RETHINKING
AIDS HOMEPAGE
RETROVIR ® Capsules
RETROVIR ® Syrup
RETROVIR ® Intravenous Infusion
(ZIDOVUDINE)
WARNING: RETROVIR (ZIDOVUDINE) MAY BE ASSOCIATED
WITH HEMATOLOGIC TOXICITY INCLUDING GRANULOCYTOPENIA AND SEVERE
ANEMIA PARTICULARLY IN PATIENTS WITH ADVANCED HIV DISEASE (SEE
WARNINGS).
PROLONGED USE OF RETROVIR HAS BEEN ASSOCIATED
WITH SYMPTOMATIC MYOPATHY SIMILAR TO THAT PRODUCED BY HUMAN IMMUNODEFICIENCY
VIRUS. RARE OCCURRENCES OF LACTIC ACIDOSIS IN THE ABSENCE OF
HYPOXEMIA, AND SEVERE HEPATOMEGALY WITH STEATOSIS HAVE BEEN REPORTED
WITH THE USE OF ANTIRETROVIRAL NUCLEOSIDE ANALOGUES, INCLUDING
RETROVIR AND ZALCITABINE, AND ARE POTENTIALLY FATAL (SEE WARNINGS).
DESCRIPTION
Retrovir is the brand name for zidovudine
[formerly called azidothymidine (AZT)], a pyrimidine nucleoside
analogue active against human immunodeficiency virus (HIV).
The chemical name of zidovudine is 3'-azido-3'-deoxythymidine.
Zidovudine is a white to beige, odorless,
crystalline solid with a molecular weight of 267.24 and a solubility
of 20.1 mg/ml in water at 25oC. The molecular formula is C10H13N5O4.
Capsules
Retrovir Capsules are for oral administration.
Each capsule contains 100 mg of zidovudine and the inactive ingredients
corn starch, magnesium stearate, microcrystalline cellulose,
and sodium starch glycolate. The 100 mg empty hard gelatin capsule,
printed with edible black ink, consists of black iron oxide,
dimethylpolysiloxane, gelatin, pharmaceutical shellac, soya lecithin,
and titanium dioxide. The blue band around the capsule consists
of gelatin and FD&C Blue No. 2.
Syrup
Retrovir Syrup is for oral administration.
Each teaspoonful (5 ml) of Retrovir Syrup contains 50 mg of zidovudine
and the inactive ingredients sodium benzoate 0.2% (added as a
preservative), citric acid, flavors, glycerin, and liquid sucrose.
Sodium hydroxide may be added to adjust pH.
Intravenous Infusion
Retrovir IV Infusion is a sterile solution
for intravenous infusion only. Each ml contains 10 mg zidovudine
in Water for Injection. Hydrochloric acid and/or sodium hydroxide
may have been added to adjust the pH to approximately 5.5. Retrovir
IV Infusion contains no preservatives.
CLINICAL PHARMACOLOGY
Zidovudine is an inhibitor of the in vitro
replication of some retroviruses including HIV. This drug is
a thymidine analogue in which the 3'-hydroxy (-OH) group is replaced
by an azido (-N3) group. Cellular thymidine kinase converts zidovudine
into zidovudine monophosphate. The monophosphate is further converted
into the diphosphate by cellular thymidylate kinase and to the
triphosphate derivative by other cellular enzymes. Zidovudine
triphosphate interferes with the HIV viral RNA dependent DNA
polymerase (reverse transcriptase) and thus, inhibits viral replication.
Zidovudine triphosphate also inhibits cellular alpha-DNA polymerase,
but at concentrations 100-fold higher than those required to
inhibit reverse transcriptase. In vitro, zidovudine triphosphate
has been shown to be incorporated into growing chains of DNA
by viral reverse transcriptase. When incorporation by the viral
enzyme occurs, the DNA chain is terminated. Studies in cell culture
suggest that zidovudine incorporation by cellular alpha-DNA polymerase
may occur, but only to a very small extent and not in all test
systems. Cellular y-DNA polymerase shows some sensitivity to
inhibition by the zidovudine triphosphate with 50% inhibitory
concentration (IC50) values 400 to 900 times greater than that
for HIV reverse transcriptase.
Microbiology:
The relationship between in vitro susceptibility of HIV
to zidovudine and the inhibition of HIV replication in humans
or clinical response to therapy has not been established. In
vitro sensitivity results vary greatly depending upon the
time between virus infection and zidovudine treatment of cell
cultures, the particular assay used, the cell type employed,
and the laboratory performing the test.
Zidovudine blocked 90% of detectable HIV replication
in vitro at concentrations of </=0.13 µg/ml (ID90)
when added shortly after laboratory infection of susceptible
cells. This level of antiviral effect was observed in experiments
measuring reverse transcriptase activity in HIV-infected H9 cells,
PHA stimulated peripheral blood lymphocytes, and unstimulated
peripheral blood lymphocytes. The concentration of drug required
to produce a 50% decrease in supernatant reverse transcriptase
was 0.013 µg/ml (ID50) in both HIV-infected H9 cells and
peripheral blood lymphocytes. Zidovudine at concentrations of
0.13 µg/ml also provided >90% protection from a strain
of HIV (HTLV IIIB) induced cytopathic effects in two tetanus-specific
T4 cell lines. HIV-p24 antigen expression was also undetectable
at the same concentration in these cells. Partial inhibition
of viral activity in cells with chronic HIV infection (presumed
to carry integrated HIV DNA) required concentrations of zidovudine
(8.8 µg/ml in one laboratory to 13.3 µg/ml in another)
which are approximately 100 times as high as those necessary
to block HIV replication in acutely infected cells. HIV isolates
from 18 untreated individuals with AIDS or ARC had ID50 sensitivity
values between 0.003 to 0.013 µg/ml and ID95 sensitivity
values between 0.03 to 0.3 µg/ml.
Zidovudine has been shown to act additively
or synergistically with a number of anti-HIV agents, including
zalcitabine, didanosine, and interferon-alpha, in inhibiting
the replication of HIV in cell culture.
The development of resistance to zidovudine
has been studied extensively. The emergence of resistance is
a function of both duration of zidovudine therapy and stage of
disease. Asymptomatic patients developed resistance at significantly
slower rates than patients with advanced disease. In contrast,
virus isolates from patients with AIDS who received a year or
more of zidovudine may show more than 100-fold increases in ID50
compared to isolates pre-therapy.
In vitro resistance
to zidovudine is due to the accumulation of specific mutations
in the HIV reverse transcriptase coding region. Five amino acid
substitutions (Met41->Leu, A67->Asn, Lys70->Arg, Thr215->Tyr
or Phe, and Lys219->Gin) have been described in viruses with
decreased in vitro susceptibility to zidovudine inhibition.
The extent of resistance appears to be correlated with number
of mutations in reverse transcriptase.
A significant correlation between zidovudine
resistance and poor clinical outcome in children with advanced
disease has been reported; in addition, a correlation between
reduced sensitivity to zidovudine and lower CD4 cell counts in
symptom-free adults treated with zidovudine for up to 3 years
has also been reported. However, the specific relationship between
emergence of zidovudine resistance and clinical progression of
disease in adults has not yet been defined.
Combination therapy of zidovudine plus zalcitabine
does not appear to prevent the emergence of zidovudine-resistant
isolates. In vitro studies with zidovudine-resistant virus
isolates indicate zidovudine-resistant strains are usually sensitive
to zalcitabine and didanosine.
The major metabolite of zidovudine, 3'-azido-3'-deoxy-5'-O-ß-D-glucopyranuronosylthymidine
(GZDV, formerly called GAZT), does not inhibit HIV replication
in vitro. GZDV does not antagonize the antiviral effect
of zidovudine in vitro nor does GZDV compete with zidovudine
triphosphate as an inhibitor of HIV reverse transcriptase.
The cytotoxicity of zidovudine for various
cell lines was determined using a cell growth inhibition assay.
ID50 values for several human cell lines showed little growth
inhibition by zidovudine except at concentrations >50 µg/ml.
However, one human T-lymphocyte cell line was sensitive to the
cytotoxic effect of zidovudine with an ID50 of 5 µg/ml.
Moreover, in a colony-forming unit assay designed to assess the
toxicity of zidovudine for human bone marrow, an ID50 value of
<1.25 µg/ml was estimated. Two of ten human lymphocyte
cultures tested were found to be sensitive to zidovudine at 5
µg/ml or less.
