COMBIVIR®
(lamivudine/zidovudine)
Tablets

ZIDOVUDINE, ONE OF THE TWO ACTIVE INGREDIENTS IN COMBIVIR, HAS BEEN ASSOCIATED WITH HEMATOLOGIC TOXICITY INCLUDING NEUTROPENIA AND SEVERE ANEMIA, PARTICULARLY IN PATIENTS WITH ADVANCED HUMAN IMMUNODEFICIENCY VIRUS (HIV) DISEASE (SEE WARNINGS). PROLONGED USE OF ZIDOVUDINE HAS BEEN ASSOCIATED WITH SYMPTOMATIC MYOPATHY.

LACTIC ACIDOSIS AND SEVERE 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 (SEE WARNINGS).

SEVERE ACUTE EXACERBATIONS OF HEPATITIS B HAVE BEEN REPORTED IN PATIENTS WHO ARE CO-INFECTED WITH HEPATITIS B VIRUS (HBV) AND HIV 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 AND HBV. IF APPROPRIATE, INITIATION OF ANTI-HEPATITIS B THERAPY MAY BE WARRANTED (SEE WARNINGS).

COMBIVIR Tablets are combination tablets containing lamivudine and zidovudine. Lamivudine (EPIVIR^®, 3TC^®) and zidovudine (RETROVIR^®, azidothymidine, AZT, or ZDV) are synthetic nucleoside analogues with activity against HIV.

COMBIVIR Tablets are for oral administration. Each film-coated tablet contains 150 mg of lamivudine, 300 mg of zidovudine, and the inactive ingredients colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, and titanium dioxide.

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 70 mg/mL in water at 20°C.

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 25°C.

Cross-resistance has been observed among NRTIs.

COMBIVIR may be administered with or without food. The extent of lamivudine and zidovudine absorption (AUC) following administration of COMBIVIR with food was similar when compared to fasting healthy subjects (n = 24).

See PRECAUTIONS: Pregnancy.

See PRECAUTIONS: Nursing Mothers.

The pharmacokinetics of lamivudine and zidovudine have not been studied in patients over 65 years of age.

See PRECAUTIONS: Drug Interactions.

COMBIVIR is indicated in combination with other antiretrovirals for the treatment of HIV-1 infection.

COMBIVIR Tablets are contraindicated in patients with previously demonstrated clinically significant hypersensitivity to any of the components of the product.

COMBIVIR is a fixed-dose combination of lamivudine and zidovudine. Ordinarily, COMBIVIR should not be administered concomitantly with lamivudine, zidovudine, EPZICOM^™, a fixed-dose combination of abacavir and lamivudine, or TRIZIVIR^®, a fixed-dose combination of abacavir, lamivudine, and zidovudine.

The complete prescribing information for all agents being considered for use with COMBIVIR should be consulted before combination therapy with COMBIVIR is initiated.

COMBIVIR should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count <1,000 cells/mm³ or hemoglobin <9.5 g/dL (see ADVERSE REACTIONS).

Frequent blood counts are strongly recommended in patients with advanced HIV disease who are treated with COMBIVIR. For HIV-infected individuals and patients with asymptomatic or early HIV disease, periodic blood counts are recommended.

Lactic acidosis and severe 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).

Myopathy and myositis, with pathological changes similar to that produced by HIV disease, have been associated with prolonged use of zidovudine, and therefore may occur with therapy with COMBIVIR.

In clinical trials in non-HIV-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 treatment regimens to non-lamivudine-containing regimens in patients infected with both HIV 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.

In vitro 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/HCV virologic suppression) was seen when ribavirin was coadministered with lamivudine or zidovudine in HIV/HCV co-infected patients (see CLINICAL PHARMACOLOGY: Drug Interactions), hepatic decompensation (some fatal) has occurred in HIV/HCV co-infected patients receiving combination antiretroviral therapy for HIV and interferon alfa with or without ribavirin. Patients receiving interferon alfa with or without ribavirin and 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., Childs Pugh >6) (see the complete prescribing information for interferon and ribavirin).

Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in patients dually infected with HIV and HBV. In non-HIV-infected patients treated with lamivudine for chronic hepatitis B, emergence of lamivudine-resistant HBV has been detected and has been associated with diminished treatment response (see EPIVIR-HBV package insert for additional information). Emergence of hepatitis B virus variants associated with resistance to lamivudine has also been reported in HIV-infected patients who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus. Posttreatment exacerbations of hepatitis have also been reported (see WARNINGS).

Reduction of the dosages of lamivudine and zidovudine is recommended for patients with impaired renal function. Patients with creatinine clearance <50 mL/min should not receive COMBIVIR.

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.

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 system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.

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.

COMBIVIR is not a cure for HIV infection and patients may continue to experience illnesses associated with HIV infection, including opportunistic infections. Patients should be advised that the use of COMBIVIR has not been shown to reduce the risk of transmission of HIV to others through sexual contact or blood contamination. Patients should be advised of the importance of taking COMBIVIR exactly as it is prescribed.

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.

Pregnancy Category C.

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV infection. No specific studies of lamivudine and zidovudine excretion in breast milk after dosing with COMBIVIR have been performed. Lamivudine and zidovudine are excreted in human breast milk (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Nursing Mothers).A study in lactating rats administered 45 mg/kg of lamivudine showed that lamivudine concentrations in milk were slightly greater than those in plasma.

Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving COMBIVIR.

COMBIVIR should not be administered to pediatric patients less than 12 years of age because it is a fixed-dose combination that cannot be adjusted for this patient population.

Clinical studies 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 <50 mL/min; see PRECAUTIONS: Patients with Impaired Renal Function and DOSAGE AND ADMINISTRATION).

In 4 randomized, controlled trials of EPIVIR 300 mg per day plus RETROVIR 600 mg per day, the following selected clinical and laboratory adverse events were observed (see Tables 4 and 5).

Pancreatitis was observed in 3 of the 656 adult patients (<0.5%) who received EPIVIR in controlled clinical trials.

Selected laboratory abnormalities observed during therapy are uled in Table 5.

ULN = Upper limit of normal.

ANC = Absolute neutrophil count.

n = Number of patients assessed.

* Frequencies of these laboratory abnormalities were higher in patients with mild laboratory abnormalities at baseline.

In addition to adverse events reported from clinical trials, the following events 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.

There is no known antidote for COMBIVIR.

One case of an adult ingesting 6 grams 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.

Acute overdoses of zidovudine have been reported in pediatric patients and adults. These involved exposures up to 50 grams. The only consistent findings were nausea and vomiting. Other reported occurrences included headache, dizziness, drowsiness, lethargy, confusion, and 1 report 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, GZDV, is enhanced.

The recommended oral dose of COMBIVIR for adults and adolescents (at least 12 years of age) is 1 tablet (containing 150 mg of lamivudine and 300 mg of zidovudine) twice daily.

Because it is a fixed-dose combination, COMBIVIR should not be prescribed for patients requiring dosage adjustment such as those with reduced renal function (creatinine clearance <50 mL/min), patients with hepatic impairment, or patients experiencing dose-limiting adverse events.

COMBIVIR Tablets,containing 150 mg lamivudine and 300 mg zidovudine, are white, film-coated, modified-capsule-shaped tablets engraved with “GXFC3” on one side. They are available as follows:

60 Tablets/Bottle (NDC 0173-0595-00)

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

Unit Dose Pack of 120 (NDC 0173-0595-02)

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

GlaxoSmithKline

Research Triangle Park, NC 27709

Lamivudine is manufactured under agreement from

Shire Pharmaceuticals Group plc

Basingstoke, UK

©2006, GlaxoSmithKline. All rights reserved.

October 2006 RL-2315