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| 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. |
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| 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
enzymes. 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 group.
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. |
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| CONCLUSION |
Adherence is a crucial determinant
of success with antiretroviral therapy. The combination
of zidovudine + lamivudine + nevirapine has shown good
efficacy both in patients with low as well as high viral
loads, in comparison with a nelfinavir-containing regimen.
It also penetrates well into sanctuary sites, is associated
with immune restoration and is not associated with unfavourable
metabolic alterations. This combination has also been
shown to be generally well-tolerated.
Thus, the availability of a fixed-dose formulation
of zidovudine + lamivudine + nevirapine as Duovir-N
would be expected to greatly enhance patient compliance
and ensure therapeutic success. |
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November 2001
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