Viraday

Efavirenz and Emtricitabine and Tenofovir disoproxil fumarate Tablets

WARNING

LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE USE OF NUCLEOSIDE ANALOGS ALONE OR IN COMBINATION WITH OTHER ANTIRETROVIRALS (SEE WARNINGS).

VIRADAY IS NOT INDICATED FOR THE TREATMENT OF CHRONIC HEPATITIS B VIRUS (HBV) INFECTION AND THE SAFETY AND EFFICACY OF VIRADAY HAVE NOT BEEN ESTABLISHED IN PATIENTS COINFECTED WITH HBV AND HIV.

SEVERE ACUTE EXACERBATIONS OF HEPATITIS B HAVE BEEN REPORTED IN PATIENTS WHO HAVE DISCONTINUED EMTRICITABINE OR TENOFOVIR DISOPROXIL FUMARATE, BOTH OF WHICH ARE COMPONENTS OF VIRADAY. HEPATIC FUNCTION SHOULD BE MONITORED CLOSELY WITH BOTH CLINICAL AND LABORATORY FOLLOW-UP FOR AT LEAST SEVERAL MONTHS IN PATIENTS WHO DISCONTINUE VIRADAY AND ARE CO-INFECTED WITH HIV AND HBV. IF APPROPRIATE, INITIATION OF ANTI-HEPATITIS B THERAPY MAY BE WARRANTED (SEE WARNINGS).

Composition

Each film-coated tablet contains:

• Efavirenz 600 mg
• Emtricitabine 200 mg
• Tenofovir disoproxil fumarate 300 mg
  equivalent to Tenofovir disoproxil 245 mg

Dosage form

Oral, fixed-dose tablet

Pharmacology

Pharmacodynamics

Efavirenz

Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1). Efavirenz activity is mediated predominantly by noncompetitive inhibition of HIV-1 reverse transcriptase (RT). HIV-2 RT and human cellular DNA polymerases alpha, beta, gamma, and delta are not inhibited by EFV.

Emtricitabine: Emtricitabine, a 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 DNA which results in chain termination. Emtricitabine 5'- triphosphate is a weak inhibitor of mammalian DNA polymerase alpha, beta, epsilon and mitochondrial DNA polymerase gamma.

Tenofovir disoproxil fumarate : Tenofovir disoproxil fumarate (tenofovir DF) is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir DF 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 reverse transcriptase (RT) by competing with the natural substrate deoxyadenosine 5'-triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases alpha, beta, and mitochondrial DNA polymerase gamma.

Pharmocokinetics in adults

Efavirenz

In HIV-infected patients at steady state, mean C max , mean C min , and mean AUC were dose proportional following 200-mg, 400-mg, and 600-mg daily doses. Time-to-peak plasma concentrations were approximately 3-5 hours and steady-state plasma concentrations were reached in 6-10 days. Efavirenz is highly bound (approximately 99.5-99.75%) to human plasma proteins, predominantly albumin. Efavirenz is principally metabolized by the cytochrome P450 system to hydroxylated metabolites with subsequent glucuronidation of these hydroxylated metabolites. These metabolites are essentially inactive against HIV-1. Efavirenz has been shown to induce P450 enzymes, resulting in the induction of its own metabolism.

Efavirenz has a terminal half-life of 52-76 hours after single doses and 40-55 hours after multiple doses. A one-month mass balance/excretion study was conducted using 400 mg per day with a 14 C-labeled dose administered on Day 8. Approximately 14-34% of the radiolabel was recovered in the urine and 16-61% was recovered in the feces. Nearly all of the urinary excretion of the radiolabeled drug was in the form of metabolites. Efavirenz accounted for the majority of the total radioactivity measured in feces.

Emtricitabine

The pharmacokinetic properties of emtricitabine are summarized in Table 1. Following oral administration, 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 µg/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 a combination of glomerular filtration and active tubular secretion. Following a single oral dose of emtricitabine, the plasma emtricitabine half-life is approximately 10 hours.

