Retrovir iv

Overdose

Acute overdoses of zidovudine have been reported in pediatric patients and adults. These involved exposures up to 50 grams. No specific symptoms or signs have been identified following acute overdosage with zidovudine apart from those listed as adverse events such as fatigue, headache, vomiting, and occasional reports of hematological disturbances. 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.

Contraindications

RETROVIR IV (zidovudine injection) Infusion is contraindicated for patients who have potentially life-threatening allergic reactions to any of the components of the formulation.

Retrovir IV price

Undesirable effects

The adverse events reported during intravenous administration of RETROVIR IV (zidovudine injection) Infusion are similar to those reported with oral administration; neutropenia 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.

The frequency and severity of adverse events associated with the use of RETROVIR are greater in patients with more advanced infection at the time of initiation of therapy.

Table 5 summarizes events reported at a statistically significantly greater incidence for patients receiving RETROVIR orally in a monotherapy study:

Table 5. Percentage (%) of Patients with Adverse Events* in Asymptomatic HIV Infection (ACTG 019)

In addition to the adverse events listed in Table 5, other adverse events observed in clinical studies were abdominal cramps, abdominal pain, arthralgia, chills, dyspepsia, fatigue, hyperbilirubinemia, insomnia, musculoskeletal pain, myalgia, and neuropathy.

Selected laboratory abnormalities observed during a clinical study of monotherapy with oral RETROVIR are shown in Table 6.

Table 6. Frequencies of Selected (Grade 3/4) Laboratory Abnormalities in Patients with Asymptomatic HIV Infection (ACTG 019)

Study ACTG300: Selected clinical adverse events and physical findings with a ≥ 5% frequency during therapy with EPIVIR 4 mg/kg twice daily plus RETROVIR 160 mg/m2 orally 3 times daily compared with didanosine in therapy-naive ( ≤ 56 days of antiretroviral therapy) pediatric patients are listed in Table 7.

Table 7. Selected Clinical Adverse Events and Physical Findings ( ≥ 5% Frequency) in Pediatric Patients in Study ACTG300

Selected laboratory abnormalities experienced by therapy-naive ( ≤ 56 days of antiretroviral therapy) pediatric patients are listed in Table 8.

Table 8. Frequencies of Selected (Grade 3/4) Laboratory Abnormalities in Pediatric Patients in Study ACTG300

Additional adverse events reported in open-label studies in pediatric patients receiving RETROVIR 180 mg/m2 every 6 hours were congestive heart failure, decreased reflexes, ECG abnormality, edema, hematuria, left ventricular dilation, macrocytosis, nervousness/irritability, and weight loss.

The clinical adverse events reported among adult recipients of RETROVIR may also occur in pediatric patients.

In a randomized, double-blind, placebo-controlled trial in HIV-infected women and their neonates 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 neonates beginning within 12 hours following birth. The most commonly reported adverse experiences were anemia (hemoglobin < 9.0 g/dL) and neutropenia ( < 1,000 cells/mm3). Anemia occurred in 22% of the neonates who received RETROVIR and in 12% of the neonates who received placebo. The mean difference in hemoglobin values was less than 1.0 g/dL for neonates receiving RETROVIR compared to neonates receiving placebo. No neonates 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.

In addition to adverse events reported from clinical trials, the following events have been identified during use of RETROVIR in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, potential causal connection to RETROVIR, or a combination of these factors.

Body as a Whole: Back pain, chest pain, flu-like syndrome, generalized pain.

Cardiovascular: Cardiomyopathy, syncope.

Endocrine: Gynecomastia.

Eye: Macular edema.

Gastrointestinal: Constipation, dysphagia, flatulence, oral mucosal pigmentation, mouth ulcer.

General: Sensitization reactions including anaphylaxis and angioedema, vasculitis.

Hemic and Lymphatic: Aplastic anemia, hemolytic anemia, leukopenia, lymphadenopathy, pancytopenia with marrow hypoplasia, pure red cell aplasia.

Hepatobiliary Tract and Pancreas: Hepatitis, hepatomegaly with steatosis, jaundice, lactic acidosis, pancreatitis.

Musculoskeletal: Increased CPK, increased LDH, muscle spasm, myopathy and myositis with pathological changes (similar to that produced by HIV disease), rhabdomyolysis, tremor.

Nervous: Anxiety, confusion, depression, dizziness, loss of mental acuity, mania, paresthesia, seizures, somnolence, vertigo.

