DUOVIR-E Kit (Efavirenz + Zidovudine / Lamivudine )

Table of Content

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

Black Box Warning

Hematologic toxicity, myopathy, lactic acidosis and severe hepatomegaly with steatosis, and exacerbations of hepatitis B.

Zidovudine, a component of DUOVIR-E KIT, has been associated with hematologic toxicity, including neutropenia and severe anemia, particularly in patients with advanced human immunodeficiency virus (HIV-1) disease.

Prolonged use of zidovudine has been associated with symptomatic myopathy.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including lamivudine and zidovudine. discontinue DUOVIR-E KIT if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur.

Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and HIV-1 and have discontinued lamivudine, which is one of the components of DUOVIR-E KIT. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue DUOVIR-E KIT and are co-infected with HIV-1 and HBV. if appropriate, initiation of anti-hepatitis b therapy may be warranted.

Qualitative and Quantitative Composition

Duovir-E Kit

Each kit contains:

(A) One efavirenz tablet

Each film-coated tablet contains:

Efavirenz ……… 600 mg

(B) Two lamivudine and zidovudine fixed-dose combination tablets

Each film-coated tablet contains:

Lamivudine ………. 150 mg

Zidovudine ……….. 300 mg

Dosage Form(S) And Strength(S)

Efavirenz – oral film-coated tablet of 600 mg

Lamivudine and Zidovudine – oral fixed-dose combination tablet of 150 mg of lamivudine and 300 mg of zidovudine.

Clinical Particulars

Therapeutic Indications

DUOVIR-E Kit is indicated for the treatment of HIV infection in adults.

Posology and Method of Administration

Recommended Dosage for Adults

·         One fixed-dose combination tablet containing zidovudine 300 mg and lamivudine 150 mg to be taken orally twice daily.

·         One tablet of efavirenz 600 mg to be taken orally, once daily. It is recommended that the efavirenz tablet be taken on an empty stomach, preferably at bedtime. The increased efavirenz concentrations observed following administration of efavirenz with food may lead to an increase in the frequency of adverse reactions. Bedtime dosing improves the tolerability of nervous system side effects.

Not Recommended Due to Lack of Dosage Adjustment

Because DUOVIR-E Kit has a fixed-dose tablet of zidovudine and lamivudine and cannot be dose-adjusted, DUOVIR-E Kit is not recommended in the following:

·         Patients with creatinine clearance less than 50 mL per minute (see Special Warnings and Precautions for Use).

·         Patients with hepatic impairment (see Special Warnings and Precautions for Use).

·         Patients experiencing dose-limiting adverse reactions.

Contraindications

DUOVIR-E Kit is contraindicated in patients with previous demonstrated clinically significant hypersensitivity (e.g., Stevens-Johnson syndrome, erythema multiforme or toxic skin eruptions) to any of the components of this product.

Co-administration of efavirenz with elbasvir and grazoprevir is contraindicated.

Special Warnings and Precautions for Use

Efavirenz

QTc Prolongation

QTc prolongation has been observed with the use of efavirenz. Consider alternatives to efavirenz when co-administered with a drug with a known risk of torsades de pointes or when administered to patients at higher risk for torsade de pointes.

Resistance

Efavirenz must not be used as a single agent to treat HIV-1 infection or added on as a sole agent to a failing regimen. 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.

Co-administration with Related Products

Co-administration of efavirenz with efavirenz/emtricitabine/tenofovir disoproxil fumarate is not recommended unless needed for dose adjustments (e.g., rifampicin), since efavirenz is one of its active ingredients.

Psychiatric Symptoms

Serious psychiatric adverse experiences have been reported in patients treated with efavirenz. In controlled trials of 1,008 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 (regardless of causality) 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%), non-fatal 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; 1% of efavirenz-treated patients discontinued or interrupted treatment because of one or more of these selected psychiatric symptoms. There have also been occasional post-marketing 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. Post-marketing cases of catatonia have also been reported and may be associated with increased efavirenz exposure. 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 outweigh the benefits.

Nervous System Symptoms

In controlled trials, 53% (531/1,008) of patients receiving efavirenz reported central nervous system  symptoms (any grade, regardless of causality) compared with 25% (156/635) of patients receiving control regimens. These symptoms included, but were not limited to, dizziness (28.1% of the 1,008 patients), 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 incidence of new-onset nervous system symptoms among efavirenz-treated patients were generally similar to those in the indinavir-containing control arm.

Late-onset neurotoxicity, including ataxia and encephalopathy (impaired consciousness, confusion, psychomotor slowing, psychosis, delirium), may occur months to years after beginning efavirenz therapy. Some events of late-onset neurotoxicity have occurred in patients with CYP2B6 genetic polymorphisms, which are associated with increased efavirenz levels despite standard dosing of efavirenz. Patients presenting with signs and symptoms of serious neurologic adverse experiences should be evaluated promptly to assess the possibility that these events may be related to efavirenz use, and whether discontinuation of efavirenz is warranted.

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.

Embryo-Fetal Toxicity

Efavirenz may cause fetal harm when administered during the first trimester to a pregnant woman. Advise females of reproductive potential who are receiving efavirenz to avoid pregnancy.

Rash

In controlled clinical trials, 26% (266/1,008) of adult patients treated with 600 mg efavirenz experienced new-onset skin rash compared with 17% (111/635) of those treated in control groups. Rash associated with blistering, moist desquamation or ulceration occurred in 0.9% (9/1,008) of patients treated with efavirenz. The incidence of Grade 4 rash (e.g., erythema multiforme, Stevens-Johnson syndrome) in adult patients treated with efavirenz in all studies and expanded access was 0.1%. Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first 2 weeks of initiating therapy with efavirenz (median time to onset of rash in adults was 11 days) and, in most patients continuing therapy with efavirenz, rash resolves within 1 month (median duration, 16 days). The discontinuation rate for rash in clinical trials was 1.7% (17/1,008).

Efavirenz can generally be reinitiated in patients interrupting therapy because of rash. Efavirenz should 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. For patients who have had a life-threatening cutaneous reaction (e.g., Stevens-Johnson syndrome), alternative therapy should be considered.

Hepatotoxicity

Post-marketing cases of hepatitis, including fulminant hepatitis progressing to liver failure requiring transplantation or resulting in death, have been reported in patients treated with efavirenz. Reports have included patients with underlying hepatic disease, including co-infection with hepatitis B or C, and patients without pre-existing hepatic disease or other identifiable risk factors.

Efavirenz is not recommended for patients with moderate or severe hepatic impairment. Careful monitoring is recommended for patients with mild hepatic impairment receiving efavirenz.

Monitoring of liver enzymes before and during treatment is recommended for all patients. Consider discontinuing efavirenz in patients with persistent elevations of serum transaminases to greater than five times the upper limit of the normal range.

Discontinue efavirenz if elevation of serum transaminases is accompanied by clinical signs or symptoms of hepatitis or hepatic decompensation.

Convulsions

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

Lipid Elevations

Treatment with efavirenz has resulted in increases in the concentration of total cholesterol and triglycerides. Cholesterol and triglyceride testing should be performed before initiating efavirenz therapy and at periodic intervals during therapy.

Lamivudine and Zidovudine

Hematologic Toxicity/Bone Marrow Suppression

Zidovudine, a component of DUOVIR-E Kit, has been associated with hematologic toxicity, including neutropenia and anemia, particularly in patients with advanced HIV-1 disease. DUOVIR-E Kit should be used with caution in patients who have bone marrow compromise, evidenced by granulocyte count less than 1,000 cells per mm3 or hemoglobin less than 9.5 grams per dL.

Frequent blood counts are strongly recommended in patients with advanced HIV-1 disease who are treated with DUOVIR-E Kit. Periodic blood counts are recommended for other HIV-1-infected patients. If anemia or neutropenia develops, dosage interruption may be needed.

Myopathy

Myopathy and myositis, with pathological changes similar to that produced by HIV disease, have been associated with prolonged use of zidovudine, and, therefore, may occur with therapy with DUOVIR-E Kit.

Lactic Acidosis and Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including lamivudine and zidovudine. A majority of these cases have been in women. Female sex and obesity may be risk factors for the development of lactic acidosis and severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogues. Treatment 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 Hepatitis B Virus (HBV) Co-infection

Post-Treatment Exacerbations Of Hepatitis

Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment.

Emergence Of Lamivudine-Resistant HBV

Safety and efficacy of lamivudine have not been established for the treatment of chronic hepatitis B in subjects dually infected with HIV-1 and HBV. Emergence of HBV variants associated with resistance to lamivudine has also been reported in HIV-1-infected subjects who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with HBV.

Use with Interferon- and Ribavirin-based Regimens

Patients receiving interferon-alfa with or without ribavirin and zidovudine/lamivudine should be closely monitored for treatment-associated toxicities, especially hepatic decompensation, neutropenia, and anemia. Discontinuation of zidovudine/lamivudine should be considered as medically appropriate. Dose reduction or discontinuation of interferon-alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6).

Exacerbation of anemia has been reported in HIV-1/HCV co-infected patients receiving ribavirin and zidovudine. Co-administration of ribavirin and zidovudine/lamivudine is not advised.

Pancreatitis

Lamivudine/zidovudine should be used with caution in patients with a history of pancreatitis or other significant risk factors for the development of pancreatitis. Treatment with lamivudine/zidovudine should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur.

Lipoatrophy

Treatment with zidovudine, a component of DUOVIR-E Kit, has been associated with loss of subcutaneous fat. The incidence and severity of lipoatrophy are related to cumulative exposure. This fat loss, which is most evident in the face, limbs, and buttocks, may be only partially reversible and improvement may take months to years after switching to a non-zidovudine-containing regimen. Patients should be regularly assessed for signs of lipoatrophy during therapy with zidovudine-containing products and, if feasible, therapy should be switched to an alternative regimen if there is suspicion of lipoatrophy.