Table 1: Single-dose Pharmacokinetic Parameters for Emtricitabine and Tenofovir in Adults¹

Tenofovir DF

The pharmacokinetic properties of tenofovir DF are summarized in Table 1. Following oral administration of tenofovir DF, 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 µg/mL. Approximately 70–80% of the intravenous dose of tenofovir is recovered as unchanged drug in the urine. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose of tenofovir disoproxil fumarate, the terminal elimination half-life of tenofovir is approximately 17 hours.

Indications

Viraday is indicated for the treatment of HIV-1 infection in adults.

Dosage and Administration

The dose of Viraday is one tablet once daily. It is recommended that Viraday be taken on an empty stomach, preferably at bedtime. Bedtime dosing may improve the tolerability of nervous system symptoms associated with efavirenz. The increased efavirenz concentrations observed following administration of efavirenz with food may lead to an increase in frequency of adverse events.

Renal Impairment

Because Viraday is a fixed-dose combination, it should not be prescribed for patients requiring dosage adjustment such as those with moderate or severe renal impairment (creatinine clearance <50 mL/min).

Pediatrics

Viraday is not indicated for use in pediatric patients.

Contraindications

Viraday is contraindicated in patients with previously demonstrated hypersensitivity to any of the components of the product.

Warnings and Precautions

Alert: Find out about medicines that should NOT be taken with efavirenz.

Psychiatric Symptoms

Serious psychiatric adverse experiences have been reported in patients treated with efavirenz. In controlled trials of 1008 patients treated with regimens containing efavirenz for a mean of 2.1 years and 635 patients treated with control regimens for a mean of 1.5 years, the frequency of specific serious psychiatric events among patients who received efavirenz or control regimens, respectively, were: severe depression (2.4%, 0.9%), suicidal ideation (0.7%, 0.3%), nonfatal suicide attempts (0.5%, 0%), aggressive behavior (0.4%, 0.5%), paranoid reactions (0.4%, 0.3%) and manic reactions (0.2%, 0.3%). When psychiatric symptoms similar to those noted above were combined and evaluated as a group in a multifactorial analysis of data from Study 006, treatment with efavirenz was associated with an increase in the occurrence of these selected psychiatric symptoms. Other factors associated with an increase in the occurrence of these psychiatric symptoms were history of injection drug use, psychiatric history, and receipt of psychiatric medication at study entry; similar associations were observed in both the efavirenz and control treatment groups. In Study 006, onset of new serious psychiatric symptoms occurred throughout the study for both efavirenz-treated and control-treated patients. One percent of efavirenz-treated patients discontinued or interrupted treatment because of one or more of these selected pscychiatric symptoms. There have also been occasional postmarketing reports of death by suicide, delusions, and psychosis-like behavior, although a causal relationship to the use of efavirenz cannot be determined from these reports. Patients with serious psychiatric adverse experiences should seek immediate medical evaluation to assess the possibility that the symptoms may be related to the use of efavirenz, and if so, to determine whether the risks of continued therapy outweighs the benefits.

Nervous System Symptoms

Fifty-three percent of patients receiving efavirenz in controlled trials reported central nervous system symptoms compared to 25% of patients receiving control regimens. These symptoms included, but were not limited to, dizziness (28.1%), insomnia (16.3%), impaired concentration (8.3%), somnolence (7.0%), abnormal dreams (6.2%) and hallucinations (1.2%). These symptoms were severe in 2.0% of patients, and 2.1% of patients discontinued therapy as a result. These symptoms usually begin during the first or second day of therapy and generally resolve after the first 2-4 weeks of therapy. After 4 weeks of therapy, the prevalence of nervous system symptoms of at least moderate severity ranged from 5% to 9% in patients treated with regimens containing efavirenz and from 3% to 5% in patients treated with a control regimen. Patients should be informed that these common symptoms were likely to improve with continued therapy and were not predictive of subsequent onset of the less frequent psychiatric symptoms. Dosing at bedtime may improve the tolerability of these nervous system symptoms.

Analysis of long-term data from Study 006 (median follow-up 180 weeks, 102 weeks and 76 weeks for patients treated with efavirenz + zidovudine + lamivudine, efavirenz + indinavir, and indinavir + zidovudine + lamivudine, respectively) showed that, beyond 24 weeks of therapy, the incidences of new-onset nervous system symptoms among efavirenz-treated patients were generally similar to those in the indinavir-containing control arm.

