E.F.200 CAPSULES
(Efavirenz Capsules 200mg)
Composition:
Each Capsule contains:
Efavirenz 200mg
Presentation:
10x10's
Pharmacology:
Efavirenz is a non- nucleoside reverse transcriptase (RT) inhibitor
of human immunodeficiency virus type 1 (HIV-1). Efavirenz activity
is mediated predominantly by non- competitive inhibition of HIV-1
RT. HIV-2 RT and human cellular DNA polymerases alpha, beta, gamma,
and delta are not inhibited by efavirenz.
Pharmacokinetics:
Absorption:
Peak efavirenz plasma concentrations of 1.6-9.1 m M were attained
by 5 hours following single oral doses of 100 mg to 1600 mg administered
to uninfected volunteers. Dose- related increases in C max and
AUC were seen for doses up to 1600 mg; the increases were less
than proportional suggesting diminished absorption at higher doses.
In HIV- infected patients at steady- state, mean C max , mean
C min , and mean AUC were dose proportional following 200 mg,
400 mg, and 600 mg daily doses. Time- to- peak plasma concentrations
were approximately 3-5 hours and steady-state plasma concentrations
were reached in 6-10 days. In 35 patients receiving efavirenz
600 mg QD, steady- state C max was 12.9 ± 3.7 m M (mean
± S. D.), steady-state C min was 5.6 ± 3.2 m M,
and AUC was 184 ± 73 m M"" h.
Effect of Food on Oral Absorption: In uninfected
volunteers, meals of normal composition had no appreciable effect
on the bioavailability of 100 mg of an investigational efavirenz
formulation administered twice a day for 10 days with meals (Breakfast:
662 kcal, 13.8 g protein, 27.9 g fat, 94.6 g carbohydrate; Dinner:
567 kcal, 44.5 g protein, 12.5 g fat, 73.8 g carbohydrate). The
relative bioavailability of a single 1200 mg dose of an investigational
efavirenz formulation in uninfected volunteers (N= 5) was increased
50% (range 11%- 126%) following a high fat meal (1070 kcal, 82
g fat, 69% of calories from fat)
Distribution: Efavirenz is highly bound (approximately
99.5- 99.75%) to human plasma proteins,predominantly albumin.
In HIV- 1 infected patients (N= 9) who received efavirenz 200
to 600 mg once daily for at least one month, cerebrospinal fluid
concentrations ranged from 0.26 to 1.19% (mean 0.69%) of the corresponding
plasma concentration. This proportion is approximately 3- fold
higher than the non-protein- bound (free) fraction of efavirenz
in plasma.
Metabolism: Studies in humans and in vitro studies
using human liver microsomes have demonstrated that efavirenz
is principally metabolized by the cytochrome P450 system to hydroxylated
metabolites with subsequent glucuronidation of these hydroxylated
metabolites. These metabolites are essentially inactive against
HIV-1.
The in vitro studies suggest that C.P.A. and CYP2B6 are the major
isozymes responsible for efavirenz metabolism. Efavirenz has been
shown to induce P450 enzymes, resulting in the induction of its
own metabolism. Multiple doses of 200- 400 mg per day for 10 days
resulted in a lower than predicted extent of accumulation (22-42%
lower) and a shorter terminal half- life of 40-55 hours (single
dose half-life 52-76 hours).
Elimination: Efavirenz has a terminal half-
life of 52- 76 hours after single doses and 40- 55 hours after
multiple doses. A one-month mass balance/ excretion study was
conducted using 400 mg per day with a 14 C-labeled dose administered
on Day 8. Approximately 14- 34% of the radiolabel was recovered
in the urine and 16-61% was recovered in the feces. Nearly all
of the urinary excretion of the radiolabeled drug was in the form
of metabolites. Efavirenz accounted for the majority of the total
radioactivity measured in feces.
Indications:
Efavirenz is used for the treatment of HIV infection in children
and adults. Efavirenz is most effective when used as part of a
triple combination therapy regimen with two other anti-HIV drugs.
