Abacavir, Lamivudine and ZidovudineTablets

Name: Abacavir, Lamivudine and ZidovudineTablets

Drug Interactions

Abacavir

Methadone

In a trial of 11 HIV-1-infected subjects receiving methadone-maintenance therapy with 600 mg of ZIAGEN® twice daily (twice the currently recommended dose), oral methadone clearance increased [see CLINICAL PHARMACOLOGY (12.3)]. This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients.

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
  • Doxorubicin
  • 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

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity

Abacavir: 

Abacavir was administered orally at 3 dosage levels to separate groups of mice and rats in 2-year carcinogenicity studies. Results showed an increase in the incidence of malignant and non-malignant tumors. Malignant tumors occurred in the preputial gland of males and the clitoral gland of females of both species, and in the liver of female rats. In addition, non-malignant tumors also occurred in the liver and thyroid gland of female rats.  These observations were made at systemic exposures in the range of 6 to 32 times the human exposure at the recommended dose of 600 mg.

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.

Two transplacental carcinogenicity studies were conducted in mice. One study administered zidovudine at doses of 20 mg per kg per day or 40 mg per kg per day from gestation Day 10 through parturition and lactation with dosing continuing in offspring for 24 months postnatally. At these doses, exposures were approximately 3 times the estimated human exposure at the recommended doses. After 24 months at the 40-mg-per-kg-per-day dose, an increase in incidence of vaginal tumors was noted with no increase in tumors in the liver or lung or any other organ in either gender. These findings are consistent with results of the standard oral carcinogenicity study in mice, as described earlier. A second study administered zidovudine at maximum tolerated doses of 12.5 mg per day or 25 mg per day (approximately 1,000 mg per kg nonpregnant body weight or approximately 450 mg per kg of term body weight) to pregnant mice from Days 12 through 18 of gestation. There was an increase in the number of tumors in the lung, liver, and female reproductive tracts in the offspring of mice receiving the higher dose level of zidovudine.

Mutagenicity

Abacavir: 

Abacavir induced chromosomal aberrations both in the presence and absence of metabolic activation in an in vitro cytogenetic study in human lymphocytes. Abacavir was mutagenic in the absence of metabolic activation, although it was not mutagenic in the presence of metabolic activation in an L5178Y mouse lymphoma assay. Abacavir was clastogenic in males and not clastogenic in females in an in vivo mouse bone marrow micronucleus assay. Abacavir was not mutagenic in bacterial mutagenicity assays in the presence and absence of metabolic activation.

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

Abacavir:

Abacavir did not affect male or female fertility in rats at a dose associated with exposures (AUC) approximately 3.3 times (male) or 4.1 times (female) those in humans at the clinically recommended dose.

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 (Cmax) 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.

Animal Toxicology and/or Pharmacology

Myocardial degeneration was found in mice and rats following administration of abacavir for 2 years. The systemic exposures were equivalent to 7 to 24 times the expected systemic exposure in humans at a dose of 600 mg. The clinical relevance of this finding has not been determined.

How Supplied/Storage and Handling

Abacavir, lamivudine and zidovudine is available as tablets. Each tablet contains 300 mg of abacavir as abacavir sulfate, 150 mg of lamivudine, and 300 mg of zidovudine. The tablets are blue-green colored, oval shaped, biconvex, film-coated, debossed with "LU" on one side and "N51" on the other side. They are packaged as follows:

Bottles of 60 Tablets                           NDC 68180-286-07

Bottles of 100 Tablets                         NDC 68180-286-01

Bottles of 500 Tablets                         NDC 68180-286-02

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

For Healthcare Professionals

Applies to abacavir / lamivudine / zidovudine: oral tablet

General

Many of the side effects listed occurred commonly in patients with abacavir hypersensitivity (e.g., nausea, vomiting, diarrhea, fever, lethargy, rash).[Ref]

Hypersensitivity

Common (1% to 10%): Hypersensitivity reaction

Abacavir, lamivudine, and/or zidovudine:
-Postmarketing reports: Sensitization reactions (including anaphylaxis)