Patients receiving efavirenz should be alerted to the potential for additive central nervous system effects when efavirenz is used concomitantly with alcohol or psychoactive drugs.

Patients who experience central nervous system symptoms such as dizziness, impaired concentration, and/or drowsiness should avoid potentially hazardous tasks such as driving or operating machinery.

Skin Rash

In controlled clinical trials, 26% of patients treated with 600 mg efavirenz experienced new-onset rash compared with 17% of patients treated in control groups. Rash associated with blistering, moist desquamation or ulceration occurred in 0.9% of patients treated with efavirenz. The incidence of Grade 4 rash (e.g, erythema multiforme, Stevens-Johnson Syndrome) was approximately 0.1%. The median time to onset of rash in adults was 11 days and the median duration 16 days. The discontinuation rate for rash in clinical trials was 1.7 %. Efavirenz must be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement or fever. Appropriate antihistamines and/or corticosteroids may improve the tolerability and hasten the resolution of rash.

Rash was reported in 26 of 57 pediatric patients (46%) treated with efavirenz capsules. One pediatric patient experienced Grade 3 rash (confluent rash with fever), and two patients had Grade 4 rash (erythema multiforme). The median time to onset of rash in pediatric patients was 8 days. Prophylaxis with appropriate antihistamines prior to initiating therapy with efavirenz in pediatric patients should be considered.

Liver Enzymes

In patients with known or suspected history of hepatitis B or C infection and in patients treated with other medications associated with liver toxicity, monitoring of liver enzymes is recommended. In patients with persistent elevations of serum transaminases to greater than 5 times the upper limit of normal range, the benefit of continued therapy with efavirenz needs to be weighed against the unknown risks of significant liver toxicity.

Because of the extensive cytochrome P450-mediated metabolism of efavirenz and limited clinical experience in patients with hepatic impairment, caution should be exercised in administering efavirenz to these patients.

Convulsions

Convulsions have been observed infrequently in patients receiving efavirenz, generally in the presence of known medical history of seizures. Patients who are receiving concomitant anticonvulsant medications primarily metabolized by the liver, such as phenytoin, carbamazepine and phenobarbital, may require periodic monitoring of plasma levels. Caution must be taken in any patient with a history of seizures.

Cholesterol

Monitoring of cholesterol and triglycerides should be considered in patients treated with efavirenz.

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 alone or in combination with other antiretrovirals. 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 VIRADAY 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).

Patients with HIV and Hepatitis B Virus Co-infection

It is recommended that all patients with HIV be tested for the presence of hepatitis B virus (HBV) before initiating antiretroviral therapy. The safety and efficacy of emtricitabine and tenofovir DF have not been established in patients co-infected with HBV and HIV. Severe acute exacerbations of hepatitis B have been reported in patients after the discontinuation of emtricitabine and tenofovir DF. Hepatic function should be closely monitored with both clinical and laboratory follow up for at least several months in patients who discontinue VIRADAY and are co-infected with HIV and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

Renal Impairment

Since Viraday is a combination product and the dose of the individual components cannot be altered, patients with creatinine clearance <50 mL/min should not receive Viraday.

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 tenofovir DF (see Post marketing Experience). 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.

Viraday should be avoided with concurrent or recent use of a nephrotoxic agent. Patients at risk for, or with a history of, renal dysfunction and patients receiving concomitant nephrotoxic agents should be carefully monitored for changes in serum creatinine and phosphorus.

Bone effects

Tenofovir disoproxil fumarate : In both arms of the study 903 through 48 weeks, decreases from baseline in bone mineral density (BMD) were seen at the lumbar spine and hip. At 48 weeks, percent decreases in BMD from baseline (mean ± SD) were greater in patients receiving TDF + lamivudine + efavirenz (spine, -3.3% ± 3.9; hip, -3.2% ± 3.6) compared with patients receiving stavudine + lamivudine + efavirenz (spine, -2.0% ± 3.5; hip, -1.8% ± 3.3). In addition, there were significant increases in levels of four biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C-telopeptide and urinary N-telopeptide) in the Tenofovir DF group relative to the stavudine group, suggesting increased bone turnover. Serum parathyroid hormone levels were also higher in the tenofovir DF group relative to the stavudine group. Except for bone specific alkaline phosphatase, these changes resulted in values that remained within the normal range. There was one bone fracture reported in the tenofovir DF group compared with four in the stavudine group; no pathologic fractures were identified over 48 weeks of study treatment. The clinical significance of the changes in BMD and biochemical markers is unknown and follow-up is continuing to assess long-term impact.

