Zidovudine (zidovudine 300 mg) Dailymed

Zidovudine Tablets USP are indicated for the prevention of maternal-fetal HIV-1 transmission [see Dosage and Administration (2.2) _Refi4i_dosage_admin_id_27a6de7f-fdc6-40]. The indication is based on a dosing regimen that included 3 components: 1.antepartum therapy of HIV-1 infected mothers 2.intrapartum therapy of HIV-1 infected mothers 3.post-partum therapy of HIV-1 exposed neonate Points to consider prior to initiating Zidovudine Tablets USP in pregnant women for the prevention of maternal-fetal HIV-1 transmission include: •In most cases, Zidovudine Tablets USP for prevention of maternal-fetal HIV-1 transmission should be given in combination with other antiretroviral drugs. •Prevention of HIV-1 transmission in women who have received Zidovudine Tablets USP for a prolonged period before pregnancy has not been evaluated. •Because the fetus is most susceptible to the potential teratogenic effects of drugs during the first 10 weeks of gestation and the risks of therapy with Zidovudine Tablets USP during that period are not fully known, women in the first trimester of pregnancy who do not require immediate initiation of antiretroviral therapy for their own health may consider delaying use; this indication is based on use after 14 weeks gestation.

The recommended dosage regimen for administration to pregnant women (>14 weeks of pregnancy) and their neonates is:

The recommended dosage 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 [see Clinical Studies (14.3)]. During labor and delivery, intravenous zidovudine 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 Start neonatal dosing within 12 hours after birth and continue through 6 weeks of age. Neonates unable to receive oral dosing may be administered zidovudine intravenously. See Table 2. Table 2: Recommended Neonatal Dosages of Zidovudine Route Total Daily Dose Dose and Dosage Regimen Oral 8 mg/kg/day 2 mg/kg every 6 hours IV 6 mg/kg/day 1.5 mg/kg infused over 30 minutes, every 6 hours



Pregnancy Category C In humans, treatment with zidovudine during pregnancy reduced the rate of maternal-fetal HIV-1 transmission from 24.9% for infants born to placebo-treated mothers to 7.8% for infants born to mothers treated with zidovudine [see Clinical Studies (14.3)]. There were no differences in pregnancy-related adverse events between the treatment groups. Animal reproduction studies in rats and rabbits showed evidence of embryotoxicity and increased fetal malformations. A randomized, double-blind, placebo-controlled trial was conducted in HIV-1-infected pregnant women to determine the utility of zidovudine for the prevention of maternal-fetal HIV-1-transmission [see Clinical Studies (14.3)]. Congenital abnormalities occurred with similar frequency between neonates born to mothers who received zidovudine and neonates born to mothers who received placebo. The observed abnormalities included problems in embryogenesis (prior to 14 weeks) or were recognized on ultrasound before or immediately after initiation of study drug. Increased fetal resorptions occurred in pregnant rats and rabbits treated with doses of zidovudine that produced drug plasma concentrations 66 to 226 times (rats) and 12 to 87 times (rabbits) the mean steady-state peak human plasma concentration following a single 100-mg dose of zidovudine. There were no other reported developmental anomalies. In another developmental toxicity study, pregnant rats received zidovudine up to near-lethal doses that produced peak plasma concentrations 350 times peak human plasma concentrations (300 times the daily exposure [AUC] in humans given 600 mg/day zidovudine). This dose was associated with marked maternal toxicity and an increased incidence of fetal malformations. However, there were no signs of teratogenicity at doses up to one fifth the lethal dose [see Nonclinical Toxicology (13.2)]. Antiretroviral Pregnancy Registry To monitor maternal-fetal outcomes of pregnant women exposed to zidovudine, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

Zidovudine is excreted in human milk [see ].

