Truvada 200mg/300mg

Interactions of TRUVADA with food have not been established (see Actions and Clinical Pharmacology, Effects of Food on Oral Absorption).

Interactions of TRUVADA with laboratory tests have not been established.

The 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 CYP450 mediated interactions involving emtricitabine and tenofovir with other medicinal products is low.

Emtricitabine and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. No drug-drug interactions due to competition for renal excretion have been observed. Since emtricitabine and tenofovir are primarily eliminated by the kidneys, coadministration of TRUVADA with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of emtricitabine, tenofovir, and/or other renally eliminated drugs. Some examples include, but are not limited to cidofovir, acyclovir, valacyclovir, ganciclovir, and valganciclovir.

TRUVADA should not be administered with HEPSERA (adefovir dipivoxil).

No clinically significant drug interactions have been observed between emtricitabine and famciclovir, indinavir, zidovudine, stavudine, and tenofovir disoproxil fumarate (see Table 5 and Table 6). Similarly, no clinically significant drug interactions have been observed between tenofovir disoproxil fumarate and abacavir, efavirenz, emtricitabine, entecavir, indinavir, lamivudine, methadone, nelfinavir, oral contraceptives, ribavirin, saquinavir/ritonavir and tacrolimus in studies conducted in healthy volunteers (see Table 7 and Table 8).

No drug interaction studies have been conducted using TRUVADA Tablets.

Interactions of TRUVADA with herbs have not been established.

Serious Drug Interactions

• Atazanavir and lopinavir/ritonavir increase tenofovir disoproxil fumarate concentrations which may lead to tenofovir-associated adverse events (see Warnings and Precautions)

  
  

• Tenofovir disoproxil fumarate decreases atazanavir concentrations—administer atazanavir with ritonavir (see below)

  
  

• Tenofovir disoproxil fumarate increases didanosine (ddI) concentrations—the dose of ddI may be reduced but use with caution and monitor for ddI-related adverse events and clinical response (see below)

If a patient misses a dose at the regularly scheduled time, but then remembers it that same day, the patient should take the missed dose immediately. The patient should not take more than 1 dose of TRUVADA in a day, or 2 doses of TRUVADA at the same time to make up for missing a dose.

lactic acidosis, hypokalemia, hypophosphatemia.

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

asthenia.

The following adverse reactions, listed under the body system headings above sometimes appeared to be concurrent with proximal renal tubulopathy: rhabdomyolysis, osteomalacia (manifested as bone pain and infrequently contributing to fractures), hypokalemia, muscular weakness, myopathy, hypophosphatemia.

There have been three post marketing reports of acute renal failure in patients on concomitant NSAIDS therapy where a relationship to VIREAD could not be excluded. These events mostly occurred in medically complex patients, where underlying disease processes confound interpretation.

The following adverse experiences have been reported in post-marketing experience without regard to causality. Because these events are voluntarily reported from a population of unknown size, estimates of frequency cannot be made.

Four hundred and forty-seven HIV-1 infected patients have received combination therapy with EMTRIVA or VIREAD with either a non-nucleoside reverse transcriptase inhibitor or protease inhibitor for 48 weeks in ongoing clinical studies.

dyspnea.

acute 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, polyuria.

rash.

rhabdomyolysis, osteomalacia (manifested as bone pain and infrequently contributing to fractures), muscular weakness, myopathy.

pyrexia.

hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT, GGT).

In HIV-infected patients with severe immune deficiency at the time of initiation of antiretroviral therapy an inflammatory reaction to infectious pathogens (active or inactive) may arise (see Warnings and Precautions).

In HIV infected patients coinfected with HBV, clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of treatment (see Warnings and Precautions).

thrombocytopenia.

allergic reaction (including angioedema).

pancreatitis, increased amylase, abdominal pain.

Safety and effectiveness in pediatric patients have not been established.

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.

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 8 patients orally for 28 days. 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 a single 300 mg dose of VIREAD, a four-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.

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 patients. No severe adverse reactions were reported. The effects of higher doses are not known.

Hemodialysis treatment removes approximately 30% of the emtricitabine dose over a 3 hour dialysis period starting within 1.5 hours of emtricitabine dosing (blood flow rate of 400 mL/min and a dialysate flow rate of 600 mL/min), however, a single treatment does not significantly affect emtricitabine C_max or AUC. It is not known whether emtricitabine can be removed by peritoneal dialysis.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of antiretroviral nucleoside analogs, including tenofovir disoproxil fumarate, a component of TRUVADA, alone or in combination with other antiretrovirals in the treatment of HIV infection. A 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).

Tenofovir and tenofovir disoproxil are not metabolized by liver enzymes. Clinically relevant pharmacokinetic changes in patients with hepatic impairment are not observed. Therefore, no dose adjustment is required in patients with hepatic impairment. Emtricitabine has not been evaluated in patients with hepatic impairment; however, emtricitabine has not been shown to be metabolized by liver enzymes, so the impact of liver impairment is likely to be limited. The safety and efficacy of TRUVADA has not been established or specifically studied in patients with underlying liver disorders. Patients with chronic hepatitis B or C and treated with antiretroviral therapy are at increased risk for severe and potentially fatal hepatic adverse events. In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product information for these medicinal products.

In Study 903 through 144 weeks, decreases from baseline in bone mineral density (BMD) were seen at the lumbar spine and hip in both VIREAD and stavudine treatment arms of the study and significantly greater decreases were seen in the lumbar spine measurement in the VIREAD group relative to the stavudine group. Clinically relevant fractures were reported in both treatment groups. Increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C-telopeptide, and urinary N-telopeptide) were observed, suggesting increased bone turnover. Except for bone specific alkaline phosphatase, these changes resulted in values that remained within the normal range. The effects of VIREAD-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown.