Zidovudine has antiviral activity against
some other mammalian retroviruses in addition to HIV. Human immunodeficiency
virus-2 (HIV-2) replication in vitro is inhibited by zidovudine
with an ID50 of 0.015 µg/ml, while HTLV-1 transmission
to susceptible cells is inhibited by 1 to 3 µg/ml concentrations
of drug. Several strains of simian immunodeficiency virus (SIV)
are also inhibited by zidovudine with ID50 values ranging from
0.13 to 6.5 µg/ml, depending upon species of origin and
assay method used. No significant inhibitory activity was exhibited
against a variety of other human and animal viruses, except an
ID50 of 1.4 to 2.7 µg/ml against the Epstein-Barr virus,
the clinical significance of which is unknown.
The following microbiological activities of
zidovudine have been observed in vitro, but the clinical
significance is unknown. Many Enterobacteriaceae, including strains
of Shigella, Salmonella, Klebsiella, Enterobacter, Citrobacter,
and Escherichia coli are inhibited in vitro by low concentrations
of zidovudine (0.005 to 0.5 µg/ml). Synergy of zidovudine
with trimethoprim has been observed against some of these bacteria
in vitro. Limited data suggest that bacterial resistance
to zidovudine develops rapidly. Zidovudine has no activity against
gram positive organisms, anaerobes, mycobacteria, or fungal pathogens
including Candida albicans and Cryptococcus neoformans. Although
Giardia lamblia is inhibited by 1.9 µg/ml of zidovudine,
no activity was observed against other protozoal pathogens.
Pharmacokinetics: Adults:
Capsules and Syrup
The pharmacokinetics of zidovudine has been
evaluated in 22 adult HIV-infected patients in a Phase 1 dose-escalation
study. After oral dosing, 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-ß-D-glucopyranuronosylthymidine
(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 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 3-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/70 kg and the apparent volume of distribution was
1.6 l/kg. Renal clearance is estimated to be 400 ml/min/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 Retrovir. The median ratio measured in 50 paired
samples drawn 1 to 8 hours after the last dose of Retrovir was
0.6.
Intravenous Infusion
The pharmacokinetics of zidovudine has been
evaluated in 22 adult HIV-infected patients in a Phase 1 dose-escalation
study. Following intravenous dosing, dose-dependent kinetics
was observed 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/70 kg, and the apparent volume
of distribution was 1.6 l/kg. At a dose of 7.5 mg/kg every 4
hours, total body clearance was calculated to be about 1200 ml/min/70
kg, with no change in half-life. Renal clearance is estimated
to be 400 ml/min/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 mean steady-state peak and trough concentrations
of zidovudine at 2.5 mg/kg every 4 hours were 1.06 and 0.12 µg/ml,
respectively.
The zidovudine cerebrospinal fluid (CSF)/plasma
concentration ratio was determined in 39 patients receiving chronic
therapy with Retrovir. The median ratio measured in 50 paired
samples drawn 1 to 8 hours after the last dose of Retrovir was
0.6.
Zidovudine is rapidly metabolized to 3'-azido-3'-deoxy-5'-O-ß-D-glucopyranuronosylthymidine
(GZDV) which has an apparent elimination half-life of 1 hour
(range 0.61 to 1.73 hours). A second metabolite, 3'-amino-3'-deoxythymidine
(AMT), has been identified in the plasma following single dose
intravenous 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 3-fold
greater than the AUC of zidovudine. Following intravenous administration,
urinary recoveries of zidovudine and GZDV accounted for 18% and
60% of the dose, respectively, and the total urinary recovery
averaged 77% (range 64% to 98%).
Capsules, Syrup, and Intravenous Infusion
Adults with Impaired Renal Function: The pharmacokinetics of zidovudine has been evaluated
in patients with impaired renal function following a single 200
mg oral dose. In 14 patients (mean creatinine clearance 18±2
ml/min), the half-life of zidovudine was 1.4 hours compared to
1.0 hour for control subjects with normal renal function; AUC
values were approximately twice those of controls. Additionally,
GZDV half-life in these patients was 8.0 hours (vs 0.9 hours
for control) and AUC was 17 times higher than for control subjects.
The pharmacokinetics and tolerance were evaluated in a multiple-dose
study in patients undergoing hemodialysis (n=5) or peritoneal
dialysis (n=6). Patients received escalating doses of zidovudine
up to 200 mg five times daily for 8 weeks. Daily doses of 500
mg or less were well tolerated despite significantly elevated
plasma levels of GZDV. Apparent oral clearance of zidovudine
was approximately 50% of that reported in patients with normal
renal function. The plasma concentrations of AMT are not known
in patients with renal insufficiency. Daily oral doses of 300
to 400 mg should be appropriate in HIV-infected patients with
severe renal dysfunction (see DOSAGE AND ADMINISTRATION: Dose
Adjustment). Hemodialysis and peritoneal dialysis appear to have
a negligible effect on the removal of zidovudine, whereas GZDV
elimination is enhanced.
Children and Infants:
The pharmacokinetics and bioavailability of zidovudine have been
evaluated in 21 HIV-infected children, aged 6 months through
12 years, following intravenous doses administered over the range
of 80 to 160 mg/m2 every 6 hours, and following oral doses of
the intravenous solution administered over the range of 90 to
240 mg/m2 every 6 hours. After discontinuation of the IV infusion,
zidovudine plasma concentrations decayed biexponentially, consistent
with two-compartment pharmacokinetics. Proportional increases
in AUC and in zidovudine concentrations were observed with increasing
dose, consistent with dose-independent kinetics over the dose
range studied. The mean terminal half-life and total body clearance
across all dose levels administered were 1.5 hours and 30.9 ml/min/kg,
respectively. These values compare to mean half-life and total
body clearance in adults of 1.1 hours and 27.1 ml/min/kg.
Capsules and Syrup
The mean oral bioavailability of 65% was independent
of dose. This value is the same as the bioavailability in adults.
Doses of 180 mg/m2 four times daily in pediatric patients produced
similar systemic exposure (24 hour AUC 10.7 hr µg/ml) as
doses of 200 mg six times daily in adult patients (10.9 hr µg/ml).
Capsules, Syrup, and Intravenous Infusion
The pharmacokinetics of zidovudine has been
studied in neonates from birth to 3 months of life. In one study
of the pharmacokinetics of zidovudine in women during the last
trimester of pregnancy, zidovudine elimination was determined
immediately after birth in 8 infants who were exposed to zidovudine
in utero. The half-life was 13.0±5.8 hours. In another
study, the pharmacokinetics of zidovudine was evaluated in infants
(ranging in age of 1 day to 3 months) of normal birth weight
for gestational age and with normal renal and hepatic function.
In infants less than or equal to 14 days old, mean±SD
total body clearance was 10.9±4.8 ml/min/kg (n=18) and
half-life was 3.1±1.2 hours (n=21). In infants greater
than 14 days, total body clearance was 19.0±4.0 ml/min/kg
(n=16) and half-life was 1.9±0.7 hours (n=18).
Capsules and Syrup
Bioavailability was 89%±19% (n=15)
in the younger age group and decreased to 61%±19% (n=17)
in infants older than 14 days.
Capsules, Syrup, and Intravenous Infusion
Concentrations of zidovudine in cerebrospinal
fluid were measured after both intermittent oral and IV drug
administration in 21 children during Phase 1 and Phase 2 studies.
The mean zidovudine CSF/plasma concentration ratio measured at
an average time of 2.2 hours postdose at oral doses of 120 to
240 mg/m2 was 0.52±0.44 (n=28); after an IV infusion of
doses of 80 to 160 mg/m2 over 1 hour, the mean CSF/plasma concentration
ratio was 0.87±0.66 (n=23) at 3.2 hours after the start
of the infusion. During continuous IV infusion, mean steady-state
CSF/plasma ratio was 0.26±0.17 (n=28).
As in adult patients, the major route of elimination
in children was by metabolism to GZDV. After IV dosing, about
29% of the dose was excreted in the urine unchanged and about
45% of the dose was excreted as GZDV. Overall, the pharmacokinetics
of zidovudine in pediatric patients greater than 3 months of
age is similar to that of zidovudine in adult patients.
Pregnancy: The
pharmacokinetics of zidovudine has been studied in a Phase 1
study of eight women during the last trimester of pregnancy.
