HOW SUPPLIED SECTION.


16HOW SUPPLIED/STORAGE AND HANDLING. The blue, capsule-shaped, film-coated, tablets contain 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate (which is equivalent to 245 mg of tenofovir disoproxil), are debossed with GILEAD on one side and with 701 on the other side.They are supplied by State of Florida DOH Central Pharmacy as follows:NDCStrengthQuantity/FormColorSource Prod. Code53808-0805-1200 mg 300 mg30 Tablets in Blister PackBLUE61958-0701. Store at 25 (77 F), excursions permitted to 15-30 (59-86 F) (see USP Controlled Room Temperature).Keep container tightly closedDispense only in original containerDo not use if seal over bottle opening is broken or missing.. Keep container tightly closed. Dispense only in original container. Do not use if seal over bottle opening is broken or missing.

PEDIATRIC USE SECTION.


8.4Pediatric Use. Truvada is not recommended for patients less than 18 years of age because it is fixed-dose combination tablet containing component, VIREAD, for which safety and efficacy have not been established in this age group.

PHARMACOKINETICS SECTION.


12.3Pharmacokinetics.

PREGNULLNCY SECTION.


8.1Pregnancy.

RECENT MAJOR CHANGES SECTION.


Warnings and Precautions New Onset or Worsening Renal Impairment (5.3)11/2009.

SPL PATIENT PACKAGE INSERT SECTION.


