Data from FDA - Curated by Toby Galbraith - Last updated 22 December 2016

Indication(s)

1 INDICATIONS AND USAGE Abacavir, lamivudine and zidovudine tablet, a combination of abacavir, lamivudine, and zidovudine, each nucleoside analogue HIV-1 reverse transcriptase inhibitors, is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.

(1) 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)].

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Advisory information

contraindications

4 CONTRAINDICATIONS Presence of HLA-B * 5701 allele.

(4) Prior hypersensitivity reaction to abacavir, lamivudine, or zidovudine (4) Moderate or severe hepatic impairment.

(4, 8.7) 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)].

Adverse reactions

6 ADVERSE REACTIONS The most commonly reported adverse reactions (incidence at least 10 %) in clinical trials were nausea, headache, malaise and fatigue, and nausea and vomiting.

(6.1) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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)].

Fat redistribution [see WARNINGS AND PRECAUTIONS (5.8)].

Myocardial infarction [see WARNINGS AND PRECAUTIONS (5.9)].

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug can not 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 Table 1.

Treatment-Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades 2 to 4, Greater than or Equal to 5 % Frequency) in Therapy-naive Adults (CNA3005) through 48 Weeks of Treatment Adverse Reaction ZIAGEN ® plus Lamivudine/Zidovudine (n = 262) Indinavir plus Lamivudine/

Zidovudine (n = 264) Nausea 19 % 17 % Headache 13 % 9 % Malaise and fatigue 12 % 12 % Nausea and vomiting 10 % 10 % Hypersensitivity reaction 8 % 2 % Diarrhea 7 % 5 % Fever and/or chills 6 % 3 % Depressive disorders 6 % 4 % Musculoskeletal pain 5 % 7 % Skin rashes 5 % 4 % Ear/nose/throat infections 5 % 4 % Viral respiratory infections 5 % 5 % Anxiety 5 % 3 % Renal signs/symptoms <1 % 5 % Pain (non-site-specific) <1 % 5 % 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.

Table 2.

Treatment-emergent Laboratory Abnormalities (Grades 3/4) in CNA3005 ULN = Upper limit of normal.

n = Number of subjects assessed.

Laboratory Parameter ZIAGEN plus Lamivudine/Zidovudine (n = 262) Indinavir plus Lamivudine/Zidovudine (n = 264) Elevated CPK (>4 x ULN) 18 (7 %) 18 (7 %) ALT (>5.0 x ULN) 16 (6 %) 16 (6 %) Neutropenia (<750/ mm3) 13 (5 %) 13 (5 %) Hypertriglyceridemia (>750 mg/dL) 5 (2 %) 3 (1 %) Hyperamylasemia (>2.0 x ULN) 5 (2 %) 1 (<1 %) Hyperglycemia (>13.9 mmol/L) 2 (<1 %) 2 (<1 %) Anemia (Hgb?6.9 g/dL) 0 (0 %) 3 (1 %) 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. 6.2 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 [see WARNINGS AND PRECAUTIONS (5.8)].

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.

Usage information

Dosing and administration

2 DOSAGE AND ADMINISTRATION Before initiating abacavir, lamivudine and zidovudine tablets, screen for the HLA-B * 5701 allele because abacavir, lamivudine and zidovudine tablets contains abacavir.

(2.1) Adults and pediatric patients weighing at least 40 kg: 1 tablet twice daily.

(2.2) Because abacavir, lamivudine and zidovudine tablet is a fixed-dose tablet and can not be dose adjusted, abacavir, lamivudine and zidovudine tablets are not recommended in patients requiring dosage adjustment or patients with hepatic impairment.

(2.3, 4) 2.1 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)].

2.2 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.

2.3 Not recommended Due to Lack of Dosage Adjustment Because abacavir, lamivudine and zidovudine tablet is a fixed-dose tablet and can not be dose adjusted, abacavir, lamivudine and zidovudine tablet is not recommended in: 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)].

Use in special populations

8 USE IN SPECIFIC POPULATIONS Lactation: Breastfeeding not recommended.

(8.2) 8.1 Pregnancy Teratogenic Effects Pregnancy Category C: There are no adequate and well-controlled studies of abacavir, lamivudine and zidovudine tablets in pregnant women.

Reproduction studies with abacavir, lamivudine, and zidovudine have been performed in animals (see Abacavir, Lamivudine, and Zidovudine sections below).

Abacavir, lamivudine and zidovudine tablets should be used during pregnancy only if the potential benefits outweigh the risks.

Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to abacavir, lamivudine and zidovudine tablets during pregnancy.

Physicians are encouraged to register patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263.

Abacavir: Studies in pregnant rats showed that abacavir is transferred to the fetus through the placenta.