Lamivudine, Zidovudine and Efavirenz

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including efavirenz. 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 , or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) 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.

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.

Drug Interactions

Efavirenz

Potential for Efavirenz to Affect Other Drugs:

Efavirenz has been shown in vivo to induce CYP3A and CYP2B6. Other compounds that are substrates of CYP3A or CYP2B6 may have decreased plasma concentrations when co-administered with efavirenz.

Potential for Other Drugs to Affect Efavirenz

Drugs that induce CYP3A activity (e.g., phenobarbital, rifampin, rifabutin) would be expected to increase the clearance of efavirenz, resulting in lowered plasma concentrations.

QT-Prolonging Drugs

There is limited information available on the potential for a pharmacodynamic interaction between efavirenz and drugs that prolong the QTc interval. QTc prolongation has been observed with the use of efavirenz. Consider alternatives to efavirenz when co-administered with a drug with a known risk of torsade de pointes.

Established and Other Potentially Significant Drug Interactions

Drug interactions with efavirenz are summarized in Table 1.

Table 1: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction

Concomitant Drug Class: Drug Name

 

Effect

Clinical Comment

HIV Antiviral Agents

Protease inhibitor: Fosamprenavir calcium

 

↓ amprenavir

Fosamprenavir (unboosted): Appropriate doses of the combinations with respect to safety and efficacy have not been established.

Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when efavirenz is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when efavirenz is administered with fosamprenavir plus ritonavir twice daily.

Protease inhibitor: Atazanavir

↓ atazanavir*

Treatment-naïve patients: When co-administered with efavirenz, the recommended dose of atazanavir is 400 mg with ritonavir 100 mg (together once daily with food) and efavirenz 600 mg (once daily on an empty stomach, preferably at bedtime).

Treatment-experienced patients: Co-administration of efavirenz and atazanavir is not recommended.

Protease inhibitor: Indinavir

↓ indinavir*

The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1,000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz.

Protease inhibitor: Lopinavir/ritonavir

↓ lopinavir*

Lopinavir/ritonavir once-daily dosing is not recommended when co-administered with efavirenz. The dose of lopinavir/ritonavir must be increased when co-administered with efavirenz. See the lopinavir/ritonavir prescribing information for dose adjustments of lopinavir/ritonavir when co-administered with efavirenz in adult patients.

Protease inhibitor: Ritonavir

↑ ritonavir*

↑ efavirenz*

Monitoring for elevation of liver enzymes and for adverse clinical experiences (e.g., dizziness, nausea, paresthesia) when efavirenz is co-administered with ritonavir.

Protease inhibitor:

Saquinavir

↓ saquinavir*

Appropriate doses of the combination of efavirenz and saquinavir/ritonavir with respect to safety and efficacy have not been established.

NNRTI: Other NNRTIs

↑ or ↓ efavirenz and/or NNRTI

Combining two NNRTIs has not been shown to be beneficial. Efavirenz should not be co-administered with other NNRTIs.

CCR5 co-receptor antagonist:

Maraviroc

 

↓ maraviroc*

Refer to the full prescribing information for maraviroc for guidance on co-administration with efavirenz.

Hepatitis C antiviral agents

Boceprevir

 

↓ boceprevir*

Concomitant administration of boceprevir with efavirenz is not recommended because it may result in loss of therapeutic effect of boceprevir.

Elbasvir/

Grazoprevir

 

↓ elbasvir

↓ grazoprevir

 

Co-administration of efavirenz with elbasvir/grazoprevir is contraindicated (see Contraindications) because it may lead to loss of virologic response to elbasvir/grazoprevir.

Pibrentasvir/

Glecaprevir

↓ pibrentasvir

↓ glecaprevir

Co-administration of efavirenz is not recommended because it may lead to reduced therapeutic effect of pibrentasvir/glecaprevir.

Simeprevir

 

↓ simeprevir*

↔ efavirenz*

Concomitant administration of simeprevir with efavirenz is not recommended because it may result in loss of therapeutic effect of simeprevir.

Velpatasvir/

Sofosbuvir

↓ velpatasvir

Co-administration of efavirenz and sofosbuvir/velpatasvir is not recommended because it may result in loss of therapeutic effect of sofosbuvir/velpatasvir

Velpatasvir/ Sofosbuvir/ Voxilaprevir

↓ velpatasvir

↓ voxilaprevir

Co-administration of efavirenz and sofosbuvir/velpatasvir/voxilaprevir is not recommended because it may result in loss of therapeutic effect of sofosbuvir/velpatasvir/ voxilaprevir.

Other agents

Anticoagulant:
Warfarin

↑ or ↓ warfarin

Monitor INR and adjust warfarin dosage if necessary.

Anticonvulsants:
Carbamazepine

 

 

 

Phenytoin
Phenobarbital

 

↓ carbamazepine*
↓ efavirenz*

 

 

 

↓ anticonvulsant

↓ efavirenz

There are insufficient data to make a dose recommendation for efavirenz. Alternative anticonvulsant treatment should be used.

Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.

Antidepressants:

Bupropion

 

 

 

Sertraline

 

↓ bupropion*

 

 

 

↓ sertraline*

 

Increases in bupropion dosage should be guided by clinical response. Bupropion dose should not exceed the maximum recommended dose.

Increases in sertraline dosage should be guided by clinical response.

Antifungals:

Voriconazole

 

 

 

 

 

 

Itraconazole

 

 

 

 

Ketoconazole

 

Posaconazole

 

↓voriconazole*

↑efavirenz*

 

 

 

 

 

↓ itraconazole*

↓ hydroxy-itraconazole*

 

 

↓ ketoconazole*

 

 

↓ posaconazole*

Efavirenz and voriconazole should not be co-administered at standard doses. When voriconazole is co-administered with efavirenz, voriconazole maintenance dose should be increased to 400 mg every 12 hours and efavirenz dose should be decreased to 300 mg once daily using the capsule formulation. Efavirenz tablet should not be broken.

 

Consider alternative antifungal treatment because no dose recommendation for itraconazole can be made.

 

 

Consider alternative antifungal treatment because no dose recommendation for ketoconazole can be made.

 

Avoid concomitant use unless the

benefit outweighs the risks.

Anti-infective:

Clarithromycin

↓ clarithromycin*
↑ 14-OH metabolite*

 

Consider alternatives to macrolide antibiotics because of the risk of QT interval prolongation.

Antimycobacterial: Rifabutin

 

 

Rifampin

↓ rifabutin*

 

 

↓ efavirenz*

Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given two or three times a week.

Increase efavirenz to 800 mg once daily when co-administered with rifampicin to patients weighing 50 kg or more.

Antimalarials:

Artemether/

Lumefantrine

 

 

 

Atovaquone/

Proguanil

 

↓ artemether*

↓ dihydroartemisinin*

↓ lumefantrine*

 

 

↓ atovaquone

↓ proguanil

 

Consider alternatives to artemether/lumefantrine because of the risk of QT interval prolongation.

 

Concomitant administration is not recommended.

Calcium channel blockers:

Diltiazem

 

 

 

 

 

Others

(e.g., felodipine, nicardipine, nifedipine, verapamil)

 

↓ diltiazem*
↓ desacetyl diltiazem*
↓ N-monodesmethyl diltiazem*

 

 

 

↓ calcium channel blocker

Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of efavirenz is necessary when administered with diltiazem.

 

When co-administered with efavirenz, dosage adjustment of calcium channels blocker may be needed and should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker).

HMG-CoA reductase inhibitors:

Atorvastatin

Pravastatin
Simvastatin

 

 

 

↓ atorvastatin*
↓ pravastatin*
↓ simvastatin*

Plasma concentrations of atorvastatin, pravastatin and simvastatin decreased. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.

Hormonal contraceptives: Oral

Ethinyl estradiol/ Norgestimate

 

 

Implant

Etonogestrel

 

 

↓ active metabolites of

norgestimate*

 

 

 

↓ etonogestrel

 

 

A reliable method of barrier contraception must be used in addition to hormonal contraceptives.

 

A reliable method of barrier contraception should be used in addition to hormonal contraceptives. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients.

Immuno-suppressants:

Cyclosporine, tacrolimus, sirolimus and others metabolized by CYP3A

 

¯ immunosuppressant

Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with efavirenz.

Narcotic analgesic: Methadone

 

↓ methadone*

Monitor for signs of methadone withdrawal and increase methadone dose if required to alleviate withdrawal symptoms.

       

*The interaction between efavirenz and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.

This table is not all-inclusive.

Drugs Without Clinically Significant Interactions with Efavirenz

No dosage adjustment is recommended when efavirenz is given with the following: aluminum/magnesium hydroxide antacids, azithromycin, cetirizine, famotidine, fluconazole, lorazepam, nelfinavir, nucleoside reverse transcriptase inhibitors (abacavir, emtricitabine, lamivudine, stavudine, tenofovir disoproxil fumarate, zidovudine), paroxetine, and raltegravir.

Cannabinoid Test Interaction

Efavirenz does not bind to cannabinoid receptors. False-positive urine cannabinoid test results have been reported with some screening assays in uninfected and HIV-infected subjects receiving efavirenz. Confirmation of positive screening tests for cannabinoids by a more specific method is recommended.

