Generic name: abacavir sulfate, lamivudine and zidovudine
Dosage form: tablet
Drug class:  Antiviral combinations

WARNING: HYPERSENSITIVITY REACTIONS, HEMATOLOGIC TOXICITY, MYOPATHY, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, and EXACERBATIONS OF HEPATITIS B

Hypersensitivity Reactions

Serious and sometimes fatal hypersensitivity reactions, with multiple organ involvement, have occurred with abacavir, a component of Abacavir, Lamivudine and Zidovudine Tablets. Patients who carry the HLA-B*5701 allele are at a higher risk of a hypersensitivity reaction to abacavir; although, hypersensitivity reactions have occurred in patients who do not carry the HLA-B*5701 allele [see WARNINGS AND PRECAUTIONS ( 5.1 )].

Abacavir, Lamivudine and Zidovudine Tablets are contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients [see CONTRAINDICATIONS ( 4 ), WARNINGS AND PRECAUTIONS ( 5.1 )]. All patients should be screened for the HLA-B*5701 allele prior to initiating therapy with Abacavir, Lamivudine and Zidovudine Tablets or reinitiation of therapy with Abacavir, Lamivudine and Zidovudine Tablets, unless patients have a previously documented HLA-B*5701 allele assessment. Discontinue Abacavir, Lamivudine and Zidovudine Tablets immediately if a hypersensitivity reaction is suspected, regardless of HLA-B*5701 status and even when other diagnoses are possible [see CONTRAINDICATIONS ( 4 ), WARNINGS AND PRECAUTIONS ( 5.1 )].

Following a hypersensitivity reaction to Abacavir, Lamivudine and Zidovudine Tablets, NEVER restart Abacavir, Lamivudine and Zidovudine Tablets or any other abacavir-containing product because more severe symptoms, including death, can occur within hours. Similar severe reactions have also occurred rarely following the reintroduction of abacavir-containing products in patients who have no history of abacavir hypersensitivity [see WARNINGS AND PRECAUTIONS ( 5.1 )].

Hematologic Toxicity

Zidovudine, a component of Abacavir, Lamivudine and Zidovudine Tablets, has been associated with hematologic toxicity, including neutropenia and severe anemia, particularly in patients with advanced Human Immunodeficiency Virus (HIV-1) disease [see WARNINGS AND PRECAUTIONS ( 5.2 )].

Myopathy

Prolonged use of zidovudine has been associated with symptomatic myopathy [see WARNINGS AND PRECAUTIONS ( 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 abacavir, lamivudine, and zidovudine (components of Abacavir, Lamivudine and Zidovudine Tablets). Discontinue Abacavir, Lamivudine and Zidovudine Tablets if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur [see WARNINGS AND PRECAUTIONS ( 5.4 )].

Exacerbations of Hepatitis B

Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and HIV-1 and have discontinued lamivudine, a component of Abacavir, Lamivudine and Zidovudine Tablets. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue Abacavir, Lamivudine and Zidovudine Tablets and are co-infected with HIV-1 and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted [see WARNINGS AND PRECAUTIONS ( 5.5 )].

Indications and Usage for Abacavir, Lamivudine and Zidovudine Tablets

Abacavir, lamivudine and zidovudine tablet is indicated in combination with other antiretrovirals or alone for the treatment of human immunodeficiency virus type 1 (HIV-1) infection.

Limitations of Use:

• Limited data exist on the use of Abacavir, Lamivudine and Zidovudine Tablets alone in patients with higher baseline viral load levels (greater than 100,000 copies per mL) [see CLINICAL STUDIES ( 14 )] .

Abacavir, Lamivudine and Zidovudine Tablets Dosage and Administration

Screening for HLA-B*5701 Allele prior to Starting Abacavir, Lamivudine and Zidovudine Tablets

Screen for the HLA-B*5701 allele prior to initiating therapy with Abacavir, Lamivudine and Zidovudine Tablets [see  BOXED WARNING , WARNINGS AND PRECAUTIONS ( 5.1 )].

