USE IN SPECIFIC POPULATIONS SECTION.


Pregnancy: Physicians are encouraged to register patients in the Antiretroviral Pregnancy Registry by calling 1-800-258-4263. (8.1)</item Nursing Mothers: HIV-1 infected mothers in the United States should not breastfeed to avoid potential postnatal transmission of HIV-1. (8.3)</item </list </text </highlight </excerpt 8.1 Pregnancy Pregnancy Category C. Fetal Risk Summary: There are no adequate and well-controlled trials of COMBIVIR (lamivudine and zidovudine) in pregnant women. Clinical trial data demonstrate that maternal zidovudine treatment during pregnancy reduces vertical transmission of HIV-1 infection to the fetus. Animal reproduction studies performed with lamivudine and zidovudine showed increased embryotoxicity and fetal malformations (zidovudine), and increased embryolethality (lamivudine). COMBIVIR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to COMBIVIR and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263. Clinical Considerations: Treatment of HIV during pregnancy optimizes the health of both mother and fetus. Clinical trial data reviewed by FDA demonstrate that maternal zidovudine treatment significantly reduces vertical transmission of HIV-1 infection to the fetus [see Clinical Studies (14.2)]. Published data suggest that combination antiretroviral regimens may reduce the rate of vertical transmission even further. Pharmacokinetics of lamivudine and zidovudine in pregnant women are similar to the pharmacokinetics in nonpregnant women. No dose adjustments are needed during pregnancy. In a clinical trial, adverse events among HIV-1-infected women were not different among untreated women and women treated with zidovudine. It is not known whether risks of adverse events associated with lamivudine are altered in pregnant women compared with other HIV-1-infected patients (see Human data below). Data : Human Data: Lamivudine: Lamivudine pharmacokinetics were studied in pregnant women during 2clinical trials conducted in South Africa. The trial assessed pharmacokinetics in: 16women at 36weeks gestation using 150mg lamivudine twice daily with zidovudine, 10women at 38weeks gestation using 150mg lamivudine twice daily with zidovudine, and 10women at 38weeks gestation using lamivudine 300mg twice daily without other antiretrovirals. Lamivudine pharmacokinetics in pregnant women were similar to those seen in nonpregnant adults and in postpartum women. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. Zidovudine: 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. Zidovudine treatment 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. There were no differences in pregnancy-related adverse events between the treatment groups. 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 trial drug [see Clinical Studies (14.2)]. Zidovudine pharmacokinetics were studied in a Phase1 trial of 8women during the last trimester of pregnancy. As pregnancy progressed, there was no evidence of drug accumulation. The pharmacokinetics of zidovudine were similar to that 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. Animal Data: Lamivudine: Animal reproduction studies performed at oral doses up to 130 and 60times the adult dose in rats and rabbits, respectively, revealed no evidence of teratogenicity due to lamivudine. Increased early embryolethality occurred in rabbits at exposure levels similar to those in humans. However, there was no indication of this effect in rats at exposure levels up to 35times those in humans. Based on animal studies, lamivudine crosses the placenta and is transferred to the fetus [see Nonclinical Toxicology (13.2)]. Zidovudine: Increased fetal resorptions occurred in pregnant rats and rabbits treated with doses of zidovudine that produced drug plasma concentrations 66 to 226times (rats) and 12to 87times (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 (300times the daily exposure [AUC] in humans given 600mg/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)]. 8.3 Nursing Mothers The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Because of both the potential for HIV-1 transmission and serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving COMBIVIR. Although no trials of COMBIVIR excretion in breast milk have been performed, lactation trials performed with lamivudine and zidovudine show that both drugs are excreted in human breast milk. Samples of breast milk obtained from 20mothers receiving lamivudine monotherapy (300mg twice daily) or combination therapy (150mg lamivudine twice daily and 300mg zidovudine twice daily) had measurable concentrations of lamivudine. In another trial, after administration of a single dose of 200mg zidovudine to 13HIV1infected women, the mean concentration of zidovudine was similar in human milk and serum. 8.4 Pediatric Use COMBIVIR should not be administered to pediatric patients weighing less than 30kg, because it is a fixed-dose combination that cannot be adjusted for this patient population. 8.5 Geriatric Use Clinical trials of COMBIVIR did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 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. COMBIVIR is not recommended for patients with impaired renal function (i.e., creatinine clearance less than 50mL/min) because it is a fixed-dose combination that cannot be adjusted. 8.6 Renal Impairment Reduction of the dosages of lamivudine and zidovudine is recommended for patients with impaired renal function. Patients with creatinine clearance less than 50mL/min should not receive COMBIVIR because it is a fixed-dose combination that cannot be adjusted. 8.7 Hepatic Impairment A reduction in the daily dose of zidovudine may be necessary in patients with mild to moderate impaired hepatic function or liver cirrhosis. COMBIVIR is not recommended for patients with impaired hepatic function because it is a fixed-dose combination that cannot be adjusted.