Zidovudine

Agents Antagonistic with Zidovudine

Concomitant use of zidovudine with the following drugs should be avoided since an antagonistic relationship has been demonstrated in vitro:

·         Stavudine

·         Doxorubicine

·         Nucleoside analogues, e.g., ribavirin

Hematologic/Bone Marrow Suppressive/Cytotoxic Agents

Co-administration with the following drugs may increase the hematologic toxicity of zidovudine:

·         Ganciclovir

·         Interferon-alfa

·         Ribavirin

·         Other bone marrow suppressive or cytotoxic agents

Lamivudine

Sorbitol

Co-administration of single doses of lamivudine and sorbitol resulted in a sorbitol dose-dependent reduction in lamivudine exposures. When possible, avoid use of sorbitol-containing medicines with lamivudine-containing medicines.

Use in Special Populations

Pregnant Women

DUOVIR–e Kit should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Efavirenz

Risk Summary

There are retrospective case reports of neural tube defects in infants whose mothers were exposed to efavirenz-containing regimens in the first trimester of pregnancy. Prospective pregnancy data from the Antiretroviral Pregnancy Registry (APR) are not sufficient to adequately assess this risk. Available data from the APR show no difference in the risk of overall major birth defects compared to the background rate for major birth defects of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). Although a causal relationship has not been established between exposure to efavirenz in the first trimester and neural tube defects, similar malformations have been observed in studies conducted in monkeys at doses similar to the human dose. In addition, fetal and embryonic toxicities occurred in rats at a dose ten times less than the human exposure at recommended clinical dose. Because of the potential risk of neural tube defects, efavirenz should not be used in the first trimester of pregnancy. Advise pregnant women of the potential risk to the fetus.

Data

Human Data

There are retrospective post-marketing reports of findings consistent with neural tube defects, including meningomyelocele, in infants of mothers exposed to efavirenz-containing regimens in the first trimester.

Based on prospective reports from the APR of approximately 1,000 live births following exposure to efavirenz-containing regimens (including over 800 live births exposed in the first trimester), there was no difference between efavirenz and overall birth defects compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. As of the interim APR report issued December 2014, the prevalence of birth defects following first-trimester exposure was 2.3% (95% CI: 1.4–3.6%). One of these prospectively reported defects with first-trimester exposure was a neural tube defect. A single case of anophthalmia with first-trimester exposure to efavirenz has also been prospectively reported. This case also included severe oblique facial clefts and amniotic banding, which have a known association with anophthalmia.

Animal Data

Effects of efavirenz on embryo-fetal development have been studied in three nonclinical species (cynomolgus monkeys, rats, and rabbits). In monkeys, efavirenz 60 mg/kg/day was administered to pregnant females throughout pregnancy (gestation days 20 through 150). The maternal systemic drug exposures (AUC) were 1.3 times the exposure in humans at the recommended clinical dose (600 mg/day), with fetal umbilical venous drug concentrations approximately 0.7 times the maternal values. Three fetuses of 20 fetuses/infants had one or more malformations; there were no malformed fetuses or infants from placebo-treated mothers. The malformations that occurred in these three monkey fetuses included anencephaly and unilateral anophthalmia in one fetus, microophthalmia in a second, and cleft palate in the third. There was no NOAEL (no-observable-adverse-effect level) established for this study because only one dosage was evaluated. In rats, efavirenz was administered either during organogenesis (gestation days 7 to 18) or from gestation day 7 through lactation day 21 at 50, 100, or 200 mg/kg/day. Administration of 200 mg/kg/day in rats was associated with increase in the incidence of early resorptions; and doses 100 mg/kg/day and greater were associated with early neonatal mortality. The AUC at the NOAEL (50 mg/kg/day) in this rat study was 0.1 times that in humans at the recommended clinical dose. Drug concentrations in the milk on lactation day 10 were approximately 8 times higher than those in maternal plasma. In pregnant rabbits, efavirenz was neither embryo lethal nor teratogenic when administered at doses of 25, 50, and 75 mg/kg/day over the period of organogenesis (gestation days 6 through 18). The AUC at the NOAEL (75 mg/kg/day) in rabbits was 0.4 times that in humans at the recommended clinical dose.

Lamivudine and Zidovudine

Risk Summary

Available data from the APR show no difference in the overall risk of birth defects for lamivudine or zidovudine compared with the background rate for birth defects of 2.7% in the MACDP reference population (see DATA). The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks’ gestation. The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15–20%. The background risk for major birth defects and miscarriage for the indicated population is unknown.

Hyperlactatemia, which may be due to mitochondrial dysfunction, has been reported in infants with in utero exposure to zidovudine-containing products. These events were transient and asymptomatic in most cases. There have been few reports of developmental delay, seizures, and other neurological disease. However, a causal relationship between these events and exposure to zidovudine-containing products in utero or peri-partum has not been established.

In animal reproduction studies, oral administration of lamivudine to pregnant rabbits during organogenesis resulted in embryolethality at systemic exposure (AUC) similar to the recommended clinical dose; however, no adverse development effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (Cmax) 35 times the recommended clinical dose. Administration of oral zidovudine to female rats prior to mating and throughout gestation resulted in embryotoxicity at doses that produced systemic exposure (AUC) approximately 33 times higher than exposure at the recommended clinical dose. However, no embryotoxicity was observed after oral administration of zidovudine to pregnant rats during organogenesis at doses that produced systemic exposure (AUC) approximately 117 times higher than exposures at the recommended clinical dose. Administration of oral zidovudine to pregnant rabbits during organogenesis resulted in embryotoxicity at doses that produced systemic exposure (AUC) approximately 108 times higher than exposure at the recommended clinical dose. However, no embryotoxicity was observed at doses that produced systemic exposure (AUC) approximately 23 times higher than exposures at the recommended clinical dose (see DATA).

Data

Human Data

Lamivudine: Based on prospective reports to the APR of over 11,000 exposures to lamivudine during pregnancy resulting in live births (including over 4,500 exposed in the first trimester), there was no difference between the overall risk of birth defects for lamivudine compared with the background birth defect rate of 2.7% in a U.S. reference population of the MACDP. The prevalence of birth defects in live births was 3.1% (95% CI: 2.6–3.6%) following first trimester exposure to lamivudine-containing regimens and 2.8% (95% CI: 2.5–3.3%) following second/third trimester exposure to lamivudine-containing regimens.

Lamivudine pharmacokinetics were studied in pregnant women during two clinical studies conducted in South Africa. The trial assessed pharmacokinetics in 16 women at 36 weeks’ gestation using 150 mg lamivudine twice daily with zidovudine, 10 women at 38 weeks’ gestation using 150 mg lamivudine twice daily with zidovudine, and 10 women at 38 weeks gestation using lamivudine 300 mg twice daily without other antiretrovirals. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. In a subset of subjects, amniotic fluid specimens were collected following natural rupture of membranes and confirmed that lamivudine crosses the placenta in humans. Based on limited data at delivery, median (range) amniotic fluid concentrations of lamivudine were 3.9 (1.2 to 12.8)-fold greater compared with paired maternal serum concentration (n=8).

Zidovudine: Based on prospective reports to the APR of over 13,000 exposures to zidovudine during pregnancy resulting in live births (including over 4,000 exposed in the first trimester), there was no difference between the overall risk of birth defects for zidovudine compared with the background birth defect rate of 2.7% in a U.S. reference population of the MACDP. The prevalence of birth defects in live births was 3.2% (95% CI: 2.7–3.8%) following first trimester exposure to zidovudine-containing regimens and 2.8% (95% CI: 2.5–3.2%) following second/third trimester exposure to zidovudine-containing regimens.

A randomized, double-blind, placebo-controlled trial was conducted in HIV-1-infected pregnant women to determine the utility of zidovudine for the prevention of maternal-fetal HIV-1 transmission. Zidovudine treatment during pregnancy reduced the rate of materal-fetal HIV-1 transmission from 24.9% for infants born to placebo-treated mothers to 7.8% for infants born to mothers treated with zidovudine. There were no differences in pregnancy-related adverse events between the treatment groups. Of the 363 neonates that were evaluated, congenital abnormalities occurred with similar frequency between neonates born to mothers who received zidovudine and neonates born to mothers who received placebo. The observed abnormalities included problems in embryogenesis (prior to 14 weeks) or were recognized on ultrasound before or immediately after initiation of trial drug.

Zidovudine has been shown to cross the placenta and concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery. There have been reports of mild, transient elevations in serum lactate levels, which may be due to mitochondrial dysfunction, in neonates and infants exposed in utero or peri-partum to zidovudine-containing products. There have been few reports of developmental delay, seizures, and other neurological disease. However, a causal relationship between these events and exposure to zidovudine-containing products in utero or peri-partum has not been established. The clinical relevance of transient elevations in serum lactate is unknown.

Animal Data

Lamivudine: Lamivudine was administered orally to pregnant rats (at 90, 600, and 4,000 mg per kg per day) and rabbits (at 90, 300, and 1,000 mg per kg per day and at 15, 40, and 90 mg per kg per day) during organogenesis (on gestation days 7 through 16 and 8 through 20, respectively). No evidence of fetal malformations due to lamivudine was observed in rats and rabbits at doses producing plasma concentrations (Cmax) approximately 35 times higher than human exposure at the recommended daily dose. Evidence of early embryolethality was seen in the rabbit at system exposures (AUC) similar to those observed in humans, but there was no indication of this effect in the rat at plasma concentrations (Cmax) 35 times higher than human exposure at the recommended daily dose. Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta. In the pre-and postnatal development study in rats, lamivudine was administered orally at doses of 180, 900, and 4,000 mg per kg per day (from gestation day 6 through postnatal day 20). In the study, development of the offspring, including fertility and reproductive performance, was not affected by maternal administration of lamivudine.