Abacavir:
-Common (1% to 10%): Hypersensitivity reactions (including fever, rash [maculopapular, urticarial], fatigue, nausea, vomiting, diarrhea, abdominal pain, pharyngitis, malaise, achiness, dyspnea, cough, lethargy, headache, myalgia, arthralgia, myolysis, edema, abnormal chest X-ray findings [mainly localized infiltrates], paresthesia, anaphylaxis, hepatitis, liver failure, renal failure, hypotension, sore throat, adult respiratory distress syndrome, respiratory failure, death, lymphadenopathy, mucous membrane lesions [conjunctivitis, mouth ulceration], erythema multiforme, elevated liver function tests, elevated creatine phosphokinase, elevated creatinine, lymphopenia)[Ref]

Serious and sometimes fatal hypersensitivity reactions have been reported with abacavir. Such reactions have included multi-organ failure and anaphylaxis and usually occurred within the first 6 weeks of abacavir therapy (median onset: 9 to 11 days); however, abacavir hypersensitivity reactions have occurred any time during therapy.

Patients with the human leukocyte antigen subtype B*5701 (HLA-B*5701) allele are at higher risk of abacavir hypersensitivity reactions; however, such reactions have occurred in patients without the HLA-B*5701 allele. Abacavir hypersensitivity was reported in about 8% of patients in 9 clinical trials with abacavir-containing products where patients were not screened for the HLA-B*5701 allele; incidence of suspected abacavir hypersensitivity reactions was 1% in clinical trials where HLA-B*5701 carriers were excluded.

Abacavir hypersensitivity reactions have been characterized by at least 2 of the following key signs/symptoms: (1) fever; (2) rash; (3) gastrointestinal symptoms (including nausea, vomiting, diarrhea, abdominal pain); (4) constitutional symptoms (including generalized malaise, fatigue, achiness); (5) respiratory symptoms (including dyspnea, cough, pharyngitis). Almost all reactions have included fever and/or rash (usually maculopapular or urticarial); however, reactions also reported without fever or rash. Signs/symptoms reported in at least 10% of patients with hypersensitivity reaction have included rash, nausea, vomiting, diarrhea, abdominal pain, dyspnea, cough, fever, fatigue/lethargy, malaise, headache, elevated liver function tests, and myalgia. Other signs/symptoms of hypersensitivity have included mouth ulceration, sore throat, adult respiratory distress syndrome, respiratory failure, edema, lymphadenopathy, hypotension, conjunctivitis, anaphylaxis, paresthesia, lymphopenia, hepatitis, liver failure, myolysis, arthralgia, elevated creatine phosphokinase, elevated creatinine, renal failure, abnormal chest x-ray findings (mainly infiltrates, which were localized), and death.

Symptoms of abacavir hypersensitivity reaction worsened with continued therapy and generally resolved when abacavir was discontinued. Restarting abacavir after a hypersensitivity reaction has resulted in more severe symptoms within hours and included life-threatening hypotension and death. Rarely, life-threatening reactions have occurred within hours after restarting abacavir in patients who stopped it for reasons other than symptoms of hypersensitivity (or who stopped it with only 1 key symptom of hypersensitivity).[Ref]

Gastrointestinal

Very common (10% or more): Nausea (up to 52%), nausea and vomiting (up to 22%), diarrhea (up to 15%)
Common (1% to 10%): Abdominal distension, abdominal discomfort and pain, gaseous symptoms, dyspeptic symptoms, constipation
Uncommon (0.1% to 1%): Dry mouth/hyposalivation
Frequency not reported: Abdominal cramps

Abacavir, lamivudine, and/or zidovudine:
-Postmarketing reports: Abdominal pain, oral mucosal pigmentation, stomatitis, dyspepsia

Abacavir:
-Common (1% to 10%): Nausea, vomiting, diarrhea
-Rare (0.01% to 0.1%): Pancreatitis

Lamivudine:
-Common (1% to 10%): Nausea, vomiting, diarrhea, abdominal pain, upper abdominal pain
-Rare (0.01% to 0.1%): Elevated serum amylase, pancreatitis
-Frequency not reported: Oral ulcerations and lesions

Zidovudine:
-Very common (10% or more): Nausea
-Common (1% to 10%): Vomiting, abdominal pain, diarrhea
-Uncommon (0.1% to 1%): Flatulence
-Rare (0.01% to 0.1%): Oral mucosa pigmentation, dyspepsia, pancreatitis[Ref]

Pancreatitis was observed in the expanded access program for abacavir.[Ref]

Other

Very common (10% or more): Malaise and fatigue (up to 29%)
Common (1% to 10%): Temperature regulation disturbance (fever and/or chills), pain, ear/nose/throat infections