FDA-Approved Patient LabelingTRUVADA(R) (tru-VAH-dah) tabletsGeneric name: emtricitabine and tenofovir disoproxil fumarate(em tri SIT uh bean and te NOE fo veer dye soe PROX il FYOU mar ate)Read the Patient Information that comes with TRUVADA before you start taking it and each time you get refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. You should stay under healthcare providers care when taking TRUVADA. Do not change or stop your medicine without first talking with your healthcare provider. Talk to your healthcare provider or pharmacist if you have any questions about TRUVADA.What is the most important information should know about TRUVADASome people who have taken medicine like TRUVADA (nucleoside analogs) have developed serious condition called lactic acidosis (build up of an acid in the blood). Lactic acidosis can be medical emergency and may need to be treated in the hospital. Call your healthcare provider right away if you get the following signs or symptoms of lactic acidosis. You feel very weak or tired.You have unusual (not normal) muscle pain.You have trouble breathing.You have stomach pain with nausea and vomiting.You feel cold, especially in your arms and legs.You feel dizzy or lightheaded.You have fast or irregular heartbeat. Some people who have taken medicines like TRUVADA have developed serious liver problems called hepatotoxicity, with liver enlargement (hepatomegaly) and fat in the liver (steatosis). Call your healthcare provider right away if you get the following signs or symptoms of liver problems.Your skin or the white part of your eyes turns yellow (jaundice).Your urine turns dark.Your bowel movements (stools) turn light in color.You dont feel like eating food for several days or longer.You feel sick to your stomach (nausea).You have lower stomach area (abdominal) pain.You may be more likely to get lactic acidosis or liver problems if you are female, very overweight (obese), or have been taking nucleoside analog medicines, like TRUVADA, for long time.If you are also infected with the hepatitis virus (HBV), you need close medical follow-up for several months after stopping treatment with TRUVADA. Follow-up includes medical exams and blood tests to check for HBV that could be getting worse. Patients with hepatitis virus infection, who take TRUVADA and then stop it, may get flare-ups of their hepatitis. flare-up is when the disease suddenly returns in worse way than before. What is TRUVADATRUVADA is type of medicine called an HIV-1 (human immunodeficiency virus) nucleoside analog reverse transcriptase inhibitor (NRTI). TRUVADA contains medicines, EMTRIVA(R) (emtricitabine) and VIREAD(R) (tenofovir disoproxil fumarate, or tenofovir DF) combined in one pill. TRUVADA is always used with other anti-HIV-1 medicines to treat people with HIV-1 infection. TRUVADA is for adults age 18 and older. TRUVADA has not been studied in children under age 18 or adults over age 65.HIV infection destroys CD4+ cells, which are important to the immune system. The immune system helps fight infection. After large number of cells are destroyed, acquired immune deficiency syndrome (AIDS) develops.TRUVADA helps block HIV-1 reverse transcriptase, chemical in your body (enzyme) that is needed for HIV-1 to multiply. TRUVADA lowers the amount of HIV-1 in the blood (viral load). TRUVADA may also help to increase the number of cells (CD4+ cells). Lowering the amount of HIV-1 in the blood lowers the chance of death or infections that happen when your immune system is weak (opportunistic infections).TRUVADA does not cure HIV-1 infection or AIDS. The long-term effects of TRUVADA are not known at this time. People taking TRUVADA may still get opportunistic infections or other conditions that happen with HIV-1 infection. Opportunistic infections are infections that develop because the immune system is weak. Some of these conditions are pneumonia, herpes virus infections, and Mycobacterium avium complex (MAC) infection. It is very important that you see your healthcare provider regularly while taking TRUVADA. TRUVADA does not lower your chance of passing HIV-1 to other people through sexual contact, sharing needles, or being exposed to your blood. For your health and the health of others, it is important to always practice safer sex by using latex or polyurethane condom or other barrier to lower the chance of sexual contact with semen, vaginal secretions, or blood. Never use or share dirty needles.Who should not take TRUVADADo not take TRUVADA if you are allergic to TRUVADA or any of its ingredients. The active ingredients of TRUVADA are emtricitabine and tenofovir DF. See the end of this leaflet for complete list of ingredients. Do not take TRUVADA if you are already taking ATRIPLA(R), Combivir (lamivudine/zidovudine), EMTRIVA, Epivir or Epivir-HBV (lamivudine), Epzicom (abacavir sulfate/lamivudine), Trizivir (abacavir sulfate/lamivudine/zidovudine), or VIREAD because these medicines contain the same or similar active ingredients.Do not take TRUVADA to treat your HIV infection if you are also taking HEPSERA(R) to treat your HBV infection.What should tell my healthcare provider before taking TRUVADATell your healthcare provider if you:are pregnant or planning to become pregnant. We do not know if TRUVADA can harm your unborn child. You and your healthcare provider will need to decide if TRUVADA is right for you. If you use TRUVADA while you are pregnant, talk to your healthcare provider about how you can be on the TRUVADA Antiviral Pregnancy Registry.are breast-feeding. You should not breast feed if you are HIV-positive because of the chance of passing the HIV virus to your baby. Also, it is not known if TRUVADA can pass into your breast milk and if it can harm your baby. If you are woman who has or will have baby, talk with your healthcare provider about the best way to feed your baby.have kidney problems or are undergoing kidney dialysis treatment.have bone problems.have liver problems including hepatitis virus infection.Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your healthcare provider if you take: Videx, Videx EC (didanosine). Tenofovir DF (a component of TRUVADA) may increase the amount of Videx in your blood. You may need to be followed more carefully if you are taking TRUVADA and Videx together. Also, the dose of didanosine may need to be reduced.Reyataz (atazanavir sulfate) or Kaletra (lopinavir/ritonavir). These medicines may increase the amount of tenofovir DF (a component of TRUVADA) in your blood, which could result in more side effects. You may need to be followed more carefully if you are taking TRUVADA and Reyataz or Kaletra together. TRUVADA may decrease the amount of Reyataz in your blood. If you are taking TRUVADA and Reyataz together, you should also be taking Norvir (ritonavir).Keep complete list of all the medicines that you take. Make new list when medicines are added or stopped. Give copies of this list to all of your healthcare providers and pharmacist every time you visit your healthcare provider or fill prescription.How should take TRUVADATake TRUVADA exactly as your healthcare provider prescribed it. Follow the directions from your healthcare provider, exactly as written on the label.The usual dose of TRUVADA is tablet once day. TRUVADA is always used with other anti-HIV-1 medicines. If you have kidney problems, you may need to take TRUVADA less often.TRUVADA may be taken with or without meal. Food does not affect how TRUVADA works. Take TRUVADA at the same time each day.If you forget to take TRUVADA, take it as soon as you remember that day. Do not take more than dose of TRUVADA in day. Do not take doses at the same time. Call your healthcare provider or pharmacist if you are not sure what to do. It is important that you do not miss any doses of TRUVADA or your anti-HIV-1 medicines. When your TRUVADA supply starts to run low, get more from your healthcare provider or pharmacy. This is very important because the amount of virus in your blood may increase if the medicine is stopped for even short time. The virus may develop resistance to TRUVADA and become harder to treat.Do not change your dose or stop taking TRUVADA without first talking with your healthcare provider. Stay under healthcare providers care when taking TRUVADA.If you take too much TRUVADA, call your local poison control center or emergency room right away.What should avoid while taking TRUVADADo not breast-feed. See What should tell my healthcare provider before taking TRUVADAAvoid doing things that can spread HIV infection since TRUVADA does not stop you from passing the HIV infection to others. Do not share needles or other injection equipment.Do not share personal texts that can have blood or body fluids on them, like toothbrushes or razor blades.Do not have any kind of sex without protection. Always practice safer sex by using latex or polyurethane condom or other barrier to reduce the chance of sexual contact with semen, vaginal secretions, or blood. ATRIPLA, Combivir (lamivudine/zidovudine), EMTRIVA, Epivir or Epivir-HBV (lamivudine), Epzicom (abacavir sulfate/lamivudine), Trizivir (abacavir sulfate/lamivudine/zidovudine), or VIREAD. TRUVADA should not be used with these medicines. TRUVADA should not be used with HEPSERA.What are the possible side effects of TRUVADATRUVADA may cause the following serious side effects (see What is the most important information should know about TRUVADA):Lactic acidosis (buildup of an acid in the blood). Lactic acidosis can be medical emergency and may need to be treated in the hospital. Call your doctor right away if you get signs of lactic acidosis. (See What is the most important information should know about TRUVADA)Serious liver problems (hepatotoxicity), with liver enlargement (hepatomegaly) and fat in the liver (steatosis). Call your healthcare provider right away if you get any signs of liver problems. (See What is the most important information should know about TRUVADA)Flare-ups of hepatitis virus infection, in which the disease suddenly returns in worse way than before, can occur if you stop taking TRUVADA. Your healthcare provider will monitor your condition for several months after stopping TRUVADA if you have both HIV-1 and HBV infection. TRUVADA is not approved for the treatment of hepatitis virus infection. If you have advanced liver disease and stop treatment with TRUVADA, the flare-up of hepatitis may cause your liver function to decline.Kidney problems. If you have had kidney problems in the past or take other medicines that can cause kidney problems, your healthcare provider should do regular blood tests to check your kidneys.Changes in bone mineral density (thinning bones). Laboratory tests show changes in the bones of patients treated with VIREAD, component of TRUVADA. Some HIV patients treated with VIREAD developed thinning of the bones (osteopenia) which could lead to fractures. If you have had bone problems in the past, your healthcare provider may need to do tests to check your bone mineral density or may prescribe medicines to help your bone mineral density. Additionally, bone pain and softening of the bone (which may contribute to fractures) may occur as consequence of kidney problems.Other side effects with TRUVADA when used with other anti-HIV-1 medicines include:Changes in body fat have been seen in some patients taking TRUVADA and other anti-HIV-1 medicines. These changes may include increased amount of fat in the upper back and neck (buffalo hump), breast, and around the main part of your body (trunk). Loss of fat from the legs, arms and face may also happen. The cause and long term health effect of these conditions are not known at this time.In some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the bodys immune response, enabling the body to fight infections that may have been present with no obvious symptoms. If you notice any symptoms of infection, please inform your doctor immediately.The most common side effects of EMTRIVA or VIREAD when used with other anti-HIV-1 medicines are: diarrhea, dizziness, nausea, headache, fatigue, abnormal dreams, sleeping problems, rash, depression, and vomiting. Additional side effects are lactic acidosis, kidney problems (including decline or failure of kidney function), inflammation of the pancreas, inflammation of the liver, allergic reaction (including swelling of the face, lips, tongue, or throat), shortness of breath, pain, fatty liver, stomach pain, weakness, indigestion, intestinal gas, and high volume of urine and thirst caused by kidney problems. Muscle pain and muscle weakness, bone pain, and softening of the bone (which may contribute to fractures) as consequence of kidney problems have been reported. Skin discoloration (small spots or freckles) may also happen with TRUVADA.These are not all the side effects of TRUVADA. If you have questions about side effects, ask your healthcare provider. Report any new or continuing symptoms to your healthcare provider right away. Your healthcare provider may be able to help you manage these side effects.How do store TRUVADAKeep TRUVADA and all other medicines out of reach of children.Store TRUVADA at room temperature 77 (25 C).Keep TRUVADA in its original container and keep the container tightly closed.Do not keep medicine that is out of date or that you no longer need. If you throw any medicines away make sure that children will not find them.General information about TRUVADA:Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use TRUVADA for condition for which it was not prescribed. Do not give TRUVADA to other people, even if they have the same symptoms you have. It may harm them.This leaflet summarizes the most important information about TRUVADA. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about TRUVADA that is written for health professionals. For more information, you may also call 1-800-GILEAD-5 or access the TRUVADA website at www.TRUVADA.com.Do not use TRUVADA if seal over bottle opening is broken or missing.What are the ingredients of TRUVADAActive Ingredients: emtricitabine and tenofovir disoproxil fumarate Inactive Ingredients: Croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch (gluten free). The tablets are coated with Opadry II Blue Y-30-10701 containing FD&C Blue aluminum lake, hydroxypropyl methylcellulose 2910, lactose monohydrate, titanium dioxide, and triacetin.Rx OnlyTRUVADA, EMTRIVA, HEPSERA and VIREAD are registered trademarks of Gilead Sciences, Inc. ATRIPLA is trademark of Bristol-Myers Squibb Gilead Sciences, LLC. All other trademarks referenced herein are the property of their respective owners.This Product was Repackaged By:State of Florida DOH Central Pharmacy104-2 Hamilton Park DriveTallahassee, FL 32304United States Some people who have taken medicine like TRUVADA (nucleoside analogs) have developed serious condition called lactic acidosis (build up of an acid in the blood). Lactic acidosis can be medical emergency and may need to be treated in the hospital. Call your healthcare provider right away if you get the following signs or symptoms of lactic acidosis. You feel very weak or tired.You have unusual (not normal) muscle pain.You have trouble breathing.You have stomach pain with nausea and vomiting.You feel cold, especially in your arms and legs.You feel dizzy or lightheaded.You have fast or irregular heartbeat. You feel very weak or tired.. You have unusual (not normal) muscle pain.. You have trouble breathing.. You have stomach pain with nausea and vomiting.. You feel cold, especially in your arms and legs.. You feel dizzy or lightheaded.. You have fast or irregular heartbeat.. Some people who have taken medicines like TRUVADA have developed serious liver problems called hepatotoxicity, with liver enlargement (hepatomegaly) and fat in the liver (steatosis). Call your healthcare provider right away if you get the following signs or symptoms of liver problems.Your skin or the white part of your eyes turns yellow (jaundice).Your urine turns dark.Your bowel movements (stools) turn light in color.You dont feel like eating food for several days or longer.You feel sick to your stomach (nausea).You have lower stomach area (abdominal) pain.. Your skin or the white part of your eyes turns yellow (jaundice).. Your urine turns dark.. Your bowel movements (stools) turn light in color.. You dont feel like eating food for several days or longer.. You feel sick to your stomach (nausea).. You have lower stomach area (abdominal) pain.. You may be more likely to get lactic acidosis or liver problems if you are female, very overweight (obese), or have been taking nucleoside analog medicines, like TRUVADA, for long time.. If you are also infected with the hepatitis virus (HBV), you need close medical follow-up for several months after stopping treatment with TRUVADA. Follow-up includes medical exams and blood tests to check for HBV that could be getting worse. Patients with hepatitis virus infection, who take TRUVADA and then stop it, may get flare-ups of their hepatitis. flare-up is when the disease suddenly returns in worse way than before. Do not take TRUVADA if you are allergic to TRUVADA or any of its ingredients. The active ingredients of TRUVADA are emtricitabine and tenofovir DF. See the end of this leaflet for complete list of ingredients. Do not take TRUVADA if you are already taking ATRIPLA(R), Combivir (lamivudine/zidovudine), EMTRIVA, Epivir or Epivir-HBV (lamivudine), Epzicom (abacavir sulfate/lamivudine), Trizivir (abacavir sulfate/lamivudine/zidovudine), or VIREAD because these medicines contain the same or similar active ingredients.. Do not take TRUVADA to treat your HIV infection if you are also taking HEPSERA(R) to treat your HBV infection.. are pregnant or planning to become pregnant. We do not know if TRUVADA can harm your unborn child. You and your healthcare provider will need to decide if TRUVADA is right for you. If you use TRUVADA while you are pregnant, talk to your healthcare provider about how you can be on the TRUVADA Antiviral Pregnancy Registry.. are breast-feeding. You should not breast feed if you are HIV-positive because of the chance of passing the HIV virus to your baby. Also, it is not known if TRUVADA can pass into your breast milk and if it can harm your baby. If you are woman who has or will have baby, talk with your healthcare provider about the best way to feed your baby.. have kidney problems or are undergoing kidney dialysis treatment.. have bone problems.. have liver problems including hepatitis virus infection.. Videx, Videx EC (didanosine). Tenofovir DF (a component of TRUVADA) may increase the amount of Videx in your blood. You may need to be followed more carefully if you are taking TRUVADA and Videx together. Also, the dose of didanosine may need to be reduced.. Reyataz (atazanavir sulfate) or Kaletra (lopinavir/ritonavir). These medicines may increase the amount of tenofovir DF (a component of TRUVADA) in your blood, which could result in more side effects. You may need to be followed more carefully if you are taking TRUVADA and Reyataz or Kaletra together. TRUVADA may decrease the amount of Reyataz in your blood. If you are taking TRUVADA and Reyataz together, you should also be taking Norvir (ritonavir).. Take TRUVADA exactly as your healthcare provider prescribed it. Follow the directions from your healthcare provider, exactly as written on the label.. The usual dose of TRUVADA is tablet once day. TRUVADA is always used with other anti-HIV-1 medicines. If you have kidney problems, you may need to take TRUVADA less often.. TRUVADA may be taken with or without meal. Food does not affect how TRUVADA works. Take TRUVADA at the same time each day.. If you forget to take TRUVADA, take it as soon as you remember that day. Do not take more than dose of TRUVADA in day. Do not take doses at the same time. Call your healthcare provider or pharmacist if you are not sure what to do. It is important that you do not miss any doses of TRUVADA or your anti-HIV-1 medicines. When your TRUVADA supply starts to run low, get more from your healthcare provider or pharmacy. This is very important because the amount of virus in your blood may increase if the medicine is stopped for even short time. The virus may develop resistance to TRUVADA and become harder to treat.. Do not change your dose or stop taking TRUVADA without first talking with your healthcare provider. Stay under healthcare providers care when taking TRUVADA.. If you take too much TRUVADA, call your local poison control center or emergency room right away.. Do not breast-feed. See What should tell my healthcare provider before taking TRUVADA. Avoid doing things that can spread HIV infection since TRUVADA does not stop you from passing the HIV infection to others. Do not share needles or other injection equipment.Do not share personal texts that can have blood or body fluids on them, like toothbrushes or razor blades.Do not have any kind of sex without protection. Always practice safer sex by using latex or polyurethane condom or other barrier to reduce the chance of sexual contact with semen, vaginal secretions, or blood. Do not share needles or other injection equipment.. Do not share personal texts that can have blood or body fluids on them, like toothbrushes or razor blades.. Do not have any kind of sex without protection. Always practice safer sex by using latex or polyurethane condom or other barrier to reduce the chance of sexual contact with semen, vaginal secretions, or blood.. ATRIPLA, Combivir (lamivudine/zidovudine), EMTRIVA, Epivir or Epivir-HBV (lamivudine), Epzicom (abacavir sulfate/lamivudine), Trizivir (abacavir sulfate/lamivudine/zidovudine), or VIREAD. TRUVADA should not be used with these medicines. TRUVADA should not be used with HEPSERA.. Lactic acidosis (buildup of an acid in the blood). Lactic acidosis can be medical emergency and may need to be treated in the hospital. Call your doctor right away if you get signs of lactic acidosis. (See What is the most important information should know about TRUVADA). Serious liver problems (hepatotoxicity), with liver enlargement (hepatomegaly) and fat in the liver (steatosis). Call your healthcare provider right away if you get any signs of liver problems. (See What is the most important information should know about TRUVADA). Flare-ups of hepatitis virus infection, in which the disease suddenly returns in worse way than before, can occur if you stop taking TRUVADA. Your healthcare provider will monitor your condition for several months after stopping TRUVADA if you have both HIV-1 and HBV infection. TRUVADA is not approved for the treatment of hepatitis virus infection. If you have advanced liver disease and stop treatment with TRUVADA, the flare-up of hepatitis may cause your liver function to decline.. Kidney problems. If you have had kidney problems in the past or take other medicines that can cause kidney problems, your healthcare provider should do regular blood tests to check your kidneys.. Changes in bone mineral density (thinning bones). Laboratory tests show changes in the bones of patients treated with VIREAD, component of TRUVADA. Some HIV patients treated with VIREAD developed thinning of the bones (osteopenia) which could lead to fractures. If you have had bone problems in the past, your healthcare provider may need to do tests to check your bone mineral density or may prescribe medicines to help your bone mineral density. Additionally, bone pain and softening of the bone (which may contribute to fractures) may occur as consequence of kidney problems.. Changes in body fat have been seen in some patients taking TRUVADA and other anti-HIV-1 medicines. These changes may include increased amount of fat in the upper back and neck (buffalo hump), breast, and around the main part of your body (trunk). Loss of fat from the legs, arms and face may also happen. The cause and long term health effect of these conditions are not known at this time.. In some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the bodys immune response, enabling the body to fight infections that may have been present with no obvious symptoms. If you notice any symptoms of infection, please inform your doctor immediately.. Keep TRUVADA and all other medicines out of reach of children.. Store TRUVADA at room temperature 77 (25 C).. Keep TRUVADA in its original container and keep the container tightly closed.. Do not keep medicine that is out of date or that you no longer need. If you throw any medicines away make sure that children will not find them.