Zidovudine: A study in pregnant rats (at 50, 150, or 450 mg per kg per day starting 26 days prior to mating through gestation to postnatal Day 21) showed increased fetal resorptions at doses that produced systemic exposures (AUC) approximately 33 times higher than exposure at the recommended daily human dose (300 mg twice daily). However, in an oral embryo-fetal development study in rats (at 125, 250, or 500 mg per kg per day on gestation days 6 through 15), no fetal resorptions were observed at doses that produced systemic exposure (AUC) approximately 117 times higher than exposures at the recommended daily human dose. An oral embryo-fetal development study in rabbits (at 75, 150, or 500 mg per kg per day on gestation days 6 through 18) showed increased fetal resorptions at the dose of 500 mg per kg per day dose, which produced systemic exposures (AUC) approximately 108 times higher than exposure at the recommended daily human dose; however, no fetal resorptions were noted at doses up to 150 mg per kg per day, which produced systemic exposure (AUC) approximately 23 times higher than exposures at the recommended daily human dose. These oral embryo-fetal development studies in the rat and rabbit revealed no evidence of fetal malformations with zidovudine. In another developmental toxicity study, pregnant rats (dosed at 3,000 mg per kg per day from days 6 through 15 of gestation) showed marked maternal toxicity and an increased incidence of fetal malformations at exposures greater than 300 times the recommended daily human dose based on AUC. However, there were no signs of fetal malformations at doses up to 600 mg per kg per day.

Lactating Women

Efavirenz

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking post-natal transmission of HIV. Because of the potential for HIV transmission in breastfed infants, advise women not to breastfeed.

Zidovudine/Lamivudine

The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Lamivudine and zidovudine are present in human milk. There is no information on the effects of lamivudine or zidovudine on the breastfed infant or the effects of the drugs on milk production. Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) serious adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving zidovudine/lamivudine.

Females and Males of Reproductive Potential

Efavirenz

Because of potential teratogenic effects, pregnancy should be avoided in women receiving efavirenz.

Pregnancy Testing                                                                                   

Females of reproductive potential should undergo pregnancy testing before initiation of efavirenz.

Contraception

Females of reproductive potential should use effective contraception during treatment with efavirenz and for 12 weeks after discontinuing efavirenz due to the long half-life of efavirenz. Barrier contraception should always be used in combination with other methods of contraception. Hormonal methods that contain progesterone may have decreased effectiveness.

Pediatric Patients

DUOVIR-E Kit is not indicated for use in children.

Geriatric Patients

Clinical studies of lamivudine plus zidovudine and also efavirenz did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

Patients with Renal Impairment

Zidovudine/lamivudine is not recommended for patients with creatinine clearance less than 50 mL per minute because it is a fixed-dose combination and the dosage of the individual components cannot be adjusted. If a dose reduction of the lamivudine or zidovudine is required for patients with renal impairment then the individual components should be used.

Patients with Hepatic Impairment

Efavirenz is not recommended for patients with moderate or severe hepatic impairment because there are insufficient data to determine whether dose adjustment is necessary. Patients with mild hepatic impairment may be treated with efavirenz without any adjustment in dose. 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.

Zidovudine/lamivudine is a fixed-dose combination and the dosage of the individual components cannot be adjusted. Zidovudine is primarily eliminated by hepatic metabolism and zidovudine concentrations are increased in patients with impaired hepatic function, which may increase the risk of hematologic toxicity. Frequent monitoring of hematologic toxicities is advised.

Effects on Ability to Drive and Use of Machines

No studies on the effects on the ability to drive and use machines have been performed with lamivudine and zidovudine fixed-dose combination tablets. Adverse reactions such as insomnia and other sleep disorders, dizziness, and depressive disorders have been reported with the use of lamivudine and zidovudine fixed-dose combination tablets. If they occur, such effects may affect tasks requiring alertness, including the patient's ability to drive and operate machinery.

Efavirenz may cause dizziness, impaired concentration, and/or somnolence. Patients should be instructed that if they experience these symptoms they should avoid potentially hazardous tasks such as driving or operating machinery.

Undesirable Effects

Zidovudine and Lamivudine

The following adverse reactions are discussed in other sections of the labeling:

·         Hematologic toxicity, including neutropenia and anemia

·         Symptomatic myopathy

·         Lactic acidosis and severe hepatomegaly with steatosis

·         Exacerbations of hepatitis B

·         Hepatic decompensation in patients co-infected with HIV-1 and hepatitis C

·         Exacerbation of anemia in HIV-1/ hepatitis C virus (HCV) co-infected patients receiving ribavirin and zidovudine

·         Pancreatitis

·         Immune reconstitution syndrome

·         Lipoatrophy  

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Lamivudine Plus Zidovudine Administered As Separate Formulations

In four randomized, controlled trials of lamivudine 300 mg per day plus zidovudine 600 mg per day, the following selected clinical and laboratory adverse events were observed (see Tables 2 and 3).

Table 2: Selected Clinical Adverse Reactions (Greater than or Equal to 5% Frequency) in Four Controlled Clinical Trials with Lamivudine 300 mg per day and Zidovudine 600 mg per day  

Adverse Reaction

Lamivudine plus Zidovudine

(n=251)

Body as a Whole

 

Headache

35%

Malaise and fatigue

27%

Fever or chills

10%

Digestive

 

Nausea

33%

Diarrhea

18%

Nausea and vomiting

13%

Anorexia and/or decreased appetite

10%

Abdominal pain

9%

Abdominal cramps

6%

Dyspepsia

5%

Nervous System

 

Neuropathy

12%

Insomnia and other sleep disorders

11%

Dizziness

10%

Depressive disorders

9%

Respiratory

 

Nasal signs and symptoms

20%

Cough

18%

Skin

 

Skin rashes

9%

Musculoskeletal

 

Musculoskeletal pain

12%

Myalgia

8%

Arthralgia

5%

Pancreatitis was observed in 9 of the 2,613 adult patients (0.3%) who received lamivudine in controlled clinical trials.

Selected laboratory abnormalities observed during therapy are listed in Table 3.

Table 3: Frequencies of Selected Laboratory Abnormalities Among Adults in Four Controlled Clinical Trials of Lamivudine 300 mg per day Plus Zidovudine 600 mg per day*

Test

(Abnormal Level)

Lamivudine plus zidovudine

% (n)

Neutropenia (ANC <750/mm3)

7.2% (237)

Anemia (Hgb <8.0 g/dL)

2.9% (241)

Thrombocytopenia (platelets <50,000/mm3)

0.4% (240)

ALT (>5.0 × ULN)

3.7% (241)

AST (>5.0 × ULN)

1.7% (241)

Bilirubin (>2.5 × ULN)

0.8% (241)

Amylase (>2.0 × ULN)

4.2% (72)

ULN = Upper limit of normal.

ANC = Absolute neutrophil count.

n = Number of patients assessed.

* Frequencies of these laboratory abnormalities were higher in subjects with mild laboratory abnormalities at baseline.

Postmarketing Experience

The following adverse reactions have been identified during post-marketing use. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a whole: Redistribution/accumulation of body fat.

Cardiovascular: Cardiomyopathy.

Endocrine and metabolic: Gynecomastia, hyperglycemia.

Gastrointestinal: Oral mucosal pigmentation, stomatitis.

General: Vasculitis, weakness.

Hemic and lymphatic: Anemia (including pure red cell aplasia and anemias progressing on therapy), lymphadenopathy, splenomegaly.

Hepatic and pancreatic: Lactic acidosis and hepatic steatosis, pancreatitis, post-treatment exacerbation of hepatitis B.

Hypersensitivity: Sensitization reactions (including anaphylaxis), urticaria.

Musculoskeletal: Muscle weakness, CPK elevation, rhabdomyolysis.

Nervous: Paresthesia, peripheral neuropathy, seizures.

Respiratory: Abnormal breath sounds/wheezing.

Skin: Alopecia, erythema multiforme, Stevens-Johnson syndrome.

Postmarketing reports of lamivudine received by the National Pharmacovigilance Program of India (PvPI) include hearing loss.

Efavirenz

The most significant adverse reactions observed in patients treated with efavirenz are as below:

·         Psychiatric symptoms

·         Nervous system symptoms

·         Rash

·         Hepatotoxicity

Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, the adverse reaction rates reported cannot be directly compared to rates in other clinical studies and may not reflect the rates observed in clinical practice.

Adverse Reactions In Adults

The most common (>5% in either efavirenz treatment group) adverse reactions of at least moderate severity among patients in Study 006, treated with efavirenz in combination with zidovudine/lamivudine or indinavir, were rash, dizziness, nausea, headache, fatigue, insomnia, and vomiting.

Selected clinical adverse reactions of moderate or severe intensity observed in ≥2% of efavirenz-treated patients in two controlled clinical trials are presented in Table 4.