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION 17.1 Advice for the Patient Neutropenia and Anemia: Patients should be informed that the important toxicities associated with zidovudine are neutropenia and/or anemia. They should be told of the extreme importance of having their blood counts followed closely while on therapy, especially for patients with advanced 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 Warnings and Precautions (5.2)]. Lactic Acidosis/Hepatomegaly: Patients should be informed that some HIV medicines, including COMBIVIR, can cause a rare, but serious condition called lactic acidosis with liver enlargement (hepatomegaly) [see Warnings and Precautions (5.3)]. HIV-1/HBV Co-infection: Patients co-infected with HIV-1 and HBV should be informed that deterioration of liver disease has occurred in some cases when treatment with lamivudine was discontinued. Patients should be advised to discuss any changes in regimen with their physician [see Warnings and Precautions (5.4)]. Use With Other Lamivudine-, Zidovudine-, and/or Emtricitabine-Containing Products: COMBIVIR should not be coadministered with drugs containing lamivudine, zidovudine, or emtricitabine, including EPIVIR (lamivudine), EPIVIR-HBV (lamivudine), RETROVIR (zidovudine), EPZICOM (abacavir sulfate and lamivudine), TRIZIVIR (abacavir sulfate, lamivudine, and zidovudine), ATRIPLA (efavirenz, emtricitabine, and tenofovir), EMTRIVA (emtricitabine), TRUVADA (emtricitabine and tenofovir), or COMPLERA (rilpivirine/emtricitabine/tenofovir) [see Warnings and Precautions (5.5)]. 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 (5.6)]. 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 (7.3)]. Redistribution/Accumulation of Body Fat: Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time [see Warnings and Precautions (5.9)]. Information About HIV-1 Infection: COMBIVIR 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 COMBIVIR. 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 items 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. Lamivudine and zidovudine are 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. EPIVIR, RETROVIR, EPZICOM, and TRIZIVIR are registered trademarks of ViiV Healthcare. The other brands listed are trademarks of their respective owners and are not trademarks of ViiV Healthcare. The makers of these brands are not affiliated with and do not endorse ViiV Healthcare or its products. Manufactured for: ViiV Healthcare Research Triangle Park, NC 27709 by GlaxoSmithKline Research Triangle Park, NC 27709 Lamivudine is manufactured under agreement from Shire Pharmaceuticals Group plc Basingstoke, UK 2013, ViiV Healthcare. All rights reserved. This Product was Repackaged By: State of Florida DOH Central Pharmacy 104-2 Hamilton Park Drive Tallahassee, FL 32304 USA

CLINICAL STUDIES SECTION.


14 CLINICAL STUDIES There have been no clinical trials conducted with COMBIVIR. See Clinical Pharmacology (12.3) for information about bioequivalence. One COMBIVIR Tablet given twice daily is an alternative regimen to EPIVIR Tablets 150mg twice daily plus RETROVIR 600mg per day in divided doses. 14.1 Adults Lamivudine Plus Zidovudine: The NUCB3007 (CAESAR) trial was conducted using EPIVIR 150mg Tablets (150mg twice daily) and RETROVIR 100mg Capsules (2 x 100mg 3 times daily). CAESAR was a multicenter, double-blind, placebo-controlled trial comparing continued current therapy (zidovudine alone [62% of subjects] or zidovudine with didanosine or zalcitabine [38% of subjects]) to the addition of EPIVIR or EPIVIR plus an investigational non-nucleoside reverse transcriptase inhibitor, randomized 1:2:1. A total of 1,816HIV1infected adults with 25 to 250 (median 122) CD4cells/mm3 at baseline were enrolled: median age was 36years, 87% were male, 84% were nucleoside-experienced, and 16% were therapynaive. The median duration on trial was 12months. Results are summarized in Table5. Table 5. Number of Subjects (%) With At Least 1 HIV-1 Disease-Progression Event or Death Endpoint Current Therapy (n=460) EPIVIR plus Current Therapy (n=896) EPIVIR plus a NNRTIa plus Current Therapy (n=460) HIV-1 progression or death 90 (19.6%) 86 (9.6%) 41 (8.9%) Death 27 (5.9%) 23 (2.6%) 14 (3.0%) a An investigational non-nucleoside reverse transcriptase inhibitor not approved in the United States. 14.2 Prevention of Maternal-Fetal HIV-1 Transmission The utility of zidovudine alone for the prevention of maternal-fetal HIV-1 transmission was demonstrated in a randomized, double-blind, placebo-controlled trial conducted in HIV-1-infected pregnant women with CD4+ cell counts of 200 to 1,818cells/mm3 (median in the treated group: 560cells/mm3) who had little or no previous exposure to zidovudine. Oral zidovudine was initiated between 14 and 34weeks of gestation (median 11weeks of therapy) followed by IV administration of zidovudine during labor and delivery. Following birth, neonates received oral zidovudine syrup for 6weeks. The trial showed a statistically significant difference in the incidence of HIV1 infection in the neonates (based on viral culture from peripheral blood) between the group receiving zidovudine and the group receiving placebo. Of 363neonates evaluated in the trial, the estimated risk of HIV1 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.