SPL UNCLASSIFIED SECTION.


2.1Recommended Dose. The dose of TRUVADA is one tablet (containing 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate) once daily taken orally with or without food.

ADVERSE REACTIONS SECTION.


6ADVERSE REACTIONS. The following adverse reactions are discussed in other sections of the labeling:Lactic Acidosis/Severe Hepatomegaly with Steatosis [See Boxed Warning, Warnings and Precautions (5.1)].Severe Acute Exacerbations of hepatitis [See Boxed Warning, Warnings and Precautions (5.2)].New Onset or Worsening Renal Impairment [See Warnings and Precautions (5.3)].Decreases in Bone Mineral Density [See Warnings and Precautions (5.5)].Immune Reconstitution Syndrome [See Warnings and Precautions (5.7)].. Lactic Acidosis/Severe Hepatomegaly with Steatosis [See Boxed Warning, Warnings and Precautions (5.1)].. Severe Acute Exacerbations of hepatitis [See Boxed Warning, Warnings and Precautions (5.2)].. New Onset or Worsening Renal Impairment [See Warnings and Precautions (5.3)].. Decreases in Bone Mineral Density [See Warnings and Precautions (5.5)].. Immune Reconstitution Syndrome [See Warnings and Precautions (5.7)].. Most common adverse reactions (incidence >=10%) are diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. (6) To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1Adverse Reactions from Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The most common adverse reactions (incidence >=10%, any severity) occurring in Study 934, an active-controlled clinical study of efavirenz, emtricitabine, and tenofovir disoproxil fumarate, include diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. See also Table for the frequency of treatment-emergent adverse reactions (Grade 2-4) occurring in >=5% of subjects treated with efavirenz, emtricitabine, and tenofovir disoproxil fumarate in this study.Skin discoloration, manifested by hyperpigmentation on the palms and/or soles was generally mild and asymptomatic. The mechanism and clinical significance are unknown.. Study 934 Treatment Emergent Adverse Reactions: In Study 934, 511 antiretroviral-naive subjects received either VIREAD EMTRIVA administered in combination with efavirenz (N=257) or zidovudine/lamivudine administered in combination with efavirenz (N=254). Adverse reactions observed in this study were generally consistent with those seen in other studies in treatment-experienced or treatment-naive subjects receiving VIREAD and/or EMTRIVA (Table 2).Table Selected Treatment-Emergent Adverse ReactionsFrequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. (Grades 2-4) Reported in >=5% in Any Treatment Group in Study 934 (0-144 Weeks)FTC TDF EFVFrom Weeks 96 to 144 of the study, subjects received TRUVADA with efavirenz in place of VIREAD EMTRIVA with efavirenz. AZT/3TC EFVN=257N=254Gastrointestinal Disorder Diarrhea9%5% Nausea9%7% Vomiting2%5%General Disorders and Administration Site Condition Fatigue9%8%Infections and Infestations Sinusitis8%4% Upper respiratory tract infections8%5% Nasopharyngitis5%3%Nervous System Disorders Headache6%5% Dizziness8%7%Psychiatric Disorders Depression9%7% Insomnia5%7%Skin and Subcutaneous Tissue Disorders Rash eventRash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and rash vesicular. 7%9%. Laboratory Abnormalities: Laboratory abnormalities observed in this study were generally consistent with those seen in other studies of VIREAD and/or EMTRIVA (Table 3).Table Significant Laboratory Abnormalities Reported in >=1% of Subjects in Any Treatment Group in Study 934 (0-144 Weeks)FTC TDF EFVFrom Weeks 96 to 144 of the study, subjects received TRUVADA with efavirenz in place of VIREAD EMTRIVA with efavirenz. AZT/3TC EFVN=257N=254Any >= Grade Laboratory Abnormality30%26%Fasting Cholesterol (>240 mg/dL)22%24%Creatine Kinase (M: >990 U/L) (F: >845 U/L)9%7%Serum Amylase (>175 U/L)8%4%Alkaline Phosphatase (>550 U/L)1%0%AST (M: >180 U/L) (F: >170 U/L)3%3%ALT (M: >215 U/L) (F: >170 U/L)2%3%Hemoglobin (<8.0 mg/dL)0%4%Hyperglycemia (>250 mg/dL)2%1%Hematuria (>75 RBC/HPF)3%2%Glycosuria (>=3+)<1%1%Neutrophils (<750/mm3)3%5%Fasting Triglycerides (>750 mg/dL)4%2%In addition to the events described above for Study 934, other adverse reactions that occurred in at least 5% of subjects receiving EMTRIVA or VIREAD with other antiretroviral agents in clinical trials include anxiety, arthralgia, increased cough, dyspepsia, fever, myalgia, pain, abdominal pain, back pain, paresthesia, peripheral neuropathy (including peripheral neuritis and neuropathy), pneumonia, and rhinitis.In addition to the laboratory abnormalities described above for Study 934, Grade 3/4 elevations of bilirubin (>2.5 ULN), pancreatic amylase (>2.0 ULN), serum glucose (<40 or >250 mg/dL), and serum lipase (>2.0 ULN) occurred in up to 3% of subjects treated with EMTRIVA or VIREAD with other antiretroviral agents in clinical trials.. 6.2Postmarketing Experience. The following adverse reactions have been identified during postapproval use of VIREAD. No additional adverse reactions have been identified during postapproval use of EMTRIVA. Because postmarketing reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Immune System Disorders allergic reaction, including angioedemaMetabolism and Nutrition Disorders lactic acidosis, hypokalemia, hypophosphatemiaRespiratory, Thoracic, and Mediastinal Disorders dyspneaGastrointestinal Disorderspancreatitis, increased amylase, abdominal painHepatobiliary Disordershepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma GT)Skin and Subcutaneous Tissue Disorders rashMusculoskeletal and Connective Tissue Disordersrhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathyRenal and Urinary Disordersacute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuriaGeneral Disorders and Administration Site ConditionsastheniaThe following adverse reactions, listed under the body system headings above, may occur as consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.


13.2Animal Toxicology and/or Pharmacology. Tenofovir and tenofovir disoproxil fumarate administered in toxicology studies to rats, dogs and monkeys at exposures (based on AUCs) greater than or equal to 6-fold those observed in humans caused bone toxicity. In monkeys the bone toxicity was diagnosed as osteomalacia. Osteomalacia observed in monkeys appeared to be reversible upon dose reduction or discontinuation of tenofovir. In rats and dogs, the bone toxicity manifested as reduced bone mineral density. The mechanism(s) underlying bone toxicity is unknown.Evidence of renal toxicity was noted in animal species. Increases in serum creatinine, BUN, glycosuria, proteinuria, phosphaturia, and/or calciuria and decreases in serum phosphate were observed to varying degrees in these animals. These toxicities were noted at exposures (based on AUCs) 2-20 times higher than those observed in humans. The relationship of the renal abnormalities, particularly the phosphaturia, to the bone toxicity is not known.

BOXED WARNING SECTION.


WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including VIREAD, component of TRUVADA, in combination with other antiretrovirals [See Warnings and Precautions (5.1)].TRUVADA is not approved for the treatment of chronic hepatitis virus (HBV) infection and the safety and efficacy of TRUVADA have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued TRUVADA. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue TRUVADA. If appropriate, initiation of anti-hepatitis therapy may be warranted [See Warnings and Precautions (5.2)].. WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS BSee full prescribing information for complete boxed warning.Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including VIREAD, component of TRUVADA. (5.1)TRUVADA is not approved for the treatment of chronic hepatitis virus (HBV) infection. Severe acute exacerbations of hepatitis have been reported in patients coinfected with HIV-1 and HBV who have discontinued TRUVADA. Hepatic function should be monitored closely in these patients. If appropriate, initiation of anti-hepatitis therapy may be warranted. (5.2). Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including VIREAD, component of TRUVADA. (5.1). TRUVADA is not approved for the treatment of chronic hepatitis virus (HBV) infection. Severe acute exacerbations of hepatitis have been reported in patients coinfected with HIV-1 and HBV who have discontinued TRUVADA. Hepatic function should be monitored closely in these patients. If appropriate, initiation of anti-hepatitis therapy may be warranted. (5.2).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


13.1Carcinogenesis, Mutagenesis, Impairment of Fertility.

