Professional Information
Lamivudine and Zidovudine (Systemic)
VA CLASSIFICATION
Primary: AM840
Commonly used brand name(s): Combivir.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
Category:
Antiviral (systemic)—
Indications
General considerations
Lamivudine and zidovudine are nucleoside inhibitors of reverse transcriptase in human immunodeficiency virus (HIV). Monotherapy with lamivudine or combination therapy with lamivudine and zidovudine has resulted in HIV isolates that were phenotypically and genotypically resistant to lamivudine within 12 weeks. In some patients harboring zidovudine-resistant virus at baseline, phenotypic sensitivity to zidovudine was restored by 12 weeks of therapy with lamivudine and zidovudine. Combination therapy with lamivudine and zidovudine delayed the emergence of mutations conferring resistance to zidovudine. {01}
HIV strains resistant to both lamivudine and zidovudine have been isolated from patients after prolonged therapy with lamivudine and zidovudine. Dual resistance requires the presence of multiple mutations, the most essential of which appears to be at codon 333. The incidence of dual resistance and the duration of combination therapy required before dual resistance develops are unknown. {01}
Cross-resistance among certain reverse transcriptase inhibitors has been recognized. However, cross-resistance between lamivudine and zidovudine has not been reported. In some patients treated with lamivudine alone or in combination with zidovudine, HIV isolates have emerged with a mutation at codon 184, which confers resistance to lamivudine. In the presence of this mutation, cross-resistance to didanosine and zalcitabine has been seen in some patients; the clinical significance of this is unknown. In some patients treated with zidovudine plus didanosine or zalcitabine, HIV isolates that are resistant to multiple drugs, including lamivudine, have emerged. Multiple drug resistance has been observed in 2 of 39 patients receiving zidovudine and didanosine combination therapy for 2 years. {01}
Accepted
Human immunodeficiency virus (HIV) infection (treatment)—Lamivudine and zidovudine combination is indicated in the treatment of HIV infection. {01}
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Molecular weight—
Lamivudine: 229.3 {01}
Zidovudine: 267.2 {01}
Mechanism of action/Effect:
Lamivudine and zidovudine are synthetic nucleoside analogs of cytidine and thymidine, respectively. Intracellularly, lamivudine and zidovudine are phosphorylated to their respective active metabolites, lamivudine triphosphate and zidovudine triphosphate. HIV reverse transcriptase utilizes these nucleotide analogs when transcribing viral RNA to DNA. Incorporation of lamivudine triphosphate and zidovudine triphosphate into the growing chain of viral DNA results in termination of reverse transcription and thus inhibition of HIV reverse transcriptase. {01}
Lamivudine triphosphate is a weak inhibitor of mammalian DNA polymerases alpha and beta, and of mitochondrial DNA polymerase gamma. Zidovudine triphosphate is a weak inhibitor of mammalian DNA polymerase alpha and mitochondrial DNA polymerase gamma; it also has been reported to be incorporated into the DNA of cells in culture. {01}
Absorption:
Lamivudine—Rapidly absorbed {01}; oral bioavailability is 86 ± 16% (mean ± SD) {01}.
Zidovudine—Rapidly absorbed {01}; oral bioavailability is 64 ± 10% (mean ± SD) {01}.
Distribution:
Lamivudine—Vol D is approximately 1.3 ± 0.4 L per kg {01}.
Zidovudine—Vol D is approximately 1.6 ± 0.6 L per kg {01}.
Protein binding:
Lamivudine—Low to moderate (< 36%) {01}.
Zidovudine—Low to moderate (< 38%) {01}.
Biotransformation:
Lamivudine—In humans, the only known metabolite is the trans-sulfoxide metabolite, which accounts for approximately 5% of an oral dose after 12 hours {01}.
Zidovudine—The major metabolites are 3'-azido-3'-deoxy-5'- O-beta- D-glucopyranuronosylthymidine (GZDV) and 3'-amino-3'-deoxythymidine (AMT) {01}.
Half-life:
Elimination:
Lamivudine: 5 to 7 hours {01}.
Zidovudine: 0.5 to 3 hours {01}.
Elimination:
Lamivudine—Renal; approximately 70% of an intravenous dose is recovered unchanged in the urine {01}.
Zidovudine—Primarily hepatic {01}; following oral administration, unchanged zidovudine and GZDV account for 14% and 74% of the dose, respectively, recovered in the urine {01}.