Abacavir, lamivudine, and/or zidovudine:
-Postmarketing reports: Weakness

Abacavir:
-Common (1% to 10%): Fever, lethargy, fatigue

Lamivudine:
-Common (1% to 10%): Fatigue, malaise, fever
-Frequency not reported: Drug-resistant hepatitis B virus (HBV)

Zidovudine:
-Common (1% to 10%): Malaise
-Uncommon (0.1% to 1%): Fever, generalized pain, asthenia
-Rare (0.01% to 0.1%): Chills, chest pain, influenza-like syndrome

The emergence of lamivudine-resistant HBV has been reported in HIV-1/HBV-coinfected patients using lamivudine-containing antiretroviral regimens.

Dermatologic

Suspected Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients using abacavir primarily in combination with agents known to be associated with SJS and TEN, respectively.

Cases of erythema multiforme, SJS, or TEN have been reported very rarely when abacavir hypersensitivity could not be ruled out.

Bluish or brownish-black discoloration of nails has developed during the first 1 or 2 months of zidovudine therapy and usually disappeared within 2 months if the drug was discontinued. Discoloration has occurred as longitudinal streaks or transverse bands.[Ref]

Very common (10% or more): Disorders of sweat and sebum (primarily dry skin; up to 19%)
Common (1% to 10%): Skin rashes, pruritus

Abacavir, lamivudine, and/or zidovudine:
-Postmarketing reports: Alopecia, erythema multiforme, Stevens-Johnson syndrome, urticaria

Abacavir:
-Common (1% to 10%): Rash (without systemic symptoms)
-Very rare (less than 0.01%): Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme
-Frequency not reported: Sweet's syndrome

Lamivudine:
-Common (1% to 10%): Rash, alopecia

Zidovudine:
-Uncommon (0.1% to 1%): Rash, pruritus
-Rare (0.01% to 0.1%): Nail and skin pigmentation, urticaria, sweating
-Frequency not reported: Nail discoloration, nailbed hyperpigmentation, leukocytoclastic vasculitis (with eosinophilia and fever)[Ref]

Nervous system

Very common (10% or more): Headache (up to 18%)
Common (1% to 10%): Dizziness, taste impairment

Abacavir, lamivudine, and/or zidovudine:
-Postmarketing reports: Paresthesia, peripheral neuropathy, seizures, dizziness

Abacavir:
-Common (1% to 10%): Headache

Lamivudine:
-Common (1% to 10%): Headache
-Very rare (less than 0.01%): Peripheral neuropathy, paresthesia

Zidovudine:
-Very common (10% or more): Headache
-Common (1% to 10%): Dizziness
-Rare (0.01% to 0.1%): Paresthesia, somnolence, convulsions, taste disturbance, syncope
-Frequency not reported: Generalized seizures, status epilepticus, vertigo, Wernicke's syndrome[Ref]

Hepatic

Common (1% to 10%): Elevated ALT, abnormal liver function tests

Abacavir, lamivudine, and/or zidovudine:
-Postmarketing reports: Hepatic steatosis, elevated bilirubin, elevated transaminases, posttreatment exacerbations of hepatitis B

Abacavir:
-Frequency not reported: Elevated GGT

Lamivudine:
-Uncommon (0.1% to 1%): Elevated liver enzymes (AST, ALT)
-Rare (0.01% to 0.1%): Hepatitis
-Frequency not reported: Hepatic decompensation

Zidovudine:
-Common (1% to 10%): Elevated liver enzyme levels in blood, elevated bilirubin levels in blood
-Rare (0.01% to 0.1%): Liver disorders (e.g., severe hepatomegaly with steatosis)
-Frequency not reported: Acute hepatic failure[Ref]

Elevated ALT (greater than 5 times the upper limit of normal [5 x ULN]) has been reported in 6% of patients.

Lactic acidosis and severe hepatomegaly with steatosis (including fatal cases) have been reported with the use of nucleoside analogs.

Elevated GGT was observed in the expanded access program for abacavir.

Hepatic decompensation (some fatal) has been reported in patients coinfected with HIV-1 and hepatitis C virus (HCV) receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin.

Severe acute exacerbations of hepatitis have been reported in patients with hepatitis B after discontinuation of lamivudine.