As pregnancy progressed, there was no evidence of drug accumulation.
The pharmacokinetics of zidovudine was similar to that of nonpregnant
adults. Consistent with passive transmission of the drug across
the placenta, zidovudine concentrations in infant plasma at birth
were essentially equal to those in maternal plasma at delivery.
Although data are limited, methadone maintenance therapy in five
pregnant women did not appear to alter zidovudine pharmacokinetics.
However, in another patient population, a potential for interaction
has been identified (see PRECAUTIONS).
Capsules: Steady-state
serum concentrations of zidovudine following chronic oral administration
of 250 mg every 4 hours were determined in 21 adult patients
in a controlled trial. Mean steady-state predose and 1.5 hours
post-dose zidovudine concentrations were 0.16 µg/ml (range
0 to 0.84 µg/ml) and 0.62 µg/ml (range 0.05 to 1.46
µg/ml), respectively.
Syrup: In a
multiple dose bioavailability study conducted in 12 HIV-infected
adults receiving doses of 100 or 200 mg every 4 hours, Retrovir
Syrup was demonstrated to be bioequivalent to Retrovir Capsules
with respect to area under the zidovudine plasma concentration-time
curve (AUC). The rate of absorption of Retrovir Syrup was greater
than that of Retrovir Capsules, as indicated by mean times to
peak concentration of 0.5 and 0.8 hours, respectively. Mean values
for steady-state peak concentration (dose-normalized to 200 mg)
were 1.5 and 1.2 µg/ml for syrup and capsules, respectively.
Effect of Food on Absorption: Administration of Retrovir Capsules with food decreased
peak plasma concentrations by greater than 50%, however bioavailability
as determined by AUC may not be affected.
Capsules, Syrup, and Intravenous Infusion
Description of Clinical Studies: Monotherapy-Adults: Randomized double-blind studies
have demonstrated clinical benefit of initial treatment with
Retrovir compared to placebo, didanosine, or zalcitabine. Therapy
with Retrovir has been shown to prolong survival and decrease
the incidence of opportunistic infections in patients with advanced
HIV disease at the initiation of therapy and to delay disease
progression in asymptomatic HIV-infected patients.
Other randomized studies suggest that the
duration of the clinical benefit of monotherapy with Retrovir
is time-limited. Patients randomized to other antiviral regimens
after initial therapy with Retrovir had fewer AIDS progression
end-points than those randomized to continue monotherapy with
Retrovir. The design of those studies did not define optimally
when and how the antiviral regimen should be monitored. Factors
which may contribute to the development of disease progression
while on therapy with Retrovir are under clinical investigation
and may include suppression of viral replication and development
of decreased viral susceptibility to Retrovir.
Advanced HIV Disease:
A randomized, double-blind, placebo-controlled trial (BW 02)
of oral Retrovir (1500 mg/day) was conducted in 281 adults with
advanced HIV disease which included 160 patients with AIDS and
121 patients with ARC.1,2
There were 19 deaths (12 in patients with
AIDS, 7 in patients with ARC) in the placebo group and 1 death
(patient with AIDS) in the group receiving Retrovir. Treatment
with Retrovir significantly improved the probability of survival
for 24 weeks in both the AIDS and ARC subgroups. During a follow-up
protocol with open-label treatment with Retrovir, patients who
were initially randomized to receive Retrovir continued to have
better overall survival than did patients initially randomized
to placebo. Survival rates in the group of patients originally
randomized to receive Retrovir declined 85% after 1 year, 41%
after 2 years, and 23% after 3 years. These survival rates may
be lower than currently observed due to the absence of opportunistic
infection (OI) prophylaxis in this study. Retrovir also significantly
reduced the risk of acquiring an AIDS-defining opportunistic
infection, and patients who received Retrovir generally did better
than the placebo group in terms of several other measures of
efficacy including performance level, neuropsychiatric function,
maintenance of body weight, and the number and severity of symptoms
associated with HIV disease.
In separate studies, initial therapy with
Retrovir was compared to initial therapy with either didanosine
or zalcitabine. Survival rates in patients with no prior exposure
to Retrovir were significantly better for patients treated with
Retrovir than for patients treated with alternative monotherapy.
Asymptomatic HIV Infection and Early HIV
Disease (CD4 between 200 to 500 cells/mm3):
The population indicated for monotherapy with Retrovir was extended
to asymptomatic or symptomatic adults with CD4 cell counts of
500 cells/mm3 or less based on the results of two randomized
double-blind placebo-controlled trials (ACTG 0193, ACTG 0164)
of 2051 adults. Treatment with Retrovir reduced the risk of progression
to advanced HIV disease [advanced AIDS Related Complex (ARC),
AIDS, or death] and significantly improved CD4 cell count. Survival
benefit could not be assessed due to limited duration of follow-up
at the time the placebo arms were discontinued. Other large studies
of longer duration have not shown additional survival benefit
of early versus delayed therapy with Retrovir above that seen
for patients with advanced HIV disease.
Monotherapy-Pediatrics: Pediatric HIV Disease: Two open-label studies (n=36:
mean follow-up 465 days, and n=88: mean follow-up 186 days) have
evaluated the pharmacokinetics, safety, and efficacy of Retrovir
in children with advanced HIV disease (84 with AIDS and 40 with
other clinical and laboratory evidence of advanced HIV disease).
The median age at entry was 3.3 years (range: 3.5 months to 12
years) with 17 subjects younger than 12 months of age. In 73%
of the cases, HIV was acquired by vertical transmission from
an HIV-infected mother.
Clinical, immunologic, and virologic improvements
were observed among some of the children receiving Retrovir in
these open-label studies. Clinical improvements included reductions
in hepatosplenomegaly and increases in weight percentiles in
children with delayed growth. The probability of remaining free
of opportunistic infections through 12 months of follow-up was
0.76 and the probability of survival at 12 months was 0.87 for
these patients.
Improvements in CD4 cell counts and normalization
of immunoglobulin concentration were observed among the patients
receiving Retrovir. An antiretroviral effect was demonstrated
by reductions in serum and CSF p24 antigen concentrations, as
well as by a reduction in the number of patients with positive
CSF HIV cultures.
Pregnant Women and Their Newborn Infants: The utility of Retrovir for the prevention of maternal-fetal
HIV transmission was demonstrated in a randomized, double-blind,
placebo-controlled trial (ACTG 076) conducted in HIV-infected
pregnant women who had little or no previous exposure to Retrovir
and CD4 cell counts of 200 to 1818 cells/mm3 (median in the treated
group: 560 cells/mm3). Oral Retrovir was initiated between 14
and 34 weeks of gestation (median 11 weeks of therapy) followed
by intravenous administration of Retrovir during labor and delivery.
After birth, infants received oral Retrovir Syrup for 6 weeks.
The study showed a statistically significant difference in the
incidence of HIV infection in the infants (based on viral culture
from peripheral blood) between the group receiving Retrovir and
the group receiving placebo. Of 363 infants evaluated in the
study, the estimated risk of HIV infection was 8.3% in the group
receiving Retrovir and 25.5% in the placebo group, a relative
reduction in transmission risk of 67.5%.
Retrovir was well tolerated by mothers and
infants. There was no difference in pregnancy-related adverse
events between the treatment groups. The mean difference in hemoglobin
values was less than 1.0 g/dl for infants receiving Retrovir
compared to infants receiving placebo. Infants did not require
transfusion and hemoglobin values spontaneously returned to normal
within 6 weeks after completion of therapy with Retrovir. The
long-term consequences of in utero and infant exposure to Retrovir
are unknown.
Capsules and Syrup
Combination Therapy with Retrovir and Zalcitabine: Patients with Prior Exposure to Retrovir: The use
of Retrovir in combination with zalcitabine in patients who have
previously received Retrovir is based on the results from a subgroup
analysis of a Phase 3, randomized, double-blind clinical trial
(ACTG 155). ACTG 155 was a comparative study (n=1001) of zalcitabine
alone or in combination with Retrovir versus Retrovir alone in
patients with an entry CD4 cell count </=300 cells/mm3 who
had previously received Retrovir for 6 months or more (median
18 months).