CLINICAL PHARMACOLOGY SECTION.


12CLINICAL PHARMACOLOGY. For additional information on Mechanism of Action, Antiviral Activity, Resistance and Cross Resistance, please consult the EMTRIVA and VIREAD prescribing information.. 12.1Mechanism of Action. TRUVADA is fixed-dose combination of antiviral drugs emtricitabine and tenofovir disoproxil fumarate. [See Clinical Pharmacology (12.4)]. 12.3Pharmacokinetics. TRUVADA: One TRUVADA tablet was bioequivalent to one EMTRIVA capsule (200 mg) plus one VIREAD tablet (300 mg) following single-dose administration to fasting healthy subjects (N=39). . Emtricitabine: The pharmacokinetic properties of emtricitabine are summarized in Table 4. Following oral administration of EMTRIVA, emtricitabine is rapidly absorbed with peak plasma concentrations occurring at 1-2 hours post-dose. In vitro binding of emtricitabine to human plasma proteins is <4% and is independent of concentration over the range of 0.02-200 ug/mL. Following administration of radiolabelled emtricitabine, approximately 86% is recovered in the urine and 13% is recovered as metabolites. The metabolites of emtricitabine include 3-sulfoxide diastereomers and their glucuronic acid conjugate. Emtricitabine is eliminated by combination of glomerular filtration and active tubular secretion. Following single oral dose of EMTRIVA, the plasma emtricitabine half-life is approximately 10 hours.. Tenofovir Disoproxil Fumarate: The pharmacokinetic properties of tenofovir disoproxil fumarate are summarized in Table 4. Following oral administration of VIREAD, maximum tenofovir serum concentrations are achieved in 1.0 +- 0.4 hour. In vitro binding of tenofovir to human plasma proteins is <0.7% and is independent of concentration over the range of 0.01-25 ug/mL. Approximately 70-80% of the intravenous dose of tenofovir is recovered as unchanged drug in the urine. Tenofovir is eliminated by combination of glomerular filtration and active tubular secretion. Following single oral dose of VIREAD, the terminal elimination half-life of tenofovir is approximately 17 hours.Table Single Dose Pharmacokinetic Parameters for Emtricitabine and Tenofovir in AdultsNC Not calculated EmtricitabineTenofovirFasted Oral BioavailabilityMedian (range) (%)92 (83.1-106.4)25 (NC-45.0)Plasma Terminal Elimination Half-Life (hr)10 (7.4-18.0)17 (12.0-25.7)Cmax Mean (+- SD) (ug/mL)1.8 +- 0.72Data presented as steady state values. 0.30 +- 0.09AUC (ughr/mL)10.0 +- 3.12 2.29 +- 0.69CL/F (mL/min)302 +- 941043 +- 115CLrenal (mL/min)213 +- 89243 +- 33. Effects of Food on Oral AbsorptionTRUVADA may be administered with or without food. Administration of TRUVADA following high fat meal (784 kcal; 49 grams of fat) or light meal (373 kcal; grams of fat) delayed the time of tenofovir Cmax by approximately 0.75 hour. The mean increases in tenofovir AUC and Cmax were approximately 35% and 15%, respectively, when administered with high fat or light meal, compared to administration in the fasted state. In previous safety and efficacy studies, VIREAD (tenofovir) was taken under fed conditions. Emtricitabine systemic exposures (AUC and Cmax) were unaffected when TRUVADA was administered with either high fat or light meal.. Special Populations. Race. Emtricitabine: No pharmacokinetic differences due to race have been identified following the administration of EMTRIVA.. Tenofovir Disoproxil Fumarate: There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations following the administration of VIREAD.. Gender. Emtricitabine and Tenofovir Disoproxil Fumarate: Emtricitabine and tenofovir pharmacokinetics are similar in male and female subjects.. Pediatric and Geriatric PatientsPharmacokinetic studies of tenofovir have not been performed in pediatric subjects (<18 years). Pharmacokinetics of emtricitabine and tenofovir have not been fully evaluated in the elderly (>65 years).. Patients with Impaired Renal FunctionThe pharmacokinetics of emtricitabine and tenofovir are altered in subjects with renal impairment [See Warnings and Precautions (5.3)]. In subjects with creatinine clearance <50 mL/min, Cmax, and AUC0- of emtricitabine and tenofovir were increased. It is recommended that the dosing interval for TRUVADA be modified in patients with creatinine clearance 30-49 mL/min. TRUVADA should not be used in patients with creatinine clearance <30 mL/min and in patients with end-stage renal disease requiring dialysis [See Dosage and Administration (2.2)].. Patients with Hepatic ImpairmentThe pharmacokinetics of tenofovir following 300 mg dose of VIREAD have been studied in non-HIV infected subjects with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in subjects with hepatic impairment compared with unimpaired subjects. The pharmacokinetics of TRUVADA or emtricitabine have not been studied in subjects with hepatic impairment; however, emtricitabine is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited.. Assessment of Drug InteractionsThe steady state pharmacokinetics of emtricitabine and tenofovir were unaffected when emtricitabine and tenofovir disoproxil fumarate were administered together versus each agent dosed alone.In vitro and clinical pharmacokinetic drug-drug interaction studies have shown that the potential for CYP mediated interactions involving emtricitabine and tenofovir with other medicinal products is low.No clinically significant drug interactions have been observed between emtricitabine and famciclovir, indinavir, stavudine, tenofovir disoproxil fumarate, and zidovudine (see Tables and 6). Similarly, no clinically significant drug interactions have been observed between tenofovir disoproxil fumarate and abacavir, efavirenz, emtricitabine, entecavir, indinavir, lamivudine, lopinavir/ritonavir, methadone, nelfinavir, oral contraceptives, ribavirin, saquinavir/ritonavir, and tacrolimus in studies conducted in healthy volunteers (see Tables and 8). Table Drug Interactions: Changes in Pharmacokinetic Parameters for Emtricitabine in the Presence of the Coadministered DrugAll interaction studies conducted in healthy volunteers. Coadministered DrugDose of Coadministered Drug (mg)Emtricitabine Dose (mg)N% Change of Emtricitabine Pharmacokinetic Parameters Increase; Decrease; No Effect; NULL Not Applicable (90% CI)Cmax AUCCmin Tenofovir DF300 once daily 7 days200 once daily 7 days17 20 12 to 29)Zidovudine300 twice daily 7 days200 once daily 7 days27Indinavir800 1200 112NULLFamciclovir500 1200 112NULLStavudine40 1200 16NULLTable Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of EmtricitabineAll interaction studies conducted in healthy volunteers. Coadministered DrugDose of Coadministered Drug (mg)Emtricitabine Dose (mg)N% Change of Coadministered Drug Pharmacokinetic Parameters Increase; Decrease; No Effect; NULL Not Applicable (90% CI)Cmax AUCCmin Tenofovir DF300 once daily 7 days200 once daily 7 days17Zidovudine300 twice daily 7 days200 once daily 7 days27 17 0 to 38) 13 5 to 20)Indinavir800 1200 112NULLFamciclovir500 1200 112NULLStavudine40 1200 16NULLTable Drug Interactions: Changes in Pharmacokinetic Parameters for TenofovirPatients received VIREAD 300 mg once daily. in the Presence of the Coadministered DrugCoadministered DrugDose of Coadministered Drug (mg)N% Change of Tenofovir Pharmacokinetic ParametersIncrease ; Decrease ; No Effect ; NC Not Calculated (90% CI)Cmax AUCCmin Abacavir300 once8NCAtazanavirReyataz Prescribing Information 400 once daily 14 days33 14 8 to 20) 24 21 to 28) 22 15 to 30)Didanosine (enteric-coated)400 once25Didanosine (buffered)250 or 400 once daily 7 days14Efavirenz 600 once daily 14 days29Emtricitabine200 once daily 7 days17Entecavir1 mg once daily 10 days28Indinavir800 three times daily 7 days13 14 3 to 33)Lamivudine150 twice daily 7 days15Lopinavir/Ritonavir 400/100 twice daily 14 days24 32 25 to 38) 51 37 to 66)Nelfinavir1250 twice daily 14 days29Saquinavir/Ritonavir1000/100 twice daily 14 days35 23 16 to 30)Tacrolimus0.05 mg/kg twice daily 7 days21 13( to 27)Table Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of TenofovirCoadministered DrugDose of Coadministered Drug (mg)N% Change of Coadministered Drug Pharmacokinetic ParametersIncrease ; Decrease ; No Effect ; NULL Not Applicable (90% CI)Cmax AUCCmin Abacavir300 once8 12 1 to 26)NULLAtazanavirReyataz Prescribing Information 400 once daily 14 days34 21 27 to 14) 25 30 to 19) 40 48 to 32)Atazanavir Atazanavir/Ritonavir 300/100 once daily 42 days10 28 50 to 5) 25In HIV-infected subjects, addition of tenofovir DF to atazanavir 300 mg plus ritonavir 100 mg, resulted in AUC and Cmin values of atazanavir that were 2.3 and 4-fold higher than the respective values observed for atazanavir 400 mg when given alone. 42 to 3) 23 46 to 10)Efavirenz 600 once daily 14 days30Emtricitabine200 once daily 7 days17 20 12 to 29)Indinavir800 three times daily 7 days12 11 30 to 12)Entecavir1 mg once daily 10 days28 13( 11 to 15)Lamivudine150 twice daily 7 days15 24 34 to 12)LopinavirLopinavir/Ritonavir 400/100 twice daily 14 days24RitonavirMethadoneR-(active), S- and total methadone exposures were equivalent when dosed alone or with VIREAD. 40-110 once daily 14 daysIndividual subjects were maintained on their stable methadone dose. No pharmacodynamic alterations (opiate toxicity or withdrawal signs or symptoms) were reported. 13Nelfinavir1250 twice daily 14 days29M8 metaboliteOral ContraceptivesEthinyl estradiol and 17-deacetyl norgestimate (pharmacologically active metabolite) exposures were equivalent when dosed alone or with VIREAD. Ethinyl Estradiol/ Norgestimate (Ortho-Tricyclen) Once daily 7 days20Ribavirin600 once22NULLSaquinavirSaquinavir/Ritonavir 1000/100 twice daily 14 days32 22 6 to 41) 29Increases in AUC and Cmin are not expected to be clinically relevant; hence no dose adjustments are required when tenofovir DF and ritonavir-boosted saquinavir are coadministered. 12 to 48) 47 23 to 76)Ritonavir 23 3 to 46)Tacrolimus0.05 mg/kg twice daily 7 days21Following multiple dosing to HIV-negative subjects receiving either chronic methadone maintenance therapy or oral contraceptives, or single doses of ribavirin, steady state tenofovir pharmacokinetics were similar to those observed in previous studies, indicating lack of clinically significant drug interactions between these agents and VIREAD.Coadministration of tenofovir disoproxil fumarate with didanosine results in changes in the pharmacokinetics of didanosine that may be of clinical significance. Table summarizes the effects of tenofovir disoproxil fumarate on the pharmacokinetics of didanosine. Concomitant dosing of tenofovir disoproxil fumarate with didanosine buffered tablets or enteric-coated capsules significantly increases the Cmax and AUC of didanosine. When didanosine 250 mg enteric-coated capsules were administered with tenofovir disoproxil fumarate, systemic exposures of didanosine were similar to those seen with the 400 mg enteric-coated capsules alone under fasted conditions. The mechanism of this interaction is unknown. See Drug Interactions (7.1) regarding use of didanosine with VIREAD.Table Drug Interactions: Pharmacokinetic Parameters for Didanosine in the Presence of VIREADDidanosineAdministration with food was with light meal (~373 kcal, 20% fat). Dose (mg)/Method of Administration VIREAD Method of Administration N% Difference (90% CI) vs. Didanosine 400 mg Alone, FastedIncrease ; Decrease ; No Effect Cmax AUCBuffered tablets400 once dailyIncludes subjects weighing <60 kg receiving ddI 250 mg. 7 daysFasted hour after didanosine14 28 11 to 48) 44 31 to 59)Enteric coated capsules400 once, fastedWith food, hours after didanosine26 48 25 to 76) 48 31 to 67)400 once, with foodSimultaneously with didanosine26 64 41 to 89) 60 44 to 79)250 once, fastedWith food, hours after didanosine28 10 22 to 3)250 once, fastedSimultaneously with didanosine28 14 (0 to 31)250 once, with foodSimultaneously with didanosine28 29 39 to 18) 11 23 to 2). 12.4Microbiology. Mechanism of Action. Emtricitabine: Emtricitabine, synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5-triphosphate. Emtricitabine 5-triphosphate inhibits the activity of the HIV-1 reverse transcriptase (RT) by competing with the natural substrate deoxycytidine 5-triphosphate and by being incorporated into nascent viral DNULL which results in chain termination. Emtricitabine 5-triphosphate is weak inhibitor of mammalian DNULL polymerase , and mitochondrial DNULL polymerase .. Tenofovir Disoproxil Fumarate: Tenofovir disoproxil fumarate is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir disoproxil fumarate requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 RT by competing with the natural substrate deoxyadenosine 5-triphosphate and, after incorporation into DNULL, by DNULL chain termination. Tenofovir diphosphate is weak inhibitor of mammalian DNULL polymerases , and mitochondrial DNULL polymerase .. Antiviral Activity. Emtricitabine and Tenofovir Disoproxil Fumarate: In combination studies evaluating the cell culture antiviral activity of emtricitabine and tenofovir together, synergistic antiviral effects were observed.. Emtricitabine: The antiviral activity of emtricitabine against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, the MAGI-CCR5 cell line, and peripheral blood mononuclear cells. The 50% effective concentration (EC50) values for emtricitabine were in the range of 0.0013-0.64 uM (0.0003-0.158 ug/mL). In drug combination studies of emtricitabine with nucleoside reverse transcriptase inhibitors (abacavir, lamivudine, stavudine, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, nelfinavir, ritonavir, saquinavir), additive to synergistic effects were observed. Emtricitabine displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and (EC50 values ranged from 0.007-0.075 uM) and showed strain specific activity against HIV-2 (EC50 values ranged from 0.007-1.5 uM).. Tenofovir Disoproxil Fumarate: The antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The EC50 values for tenofovir were in the range of 0.04-8.5 uM. In drug combination studies of tenofovir with nucleoside reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir), additive to synergistic effects were observed. Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and (EC50 values ranged from 0.5-2.2 uM) and showed strain specific activity against HIV-2 (EC50 values ranged from 1.6 uM to 5.5 uM).. Resistance. Emtricitabine and Tenofovir Disoproxil Fumarate: HIV-1 isolates with reduced susceptibility to the combination of emtricitabine and tenofovir have been selected in cell culture. Genotypic analysis of these isolates identified the M184V/I and/or K65R amino acid substitutions in the viral RT.In clinical study of treatment-naive subjects [Study 934, see Clinical Studies (14.1)], resistance analysis was performed on HIV-1 isolates from all confirmed virologic failure subjects with >400 copies/mL of HIV-1 RNULL at Week 144 or early discontinuation. Development of efavirenz resistance-associated substitutions occurred most frequently and was similar between the treatment arms. The M184V amino acid substitution, associated with resistance to EMTRIVA and lamivudine, was observed in 2/19 analyzed subjects isolates in the EMTRIVA VIREAD group and in 10/29 analyzed subjects isolates in the zidovudine/lamivudine group. Through 144 weeks of Study 934, no subjects have developed detectable K65R substitution in their HIV-1 as analyzed through standard genotypic analysis.. Emtricitabine: Emtricitabine-resistant isolates of HIV-1 have been selected in cell culture and in vivo. Genotypic analysis of these isolates showed that the reduced susceptibility to emtricitabine was associated with substitution in the HIV-1 RT gene at codon 184 which resulted in an amino acid substitution of methionine by valine or isoleucine (M184V/I).. Tenofovir Disoproxil Fumarate: HIV-1 isolates with reduced susceptibility to tenofovir have been selected in cell culture. These viruses expressed K65R substitution in RT and showed 2-4 fold reduction in susceptibility to tenofovir.In treatment-naive subjects, isolates from 8/47 (17%) analyzed subjects developed the K65R substitution in the VIREAD arm through 144 weeks; occurred in the first 48 weeks of treatment and at Week 96. In treatment-experienced subjects, 14/304 (5%) isolates from subjects failing VIREAD through Week 96 showed >1.4 fold (median 2.7) reduced susceptibility to tenofovir. Genotypic analysis of the resistant isolates showed substitution in the HIV-1 RT gene resulting in the K65R amino acid substitution.. Cross Resistance. Emtricitabine and Tenofovir Disoproxil Fumarate: Cross-resistance among certain nucleoside reverse transcriptase inhibitors (NRTIs) has been recognized. The M184V/I and/or K65R substitutions selected in cell culture by the combination of emtricitabine and tenofovir are also observed in some HIV-1 isolates from subjects failing treatment with tenofovir in combination with either lamivudine or emtricitabine, and either abacavir or didanosine. Therefore, cross-resistance among these drugs may occur in patients whose virus harbors either or both of these amino acid substitutions.. Emtricitabine: Emtricitabine-resistant isolates (M184V/I) were cross-resistant to lamivudine and zalcitabine but retained susceptibility in cell culture to didanosine, stavudine, tenofovir, zidovudine, and NNRTIs (delavirdine, efavirenz, and nevirapine). HIV-1 isolates containing the K65R substitution, selected in vivo by abacavir, didanosine, tenofovir, and zalcitabine, demonstrated reduced susceptibility to inhibition by emtricitabine. Viruses harboring substitutions conferring reduced susceptibility to stavudine and zidovudine (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E), or didanosine (L74V) remained sensitive to emtricitabine. HIV-1 containing the K103N substitution associated with resistance to NNRTIs was susceptible to emtricitabine.. Tenofovir Disoproxil Fumarate: HIV-1 isolates from patients (N=20) whose HIV-1 expressed mean of zidovudine-associated RT amino acid substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N) showed 3.1-fold decrease in the susceptibility to tenofovir. Subjects whose virus expressed an L74V substitution without zidovudine resistance associated substitutions (N=8) had reduced response to VIREAD. Limited data are available for patients whose virus expressed Y115F substitution (N=3), Q151M substitution (N=2), or T69 insertion (N=4), all of whom had reduced response.

