily). There were no carcinogenic effects seen in females at the dosages tested. The exposure at the high dose was approximately 0.6-fold for the females that of the exposure in humans. In rats dosed at levels of 7, 15 or 30 mg per kg per day there were no carcinogenic effects. In this study, the exposure at the high dose was approximately 6% that of the exposure in humans with the recommended therapeutic dose. Based on the exposures achieved in the animal studies, the significance of the observed effects is not known. MutagenesisHowever, ritonavir was found to be negative for mutagenic or clastogenic activity in battery of in vitro and in vivo assays including the Ames bacterial reverse mutation assay using S. typhimurium and E. coli, the mouse lymphoma assay, the mouse micronucleus test and chromosomal aberration assays in human lymphocytes. Impairment of FertilityRitonavir produced no effects on fertility in rats at drug exposures approximately 40% (male) and 60% (female) of that achieved with the proposed therapeutic dose. Higher dosages were not feasible due to hepatic toxicity.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trial Experience. Because clinical trials are conducted under widely varying conditions, adverse reactions 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. Adverse Reactions in AdultsThe safety of NORVIR alone and in combination with other antiretroviral agents was studied in 1,755 adult patients. Table lists treatment-emergent Adverse Reactions (with possible or probable relationship to study drug) occurring in greater than or equal to 1% of adult patients receiving NORVIR in combined Phase II/IV studies. The most frequently reported adverse drug reactions among patients receiving NORVIR alone or in combination with other antiretroviral drugs were gastrointestinal (including diarrhea, nausea, vomiting, abdominal pain (upper and lower)), neurological disturbances (including paresthesia and oral paresthesia), rash, and fatigue/asthenia. Table 2. Treatment-Emergent Adverse Reactions (With Possible or Probable Relationship to Study Drug) Occurring in greater than or equal to 1% of Adult Patients Receiving NORVIR in Combined Phase II/IV Studies (N 1,755) Adverse Reactionsn%Eye disorders Blurred vision1136.4Gastrointestinal disorders Abdominal Pain (upper and lower)46426.4 Diarrhea including severe with electrolyte imbalance1,19267.9 Dyspepsia20111.5 Flatulence1428.1 Gastrointestinal hemorrhage412.3 Gastroesophageal reflux disease (GERD)191.1 Nausea1,00757.4 Vomiting55931.9General disorders and administration site conditions Fatigue including asthenia81146.2Hepatobiliary disorders Blood bilirubin increased (including jaundice)251.4 Hepatitis (including increased AST, ALT, GGT)1538.7Immune system disorders Hypersensitivity including urticaria and face edema1148.2Metabolism and nutrition disorders Edema and peripheral edema1106.3 Gout241.4 Hypercholesterolemia523.0 Hypertriglyceridemia1589.0 Lipodystrophy acquired512.9Musculoskeletal and connective tissue disorders Arthralgia and back pain32618.6 Myopathy/creatine phosphokinase increased663.8 Myalgia1568.9Nervous system disorders Dizziness27415.6 Dysgeusia28516.2 Paresthesia (including oral paresthesia)88950.7 Peripheral neuropathy17810.1 Syncope583.3Psychiatric disorders Confusion523.0 Disturbance in attention442.5Renal and urinary disorders Increased urination744.2Respiratory, thoracic and mediastinal disorders Coughing38021.7 Oropharyngeal Pain27915.9Skin and subcutaneous tissue disorders Acne673.8 Pruritus21412.2 Rash (includes erythematous and maculopapular) 47527.1Vascular disorders Flushing, feeling hot23213.2 Hypertension583.3 Hypotension including orthostatic hypotension301.7 Peripheral coldness211.2 Represents medical concept including several similar MedDRA PTsLaboratory Abnormalities in AdultsTable shows the percentage of adult patients who developed marked laboratory abnormalities. Table 3. Percentage of Adult Patients, by Study and Treatment Group, with Chemistry and Hematology Abnormalities Occurring in greater than 3% of Patients Receiving NORVIR Study 245Naive PatientsStudy 247Advanced PatientsStudy 462 PI-Naive PatientsVariableLimitNORVIR plus ZDVNORVIR ZDV NORVIR Placebo NORVIR plus SaquinavirChemistryHigh Cholesterol> 240 mg/dL30.744.89.336.58.065.2CPK> 1000 IU/L9.612.111.09.16.39.9GGT> 300 IU/L1.85.21.719.611.39.2SGOT (AST)> 180 IU/L5.39.52.56.47.07.8SGPT (ALT)> 215 IU/L5.37.83.48.54.49.2Triglycerides> 800 mg/dL9.617.23.433.69.423.4Triglycerides> 1500 mg/dL1.82.6-12.60.411.3Triglycerides Fasting> 1500 mg/dL1.51.3-9.90.3-Uric Acid> 12 mg/dL---3.80.21.4HematologyLow Hematocrit< 30%2.6-0.817.322.00.7Hemoglobin< 8.0 g/dL0.9--3.83.9-Neutrophils<= 0.5 109/L ---6.08.3-RBC< 3.0 1012/L 1.8-5.918.624.4-WBC< 2.5 109/L -0.96.836.959.43.5- Indicates no events reported.Adverse Reactions in Pediatric PatientsNORVIR has been studied in 265 pediatric patients greater than month to 21 years of age. The adverse event profile observed during pediatric clinical trials was similar to that for adult patients. Vomiting, diarrhea, and skin rash/allergy were the only drug-related clinical adverse events of moderate to severe intensity observed in greater than or equal to 2% of pediatric patients enrolled in NORVIR clinical trials. Laboratory Abnormalities in Pediatric PatientsThe following Grade 3-4 laboratory abnormalities occurred in greater than 3% of pediatric patients who received treatment with NORVIR either alone or in combination with reverse transcriptase inhibitors: neutropenia (9%), hyperamylasemia (7%), thrombocytopenia (5%), anemia (4%), and elevated AST (3%).