Recommended Dosage for Adults and Pediatric Patients Weighing at Least 40 kg

The recommended dosage of abacavir, lamivudine and zidovudine tablet is one tablet taken orally twice daily with or without food.

Not Recommended Due to Lack of Dosage Adjustment

Because abacavir, lamivudine and zidovudine tablet is a fixed-dose tablet and cannot be dose adjusted, abacavir, lamivudine and zidovudine tablet is not recommended for:

• pediatric patients who weigh less than 40 kg [see USE IN SPECIFIC POPULATIONS ( 8.4 )].
• patients with creatinine clearance less than 50 mL per minute [see USE IN SPECIFIC POPULATIONS ( 8.6 )].
• patients with mild hepatic impairment. Abacavir, lamivudine and zidovudine tablet is contraindicated in patients with moderate or severe hepatic impairment [see CONTRAINDICATIONS ( 4 ), USE IN SPECIFIC POPULATIONS ( 8.7 )] .

Dosage Forms and Strengths

Abacavir, Lamivudine and Zidovudine Tablets contain 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.

Contraindications

Abacavir, Lamivudine and Zidovudine Tablets are contraindicated in patients:

• who have the HLA-B*5701 allele [see WARNINGS AND PRECAUTIONS ( 5.1 )].
• with prior hypersensitivity reaction to abacavir [see WARNINGS AND PRECAUTIONS ( 5.1 )], lamivudine, or zidovudine.
• with moderate or severe hepatic impairment [see USE IN SPECIFIC POPULATIONS ( 8.7 )] .

Warnings and Precautions

Hypersensitivity Reactions

Serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, a component of Abacavir, Lamivudine and Zidovudine Tablets. These hypersensitivity reactions have included multi-organ failure and anaphylaxis and typically occurred within the first 6 weeks of treatment with abacavir (median time to onset was 9 days); although abacavir hypersensitivity reactions have occurred any time during treatment [see ADVERSE REACTIONS ( 6.1 )]. Patients who carry the HLA-B*5701 allele are at a higher risk of abacavir hypersensitivity reactions; although, patients who do not carry the HLA-B*5701 allele have developed hypersensitivity reactions. Hypersensitivity to abacavir was reported in approximately 206 (8%) of 2,670 patients in 9 clinical trials with abacavir-containing products where HLA-B*5701 screening was not performed. The incidence of suspected abacavir hypersensitivity reactions in clinical trials was 1% when subjects carrying the HLA-B*5701 allele were excluded. In any patient treated with abacavir, the clinical diagnosis of hypersensitivity reaction must remain the basis of clinical decision making.

Due to the potential for severe, serious, and possibly fatal hypersensitivity reactions with abacavir:

• All patients should be screened for the HLA-B*5701 allele prior to initiating therapy with Abacavir, Lamivudine and Zidovudine Tablets or reinitiation of therapy with Abacavir, Lamivudine and Zidovudine Tablets, unless patients have a previously documented HLA-B*5701 allele assessment.
• Abacavir, lamivudine, and zidovudine tablets are contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients.
• Before starting Abacavir, Lamivudine and Zidovudine Tablets, review medical history for prior exposure to any abacavir-containing product. NEVER restart Abacavir, Lamivudine and Zidovudine Tablets or any other abacavir-containing product following a hypersensitivity reaction to abacavir, regardless of HLA-B*5701 status.
• To reduce the risk of a life-threatening hypersensitivity reaction, regardless of HLA-B*5701 status, discontinue Abacavir, Lamivudine and Zidovudine Tablets immediately if a hypersensitivity reaction is suspected, even when other diagnoses are possible (e.g., acute onset respiratory diseases such as pneumonia, bronchitis, pharyngitis, or influenza; gastroenteritis; or reactions to other medications).
• If a hypersensitivity reaction cannot be ruled out, do not restart Abacavir, Lamivudine and Zidovudine Tablets or any other abacavir-containing products because more severe symptoms, which may include life-threatening hypotension and death, can occur within hours.
• If a hypersensitivity reaction is ruled out, patients may restart Abacavir, Lamivudine and Zidovudine Tablets. Rarely, patients who have stopped abacavir for reasons other than symptoms of hypersensitivity have also experienced life-threatening reactions within hours of reinitiating abacavir therapy. Therefore, reintroduction of Abacavir, Lamivudine and Zidovudine Tablets or any other abacavir-containing product is recommended only if medical care can be readily accessed.
• A Medication Guide and Warning Card that provide information about recognition of abacavir hypersensitivity reactions should be dispensed with each new prescription and refill.

