PRESCRIBING INFORMATION

ODIVIR-250 Kit

Each kit contains

(A)   One Efavirenz tablet 600 mg
        Each film-coated tablet contains
        Efavirenz ...................... 600 mg
        Colours: Yellow oxide of iron & Titanium Dioxide

(B)   One Lamivudine tablet 300 mg
        Each film-coated tablet contains
        Lamivudine ...................... 300 mg
        Colour: Titanium Dioxide

(C)   One Didanosine Delayed-release
         capsule 250 mg
         Each capsule contains
         Didanosine ... 250 mg (as enteric-coated beadlets)

ODIVIR-400 Kit

Each kit contains

(A)   One Efavirenz tablet 600 mg
        Each film-coated tablet contains
        Efavirenz ...................... 600 mg
        Colours: Yellow oxide of iron & Titanium Dioxide

(B)   One Lamivudine tablet 300 mg
         Each film-coated tablet contains
         Lamivudine ................... 300 mg
         Colour : Titanium Dioxide

(C)   One Didanosine Delayed-release capsule 400 mg
         Each capsule contains
         Didanosine ... 400 mg (as enteric-coated beadlets)

Odivir Kit is indicated for treatment of HIV infection, when therapy is warranted. Each kit contains once-daily doses of three commonly used antiretroviral drugs.

For patients weighing <60 kg, one Odivir-250 Kit (all 3 drugs) to be taken in the evening.

For patients weighing ³60 kg, one Odivir-400 Kit (all 3 drugs to be taken in the evening.

It is important to take all 3 drugs before meals on an empty stomach, or at least 2 hours after a meal. Since the green/white (or blue/white) capsule of didanosine contains the drug as enteric-coated beadlets, it should be swallowed intact and not be opened, chewed or enshed.

Dosage Adjustment

Patients with reduced renal function (creatinine clearance £ 50 ml/min) or those with low body weight (< 50 kg or 110 lb) require the dose of lamivudine to be adjusted. Patients with renal impairment may also be at risk of toxicity from didanosine. Hence, Odivir Kit is not suitable for these patients.

Odivir Kit is contraindicated in patients with clinically significant hypersensitivity to any of the components of the kit. It is also contraindicated in patients with reduced renal function (< 50 ml/min) or low body weight (< 50 kg or 110 lb).

Psychiatric symptoms
Serious psychiatric adverse experiences have been reported in patients treated with efavirenz. These include severe depression, suicidal ideation/attempts, aggressive behaviour, paranoid reactions and manic reactions. Patients with a prior history of psychiatric disorders appear to be at greater risk for these psychiatric adverse experiences. Patients with serious psychiatric adverse experiences should seek immediate medical evaluation to assess the possibility that the symptoms may be related to the use of efavirenz, and if so, to determine whether the risk of continued therapy outweighs the benefits.

Rash
Rash associated with blistering, moist desquamation or ulceration has been reported in clinical trials with efavirenz. The incidence of erythema multiforme or Stevens-Johnson Syndrome was approximately 0.1%. The median time to onset of rash in adults was 11 days and the median duration 16 days. Appropriate antihistamines and/or corticosteroids may improve the tolerability and hasten the resolution of rash. Efavirenz must be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement or fever. If therapy with efavirenz is discontinued, consideration should also be given to interrupting therapy with other antiretroviral agents to avoid development of resistant virus.

Nervous system symptoms
These have been observed with efavirenz and include dizziness, insomnia, impaired concentration, somnolence, abnormal dreams and hallucinations.

Nervous system symptoms usually begin during the first one or two days of therapy and generally resolve after the first 2-4 weeks. Patients should be informed that these common symptoms are likely to improve with continued therapy. Dosing at bedtime seems to improve the tolerability of these symptoms and can be recommended during the first weeks of therapy and in patients who continue to experience these symptoms. Patients should be 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.

Liver enzymes
In patients with known or suspected history of hepatitis B or C infection and in patients treated with other medications associated with liver toxicity, monitoring of liver enzymes is recommended. In patients with persistent elevations of serum transaminases to greater than 5 times the upper limit of normal, the benefit of continued therapy with efavirenz needs to be weighed against the unknown risks of significant liver toxicity.

Cholesterol
Monitoring of cholesterol should be considered in patients treated with efavirenz.

Patients co-infected with hepatitis B virus
Data suggest that some patients with chronic hepatitis B virus (HBV) disease may experience clinical or laboratory evidence of recurrent hepatitis upon discontinuation of lamivudine, which may have more severe consequences in patients with decompensated liver disease. If lamivudine is discontinued in patients co-infected with HBV, periodic monitoring of both liver function tests and markers of HBV replication should be considered.

