Prescribing Information:

For the use of a Registered Medical Practitioner or Hospital or Laboratory only

Lamivudine with Zidovudine Tablets IP & Efavirenz Tablets IP


Composition:

Each kit contains, two tablets in Part A and one tablet in Part B, with composition as follows:

Part A:Lamivudine with Zidovudine Tablets IPPart B: Efavirenz Tablet IP
Each film-coated tablet contains:Each film-coated tablet contains:
Lamivudine IP - 150 mgEfavirenz IP - 600 mg
Zidovudine IP - 300 mgColour: Iron Oxide Yellow & Titanium Dioxide IP

Description:

This combination kit contains the nucleoside reverse transcriptase inhibitors Lamivudine & Zidovudine and the non-nucleoside reverse transcriptase inhibitor Efavirenz. Chemically Lamivudine it is (2R, cis)-4-amino-1-(2-hydroxymethyl-1, 3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one with molecular formula of C8H11N3O3S & molecular weight of 229.3. The chemical name of Zidovudine is 3’azido-3’-deoxythymidine. The molecular formula is C10H13N5O4 with a molecular weight of 267.24. Efavirenz is chemically described as (S)-6-chloro-(cyclopropylethynyl)-1, 4-dihydro-4-(trifluoromethyl)-2H-3, 1-benzoxazin-2-one. Its empirical formula is C14 H9 ClF3 NO2 with a molecular mass of 315.68.


Clinical Pharmacology:

Mechanism of Action: Lamivudine is a synthetic nucleoside analogue. Intracellularly, Lamivudine is phosphorylated to its active 5’-triphosphate metabolite (L-TP). The principal mode of action of L-TP is inhibition of HIV reverse transcription via viral DNA chain termination. L-TP also inhibits the RNA-and DNA-dependent DNA polymerase activities of reverse transcriptase (RI). Zidovudine is a synthetic nucleoside analogue of the naturally occurring nucleoside, thymidine, in which the 3’-hydroxy (-OH) group is replaced by an azido (-N3) group. Within cells, Zidovudine is converted to the active metabolite, Zidovudine 5’-triphosphate (AztTP), by the sequential action of the cellular enzymes. Zidovudine 5’-triphosphate inhibits the activity of the HIV reverse transcriptase both by competing for utilization with the natural substrate, deoxythymidine 5’-triphosphate (dTTP), and by its incorporation into viral DNA. The lack of a 3’-OH group in the incorporated nucleoside analogue prevents the formation of the 5’ to 3’ phosphodiester linkage essential for DNA chain elongation and, therefore, the viral DNA growth is terminated.

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


Pharmacokinetics:

Lamivudine: Oral absorption is rapid, with a mean absolute bioavailability of 82-87%. Food has no significant effect on systemic exposure to Lamivudine. Cmax is achieved within 1-1.5 hours. Plasma protein binding is <36%. Its volume of distribution is 0.9 to 1.7 L/kg. Intracellularly, Lamivudine is phosphorylated to its active 5'-triphosphate metabolite (L-TP). Hepatic metabolism is a minor route of elimination for Lamivudine. Most of an oral dose of Lamivudine (70-71%) is excreted unchanged in the urine. The only known metabolite of Lamivudine in humans is the trans-sulfoxide metabolite, which accounts for less than 5% of a dose appearing in the urine. The mean elimination half-life after a single dose of Lamivudine ranges 3-7 hours.

Zidovudine: Following oral administration, Zidovudine is rapidly absorbed and extensively distributed, with peak serum concentrations occurring within 0.5-1.5 hours. Oral bioavailability of Zidovudine is 54%-74%. Plasma protein binding is low (<38%). Zidovudine is primarily eliminated by hepatic metabolism. Elimination half-life is 0.5-3 hrs. The major metabolite of Zidovudine is 3’-azido-3’-deoxy-5’-O-ß-D-glucopyranuronosylthymidine (GZDV). Urinary recovery of Zidovudine and GZDV accounts for 14% and 74%, respectively.