Table 4: Selected Treatment-Emergenta Adverse Reactions of Moderate or Severe Intensity Reported in ≥2% of Efavirenz-treated Patients in Studies 006 and ACTG 364

Adverse Reactions

Study 006

LAM-, NNRTI- and Protease Inhibitor-Naïve Patients

Study ACTG 364

NRTI-experienced, NNRTI- and Protease Inhibitor-Naïve Patients

 

Efavirenzb +
ZDV/LAM
(n=412)
180
weeks
c

Efavirenzb
+
Indinavir (n=415)
102
weeks
c

Indinavir
+
ZDV/LAM
(n=401)
76 weeks
c

Efavirenzb + Nelfinavir + NRTIs (n=64)
71.1 weeks
c

Efavirenzb
+
NRTIs
(n=65)
70.9 weeks
c

Nelfinavir
+
NRTIs

(n=66)
62.7 weeks
c

Body as a Whole

Fatigue

8%

5%

9%

0

2%

3%

Pain

1%

2%

8%

13%

6%

17%

Central and Peripheral Nervous System

Dizziness

9%

9%

2%

2%

6%

6%

Headache

8%

5%

3%

5%

2%

3%

Insomnia

7%

7%

2%

0

0

2%

Concen-tration impaired

5%

3%

<1%

0

0

0

Abnormal dreams

3%

1%

0

Somno-lence

2%

2%

<1%

0

0

0

Anorexia

1%

<1%

<1%

0

2%

2%

Gastrointestinal

Nausea

10%

6%

24%

3%

2%

2%

Vomiting

6%

3%

14%

Diarrhea

3%

5%

6%

14%

3%

9%

Dyspepsia

4%

4%

6%

0

0

2%

Abdominal pain

2%

2%

5%

3%

3%

3%

Psychiatric

Anxiety

2%

4%

<1%

Depression

5%

4%

<1%

3%

0

5%

Nervous-ness

2%

2%

0

2%

0

2%

Skin and Appendages

Rashd

11%

16%

5%

9%

5%

9%

Pruritus

<1%

1%

1%

9%

5%

9%

               

a Includes adverse events at least possibly related to the study drug or of unknown relationship for Study 006. Includes all adverse events regardless of relationship to study drug for Study ACTG 364.

b Efavirenz provided as 600 mg once daily.

c Median duration of treatment.

d Includes erythema multiforme, rash, rash erythematous, rash follicular, rash maculopapular, rash petechial, rash pustular, and urticaria for Study 006 and macules, papules, rash, erythema, redness, inflammation, allergic rash, urticaria, welts, hives, itchy, and pruritus for ACTG 364.

ZDV = zidovudine; LAM = lamivudine

– = Not Specified.

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.

Nervous System Symptoms

For 1,008 patients treated with regimens containing efavirenz and 635 patients treated with a control regimen in controlled trials, Table 6 lists the frequency of symptoms of different degrees of severity and gives the discontinuation rates in clinical trials for one or more of the following nervous system symptoms: dizziness, insomnia, impaired concentration, somnolence, abnormal dreaming, euphoria, confusion, agitation, amnesia, hallucinations, stupor, abnormal thinking, and depersonalization. The frequencies of specific central and peripheral nervous system symptoms are provided in Table 5.

Table 5: Percent of Patients with One or More Selected Nervous System Symptomsa,b

Percent of Patients with:

Efavirenz 600 mg Once Daily

(n=1,008)
%

Control Groups (n=635)
%

Symptoms of any severity

52.7

24.6

Mild symptoms c

33.3

15.6

Moderate symptoms d

17.4

7.7

Severe symptoms e

2.0

1.3

Treatment discontinuation as a result of symptoms

2.1

1.1

a Includes events reported regardless of causality.

b Data from Study 006 and three Phase 2/3 studies.

c “Mild” = symptoms which do not interfere with a patient’s daily activities.

d “Moderate” = symptoms that may interfere with daily activities.

e “Severe” = events which that interrupt a patient’s usual daily activities.

Psychiatric Symptoms

Serious psychiatric adverse experiences have been reported in patients treated with efavirenz. In controlled trials, psychiatric symptoms observed at a frequency of greater than 2% among patients treated with efavirenz or control regimens, respectively, were depression (19%, 16%), anxiety (13%, 9%), and nervousness (7%, 2%).

Rash

In controlled clinical trials, the frequency of rash (all grades, regardless of causality) was 26% for 1,008 adults treated with regimens containing efavirenz and 17% for 635 adults treated with a control regimen. Most reports of rash were mild or moderate in severity. The frequency of Grade 3 rash was 0.8% for efavirenz-treated patients and 0.3% for control groups, and the frequency of Grade 4 rash was 0.1% for efavirenz and 0 for control groups. The discontinuation rates as a result of rash were 1.7% for efavirenz-treated patients and 0.3% for control groups.

Experience with efavirenz in patients who discontinued other antiretroviral agents of the NNRTI class is limited. Nineteen patients who discontinued nevirapine because of rash have been treated with efavirenz. Nine of these patients, developed mild-to-moderate rash while receiving therapy with efavirenz, and two of these patients discontinued because of rash.

Laboratory Abnormalities

Selected Grade 3–4 laboratory abnormalities reported in >2% of efavirenz-treated patients in two clinical trials are presented in Table 6.

Table 6: Selected Grade 3–4 Laboratory Abnormalites Reported in >2% of Efavirenz-treated Patients in Studies 006 and ACTG 364  

 

Study 006
LAM-, NNRTI- and
Protease Inhibitor-Naïve Patients

Study ACTG 364
NRTI-experienced, NNRTI- and
Protease Inhibitor-Naïve Patients

 

 

Efavirenza
+ ZDV/LAM
(n=412)

Efavirenza
+ Indinavir
(n=415)

Indinavir
+ ZDV / LAM
(n=401)

Efavirenza
+ Nelfinavir
+ NRTIs
(n=64)

Efavirenza
+ NRTIs
(n=65)

Nelfinavir
+ NRTIs
(n=66)

Variable

Limit

180

weeksb

102

weeksb

76 weeksb

71.1

weeks b

70.9 weeksb

62.7 weeksb

Chemistry

   ALT

>5 × ULN

5%

8%

5%

2%

6%

3%

   AST

>5 × ULN

5%

6%

5%

6%

8%

8%

   GGTc

>5 × ULN

8%

7%

3%

5%

0

5%

   Amylase

>2 × ULN

4%

4%

1%

0

6%

2%

   Glucose

>250 mg/dL

3%

3%

3%

5%

2%

3%

Triglyceridesd

 

≥751 mg/dL

9%

6%

6%

11%

8%

17%

Hematology

 Neutrophils

<750/mm3

10%

3%

5%

2%

3%

2%

a Efavirenz provided as 600 mg once daily.

b Median duration of treatment.

 c Isolated elevations of GGT in patients receiving efavirenz may reflect enzyme induction not associated with liver toxicity.

d Non-fasting.

ZDV = zidovudine, LAM = lamivudine, ULN = Upper limit of normal, ALT = alanine aminotransferase, AST = aspartate aminotransferase, GGT = gamma-glutamyltransferase.

Patients Co-Infected with Hepatitis B Or C

Liver function tests should be monitored in patients with a history of hepatitis B and/or C. In the long-term data set from Study 006, 137 patients treated with efavirenz-containing regimens (median duration of therapy, 68 weeks) and 84 treated with a control regimen (median duration, 56 weeks) were seropositive at screening for hepatitis B (surface antigen-positive) and/or C (hepatitis C antibody-positive). Among these co-infected patients, elevations in AST to greater than five times the ULN developed in 13% of patients in the efavirenz arms and 7% of those in the control arm, and elevations in ALT to greater than five times the ULN developed in 20% of patients in the efavirenz arms and 7% of patients in the control arm. Among co-infected patients, 3% of those treated with efavirenz-containing regimens and 2% in the control arm discontinued from the study because of liver or biliary system disorders.

Lipids

Increases from baseline in total cholesterol of 10–20% have been observed in some uninfected volunteers receiving efavirenz. In patients treated with efavirenz + zidovudine + lamivudine, increases from baseline in non-fasting total cholesterol and high-density lipids (HDL) of approximately 20% and 25%, respectively, were observed. In patients treated with efavirenz + indinavir, increases from baseline in non-fasting cholesterol and HDL of approximately 40% and 35%, respectively, were observed. Non-fasting total cholesterol levels  ≥240 mg/dL and ≥300 mg/dL were reported in 34% and 9%, respectively, of patients treated with efavirenz + zidovudine + lamivudine; 54% and 20%, respectively, of patients treated with efavirenz + indinavir; and 28% and 4%, respectively, of patients treated with indinavir + zidovudine + lamivudine. The effects of efavirenz on triglycerides and low-density lipids (LDL) were not well characterized since samples were taken from non-fasting patients. The clinical significance of these findings is unknown.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of efavirenz. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a whole:  Allergic reactions, asthenia, redistribution/accumulation of body fat.

Central and peripheral nervous system: Abnormal coordination, ataxia, cerebellar coordination and balance disturbances, convulsions, hypoesthesia, paresthesia, neuropathy, tremor, vertigo.

Endocrine:  Gynecomastia.

Gastrointestinal:  Constipation, malabsorption.

Cardiovascular:  Flushing, palpitations.

Liver and biliary system: hepatic enzyme increase, hepatic failure, hepatitis.

Metabolic and nutritional: hypercholesterolemia, hypertriglyceridemia.

Musculoskeletal:  arthralgia, myalgia, myopathy.

Psychiatric:  aggressive reactions, agitation, delusions, emotional lability, mania, neurosis, paranoia, psychosis, suicide, catatonia.

Respiratory:  dyspnea.

Skin and appendages: erythema multiforme, photo-allergic dermatitis, Stevens-Johnson syndrome.

Special senses:  abnormal vision, tinnitus.

Reporting of Side Effects

If you experience any side effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the National Pharmacovigilance Program of India (PvPI)by calling on 1800 180 3024 or you can report to Cipla Ltd. on 1800 267 7779. By reporting side effects, you can help provide more information on the safety of this product.

Overdose

Lamivudine: Because a negligible amount of lamivudine was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known whether lamivudine can be removed by peritoneal dialysis or hemodialysis.

Zidovudine: Acute overdoses of zidovudine have been reported in adults. These involved exposure up to 50 grams. The only consistent findings were nausea and vomiting. Other reported occurrences included headache, dizziness, drowsiness, lethargy, confusion, and one report of grand mal seizure. Hematologic changes were transient. All patients recovered. Hemodialysis and peritoneal dialysis appear to have a negligible effect on the removal of zidovudine, while elimination of its primary metabolite, GZDV, is enhanced.