Lactic acidosis/severe hepatomegaly with steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including didanosine, lamivudine and other antiretrovirals. A majority of these have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering didanosine or lamivudine to any patient with known risk factors for liver disease. Treatment with didanosine or lamivudine should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity.

Pancreatitis
Fatal and non-fatal pancreatitis have occurred during therapy with didanosine used alone or in combination regimens in both treatment-naïve and treatment-experienced patients, regardless of degree of immunosuppression. Use of didanosine should be suspended in patients with signs or symptoms of pancreatitis.

When treatment with life-sustaining drugs known to cause pancreatic toxicity is required, suspension of didanosine therapy is recommended. In patients with risk factors for pancreatitis, didanosine should be used with extreme caution and only if clearly indicated. Patients with advanced HIV infection, especially the elderly, are at increased risk of pancreatitis and should be followed closely. Patients with renal impairment may be at greater risk for pancreatitis if treated without dose adjustment.

Retinal changes and optic neuritis
Retinal changes and optic neuritis have been reported in patients taking didanosine.

Peripheral neuropathy
Peripheral neuropathy, manifested by numbness, tingling or pain in the hands or feet, has been reported in patients receiving didanosine therapy. It has occurred more frequently in patients with advanced HIV disease, in patients with a history of neuropathy or in patients being treated with neurotoxic therapy.

Hyperuricemia
Didanosine has been associated with asymptomatic hyperuricemia; treatment suspension may be necessary if clinical measures aimed at reducing uric acid levels fail.

Drug interactions

(A) Drug interactions with efavirenz
Efavirenz is an inducer of CYP3A4 in vivo. Other compounds that are substrates of CYP3A4 may have decreased plasma concentrations when coadministered with efavirenz. In vitro studies have demonstrated that efavirenz inhibits 2C9, 2C19 and 3A4 isoenzymes in the range of observed efavirenz concentrations. Coadministration of efavirenz with drugs primarily metabolized by these isoenzymes may result in altered plasma concentrations of the coadministered drug. Therefore, appropriate dose adjustments may be necessary for these drugs.

Drugs which induce CYP3A4 activity (e.g. Phenobarbital, rifampin, rifabutin) would be expected to increase the clearance of efavirenz resulting in lowered plasma concentrations. Drug interactions with efavirenz are summarized in the following table:

                                          Table 1: Drugs that should not be
                                                     coadministered with efavirenz

                                           Table 2: Drugs that require a dose adjustment
                                                      when coadministered with efavirenz

Drug Class	Drug Within Class Requiring Dose Increase
Anti-HIV Protease Inhibitor	Indinavir (Increase dose from 800 mg to 1000 mg every 8 hours)

Indinavir: It is recommended to increase the dose of indinavir from 800 mg every 8 hours to 1000 mg every 8 hours when efavirenz and indinavir are co-administered.

Nelfinavir: No dose adjustment is necessary when nelfinavir is administered in combination with efavirenz.

Amprenavir: Efavirenz has the potential to decrease serum concentrations of amprenavir.

Ritonavir: The combination of ritonavir and efavirenz was associated with a higher frequency of adverse clinical experiences (for example dizziness, nausea, paraesthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when efavirenz is used in combination with ritonavir.

                                 Table 3: Other potentially clinically significant
                                                       drug interactions with efavirenz

Saquinavir: When saquinavir (1,200 mg q 8 h, soft capsule formulation) was given with efavirenz, the saquinavir AUC and Cmax were decreased by 62% and 50% respectively. Use of efavirenz in combination with saquinavir as the sole protease inhibitor is not recommended.

Saquinavir/Ritonavir: No data are available on the potential interactions of efavirenz with the combination saquinavir and ritonavir.

Rifampin: Rifampin (600 mg daily) reduced efavirenz AUC by 26% and Cmax by 20% in 12 uninfected volunteers. The clinical significance of the reduced efavirenz levels is not known. No dose adjustment of rifampin is recommended when given with efavirenz.

Clarithromycin: Efavirenz significantly affects the pharmacokinetics of clarithromycin. 46% of uninfected volunteers developed rash while receiving efavirenz and clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered.

Oral contraceptives: Because the potential interaction of efavirenz with oral contraceptives has not been characterized, a reliable method of barrier contraception must be used in addition to contraceptives.

(B) Drug interactions with lamivudine
The likelihood of metabolic interactions is low due to limited metabolism and plasma protein binding and almost complete renal clearance. Lamivudine metabolism does not involve CYP3A, making interactions with medicinal products metabolized by this system (e.g. protease inhibitors) unlikely. The possibility of interactions with other medicinal products administered concurrently should be considered, particularly when the main route of elimination is active renal secretion via the organic cationic transport system e.g. trimethoprim.