Hematologic Toxicity/Bone Marrow Suppression

Zidovudine, a component of abacavir, lamivudine and zidovudine tablet, has been associated with hematologic toxicity including neutropenia and anemia, particularly in patients with advanced HIV-1 disease. Abacavir, Lamivudine and Zidovudine Tablets should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count less than 1,000 cells per mm3 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 Abacavir, Lamivudine and Zidovudine Tablets. Periodic blood counts are recommended for other HIV-1-infected patients. If anemia or neutropenia develops, dosage interruption may be needed.

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 Abacavir, Lamivudine and Zidovudine Tablets.

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 abacavir, lamivudine and zidovudine (components of Abacavir, Lamivudine and Zidovudine Tablets). 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 ZIAGEN® (abacavir), EPIVIR® (lamivudine), and RETROVIR® (zidovudine). Treatment with Abacavir, Lamivudine and Zidovudine Tablets 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).

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).

Use with Interferon- and Ribavirin-Based Regimens

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

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Abacavir, Lamivudine and Zidovudine Tablets. 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.

Lipoatrophy

Treatment with zidovudine, a component of Abacavir, 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.

Myocardial Infarction

Several prospective, observational, epidemiological studies have reported an association with the use of abacavir and the risk of myocardial infarction (MI). Meta-analyses of randomized, controlled clinical trials have observed no excess risk of MI in abacavir-treated subjects as compared with control subjects. To date, there is no established biological mechanism to explain a potential increase in risk. In totality, the available data from the observational studies and from controlled clinical trials show inconsistency; therefore, evidence for a causal relationship between abacavir treatment and the risk of MI is inconclusive.

As a precaution, the underlying risk of coronary heart disease should be considered when prescribing antiretroviral therapies, including abacavir, and action taken to minimize all modifiable risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, smoking).

Therapy-Experienced Patients

In clinical trials, subjects with prolonged prior nucleoside reverse transcriptase inhibitor (NRTI) exposure or who had HIV-1 isolates that contained multiple mutations conferring resistance to NRTIs had limited response to abacavir. The potential for cross-resistance between abacavir and other NRTIs should be considered when choosing new therapeutic regimens in therapy- experienced patients [see Microbiology ( 12.4 )].

Adverse Reactions

The following adverse reactions are discussed in other sections of the labeling:

• Serious and sometimes fatal hypersensitivity reactions [see  BOXED WARNING , WARNINGS AND PRECAUTIONS ( 5.1 )] .
• Hematologic toxicity, including neutropenia and anemia [see  BOXED WARNING , WARNINGS AND PRECAUTIONS ( 5.2 )] .
• Symptomatic myopathy [see  BOXED WARNING , WARNINGS AND PRECAUTIONS ( 5.3 )] .
• Lactic acidosis and severe hepatomegaly with steatosis [see  BOXED WARNING , WARNINGS AND PRECAUTIONS ( 5.4 )] .
• Exacerbations of hepatitis B [see BOXED WARNING , WARNINGS AND PRECAUTIONS ( 5.5 )] .
• Hepatic decompensation in patients co-infected with HIV-1 and hepatitis C [see WARNINGS AND PRECAUTIONS ( 5.6 )] .
• Exacerbation of anemia in HIV-1/HCV co-infected patients receiving ribavirin and zidovudine [see WARNINGS AND PRECAUTIONS ( 5.6 )] .
• Immune reconstitution syndrome [see WARNINGS AND PRECAUTIONS ( 5.7 )] .
• Lipoatrophy [see WARNINGS AND PRECAUTIONS ( 5.8 )] .
• Myocardial infarction [see WARNINGS AND PRECAUTIONS ( 5.9 )] .

