NEV 200 TABLETS
(Nevirapine Tablets 200mg)
Composition:
Each uncoated tablet contains:
Nevirapine 200mg
Presentation:
10x10's
Pharmacology:
Nevirapine is a non-nucleoside reverse transcriptase inhibitor
(NNRTI) of HIV-1. Nevirapine binds directly to reverse transcriptase
(RT) and blocks the RNA-dependent and DNA-dependent DNA polymerase
activities by causing a disruption of the enzyme's catalytic site.
The activity of nevirapine does not compete with template or nucleoside
triphosphates. HIV-2 RT and eukaryotic DNA polymerases (such as
human DNA polymerases a , ß, g , or d ) are not inhibited
by nevirapine.
Pharmacokinetics:
Absorption:
Nevirapine is readily absorbed (>90%) after oral administration
in healthy volunteers and in adults with HIV-1 infection. Peak
plasma nevirapine concentrations of 2 ± 0.4 mc g/mL (7.5
mc M) were attained by 4 hours following a single 200 mg dose.
Following multiple doses, nevirapine peak concentrations appear
to increase linearly in the dose range of 200 to 400 mg/day. Steady
state trough nevirapine concentrations of 4.5 ± 1.9 mc
g/mL (17 ± 7 mc M), (n = 242) were attained at 400 mg/day.
When Nevirapine (200 mg) was administered to 24 healthy adults
(12 female, 12 male), with either a high fat breakfast (857 kcal,
50 g fat, 53% of calories from fat) or antacid (Maalox® 30
mL), the extent of nevirapine absorption (AUC) was comparable
to that observed under fasting conditions. In a separate study
in HIV-1-infected patients (n=6), nevirapine steady-state systemic
exposure (AUCt ) was not significantly altered by ddI, which is
formulated with an alkaline buffering agent. Nevirapine may be
administered with or without food, antacid or ddI.
Distribution:
Nevirapine is highly lipophilic and is essentially nonionized
at physiologic pH. Following intravenous administration to healthy
adults, the apparent volume of distribution (Vdss) of nevirapine
was 1.21 ± 0.09 L/kg, suggesting that nevirapine is widely
distributed in humans. Nevirapine readily crosses the placenta
and is found in breast milk. Nevirapine is about 60% bound to
plasma proteins in the plasma concentration range of 1-10 mc g/mL.
Nevirapine concentrations in human cerebrospinal fluid (n=6) were
45% (± 5%) of the concentrations in plasma; this ratio
is approximately equal to the fraction not bound to plasma protein.
Metabolism/Elimination:
In vivo studies in humans and in vitro studies with human liver
microsomes have shown that nevirapine is extensively biotransformed
via cytochrome P450 (oxidative) metabolism to several hydroxylated
metabolites. In vitro studies with human liver microsomes suggest
that oxidative metabolism of nevirapine is mediated primarily
by cytochrome P450 isozymes from the CYP3A family, although other
isozymes may have a secondary role. In a mass balance/excretion
study in eight healthy male volunteers dosed to steady state with
nevirapine 200 mg given twice daily followed by a single 50 mg
dose of 14C-nevirapine, approximately 91.4 ± 10.5% of the
radiolabeled dose was recovered, with urine (81.3 ± 11.1%)
representing the primary route of excretion compared to feces
(10.1 ± 1.5%). Greater than 80% of the radioactivity in
urine was made up of glucuronide conjugates of hydroxylated metabolites.
Thus cytochrome P450 metabolism, glucuronide conjugation, and
urinary excretion of glucuronidated metabolites represent the
primary route of nevirapine biotransformation and elimination
in humans. Only a small fraction (<5%) of the radioactivity
in urine (representing <3% of the total dose) was made up of
parent compound; therefore, renal excretion plays a minor role
in elimination of the parent compound.
Nevirapine has been shown to be an inducer of hepatic cytochrome
P450 metabolic enzymes. The pharmacokinetics of autoinduction
are characterized by an approximately 1.5 to 2 fold increase in
the apparent oral clearance of nevirapine as treatment continues
from a single dose to two-to-four weeks of dosing with 200 - 400
mg/day. Autoinduction also results in a corresponding decrease
in the terminal phase half-life of nevirapine in plasma from approximately
45 hours (single dose) to approximately 25-30 hours following
multiple dosing with 200 - 400 mg/day.