Respiratory: Cough, dyspnea, rhinitis, sinusitis.

Skin: Changes in skin and nail pigmentation, pruritus, rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, sweat, urticaria.

Special Senses: Amblyopia, hearing loss, photophobia, taste perversion.

Urogenital:Urinary frequency, urinary hesitancy.

Therapeutic indications

RETROVIR IV (zidovudine injection) Infusion in combination with other antiretroviral agents is indicated for the treatment of HIV infection.

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 neonate after birth. 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 Description of Clinical Studies).

Pharmacokinetic properties

Hepatic Impairment: There are insufficient data to recommend dose adjustment of RETROVIR in patients with mild to moderate impaired hepatic function or liver cirrhosis. Since RETROVIR is primarily eliminated by hepatic metabolism, a reduction in the daily dose may be necessary in these patients. Frequent monitoring of hematologic toxicities is advised (see CLINICAL PHARMACOLOGY: Pharmacokinetics and PRECAUTIONS: General).

RETROVIR IV (zidovudine injection) 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 2° to 8°C (36° to 46°F). 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 25°C (77°F) or 24 hours if refrigerated at 2° to 8°C 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.

RETROVIR IV (zidovudine injection) Infusion is administered intravenously at a constant rate over 1 hour. Rapid infusion or bolus injection should be avoided. RETROVIR IV (zidovudine injection) Infusion should not be given intramuscularly.

RETROVIR IV Infusion, 10 mg zidovudine in each mL.

20-mL Single-Use Vial, Tray of 10 (NDC 0173-0107-93).

Store vials at 15° to 25°C (59° to 77°F) and protect from light.

GlaxoSmithKline Research Triangle Park, NC 27709. October 2006.

The adverse events reported during intravenous administration of RETROVIR IV (zidovudine injection) Infusion are similar to those reported with oral administration; neutropenia 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.

The frequency and severity of adverse events associated with the use of RETROVIR are greater in patients with more advanced infection at the time of initiation of therapy.

Table 5 summarizes events reported at a statistically significantly greater incidence for patients receiving RETROVIR orally in a monotherapy study:

Table 5. Percentage (%) of Patients with Adverse Events* in Asymptomatic HIV Infection (ACTG 019)

In addition to the adverse events listed in Table 5, other adverse events observed in clinical studies were abdominal cramps, abdominal pain, arthralgia, chills, dyspepsia, fatigue, hyperbilirubinemia, insomnia, musculoskeletal pain, myalgia, and neuropathy.

Selected laboratory abnormalities observed during a clinical study of monotherapy with oral RETROVIR are shown in Table 6.

Table 6. Frequencies of Selected (Grade 3/4) Laboratory Abnormalities in Patients with Asymptomatic HIV Infection (ACTG 019)

Study ACTG300: Selected clinical adverse events and physical findings with a ≥ 5% frequency during therapy with EPIVIR 4 mg/kg twice daily plus RETROVIR 160 mg/m2 orally 3 times daily compared with didanosine in therapy-naive ( ≤ 56 days of antiretroviral therapy) pediatric patients are listed in Table 7.

Table 7. Selected Clinical Adverse Events and Physical Findings ( ≥ 5% Frequency) in Pediatric Patients in Study ACTG300

Selected laboratory abnormalities experienced by therapy-naive ( ≤ 56 days of antiretroviral therapy) pediatric patients are listed in Table 8.

Table 8. Frequencies of Selected (Grade 3/4) Laboratory Abnormalities in Pediatric Patients in Study ACTG300

Additional adverse events reported in open-label studies in pediatric patients receiving RETROVIR 180 mg/m2 every 6 hours were congestive heart failure, decreased reflexes, ECG abnormality, edema, hematuria, left ventricular dilation, macrocytosis, nervousness/irritability, and weight loss.

The clinical adverse events reported among adult recipients of RETROVIR may also occur in pediatric patients.

In a randomized, double-blind, placebo-controlled trial in HIV-infected women and their neonates 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 neonates beginning within 12 hours following birth. The most commonly reported adverse experiences were anemia (hemoglobin < 9.0 g/dL) and neutropenia ( < 1,000 cells/mm3). Anemia occurred in 22% of the neonates who received RETROVIR and in 12% of the neonates who received placebo. The mean difference in hemoglobin values was less than 1.0 g/dL for neonates receiving RETROVIR compared to neonates receiving placebo. No neonates 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.