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.

Serious and Fatal Abacavir-Associated Hypersensitivity Reactions

In clinical trials, serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, a component of Abacavir, Lamivudine and Zidovudine Tablets [see  BOXED WARNING , WARNINGS AND PRECAUTIONS ( 5.1 )]. These reactions have been characterized by 2 or more of the following signs or symptoms: (1) fever; (2) rash; (3) gastrointestinal symptoms (including nausea, vomiting, diarrhea, or abdominal pain); (4) constitutional symptoms (including generalized malaise, fatigue, or achiness); (5) respiratory symptoms (including dyspnea, cough, or pharyngitis). Almost all abacavir hypersensitivity reactions include fever and/or rash as part of the syndrome.

Other signs and symptoms have included lethargy, headache, myalgia, edema, arthralgia, and paresthesia. Anaphylaxis, liver failure, renal failure, hypotension, adult respiratory distress syndrome, respiratory failure, myolysis, and death have occurred in association with these hypersensitivity reactions. Physical findings have included lymphadenopathy, mucous membrane lesions (conjunctivitis and mouth ulcerations), and maculopapular or urticarial rash (although some patients had other types of rashes and others did not have a rash). There were reports of erythema multiforme. Laboratory abnormalities included elevated liver chemistries, elevated creatine phosphokinase, elevated creatinine, and lymphopenia, and abnormal chest x-ray findings (predominantly infiltrates, which were localized).

Additional Adverse Reactions with Use of Abacavir, Lamivudine and Zidovudine Tablets

Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a frequency greater than or equal to 5% during therapy with abacavir 300 mg twice daily, lamivudine 150 mg twice daily, and zidovudine 300 mg twice daily compared with indinavir 800 mg 3 times daily, lamivudine 150 mg twice daily, and zidovudine 300 mg twice daily from CNA3005 are listed in Table 1.

Five subjects receiving abacavir in CNA3005 experienced worsening of pre-existing depression compared to none in the indinavir arm. The background rates of pre-existing depression were similar in the 2 treatment arms.

Laboratory Abnormalities

Laboratory abnormalities in CNA3005 are listed in Table 2.

Other Adverse Events

In addition to adverse reactions in Tables 1 and 2, other adverse events observed in the expanded access program for abacavir were pancreatitis and increased GGT.

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.

Abacavir

Cardiovascular:

Myocardial infarction.

Skin:

Suspected Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving abacavir primarily in combination with medications known to be associated with SJS and TEN, respectively. Because of the overlap of clinical signs and symptoms between hypersensitivity to abacavir and SJS and TEN, and the possibility of multiple drug sensitivities in some patients, abacavir should be discontinued and not restarted in such cases. There have also been reports of erythema multiforme with abacavir use [see ADVERSE REACTIONS ( 6.1 )].

Abacavir, Lamivudine, and/or Zidovudine

Body as a Whole:

Redistribution/accumulation of body fat.

Cardiovascular:

Cardiomyopathy.

Digestive:

Stomatitis.

Endocrine and Metabolic:

Gynecomastia.

Gastrointestinal:

Anorexia and/or decreased appetite, abdominal pain, dyspepsia, oral mucosal pigmentation.

General:

Vasculitis, weakness.

Hemic and Lymphatic:

Aplastic anemia, anemia (including pure red cell aplasia and severe anemias progressing on therapy), lymphadenopathy, splenomegaly, thrombocytopenia.

Hepatic:

Lactic acidosis and hepatic steatosis [see WARNINGS AND PRECAUTIONS ( 5.4 )], elevated bilirubin, elevated transaminases, posttreatment exacerbations of hepatitis B [see WARNINGS AND PRECAUTIONS (5.5)].

Hypersensitivity:

Sensitization reactions (including anaphylaxis), urticaria.

Musculoskeletal:

Arthralgia, myalgia, muscle weakness, rhabdomyolysis.