One patient with preexisting hepatitis B developed acute hepatic failure 2 weeks after starting zidovudine therapy.[Ref]

Hematologic

Common (1% to 10%): Neutropenia, decreased WBCs

Abacavir, lamivudine, and/or zidovudine:
-Postmarketing reports: Aplastic anemia, anemia (including pure red cell aplasia and severe anemias progressing on therapy), lymphadenopathy, thrombocytopenia, splenomegaly

Abacavir:
-Frequency not reported: Agranulocytosis

Lamivudine:
-Uncommon (0.1% to 1%): Neutropenia, anemia, thrombocytopenia
-Very rare (less than 0.01%): Pure red cell aplasia

Zidovudine:
-Common (1% to 10%): Anemia, neutropenia, leukopenia
-Uncommon (0.1% to 1%): Thrombocytopenia, pancytopenia (with marrow hypoplasia)
-Rare (0.01% to 0.1%): Pure red cell aplasia
-Very rare (less than 0.01%): Aplastic anemia
-Frequency not reported: Hematologic toxicity (including neutropenia, severe anemia), exacerbation of anemia[Ref]

Neutropenia (less than 750/mm3) has been reported in 5% of patients.

Agranulocytosis has been reported after the addition of abacavir to a multi-drug regimen.

Occasionally, neutropenia and anemia reported with lamivudine were severe.

Zidovudine has been associated with hematologic toxicity (including neutropenia and severe anemia), particularly in patients with advanced HIV-1 disease. Anemia, neutropenia, and leukopenia were reported more often with higher doses (1200 to 1500 mg/day) and in patients with advanced HIV disease (especially with poor bone marrow reserve at baseline) and particularly in those with CD4 cell counts less than 100/mm3. These hematological effects were generally observed after 4 to 6 weeks of therapy. Incidence of neutropenia increased in patients with low neutrophil counts, hemoglobin levels, and serum vitamin B12 levels at baseline.

Exacerbation of anemia has been reported in HIV-1/HCV-coinfected patients using zidovudine and ribavirin.[Ref]

Metabolic

Common (1% to 10%): Feeding problems (primarily anorexia/loss of appetite), hypertriglyceridemia, hyperamylasemia
Frequency not reported: Hyperglycemia

Abacavir, lamivudine, and/or zidovudine:
-Postmarketing reports: Hyperlactatemia (common), lactic acidosis (rare), anorexia/decreased appetite, redistribution/accumulation of body fat

Abacavir:
-Common (1% to 10%): Anorexia
-Frequency not reported: Lactic acidosis, hyperlactatemia, redistribution/accumulation of body fat

Lamivudine:
-Frequency not reported: Lactic acidosis, hyperlactatemia, redistribution/accumulation of body fat

Zidovudine:
-Common (1% to 10%): Anorexia
-Rare (0.01% to 0.1%): Lactic acidosis (without hypoxemia)
-Frequency not reported: Lactic acidosis, hyperlactatemia, redistribution/accumulation of body fat

Combination antiretroviral therapy:
-Frequency not reported: Redistribution/accumulation of body fat (including central obesity, dorsocervical fat enlargement, peripheral wasting, facial wasting, breast enlargement, "cushingoid appearance"), metabolic abnormalities (e.g., hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia, hyperlactatemia)[Ref]

Hypertriglyceridemia (greater than 750 mg/dL), hyperamylasemia (greater than 2 x ULN), and hyperglycemia (greater than 13.9 mmol/L) have been reported in 2%, 2%, and less than 1% of patients, respectively.

Lactic acidosis and severe hepatomegaly with steatosis (including fatal cases) have been reported with the use of nucleoside analogs.

Redistribution/accumulation of body fat has been reported with antiretroviral therapy; causality has not been established.[Ref]

Musculoskeletal

Elevated CPK (greater than 4 x ULN) has been reported in 7% of patients.

Myopathy and myositis (with pathological changes similar to that produced by HIV-1 disease) have been associated with prolonged zidovudine use.