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 significantly   remove drug from blood.

Pharmacological Properties

Mechanism of Action

DUOVIR-E Kit is an antiretroviral agent.

Pharmacodynamics

Lamivudine: Lamivudine is a synthetic nucleoside analogue. Intracellularly, lamivudine is phosphorylated to its active 5΄-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of reverse transciptase (RT) via DNA chain termination after incorporation of the nucleoside analogue.

Zidovudine: Zidovudine is a synthetic nucleoside analogue. Intracellularly, zidovudine is phosphorylated to its active 5΄-triphosphate metabolite, zidovudine triphosphate (ZDV-TP). The principal mode of action of ZDV-TP is inhibition of RT via DNA chain termination after incorporation of the nucleotide analogue.

Efavirenz:  Efavirenz is an NNRTI of HIV-1. Efavirenz activity is mediated predominantly by noncompetitive inhibition of HIV-1 reverse transcriptase (RT). HIV-2 RT and human cellular DNA polymerases alfa, beta, gamma or delta are not inhibited by efavirenz.

Pharmacokinetics

Lamivudine/Zidovudine

Adults

One lamivudine/zidovudine tablet was bio-equivalent to one lamivudine tablet (150 mg) plus one zidovudine tablet (300 mg) following single-dose administration to fasting healthy subjects (n=24).

Lamivudine

Following oral administration, lamivudine is rapidly absorbed and extensively distributed. Binding to plasma protein is low. Approximately 70% of an intravenous dose of lamivudine is recovered as unchanged drug in the urine. Metabolism of lamivudine is a minor route of elimination (approximately 5% of an oral dose after 12 hours). In humans, the only known metabolite is the trans-sulfoxide metabolite (approximately 5% of an oral dose after 12 hours).

Zidovudine

Following oral administration, zidovudine is rapidly absorbed and extensively distributed. Binding to plasma protein is low. Zidovudine is eliminated primarily by hepatic metabolism. The major metabolite of zidovudine is (3`-azido-3`-deoxy-5`- O-(ß)-D-glucopyranuronosylthymidine (GZDV)). The area under the curve (AUC) of GZDV is about three-fold greater than the zidovudine AUC. Urinary recovery of zidovudine and GZDV accounts for 14% and 74% of the dose following oral administration, respectively. A second metabolite, 3`-amino-3`-deoxythymidine (AMT), has been identified in plasma. The AMT AUC was one-fifth of the zidovudine AUC.

In humans, lamivudine and zidovudine are not significantly metabolized by cytochrome P450 enzymes.

The pharmacokinetic properties of lamivudine and zidovudine in fasting subjects are summarized in Table 7.

Table 7: Pharmacokinetic Parameters* for Lamivudine and Zidovudine in Adults

Parameter

Lamivudine

Zidovudine

Oral bioavailability (%)

86 ± 16

n=12

64 ± 10

n=5

Apparent volume of distribution (L/kg)

1.3 ± 0.4

n=20

1.6 ± 0.6

n=8

Plasma protein binding (%)

<36

<38

CSF:plasma ratio

0.12

n=38

0.60

n=39 §

Systemic clearance (L/hr/kg)

0.33 ± 0.06

n=20

1.6 ± 0.6

n=6

Renal clearance (L/hr/kg)

0.22 ± 0.06

n=20

0.34 ± 0.05

n=9

Elimination half-life(hr)#

5 to 7

0.5 to 3

* Data presented as mean ± standard deviation except where noted.

Median .

 ‡ Children.         

 § Adults.

# Approximate range.

Effect of Food on Absorption of Zidovudine/Lamivudine

Zidovudine/lamivudine may be administered with or without food. The lamivudine and zidovudine AUC following administration of zidovudine/lamivudine with food was similar when compared with fasting healthy subjects (n=24).

Efavirenz

Absorption

Peak efavirenz plasma concentrations of 1.6–9.1 µM were attained by 5 hours following single oral doses of 100 mg to 1,600 mg administered to uninfected volunteers. Dose-related increases in Cmax and AUC were seen for doses up to 1,600 mg; the increases were less than proportional, suggesting diminished absorption at higher doses.

In HIV-1-infected patients at steady state, mean Cmax, mean Cmin, 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. In 35 patients receiving efavirenz 600 mg once daily, steady-state Cmax was 12.9 ± 3.7 µM (mean ± SD), steady-state Cmin was 5.6 ± 3.2 µM, and the AUC was 184 ± 73 µM•h.

Effect Of Food On Oral Absorption

Administration of a single 600 mg dose of efavirenz tablet with a high-fat/high-caloric meal (approximately 1,000 kcal, 500–600 kcal from fat) was associated with a 28% increase in mean AUC of efavirenz and a 79% increase in mean Cmax of efavirenz relative to the exposures achieved under fasted conditions.

Distribution

Efavirenz is highly bound (approximately 99.5–99.75%) to human plasma proteins, predominantly albumin. In HIV-1 infected patients (n=9) who received efavirenz 200 to 600 mg once daily for at least 1 month, cerebrospinal fluid concentrations ranged from 0.26% to 1.19% (mean: 0.69%) of the corresponding plasma concentration. This proportion is approximately 3-fold higher than the non-protein-bound (free) fraction of efavirenz in plasma.

Metabolism

Studies in humans and in vitro studies using human liver microsomes have demonstrated that 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. The in vitro studies suggest that CYP3A and CYP2B6 are the major isozymes responsible for efavirenz metabolism.

Efavirenz has been shown to induce CYP enzymes, resulting in the induction of its own metabolism. Multiple doses of 200–400 mg per day for 10 days resulted in a lower than predicted extent of accumulation (22–42% lower) and a shorter terminal half-life of 40–55 hours (single dose half-life: 52–76 hours).

Elimination

Efavirenz has a terminal half-life of 52–76 hours after single doses and 40–55 hours after multiple doses. A 1-month mass balance/excretion study was conducted using 400 mg per day with a 14C-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 the feces.

Special Populations

Patients with Renal Impairment

Zidovudine/Lamivudine: The effect of renal impairment on the combination of lamivudine and zidovudine has not been evaluated (see the prescribing information for the individual lamivudine and zidovudine components).

Efavirenz: 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.

Patients with Hepatic Impairment

Zidovudine/Lamivudine: The effect of hepatic impairment on the combination of lamivudine, and zidovudine has not been evaluated (see the prescribing information for the individual lamivudine and zidovudine components).

Efavirenz: A multiple-dose study showed no significant effect on efavirenz pharmacokinetics in patients with mild hepatic impairment (Child-Pugh class A) compared with controls. There were insufficient data to determine whether moderate or severe hepatic impairment (Child-Pugh class B or C) affects efavirenz pharmacokinetics.

Pregnant Women

Lamivudine: Lamivudine pharmacokinetics was studied in 36 pregnant women during two clinical trials conducted in South Africa. Lamivudine pharmacokinetics in pregnant women were similar to those seen in non-pregnant adults and in postpartum women. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples.

Zidovudine: Zidovudine pharmacokinetics have been studied in a Phase 1 trial of 8 women during the last trimester of pregnancy. Zidovudine pharmacokinetics were similar to those of non-pregnant adults. Consistent with passive transmission of the drug across the placenta, zidovudine concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery.

Although data are limited, methadone maintenance therapy in 5 pregnant women did not appear to alter zidovudine pharmacokinetics.

Geriatric Patients

The pharmacokinetics of lamivudine and zidovudine have not been studied in subjects over 65 years of age.

Gender

There are no significant or clinically relevant gender differences in the pharmacokinetics of the individual components (lamivudine or zidovudine) based on the available information that was analyzed for each of the individual components.

Race

Lamivudine: There are no significant or clinically relevant racial differences in lamivudine pharmacokinetics based on the available information that was analyzed for the individual lamivudine component.

Zidovudine: The pharmacokinetics of zidovudine with respect to race have not been determined.

Nonclinical Properties

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity

Lamivudine: Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 10 times (mice) and 58 times (rats) the human exposures at the recommended dose of 300 mg.

Zidovudine: Zidovudine was administered orally at 3 dosage levels to separate groups of mice and rats (60 females and 60 males in each group). Initial single daily doses were 30, 60, and 120 mg per kg per day in mice and 80, 220, and 600 mg per kg per day in rats. The doses in mice were reduced to 20, 30, and 40 mg per kg per day after day 90 because of treatment-related anemia, whereas in rats only the high dose was reduced to 450 mg per kg per day on day 91 and then to 300 mg per kg per day on day 279.

In mice, 7 late-appearing (after 19 months) vaginal neoplasms (5 non-metastasizing squamous cell carcinomas, 1 squamous cell papilloma, and 1 squamous polyp) occurred in animals given the highest dose. One late-appearing squamous cell papilloma occurred in the vagina of a middle-dose animal. No vaginal tumors were found at the lowest dose.

In rats, 2 late-appearing (after 20 months), non-metastasizing vaginal squamous cell carcinomas occurred in animals given the highest dose. No vaginal tumors occurred at the low or middle dose in rats. No other drug-related tumors were observed in either sex of either species.

At doses that produced tumors in mice and rats, the estimated drug exposure (as measured by AUC) was approximately 3 times (mouse) and 24 times (rat) the estimated human exposure at the recommended therapeutic dose of 100 mg every 4 hours.

It is not known how predictive the results of rodent carcinogenicity studies may be for humans.

