Indications
Duovir-N is indicated for the treatment of HIV infection, once patients have been stabilized on the maintenance regimen of nevirapine 200 mg bd, and have demonstrated adequate tolerability to nevirapine.
Description
Duovir-N is a combination of 3 drugs commonly used in the management of Human Immunodeficiency Virus (HIV) infection. Both zidovudine and lamivudine belong to the nucleoside analogue class of antiretroviral drugs. Both drugs act by terminating the growth of the DNA chain and inhibiting the reverse transcriptase enzyme of HIV. Nevirapine is a non-nucleoside reverse transcriptase inhibitor. It acts by directly inhibiting reverse transcriptase.
Each tablet of Duovir-N contains half of the commonly prescribed daily doses of zidovudine, lamivudine and nevirapine. All three drugs are to be administered twice daily, permitting a fixed-dose combination to be formulated. With the availability of this combination formulation, patients may be better able to adhere to triple drug regimens, thereby enhancing compliance.
WARNING
LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE USE OF NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION, INCLUDING LAMIVUDINE, ZIDOVUDINE AND OTHER ANTIRETROVIRALS(SEE "WARNINGS AND PRECAUTIONS" SECTION).
ZIDOVUDINE HAS BEEN ASSOCIATED WITH HEMATOLOGIC TOXICITY INCLUDING NEUTROPENIA AND SEVERE ANEMIA, PARTICULARLY IN PATIENTS WITH ADVANCED DISEASE (SEE WARNINGS). PROLONGED USE OF ZIDOVUDINE HAS BEEN ASSOCIATED WITH SYMPTOMATIC MYOPATHY.
SEVERE, LIFE-THREATENING SKIN REACTIONS, INCLUDING FATAL CASES, HAVE OCCURRED IN PATIENTS TREATED WITH NEVIRAPINE. THESE HAVE INCLUDED CASES OF STEVENS-JOHNSON SYNDROME, TOXIC EPIDERMAL NECROLYSIS, AND HYPERSENSITIVITY REACTIONS CHARACTERIZED BY RASH, CONSTITUTIONAL FINDINGS AND ORGAN DYSFUNCTION. PATIENTS DEVELOPING SIGNS OR SYMPTOMS OF SEVERE SKIN REACTIONS OR HYPERSENSITIVITY REACTIONS MUST DISCONTINUE NEVIRAPINE AS SOON AS POSSIBLE (SEE WARNINGS).SEVERE AND LIFE-THREATENING HEPATOTOXICITY, INCLUDING FATAL HEPATIC NECROSIS, HAS OCCURRED IN PATIENTS TREATED WITH NEVIRAPINE (SEE WARNINGS).
Composition
Each film-coated tablet contains:
Lamivudine ........................ 150 mg
Zidovudine USP ................. 300 mg
Nevirapine ......................... 200 mg
Colour: Titanium Dioxide
Dosage and Administration
Adults: 1 tablet twice daily.
Duovir-N should not be administered to patients who have just initiated therapy with nevirapine. This is because an initial lead-in dosing of 200 mg nevirapine once daily for 2 weeks is recommended. Following this lead-in dose, a dose escalation (maintenance dose) to 200 mg nevirapine bd may be carried out in the absence of any hypersensitivity reactions (e.g. rash, liver function test abnormalities; see Warnings and Precautions).
Monitoring of patients
Clinical chemistry tests, which include liver function tests, should be performed prior to initiating lead-in nevirapine therapy and at appropriate intervals during therapy (see Warnings and Precautions).
Dosage Adjustment
Lamivudine: Because it is a fixed-dose combination, Duovir-N should not be prescribed for patients requiring dosage adjustment, such as those with low body weight (<50 kg).
Zidovudine: Because it is a fixed-dose combination, this formulation should not be prescribed for patients requiring dosage adjustment, such as those with reduced renal function (creatinine clearance ? 50 ml/min) or those experiencing dose-limiting adverse events.
Nevirapine: Duovir-N should be discontinued if patients experience severe rash or a rash accompanied by constitutional findings (See Warnings and Precautions). Patients experiencing mild to moderate rash during the 14-day lead-in period of 200 mg/day should not have their nevirapine dose increased or start therapy with Duovir-N until the rash has resolved (see Warnings and Precautions).
Duovir-N administration should be interrupted in patients experiencing moderate or severe liver function tests abnormalities (excluding GGT), until the liver function test elevations have returned to baseline. Nevirapine (using Nevimune Tablets) may then be restarted at 200 mg per day. Increasing the daily dose to 200 mg twice daily (using Duovir-N) should be done with caution, after extended observation. Nevirapine should be permanently discontinued if moderate or severe liver function test abnormalities recur (see Warnings and Precautions).
