Combivir Information
Combivir () Indications And Usage
Combivir () , a combination of two nucleoside analogues, is indicated in combination with other antiretrovirals for the treatment of HIV-1 infection.
Combivir () Dosage And Administration
The recommended oral dosage of scored Combivir () Tablets for pediatric patients who weigh greater than or equal to 30 kg and for whom a solid oral dosage form is appropriate is 1 tablet 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.
Combivir () Dosage Forms And Strengths
Combivir () 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).
Combivir () 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 () Warnings And Precautions
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 1,000 cells/mm or hemoglobin less than 9.5 g/dL .
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.
Posttreatment Exacerbations of Hepatitis:
Important Differences Among Lamivudine-Containing Products:
®
Emergence of Lamivudine-Resistant HBV:
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-1/HCV virologic suppression) was seen when ribavirin was coadministered with lamivudine or zidovudine 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. 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. Co-administration of ribavirin and zidovudine is not advised.
Combivir () Adverse Reactions
The following adverse reactions are discussed in greater detail in other sections of the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Lamivudine Plus Zidovudine Administered As Separate Formulations:
Pancreatitis was observed in 9 of the 2,613 adult patients (0.3%) who received EPIVIR in controlled clinical trials.
Selected laboratory abnormalities observed during therapy are listed in Table 2.
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 () .
Cardiovascular:
Endocrine and Metabolic:
Gastrointestinal:
General:
Hemic and Lymphatic:
Hypersensitivity:
Musculoskeletal:
Nervous:
Respiratory:
Skin:
Combivir () Drug Interactions
No drug interaction studies have been conducted using Combivir () Tablets .
Nucleoside Analogues Affecting DNA Replication:
Zidovudine:
Zidovudine:
Lamivudine:
[see Warnings and Precautions (5.5), Clinical Pharmacology (12.3)]
Lamivudine:
Combivir () Use In Specific Populations
Pregnancy Category C.
Fetal Risk Summary:
Antiretroviral Pregnancy Registry:
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).
Zidovudine pharmacokinetics were studied in a Phase 1 study of 8 women 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.
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 studies of Combivir () excretion in breast milk have been performed, lactation studies performed with lamivudine and zidovudine show that both drugs are excreted in human breast milk. Samples of breast milk obtained from 20 mothers receiving lamivudine monotherapy (300 mg twice daily) or combination therapy (150 mg lamivudine twice daily and 300 mg zidovudine twice daily) had measurable concentrations of lamivudine. In another study, after administration of a single dose of 200 mg zidovudine to 13 HIV-1-infected women, the mean concentration of zidovudine was similar in human milk and serum.
Combivir () Description
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.
Lamivudine is a white to off-white crystalline solid with a solubility of approximately 70 mg/mL in water at 20°C.
Zidovudine is a white to beige, odorless, crystalline solid with a solubility of 20.1 mg/mL in water at 25°C.
Combivir () Clinical Pharmacology
Lamivudine:
Zidovudine:
Effect of Food on Absorption of Combivir () :
Special Populations:
Combivir () :
Zidovudine:
Pediatric Patients:
Geriatric Patients:
Gender:
Zidovudine:
No drug interaction studies have been conducted using Combivir () Tablets. However, Table 4 presents drug interaction information for the individual components of Combivir () .
Lamivudine Plus Zidovudine:
Zidovudine:
Lamivudine:
Zidovudine:
HIV-1 strains resistant to both lamivudine and zidovudine have been isolated from patients 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:
Zidovudine:
Cross-Resistance:
Lamivudine Plus Zidovudine:
Lamivudine:
Zidovudine:
Combivir () Nonclinical Toxicology
Zidovudine:
In mice, 7 late-appearing (after 19 months) vaginal neoplasms (5 nonmetastasizing squamous cell carcinomas, 1 squamous cell papilloma, and 1 squamous polyp) occurred in animals given the highest dose. One late-appearing squamous cell papilloma occurred in the vagina of a middle-dose animal. No vaginal tumors were found at the lowest dose.
In rats, 2 late-appearing (after 20 months), nonmetastasizing vaginal squamous cell carcinomas occurred in animals given the highest dose. No vaginal tumors occurred at the low or middle dose in rats. No other drug-related tumors were observed in either sex of either species.
At doses that produced tumors in mice and rats, the estimated drug exposure (as measured by AUC) was approximately 3 times (mouse) and 24 times (rat) the estimated human exposure at the recommended therapeutic dose of 100 mg every 4 hours.
It is not known how predictive the results of rodent carcinogenicity studies may be for humans.
+/-
Zidovudine:
+/-
Zidovudine:
Lamivudine:
Zidovudine:
Combivir () Clinical Studies
There have been no clinical trials conducted with Combivir () . See 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.
Lamivudine Plus Zidovudine:
3
Combivir () 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 0173-0595-00).
Unit Dose Pack of 120 (NDC 0173-0595-02).
Combivir ()