Overall, there were no significant differences
in disease progression or death for the three study groups. However,
for those patients on combination Retrovir and zalcitabine with
baseline CD4 cell counts between 150 to 300 cells/mm3 at entry,
there were fewer study endpoints of disease progression when
compared to the group receiving monotherapy with Retrovir but
not the zalcitabine monotherapy group. There were too few deaths
in the >/=150 cells/mm3 subgroup for an effect on survival
alone to be assessed. All treatment arms eventually showed decline
in CD4 cell count despite treatment, although for the combination
arm there was an initial increase for patients with CD4 cell
counts >/=150 cells/mm3. Further studies are ongoing to confirm
clinical benefit from combination therapy.
Patients without Prior Exposure to Retrovir: The use of Retrovir in combination with zalcitabine
in patients without prior exposure to Retrovir (<4 weeks prior
therapy) is based on two small clinical studies (ACTG 106 and
BW 34,225-02) showing a greater rise in CD4 cell counts, which
was maintained longer with combination therapy when compared
to monotherapy with Retrovir.5,6
There have been no results from controlled
studies of combination therapy with primary clinical endpoints
of disease progression or death in patients who were naive to
antiretroviral therapy when combination therapy was initiated.
INDICATIONS
Monotherapy: Adults:
Retrovir is indicated for the initial treatment of HIV-infected
adults with CD4 cell counts of 500 cells/mm3 or less (see CLINICAL
PHARMACOLOGY: Description of Clinical Studies). Therapy with
Retrovir has been shown to prolong survival and decrease the
incidence of opportunistic infections in patients with advanced
HIV disease at the time of initiation of therapy and to delay
disease progression in asymptomatic HIV-infected patients.
Studies in adults found monotherapy with Retrovir
to be clinically superior to didanosine or zalcitabine monotherapy
for the initial management of HIV-infected patients who have
not received previous antiretroviral treatment. However, randomized
studies have shown that for some patients with advanced disease
on prolonged therapy with Retrovir, modifying the antiviral regimen
may be more effective in delaying disease progression than remaining
on monotherapy with Retrovir.
Pediatrics:
Retrovir is indicated for the HIV-infected children over 3 months
of age who have HIV-related symptoms or who are asymptomatic
with abnormal laboratory values indicating significant HIV-related
immunosuppression (see CLINICAL PHARMACOLOGY: Description of
Clinical Studies).
Maternal-Fetal HIV Transmission: Retrovir is also indicated for the prevention of
maternal-fetal HIV transmission as part of a regimen that includes
oral Retrovir beginning between 14 and 34 weeks of gestation,
intravenous Retrovir during labor, and administration of Retrovir
Syrup to the newborn after birth. However, transmission to infants
may still occur in some cases despite the use of this regimen.
The efficacy of this regimen for preventing HIV transmission
in women who have received Retrovir for a prolonged period before
pregnancy has not been evaluated. The safety of Retrovir for
the mother or fetus during the first trimester of pregnancy has
not been assessed (see CLINICAL PHARMACOLOGY: Description of
Clinical Studies).
Capsules and Syrup
Combination Therapy with Retrovir and Zalcitabine: Retrovir in combination with zalcitabine is indicated
for the treatment of selected patients with advanced HIV disease
(CD4 cell count </=300 cells/mm3). In patients without prior
exposure to Retrovir, this indication is based on greater increases
in CD4 cell counts that were maintained longer for patients treated
with combination therapy as compared to monotherapy with Retrovir.
In patients with no prior exposure to Retrovir, there have been
no studies showing clinical benefit from combination therapy
compared to Retrovir alone. For patients with prior exposure
to Retrovir, this indication is based on a subgroup analysis
of clinical data that showed a clinical benefit only for those
patients with a CD4 cell count >/=150 cells/mm3 at the time
of initiation of therapy. No benefit from combination therapy
has been observed in a study of patients with extensive prior
exposure to Retrovir (median 18 months) and CD4 cell counts <150
cells/mm3; combination therapy is therefore not recommended for
these patients (see CLINICAL PHARMACOLOGY: Description of Clinical
Studies).
CONTRAINDICATION
Retrovir Capsules, Syrup, and IV Infusion
are contraindicated for patients who have potentially life-threatening
allergic reactions to any of the components of the formulations.
WARNING
Note: The full
safety and efficacy profile of Retrovir has not been defined,
particularly in regard to prolonged use in HIV-infected individuals
who have less advanced disease (see INDICATIONS AND USAGE, CLINICAL
PHARMACOLOGY: Microbiology, and PRECAUTIONS: Carcinogenesis,
Mutagenesis, Impairment of Fertility). The incidence of adverse
reactions appears to increase with disease progression, and patients
should be monitored carefully, especially as disease progression
occurs.
Capsules and Syrup
The safety profile of combination therapy
with Retrovir and zalcitabine reflects the individual safety
profiles of each component. The complete prescribing information
for zalcitabine should be consulted before combination therapy
with Retrovir and zalcitabine is initiated.
Capsules, Syrup, and Intravenous Infusion
Bone Marrow Suppression: Retrovir should be used with extreme caution in patients
who have bone marrow compromise evidenced by granulocyte count
<1000 cells/mm3 or hemoglobin <9.5 g/dl. In all of the
placebo-controlled studies, but most frequently in patients with
advanced symptomatic HIV disease, anemia and granulocytopenia
were the most significant adverse events observed (see ADVERSE
REACTIONS). There have been reports of pancytopenia associated
with the use of Retrovir, which was reversible in most instances
after discontinuance of the drug.
Significant anemia most commonly occurred
after 4 to 6 weeks of therapy and in many cases required dose
adjustment, discontinuation of Retrovir, and/or blood transfusions.
Frequent blood counts are strongly recommended in patients with
advanced HIV disease taking Retrovir. For asymptomatic HIV-infected
individuals and patients with early HIV disease, most of whom
have better marrow reserve, blood counts may be obtained less
frequently, depending upon the patient's overall status. If anemia
or granulocytopenia develops, dosage adjustments may be necessary
(see DOSAGE AND ADMINISTRATION).
Myopathy: Myopathy
and myositis with pathological changes, similar to that produced
by HIV disease, have been associated with prolonged use of Retrovir.
Lactic Acidosis/Severe Hepatomegaly with
Steatosis: Rare occurrences of lactic
acidosis in the absence of hypoxemia, and severe hepatomegaly
with steatosis have been reported with the use of antiretroviral
nucleoside analogues, including Retrovir and zalcitabine, and
are potentially fatal; it is not known whether these events are
causally related to the use of these drugs. Lactic acidosis should
be considered whenever a patient receiving therapy with Retrovir
develops unexplained tachypnea, dyspnea, or fall in serum bicarbonate
level. Under these circumstances, therapy with Retrovir should
be suspended until the diagnosis of lactic acidosis has been
excluded. Caution should be exercised when administering Retrovir
to any patient, particularly obese women, with hepatomegaly,
hepatitis, or other known risk factor for liver disease. These
patients should be followed closely while on therapy with Retrovir.
The significance of elevated aminotransferase levels suggesting
hepatic injury in HIV-infected patients prior to starting Retrovir
or while on Retrovir is unclear. Treatment with Retrovir should
be suspended in the setting of rapidly elevating aminotransferase
levels, progressive hepatomegaly, or metabolic/lactic acidosis
of unknown etiology.
Other Serious Adverse Reactions: Several serious adverse events have been reported
with use of Retrovir in clinical practice. Reports of pancreatitis,
sensitization reactions (including anaphylaxis in one patient),
vasculitis, and seizures have been rare. These adverse events,
except for sensitization, have also been associated with HIV
disease. Changes in skin and nail pigmentation have been associated
with the use of Retrovir.
Use in Infancy:
A positive test for HIV-antibody in children under 15 months
of age may represent passively acquired maternal antibodies,
rather than an active antibody response to infection in the infant.
Thus, the presence of HIV antibody in a child less than 15 months
of age must be interpreted with caution, especially in the asymptomatic
infant. Confirmatory tests such as serum p24 antigen or viral
culture should be pursued in such children.
PRECAUTIONS
General: Zidovudine
is eliminated from the body primarily by renal excretion following
metabolism in the liver (glucuronidation). In patients with severely
impaired renal function, dosage reduction is recommended (see
CLINICAL PHARMACOLOGY: Pharmacokinetics and DOSAGE AND ADMINISTRATION).
Although very little data are available, patients with severely
impaired hepatic function may be at greater risk of toxicity.
Information for Patients: Retrovir is not a cure for HIV infections, and patients
may continue to acquire illnesses associated with HIV infection,
including opportunistic infections. Therefore, patients should
be advised to seek medical care for any significant change in
their health status.