Precautions to Consider
Carcinogenicity/Tumorigenicity
Lamivudine
Long-term carcinogenicity studies in mice and rats showed no evidence of carcinogenic potential at exposures of up to 10 and 58 times, respectively, those observed in humans at the recommended therapeutic dose. {01}
Zidovudine
In mice given 120 mg per kg of body weight (mg/kg) per day for 90 days then 40 mg/kg per day thereafter, seven vaginal neoplasms (five nonmetastasizing squamous cell carcinomas, one squamous cell papilloma, and one squamous polyp) occurred after 19 months of treatment. In mice given 60 mg/kg per day for 90 days then 30 mg/kg per day thereafter, one vaginal squamous cell papilloma occurred after 19 months of treatment. No vaginal tumors were found in mice given 30 mg/kg per day for 90 days then 20 mg/kg per day thereafter. No other medication-related tumors were observed in any of the male or female mice. At doses that produced tumors in mice, the estimated exposure of zidovudine (as measured by the area under the plasma concentration–time curve [AUC]) was approximately three times the estimated human exposure at the recommended therapeutic dose of 100 mg every 4 hours. {01}
In rats given 600 mg/kg per day for 90 days, then 450 mg/kg per day until day 279, then 300 mg/kg per day thereafter, two nonmetastasizing vaginal squamous cell carcinomas occurred after 20 months of treatment; no vaginal tumors were found in rats given 80 or 220 mg/kg per day. No other medication-related tumors were observed in any of the male or female rats. At doses that produced tumors in rats, the estimated exposure of zidovudine (as measured by the AUC) was approximately 24 times the estimated human exposure at the recommended therapeutic dose. {01}
Two transplacental carcinogenicity studies were conducted in mice. In the first study, pregnant mice were administered zidovudine at doses of 20 or 40 mg/kg per day from gestation day 10 through parturition and lactation with dosing continuing in offspring for 24 months postnatally. After 24 months, an increase in the incidence of vaginal tumors was noted in the offspring of mice receiving 40 mg/kg per day with no increase in the incidence of any other tumors in male or female offspring. In the second study, pregnant mice were administered zidovudine at maximum tolerated doses of 12.5 or 25 mg per day (approximately 1000 or 450 mg/kg of nonpregnant or term body weight, respectively) from days 12 through 18 of gestation. There was an increase in the number of tumors in the liver, lung, and female reproductive tracts in the offspring of mice receiving the higher dose of zidovudine. {01}
Mutagenicity
Lamivudine:
Lamivudine was mutagenic in the L5178Y/TK +/- mouse lymphoma assay and clastogenic in a cytogenetic assay using cultured human lymphocytes. Lamivudine was not mutagenic in a microbial mutagenicity screen, an in vitro cell transformation assay, the rat micronucleus test, a rat bone marrow cytogenetic assay, or the unscheduled DNA synthesis test in rat liver. {01}
Zidovudine:
Zidovudine was mutagenic in the L5178Y/TK +/- mouse lymphoma assay, an in vitro cell transformation assay, and mouse and rat micronucleus tests after repeated doses, and clastogenic in a cytogenetic assay using cultured human lymphocytes. Zidovudine was not mutagenic in rats given a single dose in a cytogenetic study. {01}
Pregnancy/Reproduction
Fertility—
Lamivudine
At doses of up to 130 times the usual adult human dose (on a body surface area basis), lamivudine administered to male and female rats showed no evidence of impairing fertility and had no effect on the survival, growth, or development of offspring to weaning. {01}
Zidovudine
At doses of up to seven times the usual adult human dose (on a body surface area basis), zidovudine administered to male and female rats had no effects on fertility. {01}
Pregnancy—
Adequate and well-controlled studies of lamivudine and zidovudine combination have not been done in humans. However, zidovudine has been shown to cross the placenta. {01}
Lamivudine
Studies in rats and rabbits revealed no evidence of teratogenicity at doses of 130 and 60 times, respectively, the usual adult human dose (on a body surface area basis). Early embryo lethality was observed in rabbits at doses similar to those produced by the usual adult human dose and higher; embryo lethality was not observed in rats administered doses of up to 130 times the usual adult human dose. Lamivudine crosses the placenta in rats and rabbits. {01}
Zidovudine
Studies in rats and rabbits revealed no evidence of teratogenicity at doses of up to 500 mg/kg per day. Zidovudine was embryotoxic or fetotoxic in rats given 150 or 450 mg/kg per day and in rabbits given 500 mg/kg per day. In rats, 3000 mg/kg per day (resulting in peak plasma concentrations of 350 times the peak human plasma concentration) caused marked maternal toxicity and an increase in the incidence of fetal malformations. {01}
FDA Pregnancy Category C {01}.