CLINICAL PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action COMBIVIR is an antiviral agent [see Clinical Pharmacology (12.4)]. 12.3 Pharmacokinetics Pharmacokinetics in Adults : COMBIVIR : One COMBIVIR Tablet was bioequivalent to 1 EPIVIR Tablet (150mg) plus 1 RETROVIR Tablet (300mg) following single-dose administration to fasting healthy subjects (n=24). Lamivudine: The pharmacokinetic properties of lamivudine in fasting subjects are summarized in Table3. Following oral administration, lamivudine is rapidly absorbed and extensively distributed. Binding to plasma protein is low. Approximately 70% of an intravenous dose of lamivudine is recovered as unchanged drug in the urine. Metabolism of lamivudine is a minor route of elimination. In humans, the only known metabolite is the trans-sulfoxide metabolite (approximately 5% of an oral dose after 12hours). Zidovudine: The pharmacokinetic properties of zidovudine in fasting subjects are summarized in Table3. Following oral administration, zidovudine is rapidly absorbed and extensively distributed. Binding to plasma protein is low. Zidovudine is eliminated primarily by hepatic metabolism. The major metabolite of zidovudine is GZDV. GZDV area under the curve (AUC) is about 3-fold greater than the zidovudine AUC. Urinary recovery of zidovudine and GZDV accounts for 14% and 74% of the dose following oral administration, respectively. A second metabolite, 3-amino-3-deoxythymidine (AMT), has been identified in plasma. The AMT AUC was one fifth of the zidovudine AUC. Table 3. Pharmacokinetic Parametersa for Lamivudine and Zidovudine in Adults Parameter Lamivudine Zidovudine Oral bioavailability (%) 86 16 N=12 64 10 n=5 Apparent volume of distribution (L/kg) 1.3 0.4 N=20 1.6 0.6 n=8 Plasma protein binding (%) <36 <38 CSF:plasma ratiob 0.12 [0.04 to 0.47] n=38c 0.60 [0.04 to 2.62] N=39d Systemic clearance (L/hr/kg) 0.33 0.06 N=20 1.6 0.6 n=6 Renal clearance (L/hr/kg) 0.220.06 N=20 0.34 0.05 n=9 Elimination half-life (hr)e 5 to 7 0.5 to 3 a Data presented as mean standard deviation except where noted. b Median [range]. c Children. d Adults. e Approximate range. Effect of Food on Absorption of COMBIVIR: COMBIVIR may be administered with or without food. The lamivudine and zidovudine AUC following administration of COMBIVIR with food was similar when compared with fasting healthy subjects (n=24). Special Populations: Pregnancy: See Use in Specific Populations (8.1). COMBIVIR: No data are available. Zidovudine: Zidovudine pharmacokinetics has been studied in a Phase1 trial of 8women 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 neonatal plasma at birth were essentially equal to those in maternal plasma at delivery. Although data are limited, methadone maintenance therapy in 5pregnant women did not appear to alter zidovudine pharmacokinetics. In a nonpregnant adult population, a potential for interaction has been identified. Nursing Mothers: See Use in Specific Populations (8.3). Pediatric Patients: COMBIVIR should not be administered to pediatric patients weighing less than 30kg. Geriatric Patients: The pharmacokinetics of lamivudine and zidovudine have not been studied in patients over 65years of age. Gender: A pharmacokinetic trial in healthy male (n=12) and female (n=12) subjects showed no gender differences in zidovudine AUC or lamivudine AUC normalized for body weight. Race: Lamivudine: There are no significant racial differences in lamivudine pharmacokinetics. Zidovudine: The pharmacokinetics of zidovudine with respect to race have not been determined. Drug Interactions: See Drug Interactions (7). No drug interaction trials have been conducted using COMBIVIR Tablets. However, Table 4 presents drug interaction information for the individual components of COMBIVIR. Lamivudine Plus Zidovudine: No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12asymptomatic HIV-1-infected adult subjects given a single dose of zidovudine (200mg) in combination with multiple doses of lamivudine (300mg q 12hr). Table 4. Effect of Coadministered Drugs on Lamivudine and Zidovudine AUCa Note: ROUTINE DOSE MODIFICATION OF LAMIVUDINE AND ZIDOVUDINE IS NOT WARRANTED WITH COADMINISTRATION OF THE FOLLOWING DRUGS. Drugs That May Alter Lamivudine Blood Concentrations Coadministered Drug and Dose Lamivudine Dose n Lamivudine Concentrations Concentration of Coadministered Drug AUC Variability Nelfinavir 750mg q8hr x 7 to 10days single 150mg 11 AUC 10% 95% CI: 1% to 20% Trimethoprim 160mg/Sulfamethoxazole 800mg daily x 5days single 300mg 14 AUC 43% 90% CI: 32% to 55% Drugs That May Alter Zidovudine Blood Concentrations Coadministered Drug and Dose Zidovudine Dose n Zidovudine Concentrations Concentration of Coadministered Drug AUC Variability Atovaquone 750mg q 12hr with food 200mg q 8hr 14 AUC 31% Range 23% to 78%b Clarithromycin 500 mg twice daily 100 mg q 4 hr x 7 days 4 AUC 12% Range 34% to 14% Not Reported Fluconazole 400mg daily 200mg q 8hr 12 AUC 74% 95% CI: 54% to 98% Not Reported Methadone 30 to 90mg daily 200mg q 4hr 9 AUC 43% Range 16% to 64%b Nelfinavir 750mgq 8hr x 7 to 10days single 200mg 11 AUC 35% Range 28% to 41% Probenecid 500 mg q 6hr x 2days 2mg/kg q 8hr x 3days 3 AUC 106% Range 100% to 170%b Not Assessed Rifampin 600mg daily x 14 days 200mg q 8hr X 14days 8 AUC 47% 90% CI: 41% to 53% Not Assessed Ritonavir 300mg q 6hr x 4days 200 mg q 8hr x 4days 9 AUC 25% 95% CI: 15% to 34% Valproic acid 250mg or 500mg q 8hr x 4days 100 mg q 8hr x 4days 6 AUC 80% Range 64% to 130%b Not Assessed = Increase; = Decrease; =no significant change; AUC = area under the concentration versus time curve; CI = confidence interval. a This table is not all inclusive. b Estimated range of percent difference. Ribavirin: Invitro 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 coadministered as part of a multi-drug regimen to HIV-1/HCV co-infected subjects [see Warnings and Precautions (5.5)]. 