Bone monitoring should be considered for HIV infected patients who have a history of pathologic bone fracture or are at substantial risk for osteopenia. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be considered for HIV-associated osteopenia or osteoporosis. If bone abnormalities are suspected then appropriate consultation should be obtained.

Fat Redistribution

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including efavirenz, emtricitabine and tenofovir. 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.

Pregnancy

Category D. Efavirenz may cause fetal harm when administered during the first trimester to a pregnant woman. Pregnancy should be avoided in women receiving VIRADAY . Barrier contraception should always be used in combination with the other methods of contraception (e.g. oral or other hormonal contraceptives). Women of childbearing potential should undergo pregnancy testing prior to initiation of VIRADAY . If VIRADAY is used during the first trimester of pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus.

Lactation

It is recommended that HIV-infected women do not breast-feed their infants to avoid risking postnatal transmission of HIV. Studies in rats have demonstrated that both tenofovir and efavirenz are secreted in milk. It is not known whether efavirenz, tenofovir or emtricitabine 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 Viraday.

Drug Interactions

Efavirenz

Efavirenz has been shown in vivo to induce CYP3A4. Other compounds that are substrates of CYP3A4 may have decreased plasma concentrations when co administered with efavirenz. In vitro studies have demonstrated that efavirenz inhibits 2C9, 2C19, and 3A4 isozymes in the range of observed efavirenz plasma concentrations. Co administration of efavirenz with drugs primarily metabolized by these isozymes may result in altered plasma concentrations of the co-administered drug. Therefore, appropriate dose adjustments may be necessary for these drugs.

Drugs which induce CYP3A4 activity (eg, phenobarbital, rifampin, rifabutin) would be expected to increase the clearance of efavirenz resulting in lowered plasma concentrations. Drug interactions with efavirenz are summarized in Table 2.

Table 2: Drugs That Should Not be Co-administered with Efavirenz

Concomitant use of efavirenz and St. John's wort ( Hypericum perforatum ) or St. John's wort-containing products is not recommended. Co-administration of non-nucleoside reverse transcriptase inhibitors (NNRTIs), including efavirenz, with St. John's wort is expected to substantially decrease NNRTI concentrations and may result in suboptimal levels of efavirenz and lead to loss of virologic response and possible resistance to efavirenz or to the class of NNRTIs.

Table 3: Established Drug Interactions

Table 4: Other Potentially Clinically Significant Drug or Herbal Product Interactions with Efavirenz

Table 5: Effect of Efavirenz on Co administered Drug Plasma C_maxand AUC

Table 6: Effect of Co administered Drug on Efavirenz Plasma C max and AUC

Based on the results of drug interaction studies, no dosage adjustment is recommended when efavirenz is given with the following: aluminium/magnesium hydroxide, antacids, azithromycin, cetirizine, famotidine, fluconazole, lamivudine, lorazepam, nelfinavir, paroxetine and zidovudine.

Specific drug interaction studies have not been performed with efavirenz and NRTIs other than lamivudine and zidovudine. Clinically significant interactions would not be expected since the NRTIs are metabolized via a different route than efavirenz and would be unlikely to complete for the same metabolic enzymes and elimination pathways.

Emtricitabine and tenofovir DF : The steady state pharmacokinetics of emtricitabine and tenofovir were unaffected when emtricitabine and tenofovir DF were administered together versus each agent dosed alone.

In vitro and clinical pharmacokinetic drug-drug interaction studies have shown 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. Co-administration of Viraday 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 adefovir dipivoxil, cidofovir, acyclovir, valacyclovir, ganciclovir and valganciclovir.