Indications:
Nevirapine is indicated for use in combination with other antiretroviral
agents for the treatment of HIV-1 infection.
Resistant virus emerges rapidly and uniformly when nevirapine
is administered as monotherapy. Therefore, nevirapine should always
be administered in combination with at least one additional antiretroviral
agent.
Contra-indications:
Nevirapine is contraindicated in patients with clinically significant
hypersensitivity to any of the components contained in the tablet.
Dosage and directions for use:
Adults/adolescents:
The recommended dose is one 200-mg tablet once daily for the first
14 days of therapy (the "lead-in" period) followed by
the standard dose of one 200-mg tablet twice daily. The lead-in
period may reduce the incidence of drug-related rash.
Nevirapine may be taken with or without food.
Pediatric (2 months up to 8 years):
4 mg/kg once daily for the first 14 days followed by 7 mg/kg twice
daily thereafter, not to exceed 400 mg. Because of nevirapine's
long half-life, patients discontinuing antiretroviral therapy
should stop taking nevirapine 1 or 2 days before stopping NRTIs
to minimize the risk of acquiring NNRTI resistance during the
washout period.
Warnings:
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 should not occur until
the rash has resolved.
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 pertpanently
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.
The duration of clinical benefit from antiretroviral therapy may
be limited. Patients receiving nevirapine or any other antiretroviral
therapy may continue to develop opportunistic infections and other
complications of HIV infection, and therefore should remain under
close clinical observation by physicians experienced in the treatment
of patients with associated HIV diseases.
When administering nevirapine as part of an antiretroviral regimen,
the complete product information for each therapeutic component
should be consulted before initiation of treatment.
Side-effects and special precautions:
Rash, usually within first six weeks of therapy. D/C drug for
severe rash or rash accompanied by other symptoms; Stevens-Johnson
syndrome has occurred. Fever, headache, nausea, diarrhea, abdominal
pain, thrombocytopenia, anemia, leukopenia, ulcerative stomatitis,
hepatitis, peripheral neuropathy, paresthesia, or myalgia may
also occur.
Grenulocytopenia has been more commonly observed in children.
The safety profile of nevirapine in neonates has not been established.
Precautions:
Pregnancy:
Category C. 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.
Lactation: Data indicate that nevirapine is found in breast milk.
It is recommended that HIV-infected mothers not breast-feed their
infants to avoid risking postnatal transmission of HIV. Mothers
should discontinue nursing if they are receiving nevirapine.
Impaired renal and hepatic function: Nevirapine is extensively
metabolized by the liver and nevirapine metabolites are extensively
eliminated by the kidney. However, the pharmacokinetics of nevirapine
have not been evaluated in patients with either hepatic or renal
dysfunction. Therefore, nevirapine should be used with caution
in these patient populations.
Drug Interactions:
Oral contraceptives, beta-blockers, doxycycline, griseofulvin,
methadone, metronidazole, nifedipine, quinidine, steroids, theophyllin,
coumadin may have decreased plasma levels. Saquinavir and indinavir
levels are decreased by 27-28%. Rifampin and rifabutin may decrease
nevirapine concentrations. Nevirapine may decrease levels of protease
inhibitors, and should not be used with them. Oral contraceptives
or other hormonal birth control methods, and the usual protease
inhibitor dosages should not be used with nevirapine due to potential
decreases in their levels (indinavir dose can be increased to
1000 mg po q8h to compensate.) Macrolides and cimetidine may somewhat
increase nevirapine levels.
Known symptoms of overdosage and particulars of its treatment:
There is no known antidote for nevirapine overdosage. Cases of
nevirapine overdose 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,
insomnia, nausea, pulmonary infiltrates, rash, vertigo, vomiting
and weight decrease. All events subsided following discontinuation
of nevirapine.
Storage conditions and period.
Store in cool, dry & dark place, preferably below 25°C.
Shelf life is 2 years.
Package: 10 tablets packed in blister strip,
10 such blisters packed in a carton.