12.4 Microbiology Mechanism of Action: Lamivudine: Intracellularly, lamivudine is phosphorylated to its active 5-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue. 3TC-TP is a weak inhibitor of cellular DNA polymerases , , and . Zidovudine: 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 RT via DNA chain termination after incorporation of the nucleotide analogue. ZDV-TP is a weak inhibitor of the cellular DNA polymerases and and has been reported to be incorporated into the DNA of cells in culture. Antiviral Activity: Lamivudine Plus Zidovudine: In HIV-1infected MT-4 cells, lamivudine in combination with zidovudine at various ratios exhibited synergistic antiretroviral activity. Lamivudine: The antiviral activity of lamivudine against HIV-1 was assessed in a number of cell lines (including monocytes and fresh human peripheral blood lymphocytes) using standard susceptibility assays. EC50 values (50% effective concentrations) were in the range of 0.003 to 15M (1M=0.23mcg/mL). HIV-1 from therapy-naive subjects with no amino acid substitutions associated with resistance gave median EC50 values of 0.429M (range: 0.200 to 2.007M) from Virco (n=92 baseline samples from COL40263) and 2.35M (1.37 to 3.68M) from Monogram Biosciences (n=135 baseline samples from ESS30009). The EC50 values of lamivudine against different HIV-1 clades (A-G) ranged from 0.001 to 0.120M, and against HIV-2 isolates from 0.003 to 0.120M in peripheral blood mononuclear cells. Ribavirin (50M) decreased the anti-HIV-1 activity of lamivudine by 3.5 fold in MT-4 cells. Zidovudine: The antiviral 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 0.49M (1M=0.27mcg/mL) and 0.1 to 9M, respectively. HIV-1 from therapy-naive subjects with no amino acid substitutions associated with resistance gave median EC50 values of 0.011M (range: 0.005 to 0.110M) from Virco (n=92 baseline samples from COL40263) and 0.0017M (0.006 to 0.0340M) 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 0.02M, and against HIV-2 isolates from 0.00049 to 0.004M. 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. Resistance: Lamivudine Plus Zidovudine Administered As Separate Formulations: In subjects receiving lamivudine monotherapy or combination therapy with lamivudine plus zidovudine, HIV1 isolates from most subjects became phenotypically and genotypically resistant to lamivudine within 12weeks. In some subjects harboring zidovudineresistant virus at baseline, phenotypic sensitivity to zidovudine was restored by 12weeks of treatment with lamivudine and zidovudine. Combination therapy with lamivudine plus zidovudine delayed the emergence of amino acid substitutions conferring resistance to zidovudine. HIV-1 strains resistant to both lamivudine and zidovudine have been isolated from subjects after prolonged lamivudine/zidovudine therapy. Dual resistance required the presence of multiple amino acid substitutions, the most essential of which may be G333E. The incidence of dual resistance and the duration of combination therapy required before dual resistance occurs are unknown. Lamivudine: Lamivudineresistant isolates of HIV1 have been selected in cell culture and have also been recovered from subjects treated with lamivudine or lamivudine plus zidovudine. Genotypic analysis of isolates selected in cell culture and recovered from lamivudinetreated subjects showed that the resistance was due to a specific amino acid substitution in the HIV1 reverse transcriptase at codon184 changing the methionine to either isoleucine or valine (M184V/I). Zidovudine: HIV1 isolates with reduced susceptibility to zidovudine have been selected in cell culture and were also recovered from subjects treated with zidovudine. Genotypic analyses of the isolates selected in cell culture and recovered from zidovudinetreated subjects showed substitutions in the HIV-1 RT gene resulting in 6amino 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 amino acid substitutions. Cross-Resistance: Cross-resistance has been observed among NRTIs. Lamivudine Plus Zidovudine: Crossresistance between lamivudine and zidovudine has not been reported. In some subjects treated with lamivudine alone or in combination with zidovudine, isolates have emerged with a substitution at codon184, which confers resistance to lamivudine. Cross-resistance to abacavir, didanosine, tenofovir, and zalcitabine has been observed in some subjects harboring lamivudineresistant HIV1 isolates. In some subjects treated with zidovudine plus didanosine or zalcitabine, isolates resistant to multiple drugs, including lamivudine, have emerged (see under Zidovudine below). Lamivudine: See Lamivudine Plus Zidovudine (above). Zidovudine: In a trial of 167HIV1infected subjects, isolates (n=2) with multidrug resistance to didanosine, lamivudine, stavudine, zalcitabine, and zidovudine were recovered from subjects treated for 1year with zidovudine plus didanosine or zidovudine plus zalcitabine. The pattern of resistanceassociated amino acid substitutions with such combination therapies was different (A62V, V75I, F77L, F116Y, Q151M) from the pattern with zidovudine monotherapy, with the Q151Msubstitution being most commonly associated with multidrug resistance. The substitution at codon151 in combination with substitutions 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 crossresistance to abacavir, didanosine, stavudine, tenofovir, and zalcitabine.