Absorption and Bioavailability In adults, following oral administration, zidovudine is rapidly absorbed and extensively distributed, with peak serum concentrations occurring within 0.5 to 1.5 hours. The AUC was equivalent when zidovudine was administered as zidovudine tablets or oral solution compared with zidovudine capsules. The pharmacokinetic properties of zidovudine in fasting adult patients are summarized in Table 7. Table 7: Zidovudine Pharmacokinetic Parameters in Fasting Adult Patients Parameter Mean ± SD (except where noted) Oral bioavailability (%) 64 ± 10(n=5) Apparent volume of distribution (L/kg) 1.6 ± 0.6(n=8) Plasma protein binding (%) <38 CSF:plasma ratioMedian [range]. 0.6 [0.04 to 2.62](n=39) Systemic clearance (L/hr/kg) 1.6 ± 0.6(n=6) Renal clearance (L/hr/kg) 0.34 ± 0.05(n=9) Elimination half-life (hr)Approximate range. 0.5 to 3(n=19) Distribution The apparent volume of distribution of zidovudine, following oral administration, is 1.6 ± 0.6 L/kg; and binding to plasma protein is low, <38% (Table 7). Metabolism and Elimination Zidovudine is primarily eliminated by hepatic metabolism. The major metabolite of zidovudine is GZDV. GZDV AUC is about 3-fold greater than the zidovudine AUC. Urinary recovery of zidovudine and GZDV accounts for 14% and 74%, respectively, of the dose following oral administration. A second metabolite, 3'-amino-3'-deoxythymidine (AMT), has been identified in the plasma following single-dose intravenous (IV) administration of zidovudine. The AMT AUC was one fifth of the zidovudine AUC. Pharmacokinetics of zidovudine were dose independent at oral dosing regimens ranging from 2 mg/kg every 8 hours to 10 mg/kg every 4 hours. Effect of Food on Absorption Zidovudine may be administered with or without food. The zidovudine AUC was similar when a single dose of zidovudine was administered with food. Special Populations Renal Impairment Zidovudine clearance was decreased resulting in increased zidovudine and GZDV half-life and AUC in patients with impaired renal function (n=14) following a single 200 mg oral dose (Table 8). Plasma concentrations of AMT were not determined. A dose adjustment should not be necessary for patients with creatinine clearance (CrCl) ≥15 mL/min. Table 8: Zidovudine Pharmacokinetic Parameters in Patients With Severe Renal ImpairmentData are expressed as mean ± standard deviation. Parameter Control Subjects (Normal Renal Function) (n=6) Patients With Renal Impairment (n=14) CrCl (mL/min) 120 ± 8 18 ± 2 Zidovudine AUC (ng•hr/mL) 1,400 ± 200 3,100 ± 300 Zidovudine half-life (hr) 1.0 ± 0.2 1.4 ± 0.1 Hemodialysis and Peritoneal Dialysis The pharmacokinetics and tolerance of zidovudine were evaluated in a multiple-dose study in patients undergoing hemodialysis (n=5) or peritoneal dialysis (n=6) receiving escalating doses up to 200 mg 5 times daily for 8 weeks. Daily doses of 500 mg or less were well tolerated despite significantly elevated GZDV plasma concentrations. Apparent zidovudine oral clearance was approximately 50% of that reported in patients with normal renal function. Hemodialysis and peritoneal dialysis appeared to have a negligible effect on the removal of zidovudine, whereas GZDV elimination was enhanced. A dosage adjustment is recommended for patients undergoing hemodialysis or peritoneal dialysis [see Dosage and Administration (2.4)]. Hepatic Impairment Data describing the effect of hepatic impairment on the pharmacokinetics of zidovudine are limited. However, because zidovudine is eliminated primarily by hepatic metabolism, it is expected that zidovudine clearance would be decreased and plasma concentrations would be increased following administration of the recommended adult doses to patients with hepatic impairment [see Dosage and Administration (2.5)]. Pediatric Patients Zidovudine pharmacokinetics have been evaluated in HIV-1-infected pediatric patients (Table 9). Patients Aged 3 Months to 12 Years Overall, zidovudine pharmacokinetics in pediatric patients greater than 3 months of age are similar to those in adult patients. Proportional increases in plasma zidovudine concentrations were observed following administration of oral solution from 90 to 240 mg/m2 every 6 hours. Oral bioavailability, terminal half-life, and oral clearance were comparable to adult values. As