Efavirenz: Food increases the absorption of Efavirenz. A mean increase of 28% for AUC and 79% for Cmax is seen when administered with food. Total protein binding is 99%. Elimination half-life is 52 to 76 hours after a single dose. Efavirenz is metabolized in the liver via the cytochrome P450 system (P450CYP3A4 and P450CYP2B6). Efavirenz can induce its own metabolism. Renal excretion is 14% to 34%. The majority is excreted as changed drug. Excretion in feces is 16 % to 61%.


Indication:

In the management of Human Immunodeficiency Virus (HIV) infection in adults


Dosage And Administration:

One tablet from Part A [containing Lamivudine (150 mg) and Zidovudine (300mg)] is to be taken once in the morning and once in the evening. One tablet of Part B [containing Efavirenz (600 mg)] is to be taken once daily on an empty stomach, preferably at bed-time.

Dose adjustment: Lamivudine dosage adjustment is necessary in patients with renal impairment. Zidovudine dose reduction may be necessary in patients with impaired hepatic function. Therefore, this kit should not be used in patients with clinical need for dose adjustment i.e. in renal impairment, hepatic impairment and in case of dose-limiting adverse effects.


Adverse Reactions:

Lamivudine: Adverse effects of Lamivudine include diarrhea and other gastrointestinal disturbances, headache, fatigue, insomnia, arthralgias, myalgias, neuropathy, nasal signs and symptoms, elevated liver enzymes, skin rash, fever or chills, ear, nose, and throat infections. Neutropenia has not been frequent with recommended doses of Lamivudine. Lactic acidosis and severe hepatomegaly with steatosis, including fatalities, have been reported. Pancreatitis has been reported.

Zidovudine: The frequency and severity of adverse events associated with the use of Zidovudine in adults is greater in patients with more advanced infection at the time of initiation of therapy. Anaemia in patients with advanced HIV disease receiving Zidovudine appears to be the result of impaired erythrocyte maturation. Other adverse events are fever, headache, nausea, vomiting, anorexia, myalgia, insomnia, dizziness, paraesthesia, dyspnoea, rash, malaise, gastrointestinal pain, dyspepsia, and taste perversion.

Efavirenz: The most significant adverse events observed in patients treated with Efavirenz are nervous system symptoms, psychiatric symptoms and rash. A few cases of pancreatitis have been described, 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. Increases in total cholesterol of 10-20% have been observed in some uninfected volunteers receiving Efavirenz. Other side effects are allergic reactions, asthenia, abnormal coordination, ataxia, convulsions, hypoesthesia, paraesthesia, neuropathy, tremor, gynaecomastia, constipation, malabsorption, flushing, palpitations, hepatic enzyme increase, hepatic failure, hypercholesterolaemia, hypertriglyceridaemia, arthralgia, myalgia, myopathy aggressive reactions, agitation, delusions, emotional lability, mania, neurosis, paranoia, psychosis, suicide, dyspnoea, erythema multiforme, nail disorders, skin discoloration, Stevens-Johnson Syndrome, abnormal vision and tinnitus.


Warnings And Precautions:

Lamivudine: Use Lamivudine with extreme caution in pediatric patients with a history of prior antiretroviral nucleoside exposure, pancreatitis, or other risk factors for developing pancreatitis; caution should be exercised when administering Lamivudine to those patients with known risk factors for liver disease; treatment with Lamivudine should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity; some patients with HIV and chronic liver disease due to hepatitis B have experienced recurrent hepatitis B upon disontinuation of Lamivudine; in individuals with hepatitis B and HIV co-infection safety and efficacy have not been established; renal impairment.

Zidovudine: Bone marrow suppression: Zidovudine should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count <1000 cells/mm3 or hemoglobin <9.5 g/dL. Frequent blood counts are strongly recommended in patients with advanced HIV disease who are treated with Zidovudine. For patients with asymptomatic or early HIV disease, periodic blood counts are recommended. If anaemia or neutropenia develops, dosage adjustments may be necessary

Myopathy: Myopathy and myositis with pathological changes, similar to that produced by HIV disease, have been associated with prolonged use of Zidovudine.