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS COMBIVIR Tablets are contraindicated in patients with previously demonstrated clinically significant hypersensitivity (e.g., anaphylaxis, Stevens-Johnson syndrome) to any of the components of the product. COMBIVIR Tablets are contraindicated in patients with previously demonstrated clinically significant hypersensitivity (e.g., anaphylaxis, Stevens-Johnson syndrome). (4)

DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS COMBIVIR Tablets contain 150mg of lamivudine and 300mg of zidovudine. The tablets are white, scored, film-coated, modified capsule-shaped tablets, debossed on both tablet faces, such that when broken in half, the full GX FC3 code is present on both halves of the tablet (GX on one face and FC3 on the opposite face of the tablet). Tablets: Scored 150 mg lamivudine and 300 mg zidovudine (3)

BOXED WARNING SECTION.


WARNING: HEMATOLOGIC TOXICITY, MYOPATHY, LACTIC ACIDOSIS, EXACERBATIONS OF HEPATITIS B Hematologic Toxicity: Zidovudine, one of the 2 active ingredients in COMBIVIR (lamivudine and zidovudine) Tablets, has been associated with hematologic toxicity including neutropenia and anemia, particularly in patients with advanced HIV-1 disease [see Warnings and Precautions (5.1)]. Myopathy: Prolonged use of zidovudine has been associated with symptomatic myopathy [see Warnings and Precautions (5.2)]. Lactic Acidosis and Severe Hepatomegaly: Lactic acidosis and hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including lamivudine, zidovudine, and other antiretrovirals. Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur[ see Warnings and Precautions (5.3)]. Exacerbations of Hepatitis B: Severe, acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and HIV-1 and have discontinued lamivudine, which is one component of COMBIVIR. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue COMBIVIR and are co-infected with HIV-1 and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted [see Warnings and Precautions (5.4)]. WARNING: RISK OF HEMATOLOGIC TOXICITY, MYOPATHY, LACTIC ACIDOSIS, EXACERBATIONS OF HEPATITIS B See full prescribing information for complete boxed warning Hematologic toxicity including neutropenia and anemia have been associated with the use of zidovudine, one of the components of COMBIVIR (5.1) Symptomatic myopathy associated with prolonged use of zidovudine. (5.2) Lactic acidosis and hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues including zidovudine. Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur . (5.3) Severe, acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV-1) and have discontinued lamivudine, a component of COMBIVIR. Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis B treatment. (5.4)

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PACKAGE LABEL Label Image for 53808-0895 150mg / 300mg

ADVERSE REACTIONS SECTION.


6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Hematologic toxicity, including neutropenia and anemia [see Boxed Warning, Warnings and Precautions (5.1)]. Symptomatic myopathy [see Boxed Warning, Warnings and Precautions (5.2)]. Lactic acidosis and hepatomegaly with steatosis [see Boxed Warning, Warnings and Precautions (5.3)]. Acute exacerbations of hepatitis B [see Boxed Warning, Warnings and Precautions (5.4)]. Hepatic decompensation in patients co-infected with HIV-1 and hepatitis C [see Warnings and Precautions (5.6)]. Exacerbation of anemia in HIV-1/HCV co-infected patients receiving ribavirin and zidovudine [see Warnings and Precautions (5.6)]. Pancreatitis [see Warnings and Precautions (5.7)]. Most commonly reported adverse reactions (incidence greater than or equal to 15%) in adult and pediatric HIV-1 clinical trials of combination lamivudine and zidovudine were headache, nausea, malaise and fatigue, nasal signs and symptoms, diarrhea, and cough. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact ViiV Healthcare at 1-877-844-8872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Lamivudine Plus Zidovudine Administered As Separate Formulations: In 4randomized, controlled trials of EPIVIR 300mg per day plus RETROVIR 600mg per day, the following selected adverse reactions and laboratory abnormalities were observed (see Tables 1 and 2). Table 1. Selected Clinical Adverse Reactions (5% Frequency) in 4 Controlled Clinical Trials With EPIVIR 300mg/day and RETROVIR 600mg/day Adverse Reaction EPIVIR plus RETROVIR (n=251) Body as a whole Headache 35% Malaise & fatigue 27% Fever or chills 10% Digestive Nausea 33% Diarrhea 18% Nausea & vomiting 13% Anorexia and/or decreased appetite 10% Abdominal pain 9% Abdominal cramps 6% Dyspepsia 5% Nervous system Neuropathy 12% Insomnia & other sleep disorders 11% Dizziness 10% Depressive disorders 9% Respiratory Nasal signs & symptoms 20% Cough 18% Skin Skin rashes 9% Musculoskeletal Musculoskeletal pain 12% Myalgia 8% Arthralgia 5% Pancreatitis was observed in 9 of the 2,613adult subjects (0.3%) who received EPIVIR in controlled clinical trials [see Warnings and Precautions (5.7)]. Selected laboratory abnormalities observed during therapy are listed in Table2. Table 2. Frequencies of Selected Laboratory Abnormalities Among Adults in 4 Controlled Clinical Trials of EPIVIR 300mg/day plus RETROVIR 600mg/daya Test (Abnormal Level) EPIVIR plus RETROVIR %(n) Neutropenia (ANC5.0 x ULN) 3.7% (241) AST (>5.0 x ULN) 1.7% (241) Bilirubin (>2.5 x ULN) 0.8% (241) Amylase (>2.0 x ULN) 4.2% (72) ULN=Upper limit of normal. ANC=Absolute neutrophil count. n=Number of subjects assessed. a Frequencies of these laboratory abnormalities were higher in subjects with mild laboratory abnormalities at baseline. 6.2 Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following reactions have been identified during post-approval use of EPIVIR, RETROVIR, and/or COMBIVIR. 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 a combination of their seriousness, frequency of reporting, or potential causal connection to EPIVIR, RETROVIR, and/or COMBIVIR. Body as a Whole: Redistribution/accumulation of body fat [see Warnings and Precautions (5.9)]. Cardiovascular: Cardiomyopathy. Endocrine and Metabolic: Gynecomastia, hyperglycemia. Gastrointestinal: Oral mucosal pigmentation, stomatitis. General: Vasculitis, weakness. Hemic and Lymphatic: Anemia, (including pure red cell aplasia and anemias progressing on therapy), lymphadenopathy, splenomegaly. Hepatic and Pancreatic: Lactic acidosis and hepatic steatosis, pancreatitis, posttreatment exacerbation of hepatitis B [see Boxed Warning, Warnings and Precautions (5.3), (5.4), (5.7)]. Hypersensitivity: Sensitization reactions (including anaphylaxis), urticaria. Musculoskeletal: Muscle weakness, CPK elevation, rhabdomyolysis. Nervous: Paresthesia, peripheral neuropathy, seizures. Respiratory: Abnormal breath sounds/wheezing. Skin: Alopecia, erythema multiforme, Stevens-Johnson syndrome.