in adult patients, the major route of elimination was by metabolism to GZDV. After intravenous dosing, about 29% of the dose was excreted in the urine unchanged, and about 45% of the dose was excreted as GZDV [see Dosage and Administration (2.1)]. Patients Aged Less Than 3 Months Zidovudine pharmacokinetics have been evaluated in pediatric patients from birth to 3 months of life. Zidovudine elimination was determined immediately following birth in 8 neonates who were exposed to zidovudine in utero. The half-life was 13.0 ± 5.8 hours. In neonates ≤14 days old, bioavailability was greater, total body clearance was slower, and half-life was longer than in pediatric patients >14 days old. For dose recommendations for neonates [see Dosage and Administration (2.2)]. Table 9: Zidovudine Pharmacokinetic Parameters in Pediatric PatientsData presented as mean ± standard deviation except where noted. Parameter Birth to 14 Days Aged 14 Days to 3 Months Aged 3 Months to 12 Years Oral bioavailability (%) 89 ± 19(n=15) 61 ± 19(n=17) 65 ± 24(n=18) CSF:plasma ratio no data no data 0.68 [0.03 to 3.25]Median [range]. (n=38) CL (L/hr/kg) 0.65 ± 0.29(n=18) 1.14 ± 0.24(n=16) 1.85 ± 0.47(n=20) Elimination half-life (hr) 3.1 ± 1.2(n=21) 1.9 ± 0.7(n=18) 1.5 ± 0.7(n=21) Pregnancy Zidovudine pharmacokinetics have been studied in a Phase 1 study of 8 women during the last trimester of pregnancy. Zidovudine pharmacokinetics were similar to those of nonpregnant adults. Consistent with passive transmission of the drug across the placenta, zidovudine concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery [see Use in Specific Populations (8.1)]. Although data are limited, methadone maintenance therapy in 5 pregnant women did not appear to alter zidovudine pharmacokinetics. Nursing Mothers The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1. After administration of a single dose of 200 mg zidovudine to 13 HIV-1-infected women, the mean concentration of zidovudine was similar in human milk and serum [see Use in Specific Populations (8.3)]. Geriatric Patients Zidovudine pharmacokinetics have not been studied in patients over 65 years of age. Gender A pharmacokinetic study in healthy male (n=12) and female (n=12) subjects showed no differences in zidovudine AUC when a single dose of zidovudine was administered as the 300 mg zidovudine tablet. Drug Interactions [See Drug Interactions (7)]. Table 10: Effect of Coadministered Drugs on Zidovudine AUCThis table is not all inclusive. Note: ROUTINE DOSE MODIFICATION OF ZIDOVUDINE IS NOT WARRANTED WITH COADMINISTRATION OF THE FOLLOWING DRUGS. CoadministeredDrug and Dose ZidovudineDose n ZidovudineConcentrations Concentration of CoadministeredDrug AUC Variability Atovaquone750 mg q 12 hrwith food 200 mg q 8 hr 14 ↑AUC31% Range23% to 78%Estimated range of percent difference. ↔ Clarithromycin 500 mg twice daily 100 mg q 4 hr x 7 days 4 ↓AUC 12% Range ↓34% to ↑14% Not Reported Fluconazole400 mg daily 200 mg q 8 hr 12 ↑AUC 74% 95% CI:54% to 98% Not Reported Lamivudine 300 mg q 12 hr single 200 mg 12 ↑AUC13% 90% CI:2% to 27% ↔ Methadone30 to 90 mg daily 200 mg q 4 hr 9 ↑AUC43% Range16% to 64% ↔ Nelfinavir750 mg q 8 hr x 7to 10 days single 200 mg 11 ↓AUC35%  Range 28% to 41% ↔ Probenecid500 mg q 6 hr x2 days 2 mg/kg q 8 hr x3 days 3 ↑AUC106% Range100% to170% Not Assessed Rifampin600 mg daily x14 days 200 mg q 8 hr x14 days 8 ↓AUC47% 90% CI:41% to 53% Not Assessed Ritonavir300 mg q 6 hr x4 days 200 mg q 8 hr x4 days 9 ↓AUC 25% 95% CI:15% to 34% ↔ Valproic acid250 mg or 500 mgq 8 hr x 4 days 100 mg q 8 hr x4 days 6 ↑AUC80% Range64% to130% Not Assessed ↑ = Increase; ↓ = Decrease; ↔ = no significant change; AUC = area under the concentration versus time curve; CI = confidence interval. Phenytoin Phenytoin plasma levels have been reported to be low in some patients receiving zidovudine, while in one case a high level was documented. However, in a pharmacokinetic interaction study in which 12 HIV-1-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. 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-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n=18), stavudine (n=10), or zidovudine (n=6) were co-administered as part of a multi-drug regimen to HIV-1/HCV co-infected patients [see Warnings and Precautions (5.4)].

