ZVD PLUS TABLETS
(Zidovudine & Lamivudine Tablets)
Composition:
Each tablet contains:
Zidovudine BP 300mg
Lamivudine 150mg
Presentation:
10x10's
Pharmacology:
It is a combination of two drugs commonly used in the management
of Human Immunodeficiency Virus (HIV) infection. Both lamivudine
and zidovudine belong to the nucleoside analogue class of antiretroviral
drugs. Both drugs act by inhibiting the reverse transcriptase
enzyme of HIV, and by terminating the growth of the DNA chain.
Lamivudine in combination with zidovudine has been shown to have
synergistic antiretroviral activity.
Pharmacokinetics:
Lamivudine:
Lamivudine was rapidly absorbed after oral administration in HIV-infected
patients. Absolute bioavailability in 12 adult patients was 86%
± 16% (mean ± SD) for the tablet and 87% ±
13% for the oral solution. After oral administration of 2 mg/kg
twice a day to nine adults with HIV, the peak serum lamivudine
concentration (Cmax) was 1.5 ± 0.5 µg/ml (mean ±
SD). The area under the plasma concentration versus time curve
(AUC) and Cmax increased in proportion to oral dose over the range
from 0.25 to 10 mg/kg.
An investigational 25-mg dosage form of lamivudine was administered
orally to 12 asymptomatic, HIV-infected patients on two occasions,
once in the fasted state and once with food (1099 kcal; 75 grams
fat, 34 grams protein, 72 grams carbohydrate). Absorption of lamivudine
was slower in the fed state (Tmax: 3.2 ± 1.3 hours) compared
with the fasted state (Tmax: 0.9 ± 0.3 hours); Cmax in
the fed state was 40% ± 23% (mean ± SD) lower than
in the fasted state. There was no significant difference in systemic
exposure (AUC¥) in the fed and fasted states; therefore, Lamivudine
may be administered with or without food.
The accumulation ratio of lamivudine in HIV-positive asymptomatic
adults with normal renal function was 1.50 following 15 days of
oral administration of 2mg/kg b.i.d.
The apparent volume of distribution after IV administration of
lamivudine to 20 patients was 1.3 ± 0.4 L/kg, suggesting
that lamivudine distributes into extravascular spaces. Volume
of distribution was independent of dose and did not correlate
with body weight.
Binding of lamivudine to human plasma proteins is low (<36%).
In vitro studies showed that, over the concentration range of
0.1 to 100 mg/mL, the amount of lamivudine associated with erythrocytes
ranged from 53% to 57% and was independent of concentration.
Metabolism of lamivudine is a minor route of elimination. In
man, the only known metabolite of lamivudine is the trans-sulfoxide
metabolite. Within 12 hours after a single oral dose of lamivudine
in six HIV-infected adults, 5.2% ± 1.4% (mean ±
SD) of the dose was excreted as the trans-sulfoxide metabolite
in the urine. Serum concentrations of this metabolite have not
been determined.
The majority of lamivudine is eliminated unchanged in urine. In
20 patients given a single IV dose, renal clearance was 0.22 ±
0.06 L/hrkg (mean ± SD), representing 71% ± 16%
(mean ± SD) of total clearance of lamivudine.
In most single-dose studies in HIV-infected patients with serum
sampling for 24 hours after dosing, the observed mean elimination
half-life (T 1/2) ranged from 5 to 7 hours. Total clearance was
0.37 ± 0.05 L/hrkg (mean ± SD). Oral clearance and
elimination half-life were independent of dose and body weight
over an oral dosing range from 0.25 to 10 mg/kg.
Zidovudine:
The pharmacokinetics of zidovudine has been evaluated in 22 adult
HIV-infected patients in a Phase 1 dose-escalation study. After
oral dosing (capsules), zidovudine was rapidly absorbed from the
gastrointestinal tract with peak serum concentrations occurring
within 0.5 to 1.5 hours. Dose-independent kinetics was observed
over the range of 2 mg/kg every 8 hours to 10 mg/kg every 4 hours.
The mean zidovudine half-life was approximately 1 hour and ranged
from 0.78 to 1.93 hours following oral dosing.
Zidovudine is rapidly metabolized to 3'-azido-3'-deoxy-5'-O-?-D-glucopyra-nuronosylthymidine
(GZDV) which has an apparent elimination half-life of 1 hour (range
0.61 to 1.73 hours). Following oral administration, urinary recovery
of zidovudine and GZDV accounted for 14% and 74% of the dose,
respectively, and the total urinary recovery averaged 90% (range
63% to 95%), indicating a high degree of absorption. However,
as a result of first-pass metabolism, the average oral capsule
bioavailability of zidovudine is 65% (range 52% to 75%). A second
metabolite, 3-amino- 3-deoxythymidine (AMT), has been identified
in the plasma following single-dose intravenous (IV) administration
of zidovudine. AMT area-under-the-curve (AUC) was one fifth of
the AUC of zidovudine and had a half-life of 2.7 ± 0.7
hours. In comparison, GZDV AUC was about three-fold greater than
the AUC of zidovudine.