Contra-indications:
Efavirenz is contraindicated in patients with clinically significant
hypersensitivity to the active substance or to any of the excipients.
Efavirenz should not be used in patients with severe hepatic impairment
(Child Pugh Grade C).
Efavirenz must not be administered concurrently with astemizole,
cisapride, midazolam, triazolam or ergot alkaloids because competition
for the cytochrome P450 3A4 enzyme by efavirenz could result in
inhibition of metabolism of these drugs and create the potential
for serious and/or life-threatening adverse events (for example,
cardiac arrhythmias, prolonged sedation or respiratory depression).
Dosage and directions for use:
Adults:
Orally 600 mg once daily (three 200-mg capsules). It is recommended
that efavirenz be taken on an empty stomach, preferably at bedtime.
Increased absorption occurs when efavirenz is taken with food
and may lead to adverse events. Taking efavirenz before bedtime
may improve the tolerability of neurological side effects.
Pediatric:
For children older than 3 years, administer efavirenz once daily
as follows: 200 mg (10 to <15 kg); 250 mg (15 to <20 kg);
300 mg (20 to <25 kg); 350 mg (25 to <32.5 kg); 400 mg (32.5
to 40 kg); 600 mg (>40 kg).
Because of efavirenz's long half-life, patients discontinuing
antiretroviral therapy have been advised to stop taking efavirenz
1 or 2 days before stopping NRTIs to minimize the risk of acquiring
NNRTI resistance during the washout period.
Warning:
Efavirenz must not be used as a single agent to treat HIV or added
on as a sole agent to a failing regimen. As with all other non-nucleoside
reverse transcriptase inhibitors, resistant virus emerges rapidly
when efavirenz is administered as monotherapy. The choice of new
antiretroviral agent(s) to be used in combination with efavirenz
should take into consideration the potential for viral cross-resistance.
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. The incidence of erythema
multiforme or Stevens-Johnson Syndrome was approximately 0.1%.
The median time to onset of rash in adults was II 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 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
monthss. Patients should be informed that these common symptoms
were likely to improve with continued therapy. Dosing at bedtime
seems to improve the tolerability of these symptoms and can be
recommended during the first monthss of therapy and in patients
who continue to experience these symptoms. Patients should be
altered 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 mediations 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.
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.
Renal impairment
The pharmacokinetics of efavirenz has 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.
Cholesterol
Monitoring of cholesterol should be considered in patients treated
with efavirenz.
Side-effects & special precautions:
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 reveals 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: gynaecomastia
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 discoloration, Stevens-Johnson Syndrome.
Special Senses: abnormal vision, tinnitus
Special precautions:
Pregnancy:
Efavirenz has not been formally studied in pregnant women, but
preliminary studies indicate that women should avoid becoming
pregnant while on this drug. A study conducted in pregnant monkeys
showed that there were malformations in fetuses after the monkeys
were given a dose similar to the recommended human dose.
Lactation:
Women should also be cautious of breast-feeding while taking efavirenz
because it may be passed through breast milk resulting in potential
toxicity to the child. A study is planned to look at whether efavirenz
can prevent or reduce the risk of transmission of HIV from mother
to child.
Drug Interaction:
Grapefruit juice may effect plasma efavirenz concentration. Antibacterials:
increased risk of rash with clarithromycin. Rifampicin reduces
plasma concentration of efavirenz. Antidepressants: avoid concomitant
use of st. john's wort Antihistaminics: increased risk of ventricular
arrhythmias when used with terfenadine. Other antivirals: Efavirenz
reduces plasma concentration of amprenavir, indinavir and lipinavir.
Efavirenz reduces plasma concentration of saquinavir. Anxiolytics:
Risk of prolonged sedation with midazolam. Oestrogen and progestogens:
possibly reduced efficacy of oral contraceptives.
Known symptoms of overdosage and particulars of its treatment:
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.
Storage conditions and period.
Store in cool, dry & dark place, preferably below 25°C.
Storage life is 2 years.
Package: 10 capsules packed in blister strip,
10 such blisters packed in a carton.