STORAGE AND HANDLING SECTION.


Store at 25 (77 F), excursions permitted to 15-30 (59-86 F) (see USP Controlled Room Temperature).Keep container tightly closedDispense only in original containerDo not use if seal over bottle opening is broken or missing.. Keep container tightly closed. Dispense only in original container. Do not use if seal over bottle opening is broken or missing.

CLINICAL STUDIES SECTION.


14CLINICAL STUDIES. Clinical Study 934 supports the use of TRUVADA tablets for the treatment of HIV-1 infection. Additional data in support of the use of TRUVADA are derived from Study 903, in which lamivudine and tenofovir disoproxil fumarate (tenofovir DF) were used in combination in treatment-naive adults, and clinical Study 303 in which emtricitabine and lamivudine demonstrated comparable efficacy, safety and resistance patterns as part of multidrug regimens. For additional information about these studies, please consult the prescribing information for tenofovir DF and emtricitabine.. 14.1Study 934. Data through 144 weeks are reported for Study 934, randomized, open-label, active-controlled multicenter study comparing emtricitabine tenofovir DF administered in combination with efavirenz versus zidovudine/lamivudine fixed-dose combination administered in combination with efavirenz in 511 antiretroviral-naive subjects. From Weeks 96 to 144 of the study, subjects received TRUVADA with efavirenz in place of emtricitabine tenofovir DF with efavirenz. Subjects had mean age of 38 years (range 18-80), 86% were male, 59% were Caucasian and 23% were Black. The mean baseline CD4+ cell count was 245 cells/mm3 (range 2-1191) and median baseline plasma HIV-1 RNULL was 5.01 log10 copies/mL (range 3.56-6.54). Subjects were stratified by baseline CD4+ cell count (< or >=200 cells/mm3); 41% had CD4+ cell counts <200 cells/mm3 and 51% of subjects had baseline viral loads >100,000 copies/mL. Treatment outcomes through 48 and 144 weeks for those subjects who did not have efavirenz resistance at baseline are presented in Table 10.Table 10 Outcomes of Randomized Treatment at Week 48 and 144 (Study 934)OutcomesAt Week 48At Week 144FTC TDF+ EFV(N=244)AZT/3TC EFV (N=243)FTC TDF EFV (N=227)Subjects who were responders at Week 48 or Week 96 (HIV-1 RNULL <400 copies/mL) but did not consent to continue study after Week 48 or Week 96 were excluded from analysis. AZT/3TC EFV (N=229) ResponderSubjects achieved and maintained confirmed HIV-1 RNULL <400 copies/mL through Weeks 48 and 144. 84%73%71%58%Virologic failureIncludes confirmed viral rebound and failure to achieve confirmed <400 copies/mL through Weeks 48 and 144. 2%4%3%6% Rebound1%3%2%5% Never suppressed0%0%0%0% Change in antiretroviral regimen1%1%1%1%Death<1%1%1%1%Discontinued due to adverse event4%9%5%12%Discontinued for other reasonsIncludes lost to follow-up, subject withdrawal, noncompliance, protocol violation and other reasons. 10%14%20%22%Through Week 48, 84% and 73% of subjects in the emtricitabine tenofovir DF group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNULL <400 copies/mL (71% and 58% through Week 144). The difference in the proportion of subjects who achieved and maintained HIV-1 RNULL <400 copies/mL through 48 weeks largely results from the higher number of discontinuations due to adverse events and other reasons in the zidovudine/lamivudine group in this open-label study. In addition, 80% and 70% of subjects in the emtricitabine tenofovir DF group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNULL <50 copies/mL through Week 48 (64% and 56% through Week 144). The mean increase from baseline in CD4+ cell count was 190 cells/mm3 in the emtricitabine tenofovir DF group and 158 cells/mm3 in the zidovudine/lamivudine group at Week 48 (312 and 271 cells/mm3 at Week 144).Through 48 weeks, subjects in the emtricitabine tenofovir DF group and subjects in the zidovudine/lamivudine group experienced new CDC Class event (10 and subjects through 144 weeks).

CONTRAINDICATIONS SECTION.


4CONTRAINDICATIONS. None.. None. (4).

DESCRIPTION SECTION.


11DESCRIPTION. TRUVADA tablets are fixed dose combination tablets containing emtricitabine and tenofovir disoproxil fumarate. EMTRIVA is the brand name for emtricitabine, synthetic nucleoside analog of cytidine. Tenofovir disoproxil fumarate (tenofovir DF) is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5-monophosphate. Both emtricitabine and tenofovir exhibit inhibitory activity against HIV-1 reverse transcriptase.. Emtricitabine: The chemical name of emtricitabine is 5-fluoro-1-(2R,5S)-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. Emtricitabine is the (-) enantiomer of thio analog of cytidine, which differs from other cytidine analogs in that it has fluorine in the 5-position.It has molecular formula of C8H10FN3O3S and molecular weight of 247.24. It has the following structural formula:Emtricitabine is white to off-white crystalline powder with solubility of approximately 112 mg/mL in water at 25 C. The partition coefficient (log p) for emtricitabine is -0.43 and the pKa is 2.65.. Tenofovir Disoproxil Fumarate: Tenofovir disoproxil fumarate is fumaric acid salt of the bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. The chemical name of tenofovir disoproxil fumarate is 9-[(R)-2 [[bis[[(isopropoxycarbonyl)oxy]- methoxy]phosphinyl]methoxy]propyl]adenine fumarate (1:1). It has molecular formula of C19H30N5O10P C4H4O4 and molecular weight of 635.52. It has the following structural formula:Tenofovir disoproxil fumarate is white to off-white crystalline powder with solubility of 13.4 mg/mL in water at 25 C. The partition coefficient (log p) for tenofovir disoproxil is 1.25 and the pKa is 3.75. All dosages are expressed in terms of tenofovir disoproxil fumarate except where otherwise noted.. TRUVADA tablets are for oral administration. Each film-coated tablet contains 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate, (which is equivalent to 245 mg of tenofovir disoproxil), as active ingredients. The tablets also include the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch (gluten free). The tablets are coated with Opadry II Blue Y-30-10701, which contains FD&C Blue aluminum lake, hydroxypropyl methylcellulose 2910, lactose monohydrate, titanium dioxide, and triacetin.. Chemical Structure. Chemical Structure. Symbol.

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION. Recommended dose: One tablet (containing 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate) once daily taken orally with or without food. (2.1)Dose recommended in renal impairment: Creatinine clearance 30-49 mL/min: tablet every 48 hours. (2.2) CrCl <30 mL/min or hemodialysis: Do not use TRUVADA. (2.2). Recommended dose: One tablet (containing 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate) once daily taken orally with or without food. (2.1). Dose recommended in renal impairment: Creatinine clearance 30-49 mL/min: tablet every 48 hours. (2.2) CrCl <30 mL/min or hemodialysis: Do not use TRUVADA. (2.2). 2.1Recommended Dose. The dose of TRUVADA is one tablet (containing 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate) once daily taken orally with or without food.. 2.2Dose Adjustment for Renal Impairment. Significantly increased drug exposures occurred when EMTRIVA or VIREAD were administered to subjects with moderate to severe renal impairment [see EMTRIVA or VIREAD Package Insert]. Therefore, the dosing interval of TRUVADA should be adjusted in patients with baseline creatinine clearance 30-49 mL/min using the recommendations in Table 1. These dosing interval recommendations are based on modeling of single-dose pharmacokinetic data in non-HIV infected subjects. The safety and effectiveness of these dosing interval adjustment recommendations have not been clinically evaluated in patients with moderate renal impairment, therefore clinical response to treatment and renal function should be closely monitored in these patients [See Warnings and Precautions (5.3)].No dose adjustment is necessary for patients with mild renal impairment (creatinine clearance 50-80 mL/min). Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients with mild renal impairment [See Warnings and Precautions (5.3)].Table Dosage Adjustment for Patients with Altered Creatinine ClearanceCreatinine Clearance (mL/min)Calculated using ideal (lean) body weight >=5030-49<30 (Including Patients Requiring Hemodialysis)Recommended Dosing IntervalEvery 24 hoursEvery 48 hoursTRUVADA should not be administered.

DOSAGE FORMS & STRENGTHS SECTION.


3DOSAGE FORMS AND STRENGTHS. TRUVADA is available as tablets. Each tablet contains 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate (which is equivalent to 245 mg of tenofovir disoproxil). The tablets are blue, capsule-shaped, film-coated, debossed with GILEAD on one side and with 701 on the other side.. Tablets: 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate. (3).

DRUG INTERACTIONS SECTION.


7DRUG INTERACTIONS. No drug interaction studies have been conducted using TRUVADA tablets. Drug interaction studies have been conducted with emtricitabine and tenofovir disoproxil fumarate, the components of TRUVADA. This section describes clinically relevant drug interactions observed with emtricitabine and tenofovir disoproxil fumarate [See Clinical Pharmacology (12.3)].. Didanosine: Tenofovir disoproxil fumarate increases didanosine concentrations. Use with caution and monitor for evidence of didanosine toxicity (e.g., pancreatitis, neuropathy) when coadministered. Consider dose reductions or discontinuations of didanosine if warranted. (7.1)Atazanavir: Coadministration decreases atazanavir concentrations and increases tenofovir concentrations. Use atazanavir with TRUVADA only with ritonavir; monitor for evidence of tenofovir toxicity. (7.2)Lopinavir/ritonavir: Coadministration increases tenofovir concentrations. Monitor for evidence of tenofovir toxicity. (7.2). Didanosine: Tenofovir disoproxil fumarate increases didanosine concentrations. Use with caution and monitor for evidence of didanosine toxicity (e.g., pancreatitis, neuropathy) when coadministered. Consider dose reductions or discontinuations of didanosine if warranted. (7.1). Atazanavir: Coadministration decreases atazanavir concentrations and increases tenofovir concentrations. Use atazanavir with TRUVADA only with ritonavir; monitor for evidence of tenofovir toxicity. (7.2). Lopinavir/ritonavir: Coadministration increases tenofovir concentrations. Monitor for evidence of tenofovir toxicity. (7.2). 7.1Didanosine. Coadministration of TRUVADA and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions. Didanosine should be discontinued in patients who develop didanosine-associated adverse reactions.When tenofovir disoproxil fumarate was administered with didanosine the Cmax and AUC of didanosine administered as either the buffered or enteric-coated formulation increased significantly [See Clinical Pharmacology (12.3)]. The mechanism of this interaction is unknown. Higher didanosine concentrations could potentiate didanosine-associated adverse reactions, including pancreatitis, and neuropathy. Suppression of CD4+ cell counts has been observed in patients receiving tenofovir DF with didanosine 400 mg daily.In adults weighing >60 kg, the didanosine dose should be reduced to 250 mg when it is coadministered with TRUVADA. Data are not available to recommend dose adjustment of didanosine for patients weighing <60 kg. When coadministered, TRUVADA and Videx EC may be taken under fasted conditions or with light meal (<400 kcal, 20% fat). Coadministration of didanosine buffered tablet formulation with TRUVADA should be under fasted conditions.. 7.2Atazanavir. Atazanavir has been shown to increase tenofovir concentrations [See Clinical Pharmacology (12.3)]. The mechanism of this interaction is unknown. Patients receiving atazanavir and TRUVADA should be monitored for TRUVADA-associated adverse reactions. TRUVADA should be discontinued in patients who develop TRUVADA-associated adverse reactions. Tenofovir decreases the AUC and Cmin of atazanavir [See Clinical Pharmacology (12.3)]. When coadministered with TRUVADA, it is recommended that atazanavir 300 mg is given with ritonavir 100 mg. Atazanavir without ritonavir should not be coadministered with TRUVADA. 7.3Lopinavir/Ritonavir. Lopinavir/ritonavir has been shown to increase tenofovir concentrations [See Clinical Pharmacology (12.3)]. The mechanism of this interaction is unknown. Patients receiving lopinavir/ritonavir and TRUVADA should be monitored for TRUVADA-associated adverse reactions. TRUVADA should be discontinued in patients who develop TRUVADA-associated adverse reactions.. 7.4Drugs Affecting Renal Function. Emtricitabine and tenofovir are primarily excreted by the kidneys by combination of glomerular filtration and active tubular secretion [See Clinical Pharmacology (12.3)]. No drug-drug interactions due to competition for renal excretion have been observed; however, coadministration of TRUVADA with drugs that are eliminated by active tubular secretion may increase concentrations of emtricitabine, tenofovir, and/or the coadministered drug. Some examples include, but are not limited to acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir, and valganciclovir. Drugs that decrease renal function may increase concentrations of emtricitabine and/or tenofovir.