Patients who interrupt nevirapine dosing for more than 7 days should restart the recommended dosing, using one 200 mg Nevimune tablet daily for the first 14 days (lead-in) in combination with the other antiretrovirals, followed by 200 mg twice daily using Duovir-N in the absence of any signs of hypersensitivity.
No data are available to recommend a dosage of nevirapine in patients with hepatic dysfunction, renal insufficiency or undergoing dialysis.
Contraindications
Duovir-N is contraindicated in patients with clinically significant hypersensitivity to any of the components contained in the formulation.
Duovir-N is also contraindicated for patients who are just initiating therapy with nevirapine. These patients require a lead-in dose of nevirapine 200 mg o.d., whereas this formulation contains the maintenance dose of nevirapine 200 mg b.d. (see Indications).
Warnings and Precautions
Lactic acidosis/severe hepatomegaly with steatosis
Lactic acidosis/severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of antiretroviral nucleoside analogues alone or in combination, including stavudine and lamivudine. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Caution should be exercised when administering zidovudine and lamivudine to any patient, and particularly to those with known risk factors for liver disease. Cases have also been reported in patients with no known risk factors. Treatment should be discontinued in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity (which may include hepatomegaly and steatosis), even in the absence of marked amino-transferase elevations.
Bone marrow suppression
Duovir-N should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count < 1000 cells/mm3 or hemoglobin < 9.5 g/dl (see Side Effects).
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-N.
Patients with HIV and hepatitis B virus coinfection
In clinical trials, some patients with HIV infection who have chronic liver disease due to hepatitis B virus infection experienced clinical or laboratory evidence of recurrent hepatitis upon discontinuation of lamivudine. Consequences may be more severe in patients with decompensated liver disease.
Hypersensitivity reactions
Severe, life-threatening skin reactions, including fatal cases, have occurred in patients treated with nevirapine. These have included cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction. Patients developing signs or symptoms of severe skin reactions or hypersensitivity reactions (including, but not limited to, severe rash or rash accompanied by fever, blisters, oral lesions, conjunctivitis, facial edema, muscle or joint aches, general malaise and/or significant hepatic abnormalities must discontinue nevirapine as soon as possible. Nevirapine therapy must be initiated with a 14-day lead - in period of 200 mg/day (4 mg/kg/day in paediatric patients), which has been shown to reduce the frequency of rash. If rash is observed during this lead-in period, dose escalation and administration of Duovir-N should not occur until the rash has resolved (See Dosage and Administration).
Severe or life-threatening hepatotoxicity, including fatal fulminant hepatitis (transaminase elevations, with or without hyperbilirubinemia, prolonged partial thromboplastin time, or eosinophilia), has occurred in patients treated with nevirapine. Some of these cases began in the first few weeks of therapy, and some were accompanied by rash. Nevirapine administration should be interrupted in patients experiencing moderate or severe ALT or AST abnormalities until these return to baseline values. Nevirapine should be permanently discontinued if liver function abnormalities recur upon readministration. Monitoring of ALT and AST is strongly recommended, especially during the first six months of nevirapine treatment (See Side Effects, Dosage and Administration).
Drug Interactions
With Lamivudine
Trimethoprim 160 mg/sulphamethoxazole 800 mg once daily has been shown to increase lamivudine exposure (AUC).
With Zidovudine
Co-administration of ganciclovir, interferon-alpha, and other bone marrow suppressive or cytotoxic agents may increase the hematologic toxicity of zidovudine.
With Nevirapine
The induction of CYP3A by nevirapine may result in lower plasma concentrations of other concomitantly administered drugs that are extensively metabolized by CYP3A. Thus, if a patient has been stabilized on a dosage regimen for a drug metabolized by CYP3A, and begins treatment with nevirapine, dose adjustments may be necessary.
Rifampin/Rifabutin: There are insufficient data to assess whether dose adjustments are necessary when nevirapine and rifampin or rifabutin are coadministered. Therefore, these drugs should only be used in combination if clearly indicated and with careful monitoring.
Ketoconazole: Nevirapine and ketoconazole should not be administered concomitantly. Coadministration of nevirapine and ketoconazole results in a significant reduction in ketoconazole plasma concentrations.
Oral Contraceptives: There are no clinical data on the effects of nevirapine on the pharmacokinetics of oral contraceptives. Nevirapine may decrease plasma concentrations of oral contraceptives (also other hormonal contraceptives); therefore, these drugs should not be administered concomitantly with nevirapine.