Lactic acidosis/severe hepatomegaly with steatosis: Therapy with Zidovudine should be suspended until the diagnosis of lactic acidosis has been excluded. Caution should be exercised when administering Zidovudine to any patient, particularly obese women, with hepatomegaly, hepatitis, or other known risk factors for liver disease. Treatment with Zidovudine should be suspended in the setting of rapidly elevating aminotransferase levels, progressive hepatomegaly, or metabolic/lactic acidosis of unknown etiology.

Impaired renal and hepatic function: Zidovudine is eliminated from the body primarily by renal excretion following metabolism in the liver. In patients with severely impaired renal function, dosage reduction is recommended. Although very little data are available, patients with severely impaired hepatic function may be at greater risk of toxicity.

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.

Efavirenz: General: Efavirenz must not be used as a single agent to treat HIV or added on as a sole agent to a failing regimen. As with all other non-nucleoside reverse transcriptase inhibitors, resistant virus emerges rapidly when Efavirenz is administered as monotherapy. The choice of new antiretroviral agent(s) to be used in combination with Efavirenz should take into consideration the potential for viral cross-resistance.

Psychiatric Symptoms: Serious psychiatric adverse experiences have been reported in patients treated with Efavirenz. These include severe depression, suicidal ideation/attempts, aggressive behaviour, paranoid reactions and manic reactions. Patients with a prior history of psychiatric disorders appear to be at greater risk for these psychiatric adverse experiences. 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 risk of continued therapy outweighs the benefits.

Skin Rash: Rash associated with blistering, moist desquamation or ulceration, erythema multiforme or Stevens-Johnson syndrome have been reported in patients treated with Efavirez. 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.

Nervous System Symptoms: These include dizziness, insomnia, impaired concentration, somnolence, abnormal dreams and hallucinations. Nervous system symptoms usually begin during the first one or two days of therapy and generally resolve after the first 2-4 weeks. 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 seems to improve the tolerability of these symptoms and can be recommended during the first weeks of therapy and in patients who continue to experience these symptoms. Patients should be altered 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.

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.

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 must be exercised in administering Efavirenz to these patients.

Cholesterol: Monitoring of cholesterol and triglycerides should be considered in patients treated with Efavirenz.

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.

Renal Impairment: The pharmacokinetics of Efavirenz have not been studied in patients with renal insufficiency. However, less than 1% of Efavirenz is excreted unchanged in the urine, so the impact of renal impairment on Efavirenz elimination should be minimal.

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 Efavirenz. Barrier contraception should always be used in combination with other methods of contraception (eg, oral or other hormonal contraceptives). Women of childbearing potential should undergo pregnancy testing before initiation of Efavirenz. If this drug 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. There are no adequate and well controlled studies of Zidovudine and Lamivudine in pregnant women. Zidovudine and Lamivudine should be used in pregnant women only if potential benefits overweigh the risks.

Nursing mother: It is recommended that HIV-infected mothers do not breast-feed their infants to avoid the risk of postnatal transmission of HIV infection. Zidovudine is excreted in human milk. Although it is not known whether Lamivudine is excreted in human milk, there is a potential for adverse effects in nursing infants. Animal data suggest that Efavirenz may be passed into breast milk. Therefore, Mothers should be instructed not to breastfeed if they are receiving this kit.


Drug interactions:

Lamivudine: Trimethoprim 160 mg and sulfamethoxazole 800 mg once daily has been shown to increase Lamivudine exposure (AUC). The effect of higher doses of trimethoprim and sulfamethoxazole on Lamivudine pharmacokinetics has not been investigated. Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of one another. Therefore, use of Lamivudine in combination with zalcitabine is not recommended.

Zidovudine: Concomitant use of Zidovudine with Stavudine and Zidovudine with doxorubicin should be avoided since an antagonistic relationship has been demonstrated. Some nucleoside analogues affecting DNA replication, such as ribavirin, antagonize the in vitro antiviral activity of Zidovudine against HIV; concomitant use of such drugs should be avoided. Coadministration of ganciclovir, interferon-alpha, and other bone marrow suppressive or cytotoxic agents may increase the hematological toxicity of Zidovudine. For patients experiencing pronounced anemia or other severe Zidovudine-associated events while receiving chronic administration of Zidovudine and some of the drugs (e.g., fluconazole, valproic acid), Zidovudine dose reduction may be considered.

