5 WARNINGS AND PRECAUTIONS

5.1 Hemotologic Toxicity/Bone Marrow Suppression

Zidovudine, a component of lamivudine and zidovudine tablet, has been associated with hematologic toxicity including neutropenia and anemia, particularly in patients with advanced HIV-1 disease. Lamivudine and zidovudine tablet should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count less than 1,000 cells per mm 3 or hemoglobin less than 9.5 grams per dL [see Adverse Reactions ( 6.1)].

Frequent blood counts are strongly recommended in patients with advanced HIV-1 disease who are treated with lamivudine and zidovudine tablet. 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 lamivudine and zidovudine tablet.

5.3 Lactic Acidosis and Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including lamivudine and zidovudine (components of lamivudine and zidovudine tablet). A majority of these cases have been in women. Female sex and obesity may be risk factors for the development of lactic acidosis and severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogues. See full prescribing information for EPIVIR (lamivudine) and RETROVIR (zidovudine). Treatment with lamivudine and zidovudine tablet 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 Hepatitis B Virus Co-infection

Posttreatment Exacerbations of Hepatitis
Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. See full prescribing information for EPIVIR (lamivudine). Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment.

Emergence of Lamivudine-Resistant HBV
Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in subjects dually infected with HIV-1 and HBV. Emergence of hepatitis B virus variants associated with resistance to lamivudine has been reported in HIV-1-infected subjects who have received lamivudine- containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus. See full prescribing information for EPIVIR (lamivudine).

5.5 Use with Interferon- and Ribavirin-Based Regimens

Patients receiving interferon alfa with or without ribavirin and lamivudine and zidovudine tablet should be closely monitored for treatment-associated toxicities, especially hepatic decompensation, neutropenia, and anemia. See full prescribing information for RETROVIR (zidovudine). Discontinuation of lamivudine and zidovudine tablets 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 full 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 lamivudine and zidovudine tablets are not advised.

5.6 Pancreatitis

Lamivudine and zidovudine tablet should be used with caution in patients with a history of pancreatitis or other significant risk factors for the development of pancreatitis. Treatment with lamivudine and zidovudine tablet should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur [see Adverse Reactions ( 6.1)].

5.7 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including lamivudine and zidovudine tablet. 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- Barré 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.

5.8 Lipoatrophy

Treatment with zidovudine, a component of lamivudine and zidovudine tablets, has been associated with loss of subcutaneous fat. The incidence and severity of lipoatrophy are related to cumulative exposure. This fat loss, which is most evident in the face, limbs, and buttocks, may be only partially reversible and improvement may take months to years after switching to a non- zidovudine-containing regimen. Patients should be regularly assessed for signs of lipoatrophy during therapy with zidovudine-containing products, and if feasible, therapy should be switched to an alternative regimen if there is suspicion of lipoatrophy.

6 ADVERSE REACTIONS

The following adverse reactions are discussed 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 severe hepatomegaly with steatosis [see Boxed Warning, Warnings and Precautions ( 5.3)].

• 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 ( 5.5)].

• Exacerbation of anemia in HIV-1/HCV co-infected patients receiving ribavirin and zidovudine [see Warnings and Precautions ( 5.5)].

• Pancreatitis [see Warnings and Precautions ( 5.6)].

• Immune reconstitution syndrome [see Warnings and Precautions ( 5.7)].

• Lipoatrophy [see Warnings and Precautions ( 5.8)].

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 clinical practice.

Lamivudine plus Zidovudine Administered as Separate Formulations

In 4 randomized, controlled trials of EPIVIR 300 mg per day plus RETROVIR 600 mg per day, the following selected adverse reactions and laboratory abnormalities were observed (Tables 1 and 2).
Table 1. Selected Clinical Adverse Reactions (Greater than or Equal to 5% Frequency) in 4 Controlled Clinical Trials with EPIVIR 300 mg per day and RETROVIR 600 mg per day

Adverse Reaction	EPIVIR plus RETROVIR (n = 251)
Body as a whole
Headache	35%
Malaise & fatigue	27%
Fever or chills	10%
** Digestive**
Nausea Diarrhea	33% 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 2,613 adult subjects (0.3%) who received EPIVIR in controlled clinical trials [see Warnings and Precautions ( 5.6)].