Methadone: Based on the known metabolism of methadone, nevirapine may decrease plasma concentrations of methadone by increasing its hepatic metabolism. Narcotic withdrawal syndrome has been reported in patients treated with nevirapine and methadone concomitantly. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Impaired renal function
Reduction of the dosage of both zidovudine and lamivudine is required in patients with a creatinine clearance of 50 ml/min or less. The pharmacokinetics of nevirapine have not been evaluated in patients with renal dysfunction. Hence, Duovir-N cannot be used in this patient population.
Pregnancy
Lamivudine, zidovudine and nevirapine are all classified under category C. There are no adequate and well-controlled studies in pregnant women.
Duovir-N should be used during pregnancy only if the potential benefits outweigh the potential risk.
Lactation
It is recommended that HIV-infected mothers do not breast-feed their infants to avoid risking postnatal transmission of HIV infection. It is not known whether lamivudine is excreted in human milk. Nevirapine and zidovudine are present in breast milk.
Paediatrics
Duovir-N is not intended for use in paediatric patients.
Side Effects
Lamivudine
Pancreatitis has been reported with the use of lamivudine.
Lactic acidosis and hepatic steatosis, hepatitis and liver failure have been reported with the use of antiretroviral nucleoside analogs, alone or in combination.
Other side effects associated with the use of lamivudine are diarrhea, malaise and fatigue, headache, nausea and vomiting, abdominal pain and discomfort, peripheral neuropathy, arthralgias, myalgias, skin rash, pruritus, transient neutropenia and thrombocytopenia and rarely, pancreatitis. Transiently elevated levels of hepatic enzymes and bilirubin (> 5 times the normal level) have also been observed occasionally during treatment with the drug. Resolution of transient neutropenia and raised hepatic and bilirubin levels occurred without dosage modification or discontinuation of therapy.
Zidovudine
The anaemia reported in patients with advanced HIV disease receiving zidovudine appears to be the result of impaired erythrocyte maturation. Thrombocytopenia has also been reported in patients with advanced disease. Mild drug-associated elevations in total bilirubin levels have been reported as an uncommon occurrence in patients treated for asymptomatic HIV infection.
Clinical adverse events or symptoms which occurred in at least 5% of all patients with advanced HIV disease treated with 1,500 mg/day of zidovudine were: fever, headache, nausea, vomiting, anorexia, myalgia, insomnia, dizziness, paraesthesias, dyspnoea and rash. Malaise, gastrointestinal pain, dyspepsia and taste perversion were also reported.
Nevirapine
The most clinically important adverse events associated with nevirapine therapy are rash and increases in liver function tests. Cases of hypersensitivity reactions have been observed.
The major clinical toxicity of nevirapine is rash, with nevirapine-attributable rash occurring in 16% of patients in combination regimens in Phase II/III controlled studies. Thirty-five percent of patients treated with nevirapine experienced rash compared with 19% of patients treated in control groups of either zidovudine + didanosine or zidovudine alone. Severe or life-threatening rash occurred in 6.6% of nevirapine-treated patients compared with 1.3% of patients treated in the control groups.
Rashes are usually mild to moderate, maculopapular erythematous cutaneous eruptions; with or without pruritus, located on the trunk, face and extremities. The majority of severe rashes occurred within the first 28 days of treatment. 25% of the patients with severe rashes required hospitalization, and one patient required surgical intervention. Overall, 7% of patients discontinued nevirapine due to rash.
With respect to laboratory abnormalities, asymptomatic elevations in GGT levels are more frequent in nevirapine recipients than in controls. Because clinical hepatitis has been reported in nevirapine-treated patients, monitoring of ALT (SGPT) and AST (SGOT) is strongly recommended, especially during the first six months of nevirapine treatment (See Warnings and Precautions). Decreased neutrophils (< 750/mm3), platelets (< 50,000/mm3) and Hb (< 8.0 g/dL), and increased total bilirubin (> 2.5 mg/dL) have also been reported.
Overdosage
Lamivudine
There is no known antidote for lamivudine. One case of an adult ingesting 6 grams of lamivudine was reported; there were no clinical signs or symptoms noted and hematologic tests remained normal. It is not known whether lamivudine can be removed by peritoneal dialysis or hemodialysis.
Zidovudine
Acute overdoses of zidovudine have been reported in pediatric patients and adults. These involved exposures 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 a 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 is enhanced.
Nevirapine
There is no known antidote for nevirapine overdosage. Cases of nevirapine overdosage at doses ranging from 800 to 1800 mg per day for up to 15 days have been reported. Patients have experienced events including edema, erythema nodosum, fatigue, fever, headache, imsomnia, nausea, pulmonary infiltrates, rash, vertigo, vomiting and weight decrease. All events subsided following discontinuation of nevirapine.
Storage
Store below 30C