Efavirenz: Long-term carcinogenicity studies in mice and rats were carried out with efavirenz. Mice were dosed with 0, 25, 75, 150, or 300 mg/kg/day for 2 years. Incidences of hepatocellular adenomas and carcinomas and pulmonary alveolar/bronchiolar adenomas were increased above background in females. No increases in tumor incidence above background were seen in males. There was no NOAEL in females established for this study because tumor findings occurred at all doses. AUC at the NOAEL (150 mg/kg) in the males was approximately 0.9 times that in humans at the recommended clinical dose. In the rat study, no increases in tumor incidence were observed at doses up to 100 mg/kg/day, for which AUCs were 0.1 (males) or 0.2 (females) times those in humans at the recommended clinical dose.

Mutagenicity

Lamivudine: Lamivudine was mutagenic in an L5178Y mouse lymphoma assay and clastogenic in a cytogenetic assay using cultured human lymphocytes. Lamivudine was not mutagenic in a microbial mutagenicity assay, in an in vitro cell transformation assay, in a rat micronucleus test, in a rat bone marrow cytogenetic assay, and in an assay for unscheduled DNA synthesis in rat liver.

Zidovudine: Zidovudine was mutagenic in an L5178Y mouse lymphoma assay, positive in an in vitro cell transformation assay, clastogenic in a cytogenetic assay using cultured human lymphocytes, and positive in mouse and rat micronucleus tests after repeated doses. It was negative in a cytogenetic study in rats given a single dose.

Efavirenz: Efavirenz tested negative in a battery of in vitro and in vivo genotoxicity assays. These included bacterial mutation assays in S. typhimurium and E. coli, mammalian mutation assays in Chinese hamster ovary cells, chromosome aberration assays in human peripheral blood lymphocytes or Chinese hamster ovary cells, and an in vivo mouse bone marrow micronucleus assay.

Impairment of Fertility

Lamivudine: Lamivudine did not affect male or female fertility in rats at doses up to 4,000 mg per kg per day, associated with concentrations approximately 42 times (male) or 63 times (female) higher than the concentrations (Cmax) in humans at the dose of 300 mg.

Zidovudine: Zidovudine, administered to male and female rats at doses up to 450 mg per kg per day, which is 7 times the recommended adult dose (300 mg twice daily) based on body surface area, had no effect on fertility based on conception rates.

Efavirenz: Efavirenz did not impair mating or fertility of male or female rats, and did not affect sperm of treated male rats. The reproductive performance of offspring born to female rats given efavirenz was not affected. The AUCs at the NOAEL values in male (200 mg/kg) and female (100 mg/kg) rats were approximately ≤0.15 times that in humans at the recommended clinical dose.

Animal Toxicology and/or Pharmacology

Efavirenz: Nonsustained convulsions were observed in 6 of 20 monkeys receiving efavirenz at doses yielding plasma AUC values 4-to 13-fold greater than those in humans given the recommended dose.

Description

Each DUOVIR-E Kit contains three tablets – two fixed-dose combination tablets of lamivudine and zidovudine and one tablet of efavirenz.

Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1. Both zidovudine and lamivudine belong to the nucleoside analogue class of antiretroviral drugs.

Lamivudine

The chemical name of lamivudine is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)(1H)-pyrimidin-2-one. Lamivudine is the (-) enantiomer of a dideoxy analogue of cytidine. Lamivudine has also been referred to as (-) 2’, 3’-dideoxy, 3’-thiacytidine. It has a molecular formula of C8H11N3O3S and a molecular weight of 229.3 g per mol. It has the following structural formula:

Lamivudine is a white to off-white crystalline solid and is soluble in water.

Zidovudine

The chemical name of zidovudine is 3’-azido-3’-deoxythymidine. It has a molecular formula of C10H13N5O4 and a molecular weight of 267.24 g per mol. It has the following structural formula:

Zidovudine is a white to beige, odorless, crystalline solid with a solubility of 20.1 mg per mL in water at 25°C.

Efavirenz

Efavirenz is chemically described as (S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one. Its empirical formula is C14H9ClF3NO2 and it has the following structural formula:

Pharmaceutical Particulars

Incompatibilities

Not applicable.

Shelf-life

As on the pack.

Packaging Information

DUOVIR-E Kit ……………. Carton containing 10 kits.

Storage and Handling Instructions

Store in a cool, dry place.

Patient Counseling Information

Read this Patient Counseling Information before you start taking the tablets in DUOVIR-E Kit and each time you get a refill. There may be new information. This information does not substitute for talking with your doctor about your medical condition or treatment.

● What is DUOVIR-E Kit?

DUOVIR-E Kit contains tablets that are a prescription HIV-1 (human immunodeficiency virus type 1) medicine used with other antiretroviral medicines to treat HIV-1 infection in adults. HIV is the virus that causes AIDS (acquired immune deficiency syndrome).

Each DUOVIR-E Kit contains three tabletstwo fixed-dose combination tablets of lamivudine (150 mg) and zidovudine (300 mg) and one tablet of efavirenz (600 mg).

When used with other antiretroviral medicines to treat HIV-1 infection, DUOVIR-E Kit may help to

·         reduce the amount of HIV-1 in your blood. This is called viral load.

·         increase the number of CD4+ (T) cells in your blood that help fight off other infections.

Reducing the amount of HIV-1 and increasing the CD4+ (T) cells in your blood may help improve your immune system. This may reduce your risk of death or getting infections that can happen when your immune system is weak (opportunistic infections).

DUOVIR-E Kit therapy does not cure HIV-1 infection or AIDS. You should keep taking HIV-1 medicines to control HIV-1 infection and decrease HIV-related illnesses.

Avoid doing things that can spread HIV-1 infection to others:

·         Do not share or reuse needles or other injection equipment.

·         Do not share personal items that can have blood or body fluids on them, such as toothbrushes and razor blades.

·         Do not have any kind of sex without protection. Always practice safer sex by using a latex or polyurethane condom to lower the chance of sexual contact with any body fluids such as semen, vaginal secretions, or blood.

Ask your doctor if you have any questions about how to prevent passing HIV to other people.

● Who should not take DUOVIR-E Kit tablets?

Do not take DUOVIR-E Kit tablets if you are allergic to lamivudine, zidovudine, efavirenz or any of the ingredients in DUOVIR-E Kit tablets.

Do not take DUOVIR-E Kit tablets if you are currently taking elbasvir and grazoprevir.

● What should you tell your doctor before taking DUOVIR-E Kit tablets?

Before taking DUOVIR-E Kit tablets, tell your doctor if you have any medical conditions and, in particular, if you

·         have a heart condition;

·         have kidney problems;

·         have diabetes;

·         have ever had a mental health problem;

·         have ever used street drugs or large amounts of alcohol;

·         have liver problems, including hepatitis B or C virus infection;

·         have a history of seizures;

·         are pregnant or plan to become pregnant – DUOVIR-E Kit tablets may harm your unborn baby. If you are able to become pregnant your healthcare provider should do a pregnancy test before you start taking DUOVIR-E Kit tablets. You should not become pregnant while taking DUOVIR-E Kit tablets and for 12 weeks after stopping treatment with DUOVIR-E Kit tablets.

Females who are able to become pregnant should use two effective forms of birth control during treatment and for 12 weeks after stopping treatment with DUOVIR-E Kit tablets. A barrier form of birth control should always be used along with another type of birth control.

·         Barrier forms of birth control may include latex or polyurethane condom, contraceptive sponge, diaphragm with spermicide, and cervical cap.

·         Hormonal forms of birth control, such as birth control pills, injections, vaginal rings, or implants may not work during treatment with DUOVIR-E Kit tablets.

·         Talk to your doctor about forms of birth control that may be used during treatment with DUOVIR-E Kit tablets.

·         Do not breastfeed if you take DUOVIR-E Kit tablets.

·         You should not breastfeed if you have HIV because of the risk of passing HIV to your baby.

Tell your doctor and pharmacist about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

DUOVIR-E Kit tablets may affect the way other medicines work, and other medicines may affect how DUOVIR-E Kit tablets work, and may cause serious side effects. If you take certain other medicines with DUOVIR-E Kit tablets, DUOVIR-E Kit tablets may not work effectively to help control your HIV infection. The HIV virus in your body may become resistant to DUOVIR-E Kit tablets or other HIV medicines that are like it.

You should not take DUOVIR-E Kit tablets if you take efavirenz, emtricitabine, or tenofovir disoproxil fumarate unless your doctor tells you to.

Tell your doctor and pharmacist about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medicines interact with DUOVIR-E Kit tablets.

Keep a list of your medicines to show your doctor and pharmacist.

·         You can ask your doctor or pharmacist for a list of medicines that interact with DUOVIR-E Kit tablets.

·         Do not start taking a new medicine without telling your doctor. Your doctor can tell you if it is safe to take DUOVIR-E Kit tablets with other medicines.

● How should you take DUOVIR-E Kit tablets?

·     Take DUOVIR-E Kit tablets exactly as your doctor tells you to.

·     Do not change your dose or stop taking DUOVIR-E Kit tablets unless your doctor tells you to.

·     Stay under the care of your doctor during treatment with DUOVIR-E Kit tablets.

·     DUOVIR-E Kit tablets must be used with other antiretroviral medicines.

·     DUOVIR-E Kit tablets must not be broken.

·     Swallow the DUOVIR-E Kit tablets whole with any liquid.

    How and when to take DUOVIR-E Kit tablets

·  Each DUOVIR-E Kit contains three tablets – two fixed-dose combination tablets of lamivudine and zidovudine and one tablet of efavirenz.

o   Take one fixed-dose combination tablet containing zidovudine 300 mg and lamivudine 150 mg, orally, twice daily.

o   Take one tablet of efavirenz 600 mg, orally, once daily. It is recommended that the efavirenz tablet be taken on an empty stomach, preferably at bedtime. Taking efavirenz tablet with food increases the amount of medicine in your body. Some side effects may bother you less if you take efavirenz tablets on an empty stomach and at bedtime.