In 1 zidovudine study, myalgias and elevated CPK occurred in 8% of treated patients with a CD4 cell count less than 200/mm3, and in none of the patients with higher CD4 cell counts. Dose reduction has not affected the course of myopathy, although drug discontinuation sometimes resulted in improvement of symptoms, generally within a month. Muscle biopsy has shown atrophic and sometimes necrotic fibers, ragged-red fibers, and large accumulations of mitochondrial and fibrillar sarcoplasmic inclusions.[Ref]

Common (1% to 10%): Elevated creatine phosphokinase (CPK), musculoskeletal pain, muscle pain

Abacavir, lamivudine, and/or zidovudine:
-Postmarketing reports: Myalgia, arthralgia, muscle weakness, rhabdomyolysis

Lamivudine:
-Common (1% to 10%): Arthralgia, muscle disorders
-Rare (0.01% to 0.1%): Rhabdomyolysis

Zidovudine:
-Common (1% to 10%): Myalgia
-Uncommon (0.1% to 1%): Myopathy
-Frequency not reported: Symptomatic myopathy, myositis

Combination antiretroviral therapy:
-Frequency not reported: Osteonecrosis[Ref]

Psychiatric

Common (1% to 10%): Sleep disorders, depressive disorders, anxiety
Frequency not reported: Worsening of preexisting depression

Abacavir, lamivudine, and/or zidovudine:
-Postmarketing reports: Insomnia, other sleep disorders

Lamivudine:
-Common (1% to 10%): Insomnia

Zidovudine:
-Common (1% to 10%): Insomnia
-Rare (0.01% to 0.1%): Anxiety, depression, loss of mental acuity
-Frequency not reported: Confusion, mania, grandiosity[Ref]

Respiratory

Common (1% to 10%): Viral respiratory infections

Abacavir, lamivudine, and/or zidovudine:
-Postmarketing reports: Abnormal breath sounds/wheezing

Lamivudine:
-Common (1% to 10%): Nasal symptoms, cough

Zidovudine:
-Uncommon (0.1% to 1%): Dyspnea
-Rare (0.01% to 0.1%): Cough

Immunologic

Frequency not reported: Immune reconstitution/reactivation syndrome, autoimmune disorders in the setting of immune reconstitution (e.g., Graves' disease, polymyositis, Guillain-Barre syndrome)

Renal

Frequency not reported: Renal signs/symptoms

Genitourinary

Frequency not reported: Dysuria

Zidovudine:
-Rare (0.01% to 0.1%): Urinary frequency

Cardiovascular

Abacavir, lamivudine, and/or zidovudine:
-Postmarketing reports: Cardiomyopathy, vasculitis

Abacavir:
-Postmarketing reports: Myocardial infarction (MI)

Zidovudine:
-Rare (0.01% to 0.1%): Cardiomyopathy, reversible congestive heart failure, vasodilation[Ref]

An observational study investigating the rate of MI in patients on combination antiretroviral therapy showed an increased risk of MI with the use of abacavir within the previous 6 months. A sponsor-conducted pooled analysis of clinical trials showed no excess risk of MI in abacavir-treated patients as compared with control subjects. Overall, available data from the observational cohort and from clinical trials were inconclusive.[Ref]

Endocrine

Abacavir, lamivudine, and/or zidovudine:
-Postmarketing reports: Gynecomastia

Zidovudine:
-Rare (0.01% to 0.1%): Gynecomastia[Ref]

Ocular

Zidovudine:
-Frequency not reported: Macular edema

At least 1 case of macular edema was deemed definitively associated with zidovudine in a patient with history of anterior uveitis secondary to syphilis.

Some side effects of abacavir / lamivudine / zidovudine may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Usual Adult Dose for Occupational Exposure

US Public Health Service working group recommendations: 1 tablet orally twice a day
Duration of therapy: 28 days, if tolerated

Comments:
-Only with expert consultation, as an alternative regimen for use as HIV postexposure prophylaxis
-Prophylaxis should be started as soon as possible, preferably within hours after exposure.
-The optimal duration of prophylaxis is unknown and may differ based on institution protocol.
-Current guidelines should be consulted for additional information.

Usual Pediatric Dose for HIV Infection

At least 40 kg: 1 tablet orally twice a day

Comments: Use of the individual components is recommended for patients less than 40 kg; the manufacturer product information for abacavir, lamivudine, and zidovudine should be consulted.