In addition to adverse events reported from clinical trials, the following events have been identified during use of RETROVIR in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, potential causal connection to RETROVIR, or a combination of these factors.

Body as a Whole: Back pain, chest pain, flu-like syndrome, generalized pain.

Cardiovascular: Cardiomyopathy, syncope.

Endocrine: Gynecomastia.

Eye: Macular edema.

Gastrointestinal: Constipation, dysphagia, flatulence, oral mucosal pigmentation, mouth ulcer.

General: Sensitization reactions including anaphylaxis and angioedema, vasculitis.

Hemic and Lymphatic: Aplastic anemia, hemolytic anemia, leukopenia, lymphadenopathy, pancytopenia with marrow hypoplasia, pure red cell aplasia.

Hepatobiliary Tract and Pancreas: Hepatitis, hepatomegaly with steatosis, jaundice, lactic acidosis, pancreatitis.

Musculoskeletal: Increased CPK, increased LDH, muscle spasm, myopathy and myositis with pathological changes (similar to that produced by HIV disease), rhabdomyolysis, tremor.

Nervous: Anxiety, confusion, depression, dizziness, loss of mental acuity, mania, paresthesia, seizures, somnolence, vertigo.

Respiratory: Cough, dyspnea, rhinitis, sinusitis.

Skin: Changes in skin and nail pigmentation, pruritus, rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, sweat, urticaria.

Special Senses: Amblyopia, hearing loss, photophobia, taste perversion.

Urogenital:Urinary frequency, urinary hesitancy.

See CLINICAL PHARMACOLOGY section (Table 4) for information on zidovudine concentrations when coadministered with other drugs. For patients experiencing pronounced anemia or other severe zidovudine-associated events while receiving chronic administration of zidovudine and some of the drugs (e.g., fluconazole, valproic acid) listed in Table 4, zidovudine dose reduction may be considered.

Antiretroviral Agents: Concomitant use of zidovudine with stavudine should be avoided since an antagonistic relationship has been demonstrated in vitro.

Some nucleoside analogues affecting DNA replication, such as ribavirin, antagonize the in vitroantiviral activity of RETROVIR against HIV; concomitant use of such drugs should be avoided.

Doxorubicin: Concomitant use of zidovudine with doxorubicin should be avoided since an antagonistic relationship has been demonstrated in vitro (see CLINICAL PHARMACOLOGY for additional drug interactions).

Phenytoin: Phenytoin plasma levels have been reported to be low in some patients receiving RETROVIR, while in 1 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.

Overlapping Toxicities: Coadministration of ganciclovir, interferon alfa, and other bone marrow suppressive or cytotoxic agents may increase the hematologic toxicity of zidovudine.

COMBIVIR® and TRIZIVIR® are combination product tablets that contain zidovudine as one of their components. RETROVIR should not be administered concomitantly with COMBIVIR or TRIZIVIR.

The incidence of adverse reactions appears to increase with disease progression; patients should be monitored carefully, especially as disease progression occurs.

RETROVIR should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count < 1,000 cells/mm3 or hemoglobin < 9.5 g/dL. In patients with advanced symptomatic HIV disease, anemia and neutropenia were the most significant adverse events observed. There have been reports of pancytopenia associated with the use of RETROVIR, which was reversible in most instances, after discontinuance of the drug. However, significant anemia, in many cases requiring dose adjustment, discontinuation of RETROVIR, and/or blood transfusions, has occurred during treatment with RETROVIR alone or in combination with other antiretrovirals.

Frequent blood counts are strongly recommended in patients with advanced HIV disease who are treated with RETROVIR. For HIV-infected individuals and patients with asymptomatic or early HIV disease, periodic blood counts are recommended. If anemia or neutropenia develops, dosage adjustments may be necessary (see DOSAGE AND ADMINISTRATION).