Nervous:

Dizziness, paresthesia, peripheral neuropathy, seizures.

Psychiatric:

Insomnia and other sleep disorders.

Respiratory:

Abnormal breath sounds/wheezing.

Skin:

Alopecia, erythema multiforme, Stevens-Johnson syndrome.

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.

Riociguat

Coadministration with fixed-dose abacavir/dolutegravir/lamivudine resulted in increased riociguat exposure, which may increase the risk of riociguat adverse reactions [see Clinical Pharmacology ( 12.3 )]. The riociguat dose may need to be reduced. See full prescribing information for ADEMPAS (riociguat).

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 )].

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

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Abacavir, Lamivudine and Zidovudine Tablets during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Risk Summary

Available data from the APR show no difference in the overall risk of birth defects for abacavir, lamivudine, or zidovudine compared with the background rate for birth defects of 2.7% in the Metropolitan Atlanta Congenital Defects Program (MACDP) reference population [see Data]. The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks’ gestation. The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The background risk for major birth defects and miscarriage for the indicated population is unknown.

Hyperlactatemia, which may be due to mitochondrial dysfunction, has been reported in infants with in utero exposure to zidovudine-containing products. These events were transient and asymptomatic in most cases. There have been few reports of developmental delay, seizures, and other neurological disease. However, a causal relationship between these events and exposure to zidovudine-containing products in utero or peri-partum has not been established (see Data).

In animal reproduction studies, oral administration of abacavir to pregnant rats during organogenesis resulted in fetal malformations and other embryonic and fetal toxicities at exposures 35 times the human exposure (AUC) at the recommended clinical daily dose. However, no adverse developmental effects were observed following oral administration of abacavir to pregnant rabbits during organogenesis, at exposures approximately 9 times the human exposure (AUC) at the recommended clinical dose. Oral administration of lamivudine to pregnant rabbits during organogenesis resulted in embryolethality at systemic exposure (AUC) similar to the recommended clinical dose; however, no adverse development effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (Cmax) 35 times the recommended clinical dose. Administration of oral zidovudine to female rats prior to mating and throughout gestation resulted in embryotoxicity at doses that produced systemic exposure (AUC) approximately 33 times higher than exposure at the recommended clinical dose. However, no embryotoxicity was observed after oral administration of zidovudine to pregnant rats during organogenesis at doses that produced systemic exposure (AUC) approximately 117 times higher than exposures at the recommended clinical dose. Administration of oral zidovudine to pregnant rabbits during organogenesis resulted in embryotoxicity at doses that produced systemic exposure (AUC) approximately 108 times higher than exposure at the recommended clinical dose. However, no embryotoxicity was observed at doses that produced systemic exposure (AUC) approximately 23 times higher than exposures at the recommended clinical dose (see Data).

Data

Human Data:

Abacavir

Based on prospective reports to the APR of exposures to abacavir during pregnancy resulting in live births (including over 1,300 exposed in the first trimester and over 1,300 exposed in the second/third trimester), there was no difference between the overall risk of birth defects for abacavir compared with the background birth defect rate of 2.7% in a U.S. reference population of the MACDP. The prevalence of defects in live births was 3.2% (95% CI: 2.3% to 4.3%) following first trimester exposure to abacavir-containing regimens and 2.9% (95% CI: 2.1% to 4%) following second/third trimester exposure to abacavir-containing regimens.

Abacavir has been shown to cross the placenta and concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery [see CLINICAL PHARMACOLOGY ( 12.3 )].

Lamivudine

Based on prospective reports to the APR of of exposures to lamivudine during pregnancy resulting in live births (including over 5300 exposed in the first trimester and over 7,400 exposed in the second/third trimester), there was no difference between the overall risk of birth defects for lamivudine compared with the background birth defect rate of 2.7% in a U.S. reference population of the MACDP. The prevalence of birth defects in live births was 3.1% (95% CI: 2.7% to 3.6%) following first trimester exposure to lamivudine-containing regimens and 2.9% (95% CI: 2.5% to 3.3%) following second/third trimester exposure to lamivudine-containing regimens..