No clinically significant drug interactions have been observed between emtricitabine and famciclovir, indinavir, stavudine and tenofovir DF (see Tables 7 and 8). Similarly, no clinically significant drug interactions have been observed between tenofovir DF and abacavir, adefovir dipivoxil, ribavirin, efavirenz, emtricitabine, indinavir, lamivudine, lopinavir/ritnonavir, methadone and oral contraceptives in studies conducted in healthy volunteers (see Tables 9 and 10).

Table 7. Drug Interactions: Changes in Pharmacokinetic Parameters for Emtricitabine in the Presence of the Co-administered Drug

Table 8. Drug Interactions: Changes in Pharmacokinetic Parameters for Co-administered Drug in the Presence of Emtricitabine 1

Table 9. Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovir ¹ in the Presence of the Co-administered Drug

Table 10. Drug Interactions: Changes in Pharmacokinetic Parameters for Co-administered Drug in the Presence of Tenofovir

Atazanavir and lopinavir/ritonavir have been shown to increase tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving atazanavir and lopinavir/ritonavir and Viraday should be monitored for tenofovir-associated adverse events. Viraday should be discontinued in patients who develop such undesirable effects.

Tenofovir decreases the AUC and C min of atazanavir. When co-administered with Viraday , it is recommended that atazanavir 300 mg is given with ritonavir 100 mg. Atazanavir without ritonavir should not be coadministered with Viraday.

Following 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 Tenofovir DF.

Co-administration of tenofovir disoproxil fumarate with didanosine results in changes in the pharmacokinetics of didanosine that may be of clinical significance. Table 11 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 C max and AUC of didanosine. When didanosine 250 mg enteric-coated capsules were administered with tenofovir DF, 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.

Higher didanosine concentrations could potentiate didanosine-associated adverse events, including pancreatitis, and neuropathy. In adults weighing >60 kg, the didanosine dose should be reduced to 250 mg when it is co-administered with Viraday . Data are not available to recommend a dose adjustment of didanosine for patients weighing <60 kg. When co-administered, Viraday and didanosine enteric-coated capsules may be taken under fasted conditions or with a light meal (<400 kcal, 20% fat). Co-administration of didanosine buffered tablet formulation with Viraday should be under fasted conditions. Co-administration of Viraday and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse events. Didanosine should be discontinued in patients who develop didanosine-associated adverse events.

Table 11: Drug interactions: Pharmacokinetic Parameters for Didanosine in the Presence of Tenofovir DF

No drug interaction studies have been conducted using the fixed-dose combination tablet of efavirenz, tenofovir DF and emtricitabine tablets.

Viraday is a fixed-dose combination of efavirenz, emtricitabine and tenofovir disoproxil fumarate. Viraday should not be co-administered with efavirenz, emtricitabine or tenofovir DF. Due to similarities between emtricitabine and lamivudine, Viraday should not be co-administered with other drugs containing lamivudine, including Duovir, Lamivir, Lamivir-HBV, Duovir-N, Duovir-E Kit, Triomune, Odivir Kit and Lamivir-S.

Undesirable Effects

Efavirenz

The most significant adverse events observed in patients treated with efavirenz are nervous system symptoms (see Warnings and Precautions) , psychiatric symptoms (see Warnings and Precautions) , and rash (see Warnings and Precautions).

Selected clinical adverse experiences of moderate or severe intensity observed in ? 2% of efavirenz-treated patients in two controlled clinical trials included pain, impaired concentration, anorexia, dyspepsia, abdominal pain, anxiety, nervousness, and pruritus. Pancreatitis has been reported, although a causal relationship with efavirenz has not been established. Asymptomatic increases in serum amylase levels were observed in a significantly higher number of patients treated with efavirenz 600 mg than in control patients.

Emtricitabine and tenofovir DF : Adverse events that occurred in at least 5% of patients receiving emtricitabine or tenofovir DF 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, rhinitis and rash event (including rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, pustular rash and allergic reaction).

Skin discoloration has been reported with higher frequency among emtricitabine treated patients. Skin discoloration, manifested by hyperpigmentation on the palms and/or soles was generally mild and asymptomatic. The mechanism and clinical significance are unknown.