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. ContraceptionUse of NORVIR may reduce the efficacy of combined hormonal contraceptives. Advise patients using combined hormonal contraceptives to use an effective alternative contraceptive method or an additional barrier method of contraception [see Drug Interactions 7.2 ].

HEPATIC IMPAIRMENT SUBSECTION.

5.3 Hepatotoxicity. Hepatic transaminase elevations exceeding times the upper limit of normal, clinical hepatitis, and jaundice have occurred in patients receiving NORVIR alone or in combination with other antiretroviral drugs (see Table 3). There may be an increased risk for transaminase elevations in patients with underlying hepatitis or C. Therefore, caution should be exercised when administering NORVIR to patients with pre-existing liver diseases, liver enzyme abnormalities, or hepatitis. Increased AST/ALT monitoring should be considered in these patients, especially during the first three months of NORVIR treatment [see Use in Specific Populations 8.6 ]. There have been postmarketing reports of hepatic dysfunction, including some fatalities. These have generally occurred in patients taking multiple concomitant medications and/or with advanced AIDS.

LABORATORY TESTS SECTION.

5.13 Laboratory Tests. Ritonavir has been shown to increase triglycerides, cholesterol, SGOT (AST), SGPT (ALT), GGT, CPK, and uric acid. Appropriate laboratory testing should be performed prior to initiating NORVIR therapy and at periodic intervals or if any clinical signs or symptoms occur during therapy.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThe Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Limited published data reports that ritonavir is present in human milk. There is no information on the effects of ritonavir on the breastfed infant or the effects of the drug on milk production. Because of the potential for (1) HIV transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants) and (3) serious adverse reactions in breastfed infant, instruct mothers not to breastfeed if they are receiving NORVIR.

MICROBIOLOGY SECTION.

12.4 Microbiology. Mechanism of ActionRitonavir is peptidomimetic inhibitor of the HIV-1 protease. Inhibition of HIV protease renders the enzyme incapable of processing the Gag-Pol polyprotein precursor which leads to production of non-infectious immature HIV particles. Antiviral Activity in Cell CultureThe activity of ritonavir was assessed in acutely infected lymphoblastoid cell lines and in peripheral blood lymphocytes. The concentration of drug that inhibits 50% (EC50) value of viral replication ranged from 3.8 to 153 nM depending upon the HIV-1 isolate and the cells employed. The average EC50 value for low passage clinical isolates was 22 nM (n 13). In MT4 cells, ritonavir demonstrated additive effects against HIV-1 in combination with either didanosine (ddI) or zidovudine (ZDV). Studies which measured cytotoxicity of ritonavir on several cell lines showed that greater than 20 microM was required to inhibit cellular growth by 50% resulting in cell culture therapeutic index of at least 1000. ResistanceHIV-1 isolates with reduced susceptibility to ritonavir have been selected in cell culture. Genotypic analysis of these isolates showed mutations in the HIV-1 protease gene leading to amino acid substitutions I84V, V82F, A71V, and M46I. Phenotypic (n 18) and genotypic (n 48) changes in HIV-1 isolates from selected patients treated with ritonavir were monitored in phase I/II trials over period of to 32 weeks. Substitutions associated with the HIV-1 viral protease in isolates obtained from 43 patients appeared to occur in stepwise and ordered fashion at positions V82A/F/T/S, I54V, A71V/T, and I36L, followed by combinations of substitutions at an additional specific amino acid positions (M46I/L, K20R, I84V, L33F and L90M). Of 18 patients for whom both phenotypic and genotypic analysis were performed on free virus isolated from plasma, 12 showed reduced susceptibility to ritonavir in cell culture. All 18 patients possessed one or more substitutions in the viral protease gene. The V82A/F substitution appeared to be necessary but not sufficient to confer phenotypic resistance. Phenotypic resistance was defined as greater than or equal to 5-fold decrease in viral sensitivity in cell culture from baseline. Cross-Resistance to Other AntiretroviralsAmong protease inhibitors variable cross-resistance has been recognized. Serial HIV-1 isolates obtained from six patients during ritonavir therapy showed decrease in ritonavir susceptibility in cell culture but did not demonstrate concordant decrease in susceptibility to saquinavir in cell culture when compared to matched baseline isolates. However, isolates from two of these patients demonstrated decreased susceptibility to indinavir in cell culture (8-fold). Isolates from patients were also tested for cross-resistance to amprenavir and nelfinavir; isolates from patients had decrease in susceptibility to nelfinavir (6- to 14-fold), and none to amprenavir. Cross-resistance between ritonavir and reverse transcriptase inhibitors is unlikely because of the different enzyme targets involved. One ZDV-resistant HIV-1 isolate tested in cell culture retained full susceptibility to ritonavir.