Myopathy and myositis with pathological changes, similar to that produced by HIV disease, have been associated with prolonged use of RETROVIR.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including zidovudine and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged exposure to antiretroviral nucleoside analogues may be risk factors. Particular caution should be exercised when administering RETROVIR to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with RETROVIR should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as zidovudine. Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV/HCV virologic suppression) was seen when ribavirin was coadministered with zidovudine in HIV/HCV co-infected patients (see CLINICAL PHARMACOLOGY: Drug Interactions),hepatic decompensation (some fatal) has occurred in HIV/HCV co-infected patients receiving combination antiretroviral therapy for HIV and interferon alfa with or without ribavirin. Patients receiving interferon alfa with or without ribavirin and RETROVIR should be closely monitored for treatment-associated toxicities, especially hepatic decompensation, neutropenia, and anemia. Discontinuation of RETROVIR should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Childs Pugh > 6) (see the complete prescribing information for interferon and ribavirin).

Zidovudine is eliminated from the body primarily by renal excretion following metabolism in the liver (glucuronidation). In patients with severely impaired renal function (CrCl < 15 mL/min), dosage reduction is recommended. Although the data are limited, zidovudine concentrations appear to be increased in patients with severely impaired hepatic function, which may increase the risk of hematologic toxicity (see CLINICAL PHARMACOLOGY: Pharmacokinetics and DOSAGE AND ADMINISTRATION).

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including RETROVIR. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.

Zidovudine was administered orally at 3 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, 7 late-appearing (after 19 months) vaginal neoplasms (5 nonmetastasizing squamous cell carcinomas, 1 squamous cell papilloma, and 1 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, 2 late-appearing (after 20 months), nonmetastasizing 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.

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.

Two transplacental carcinogenicity studies were conducted in mice. One study administered zidovudine at doses of 20 mg/kg/day or 40 mg/kg/day from gestation day 10 through parturition and lactation with dosing continuing in offspring for 24 months postnatally. The doses of zidovudine employed in this study produced zidovudine exposures approximately 3 times the estimated human exposure at recommended doses. After 24 months, an increase in incidence of vaginal tumors was noted with no increase in tumors in the liver or lung or any other organ in either gender. These findings are consistent with results of the standard oral carcinogenicity study in mice, as described earlier. A second study administered zidovudine at maximum tolerated doses of 12.5 mg/day or 25 mg/day (∼1,000 mg/kg nonpregnant body weight or ∼450 mg/kg of term body weight) to pregnant mice from days 12 through 18 of gestation. There was an increase in the number of tumors in the lung, liver, and female reproductive tracts in the offspring of mice receiving the higher dose level of zidovudine. It is not known how predictive the results of rodent carcinogenicity studies may be for humans.

Zidovudine was mutagenic in a 5178Y/TK+/- mouse lymphoma assay, positive in an in vitro cell transformation assay, clastogenic in a cytogenetic assay using cultured human lymphocytes, and positive in mouse and rat micronucleus tests after repeated doses. It was negative in a cytogenetic study in rats given a single dose.

Zidovudine, administered to male and female rats at doses up to 7 times the usual adult dose based on body surface area considerations, had no effect on fertility judged by conception rates.

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 3,000 mg/kg/day (very near the oral median lethal dose in rats of 3,683 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.

Two rodent transplacental carcinogenicity studies were conducted (see Carcinogenesis, Mutagenesis, Impairment of Fertility).

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 INDICATIONS: Description of Clinical Studies). Congenital abnormalities occurred with similar frequency between neonates born to mothers who received RETROVIR and neonates 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 1-800-258-4263.

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV.

Zidovudine is excreted in human milk (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Nursing Mothers). Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving RETROVIR (see Pediatric Use and INDICATIONS: Maternal-Fetal HIV Transmission).

RETROVIR has been studied in HIV-infected pediatric patients over 3 months of age who had HIV-related symptoms or who were asymptomatic with abnormal laboratory values indicating significant HIV-related immunosuppression. RETROVIR has also been studied in neonates perinatally exposed to HIV (see ADVERSE REACTIONS, DOSAGE AND ADMINISTRATION, INDICATIONS: Description of Clinical Studies, and CLINICAL PHARMACOLOGY: Pharmacokinetics).

Clinical studies of RETROVIR did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Acute overdoses of zidovudine have been reported in pediatric patients and adults. These involved exposures up to 50 grams. No specific symptoms or signs have been identified following acute overdosage with zidovudine apart from those listed as adverse events such as fatigue, headache, vomiting, and occasional reports of hematological disturbances. 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.

RETROVIR IV (zidovudine injection) Infusion is contraindicated for patients who have potentially life-threatening allergic reactions to any of the components of the formulation.

