Oral
DOSAGE AND ADMINISTRATION
Adults
1 tablet twice daily
Health 2000 Lamivudine 150 mg, Zidovudine 300 mg and Nevirapine 200mg Tablets
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, Health 2000 Lamivudine 150 mg, Zidovudine
300 mg and Nevirapine 200mg Tablets 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
Health 2000 Lamivudine 150 mg, Zidovudine 300 mg and Nevirapine 200mg Tablets
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 Health 2000
Lamivudine 150 mg, Zidovudine 300 mg and Nevirapine 200mg Tablets until the
rash has resolved (see Warnings and Precautions).
Health 2000 Lamivudine 150 mg, Zidovudine 300 mg and Nevirapine 200mg Tablets
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 may then be
restarted at 200 mg per day. Increasing the daily dose to 200 mg twice daily
(using Health 2000 Lamivudine 150 mg, Zidovudine 300 mg and Nevirapine 200mg
Tablets) 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 Nevirapine tablet daily for the first
14 days (lead-in) in combination with the other antiretrovirals, followed
by 200 mg twice daily using Health 2000 Lamivudine 150 mg, Zidovudine 300
mg and Nevirapine 200mg Tablets 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.
(ii) THERAPEUTIC / DIAGNOSTIC CLAIMS
Health 2000 Lamivudine 150 mg, Zidovudine 300 mg and Nevirapine 200mg Tablet
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.
(iii) DESCRIPTION OF DOSAGE FORM
Health 2000 Lamivudine 150 mg, Zidovudine 300 mg and Nevirapine 200mg Tablet
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 Health 2000 Lamivudine 150 mg, Zidovudine 300 mg and Nevirapine
200mg Tablet 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.
(iv) CONTRAINDICATIONS
Health 2000 Lamivudine 150 mg, Zidovudine 300 mg and Nevirapine 200mg Tablet
is contraindicated in patients with clinically significant hypersensitivity
to any of the components contained in the formulation.
Health 2000 Lamivudine 150 mg, Zidovudine 300 mg and Nevirapine 200mg Tablet
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
Lamivudine 150 mg, Zidovudine 300 mg and Nevirapine 200mg Tablets 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 Lamivudine 150 mg, Zidovudine 300 mg
and Nevirapine 200mg Tablets.
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 Health 2000 Lamivudine 150 mg,
Zidovudine 300 mg and Nevirapine 200mg Tablets 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. Lamivudine
150 mg, Zidovudine 300 mg and Nevirapine 200mg Tablets 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.
Lamivudine 150 mg, Zidovudine 300 mg and Nevirapine 200mg Tablets 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
Lamivudine 150 mg, Zidovudine 300 mg and Nevirapine 200mg Tablet is not intended
for use in paediatric patients.
(v) 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 diarrhoea, 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.
(vi) TOXIC EFFECTS:
CARCINOGENICITY
Lamivudine: Lamivudine long-term carcinogenicity studies in mice and rats showed no evidence of carcinogenic potential at exposures up to 10 times (mice) and 58 times (rats) those observed in humans at the recommended therapeutic dose.
Zidovudine : In oral carcinogenicity studies with zidovudine in mice and
rats, late appearing -vaginal epithelial tumours were observed. There were
no other zidovudine-related tumours observed in either sex of either species.
A subsequent intravaginal carcinogenicity study confirmed the hypothesis that
the vaginal tumours were the result of long term local exposure of the rodent
vaginal epithelium to high concentrations of unmetabolised zidovudine in urine.
The predictive value of rodent carcinogenicity studies for humans is uncertain
and thus the clinical significance of these findings is unclear.
In addition two transplacental carcinogenicity studies have been conducted
in mice. One study, by the US National Cancer Institute, administered zidovudine
at maximum tolerated doses to pregnant mice from day 12 to 18 of gestation.
One year post-natally, there was an increase in the incidence of tumours in
the lung, liver and female reproductive tract of offspring exposed to the
highest dose level (420mg/kg/term body weight).