Cases of osteomalacia (associated with proximal renal tubulopathy and infrequently contributing to fractures) have been reported in association with the use of VIREAD (see Adverse Reactions, Post-Market Adverse Drug Reactions).

Bone monitoring should be considered for HIV infected patients who have a history of pathologic bone fracture or are at risk for osteopenia. 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.

To monitor fetal outcomes of pregnant women exposed to ART (antiretroviral therapy) including TRUVADA, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 800-258-4263.

There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, TRUVADA should be used in pregnant women only if the potential benefits outweigh the potential risks to the fetus.

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 in association with the use of VIREAD in clinical practice (see Adverse Reactions, Post-Market Adverse Drug Reactions and Drug Interactions). The majority of these cases occurred in patients with underlying systemic or renal disease, or in patients taking nephrotoxic agents, however, some cases occurred in patients without identified risk factors.

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.

Particular caution should be exercised when administering TRUVADA to patients with known risk factors for renal disease and a history of renal dysfunction; however, cases of renal failure have also been reported in patients with no known risk factors. TRUVADA should be avoided with concurrent or recent use of a nephrotoxic agent.

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). No safety and efficacy data are available in patients with renal dysfunction who received TRUVADA using these guidelines, and so the potential benefit of TRUVADA 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.

Clinical studies of EMTRIVA or VIREAD did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. In general, dose selection for the elderly patient should be cautious, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

During the initial phase of treatment, patients responding to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as MAC, CMV, PCP and TB), which may necessitate further evaluation and treatment.

It is recommended that all patients with HIV be tested for the presence of hepatitis B 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 co-infected with HBV and HIV. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV after the discontinuation of TRUVADA. In some patients infected with HBV and treated with EMTRIVA, the exacerbations of hepatitis B were associated with liver decompensation and liver failure. Hepatic function should be closely monitored with both clinical and laboratory follow up for at least several months in patients who are co-infected with HIV and HBV and discontinue TRUVADA. If appropriate, initiation of anti-hepatitis B therapy may be warranted. In patients with advanced liver disease or cirrhosis, post-treatment exacerbation of hepatitis may lead to hepatic decompensation. Therefore, in these patients, discontinuation of treatment without initiation of alternative anti-hepatitis B therapy is not recommended.

TRUVADA is a fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate. TRUVADA should not be coadministered with EMTRIVA, VIREAD or ATRIPLA. Due to similarities between emtricitabine and lamivudine, TRUVADA should not be coadministered with other drugs containing lamivudine such as COMBIVIR, 3TC, HEPTOVIR, KIVEXA or TRIZIVIR.

TRUVADA should not be administered with HEPSERA (adefovir dipivoxil).

Clinical studies in HIV-infected patients 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 a non-nucleoside reverse transcriptase inhibitor or a HIV-1 protease inhibitor. In particular, early virological failure and high rates of resistance mutations have been reported. Triple nucleoside regimens should therefore be used with caution. Patients on a therapy utilizing a triple nucleoside-only regimen should be carefully monitored and considered for treatment modification.

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. Reduced pup body weights, survival and delay in sexual maturation was observed in a peri- and postnatal toxicity study in rats at the maternally toxic doses of 450 and 600 mg/kg (approximately 14 and 19 times the human dose based on body surface area comparisons).

Pancreatitis has occurred during therapy with combination regimens that included tenofovir disoproxil fumarate (VIREAD). Caution should be used when administering nucleoside analogues (including TRUVADA) to patients with a history of pancreatitis or risk factors for the development of pancreatitis. Therapy should be suspended in patients with suspected pancreatitis.

Safety and effectiveness in pediatric patients have not been established.

Redistribution/accumulation of body fat (lipodystrophy) 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. A causal relationship has not been established.

HIV-infected mothers should not breast-feed their infants to avoid risking postnatal transmission of HIV. Studies in rats and rhesus monkeys have demonstrated that tenofovir is secreted in milk. It is not known whether emtricitabine or tenofovir is excreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving TRUVADA.

The incidence of fetal variations and malformations was not increased in embryo-fetal 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.

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).

TRUVADA may be administered with or without food. Administration of TRUVADA following a high fat meal (784 kcal; 49 grams of fat) or a light meal (373 kcal; 8 grams of fat) delayed the time of tenofovir C_max by approximately 0.75 hour. The mean increases in tenofovir AUC and C_max were approximately 35% and 15%, respectively, when administered with a 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 C_max) were unaffected when TRUVADA was administered with either a high fat or a light meal.

Emtricitabine and tenofovir pharmacokinetics are similar in male and female patients.

The antiviral effects of emtricitabine and tenofovir disoproxil fumarate in terms of reducing HIV-1 viral load and the relationship with dose were assessed in clinical phase 1 studies in treatment-naive and treatment-experienced HIV-infected patients.

Pharmacokinetics of emtricitabine and tenofovir have not been fully evaluated in children (<18 years) or in the elderly (>65 years).

The pharmacokinetics of tenofovir following a 300 mg single 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 patients with hepatic impairment; however, emtricitabine has not been shown to be significantly metabolized by liver enzymes, so the impact of liver impairment is likely to be limited.

The pharmacokinetics of emtricitabine and tenofovir are altered in patients with renal insufficiency (see Warnings and Precautions, Nephrotoxicity). In patients with creatinine clearance <50 mL/min, C_max and AUC_0-∞ 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).

There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations.

No pharmacokinetic differences due to race have been identified following the administration of EMTRIVA.