COMBIVIR (Page 6 of 6)

13.2 Reproductive and Developmental Toxicology Studies

Lamivudine: Reproduction studies have been performed in rats and rabbits at orally administered doses up to 4,000 mg/kg/day and 1,000 mg/kg/day, respectively, producing plasma levels up to approximately 35 times 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 35 times 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 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 AUC in rats at this dose level was 300 times the daily AUC in humans given 600 mg/day.) No evidence of teratogenicity was seen in this experiment at doses of 600 mg/kg/day or less.

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 150 mg twice daily plus RETROVIR 600 mg per day in divided doses.

14.1 Adults

Lamivudine Plus Zidovudine: The NUCB3007 (CAESAR) study was conducted using EPIVIR 150-mg Tablets (150 mg twice daily) and RETROVIR 100-mg Capsules (2 x 100 mg 3 times daily). CAESAR was a multi-center, double-blind, placebo-controlled study comparing continued current therapy (zidovudine alone [62% of patients] or zidovudine with didanosine or zalcitabine [38% of patients]) to the addition of EPIVIR or EPIVIR plus an investigational non-nucleoside reverse transcriptase inhibitor, randomized 1:2:1. A total of 1,816 HIV-1-infected adults with 25 to 250 (median 122) CD4 cells/mm3 at baseline were enrolled: median age was 36 years, 87% were male, 84% were nucleoside-experienced, and 16% were therapy-naive. The median duration on study was 12 months. Results are summarized in Table 5.

Table 5. Number of Patients (%) With At Least 1 HIV-1 Disease-Progression Event or Death
Endpoint Current Therapy (n = 460)

EPIVIR

plus Current Therapy

EPIVIR

plus a NNRTIa

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 1,818 cells/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 syrup 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.

16 HOW SUPPLIED/STORAGE AND HANDLING

COMBIVIR Tablets, containing 150 mg lamivudine and 300 mg 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 available as follows:

60 Tablets/Bottle (NDC 49702-202-18).

Unit Dose Pack of 120 (NDC 49702-202-29).

Store between 2° and 30°C (36° and 86°F).

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

©2011, ViiV Healthcare. All rights reserved.

November 2011
CMB: 4PI

Repacked by:
H.J. Harkins Company, Inc.
513 Sandydale Drive
Nipomo, CA 93444

PRINCIPAL DISPLAY PANEL

NDC 49702-202-18

COMBIVIR®

(lamivudine and zidovudine)

Tablets 150 mg/300 mg

Rx only

60 Tablets

Each tablet contains 150 mg of lamivudine and 300 mg of zidovudine.

Store between 2o and 30o C (36o and 86o F).

See prescribing information for dosage information.

Do not use if printed safety seal under cap is broken or missing.

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

Made in UK

10000000082963 Rev. 8/10

Repacked by:
H.J. Harkins Company, Inc.
513 Sandydale Drive
Nipomo, CA 93444

COMBIVIR label
(click image for full-size original)
COMBIVIR
lamivudine and zidovudine tablet, film coated
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:52959-546(NDC:49702-202)
Route of Administration ORAL DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
LAMIVUDINE (LAMIVUDINE) LAMIVUDINE 150 mg
ZIDOVUDINE (ZIDOVUDINE) ZIDOVUDINE 300 mg
Inactive Ingredients
Ingredient Name Strength
COLLOIDAL SILICON DIOXIDE
HYPROMELLOSES
MAGNESIUM STEARATE
CELLULOSE, MICROCRYSTALLINE
POLYETHYLENE GLYCOL
POLYSORBATE 80
SODIUM STARCH GLYCOLATE TYPE A POTATO
TITANIUM DIOXIDE
Product Characteristics
Color WHITE Score 2 pieces
Shape OVAL (modified-capsule-shaped tablets) Size 17mm
Flavor Imprint Code GXFC3
Contains
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:52959-546-02 2 TABLET, FILM COATED (TABLET) in 1 BOTTLE None
2 NDC:52959-546-03 3 TABLET, FILM COATED (TABLET) in 1 BOTTLE None
3 NDC:52959-546-04 4 TABLET, FILM COATED (TABLET) in 1 BOTTLE None
4 NDC:52959-546-06 6 TABLET, FILM COATED (TABLET) in 1 BOTTLE None
5 NDC:52959-546-08 8 TABLET, FILM COATED (TABLET) in 1 BOTTLE None
6 NDC:52959-546-10 10 TABLET, FILM COATED (TABLET) in 1 BOTTLE None
7 NDC:52959-546-14 14 TABLET, FILM COATED (TABLET) in 1 BOTTLE None
8 NDC:52959-546-15 15 TABLET, FILM COATED (TABLET) in 1 BOTTLE None
9 NDC:52959-546-20 20 TABLET, FILM COATED (TABLET) in 1 BOTTLE None
10 NDC:52959-546-28 28 TABLET, FILM COATED (TABLET) in 1 BOTTLE None
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA020857 10/19/2010
Labeler — H.J. Harkins Company, Inc. (147681894)
Registrant — H.J. Harkins Company, Inc. (147681894)
Establishment
Name Address ID/FEI Operations
H.J. Harkins Company, Inc. 147681894 repack, relabel

Revised: 02/2012 H.J. Harkins Company, Inc.

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