In a second study, mice were administered zidovudine at doses up to 40mg/kg
for 24 months, with exposure beginning prenatally on gestation day 10. Treatment
related findings were limited to late-occurring vaginal epithelial tumours,
which were seen with a similar incidence and time of onset as in the standard
oral carcinogenicity study. The second study thus provided no evidence that
zidovudine acts as a transplacental carcinogen.
It is concluded that the transplacental carcinogenicity data from the first
study represents a hypothetical risk, whereas the reduction in risk of maternal
transfection of HIV to the uninfected child by the use of zidovudine in pregnancy
has been well proven.
Nevirapine:In carcinogenicity studies, nevirapine increased the incidence of liver tumours in mice (at doses up to 750 mg/kg/day) and rats (at doses up to 35 mg/kg/day). However, these findings are most likely related to nevirapine being a strong inducer of liver enzymes, and not due to a genotoxic mode of action.
MUTAGENICITY
Lamivudine: Lamivudine was negative in a microbial mutagenicity screen, 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. It was mutagenic in a L5178Y/TK+/- mouse lymphoma assay and clastogenic in acytogenetic assay using cultured human lymphocytes.
Zidovudine : No evidence of mutagenicity was observed in the Ames test. However, zidovudine was weakly mutagenic in a mouse lymphoma cell assay and was positive in an in vitro cell transformation assay. Clastogenic effects were observed in an in vitro study in human lymphocytes and in vivo oral repeat dose micronucleus studies in rats and mice. An in vivo cytogenetic study in rats did not show chromosomal damage. A study of the peripheral blood lymphocytes of eleven AIDS patients showed a higher chromosome breakage frequency in those who had received Retrovir than in those who had not. A pilot study has demonstrated that zidovudine is incorporated into leukocyte nuclear DNA of adults, including pregnant women, taking zidovudine as treatment for HIV-1 infection, or for the prevention of mother to child viral transmission. Zidovudine was also incorporated into DNA from cord blood leukocytes of infants from zidovudine-treated mothers. The clinical significance of these findings is unknown.
Nevirapine :In genetic toxicology assays, nevirapine showed no evidence of mutagenic or clastogenic activity in a battery of in vitro and in vivo assays including microbial assays for gene mutation (Ames: Salmonella strains and E.coli), mammalian cell gene mutation assays (CHO/HGPRT), cytogenic assays using Chinese hamster ovary cell line and a mouse bone marrow micronucleus assay following oral administration. In reproductive toxicology studies, evidence of impaired fertility was seen in female rats at doses providing systemic exposure, based on AUC, approximately equivalent to that provided with recommended clinical dose of Nevirapine.
TERATOGENECITY
Lamivudine:Reproduction studies have been performed in rats and rabbits at orally administered doses up to approximately 130 and 60 times, respectively, the usual adult dose and have revealed no evidence of harm to the fetus due to lamivudine. Some evidence of early embryolethality was seen in the rabbit at doses similar to those produced by the usual adult dose and higher, but there was no indication of this effect in the rat at orally administered doses up to 130 times the usual adult dose. Studies in pregnant rats and rabbits showed that lamivudine is transferred to the fetus through the placenta. There are no adequate and well controlled studies in pregnant women. Because animal reproductive toxicity studies are not always predictive of human response, lamivudine should be used during pregnancy only if the potential benefits outweigh the risks.
Zidovudine : Studies in pregnant rats and rabbits with zidovudine have shown increased incidences of early embryo deaths. A separate study in rats found that dosages very near the oral median lethal dose caused an increase in the incidence of foetal malformations. No evidence of teratogenicity has been observed at lower dosages tested.
Nevirapine :No observable tetratogenicity was detected in reproductive studies performed in pregnant rats and rabbits. In rats, a significant decrease in fetal body weight occurred at doses providing systemic exposure approximately 50% higher, based on AUC, than that seen at the recommended human clinical dose. The maternal and developmental no-observable effect level dosage in rats and rabbits produced systemic exposures approximately equivalent to or approximately 50% higher, respectively, than those seen at the recommended daily human dose, based on AUC. There are no adequate and well controlled studies in pregnant women. Nevirapine should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.