Efavirenz: Efavirenz is an inducer of CYP3A4 in vivo. Other compounds that are substrates of CYP3A4 may have decreased plasma concentrations when coadministered with Efavirenz. In vitro studies have demonstrated that Efavirenz inhibits 2C9, 2C19 and 3A4 isoenzymes in the range of observed Efavirenz concentrations. Coadministration of Efavirenz with drugs primarily metabolized by these isoenzymes may result in altered plasma concentrations of the coadministered drug. Therefore, appropriate dose adjustments may be necessary for these drugs. Drugs which induce CYP3A4 activity (e.g. Phenobarbital, rifampin, rifabutin) would be expected to increase the clearance of Efavirenz resulting in lowered plasma concentrations.

Drug interactions with Efavirenz are summarized in following table

Drugs That Should Not Be Co-administered With Efavirenz
Drug Class Drugs Within Class Not To Be Coadministered With Efavirenz
Antihistamines   astemizole
Benzodiazepines   midazolam, triazolam
GI Motility Agents   cisapride
Anti-Migraine   ergot derivatives
Established Drug Interactions
Drug NameEffectClinical Comment
Clarithromycin Decreased clarithromycin concentration
Increased 14-OH metabolite concentration
Plasma concentrations decreased by Efavirenz; clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving Efavirenz and clarithromycin. No dose adjustment of Efavirenz is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered (see Other Drugs, following table). Other macrolide antibiotics, such as erythromycin, have not been studied in combination with Efavirenz.
Indinavir Decreased indinavir concentration Increase indinavir dose from 800 mg to 1000 mg every 8 hours.
Methadone Decreased methadone concentration Coadministration in HIV-infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.
Ethinyl estradiol Increased ethinyl estradiol concentration Plasma concentrations increased by Efavirenz (Efavirenz); clinical significance unknown. Because the potential interaction of Efavirenz with oral contraceptives has not been fully characterized, a reliable method of barrier contraception should be used in addition to oral contraceptives.
Rifabutin Decreased rifabutin concentration Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.
Rifampin Decreased Efavirenz concentration Clinical significance of reduced Efavirenz concentrations unknown.
Ritonavir Increased ritonavir concentration
Increased Efavirenz concentration
Combination was associated with a higher frequency of adverse clinical experiences (eg, dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when Efavirenz is used in combination with ritonavir.
Saquinavir Decreased saquinavir concentration Should not be used as sole protease inhibitor in combination with Efavirenz
Other potentially clinically significant drug or herbal product interactions with Efavirenz
Anticoagulants: Warfarin Plasma concentrations and effects potentially increased or decreased by Efavirenz
Anticonvulsants: Phenytoin, Phenobarbital, Carbamazepine Potential for reduction in anticonvulsant and/or Efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.
Anti-HIV protease inhibitors:
Saquinavir/ritonavir combination
Amprenavir
No pharmacokinetic data are available.

Efavirenz has the potential to decrease serum concentrations of amprenavir.

Non-nucleoside reverse transcriptase inhibitors No studies have been performed with other NNRTIs.
St John's wort (hypericum perforatum) Expected to substantially decrease plasma levels of Efavirenz; has not been studied in combination with Efavirenz.

Contraindications:

This kit is contraindicated in patients hypersensitive to any of the components of the formulation. Efavirenz must not be administered concurrently with astemizole, cisapride, midazolam, triazolam or ergot alkaloids because competition for the cytochrome P450 3A4 enzyme by Efavirenz could result in inhibition of metabolism of these drugs and create the potential for serious and/or life-threatening adverse events (for example, cardiac arrhythmias, prolonged sedation or respiratory depression).


Overdosage:

There is no known antidote for Lamivudine. It is not known whether Lamivudine can be removed by peritoneal dialysis or hemodialysis. Acute overdosage of Zidovudine (exposure up to 50 g) in children and adults produce no specific symptoms or signs apart from those listed as adverse events such as fatigue, headache, vomiting, and occasional reports of hematological disturbances. Some patients accidentally taking Efavirenz 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.


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