Zidovudine is a synthetic nucleoside analogue. Intracellularly, zidovudine is phosphorylated to its active 5'-triphosphate metabolite, zidovudine triphosphate (ZDV-TP). The principal mode of action of ZDV-TP is inhibition of reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue. ZDV-TP is a weak inhibitor of the cellular DNA polymerases a and y and has been reported to be incorporated into the DNA of cells in culture.

Activity of zidovudine against HIV-1 was assessed in a number of cell lines (including monocytes and fresh human peripheral blood lymphocytes). The EC50 and EC90 values for zidovudine were 0.01 to 0.49 µM (1 uM = 0.27 mcg/mL) and 0.1 to 9 uM, respectively. HIV from therapy-naive subjects with no mutations associated with resistance gave median EC50 values of 0.011 µM (range: 0.005 to 0.110 µM) from Virco (n = 93 baseline samples from COLA40263) and 0.02 µM (0.01 to 0.03 µM) from Monogram Biosciences (n = 135 baseline samples from ESS30009). The EC50 values of zidovudine against different HIV-1 clades (A-G) ranged from 0.00018 to 0.02 uM, and against HIV-2 isolates from 0.00049 to 0.004 uM. In cell culture drug combination studies, zidovudine demonstrates synergistic activity with the nucleoside reverse transcriptase inhibitors (NRTIs) abacavir, didanosine, lamivudine, and zalcitabine; the non-nucleoside reverse transcriptase inhibitors (NNRTIs) delavirdine and nevirapine; and the protease inhibitors (PIs) indinavir, nelfinavir, ritonavir, and saquinavir; and additive activity with interferon alfa. Ribavirin has been found to inhibit the phosphorylation of zidovudine in cell culture.

Genotypic analyses of the isolates selected in cell culture and recovered from zidovudine-treated patients showed mutations in the HIV-1 RT gene resulting in 6 amino acid substitutions (M41L, D67N, K70R, L210W, T215Y or F, and K219Q) that confer zidovudine resistance. In general, higher levels of resistance were associated with greater number of mutations. In some patients harboring zidovudine-resistant virus at baseline, phenotypic sensitivity to zidovudine was restored by 12 weeks of treatment with lamivudine and zidovudine. Combination therapy with lamivudine plus zidovudine delayed the emergence of mutations conferring resistance to zidovudine.

In a study of 167 HIV-infected patients, isolates (n = 2) with multi-drug resistance to didanosine, lamivudine, stavudine, zalcitabine, and zidovudine were recovered from patients treated for ≥ 1 year with zidovudine plus didanosine or zidovudine plus zalcitabine. The pattern of resistance-associated mutations with such combination therapies was different (A62V, V75I, F77L, F116Y, Q151M) from the pattern with zidovudine monotherapy, with the Q151M mutation being most commonly associated with multi-drug resistance. The mutation at codon 151 in combination with mutations at 62, 75, 77, and 116 results in a virus with reduced susceptibility to didanosine, lamivudine, stavudine, zalcitabine, and zidovudine. Thymidine analogue mutations (TAMs) are selected by zidovudine and confer cross-resistance to abacavir, didanosine, stavudine, tenofovir, and zalcitabine.

Adults: The pharmacokinetics of zidovudine have been evaluated in 22 adult HIV-infected patients in a Phase 1 dose-escalation study. Following intravenous (IV) dosing, dose-independent kinetics was observed over the range of 1 to 5 mg/kg. The major metabolite of zidovudine is 3′-azido-3′-deoxy-5′-O-β-D-glucopyranuronosylthymidine (GZDV). GZDV area under the curve (AUC) is about 3-fold greater than the zidovudine AUC. Urinary recovery of zi

Name of the medicinal product

Fertility, pregnancy and lactation

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 3,000 mg/kg/day (very near the oral median lethal dose in rats of 3,683 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.

Two rodent transplacental carcinogenicity studies were conducted (see Carcinogenesis, Mutagenesis, Impairment of Fertility).

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 INDICATIONS: Description of Clinical Studies). Congenital abnormalities occurred with similar frequency between neonates born to mothers who received RETROVIR and neonates 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 1-800-258-4263.

Qualitative and quantitative composition

RETROVIR IV Infusion, 10 mg zidovudine in each mL.

20-mL Single-Use Vial, Tray of 10 (NDC 0173-0107-93).

Store vials at 15° to 25°C (59° to 77°F) and protect from light.

GlaxoSmithKline Research Triangle Park, NC 27709. October 2006.