GERIATRIC USE SECTION.


8.5Geriatric Use. Clinical studies of EMTRIVA or VIREAD 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 the elderly patients should be cautious, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

TERATOGENIC EFFECTS SECTION.


Pregnancy Category B.

INDICATIONS & USAGE SECTION.


1INDICATIONS AND USAGE. TRUVADA(R), combination of EMTRIVA(R) and VIREAD(R), is indicated in combination with other antiretroviral agents (such as non-nucleoside reverse transcriptase inhibitors or protease inhibitors) for the treatment of HIV-1 infection in adults.The following points should be considered when initiating therapy with TRUVADA for the treatment of HIV-1 infection:It is not recommended that TRUVADA be used as component of triple nucleoside regimen.TRUVADA should not be coadministered with ATRIPLA(R), EMTRIVA, VIREAD or lamivudine-containing products [See Warnings and Precautions (5.4)].In treatment experienced patients, the use of TRUVADA should be guided by laboratory testing and treatment history [See Clinical Pharmacology (12.4)].. It is not recommended that TRUVADA be used as component of triple nucleoside regimen.. TRUVADA should not be coadministered with ATRIPLA(R), EMTRIVA, VIREAD or lamivudine-containing products [See Warnings and Precautions (5.4)].. In treatment experienced patients, the use of TRUVADA should be guided by laboratory testing and treatment history [See Clinical Pharmacology (12.4)].. TRUVADA, combination of EMTRIVA and VIREAD, both nucleoside analog HIV-1 reverse transcriptase inhibitors, is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults. (1).

INFORMATION FOR PATIENTS SECTION.


17PATIENT COUNSELING INFORMATION and FDA-APPROVED PATIENT LABELING. Information for PatientsPatients should be advised that:TRUVADA 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 TRUVADA.The use of TRUVADA has not been shown to reduce the risk of transmission of HIV-1 to others through sexual contact or blood contamination. Patients should be advised to continue to practice safer sex and to use latex or polyurethane condoms to lower the chance of sexual contact with any body fluids such as semen, vaginal secretions or blood. Patients should be advised never to re-use or share needles.The long term effects of TRUVADA are unknown.TRUVADA tablets are for oral ingestion only.It is important to take TRUVADA with combination therapy on regular dosing schedule to avoid missing doses.Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported. Treatment with TRUVADA should be suspended in any patients who develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity (including nausea, vomiting, unusual or unexpected stomach discomfort, and weakness) [See Warnings and Precautions (5.1)].All patients with HIV-1 should be tested for hepatitis virus (HBV) before initiating antiretroviral therapy.Severe acute exacerbations of hepatitis have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued TRUVADA.Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported in association with the use of VIREAD. TRUVADA should be avoided with concurrent or recent use of nephrotoxic agent [See Warnings and Precautions (5.3)]. Dosing interval of TRUVADA may need adjustment in patients with renal impairment [See Dosage and Administration (2.1)].TRUVADA should not be coadministered with ATRIPLA, EMTRIVA, or VIREAD; or with drugs containing lamivudine, including Combivir (lamivudine/zidovudine), Epivir or Epivir-HBV (lamivudine), Epzicom (abacavir sulfate/lamivudine), or Trizivir (abacavir sulfate/lamivudine/zidovudine) [See Warnings and Precautions (5.4)].TRUVADA should not be administered with HEPSERA [See Warnings and Precautions (5.4)].Decreases in bone mineral density have been observed with the use of VIREAD. Bone monitoring should be considered in patients who have history of pathologic bone fracture or at risk for osteopenia [See Warnings and Precautions (5.5)]. TRUVADA 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 TRUVADA.. The use of TRUVADA has not been shown to reduce the risk of transmission of HIV-1 to others through sexual contact or blood contamination. Patients should be advised to continue to practice safer sex and to use latex or polyurethane condoms to lower the chance of sexual contact with any body fluids such as semen, vaginal secretions or blood. Patients should be advised never to re-use or share needles.. The long term effects of TRUVADA are unknown.. TRUVADA tablets are for oral ingestion only.. It is important to take TRUVADA with combination therapy on regular dosing schedule to avoid missing doses.. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported. Treatment with TRUVADA should be suspended in any patients who develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity (including nausea, vomiting, unusual or unexpected stomach discomfort, and weakness) [See Warnings and Precautions (5.1)].. All patients with HIV-1 should be tested for hepatitis virus (HBV) before initiating antiretroviral therapy.. Severe acute exacerbations of hepatitis have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued TRUVADA.. Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported in association with the use of VIREAD. TRUVADA should be avoided with concurrent or recent use of nephrotoxic agent [See Warnings and Precautions (5.3)]. Dosing interval of TRUVADA may need adjustment in patients with renal impairment [See Dosage and Administration (2.1)].. TRUVADA should not be coadministered with ATRIPLA, EMTRIVA, or VIREAD; or with drugs containing lamivudine, including Combivir (lamivudine/zidovudine), Epivir or Epivir-HBV (lamivudine), Epzicom (abacavir sulfate/lamivudine), or Trizivir (abacavir sulfate/lamivudine/zidovudine) [See Warnings and Precautions (5.4)].. TRUVADA should not be administered with HEPSERA [See Warnings and Precautions (5.4)].. Decreases in bone mineral density have been observed with the use of VIREAD. Bone monitoring should be considered in patients who have history of pathologic bone fracture or at risk for osteopenia [See Warnings and Precautions (5.5)].

MECHANISM OF ACTION SECTION.


12.1Mechanism of Action. TRUVADA is fixed-dose combination of antiviral drugs emtricitabine and tenofovir disoproxil fumarate. [See Clinical Pharmacology (12.4)].

MICROBIOLOGY SECTION.


12.4Microbiology.

NONCLINICAL TOXICOLOGY SECTION.


13NONCLINICAL TOXICOLOGY. 13.1Carcinogenesis, Mutagenesis, Impairment of Fertility. Emtricitabine: In long-term oral carcinogenicity studies of emtricitabine, no drug-related increases in tumor incidence were found in mice at doses up to 750 mg/kg/day (26 times the human systemic exposure at the therapeutic dose of 200 mg/day) or in rats at doses up to 600 mg/kg/day (31 times the human systemic exposure at the therapeutic dose). Emtricitabine was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or mouse micronucleus assays.Emtricitabine did not affect fertility in male rats at approximately 140-fold or in male and female mice at approximately 60-fold higher exposures (AUC) than in humans given the recommended 200 mg daily dose. Fertility was normal in the offspring of mice exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60-fold higher than human exposures at the recommended 200 mg daily dose.. Tenofovir Disoproxil Fumarate: Long-term oral carcinogenicity studies of tenofovir disoproxil fumarate in mice and rats were carried out at exposures up to approximately 16 times (mice) and times (rats) those observed in humans at the therapeutic dose for HIV-1 infection. At the high dose in female mice, liver adenomas were increased at exposures 16 times that in humans. In rats, the study was negative for carcinogenic findings at exposures up to times that observed in humans at the therapeutic dose.Tenofovir disoproxil fumarate was mutagenic in the in vitro mouse lymphoma assay and negative in an in vitro bacterial mutagenicity test (Ames test). In an in vivo mouse micronucleus assay, tenofovir disoproxil fumarate was negative when administered to male mice.There were no effects on fertility, mating performance or early embryonic development when tenofovir disoproxil fumarate was administered to male rats at dose equivalent to 10 times the human dose based on body surface area comparisons for 28 days prior to mating and to female rats for 15 days prior to mating through day seven of gestation. There was, however, an alteration of the estrous cycle in female rats.. 13.2Animal Toxicology and/or Pharmacology. Tenofovir and tenofovir disoproxil fumarate administered in toxicology studies to rats, dogs and monkeys at exposures (based on AUCs) greater than or equal to 6-fold those observed in humans caused bone toxicity. In monkeys the bone toxicity was diagnosed as osteomalacia. Osteomalacia observed in monkeys appeared to be reversible upon dose reduction or discontinuation of tenofovir. In rats and dogs, the bone toxicity manifested as reduced bone mineral density. The mechanism(s) underlying bone toxicity is unknown.Evidence of renal toxicity was noted in animal species. Increases in serum creatinine, BUN, glycosuria, proteinuria, phosphaturia, and/or calciuria and decreases in serum phosphate were observed to varying degrees in these animals. These toxicities were noted at exposures (based on AUCs) 2-20 times higher than those observed in humans. The relationship of the renal abnormalities, particularly the phosphaturia, to the bone toxicity is not known.