Use: In combination with other antiretroviral agents or alone, for the treatment of HIV-1 infection

Other Comments

Administration advice:
-May administer without regard to food

General:
-Screening for HLA-B*5701 allele recommended before starting this drug.
-Before starting this drug, medical history should be reviewed for prior exposure to any abacavir-containing product (to prevent reintroduction in patient with history of abacavir hypersensitivity).
-Limited data available on the use of this drug alone in patients with higher baseline viral load (more than 100,000 copies/mL)

Monitoring:
-Hematologic: Blood counts (frequently in patients with advanced HIV-1 disease; periodically in other HIV-1-infected patients)
-Hepatic: Hepatic function of HIV-1/HBV-coinfected patients with clinical and laboratory follow-up (for at least several months after stopping therapy)

Patient advice:
-Always read the Medication Guide and Warning Card (with information about abacavir hypersensitivity reaction) dispensed with each new and refill prescription; carry the Warning Card.
-Contact physician immediately if signs/symptoms of hypersensitivity develop; do not restart this or any other abacavir-containing product after a hypersensitivity reaction.
-If this drug is stopped for any reason besides hypersensitivity, do not restart it (or any other abacavir-containing product) without consulting physician; medical care must be readily accessible.

Abacavir / lamivudine / zidovudine Breastfeeding Warnings

ABACAVIR: Breast milk from 15 women and blood samples from 9 of their partially or exclusively breastfed infants were collected about 1 month postpartum; the mothers were using abacavir 300 mg twice a day for 53 to 182 days (with lamivudine and zidovudine). Breast milk was obtained right before a dose; whole breast milk abacavir levels averaged 0.057 mg/L (about 85% of maternal blood levels). Infant blood was obtained 11 to 17 hours after the last maternal dose and about 1 hour (range: 6 minutes to 35 hours) after the last breastfeeding; plasma abacavir levels were undetectable (less than 16 mcg/L) in 8 of 9 infants. LAMIVUDINE: Based on more than 200 mother/child pairs treated for HIV, serum lamivudine levels in breastfed infants of mothers treated for HIV are very low (less than 4% of maternal serum levels) and gradually decrease to undetectable levels by 24 weeks of age. Milk samples were obtained daily before breastfeeding. The milk lamivudine level averaged 1.2 mg/L (range: less than 0.5 to 6.1 mg/L) with 300 mg twice a day (n=10) and 0.9 mg/L (range: less than 0.5 to 8.2 mg/L) with 150 mg twice a day plus zidovudine (n=10). Milk samples from 20 women taking lamivudine 150 mg orally twice a day as part of combination antiretroviral therapy (cART) and serum levels from their infants were obtained at 2 or 5 months postpartum, about 4 hours (range: 1 to 8.5 hours) after the last dose. The drug level in breast milk averaged 1.8 mg/L and the infant serum lamivudine level averaged 28 mcg/L (range: less than 14 to 53 mcg/L). Breast milk from 15 women and blood samples from 24 of their partially or exclusively breastfed infants were collected about 1 month postpartum; the mothers were using lamivudine 150 mg twice a day for 53 to 182 days (with [abacavir or lopinavir-ritonavir] and zidovudine). Breast milk was obtained right before a dose; whole breast milk lamivudine levels averaged 0.14 mg/L (about 74% of maternal blood levels). Infant blood was obtained 11 to 18 hours after the last maternal dose and about 1 hour (range: 6 minutes to 35 hours) after the last breastfeeding. Plasma lamivudine levels were undetectable (less than 7 mcg/L) in all infant samples. Serum and breast milk from 58 mothers using lamivudine 150 mg twice a day (with nevirapine and zidovudine) and serum levels from their 58 infants were analyzed. Mothers started lamivudine at 34 to 36 weeks gestation and continued until 6 months postpartum; they were instructed to exclusively breastfeed for 5.5 months. Breast milk and serum samples were collected within 24 hours after delivery and at 2, 6, 14, and 24 weeks postpartum; breast milk was collected at various times after the prior dose. The breast milk lamivudine level averaged 1214 mcg/L (all visits). The infant dried blood spot lamivudine levels averaged 67 mcg/L at delivery, 32 mcg/L at week 2, 24 mcg/L at week 6, 20 mcg/L at week 14, and were not measurable (less than 16 mcg/L) at week 24 postpartum. A fully breastfed infant would receive 182 mcg/kg/day of lamivudine (estimated). Blood