Special warnings and precautions for use

COMBIVIR® and TRIZIVIR® are combination product tablets that contain zidovudine as one of their components. RETROVIR should not be administered concomitantly with COMBIVIR or TRIZIVIR.

The incidence of adverse reactions appears to increase with disease progression; patients should be monitored carefully, especially as disease progression occurs.

RETROVIR should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count < 1,000 cells/mm3 or hemoglobin < 9.5 g/dL. In patients with advanced symptomatic HIV disease, anemia and neutropenia were the most significant adverse events observed. There have been reports of pancytopenia associated with the use of RETROVIR, which was reversible in most instances, after discontinuance of the drug. However, significant anemia, in many cases requiring dose adjustment, discontinuation of RETROVIR, and/or blood transfusions, has occurred during treatment with RETROVIR alone or in combination with other antiretrovirals.

Frequent blood counts are strongly recommended in patients with advanced HIV disease who are treated with RETROVIR. For HIV-infected individuals and patients with asymptomatic or early HIV disease, periodic blood counts are recommended. If anemia or neutropenia develops, dosage adjustments may be necessary (see DOSAGE AND ADMINISTRATION).

Myopathy and myositis with pathological changes, similar to that produced by HIV disease, have been associated with prolonged use of RETROVIR.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including zidovudine and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged exposure to antiretroviral nucleoside analogues may be risk factors. Particular caution should be exercised when administering RETROVIR to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with RETROVIR should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as zidovudine. Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV/HCV virologic suppression) was seen when ribavirin was coadministered with zidovudine in HIV/HCV co-infected patients (see CLINICAL PHARMACOLOGY: Drug Interactions),hepatic decompensation (some fatal) has occurred in HIV/HCV co-infected patients receiving combination antiretroviral therapy for HIV and interferon alfa with or without ribavirin. Patients receiving interferon alfa with or without ribavirin and RETROVIR should be closely monitored for treatment-associated toxicities, especially hepatic decompensation, neutropenia, and anemia. Discontinuation of RETROVIR should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Childs Pugh > 6) (see the complete prescribing information for interferon and ribavirin).

Zidovudine is eliminated from the body primarily by renal excretion following metabolism in the liver (glucuronidation). In patients with severely impaired renal function (CrCl < 15 mL/min), dosage reduction is recommended. Although the data are limited, zidovudine concentrations appear to be increased in patients with severely impaired hepatic function, which may increase the risk of hematologic toxicity (see CLINICAL PHARMACOLOGY: Pharmacokinetics and DOSAGE AND ADMINISTRATION).

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including RETROVIR. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.

Zidovudine was administered orally at 3 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, 7 late-appearing (after 19 months) vaginal neoplasms (5 nonmetastasizing squamous cell carcinomas, 1 squamous cell papilloma, and 1 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, 2 late-appearing (after 20 months), nonmetastasizing 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.

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.

Two transplacental carcinogenicity studies were conducted in mice. One study administered zidovudine at doses of 20 mg/kg/day or 40 mg/kg/day from gestation day 10 through parturition and lactation with dosing continuing in offspring for 24 months postnatally. The doses of zidovudine employed in this study produced zidovudine exposures approximately 3 times the estimated human exposure at recommended doses. After 24 months, an increase in incidence of vaginal tumors was noted with no increase in tumors in the liver or lung or any other organ in either gender. These findings are consistent with results of the standard oral carcinogenicity study in mice, as described earlier. A second study administered zidovudine at maximum tolerated doses of 12.5 mg/day or 25 mg/day (∼1,000 mg/kg nonpregnant body weight or ∼450 mg/kg of term body weight) to pregnant mice from days 12 through 18 of gestation. There was an increase in the number of tumors in the lung, liver, and female reproductive tracts in the offspring of mice receiving the higher dose level of zidovudine. It is not known how predictive the results of rodent carcinogenicity studies may be for humans.

Zidovudine was mutagenic in a 5178Y/TK+/- mouse lymphoma assay, positive in an in vitro cell transformation assay, clastogenic in a cytogenetic assay using cultured human lymphocytes, and positive in mouse and rat micronucleus tests after repeated doses. It was negative in a cytogenetic study in rats given a single dose.

Zidovudine, administered to male and female rats at doses up to 7 times the usual adult dose based on body surface area considerations, had no effect on fertility judged by conception rates.