NURSING MOTHERS SECTION.


8.3Nursing Mothers. Nursing Mothers: The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV-1. Studies in rats have demonstrated that tenofovir is secreted in milk. It is not known whether tenofovir is excreted in human milk. It is not known whether emtricitabine is excreted in human milk. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving TRUVADA.

OVERDOSAGE SECTION.


10OVERDOSAGE. If overdose occurs the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.. Emtricitabine: Limited clinical experience is available at doses higher than the therapeutic dose of EMTRIVA. In one clinical pharmacology study single doses of emtricitabine 1200 mg were administered to 11 subjects. No severe adverse reactions were reported.Hemodialysis treatment removes approximately 30% of the emtricitabine dose over 3-hour dialysis period starting within 1.5 hours of emtricitabine dosing (blood flow rate of 400 mL/min and dialysate flow rate of 600 mL/min). It is not known whether emtricitabine can be removed by peritoneal dialysis.. Tenofovir Disoproxil Fumarate: Limited clinical experience at doses higher than the therapeutic dose of VIREAD 300 mg is available. In one study, 600 mg tenofovir disoproxil fumarate was administered to subjects orally for 28 days, and no severe adverse reactions were reported. The effects of higher doses are not known.Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following single 300 mg dose of VIREAD, four-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PRINCIPAL DISPLAY PANEL Tablet, LabelNDC 53808-0805-1Truvada(R) (emtricitabine and tenofovirdisoproxil fumarate)Tablets30 tabletsRx only. PRINCIPAL DISPLAY PANEL Tablet, Label.

USE IN SPECIFIC POPULATIONS SECTION.


8USE IN SPECIFIC POPULATIONS. Pregnancy: pregnancy registry available: Enroll patients by calling 1-800-258-4263.Nursing mothers: Women infected with HIV should be instructed not to breast feed. (8.3)Pediatrics: Safety and efficacy not established in patients less than 18 years of age. (8.4). Pregnancy: pregnancy registry available: Enroll patients by calling 1-800-258-4263.. Nursing mothers: Women infected with HIV should be instructed not to breast feed. (8.3). Pediatrics: Safety and efficacy not established in patients less than 18 years of age. (8.4). 8.1Pregnancy. Pregnancy Category B. Emtricitabine: The incidence of fetal variations and malformations was not increased in embryofetal toxicity studies performed with emtricitabine in mice at exposures (AUC) approximately 60-fold higher and in rabbits at approximately 120-fold higher than human exposures at the recommended daily dose. . Tenofovir Disoproxil Fumarate: Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the human dose based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to tenofovir.There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, TRUVADA should be used during pregnancy only if clearly needed.. Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to TRUVADA, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263.. 8.3Nursing Mothers. Nursing Mothers: The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV-1. Studies in rats have demonstrated that tenofovir is secreted in milk. It is not known whether tenofovir is excreted in human milk. It is not known whether emtricitabine is excreted in human milk. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving TRUVADA.. 8.4Pediatric Use. Truvada is not recommended for patients less than 18 years of age because it is fixed-dose combination tablet containing component, VIREAD, for which safety and efficacy have not been established in this age group.. 8.5Geriatric Use. Clinical studies of EMTRIVA or VIREAD 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 the elderly patients should be cautious, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.. 8.6Patients with Impaired Renal Function. It is recommended that the dosing interval for TRUVADA be modified in patients with creatinine clearance 30-49 mL/min. TRUVADA should not be used in patients with creatinine clearance <30 mL/min and in patients with end-stage renal disease requiring dialysis [See Dosage and Administration (2.2)].

WARNINGS AND PRECAUTIONS SECTION.


5WARNINGS AND PRECAUTIONS. New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Assess creatinine clearance (CrCl) before initiating treatment with TRUVADA. Monitor CrCl and serum phosphorus in patients at risk. Avoid administering Truvada with concurrent or recent use of nephrotoxic drugs. (5.3)Coadministration with Other Products: Do not use with drugs containing emtricitabine or tenofovir disoproxil fumarate including ATRIPLA, EMTRIVA, VIREAD; or with drugs containing lamivudine. Do not administer in combination with HEPSERA. (5.4)Decreases in bone mineral density (BMD): Consider monitoring BMD in patients with history of pathologic fracture or who are at risk for osteopenia. (5.5)Redistribution/accumulation of body fat: Observed in patients receiving antiretroviral therapy. (5.6)Immune reconstitution syndrome: May necessitate further evaluation and treatment. (5.7)Triple nucleoside-only regimens: Early virologic failure has been reported in HIV-infected patients. Monitor carefully and consider treatment modification. (5.8). New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Assess creatinine clearance (CrCl) before initiating treatment with TRUVADA. Monitor CrCl and serum phosphorus in patients at risk. Avoid administering Truvada with concurrent or recent use of nephrotoxic drugs. (5.3). Coadministration with Other Products: Do not use with drugs containing emtricitabine or tenofovir disoproxil fumarate including ATRIPLA, EMTRIVA, VIREAD; or with drugs containing lamivudine. Do not administer in combination with HEPSERA. (5.4). Decreases in bone mineral density (BMD): Consider monitoring BMD in patients with history of pathologic fracture or who are at risk for osteopenia. (5.5). Redistribution/accumulation of body fat: Observed in patients receiving antiretroviral therapy. (5.6). Immune reconstitution syndrome: May necessitate further evaluation and treatment. (5.7). Triple nucleoside-only regimens: Early virologic failure has been reported in HIV-infected patients. Monitor carefully and consider treatment modification. (5.8). 5.1Lactic Acidosis/Severe Hepatomegaly with Steatosis. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including VIREAD, component of TRUVADA, in combination with other antiretrovirals. majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with TRUVADA should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).. 5.2Patients Coinfected with HIV-1 and HBV. It is recommended that all patients with HIV-1 be tested for the presence of chronic hepatitis virus (HBV) before initiating antiretroviral therapy. TRUVADA is not approved for the treatment of chronic HBV infection and the safety and efficacy of TRUVADA have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued TRUVADA. In some patients infected with HBV and treated with EMTRIVA, the exacerbations of hepatitis were associated with liver decompensation and liver failure. Patients who are coinfected with HIV-1 and HBV should be closely monitored with both clinical and laboratory follow up for at least several months after stopping treatment with Truvada. If appropriate, initiation of anti-hepatitis therapy may be warranted.. 5.3New Onset or Worsening Renal Impairment. Emtricitabine and tenofovir are principally eliminated by the kidney. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of VIREAD [See Adverse Reactions (6.2)].It is recommended that creatinine clearance be calculated in all patients prior to initiating therapy and as clinically appropriate during therapy with TRUVADA. Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients at risk for renal impairment, including patients who have previously experienced renal events while receiving HEPSERA.Dosing interval adjustment of TRUVADA and close monitoring of renal function are recommended in all patients with creatinine clearance 30-49 mL/min, [See Dosage and Administration (2.2)]. No safety or efficacy data are available in patients with renal impairment who received TRUVADA using these dosing guidelines, so the potential benefit of TRUVADA therapy should be assessed against the potential risk of renal toxicity. TRUVADA should not be administered to patients with creatinine clearance <30 mL/min or patients requiring hemodialysis.TRUVADA should be avoided with concurrent or recent use of nephrotoxic agent.. 5.4Coadministration with Other Products. TRUVADA is fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate. TRUVADA should not be coadministered with ATRIPLA, EMTRIVA, or VIREAD. Due to similarities between emtricitabine and lamivudine, TRUVADA should not be coadministered with other drugs containing lamivudine, including Combivir (lamivudine/zidovudine), Epivir or Epivir-HBV (lamivudine), Epzicom (abacavir sulfate/lamivudine), or Trizivir (abacavir sulfate/lamivudine/zidovudine).TRUVADA should not be administered with HEPSERA(R) (adefovir dipivoxil).. 5.5Decreases in Bone Mineral Density. Bone mineral density (BMD) monitoring should be considered for HIV-1 infected patients who have history of pathologic bone fracture or are at risk for osteopenia. Although the effect of supplementation with calcium and vitamin was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected then appropriate consultation should be obtained.. Tenofovir Disoproxil Fumarate: In 144-week study of treatment-naive subjects, decreases in BMD were seen at the lumbar spine and hip in both arms of the study. At Week 144, there was significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in subjects receiving VIREAD lamivudine efavirenz compared with subjects receiving stavudine lamivudine efavirenz. Changes in BMD at the hip were similar between the two treatment groups. In both groups, the majority of the reduction in BMD occurred in the first 24-48 weeks of the study and this reduction was sustained through 144 weeks. Twenty-eight percent of VIREAD-treated subjects vs. 21% of the comparator subjects lost at least 5% of BMD at the spine or 7% of BMD at the hip. Clinically relevant fractures (excluding fingers and toes) were reported in subjects in the VIREAD group and subjects in the comparator group. Tenofovir disoproxil fumarate was associated with significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C-telopeptide, and urinary N-telopeptide), suggesting increased bone turnover. Serum parathyroid hormone levels and 1,25 Vitamin levels were also higher in subjects receiving VIREAD. The effects of VIREAD-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. For additional information, please consult the VIREAD prescribing information.Cases of osteomalacia (associated with proximal renal tubulopathy and which may contribute to fractures) have been reported in association with the use of VIREAD [See Adverse Reactions (6.2)].. 5.6Fat 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.. 5.7Immune Reconstitution Syndrome. Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including TRUVADA. 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 jirovecii pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and treatment.. 5.8Early Virologic Failure. Clinical studies in HIV-infected subjects have demonstrated that certain regimens that only contain three nucleoside reverse transcriptase inhibitors (NRTI) are generally less effective than triple drug regimens containing two NRTIs in combination with either non-nucleoside reverse transcriptase inhibitor or HIV-1 protease inhibitor. In particular, early virological failure and high rates of resistance substitutions have been reported. Triple nucleoside regimens should therefore be used with caution. Patients on therapy utilizing triple nucleoside-only regimen should be carefully monitored and considered for treatment modification.