Selected laboratory abnormalities observed during therapy are listed in Table 2.

Table 2. Frequencies of Selected Laboratory Abnormalities among Adults in 4 Controlled Clinical Trials of EPIVIR 300 mg per day plus RETROVIR 600 mg per day****a

Test (Abnormal Level)	EPIVIR plus RETROVIR % (n)
Neutropenia (ANC <750/mm 3)	7.2% (237)
Anemia (Hgb <8 g/dL)	2.9% (241)
Thrombocytopenia (platelets <50,000/mm 3)	0.4% (240)
ALT (>5.0 x ULN)	3.7% (241)
AST (>5.0 x ULN)	1.7% (241)
Bilirubin (>2.5x 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

The following adverse reactions have been identified during postmarketing use. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole
Redistribution/accumulation of body fat [see Warnings and Precautions ( 5.8)].

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 exacerbations of hepatitis B [see Boxed Warning, Warnings and Precautions ( 5.3), ( 5.4), ( 5.6)].

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.

7 DRUG INTERACTIONS

7.1 Zidovudine

Agents Antagonistic with Zidovudine

Concomitant use of zidovudine with the following drugs should be avoided since an antagonistic relationship has been demonstrated in vitro:

• Stavudine

• Doxorubicine

• Nucleoside analogues, e.g., ribavirin

Hematologic/Bone Marrow Suppressive/Cytotoxic Agents

Coadministration with the following drugs may increase the hematologic toxicity of zidovudine:

• Ganciclovir

• Interferon alfa

• Ribavirin

• Other bone marrow suppressive or cytotoxic agents

7.2 Lamivudine

Sorbitol
Coadministration of single doses of lamivudine and sorbitol resulted in a sorbitol dose-dependent reduction in lamivudine exposures. When possible, avoid use of sorbitol-containing medicines with lamivudine-containing medicines [see Clinical Pharmacology ( 12.3)].

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 10 times (mice) and 58 times (rats) the human exposures at the recommended dose of 300 mg.

Zidovudine: 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 per kg per day in mice and 80, 220, and 600 mg per kg per day in rats. The doses in mice were reduced to 20, 30, and 40 mg per kg per day after Day 90 because of treatment-related anemia, whereas in rats only the high dose was reduced to 450 mg per kg per day on Day 91 and then to 300 mg per kg per day on Day 279.

In mice, 7 late-appearing (after 19 months) vaginal neoplasms (5 non- metastasizing 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), non-metastasizing vaginal squamous cell carcinomas occurred in animals given the highest dose. No vaginal tumors occurred at the low or middle dose in rats. No other drug- related tumors were observed in either sex of either species.

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.

Mutagenicity
Lamivudine: Lamivudine was mutagenic in an L5178Y mouse lymphoma assay and clastogenic in a cytogenetic assay using cultured human lymphocytes. Lamivudine was not mutagenic in a microbial mutagenicity assay, in an in vitro 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 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.

Impairment of Fertility
Lamivudine: Lamivudine did not affect male or female fertility in rats at doses up to 4,000 mg per kg per day, associated with concentrations approximately 42 times (male) or 63 times (female) higher than the concentrations (C max) in humans at the dose of 300 mg.

Zidovudine: Zidovudine, administered to male and female rats at doses up to 450 mg per kg per day, which is 7 times the recommended adult dose (300 mg twice daily) based on body surface area, had no effect on fertility based on conception rates.

14 CLINICAL STUDIES

One lamivudine and zidovudine 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

The NUCB3007 (CAESAR) trial 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 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 1,816 HIV-1-infected adults with 25 to 250 (median 122) CD4 cells per mm 3 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 trial was 12 months. Results are summarized in Table 5.

Table 5. Number of Subjects (%) with at Least 1 HIV-1 Disease-Progression Event or Death

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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%)

aAn 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 per mm 3 (median in the treated group: 560 cells per mm 3) 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 trial 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 trial, 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.