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 3,000 mg/kg/day (very near the oral median lethal dose in rats of 3,683 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.

Two rodent transplacental carcinogenicity studies were conducted (see Carcinogenesis, Mutagenesis, Impairment of Fertility).

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 INDICATIONS: Description of Clinical Studies). Congenital abnormalities occurred with similar frequency between neonates born to mothers who received RETROVIR and neonates 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 1-800-258-4263.

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV.

Zidovudine is excreted in human milk (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Nursing Mothers). Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving RETROVIR (see Pediatric Use and INDICATIONS: Maternal-Fetal HIV Transmission).

RETROVIR has been studied in HIV-infected pediatric patients over 3 months of age who had HIV-related symptoms or who were asymptomatic with abnormal laboratory values indicating significant HIV-related immunosuppression. RETROVIR has also been studied in neonates perinatally exposed to HIV (see ADVERSE REACTIONS, DOSAGE AND ADMINISTRATION, INDICATIONS: Description of Clinical Studies, and CLINICAL PHARMACOLOGY: Pharmacokinetics).

Clinical studies of RETROVIR did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Dosage (Posology) and method of administration

Adults: The recommended intravenous dose is 1 mg/kg infused over 1 hour. This dose should be administered 5 to 6 times daily (5 to 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. 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.

Patients should receive RETROVIR IV (zidovudine injection) 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.

The recommended dosing regimen for administration to pregnant women ( > 14 weeks of pregnancy) and their neonates 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/hour (total body weight) until clamping of the umbilical cord.

Neonatal Dosing: 2 mg/kg orally every 6 hours starting within 12 hours after birth and continuing through 6 weeks of age. Neonates 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.)

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 neutropenia (see WARNINGS).

In patients who experience hematologic toxicity, reduction in hemoglobin may occur as early as 2 to 4 weeks, and neutropenia usually occurs after 6 to 8 weeks.

Anemia: Significant anemia (hemoglobin of < 7.5 g/dL or reduction of > 25% of baseline) and/or significant neutropenia (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). In patients who develop significant anemia, dose interruption does not necessarily eliminate the need for transfusion. If marrow recovery occurs following dose interruption, resumption in dose may be appropriate using adjunctive measures such as epoetin alfa at recommended doses, depending on hematologic indices such as serum erythropoetin level and patient tolerance.

For patients experiencing pronounced anemia while receiving chronic coadministration of zidovudine and some of the drugs (e.g., fluconazole, valproic acid) listed in Table 4, zidovudine dose reduction may be considered.

End-Stage Renal Disease: In patients maintained on hemodialysis or peritoneal dialysis (CrCl < 15 mL/min), recommended dosing is 1 mg/kg every 6 to 8 hours (see CLINICAL PHARMACOLOGY: Pharmacokinetics).

Hepatic Impairment: There are insufficient data to recommend dose adjustment of RETROVIR in patients with mild to moderate impaired hepatic function or liver cirrhosis. Since RETROVIR is primarily eliminated by hepatic metabolism, a reduction in the daily dose may be necessary in these patients. Frequent monitoring of hematologic toxicities is advised (see CLINICAL PHARMACOLOGY: Pharmacokinetics and PRECAUTIONS: General).

RETROVIR IV (zidovudine injection) 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 2° to 8°C (36° to 46°F). 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 25°C (77°F) or 24 hours if refrigerated at 2° to 8°C 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.

RETROVIR IV (zidovudine injection) Infusion is administered intravenously at a constant rate over 1 hour. Rapid infusion or bolus injection should be avoided. RETROVIR IV (zidovudine injection) Infusion should not be given intramuscularly.

Interaction with other medicinal products and other forms of interaction

See Table 4 and PRECAUTIONS: DRUG INTERACTIONS.

Zidovudine Plus Lamivudine: No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-infected adult patients given a single oral dose of zidovudine (200 mg) in combination with multiple oral doses of lamivudine (300 mg every 12 hours).

Table 4. Effect of Coadministered Drugs on Zidovudine AUC* Note: ROUTINE DOSE MODIFICATION OF ZIDOVUDINE IS NOT WARRANTED WITH COADMINISTRATION OF THE FOLLOWING DRUGS.

Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18), stavudine (n = 10), or zidovudine (n = 6) were coadministered as part of a multi-drug regimen to HIV/HCV co-infected patients (see WARNINGS).