INDICATIONS & USAGE SECTION.


1 INDICATIONS AND USAGE COMBIVIR, a combination of 2nucleoside analogues, is indicated in combination with other antiretrovirals for the treatment of HIV-1 infection. COMBIVIR, a combination of 2nucleoside analogue reverse transcriptase inhibitors, is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. (1)

DOSAGE & ADMINISTRATION SECTION.


Adults and Adolescents weighing 30kg: 1tablet twice daily. (2.1)</item Pediatrics: Dosage should be based on body weight not to exceed adult doses. (2.2)</item COMBIVIR, a fixed-dose product, should not be prescribed for pediatric patients weighing less than 30kg or patients requiring dosage adjustment, such as those with renal or hepatic impairment, or patients experiencing dose-limiting adverse reactions. (2.3)</item </list </text </highlight </excerpt 2.1 Adults and Adolescents Weighing 30kg The recommended oral dose of COMBIVIR in HIV-1-infected adults and adolescents weighing greater than or equal to 30kg is 1tablet (containing 150mg of lamivudine and 300mg of zidovudine) twice daily. 2.2 Pediatric Patients The recommended oral dosage of scored COMBIVIR Tablets for pediatric patients who weigh greater than or equal to 30kg and for whom a solid oral dosage form is appropriate is 1tablet administered twice daily. Before prescribing COMBIVIR Tablets, children should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow a COMBIVIR Tablet, the liquid oral formulations should be prescribed: EPIVIR (lamivudine) Oral Solution and RETROVIR(zidovudine) Syrup. 2.3 Patients Requiring Dosage Adjustment Because COMBIVIR is a fixed-dose combination tablet, it should not be prescribed for pediatric patients weighing less than 30kg or patients requiring dosage adjustment, such as those with reduced renal function (creatinine clearance less than 50mL/min), patients with hepatic impairment, or patients experiencing dose-limiting adverse reactions. Liquid and solid oral formulations of the individual components of COMBIVIR are available for these populations.

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING COMBIVIR Tablets, containing 150mg lamivudine and 300mg zidovudine, are white, scored, film-coated, modified-capsule-shaped tablets, debossed on both tablet faces, such that when broken in half, the full GXFC3 code is present on both halves of the tablet (GX on one face and FC3 on the opposite face of the tablet). They are supplied by State of Florida DOH Central Pharmacy as follows: NDC Strength Quantity/Form Color Source Prod. Code 53808-0895-1 150 MG / 300 MG 30 Tablets in a Blister Pack WHITE 49702-202 Store between 2 and 30C (36 and 86F).

DESCRIPTION SECTION.


11 DESCRIPTION COMBIVIR: COMBIVIR Tablets are combination tablets containing lamivudine and zidovudine. Lamivudine (EPIVIR) and zidovudine (RETROVIR, azidothymidine, AZT, or ZDV) are synthetic nucleoside analogues with activity against HIV-1. COMBIVIR Tablets are for oral administration. Each film-coated tablet contains 150mg of lamivudine, 300mg of zidovudine, and the inactive ingredients colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, and titanium dioxide. Lamivudine: The chemical name of lamivudine is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one. Lamivudine is the (-)enantiomer of a dideoxy analogue of cytidine. Lamivudine has also been referred to as (-)2,3-dideoxy, 3-thiacytidine. It has a molecular formula of C8H11N3O3S and a molecular weight of 229.3. It has the following structural formula: Lamivudine is a white to off-white crystalline solid with a solubility of approximately 70mg/mL in water at 20C. Zidovudine: The chemical name of zidovudine is 3-azido-3-deoxythymidine. It has a molecular formula of C10H13N5O4 and a molecular weight of 267.24. It has the following structural formula: Zidovudine is a white to beige, odorless, crystalline solid with a solubility of 20.1 mg/mL in water at 25C.

OVERDOSAGE SECTION.


10 OVERDOSAGE COMBIVIR: There is no known antidote for COMBIVIR. Lamivudine: One case of an adult ingesting 6grams of lamivudine was reported; there were no clinical signs or symptoms noted and hematologic tests remained normal. Because a negligible amount of lamivudine was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a lamivudine overdose event. Zidovudine: Acute overdoses of zidovudine have been reported in pediatric patients and adults. These involved exposures up to 50grams. The only consistent findings were nausea and vomiting. Other reported occurrences included headache, dizziness, drowsiness, lethargy, confusion, and 1report of a grand mal seizure. Hematologic changes were transient. All patients recovered. Hemodialysis and peritoneal dialysis appear to have a negligible effect on the removal of zidovudine, while elimination of its primary metabolite, 3-azido-3-deoxy-5-O--D-glucopyranuronosylthymidine (GZDV), is enhanced.