and milk samples were obtained from 40 women on postpartum prophylaxis (with lamivudine, nevirapine, and [zidovudine or stavudine]; doses not provided) once during the first 3 days postpartum and once at 7 days postpartum. Samples were collected after a dose at 5.3 hours (range: 0 to 99 hours) for the first sample and 6 hours (range: 4.3 to 20 hours) for the second sample. Breast milk lamivudine levels averaged 0.4 mg/L (n=20) for the first sample and 0.4 mg/L (n=30) for the second sample; these levels were 2.9 to 3.3 times the coinciding maternal serum levels. Mothers using lamivudine (dose not provided) as part of cART provided 47 breast milk and serum samples at 6, 12, and 24 weeks postpartum. The breast milk lamivudine levels at about 14 hours after the last dose averaged 510 (17 samples), 387 (17 samples), and 310 mcg/L (13 samples). Milk levels were about 2.6 times (interquartile range: 1.1 to 3.5 times) the maternal plasma levels; milk to plasma ratio was 2.96 in 49 patients in a related study (same authors). Infant serum levels measured about 14 hours after the last maternal dose averaged 13, 10, and 5 mcg/L at 6 (17 samples), 12 (17 samples), and 24 (13 samples) weeks of age, respectively, which was 6% of the maternal serum level. A total of 206 milk samples were obtained at birth, 1, 3, and/or 6 months postpartum from 66 mothers using lamivudine 150 mg twice a day as part of cART and 64 blood samples from their breastfed infants were analyzed at 1, 3, and/or 6 months postpartum; samples were collected at about 4.5 hours (range: 3.5 to 6 hours) after the prior maternal dose and about 30 minutes (range: 20 to 60 minutes) after nursing. Breast milk lamivudine level averaged 446 mcg/L (range: 269 to 683 mcg/L). Infant plasma lamivudine level averaged 18 mcg/L (range: 7 to 35 mcg/L), which averaged 2% (range: 0 to 4%) of the maternal serum level. In a continuation of this study, 65 breast milk samples (after the same dose at 1, 3, and 6 months postpartum) and 22 blood samples (from 17 breastfed infants [extent not provided] between 1 and 6 months) were collected for drug analysis; lamivudine levels averaged 684 mcg/L in breast milk and 29.2 mcg/L in infant blood. Unclear if some of the same patients from the first study were in the latter study. Mothers (n=30) starting lamivudine 150 mg orally twice a day (with zidovudine and lopinavir-ritonavir) at delivery provided plasma and breast milk samples at 6, 12, or 24 weeks postpartum (n=10 at each time). Maternal plasma and breast milk samples were collected about 14.9 hours after the prior evening dose, before the morning dose, and 2, 4, and 6 hours after the dose. Infant plasma samples were collected before the first maternal dose and at 2, 4, and 6 hours after the maternal dose. Breastfeeding was not restricted during the study. Detectable lamivudine levels (at least 10 mcg/L) were found in 107 of 121 breast milk samples and 107 of 115 infant plasma samples; breast milk level averaged 0.94 mg/L over the 6 hours and infant plasma level averaged 180 mcg/L. ZIDOVUDINE: After administration of a single 200 mg dose to 13 HIV-infected women, the mean zidovudine concentration was similar in human milk and serum. Milk samples were collected 1, 2, 4, and 6 hours after a single 200 mg oral dose in 6 women. Peak milk zidovudine level averaged 857 mcg/L (range: 472 to 1043 mcg/L) at 1 to 2 hours postdose in 4 women and an hour later in the others. At either 2 or 5 months postpartum, milk from 18 women using zidovudine 300 mg orally twice a day (as part of cART) and serum levels from their infants were analyzed; the infants were also receiving zidovudine 4 or 6 mg/kg orally 3 times a day (depending on age). Milk and serum samples were collected about 4 hours (range: 1 to 8.5 hours) after the last dose. Zidovudine level averaged 207 mcg/L in breast milk and 123 mcg/L (range: 14 to 3302 mcg/L) in infant serum. Blood and milk samples were obtained from 40 women on postpartum prophylaxis (with lamivudine, nevirapine, and zidovudine [or stavudine if hemoglobin less than 8 g/dL]; doses not provided) once during the first 3 days postpartum and once at 7 days postpartum. Samples were collected after a dose at 5.3 hours (range: 0 to 99 hours) for the first sample and 6 hours (range: 4.3 to 20 hours) for the second sample. Breast milk zidovudine levels averaged 130 mcg/L (n=11) for the first sample and 150 mcg/L (n=13) for the second sample; these levels were equal to the coinciding maternal serum levels. Serum and breast milk from 58 