Lamivudine pharmacokinetics were studied in pregnant women during 2 clinical trials conducted in South Africa. The trials assessed pharmacokinetics in 16 women at 36 weeks’ gestation using 150 mg lamivudine twice daily with zidovudine, 10 women at 38 weeks’ gestation using 150 mg lamivudine twice daily with zidovudine, and 10 women at 38 weeks’ gestation using lamivudine 300 mg twice daily without other antiretrovirals. These trials were not designed or powered to provide efficacy information. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. In a subset of subjects, amniotic fluid specimens were collected following natural rupture of membranes and confirmed that lamivudine crosses the placenta in humans. Based on limited data at delivery, median (range) amniotic fluid concentrations of lamivudine were 3.9 (1.2 to 12.8)–fold greater compared with paired maternal serum concentration (n = 8).

Zidovudine

Based on prospective reports to the APR of exposures to zidovudine during pregnancy resulting in live births (including over 4,200 exposed in the first trimester and over 9,700 exposed in the second/third trimester), there was no difference between the overall risk of birth defects for zidovudine compared with the background birth defect rate of 2.7% in a U.S. reference population of the MACDP. The prevalence of birth defects in live births was 3.2% (95% CI: 2.7% to 3.8%) following first trimester exposure to zidovudine-containing regimens and 2.8% (95% CI: 2.5% to 3.1%) following second/third trimester exposure to zidovudine-containing regimens.

A randomized, double-blind, placebo-controlled trial was conducted in HIV-1-infected pregnant women to determine the utility of zidovudine for the prevention of maternal-fetal HIV-1 transmission. Zidovudine treatment during pregnancy reduced the rate of maternal-fetal HIV-1 transmission from 24.9% for infants born to placebo-treated mothers to 7.8% for infants born to mothers treated with zidovudine. There were no differences in pregnancy-related adverse events between the treatment groups. Of the 363 neonates that were evaluated, congenital abnormalities occurred with similar frequency between neonates born to mothers who received zidovudine and neonates born to mothers who received placebo. The observed abnormalities included problems in embryogenesis (prior to 14 weeks) or were recognized on ultrasound before or immediately after initiation of trial drug. See full prescribing information for RETROVIR® (zidovudine) and COMBIVIR® (lamivudine and zidovudine).

Zidovudine has been shown to cross the placenta and concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery [see CLINICAL PHARMACOLOGY ( 12.3 )].

There have been reports of mild, transient elevations in serum lactate levels, which may be due to mitochondrial dysfunction, in neonates and infants exposed in utero or peri-partum to zidovudine-containing products. There have been few reports of developmental delay, seizures, and other neurological disease. However, a causal relationship between these events and exposure to zidovudine-containing products in utero or peri-partum has not been established. The clinical relevance of transient elevations in serum lactate is unknown.

Animal Data:

Abacavir

Abacavir was administered orally to pregnant rats (at 100, 300, and 1,000 mg per kg per day) and rabbits (at 125, 350, or 700 mg per kg per day) during organogenesis (on Gestation Days 6 through 17 and 6 through 20, respectively). Fetal malformations (increased incidences of fetal anasarca and skeletal malformations) or developmental toxicity (decreased fetal body weight and crown-rump length) were observed in rats at doses up to 1,000 mg per kg per day, resulting in exposures approximately 35 times the human exposure (AUC) at the recommended daily dose. No developmental effects were observed in rats at 100 mg per kg per day, resulting in exposures (AUC) 3.5 times the human exposure at the recommended daily dose. In a fertility and early embryo-fetal development study conducted in rats (at 60, 160, or 500 mg per kg per day), embryonic and fetal toxicities (increased resorptions, decreased fetal body weights) or toxicities to the offspring (increased incidence of stillbirth and lower body weights) occurred at doses up to 500 mg per kg per day. No developmental effects were observed in rats at 60 mg per kg per day, resulting in exposures (AUC) approximately 4 times the human exposure at the recommended daily dose. Studies in pregnant rats showed that abacavir is transferred to the fetus through the placenta. In pregnant rabbits, no developmental toxicities and no increases in fetal malformations occurred at up to the highest dose evaluated, resulting in exposures (AUC) approximately 9 times the human exposure at the recommended dose.