WARNINGS AND PRECAUTIONS SECTION.


See boxed warning for information about the following: hematologic toxicity, symptomatic myopathy, lactic acidosis and severe hepatomegaly, and severe acute exacerbations of hepatitis B. (5.1, 5.2, 5.3. 5.4)</item COMBIVIR should not be administered with other lamivudine- or zidovudine-containing products or emtricitabine-containing products. (5.5)</item Hepatic decompensation, some fatal, has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy and interferon alfa with/without ribavirin. Discontinue COMBIVIR as medically appropriate and consider dose reduction or discontinuation of interferon alfa, ribavirin, or both. (5.6)</item Exacerbation of anemia has been reported in HIV-1/HCV co-infected patients receiving ribavirin and zidovudine. Co-administration of ribavirin and zidovudine is not advised. (5.6)</item Pancreatitis: Use with caution in pediatric patients with a history of pancreatitis or other significant risk factors for pancreatitis. Discontinue treatment as clinically appropriate. (5.7)</item Immune reconstitution syndrome (5.8) and redistribution/accumulation of body fat (5.9) have been reported in patients treated with combination antiretroviral therapy.</item </list </text </highlight </excerpt 5.1 Hemotologic Toxicity/Bone Marrow Suppression Zidovudine, a component of COMBIVIR, has been associated with hematologic toxicity including neutropenia and anemia, particularly in patients with advanced HIV-1 disease. COMBIVIR should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count less than 1,000cells/mm3 or hemoglobin less than 9.5 g/dL [see Adverse Reactions (6.1)]. Frequent blood counts are strongly recommended in patients with advanced HIV-1 disease who are treated with COMBIVIR. Periodic blood counts are recommended for other HIV-1-infected patients. If anemia or neutropenia develops, dosage interruption may be needed. 5.2 Myopathy Myopathy and myositis, with pathological changes similar to that produced by HIV-1 disease, have been associated with prolonged use of zidovudine, and therefore may occur with therapy with COMBIVIR. 5.3 Lactic Acidosis/Hepatomegaly With Steatosis Lactic acidosis and hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including lamivudine, zidovudine, and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering COMBIVIR 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 COMBIVIR 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). 5.4 Patients With HIV-1 and Hepatitis B Virus Co-infection Posttreatment Exacerbations of Hepatitis: In clinical trials in non-HIV-1-infected patients treated with lamivudine for chronic HBV, clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. These exacerbations have been detected primarily by serum ALT elevations in addition to re-emergence of hepatitis B viral DNA (HBV DNA). Although most events appear to have been self-limited, fatalities have been reported in some cases. Similar events have been reported from post-marketing experience after changes from lamivudine-containing HIV-1 treatment regimens to non-lamivudine-containing regimens in patients infected with both HIV-1 and HBV. The causal relationship to discontinuation of lamivudine treatment is unknown. Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. There is insufficient evidence to determine whether re-initiation of lamivudine alters the course of posttreatment exacerbations of hepatitis. Important Differences Among Lamivudine-Containing Products: COMBIVIR Tablets contain a higher dose of the same active ingredient (lamivudine) than EPIVIR-HBV (lamivudine) Tablets and Oral Solution. EPIVIR-HBV was developed for treating chronic hepatitis B. Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitisB in patients co-infected with HIV-1 and HBV. Emergence of Lamivudine-Resistant HBV: In non-HIV-infected patients treated with lamivudine for chronic hepatitisB, emergence of lamivudine-resistant HBV has been detected and has been associated with diminished treatment response (see full prescribing information for EPIVIR-HBV for additional information). Emergence of hepatitisB virus variants associated with resistance to lamivudine has also been reported in HIV-1-infected patients who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitisB virus. 5.5 Use With Other, Lamivudine-, Zidovudine-, and/or Emtricitabine-Containing Products COMBIVIR is a fixed-dose combination of lamivudine and zidovudine. COMBIVIR should not be administered concomitantly with other lamivudine- or zidovudine-containing products including EPIVIR (lamivudine) Tablets and Oral Solution; EPIVIR-HBV Tablets and Oral Solution; RETROVIR (zidovudine) Tablets, Capsules, Syrup, and IV Infusion; EPZICOM (abacavir sulfate and lamivudine) Tablets; or TRIZIVIR (abacavir sulfate, lamivudine, and zidovudine) Tablets; or emtricitabine-containing products, including ATRIPLA (efavirenz, emtricitabine, and tenofovir), EMTRIVA (emtricitabine), TRUVADA (emtricitabine and tenofovir), or COMPLERA (rilpivirine/emtricitabine/tenofovir). 5.6 Use With Interferon- and Ribavirin-Based Regimens Invitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as lamivudine and zidovudine. Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when ribavirin was coadministered with lamivudine or zidovudine in HIV-1/HCV co-infected patients [see Clinical Pharmacology (12.3)], 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. Patients receiving interferon alfa with or without ribavirin and COMBIVIR should be closely monitored for treatment-associated toxicities, especially hepatic decompensation, neutropenia, and anemia. Discontinuation of COMBIVIR 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., Child-Pugh greater than 6) (see the complete prescribing information for interferon and ribavirin). Exacerbation of anemia has been reported in HIV-1/HCV co-infected patients receiving ribavirin and zidovudine. Coadministration of ribavirin and zidovudine is not advised. 5.7 Pancreatitis COMBIVIR should be used with caution in patients with a history of pancreatitis or other significant risk factors for the development of pancreatitis. Treatment with COMBIVIR should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur [see Adverse Reactions (6.1)]. 5.8 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including COMBIVIR. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond 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. Autoimmune disorders (such as Graves disease, polymyositis, and Guillain-Barr syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment. 5.9 Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

DRUG INTERACTIONS SECTION.