POSTMARKETING EXPERIENCE SECTION.

6.2 Postmarketing Experience. The following adverse events (not previously mentioned in the labeling) have been reported during post-marketing use of NORVIR. Because these reactions are reported voluntarily from population of unknown size, it is not possible to reliably estimate their frequency or establish causal relationship to NORVIR exposure. Body as WholeDehydration, usually associated with gastrointestinal symptoms, and sometimes resulting in hypotension, syncope, or renal insufficiency has been reported. Syncope, orthostatic hypotension, and renal insufficiency have also been reported without known dehydration. Co-administration of ritonavir with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system. Cardiovascular SystemFirst-degree AV block, second-degree AV block, third-degree AV block, right bundle branch block have been reported [see Warnings and Precautions 5.6 ]. Cardiac and neurologic events have been reported when ritonavir has been co-administered with disopyramide, mexiletine, nefazodone, fluoxetine, and beta blockers. The possibility of drug interaction cannot be excluded. Endocrine SystemCushings syndrome and adrenal suppression have been reported when ritonavir has been co-administered with fluticasone propionate or budesonide. Nervous SystemThere have been postmarketing reports of seizure. Also, see Cardiovascular System. Renal and Urinary DisordersNephrolithiasis Skin and subcutaneous tissue disordersToxic epidermal necrolysis (TEN) has been reported.

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to NORVIR during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk SummaryProspective pregnancy data from the Antiretroviral Pregnancy Registry (APR) are not sufficient to adequately assess the risk of birth defects or miscarriage. Available data from the APR show no difference in the rate of overall birth defects for ritonavir compared to the background rate for major birth defects of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) [see Data]. In animal reproduction studies, no evidence of adverse developmental outcomes was observed with oral administration of ritonavir to pregnant rats and rabbits. During organogenesis in the rat and rabbit, systemic exposure (AUC) was approximately 1/3 lower than human exposure at the recommended daily dose. In the rat pre- and post-natal developmental study, maternal systemic exposure to ritonavir was approximately 1/2 of the exposure in humans at the recommended daily dose, based on body surface area conversion factor [see Data]. NORVIR oral solution is not recommended during pregnancy because there is no known safe level of ethanol exposure during pregnancy [see Clinical Considerations, Dosage and Administration 2.3 and Warnings and Precautions 5.2 ]. The 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 2-4% and 15-20%, respectively. Clinical ConsiderationsDose Adjustments During Pregnancy and the Postpartum PeriodNORVIR oral solution contains approx. 43% ethanol (v/v) and approx. 27% (w/v) propylene glycol and is not recommended during pregnancy because there is no known safe level of ethanol exposure during pregnancy [see Dosage and Administration 2.3 and Warnings and Precautions 5.2 ]. DataHuman DataBased on prospective reports to the APR of approximately 6100 live births following exposure to ritonavir-containing regimens (including over 2800 live births exposed in the first trimester and over 3200 live births exposed in the second and third trimesters), there was no difference in the rate of overall birth defects for ritonavir compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 2.3% (95% CI: 1.7%-2.9%) following first-trimester exposure to ritonavir-containing regimens and 2.9% (95% CI: 2.3%-3.5%) following second and third trimester exposure to ritonavir-containing regimens. While placental transfer of ritonavir and fetal ritonavir concentrations are generally low, detectable levels have been observed in cord blood samples and neonate hair. Animal DataRitonavir was administered orally to pregnant rats (at 0, 15, 35, and 75 mg/kg/day) and rabbits (at 0, 25, 50, and 110 mg/kg/day) during organogenesis (on gestation days through 17 and through 19, respectively). No evidence of teratogenicity due to ritonavir was observed in rats and rabbits at doses producing systemic exposures (AUC) equivalent to approximately 1/3 lower than human exposure at the recommended daily dose. Developmental toxicity observed in rats (early resorptions, decreased fetal body weight and ossification delays and developmental variations) occurred at maternally toxic dose, at an exposure equivalent to approximately 1/3 lower than human exposure at the recommended daily dose. slight increase in the incidence of cryptorchidism was also noted in rats (at maternally toxic dose) at an exposure approximately 1/5 lower than human exposure at the recommended daily dose. Developmental toxicity was observed in rabbits (resorptions, decreased litter size and decreased fetal weights) at maternally toxic doses approximately 1.8 times higher than the recommended daily dose, based on body surface area conversion factor. In pre-and postnatal development study in rats, ritonavir was administered at doses of 0, 15, 35, and 60 mg/kg/day from gestation day through postnatal day 20. At doses of 60 mg/kg/day, no developmental toxicity was noted with ritonavir dosage equivalent to 1/2 of the recommended daily dose, based on body surface area conversion factor.