Zidovudine: A modest increase in C max (28%) was observed for zidovudine when administered with lamivudine. However, overall exposure (AUC) is not significantly altered. Zidovudine has no effect on the pharmacokinetics of lamivudine.

Trimethoprim/sulphamethoxazole: 160 mg/800 mg; The trimethoprim component results in a 40% increase in lamivudine exposure. However, unless the patient has renal impairment, no dosage adjustment of lamivudine is necessary. Lamivudine has no effect on the pharmacokinetics of trimethoprim or sulphamethoxazole. When concomitant administration is warranted, patients should be monitored clinically. Co-administration of lamivudine with high doses of co-trimoxazole for the treatment of Pneumocystis carinii pneumonia (PCP) and toxoplasmosis should be avoided.

Intravenous ganciclovir or foscarnet: Co-administration of lamivudine with intravenous ganciclovir or foscarnet is not recommended until further information is available.

Zalcitabine: Lamivudine may inhibit the intracellular phosphorylation of zalcitabine when the two medicinal products are used concurrently. Lamivudine is therefore not recommended to be used in combination with zalcitabine.

(C) Drug interactions with didanosine
Clinical recommendations based on results of drug interaction studies are listed in
Table 4.

Co-administration of didanosine with drugs that are known to cause pancreatitis may increase the risk of this toxicity. Predicted drug interactions with didanosine are given in Table 5.

              Table 4: Established drug interactions based on studies with buffered                formulations of didanosine and expected to occur with enteric-coated didanosine

Co-administration not recommended based on
drug interaction studies

Alteration in dose or regimen recommended based on drug interaction studies

Renal impairment

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.

Lamivudine: Reduction of the dose of lamivudine is recommended for patients with impaired renal function.

Didanosine: Patients with renal impairment (creatinine clearance < 60 ml/min) may be at greater risk of toxicity from didanosine due to decreased drug clearance. A dose reduction is recommended in these patients.

Hepatic impairment

Efavirenz: Because of the extensive cytochrome P450-mediated metabolism of efavirenz and limited clinical experience in patients with hepatic impairment, caution must be exercised in administering efavirenz to these patients.

Lamivudine: Data obtained in patients with moderate to severe hepatic impairment shows that lamivudine pharmacokinetics are not significantly affected by hepatic dysfunction. Based on these data, no dose adjustment is necessary in patients with moderate or severe hepatic impairment unless accompanied by renal impairment.

Didanosine: It is not known if hepatic impairment significantly affects didanosine pharmacokinetics. Therefore, these patients should be monitored closely for evidence of didanosine toxicity.

Pregnancy

Efavirenz : Category C. Efavirenz crosses the placenta in cynomolgus monkeys and produces fetal concentrations similar to maternal blood concentrations. Because teratogenic effects have been seen in primates at efavirenz exposures similar to those seen in the clinic at the recommended dose, pregnancy should be avoided in women receiving efavirenz. Barrier contraception should always be used in combination with the other methods of contraception (e.g. oral or other hormonal contraceptives). Women of childbearing potential should undergo pregnancy testing prior to initiation of efavirenz.

There are no adequate and well-controlled studies in pregnant women. Efavirenz should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus, such as pregnant women without other therapeutic options.

Lamivudine: The safety of lamivudine in human pregnancy has not been established. Reproductive studies in animals have not shown evidence of teratogenicity and showed no effect on male or female fertility.

Although animal reproductive studies are not always predictive of the human response, administration is not recommended during the first 3 months of pregnancy.

Didanosine: Category B: There are no adequate and well-controlled studies of didanosine in pregnant women. Didanosine should be used during pregnancy only if the potential benefit justifies the potential risk.

Fatal lactic acidosis has been reported in pregnant women who received the combination of didanosine and stavudine with other antiretroviral agents. The combination of didanosine and stavudine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk.

Lactation

It is not known whether didanosine is excreted in human milk. Some animal data suggest that efavirenz may be excreted in breast milk. Lamivudine is excreted in breast milk at similar concentrations to those found in serum.

It is recommended that HIV-infected women do not breast-feed their infants in order to avoid transmission of HIV.

Efavirenz
The most significant adverse events observed in patients treated with efavirenz are nervous system symptoms, psychiatric symptoms and rash.