Lamivudine

Lamivudine was administered orally to pregnant rats (at 90, 600, and 4,000 mg per kg per day) and rabbits (at 90, 300, and 1,000 mg per kg per day and at 15, 40, and 90 mg per kg per day) during organogenesis (on Gestation Days 7 through 16 [rat] and 8 through 20 [rabbit]). No evidence of fetal malformations due to lamivudine was observed in rats and rabbits at doses producing plasma concentrations (Cmax) approximately 35 times higher than human exposure at the recommended daily dose. Evidence of early embryolethality was seen in the rabbit at systemic exposures (AUC) similar to those observed in humans, but there was no indication of this effect in the rat at plasma concentrations (Cmax) 35 times higher than human exposure at the recommended daily dose. Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta. In the fertility/pre-and postnatal development study in rats, lamivudine was administered orally at doses of 180, 900, and 4,000 mg per kg per day (from prior to mating through postnatal Day 20). In the study, development of the offspring, including fertility and reproductive performance, was not affected by maternal administration of lamivudine.

Zidovudine

A study in pregnant rats (at 50, 150, or 450 mg per kg per day starting 26 days prior to mating through Gestation to postnatal Day 21) showed increased fetal resorptions at doses that produced systemic exposures (AUC) approximately 33 times higher than exposure at the recommended daily human dose (300 mg twice daily). However, in an oral embryo-fetal development study in rats (at 125, 250, or 500 mg per kg per day on Gestation Days 6 through 15), no fetal resorptions were observed at doses that produced systemic exposure (AUC) approximately 117 times higher than exposures at the recommended daily human dose. An oral embryo-fetal development study in rabbits (at 75, 150, or 500 mg per kg per day on gestation Days 6 through 18) showed increased fetal resorptions at the 500-mg-per-kg-per-day dose which produced systemic exposures (AUC) approximately 108 times higher than exposure at the recommended daily human dose; however, no fetal resorptions were noted at doses up to 150 mg per kg per day, which produced systemic exposure (AUC) approximately 23 times higher than exposures at the recommended daily human dose. These oral embryo-fetal development studies in the rat and rabbit revealed no evidence of fetal malformations with zidovudine. In another developmental toxicity study, pregnant rats (dosed at 3,000 mg per kg per day from Days 6 through 15 of gestation) showed marked maternal toxicity and an increased incidence of fetal malformations at exposures greater than 300 times the recommended daily human dose based on AUC. However, there were no signs of fetal malformations at doses up to 600 mg per kg per day.

Lactation

Risk Summary

The Centers for Disease Control and Prevention recommends that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Abacavir, lamivudine and zidovudine are present in human milk. There is no information on the effects of abacavir, lamivudine and zidovudine on the breastfed infant or the effects of the drug on milk production. Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving Abacavir, Lamivudine and Zidovudine Tablets.

Pediatric Use

Abacavir, lamivudine and zidovudine tablet is not recommended in children who weigh less than 40 kg because it is a fixed-dose tablet that cannot be adjusted for these patient populations [see DOSAGE AND ADMINISTRATION ( 2.3 )].

Therapy-Experienced Pediatric Trial

A randomized, double-blind trial, CNA3006, compared ZIAGEN® plus lamivudine and zidovudine versus lamivudine and zidovudine in pediatric subjects, most of whom were extensively pretreated with nucleoside analogue antiretroviral agents. Subjects in this trial had a limited response to abacavir.

Geriatric Use

Clinical trials of abacavir, lamivudine, and zidovudine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of Abacavir, Lamivudine and Zidovudine Tablets in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see CLINICAL PHARMACOLOGY ( 12.3 )].