·  Do not miss a dose of DUOVIR-E Kit tablets. If you forget to take DUOVIR-E Kit medication, take the missed dose right away, unless it is almost time for your next dose. Do not take two doses at one time. Just take your next dose at your regularly scheduled time. If you need help in planning the best times to take your medicine, ask your doctor or pharmacist.

·  If you take too much DUOVIR-E Kit tablets, call your doctor or go to the nearest hospital emergency room right away.

·  When your DUOVIR-E Kit supply starts to run low, get more from your doctor or pharmacy. It is important not to run out of DUOVIR-E Kit tablets. The amount of HIV-1 in your blood may increase if the medicine is stopped for even a short time. The virus may become resistant to DUOVIR-E Kit tablets and harder to treat.

● What are the possible side effects of DUOVIR-E Kit tablets?

DUOVIR-E KIT tablets may cause serious side effects, including the following:

·         Build-up of an acid in your blood (lactic acidosis). Lactic acidosis can happen in some people who take DUOVIR-E Kit tablets. Lactic acidosis is a serious medical emergency that can cause death. Call your healthcare provider right away if you get any of the following symptoms that could be signs of lactic acidosis:

o   Feel very weak or tired

o   Feel cold, especially in your arms and legs

o   Unusual (not normal) muscle pain

o   Feel dizzy or light-headed

o   Have trouble breathing

o   Stomach pain with nausea and vomiting

o   Have a fast or irregular heartbeat

You may be more likely to get lactic acid or severe liver problems if you are female, are very overweight (obese), or have been taking nucleoside analogue medicines for a long time.

·         Serious liver problems, including liver failure and death can happen in people who take DUOVIR-E Kit tablets.Your liver may become large (hepatomegaly) and you may develop fat in your liver (steatosis).Liver problems can happen in people without a history of liver problems. Your doctor will do blood tests to check your liver before you start taking DUOVIR-E Kit tablets and during treatment. Tell your doctor right away if you get any of the following symptoms:

o   Your skin or the white part of your eyes turns yellow (jaundice)

o   You don’t feel like eating food for several days or longer

o   You feel sick to your stomach (nausea)

o   Your urine turns dark (“tea-colored” urine)

o   Your bowel movements (stools) turn light in color

o   You have lower stomach area (abdominal) pain or pain, aching, or tenderness on the right side

·         Worsening of hepatitis B virus (HBV) in people who have HIV-1 infection. If you have HIV-1 and HBV infection, your HBV may get worse (flare-up) if you stop taking DUOVIR-E Kit tablets. A “flareup” is when your HBV infection suddenly returns in a worse way than before. Worsening liver disease is serious and may lead to death.

o   Do not run out of DUOVIR-E Kit tablets. Refill your prescription or talk to your healthcare provider before your DUOVIR-E Kit tablets is all gone.

o   Do not stop DUOVIR-E Kit therapy without first talking to your healthcare provider.

o   If you stop taking DUOVIR-E Kit tablets, your healthcare provider will need to check your health often and do blood test regularly for several months to check your liver.

·         Resistant HBV. If you have HIV-1 and hepatitis B, the hepatitis B virus can change (mutate) during your treatment with DUOVIR-E Kit medication and become harder to treat (resistant).

·         Serious mental health problems can happen in people who take DUOVIR-E Kit tablets. Tell your doctor right away if you have any of the following symptoms:

o   Feel sad or hopeless     

o   Do not trust other people                         

o   Feel anxious or restless

o   Hear or see things that are not there                          

o   Have thoughts of hurting yourself (suicide) or have tried to hurt yourself or others

o   Are not able to move or speak yourself or others normally

o   Are not able to tell the difference between what is true or real and what is false or unreal

·         Nervous system symptoms are common in people who take DUOVIR-E Kit tablets and can be severe. These symptoms usually begin during the first or second day of treatment with DUOVIR-E Kit tablets and usually go away after 2 to 4 weeks of treatment. Some symptoms may occur months to years after beginning DUOVIR-E Kit therapy. These symptoms may become worse if you drink alcohol, take a medicine for mental health problems, or use certain street drugs during treatment with DUOVIR-E Kit tablets. Symptoms may include

o   dizziness;

o   trouble concentrating;

o   trouble sleeping;

o   drowsiness;

o   unusual dreams;

o   lack of coordination or difficulty with balance

If you have dizziness, trouble concentrating or drowsiness, do not drive a car, use machinery, or do anything that needs you to be alert.

Some nervous system symptoms (e.g., confusion, slow thoughts and physical movement, and delusions or hallucinations ) may occur months to years after beginning DUOVIR-E Kit therapy. Promptly contact your health care provider should any of these symptoms occur.

·         Skin rash is common with DUOVIR-E Kit tablets but can sometimes be severe. Skin rash usually goes away without any change in treatment. If you develop a rash with any of the following symptoms, tell your doctor right away:

o   skin rash, with or without itching

o   peeling skin

o   mouth sores

o   fever

o   swelling of your face

o   red or inflamed eyes, like “pink eye” (conjunctivitis)

o   blisters or skin lesions

·         Hypersensitivity reactions. Potentially life-threatening hypersensitivity reactions (e.g., anaphylaxis, Stevens-Johnson syndrome) can occur while receiving DUOVIR-E Kit tablets. Immediately contact your healthcare provider if skin rash develops.

·         Blood problems. Zidovudine, one of the medicines in DUOVIR-E Kit, can cause serious blood cell problems. These include reduced numbers of white blood cells (neutropenia) and extremely reduced numbers of red blood cells (anemia). Your healthcare provider should check your blood cell counts regularly during treatment with DUOVIR-E Kit tablets. The frequency and severity of these toxicities are greater in patients with more advanced disease and in those who initiate therapy later in the course of their infection. If toxicity develops, contact your doctor. You may require transfusions or drug discontinuation of DUOVIR-E Kit tablets. 

·         Seizures can happen in people who take DUOVIR-E Kit tablets. Seizures are more likely to happen if you have had seizures in the past. Tell your doctor if you have had a seizure or if you take a medicine to help prevent seizures.

·         Changes in your immune system (immune reconstitution syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your doctor if you start having new symptoms after starting your HIV-1 medicine.

·         Changes in body fat can happen in people who take HIV-1 medicine. These changes may include increased amount of fat in the upper back and neck (“buffalo hump”), breast, and around the main part of your body (trunk). Loss of fat from the legs, arms, and face may also happen. The cause and long-term health effects of these conditions are not known. There may also be loss of subcutaneous fat (lipoatrophy) with DUOVIR-E Kit tablets.  You will be regularly assessed during therapy for lipoatrophy.

·         Muscle pain or weakness (myopathy). Long term use of DUOVIR-E Kit tablets may cause myopathy and myositis similar to that produced by HIV-1 disease. Zidovudine, one of the medicines in DUOVIR-E Kit, can cause muscle pain or weakness when used for a long time.

·         Risk of inflammation of the pancreas (pancreatitis). Patients may be at risk for developing pancreatitis during treatment with DUOVIR-E Kit tablets if they:

o   have taken nucleoside analogue in the past

o   have a history of pancreatitis medicines

o   have other risk factors for pancreatitis

Call your healthcare provider right away if you develop signs and symptoms of pancreatitis including severe upper stomach-area pain, with or without nausea and vomiting. Your healthcare provider may tell you to stop giving DUOVIR-E Kit tablets if the symptoms and blood test results show that you may have pancreatitis.

The most common side effects of DUOVIR-E Kit tablets include

·         skin rash;

·         abnormal dreams;

·         tiredness or malaise and fatigue;

·         dizziness;

·         nausea and /or vomiting;

·         trouble sleeping, insomnia and sleep disorders;

·         headache;

·         difficulty concentrating;

·         fever or chills;

·         diarrhea;

·         anorexia and/or decreased appetite;

·         abdominal pain;

·         abdominal cramps;

·         dyspepsia;

·         neuropathy; 

·         depressive disorders;

·         nasal signs and symptoms;

·         cough;

·         musculoskeletal pain;

·         myalgia;

·         arthralgia;

Some patients taking DUOVIR-E Kit tablets have experienced increased levels of lipids (cholesterol and triglycerides) in the blood. Tell your doctor if you have any side effect that bothers you or that does not go away.

Post-marketing reports of lamivudine received by National Pharmacovigilance Program of India (PvPI) include hearing loss.

These are not all the possible side effects of DUOVIR-E Kit tablets. For more information, ask your doctor or pharmacist.

Reporting of side effects 

If you experience any side effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the National Pharmacovigilance Program of India (PvPI) by calling on 1800 180 3024 or you can report to Cipla Ltd on 1800 267 7779.  By reporting side effects, you can help provide more information on the safety of this product.

Keep DUOVIR-E Kit tablets and all medicines out of the reach of children.

● General information about DUOVIR-E Kit tablets

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use DUOVIR-E Kit tablets for a condition for which it was not prescribed. Do not give DUOVIR-E KIT tablets to other people, even if they have the same symptoms that you have. It may harm them.

If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about DUOVIR-E Kit tablets that is written for health professionals.

Details of The Manufacturer

Manufactured by: Cipla Ltd

Registered Office: Cipla House, Peninsula Business Park, Ganpatrao Kadam Marg, Lower Parel, Mumbai – 400 013, India.

Details of Permission or Licence Number with Date

License Number: MNB/05/109 dated 14.05.2015

Date of Revision

22/07/2020