The safety and efficacy of Retrovir in treating
women, intravenous drug users, and racial minorities7-9 is not
significantly different than that observed in white males.
Patients should be informed that the major
toxicities of Retrovir are granulocytopenia and/or anemia. The
frequency and severity of these toxicities are greater in patients
with more advanced disease and in those who initiate therapy
later in the course of their infection. They should be told that
if toxicity develops, they may require transfusions or dose modifications
including possible discontinuation. They should be told of the
extreme importance of having their blood counts followed closely
while on therapy, especially for patients with advanced symptomatic
HIV disease. They should be cautioned about the use of other
medications, including ganciclovir and interferon-alpha, that
may exacerbate the toxicity of Retrovir (see PRECAUTIONS: DRUG
INTERACTIONS). Patients should be informed that other adverse
effects of Retrovir include nausea and vomiting. Patients should
also be encouraged to contact their physician if they experience
muscle weakness, shortness of breath, symptoms of hepatitis or
pancreatitis, or any other unexpected adverse events while being
treated with Retrovir.
Retrovir Capsules and Syrup are for oral ingestion
only. Patients should be told of the importance of taking Retrovir
exactly as prescribed. They should be told not to share medication
and not to exceed the recommended dose. Patients should be told
that the long-term effects of Retrovir are unknown at this time.
Pregnant women considering the use of Retrovir
during pregnancy for prevention of HIV-transmission to their
infants should be advised that transmission may still occur in
some cases despite therapy. The long-term consequences of in
utero and infant exposure to Retrovir are unknown.
HIV-infected pregnant women should be advised
not to breast-feed to avoid postnatal transmission of HIV to
a child who may not yet be infected.
Patients should be advised that therapy with
Retrovir has not been shown to reduce the risk of transmission
of HIV to others through sexual contact or blood contamination.
Carcinogenesis, Mutagenesis, Impairment
of Fertility: Zidovudine was administered
orally at three dosage levels to separate groups of mice and
rats (60 females and 60 males in each group). Initial single
daily doses were 30, 60, and 120 mg/kg/day in mice and 80, 220,
and 600 mg/kg/day in rats. The doses in mice were reduced to
20, 30, and 40 mg/kg/day after day 90 because of treatment-related
anemia, whereas in rats only the high dose was reduced to 450
mg/kg/day on day 91 and then to 300 mg/kg/day on day 279.
In mice, seven late-appearing (after 19 months)
vaginal neoplasms (5 nonmetastasizing squamous cell carcinomas,
one squamous cell papilloma, and one squamous polyp) occurred
in animals given the highest dose. One late-appearing squamous
cell papilloma occurred in the vagina of a middle dose animal.
No vaginal tumors were found at the lowest dose.
In rats, two late-appearing (after 20 months),
non-metastasizing vaginal squamous cell carcinomas occurred in
animals given the highest dose. No vaginal tumors occurred at
the low or middle dose in rats. No other drug-related tumors
were observed in either sex of either species.
It is not known how predictive the results
of rodent carcinogenicity studies may be for humans. At doses
that produced tumors in mice and rats, the estimated drug exposure
(as measured by AUC) was approximately 3 times (mouse) and 24
times (rat) the estimated human exposure at the recommended therapeutic
dose of 100 mg every 4 hours.
No evidence of mutagenicity (with or without
metabolic activation) was observed in the Ames Salmonella mutagenicity
assay at concentrations up to 10 µg per plate, which was
the maximum concentration that could be tested because of the
antimicrobial activity of zidovudine against the Salmonella species.
In a mutagenicity assay conducted in L5178Y/TK+/- mouse lymphoma
cells, zidovudine was weakly mutagenic in the absence of metabolic
activation only at the highest concentrations tested (4000 and
5000 µg/ml). In the presence of metabolic activation, the
drug was weakly mutagenic at concentrations of 1000 µg/ml
and higher. In an in vitro mammalian cell transformation
assay, zidovudine was positive at concentrations of 0.5 µg/ml
and higher. In an in vitro cytogenetic study performed
in cultured human lymphocytes, zidovudine induced dose-related
structural chromosomal abnormalities at concentrations of 3 µg/ml
and higher. No such effects were noted at the two lowest concentrations
tested, 0.3 and 1 µg/ml. In an in vivo cytogenetic
study in rats given a single intravenous injection of zidovudine
at doses of 37.5 to 300 mg/kg, there were no treatment-related
structural or numerical chromosomal alterations in spite of plasma
levels that were as high as 453 µg/ml 5 minutes after dosing.
In two in vivo micronucleus studies
(designed to measure chromosome breakage or mitotic spindle apparatus
damage) in male mice, oral doses of zidovudine 100 to 1000 mg/kg/day
administered once daily for approximately 4 weeks induced dose-related
increases in micronucleated erythrocytes. Similar results were
also seen after 4 or 7 days of dosing at 500 mg/kg/day in rats
and mice.
In a study involving 11 AIDS patients, it
was reported that the seven patients who were receiving Retrovir
(1200 mg/day) as their only medication for 4 weeks to 7 months
showed a chromosome breakage frequency of 8.29±2.65 breaks
per 100 peripheral lymphocytes. This was significantly (P<
0.05) higher than the incidence of 0.5±0.29 breaks per
100 calls that was observed in the four AIDS patients who had
not received Retrovir.
No effect on male or female fertility (judged
by conception rates) was seen in rats given zidovudine orally
at doses up to 450 mg/kg/day.
Pregnancy: Pregnancy
Category C. Oral teratology studies in the rat and in the rabbit
at doses up to 500 mg/kg/day revealed no evidence of teratogenicity
with zidovudine. Zidovudine treatment resulted in embryo/fetal
toxicity as evidenced by an increase in the incidence of fetal
resorptions in rats given 150 or 450 mg/kg/day and rabbits given
500 mg/kg/day. The doses used in the teratology studies resulted
in peak zidovudine plasma concentrations (after one-half of the
daily dose) in rats 66 to 226 times, and in rabbits 12 to 87
times, mean steady-state peak human plasma concentrations (after
one-sixth of the daily dose) achieved with the recommended daily
dose (100 mg every 4 hours). In an in vitro experiment
with fertilized mouse oocytes, zidovudine exposure resulted in
a dose-dependent reduction in blastocyst formation. In an additional
teratology study in rats, a dose of 3000 mg/kg/day (very near
the oral median lethal dose in rats of 3683 mg/kg) caused marked
maternal toxicity and an increase in the incidence of fetal malformations.
This dose resulted in peak zidovudine plasma concentrations 350
times peak human plasma concentrations. (Estimated area-under-the-curve
[AUC] in rats at this dose level was 300 times the daily AUC
in humans given 600 mg per day.) No evidence of teratogenicity
was seen in this experiment at doses of 600 mg/kg/day or less.
A randomized, double-blind, placebo-controlled
trial was conducted in HIV-infected pregnant women to determine
the utility of Retrovir for the prevention of maternal-fetal
HIV-transmission (see CLINICAL PHARMACOLOGY: Clinical Studies).
Congenital abnormalities occurred with similar frequency between
infants born to mothers who received Retrovir and infants born
to mothers who received placebo. Abnormalities were either problems
in embryogenesis (prior to 14 weeks) or were recognized on ultrasound
before or immediately after initiation of study drug.
Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women
exposed to Retrovir, an Antiretroviral Pregnancy Registry has
been established. Physicians are encouraged to register patients
by calling (800) 722-9292, ext. 58465.
Nursing Mothers:
The U.S. Public Health Service Centers for Disease Control and
Prevention advises HIV-infected women not to breast-feed to avoid
postnatal transmission of HIV to a child who may not yet be infected.
It is not known whether zidovudine is excreted
in human milk or whether Retrovir reduces the potential for transmission
of HIV in breast milk. Lactating mice administered zidovudine
(200 mg/kg intraperitoneally) were found to have milk concentrations
of zidovudine five times the corresponding serum zidovudine concentration.
Milk concentrations of zidovudine declined at a slower rate than
serum zidovudine concentrations.
Pediatric Use:
See INDICATIONS, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION
sections.
DRUG INTERACTION
Ganciclovir:
Use of Retrovir in combination with ganciclovir increases the
risk of hematologic toxicities in some patients with advanced
HIV disease. Should the use of this combination become necessary
in the treatment of patients with HIV disease, dose reduction
or interruption of one or both agents may be necessary to minimize
hematologic toxicity. Hematologic parameters, including hemoglobin,
hematocrit, and white blood cell count with differential, should
be monitored frequently in all patients receiving this combination.
