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PRODUCT TYPE:- EFAVIRENZ, EMTRICITABINE AND TENOFOVIR DISOPROXIL FUMARATE
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DESCRIPTION
VIRADAY is a fixed dose combination tablet containing efavirenz, emtricitabine, and tenofovir disoproxil fumarate (tenofovir DF).
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.
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.
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.