mothers using zidovudine 200 mg twice a day (with lamivudine and nevirapine) and serum levels from their 58 infants were analyzed. Mothers started zidovudine at 34 to 36 weeks gestation and continued until 6 months postpartum; they were instructed to exclusively breastfeed for 5.5 months. Breast milk and serum samples were collected within 24 hours after delivery and at 2, 6, 14, and 24 weeks postpartum; breast milk was collected at various times after the prior dose. The breast milk zidovudine level averaged 9 mcg/L (35 selected samples [from all visits]). The infant dried blood spot zidovudine level averaged 24 mcg/L at delivery (16 selected samples; 8 had quantifiable levels); zidovudine levels from 66 samples collected at 2, 6, 14, and 24 weeks postpartum were not measurable (less than 30 mcg/L). A total of 114 milk samples were obtained at birth, 1, 3, and/or 6 months postpartum from 38 mothers using zidovudine 300 mg twice a day as part of cART and 34 blood samples from their breastfed infants were analyzed at 1, 3, and/or 6 months postpartum; samples were collected at about 4.5 hours (range: 3.5 to 6 hours) after the prior maternal dose and about 30 minutes (range: 20 to 60 minutes) after nursing. Breast milk zidovudine level averaged 33 mcg/L (range: 5 to 117 mcg/L). Infant plasma zidovudine levels ranged from 0 to 2.5 mcg/L, which averaged 2% (range: 0 to 5%) of the maternal serum level. Breast milk samples from 15 women were collected about 1 month postpartum and blood samples from their partially or exclusively breastfed infants were collected about 1 month (n=24) and 3 months (n=9) postpartum; the mothers were using zidovudine 300 mg twice a day for 53 to 182 days (as part of cART). Breast milk was obtained right before a dose; whole breast milk zidovudine levels averaged 7 mcg/L. Infant blood was obtained at various times after the last maternal dose and about 1 hour (range: 6 minutes to 35 hours) after the last breastfeeding. Serum zidovudine levels were undetectable (less than 45 mcg/L) in all infant samples. Mothers (n=30) starting zidovudine 300 mg orally twice a day (with lamivudine and lopinavir-ritonavir) at delivery provided plasma and breast milk samples at 6, 12, or 24 weeks postpartum (n=10 at each time). Maternal plasma and breast milk samples were collected about 14.9 hours after the prior evening dose, before the morning dose, and 2, 4, and 6 hours after the dose. Infant plasma samples were collected before the first maternal dose and at 2, 4, and 6 hours after the maternal dose. Breastfeeding was not restricted during the study. Detectable zidovudine levels (at least 10 mcg/L) were found in 98 of 121 breast milk samples and 0 of 115 infant plasma samples; breast milk level averaged 0.2 mg/L over the 6 hours. In a study to prevent maternal-to-child transmission of HIV infection, pregnant women used zidovudine alone or highly-active antiretroviral therapy (HAART: zidovudine, lamivudine, and nevirapine). After delivery, all infants (some breastfed; others formula fed) received 1 month of zidovudine prophylaxis. At 1 month of age, 15.9% of infants exposed to HAART had neutropenia compared to 3.7% of those not exposed. Hematologic toxicity was transient and asymptomatic. No differences in hematologic toxicity (from 2 to 6 months postpartum) and no statistical difference in hepatic toxicity were observed between the breastfed and formula-fed infants. In another study for prevention of maternal-to-child transmission of HIV infection, rates of severe anemia were compared in 3 groups of infants who received zidovudine prophylaxis. Through 6 months of age, severe anemia was observed in 7.4% of breastfed infants whose mothers received HAART, 5.3% of breastfed infants whose mothers received only zidovudine, and 2.5% of formula-fed infants. In general, the anemia responded well to iron and multivitamin supplementation and zidovudine discontinuation.

Breastfeeding is not recommended during use of this drug; if replacement feeding is not an option, a different drug may be preferred. Excreted into human milk: Yes Comments: -The effects in the nursing infant are unknown; risk of neutropenia and severe anemia may increase with zidovudine-containing regimens. -The US CDC, American Academy of Pediatrics, and manufacturer advise HIV-infected women not to breastfeed to avoid postnatal transmission of HIV to a child who may not yet be infected. -Local guidelines should be consulted if replacement feeding is not an option.

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