Note: To monitor maternal-fetal outcomes of pregnant women exposed to lamivudine and zidovudine combination and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling (800) 722-9292, ext. 39437.
Breast-feeding
Zidovudine is distributed into breast milk; it is not known whether lamivudine is distributed into breast milk. The Centers for Disease Control and Prevention recommend that HIV-infected mothers do not breast-feed their infants to avoid potential postnatal transmission of HIV. {01}
Pediatrics
Lamivudine and zidovudine combination should not be administered to children younger than 12 years of age because the fixed-dose combination product cannot be adjusted {01}.
Adolescents
Lamivudine and zidovudine combination should not be administered to patients who weigh less than 50 kg because the fixed-dose combination product cannot be adjusted {01}.
Geriatrics
Appropriate studies on the relationship of age to the effects of lamivudine and zidovudine combination have not been performed in the geriatric population, and dose selection should be done with caution. Elderly patients are more likely to have age related problems such as decreased hepatic, renal or cardiac function, and concomitant diseases or other drug therapy.{02}
Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
Note: No drug interaction studies have been conducted using lamivudine and zidovudine combination {01}.
Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
Atovaquone{01} or
Fluconazole{01} or
Methadone{01} or
Nelfinavir{01} or
Probenicid{01} or
Ritonavir{01} or
Trimethoprim and sulfamethoxazole combination{01} or
Valproic acid{01} (concurrent use of lamivudine with nelfinavir or trimethoprim and sulfamethoxazole combination increases the area under the plasma concentration–time curve [AUC] of lamivudine {01}; no dosing modifications are necessary {01})
(concurrent use of zidovudine with atovaquone, fluconazole, methadone, probenecid, or valproic acid increases the AUC of zidovudine {01}; concurrent use with nelfinavir or ritonavir decreases the AUC of zidovudine {01}; no dosing modifications are necessary {01})
» Ganciclovir{01} or
» Interferons, alpha{01} or
» Bone marrow depressants, other{01} (see Appendix II ) (concurrent use of bone marrow depressing agents with zidovudine may increase the hematologic toxicity of zidovudine {01}; caution should be used when bone marrow depressants are administered concurrently with lamivudine and zidovudine combination {01})
» Lamivudine{01} or
» Zidovudine{01} (lamivudine and zidovudine combination is a fixed-dose product {01}; concurrent use of either lamivudine or zidovudine with the combination product is not recommended {01})
Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
With physiology/laboratory test values
» Alanine aminotransferase (ALT [SGPT]){01} and
Amylase{01} and
Aspartate aminotransferase (AST [SGOT]){01} (serum values may be increased {01})
Bilirubin{01} (serum concentrations may be increased {01})
» Hemoglobin{01} (concentration may be decreased {01})
» Neutrophils{01} and
Platelets{01} (counts may be decreased {01})
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).
Except under special circumstances, this medication should not be used when the following medical problems exist:
» Hypersensitivity to lamivudine or zidovudine{01}
» Renal function impairment{01} (reduction of the dosages of lamivudine and zidovudine is recommended for patients with renal function impairment {01}; therefore, patients with creatinine clearance £ 50 mL per minute should not receive lamivudine and zidovudine combination {01})
Risk-benefit should be considered when the following medical problems exist
» Bone marrow depression{01} (lamivudine and zidovudine combination should be used with caution in patients with bone marrow compromise evidenced by granulocyte count < 1000 cells per cubic millimeter or hemoglobin < 9.5 grams per deciliter {01})
» Hepatic function impairment{01} or
» Hepatitis B virus infection{01} (caution should be used when administering lamivudine and zidovudine combination to patients with known risk factors for hepatic dysfunction {01}; lamivudine and zidovudine combination therapy should be discontinued in patients who develop clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity {01})
(some patients with human immunodeficiency virus [HIV] infection who have chronic liver disease due to hepatitis B virus infection experienced clinical or laboratory evidence of recurrent hepatitis upon discontinuation of lamivudine {01}; consequences may be more severe in patients with decompensated hepatic disease {01})
Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):
» Complete blood counts (CBCs){01} (frequent blood counts are strongly recommended in patients with advanced HIV disease who are treated with lamivudine and zidovudine combination {01}; periodic blood counts are recommended in HIV-infected patients and patients with asymptomatic or early HIV disease {01})
Side/Adverse Effects
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of antiretroviral nucleoside analogs alone or in combination, including lamivudine and zidovudine. A majority of these effects have occurred in women. {01}
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Those indicating need for medical attention
Incidence more frequent
Anemia {01}(pale skin; unusual tiredness or weakness)
neutropenia {01}(chills; fever; sore throat)
Incidence less frequent
Hepatotoxicity {01}(abdominal pain, severe; fever; nausea; skin rash; unusual tiredness or weakness; vomiting; yellow eyes or skin)—more frequent in women
myopathy or myositis {01}(muscle tenderness and weakness)
neuropathy {01}(burning, tingling, numbness or pain in the hands, arms, feet, or legs)
Incidence rare
Pancreatitis {01}(abdominal pain, severe; nausea; vomiting)
Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
Headache {01}
nausea {01}
Incidence less frequent
Abdominal pain {01}
anorexia {01}(decreased appetite)
coughing {01}
diarrhea {01}
dizziness {01}
insomnia {01}(trouble in sleeping)
skin rash {01}
Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).