Additional pharmacokinetic data following intravenous dosing indicated
dose-independent kinetics over the range of 1 to 5 mg/kg with
a mean zidovudine half-life of 1.1 hours (range 0.48 to 2.86 hours).
Total body clearance averaged 1900 mL/min per 70 kg and the apparent
volume of distribution was 1.6 L/kg. Renal clearance is estimated
to be 400 mL/min per 70 kg, indicating glomerular filtration and
active tubular secretion by the kidneys.
Zidovudine plasma protein binding is 34% to 38%, indicating that
drug interactions involving binding site displacement are not
anticipated.
The zidovudine cerebrospinal fluid (CSF)/plasma concentration
ratio was determined in 39 patients receiving chronic therapy
with zidovudine. The median ratio measured in 50 paired samples
drawn 1 to 8 hours after the last dose of zidovudine was 0.6.
Indications:
Lamivudine + Zidovudine is indicated for the treatment of HIV
infection.
Contra-indications:
Lamivudine + Zidovudine Tablets is contraindicated in patients
with clinically significant hypersensitivity to the active substance
or to any of the excipients.
Dosage and directions for use:
The recommended oral dose of Lamivudine + Zidovudine for adults
and adolescents (at least 12 years of age) is one capsule (containing
150 mg of lamivudine and 300 mg of zidovudine) twice daily with
or without food.
Dose Adjustment:
Because it is a fixed dose combination, Lamivudine + Zidovudine
should not be prescribed for patients requiring dosage adjustment
such as those with reduced renal function (creatinine clearance
< 50 mL/min), those with low body weight (< 50 kg or II
0 lb), or those experiencing dose-limiting adverse events.
Warning:
Since it is a fixed-dose combination of lamivudine and zidovudine,
it should ordinarily not be administered concomitantly with either
lamivudine or zidovudine.
The complete prescribing information for all agents being considered
for use with Lamivudine + Zidovudine should be consulted before
combination therapy with Lamivudine + Zidovudine is initiated.
Bone marrow suppression
Lamivudine + Zidovudine should be used with caution in patients
who have bone marrow compromise evidenced by granulocyte count
<1,000 cells/ mm3 or hemoglobin < 9.5 g/dl (See Side Effects).
Frequent blood counts are strongly recommended in patients with
advanced HIV disease who are treated with Lamivudine + Zidovudine.
For HIVinfected individuals and patients with asymptomatic or
early HIV disease, periodic blood counts are recommended.
Lactic acidosis/severe hepatomegaly with steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including
fatal cases, have been reported with the use of antiretroviral
nucleoside analogues alone or in combination, including zidovudine
and lamivudine. A majority of these cases have been in women.
Caution should be exercised when administering Lamivudine + Zidovudine
to any patient, and particularly to those with known risk factors
for liver disease. Treatment with Lamivudine + Zidovudine should
be suspended in any patient who develops clinical or laboratory
findings suggestive of lactic acidosis or hepatotoxicity.
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
+ Zidovudine .
Patients with hiv and hepatitis b virus coinfection
In clinical trials and postmarketing experience, some patients
with HIV infection who have chronic liver disease due to hepatitis
B virus infection experienced clinical or laboratory evidence
of recur-rent hepatitis upon discontinuation of lamivudine. Consequences
may be more severe in patients with decompensated liver disease.
Side-effects & special precautions:
The most commonly observed side effects during clinical trials
were headache, malaise and fatigue, nausea, vomiting, diarrhoea,
anorexia, fever/chills, neuropathy, insomnia, dizziness, nasal
signs and symptoms, cough, musculoskeletal pain and neutropenia.
Special precautions:
Impaired Renal Function
Reduction of the dosages of lamivudine and zidovudine is recommended
for patients with impaired renal function. Patients with creatinine
clearance < 50 ml/min should not receive Lamivudine + Zidovudine.
Pregnancy
Category C. There are no adequate and well-controlled studies
of this combination in pregnant women. Lamivudine + Zidovudine
should be used during pregnancy only if the potential benefits
outweigh the risks.
Lactation
It is recommended that HIV-infected mothers not breast-feed their
infants to avoid risking postnatal transmission of HIV infection.
Zidovudine is excreted in breast milk. No data are available on
this combination or lamivudine. Therefore, there is a potential
for adverse effects in nursing infants. Mothers should be instructed
not to breast-feed if they are receiving Lamivudine + Zidovudine.
Paediatric Use
Lamivudine + Zidovudine should not be administered to paediatric
patients less than 12 years of age because it is a fixed-dose
combination that cannot be adjusted for this patient population.
Others
Reduction of doses of lamivudine is recommended for patients with
low body weight (less than 50 kg or 110 lb). Therefore patients
with low body weight should not receive Lamivudine + Zidovudine.
Drug Interaction:
Coadministration of ganciclovir, interferon-cc, and other bone
marrow suppressive or cytotoxic agents may increase the hematologic
toxicity of zidovudine.
Known symptoms of overdosage and particulars of its treatment:
There is no known antidote for Lamivudine + Zidovudine.
Lamivudine:
One case of an adult ingesting 6 gms of lamivudine has been 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 paediatric
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.
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.