A few cases of pancreatitis have been described, although a causal relationship with efavirenz has not been established. Asymptomatic increases in serum amylase levels were observed in a significantly higher number of patients treated with efavirenz 600 mg than in control patients. Increases in total cholesterol of 10-20% have been observed in some uninfected volunteers receiving efavirenz. Additional post-marketing surveillance data reveal the following side effects:

Body as a whole: allergic reactions, asthenia

Central and Peripheral Nervous System: abnormal coordination, ataxia, convulsions, hypoesthesia, paresthesia, neuropathy, tremor.

Endocrine: gynecomastia

Gastrointestinal: constipation, malabsorption

Cardiovascular: flushing, palpitations

Liver and Biliary System: hepatic enzyme increase, hepatic failure

Metabolic and Nutritional: hypercholesterolemia, hypertriglyceridemia

Musculoskeletal: arthralgia, myalgia, myopathy

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

Respiratory: dyspnea

Skin and Appendages: erythema multiforme, nail disorders, skin discolouration, Stevens-Johnson syndrome

Special Senses: abnormal vision, tinnitus

Lamivudine

The following side effects have been reported during therapy for HIV disease with lamivudine, although it is unclear whether they were related to lamivudine, other medications taken concurrently or are a result of the underlying disease process.

GI
Common (greater than 1%): nausea, vomiting, abdominal pain or cramps, diarrhoea.

Hematological
Uncommon (0.1-1%): neutropenia and anaemia (both occasionally severe), thrombocytopenia

Very rare (less than 0.01%): pure red cell aplasia

Liver/pancreas
Uncommon (0.1-1%): rises in liver enzymes (AST, ALT)
Rare (0.01-0.1%): hepatitis, rises in serum amylase, pancreatitis

Musculoskeletal
Common (greater than 1%): arthralgia, muscle disorders
Rare (0.01-0.1%): rhabdomyolysis

Neurological
Common (greater than 1%): headache
Very rare (less than 0.01%): peripheral neuropathy or paraesthesiae

Respiratory tract
Common (greater than 1%): cough, nasal symptoms

Skin
Common (greater than 1%): rash, alopecia

Other
Common (greater than 1%): fatigue, malaise, fever, insomnia

Cases of lactic acidosis, sometimes fatal, usually associated with severe hepatomegaly and hepatic steatosis, have been reported with the use of nucleoside analogues (See 'Warnings and Precautions').

Didanosine

When didanosine is used in combination with other agents with similar toxicities, the incidence of these toxicities may be higher than when didanosine is used alone. Thus, patients treated with didanosine in combination with stavudine, with or without hydroxyurea, may be at increased risk for pancreatitis, which may be fatal, and hepatotoxicity. Patients treated with didanosine in combination with stavudine may also be at increased risk for peripheral neuropathy.

Studies of didanosine administered as either an enteric-coated or as a buffered formulation yielded comparable safety profiles for both formulations.

The following events have been identified during post-approval use of didanosine buffered formulations.

Body as a whole: abdominal pain, alopecia, anaphylactoid reaction, asthenia, chills/fever and pain.

Digestive disorders: anorexia, dyspepsia and flatulence.

Exocrine gland disorders: pancreatitis, sialadenitis, parotid gland enlargement, dry mouth and dry eyes.

Hematologic disorders: anaemia, leukopenia and thrombocytopenia.

Liver: lactic acidosis and hepatic steatosis

Metabolic disorders: diabetes mellitus, elevated serum alkaline phosphate level, elevated serum amylase level, elevated serum gamma-glutamyltransferase level, elevated serum uric acid level, hypoglycemia and hyperglycemia.

Musculoskeletal disorders: myalgia (with or without increases in creatinine kinase), rhabdomyolysis including acute renal failure and hemodialysis, arthralgia and myopathy.

Ophthalmologic disorders: retinal depigmentation and optic neuritis.

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 remove significant quantities from blood.

Lamivudine
Administration of lamivudine at very high dose levels in acute animal studies did not result in any organ toxicity. Limited data are available on the consequences of ingestion of acute overdoses in humans. No fatalities occurred, and the patients recovered. No specific signs or symptoms have been identified following such overdose.

Didanosine
There is no known antidote for didanosine overdosage. In phase 1 studies, in which buffered formulations of didanosine were initially administered at doses ten times the currently recommended dose, toxicities included: pancreatitis, peripheral neuropathy, diarrhoea, hyperuricemia and hepatic dysfunction. Didanosine is not dialyzable by peritoneal dialysis, although there is some clearance by hemodialysis.

If overdosage occurs, the patient should be monitored and standard supportive treatment given as required. Since lamivudine is dialyzable, continuous hemodialysis could be used in the treatment of overdosage, although this has not been studied.

Odivir-250 Kit: Carton of 10 kits

Odivir-400 Kit: Carton of 10 kits