Clinical effects of overdose
For lamivudine, one case of an adult ingesting 6 grams has been reported. There were no clinical signs or symptoms noted, and hematologic tests remained normal. {01}
For zidovudine, acute overdoses in children and adults ingesting up to 50 grams have been reported. Nausea and vomiting were consistently noted among these cases. Other reported occurrences included confusion, dizziness, drowsiness, headache, lethargy, and one report of a grand mal seizure. Hematologic changes were transient, and all patients recovered. {01}
Treatment of overdose
To enhance elimination—It is not known whether lamivudine can be removed by hemodialysis or peritoneal dialysis. Hemodialysis and peritoneal dialysis have a negligible effect on the removal of zidovudine. However, either process may be used to enhance the removal of the primary metabolite of zidovudine (GZDV). {01}
Supportive care—Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.
Patient Consultation
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):
Before using this medication
» Conditions affecting use, especially:
Hypersensitivity to lamivudine or zidovudine
Pregnancy—Zidovudine crosses the placenta
Breast-feeding—Zidovudine is distributed into breast milk; it is recommended that HIV-infected mothers do not breast-feed their infants to avoid potential postnatal transmission of HIV
Use in children—Lamivudine and zidovudine combination is not recommended for use in children younger than 12 years of age
Use in adolescents—
Lamivudine and zidovudine combination is not recommended for use in patients who weigh less than 50 kg
Other medications, especially alpha interferons, ganciclovir, lamivudine, other bone marrow depressants, or zidovudine
Other medical problems, especially bone marrow depression, hepatic function impairment, hepatitis B virus infection, or renal function impairment
Proper use of this medication
» Importance of not taking more medication than prescribed; importance of not discontinuing medication without checking with physician
» Importance of not missing doses and of taking at evenly spaced times
Not sharing medication with others
» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses
» Proper storage
Precautions while using this medication
» Regular visits to physician for blood tests
» Importance of not taking other medications concurrently without checking with physician
Side/adverse effects
Signs of potential side effects, especially anemia, neutropenia, hepatotoxicity, myopathy or myositis, neuropathy, and pancreatitis
General Dosing Information
May be taken with or without food {01}.
Bioequivalence information
One lamivudine and zidovudine combination tablet is bioequivalent to 150 mg lamivudine and 300 mg zidovudine; given two times a day, this combination tablet is an alternative dosing regimen to lamivudine 150 mg two times a day plus zidovudine 600 mg per day in divided doses {01}.
Oral Dosage Forms
LAMIVUDINE AND ZIDOVUDINE TABLETS
Usual adult and adolescent dose
Human immunodeficiency virus (HIV) infection
Adults and adolescents 50 kg of body weight and over: Oral, 150 mg of lamivudine and 300 mg of zidovudine two times a day {01}.
Adults and adolescents up to 50 kg of body weight: Use is not recommended {01}.
Usual pediatric dose
Use is not recommended {01}.
Usual geriatric dose
Dose selection for elderly patients should be cautious due to the greater frequency of geriatric-specific problems.{02}
Strength(s) usually available
U.S.—
150 mg of lamivudine and 300 mg of zidovudine (Rx) [Combivir]{01}
Packaging and storage:
Store between 2 and 30 ºC (36 and 86 ºF). {01}
Developed: 11/14/1997
Revised: 03/14/2001
References
- Combivir package insert (Glaxo Wellcome—US), New 9/97, Rec 10/97.
- Product Information: Combivir®, lamivudine and zidovudine. Glaxo Wellcome, Research Triangle Park, NC (PI Revised 10/2000) PI Reviewed 3/2001.
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