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. 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, had no effect on fertility judged by conception rates. 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 administered 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.

The utility of zidovudine for the prevention of maternal-fetal HIV-1 transmission was demonstrated in a randomized, double-blind, placebo-controlled trial (ACTG 076) conducted in HIV-1-infected pregnant women with CD4+ cell counts of 200 to 1,818 celIs/mm (median in the treated group: 560 cells/mm) who had little or no previous exposure to zidovudine. Oral zidovudine was initiated between 14 and 34 weeks of gestation (median 11 weeks of therapy) followed by IV administration of zidovudine during labor and delivery. Following birth, neonates received oral zidovudine oral solution for 6 weeks. The study showed a statistically significant difference in the incidence of HIV-1 infection in the neonates (based on viral culture from peripheral blood) between the group receiving zidovudine and the group receiving placebo. Of 363 neonates evaluated in the study, the estimated risk of HIV-1 infection was 7.8% in the group receiving zidovudine and 24.9% in the placebo group, a relative reduction in transmission risk of 68.7%. Zidovudine was well tolerated by mothers and infants. There was no difference in pregnancy-related adverse events between the treatment groups.

The utility of zidovudine for the prevention of maternal-fetal HIV-1 transmission was demonstrated in a randomized, double-blind, placebo-controlled trial (ACTG 076) conducted in HIV-1-infected pregnant women with CD4+ cell counts of 200 to 1,818 celIs/mm3 (median in the treated group: 560 cells/mm3) who had little or no previous exposure to zidovudine. Oral zidovudine was initiated between 14 and 34 weeks of gestation (median 11 weeks of therapy) followed by IV administration of zidovudine during labor and delivery. Following birth, neonates received oral zidovudine oral solution for 6 weeks. The study showed a statistically significant difference in the incidence of HIV-1 infection in the neonates (based on viral culture from peripheral blood) between the group receiving zidovudine and the group receiving placebo. Of 363 neonates evaluated in the study, the estimated risk of HIV-1 infection was 7.8% in the group receiving zidovudine and 24.9% in the placebo group, a relative reduction in transmission risk of 68.7%. Zidovudine was well tolerated by mothers and infants. There was no difference in pregnancy-related adverse events between the treatment groups.

Neutropenia and Anemia Patients should be informed that the major toxicities of zidovudine are neutropenia 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. Patients should be informed that if toxicity develops, they may require transfusions or drug discontinuation. Patients should be informed of the extreme importance of having their blood counts followed closely while on therapy, especially for patients with advanced symptomatic HIV-1 disease [see Boxed Warning, Warnings and Precautions (5.1)]. Myopathy Patients should be informed that myopathy and myositis with pathological changes, similar to that produced by HIV-1 disease, have been associated with prolonged use of zidovudine [see Boxed Warning, Warnings and Precautions (5.2)]. Lactic Acidosis/Hepatomegaly Patients should be informed that some HIV medicines, including zidovudine, can cause a rare, but serious condition called lactic acidosis with liver enlargement (hepatomegaly) [see Boxed Warning, Warnings and Precautions (5.3)]. HIV-1/HCV Co-Infection Patients with HIV-1/HCV co-infection should be informed that hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin [see Warnings and Precautions (5.4)]. Use With Other Zidovudine-Containing Products Zidovudine should not be administered with combination products that contain zidovudine as one of their components (e.g., COMBIVIR [lamivudine and zidovudine] tablets or TRIZIVIR [abacavir sulfate, lamivudine, and zidovudine] tablets) [see Warnings and Precautions (5.5)]. Redistribution/Accumulation of Body Fat Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antieretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time [see Warnings and Precautions (5.7)]. Common Adverse Reactions Patients should be informed that the most commonly reported adverse reactions in adult patients being treated with zidovudine were headache, malaise, nausea, anorexia, and vomiting. The most commonly reported adverse reactions in pediatric patients receiving zidovudine were fever, cough, and digestive disorders. Patients also should 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 zidovudine [see Adverse Reactions (6)]. Drug Interactions Patients should be cautioned about the use of other medications, including ganciclovir, interferon alfa, and ribavirin, which may exacerbate the toxicity of zidovudine [see Drug Interactions (7)]. Pregnancy Pregnant women considering the use of zidovudine during pregnancy for prevention of HIV-1 transmission to their infants should be informed that transmission may still occur in some cases despite therapy. The long-term consequences of in utero and infant exposure to zidovudine are unknown, including the possible risk of cancer [see Use in Specific Populations (8.1)]. HIV-1-infected pregnant women should be informed not to breastfeed to avoid postnatal transmission of HIV to a child who may not yet be infected [see Use in Specific Populations (8.3)]. Information About HIV-1 Infection Zidovudine is not a cure for HIV-1 infection, and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should remain under the care of a physician when using zidovudine. Patients should be advised to avoid doing things that can spread HIV-1 infection to others. • Do not share needles or other injection equipment. • Do not share personal lis that can have blood or body fluids on them, like toothbrushes and razor blades. • Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom or other barrier method to lower the chance of sexual contact with semen, vaginal secretions, or blood. • Do not breastfeed. Zidovudine is excreted in human breast milk. Mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk.    Patients should be informed to take all HIV medications exactly as prescribed.   Roxane Laboratories, Inc. Columbus, Ohio 43216 10002927/07 Revised November 2012 © RLI, 2012