HIV & AIDS - AZT, Zidovudine, Retrovir

VIRUSMYTH 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

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