Interferon-alpha:
Hematologic toxicities have also been seen when Retrovir is used
concomitantly with interferon-alpha. As with the concomitant
use of Retrovir and ganciclovir, dose reduction or interruption
of one or both agents may be necessary, and hematologic parameters
should be monitored frequently.
Bone Marrow Suppressive Agents/Cytotoxic
Agents: Coadministration of Retrovir
with drugs that are cytotoxic or which interfere with RBC/WBC
number or function (e.g., dapsone, flucytosine, vincristine,
vinblastine, or adriamycin) may increase the risk of hematologic
toxicity.
Probenecid:
Limited data suggest that probenecid may increase zidovudine
levels by inhibiting glucuronidation and/or by reducing renal
excretion of zidovudine. Some patients who have used Retrovir
concomitantly with probenecid have developed flu-like symptoms
consisting of myalgia, malaise, and/or fever and maculopapular
rash.
Phenytoin: Phenytoin
plasma levels have been reported to be low in some patients receiving
Retrovir, while in one case a high level was documented. However,
in a pharmacokinetic interaction study in which 12 HIV-positive
volunteers received a single 300 mg phenytoin dose alone and
during steady-state zidovudine conditions (200 mg every 4 hours),
no change in phenytoin kinetics was observed. Although not designed
to optimally assess the effect of phenytoin on zidovudine kinetics,
a 30% decrease in oral zidovudine clearance was observed with
phenytoin.
Methadone: In
a pharmacokinetic study of nine HIV-positive patients receiving
methadone-maintenance (30 to 90 mg daily) concurrent with 200
mg of Retrovir every 4 hours, no changes were observed in the
pharmacokinetics of methadone upon initiation of therapy with
Retrovir and after 14 days of treatment with Retrovir. No adjustments
in methadone-maintenance requirements were reported. For four
patients, the mean zidovudine AUC was elevated two-fold, while
for five patients, the value was equal to that of control patients.
The exact mechanism and clinical significance of these data are
unknown.
Fluconazole:
The coadministration of fluconazole with Retrovir has been reported
to interfere with the oral clearance and metabolism of Retrovir.
In a pharmacokinetic interaction study in which 12 HIV-positive
men received Retrovir 200 mg every 8 hours alone and in combination
with fluconazole 400 mg daily, fluconazole increased the zidovudine
AUC (74%; range 28% to 173%) and the zidovudine half-life (128%;
range -4% to 189%) at steady-state. The clinical significance
of this interaction is unknown.
Other Nucleoside Analogues: Some experimental nucleoside analogues which are
being evaluated in HIV-infected patients may affect RBC/WBC number
or function and may increase the potential for hematologic toxicity
of Retrovir. Some experimental nucleoside analogues affecting
DNA replication, such as ribavirin, antagonize the in vitro
antiviral activity of Retrovir against HIV and thus, concomitant
use of such drugs should be avoided.
Other Agents:
Some drugs such as trimethoprim-sulfamethoxazole, pyrimethamine,
and acyclovir may be necessary for the management or prevention
of opportunistic infections. In the placebo-controlled trial
in patients with advanced HIV disease, increased toxicity was
not detected with limited exposure to these drugs. However, there
is one published report of neurotoxicity (profound lethargy)
associated with concomitant use of Retrovir and acyclovir. Preliminary
data from a drug interaction study (n=10) suggest that coadministration
of 200 mg Retrovir and 600 mg rifampin decreases the area under
the plasma concentration curve by an average of 48%±34%.
However, the effect of once daily dosing of rifampin on multiple
daily doses of Retrovir is unknown.
ADVERSE REACTIONS
The adverse events reported during intravenous
administration of Retrovir IV Infusion are similar to those reported
with oral administration; granulocytopenia and anemia were reported
most frequently. Long-term intravenous administration beyond
2 to 4 weeks has not been studied in adults and may enhance hematologic
adverse events. Local reaction, pain, and slight irritation during
intravenous administration occur infrequently.
Monotherapy: Adults:
The frequency and severity of adverse events associated with
the use of oral Retrovir in adults are greater in patients with
more advanced infection at the time of initiation of therapy.
The following table summarizes the relative incidence of hematologic
adverse events observed in clinical studies by severity of HIV
disease present at the start of treatment with oral Retrovir
(TABLE 1):
TABLE 1 - Zidovudine, Adverse Reactions
Stage of Retrovir Granulocytopenia Anemia
Disease Daily Dose* (<750 cells/mm3) (Hgb<8.0 g/dl)
(mg)
--------------------------------------------------------------------------
Asymptomatic
ACTG 019 (3) 500 1.8% @ 1.1% @
Early HIV Disease
(CD4 >200 cells/mm3)
ACTG 016 (4) 1200 4% 4%
Advanced HIV Disease
(CD4 >200 cells/mm3)
BW 02 (1) 1500 10% @ 3% @ +
(CD4 </=200 cells/mm3)
ACTG 002 (10) 600 37% 29%
BW 02 (1) 1500 47% 29% +
--------------------------------------------------------------------------
* The currently recommended dose is 500 to 600 mg daily.
@ Not statistically significant compared to placebo.
+ Anemia = Hgb <7.5 g/dl.
The anemia reported in patients with advanced
HIV disease receiving Retrovir appeared to be the result of impaired
erythrocyte maturation as evidenced by macrocytosis while on
drug. Although mean platelet counts in patients receiving Retrovir
were significantly increased compared to mean baseline values,
thrombocytopenia did occur in some of these patients with advanced
disease.1 Twelve percent of patients receiving Retrovir compared
to 5% of patients receiving placebo had >50% decreases from
baseline platelet count. Mild drug-associated elevations in total
bilirubin levels have been reported as an uncommon occurrence
in patients treated for asymptomatic HIV infection.
The HIV-infected adults participating in these
clinical trials often had baseline symptoms and signs of HIV
disease and/or experienced adverse events at some time during
study. It was often difficult to distinguish adverse events possibly
associated with administration of Retrovir from underlying signs
of HIV disease or intercurrent illnesses. The following table
summarizes clinical adverse events or symptoms which occurred
in at least 5% of all patients with advanced HIV disease treated
with 1500 mg/day of Retrovir in the original placebo-controlled
study.2 Of the items listed in the table, only severe headache,
nausea, insomnia, and myalgia were reported at a significantly
greater rate in patients receiving Retrovir (TABLE 2):
TABLE 2 - Zidovudine, Adverse Reactions
Percentage (%) of Patients with Clinical Events in Advanced
HIV Disease (BW 02)
-----------------------------------------------------------------------
Retrovir Placebo
Adverse Event 1500 mg/day* (n=144) % (n=137) %
-----------------------------------------------------------------------
BODY AS A WHOLE
Asthenia 19 18
Diaphoresis 5 4
Fever 16 12
Headache 42 37
Malaise 8 7
GASTROINTESTINAL
Anorexia 11 8
Diarrhea 12 18
Dyspepsia 5 4
GI Pain 20 19
Nausea 46 18
Vomiting 6 3
MUSCULOSKELETAL
Myalgia 8 2
NERVOUS
Dizziness 6 4
Insomnia 5 1
Paresthesia 6 3
Somnolence 8 9
RESPIRATORY
Dyspnea 5 3
SKIN
Rash 17 15
SPECIAL SENSES
Taste Perversion 5 8
-----------------------------------------------------------------------
* The currently recommended oral dose is 500 to 600 mg/daily.
All events of a severe or life-threatening
nature were monitored for adults in the placebo-controlled studies
in early HIV disease and asymptomatic HIV infection. Data concerning
the occurrence of additional signs or symptoms were also collected.
No distinction was made in reporting events between those possibly
associated with the administration of the study medication and
those due to the underlying disease. The following tables summarize
all those events reported at a statistically significant greater
incidence for patients receiving Retrovir in these studies:
TABLE 3 - Zidovudine, Adverse Reactions
Percentage (%) of Patients with Adverse Events in Early HIV
Disease (ACTG 016)
-----------------------------------------------------------------------
Retrovir
Adverse Event 1200 mg/day* Placebo
(n=361) % (n=352) %
-----------------------------------------------------------------------
BODY AS A WHOLE
Asthenia 69 62
GASTROINTESTINAL
Dyspepsia 6 1
Nausea 61 41
Vomiting 25 13
-----------------------------------------------------------------------
* The currently recommended oral dose is 500 to 600 mg/daily.