Patients with Impaired Renal Function

Abacavir, lamivudine and zidovudine tablet is not recommended for patients with creatinine clearance less than 50 mL per min because abacavir, lamivudine and zidovudine tablet is a fixed-dose combination and the dosage of the individual components cannot be adjusted. If a dose reduction of the lamivudine or zidovudine components of abacavir, lamivudine and zidovudine tablet is required for patients with renal impairment then the individual components should be used [see DOSAGE AND ADMINISTRATION ( 2.3 ), CLINICAL PHARMACOLOGY ( 12.3 )].

Patients with Impaired Hepatic Function

Abacavir, lamivudine and zidovudine tablet is a fixed-dose combination and the dosage of the individual components cannot be adjusted. If a dose reduction of abacavir, a component of abacavir, lamivudine and zidovudine tablet, is required for patients with mild hepatic impairment (Child-Pugh Class A), then the individual components should be used [see CLINICAL PHARMACOLOGY ( 12.3 )].

The safety, efficacy, and pharmacokinetic properties of abacavir have not been established in patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment; therefore, Abacavir, Lamivudine and Zidovudine Tablets are contraindicated in these patients [see CONTRAINDICATIONS ( 4 )].

Zidovudine is primarily eliminated by hepatic metabolism and zidovudine concentrations are increased in patients with impaired hepatic function, which may increase the risk of hematologic toxicity. Frequent monitoring of hematologic toxicities is advised.

Overdosage

There is no known specific treatment for overdose with Abacavir, Lamivudine and Zidovudine Tablets. If overdose occurs, the patient should be monitored and standard supportive treatment applied as required.

Abacavir

It is not known whether abacavir can be removed by peritoneal dialysis or hemodialysis.

Lamivudine

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.

Zidovudine

Acute overdoses of zidovudine have been reported in pediatric patients and adults. These involved exposures up to 50 grams. No specific symptoms or signs have been identified following acute overdosage with zidovudine apart from those listed as adverse events such as fatigue, headache, vomiting, and occasional reports of hematological disturbances. Patients recovered without permanent sequelae. Hemodialysis and peritoneal dialysis appear to have a negligible effect on the removal of zidovudine, while elimination of its primary metabolite, 3′- azido-3′-deoxy-5′-O-β-D-glucopyranuronosylthymidine (GZDV), is enhanced.

Abacavir, Lamivudine and Zidovudine Tablets Description

Abacavir, Lamivudine and Zidovudine Tablets contain the following 3 synthetic nucleoside analogues: abacavir (ZIAGEN®), lamivudine (also known as EPIVIR® or 3TC), and zidovudine (also known as RETROVIR®, azidothymidine, or ZDV) with inhibitory activity against HIV-1.

Abacavir, Lamivudine and Zidovudine Tablets are for oral administration. Each film-coated tablet contains the active ingredients 300 mg of abacavir as abacavir sulfate, 150 mg of lamivudine, and 300 mg of zidovudine, and the inactive ingredients crospovidone, magnesium stearate, microcrystalline cellulose, povidone, and yellow ferric oxide. The tablets are coated with a film opadry green that is made of FD&C blue no. 2, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide and yellow ferric oxide.

Abacavir Sulfate

The chemical name of abacavir sulfate is (1S,cis)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol sulfate (salt) (2:1). Abacavir sulfate is the enantiomer with 1S, 4R absolute configuration on the cyclopentene ring. It has a molecular formula of (C14H18N6O)2·H2SO4 and a molecular weight of 670.74 g per mol. It has the following structural formula:

Abacavir sulfate is a white to off-white powder and soluble in water. Dosages are expressed in terms of abacavir.

Lamivudine

The chemical name of lamivudine is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one, 0.2 hydrate. 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·0.2H2O and a molecular weight of 232.86 g per mol. It has the following structural formula:

Lamivudine is a white to off-white solid and is soluble in water.

Zidovudine

The chemical name of zidovudine is 3′-azido-3′-deoxythymidine. It has a molecular formula of C10H13N5O4 and a molecular weight of 267.24 g per mol. It has the following structural formula:

Zidovudine is a white to yellowish powder with a solubility of 20.1 mg/mL in water at 25°C.

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