emtricitabine, rilpivirine and tenofovir disoproxil fumarate

5 WARNINGS AND PRECAUTIONS • Skin and Hypersensitivity Reactions: Severe skin and hypersensitivity reactions have been reported during postmarketing experience, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). Immediately discontinue treatment if hypersensitivity or rash with systemic symptoms or elevations in hepatic serum biochemistries develops and closely monitor clinical status, including hepatic serum biochemistries. ( 5.2 ) • Hepatotoxicity: Hepatic adverse events have been reported in patients receiving a rilpivirine-containing regimen. Monitor liver-associated tests before and during treatment with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets in patients with underlying hepatic disease or marked elevations in liver-associated tests. Also consider monitoring liver-associated tests in patients without risk factors. ( 5.3 ) • Depressive disorders: Severe depressive disorders have been reported. Immediate medical evaluation is recommended for severe depressive disorders. ( 5.4 ) • New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Avoid administering emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets with concurrent or recent use of nephrotoxic drugs. ( 5.5 ) • Decreases in bone mineral density (BMD): Consider monitoring BMD in patients with a history of pathologic fracture or other risk factors of osteoporosis or bone loss. ( 5.6 ) • Concomitant use of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets with drugs with a known risk to prolong the QTc interval of the electrocardiogram may increase the risk of Torsade de Pointes. ( 5.7 ) • Lactic acidosis/severe hepatomegaly with steatosis: Discontinue treatment in patients who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity. ( 5.8 ) • Immune reconstitution syndrome: May necessitate further evaluation and treatment. ( 5.9 ) 5.1 Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV Test all patients with HIV-1 for the presence of chronic hepatitis B virus (HBV) before or when initiating antiretroviral therapy [see Dosage and Administration (2.1) ]. Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued products containing FTC and/or TDF, two of the components of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. Patients coinfected with HIV-1 and HBV who discontinue emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. If appropriate, initiation of anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since posttreatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure. 5.2 Skin and Hypersensitivity Reactions Severe skin and hypersensitivity reactions have been reported during the postmarketing experience, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) with RPV-containing regimens. While some skin reactions were accompanied by constitutional symptoms such as fever, other skin reactions were associated with organ dysfunctions, including elevations in hepatic serum biochemistries. During the Phase 3 clinical trials, treatment-related rashes with at least Grade 2 severity were reported in 1% of subjects receiving RPV plus FTC/TDF. Overall, most rashes were Grade 1 or 2 and occurred in the first four to six weeks of therapy [see Adverse Reactions (6.1 and 6.2 )]. Discontinue emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets immediately if signs or symptoms of severe skin or hypersensitivity reactions develop, including but not limited to, severe rash or rash accompanied by fever, blisters, mucosal involvement, conjunctivitis, facial edema, angioedema, hepatitis, or eosinophilia. Clinical status including laboratory parameters should be monitored and appropriate therapy should be initiated. 5.3 Hepatotoxicity Hepatic adverse events have been reported in patients receiving an RPV-containing regimen. Patients with underlying hepatitis B or C virus infection, or marked elevations in liver-associated tests prior to treatment, may be at increased risk for worsening or development of liver-associated test elevations with use of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. A few cases of hepatic toxicity have been reported in adult patients receiving an RPV-containing regimen who had no pre-existing hepatic disease or other identifiable risk factors. Appropriate laboratory testing prior to initiating therapy and monitoring for hepatotoxicity during therapy with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are recommended in patients with underlying hepatic disease such as hepatitis B or C, or in patients with marked elevations in liver-associated tests prior to treatment initiation. Liver-associated test monitoring should also be considered for patients without pre-existing hepatic dysfunction or other risk factors. 5.4 Depressive Disorders The adverse reaction depressive disorders (depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) has been reported with RPV. Patients with severe depressive symptoms should seek immediate medical evaluation to assess the possibility that the symptoms are related to emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets, and if so, to determine whether the risks of continued therapy outweigh the benefits. During the Phase 3 trials in adults (N=1,368) through 96 weeks, the incidence of depressive disorders (regardless of causality, severity) reported among RPV (n=686) or efavirenz (EFV, n=682) was 9% and 8%, respectively. Most events were mild or moderate in severity. The incidence of Grades 3 and 4 depressive disorders (regardless of causality) was 1% for both RPV and EFV. The incidence of discontinuation due to depressive disorders among RPV or EFV was 1% in each arm. Suicidal ideation was reported in 4 subjects in each arm while suicide attempt was reported in 2 subjects in the RPV arm. During the Phase 2 trial in pediatric subjects 12 to less than 18 years of age (N=36) receiving RPV through 48 weeks, the incidence of depressive disorders (regardless of causality, severity) was 19.4% (7/36). Most events were mild or moderate in severity. The incidence of Grade 3 and 4 depressive disorders (regardless of causality) was 5.6% (2/36). None of the subjects discontinued due to depressive disorders. Suicidal ideation and suicide attempt were reported in 1 subject. 5.5 New Onset or Worsening Renal Impairment Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of TDF [see Adverse Reactions (6.2) ] . Prior to initiation of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets, and during treatment with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple nonsteroidal anti-inflammatory drugs [NSAIDs]) [see Drug Interactions (7.4) ]. Cases of acute renal failure after initiation of high-dose or multiple NSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on TDF. Some patients required hospitalization and renal replacement therapy. Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction. Persistent or worsening bone pain, pain in extremities, fractures, and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in at-risk patients. Emtricitabine and TDF are principally eliminated by the kidney; however, RPV is not. Since emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are a combination product and the dose of the individual components cannot be altered, emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are not recommended in patients with estimated creatinine clearance below 50 mL per minute [see Use in Specific Populations (8.6) ] . 5.6 Bone Loss and Mineralization Defects Bone Mineral Density In clinical trials in HIV-1-infected adults, TDF, a component of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets, was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving TDF. Clinical trials evaluating TDF in pediatric and adolescent subjects were conducted. Under normal circumstances, BMD increases rapidly in pediatric patients. In HIV-1-infected subjects aged 2 years to less than 18 years, bone effects were similar to those observed in adult subjects and suggest increased bone turnover. Total body BMD gain was less in the TDF-treated HIV-1-infected pediatric subjects as compared to the control groups. Similar trends were observed in chronic hepatitis B-infected adolescent subjects aged 12 years to less than 18 years. In all pediatric trials, skeletal growth (height) appeared to be unaffected. The effects of TDF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Assessment of BMD should be considered for adult and pediatric patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and Vitamin D was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected, then appropriate consultation should be obtained. Mineralization Defects Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of TDF [see Adverse Reactions (6.2) ]. Arthralgias and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing TDF [See Warnings and Precautions (5.5) ]. 5.7 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions The concomitant use of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets and other drugs may result in potentially significant drug interactions, some of which may lead to [see Dosage and Administration (2.5) , Contraindications (4) , and Drug Interactions (7) ]: • Loss of therapeutic effect of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets and possible development of resistance due to reduced exposure to RPV. • Possible clinically significant adverse reaction from greater exposures of components of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. In healthy subjects, 75 mg once daily and 300 mg once daily doses of RPV (3 times and 12 times the dose in emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets) have been shown to prolong the QTc interval of the electrocardiogram. Consider alternatives to emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets when coadministered with a drug that is known to have a risk of Torsade de Pointes [see Drug Interactions (7) and Clinical Pharmacology (12.2) ]. See Table 4 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets therapy and review concomitant medications during emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets therapy. 5.8 Lactic 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 TDF and FTC, components of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets, alone or in combination with other antiretrovirals. Treatment with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets 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). 5.9 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including the components of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. 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. Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment.