TABLE 4 - Zidovudine, Adverse Reactions
Percentage (%) of Patients with Adverse Events* in Asymptomatic
HIV Infection (ACTG 019)
-----------------------------------------------------------------------
Retrovir
Adverse Event 500 mg/day Placebo
(n=453) % (n=428) %
-----------------------------------------------------------------------
BODY AS A WHOLE
Asthenia 8.6 + 5.8
Headache 62.5 52.6
Malaise 53.2 44.9
GASTROINTESTINAL
Anorexia 20.1 10.5
Constipation 6.4 + 3.5
Nausea 51.4 29.9
Vomiting 17.2 9.8
NERVOUS
Dizziness 17.9 + 15.2
----------------------------------------------------------------------
* Reported >/=5% of study population.
+ Not statistically significant versus placebo.
Several serious adverse events have been reported
with the use of Retrovir in clinical practice. Myopathy and myositis
with pathological changes, similar to that produced by HIV disease,
have been associated with prolonged use of Retrovir. Reports
of hepatomegaly with steatosis, hepatitis, pancreatitis, lactic
acidosis, sensitization reactions (including anaphylaxis in one
patient), hyperbilirubinemia, vasculitis, and seizures have been
rare. These adverse events, except for sensitization, have also
been associated with HIV disease. A single case of macular edema
has been reported with the use of Retrovir.
Additional adverse events reported in clinical
trials at a rate not significantly different from placebo are
listed below. Selected events from post-marketing clinical experience
with Retrovir are also included. Many of these events may also
occur as part of HIV disease. The clinical significance of the
association between treatment with Retrovir and these events
is unknown.
Body as a Whole:
abdominal pain, back pain, body odor, chest pain, chills, edema
of the lip, fever, flu syndrome, hyperalgesia.
Cardiovascular: syncope,
vasodilation.
Gastrointestinal:
bleeding gums, constipation, diarrhea, dysphagia, edema of the
tongue, eructation, flatulence, mouth ulcer, rectal hemorrhage.
Hemic and Lymphatic:
lymphadenopathy.
Musculoskeletal:
arthralgia, muscle spasm, tremor, twitch.
Nervous: anxiety,
confusion, depression, dizziness, emotional lability, loss of
mental acuity, nervousness, paresthesia, somnolence, vertigo.
Respiratory:
cough, dyspnea, epistaxis, hoarseness, pharyngitis, rhinitis,
sinusitis.
Skin: acne,
changes in skin and nail pigmentation, pruritus, rash, sweat,
urticaria.
Special senses:
amblyopia, hearing loss, photophobia, taste perversion.
Urogenital: dysuria,
polyuria, urinary frequency, urinary hesitancy.
Pediatrics:
Anemia and granulocytopenia among children with advanced HIV
disease receiving Retrovir occurred with similar incidence to
that reported for adults with AIDS or advanced ARC (see above).
Management of neutropenia and anemia included, in some cases,
dose modification and/or blood product transfusions. In the open-label
studies, 17% had their dose modified (generally a reduction in
dose by 30%) due to anemia and 25% had their dose modified (temporary
discontinuation or dose reduction by 30%) for neutropenia. Four
children had Retrovir permanently discontinued for neutropenia.
The following table summarizes the occurrence of anemia (Hgb<7.5
g/dl) and granulocytopenia (<750 cells/mm3) among 124 children
receiving Retrovir for a mean of 267 days (range 3 to 855 days)
(TABLE 5):
TABLE 5 - Zidovudine, Adverse Reactions
Granulocytopenia Anemia
(<750 cells/mm3) (Hgb<7.5 g/dl)
-----------------------------------------------------------
Advanced
Pediatric
HIV Disease n % n %
(n=124)
-----------------------------------------------------------
48 39 28 * 23
-----------------------------------------------------------
* Twenty-two children received one or more transfusions due
to a decline in hemoglobin to <7.5 g/dl; an additional 15
children were transfused for hemoglobin levels >7.5 g/dl.
Fifty-nine percent of the patients transfused had a pre-study
history of anemia or transfusion requirement.
Macrocytosis was observed among the majority
of children enrolled in the studies.
In the open-label studies involving 124 children,
16 clinical adverse events were reported by 24 children. No event
was reported by more than 5.6% of the study populations. Due
to the open-label design of the studies, it was difficult to
determine possible events related to the use of Retrovir versus
disease-related events. Therefore, all clinical events reported
as associated with therapy with Retrovir or of unknown relationship
to therapy with Retrovir are presented in the following table
(TABLE 6):
TABLE 6 - Zidovudine, Adverse Reactions
Percentage (%) of Pediatric Patients with Clinical Events
in Open Label Studies
-----------------------------------------------------------------------
Adverse Event n %
-----------------------------------------------------------------------
BODY AS A WHOLE
Fever 4 3.2
Phlebitis*/Bacteremia 2 1.6
Headache 2 1.6
-----------------------------------------------------------------------
GASTROINTESTINAL
Nausea 1 0.8
Vomiting 6 4.8
Abdominal Pain 4 3.2
Diarrhea 1 0.8
Weight Loss 1 0.8
-----------------------------------------------------------------------
NERVOUS
Insomnia 3 2.4
Nervousness/Irritability 2 1.6
Decreased Reflexes 7 5.6
Seizure 1 0.8
-----------------------------------------------------------------------
CARDIOVASCULAR
Left Ventricular Dilation 1 0.8
Cardiomyopathy 1 0.8
Gallop 1 0.8
Congestive Heart Failure 1 0.8
Generalized Edema 1 0.8
ECG Abnormality 3 2.4
-----------------------------------------------------------------------
UROGENITAL
Hematuria/Viral Cystitis 1 0.8
-----------------------------------------------------------------------
* Peripheral vein IV catheter site.
The clinical adverse events reported among
adult recipients of Retrovir may also occur in children.
Use for the Prevention of Maternal-Fetal
Transmission of HIV: In a randomized,
double-blind, placebo-controlled trial in HIV-infected women
and their infants conducted to determine the utility of Retrovir
for the prevention of maternal-fetal HIV transmission, Retrovir
Syrup at 2 mg/kg was administered every 6 hours for 6 weeks to
infants beginning within 12 hours after birth. The most commonly
reported adverse experiences were anemia (hemoglobin <9.0
g/dl) and neutropenia (<1000 cells/mm3). Anemia occurred in
22% of the infants who received Retrovir and in 12% of the infants
who received placebo. The mean difference in hemoglobin values
was less than 1.0 g/dl for infants receiving Retrovir compared
to infants receiving placebo. No infants with anemia required
transfusion and all hemoglobin values spontaneously returned
to normal within 6 weeks after completion of therapy with Retrovir.
Neutropenia was reported with similar frequency in the group
that received Retrovir (21%) and in the group that received placebo
(27%). The long-term consequences of in utero and infant exposure
to Retrovir are unknown.
Capsules and Syrup
Combination Therapy with Retrovir and Zalcitabine: The safety profile of combination therapy with Retrovir
and zalcitabine reflects the individual safety profile of each
component. The complete prescribing information for zalcitabine
should be consulted before combination therapy with Retrovir
and zalcitabine is initiated.
OVERDOSAGE
Cases of acute overdoses in both children
and adults have been reported with doses up to 50 grams. None
were fatal. The only consistent finding in these cases of overdose
was spontaneous or induced nausea and vomiting. Hematologic changes
were transient and not severe. Some patients experienced nonspecific
CNS symptoms such as headache, dizziness, drowsiness, lethargy,
and confusion. One report of a grand mal seizure possibly attributable
to Retrovir occurred in a 35-year-old male 3 hours after ingesting
36 grams of Retrovir. No other cause could be identified. All
patients recovered without permanent sequelae. Hemodialysis and
peritoneal dialysis appear to have a negligible effect on the
removal of zidovudine while elimination of its primary metabolite,
GZDV, is enhanced.