7 DRUG INTERACTIONS No drug interaction trials have been conducted using COMBIVIR Tablets [see Clinical Pharmacology (12.3)]. Concomitant use with the following drugs should be avoided: stavudine (7.1), zalcitabine (7.1), doxorubicin (7.2). Bone marrow suppressive/cytotoxic agents: May increase the hematologic toxicity of zidovudine. (7.3) 7.1 Antiretroviral Agents Lamivudine : Zalcitabine : Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of one another. Therefore, use of COMBIVIR in combination with zalcitabine is not recommended. Zidovudine : Stavudine : Concomitant use of COMBIVIR with stavudine should be avoided since an antagonistic relationship with zidovudine has been demonstrated invitro. Nucleoside Analogues Affecting DNA Replication: Some nucleoside analogues affecting DNA replication, such as ribavirin, antagonize the invitro antiviral activity of zidovudine against HIV-1; concomitant use of such drugs should be avoided. 7.2 Doxorubicin Zidovudine: Concomitant use of COMBIVIR with doxorubicin should be avoided since an antagonistic relationship with zidovudine has been demonstrated invitro. 7.3 Hematologic/Bone Marrow Suppressive/Cytotoxic Agents Zidovudine: Coadministration of ganciclovir, interferon alfa, ribavirin, and other bone marrow suppressive or cytotoxic agents may increase the hematologic toxicity of zidovudine. 7.4 Interferon- and Ribavirin-Based Regimens Lamivudine: Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when ribavirin was coadministered with lamivudine in HIV-1/HCV co-infected patients, 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 (5.5), Clinical Pharmacology (12.3)]. 7.5 Trimethoprim/Sulfamethoxazole (TMP/SMX) Lamivudine: No change in dose of either drug is recommended. There is no information regarding the effect on lamivudine pharmacokinetics of higher doses of TMP/SMX such as those used to treat PCP.

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity: Lamivudine: Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 10times (mice) and 58times (rats) those observed in humans at the recommended therapeutic dose for HIV-1 infection. Zidovudine: Zidovudine was administered orally at 3dosage levels to separate groups of mice and rats (60females and 60males in each group). Initial single daily doses were 30, 60, and 120mg/kg/day in mice and 80, 220, and 600mg/kg/day in rats. The doses in mice were reduced to 20, 30, and 40mg/kg/day after day90 because of treatment-related anemia, whereas in rats only the high dose was reduced to 450mg/kg/day on day91 and then to 300mg/kg/day on day279. In mice, 7late-appearing (after 19months) vaginal neoplasms (5nonmetastasizing squamous cell carcinomas, 1squamous cell papilloma, and 1squamous 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, 2late-appearing (after 20months), 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 3times (mouse) and 24times (rat) the estimated human exposure at the recommended therapeutic dose of 100mg every 4hours. It is not known how predictive the results of rodent carcinogenicity studies may be for humans. Mutagenicity: Lamivudine: Lamivudine was mutagenic in an L5178Y/TK+/- mouse lymphoma assay and clastogenic in a cytogenetic assay using cultured human lymphocytes. Lamivudine was negative in a microbial mutagenicity assay, in an invitro cell transformation assay, in a rat micronucleus test, in a rat bone marrow cytogenetic assay, and in an assay for unscheduled DNA synthesis in rat liver. Zidovudine: Zidovudine was mutagenic in an L5178Y/TK+/- mouse lymphoma assay, positive in an invitro 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. Impairment of Fertility: Lamivudine: In a study of reproductive performance, lamivudine, administered to male and female rats at doses up to 130times the usual adult dose based on body surface area considerations, revealed no evidence of impaired fertility (judged by conception rates) and no effect on the survival, growth, and development to weaning of the offspring. Zidovudine: Zidovudine, administered to male and female rats at doses up to 7times the usual adult dose based on body surface area considerations, had no effect on fertility judged by conception rates. 13.2 Reproductive and Developmental Toxicology Studies Lamivudine: Reproduction studies have been performed in rats and rabbits at orally administered doses up to 4,000mg/kg/day and 1,000mg/kg/day, respectively, producing plasma levels up to approximately 35times that for the adult HIV dose. No evidence of teratogenicity due to lamivudine was observed. Evidence of early embryolethality was seen in the rabbit at exposure levels similar to those observed in humans, but there was no indication of this effect in the rat at exposure levels up to 35times those in humans. Studies in pregnant rats and rabbits showed that lamivudine is transferred to the fetus through the placenta. Zidovudine: Oral teratology studies in the rat and in the rabbit at doses up to 500mg/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 450mg/kg/day and rabbits given 500mg/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 226times, and in rabbits 12 to 87times, mean steady-state peak human plasma concentrations (after one sixth of the daily dose) achieved with the recommended daily dose (100mg every 4hours). In an invitro 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 3,000mg/kg/day (very near the oral median lethal dose in rats of 3,683mg/kg) caused marked maternal toxicity and an increase in the incidence of fetal malformations. This dose resulted in peak zidovudine plasma concentrations 350times peak human plasma concentrations. (Estimated AUC in rats at this dose level was 300times the daily AUC in humans given 600mg/day.) No evidence of teratogenicity was seen in this experiment at doses of 600mg/kg/day or less.