4 CONTRAINDICATIONS Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are contraindicated when coadministered with the following drugs; coadministration may result in loss of virologic response and possible resistance to emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets or to the class of NNRTIs [see Warnings and Precautions (5.7) , Drug Interactions (7) , and Clinical Pharmacology (12.3) ]: • Anticonvulsants: carbamazepine, oxcarbazepine, phenobarbital, phenytoin • Antimycobacterials: rifampin, rifapentine • Glucocorticoid (systemic): dexamethasone (more than a single-dose) • Herbal Products: St John’s wort (Hypericum perforatum) • Proton Pump Inhibitors: e.g., dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are contraindicated when coadministered with drugs which may result in loss of virologic response and possible resistance to emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. ( 4 )

10 OVERDOSAGE If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets consists of general supportive measures, including monitoring of vital signs and ECG (QT interval) as well as observation of the clinical status of the patient. Emtricitabine: Hemodialysis treatment removes approximately 30% of the FTC dose over a 3-hour dialysis period starting within 1.5 hours of FTC dosing (blood flow rate of 400 mL per minute and a dialysate flow rate of 600 mL per minute). It is not known whether FTC can be removed by peritoneal dialysis. Rilpivirine: There is no specific antidote for overdose with RPV. Human experience of overdose with RPV is limited. Since RPV is highly bound to plasma protein, dialysis is unlikely to result in significant removal of RPV. Tenofovir DF: Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of TDF, a 4-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.