CIPLADOC - SCIENTIFIC DOSSIER Duovir-N

SCIENTIFIC DOSSIER

Duovir-N
Combining Potency with Simplicity


INDICATIONS, DOSAGE AND ADMINISTRATION
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. 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., which has been shown to reduce the incidence of rash and the development of hypersensitivity. Once patients have demonstrated adequate tolerability to nevirapine during this time period, they can then be switched to Duovir-N, which contains the maintenance dose of nevirapine 200 mg b.d. (see Indications). Thus, it is recommended that patients initiate therapy using a combination of Duovir and Nevimune during the first two weeks, and then switch to Duovir-N once adequate tolerability is demonstrated.



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 CO-INFECTION 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). 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.

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