Fetal malformations (increased incidences of fetal anasarca and skeletal malformations) and developmental toxicity (depressed fetal body weight and reduced crown-rump length) were observed in rats at a dose which produced 35 times the human exposure, based on AUC. Embryonic and fetal toxicities (increased resorptions, decreased fetal body weights) and toxicities to the offspring (increased incidence of stillbirth and lower body weights) occurred at half of the above-mentioned dose in separate fertility studies conducted in rats.

In the rabbit, no developmental toxicity and no increases in fetal malformations occurred at doses that produced 8.5 times the human exposure at the recommended dose based on AUC. Lamivudine: Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta.

Reproduction studies with orally administered lamivudine have been performed in rats and rabbits at doses producing plasma levels up to approximately 35 times that for the recommended adult HIV dose.

No evidence of teratogenicity due to lamivudine was observed.

Evidence of early embryolethality was seen in the rabbit at exposure levels similar to those observed in humans, but there was no indication of this effect in the rat at exposure levels up to 35 times those in humans.

Zidovudine: Reproduction studies with orally administered zidovudine in the rat and in the rabbit at doses up to 500 mg per kg per day revealed no evidence of teratogenicity with zidovudine.

Zidovudine treatment resulted in embryo/fetal toxicity as evidenced by an increase in the incidence of fetal resorptions in rats given 150 or 450 mg per kg per day and rabbits given 500 mg per kg per day.

The doses used in the teratology studies resulted in peak zidovudine plasma concentrations (after one-half of the daily dose) in rats 66 to 226 times, and in rabbits 12 to 87 times, mean steady-state peak human plasma concentrations (after one-sixth of the daily dose) achieved with the recommended daily dose (100 mg every 4 hours).

In an additional teratology study in rats, a dose of 3,000 mg per kg per day (very near the oral median lethal dose in rats of approximately 3,700 mg per kg) caused marked maternal toxicity and an increase in the incidence of fetal malformations.

This dose resulted in peak zidovudine plasma concentrations 350 times peak human plasma concentrations.

No evidence of teratogenicity was seen in this experiment at doses of 600 mg per kg per day or less.

Two rodent carcinogenicity studies were conducted [see NONCLINICAL TOXICOLOGY (13.1)].

8.2 Lactation The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.

Because of the potential for HIV-1 transmission mothers should be instructed not to breastfeed.

8.4 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 can not be adjusted for these patient populations [see DOSAGE AND ADMINISTRATION (2.2)].

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.

8.5 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)].

8.6 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 can not 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)].

8.7 Patients With Impaired Hepatic Function Abacavir, lamivudine and zidovudine tablet is a fixed-dose combination and the dosage of the individual components can not 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.

Pregnancy and lactation
8.2 Lactation The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Because of the potential for HIV-1 transmission mothers should be instructed not to breastfeed.

Interactions

7 DRUG INTERACTIONS Methadone: An increased methadone dose may be required in a small number of patients.

(7.1) Agents antagonistic with zidovudine: Concomitant use should be avoided (7.2).

Hematologic/bone marrow suppressive/cytotoxic agents: May increase the hematologic toxicity of zidovudine.

(7.2) 7.1 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.

7.2 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 Doxorubicine 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

More information

Category Value
Authorisation number ANDA202912
Agency product number 2T8Q726O95
Orphan designation No
Product NDC 57297-286
Date Last Revised 04-05-2016
Type HUMAN PRESCRIPTION DRUG
RXCUI 307650
Marketing authorisation holder LUPIN LIMITED
Warnings

WARNING:

RISK OF HYPERSENSITIVITY REACTIONS, HEMATOLOGIC TOXICITY, MYOPATHY, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY, EXACERBATIONS OF HEPATITIS B See full prescribing information for complete boxed warning.

Hypersensitivity Reactions Serious and sometimes fatal hypersensitivity reactions have occurred with abacavir-containing products.

(5.1) Hypersensitivity to abacavir is a multi-organ clinical syndrome.

(5.1) Patients who carry the HLA-B * 5701 allele are at a higher risk of experiencing a hypersensitivity reaction to abacavir.

(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.

(4) Discontinue abacavir, lamivudine and zidovudine tablets as soon as a hypersensitivity reaction is suspected.

Regardless of HLA-B * 5701 status, permanently discontinue abacavir, lamivudine and zidovudine tablets if hypersensitivity can not be ruled out, even when other diagnoses are possible.

(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.

(5.1) Hematologic Toxicity Hematologic toxicity, including neutropenia and anemia, has been associated with the use of zidovudine, a component of abacavir, lamivudine and zidovudine tablets.

(5.2) Myopathy Symptomatic myopathy associated with prolonged use of zidovudine.

(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.

(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 human immunodeficiency virus (HIV-1) and have discontinued lamivudine, a component of abacavir, lamivudine and zidovudine tablets.

Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis B treatment.

(5.5) WARNING:

HYPERSENSITIVITY REACTIONS, HEMATOLOGIC TOXICITY, MYOPATHY, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY, 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 and other antiretrovirals.

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)].

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