Grade 3/4 elevations of bilirubin (>2.5 × ULN), pancreatic amylase (>2.0 x ULN), serum glucose (<40 or >250 mg/dL), serum lipase (<2.0 × ULN), and urine glucose ( ≥ 3+) occurred in up to 3% of patients treated with emtricitabine or tenofovir DF with other antiretroviral agents in clinical trials.

Table 12: Selected Treatment-Emergent Adverse Events (Grades 2–4) Reported in ≥ 3% in Any Treatment Group in Study 934 (0–48 weeks)

Laboratory Abnormalities

Laboratory abnormalities observed in this study were generally consistent with those seen in other studies (Table 13).

Table 13 Significant Laboratory Abnormalities Reported in ≥1% in Any Treatment Group in Study 934 (0–48 weeks)

Post marketing Experience

In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of efavirenz, emtricitabine, or tenofovir DF. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion because of a combination of their seriousness, frequency of reporting or potential causal connection.

Efavirenz

• Cardiac disorders : palpitations
• Ear and labyrinth disorders: tinnitus
• Endocrine disorders: gynecomastia
• Eye disorders: abnormal vision
• Gastrointestinal disorders: constipation, malabsorption
• General disorders and administration site conditions: asthenia
• Hepatobiliary disorders: hepatic enzyme increase, hepatic failure, hepatitis
• Immune system disorders: allergic reactions
• Metabolism and nutrition disorders: redistribution/accumulation of body fat (see Warnings and Precautions, Fat redistribution), hypercholesterolemia, hypertriglyceridemia
• Musculoskeletal and connective tissue disorders: arthralgia, myalgia, myopathy
• Nervous system disorders: abnormal coordination, ataxia, convulsions, hypoesthesia, paresthesia, neuropathy, tremor
• Psychiatric disorders: aggressive reactions, agitation, delusions, emotional lability, mania, neurosis, paranoia, psychosis, suicide
• Respiratory, thoracic and mediastinal disorders: dyspnea
• Skin and subcutaneous tissue disorders: flushing, erythema multiforme, nail disorders, photoallergic dermatitis, skin discoloration, Stevens-johnson syndrome

Emtricitabine

No additional events have been identified for inclusion in this section.

Tenofovir DF

In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of tenofovir DF. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion because of a combination of their seriousness, frequency of reporting or potential causal connection to tenofovir DF.

• Immune system disorders: Allergic reaction
• Metabolism and nutrition disorders: Hypophosphataemia, lactic acidosis
• Respiratory, thoracic, and mediastinal disorders: Dyspnoea
• Gastrointestinal disorders: Abdominal pain, pancreatitis
• Hepatobiliary disorders: Increased liver enzymes, Hepatitis
• Renal and urinary disorders: Renal insufficiency, renal failure, fanconi syndrome, proximal tubulopathy, proteinuria, increased creatinine, acute tubular necrosis.

Overdosage

Efavirenz

Some patients accidentally taking 600 mg twice daily have reported increased nervous system symptoms. One patient experienced involuntary muscle contractions.

Treatment of overdose with efavirenz should consist of general supportive measures, including monitoring of vital signs and observation of the patient's clinical status. Administration of activated charcoal may be used to aid removal of unabsorbed efavirenz. There is no specific antidote for overdose with efavirenz. Since efavirenz is highly protein bound, dialysis is unlikely to remove significant quantities from blood.

Emtricitabine

Limited clinical experience is available at doses higher than the therapeutic dose of emtricitabine. In one clinical pharmacology study single doses of emtricitabine 1200 mg were administered to 11 patients. No severe adverse reactions were reported.

Haemodialysis treatment removes approximately 30% of the emtrictabine 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). It is not known whether emtricitabine can be removed by peritoneal dialysis.

Tenofovir DF

Limited clinical experience at doses higher than the therapeutic dose of tenofovir DF 300 mg is available. In one study, 600 mg tenofovir DF was administered to 8 patients orally for 28 days, and no severe adverse reactions were reported. The effects of higher doses are not known.

Tenofovir is efficiently removed by haemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of tenofovir DF, a 4-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.

Shelf-life

2 years

Storage

Keep in cool dry place away from moisture.

Presentation

Viraday : Container of 30 tablets

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