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 stavudine 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.

Peripheral neuropathy
Stavudine therapy can be associated with severe peripheral neuropathy, which is dose-related and occurs more frequently in patients with advanced HIV infection or who have previously experienced peripheral neuropathy.

Patients should be monitored for the development of neuropathy that is usually characterized by numbness, tingling or pain in the feet or hands. Stavudine-related peripheral neuropathy may resolve if therapy is withdrawn promptly. In some cases, symptoms may worsen temporarily following discontinuation of therapy.

If symptoms resolve completely, resumption of treatment may be considered using the following dosage schedule for adults:

20 mg twice daily for patients > 60 kg
15 mg twice daily for patients < 60 kg

In this case, therapy with Triomune is no longer appropriate.

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 Triomune 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 stavudine and lamivudine is required in patients with a creatinine clearance of 50 ml/min or less. Hence, Triomune cannot be used in this patient population. There are no data available on dosage in patients with renal insufficiency or undergoing dialysis.

Pregnancy
Lamivudine, stavudine and nevirapine are all classified under category C. There are no adequate and well-controlled studies in pregnant women. Triomune 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 stavudine or lamivudine are excreted in human milk. Nevirapine is present in breast milk.

Paediatrics
Triomune is not intended for use in paediatric patients.

Lamivudine
Trimethoprim 160 mg/sulphamethoxazole 800 mg once daily has been shown to increase lamivudine exposure (AUC).

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.

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.

Stavudine
Therapy with stavudine can be associated with severe peripheral neuropathy, which is dose related and occurs more frequently in patients with advanced HIV infection or who have previously experienced peripheral neuropathy.

Lactic acidosis and hepatic steatosis, hepatitis and liver failure have been reported with the use of antiretroviral nucleoside analogues, alone or in combination.

Rash, diarrhoea, nausea/vomiting, pancreatitis, dementia and other peripheral neurologic symptoms have also been associated with the use of stavudine.

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. It is not known whether lamivudine can be removed by peritoneal dialysis or hemodialysis.

Stavudine
Stavudine can be removed by hemodialysis. Experience with adults treated with 12 to 24 times the recommended daily dosage revealed no acute toxicity. Complications of chronic overdosage include peripheral neuropathy and hepatic toxicity.

Nevirapine
There is no known antidote for nevirapine overdosage.