DOSAGE AND ADMINISTRATION
Capsules and Syrup
Monotherapy: Adults:
For adults with symptomatic HIV infection, including AIDS, the
recommended oral dose is 100 mg (one 100 mg capsule or 2 teaspoonfuls
[10 ml] syrup) every 4 hours (600 mg total daily dose). The effectiveness
of this dose compared to higher dosing regimens in improving
the neurologic dysfunction associated with HIV disease is unknown
(see INDICATIONS AND USAGE). A small randomized study found a
greater effect of higher doses of Retrovir on improvement of
neurological symptoms in patients with pre-existing neurological
disease.
For asymptomatic HIV infection, the recommended
dose for adults is 100 mg administered orally every 4 hours while
awake (500 mg/day).
Intravenous Infusion
For adults with symptomatic HIV infection,
including AIDS, the recommended intravenous dose is 1 mg/kg infused
over 1 hour. This dose should be administered every 4 hours around
the clock (6 mg/kg/daily). The effectiveness of this dose compared
to higher dosing regimens in improving the neurologic dysfunction
associated with HIV disease is unknown (see INDICATIONS AND USAGE).
A small randomized study found a greater effect of higher doses
of Retrovir on improvement of neurological symptoms in patients
with pre-existing neurological disease.
For asymptomatic HIV infection, the recommended
intravenous dose for adults is 1 mg/kg every 4 hours while awake
(5 mg/kg daily).
Patients should receive Retrovir IV Infusion
only until oral therapy can be administered. The intravenous
dosing regimen equivalent to the oral administration of 100 mg
every 4 hours is approximately 1 mg/kg intravenously every 4
hours.
Capsules and Syrup
Pediatrics:
The recommended dose in children 3 months to 12 years of age
is 180 mg/m2 every 6 hours (720 mg/m2 per day), not to exceed
200 mg every 6 hours.
Capsules, Syrup, and Intravenous Infusion
Maternal-Fetal HIV Transmission: The recommended dosing regimen for administration
to pregnant women (>14 weeks of pregnancy) and their newborn
infants is:
Maternal Dosing:
100 mg orally 5 times per day until the start of labor. During
labor and delivery, intravenous Retrovir should be administered
at 2 mg/kg (total body weight) over 1 hour followed by a continuous
intravenous infusion of 1 mg/kg/h (total body weight) until clamping
of the umbilical cord.
Infant Dosing:
2 mg/kg orally every 6 hours starting within 12 hours after birth
and continuing through 6 weeks of age. Infants unable to receive
oral dosing may be administered Retrovir intravenously at 1.5
mg/kg, infused over 30 minutes, every 6 hours. (See PRECAUTIONS
if hepatic disease or renal insufficiency is present.)
Capsules and Syrup
Combination Therapy with Retrovir and Zalcitabine: The recommended dosage regimen consists of Retrovir
200 mg taken orally with zalcitabine 0.75 mg every 8 hours.
Capsules, Syrup, and Intravenous Infusion
Monitoring of Patients: Hematologic toxicities appear to be related to pretreatment
bone marrow reserve and to dose and duration of therapy. In patients
with poor bone marrow reserve, particularly in patients with
advanced symptomatic HIV disease, frequent monitoring of hematologic
indices is recommended to detect serious anemia or granulocytopenia
(see WARNINGS). In patients who experience hematologic toxicity,
reduction in hemoglobin may occur as early as 2 to 4 weeks, and
granulocytopenia usually occurs after 6 to 8 weeks.
Dose Adjustment: Significant
anemia (hemoglobin of <7.5 g/dl or reduction of >25% of
baseline) and/or significant granulocytopenia (granulocyte count
of <750 cells/mm3 or reduction of >50% from baseline) may
require a dose interruption until evidence of marrow recovery
is observed (see WARNINGS). For less severe anemia or granulocytopenia,
a reduction in daily dose may be adequate. In patients who develop
significant anemia, dose modification does not necessarily eliminate
the need for transfusion. If marrow recovery occurs following
dose modification, gradual increases in dose may be appropriate
depending on hematologic indices and patient tolerance.
Capsules and Syrup
In end-stage renal disease patients maintained
on hemodialysis or peritoneal dialysis, recommended dosing is
100 mg every 6 to 8 hours (see CLINICAL PHARMACOLOGY: Pharmacokinetics).
There are insufficient data to recommend dose
adjustment of Retrovir in patients with impaired hepatic function.
Intravenous Infusion
In end-stage renal disease patients maintained
on hemodialysis or peritoneal dialysis, recommended dosing is
1 mg/kg every 6 to 8 hours (see CLINICAL PHARMACOLOGY: Pharmacokinetics).
There are insufficient data to recommend dose
adjustment of zidovudine in patients with impaired hepatic function.
Method of Preparation: Retrovir IV Infusion must be diluted prior to administration.
The calculated dose should be removed from the 20 ml vial and
added to 5% Dextrose Injection solution to achieve a concentration
no greater than 4 mg/ml. Admixture in biologic or colloidal fluids
(e.g., blood products, protein solutions, etc.) is not recommended.
After dilution, the solution is physically
and chemically stable for 24 hours at room temperature and 48
hours if refrigerated at 2o to 8oC (36o to 46oF). Care should
be taken during admixture to prevent inadvertent contamination.
As an additional precaution, the diluted solution should be administered
within 8 hours if stored at 25oC (77oF) or 24 hours if refrigerated
at 2o to 8oC to minimize potential administration of a microbially
contaminated solution.
Parenteral drug products should be inspected
visually for particulate matter and discoloration prior to administration
whenever solution and container permit. Should either be observed,
the solution should be discarded and fresh solution prepared.
Administration:
Retrovir IV Infusion is administered intravenously at a constant
rate over one hour. Rapid infusion or bolus injection should
be avoided. Retrovir IV Infusion should not be given intramuscularly.
COST OF THERAPY:
$3,259.82 (AIDS; Capsule; 100 mg; 6/day; 365 days) vs. Potential
Cost of $18,872.11 (DRG 488, HIV)
REFERENCES:
1. Fischl MA, Richman DD, Grieco MH, et al.
The efficacy of azidothymidine (AZT) in the treatment of patients
with AIDS and AIDS-related complex. A double-blind, placebo-controlled
trial. N Engl J Med. 1987;317:185-191.
2. Richman DD, Fischl MA, Grieco MH, et al.
The toxicity of azidothymidine (AZT) in the treatment of patients
with AIDS and AIDS-related complex. A double-blind, placebo-controlled
trial. N Engl J Med. 1987;317:192-197.
3. Volberding PA, Lagakos SW, Koch MA, et
al. Zidovudine in asymptomatic human immunodeficiency virus infection.
A controlled trial in persons with fewer than 500 CD4-positive
cells per cubic millimeter. N Engl J Med. 1990;322:941-949.
4. Fischl MA, Richman DD, Hansen N, et al.
The safety and efficacy of zidovudine in the treatment of patients
with mildly symptomatic HIV infection. A double-blind, placebo-controlled
trial. Annals Internal Med. 1990;112:727-737. Capsules
and Syrup
5. Meng T-C, Fischl MA, Boota AM, et al. Combination
therapy with zidovudine and dideoxycytidine in patients with
advanced human immunodeficiency virus infection. Ann Intern
Med. 1992;116:13-20.
6. Schooley R and the Wellcome Resistance
Study Collaborative Group. Trial of ZDV/ddl vs ZDV/ddC vs ZDV
in HIV-infected patients with CD4 cell counts less than 300:
Preliminary Results. Fourth European Conference on Clinical Aspects
and Treatment of HIV infection, Milan, Italy, March 16-18, 1994,
052. Capsules, Syrup, and Intravenous Infusion
7. Creagh-Kirk T, Doi P, Andrews E, et al.
Survival experience among patients with AIDS receiving zidovudine.
Follow-up of patients in a compassionate plea program. JAMA.
1988;260:3009-3015.
8. Lagakos S, Fischl MA, Stein DS, Lim L,
Volberding P. Effects of zidovudine therapy in minority and other
subpopulations with early HIV infection. JAMA. 1991;266:2709-2712.
9. Easterbrook PJ, Keruly JC, Creagh-Kirk
T, et al. Racial and ethnic differences in outcome in zidovudine-treated
patients with advanced HIV disease. JAMA. 1991;266:2713-2718.
10. Fischl M, Parker C, Pettinelli C, Wulfsohn
M, Hirsch M, Collier A, et al. A randomized controlled trial
of a reduced daily dose of zidovudine in patients with the acquired
immunodeficiency syndrome. N Engl J Med. 1990;323:1009-1014.
Copyright (c) 1996 Mosby-Year Book Inc