Data from FDA - Curated by Toby Galbraith - Last updated 23 February 2017

Licensing authority

FDA (Food and Drug Administration, USA)

Indication(s)

1 INDICATIONS AND USAGE Abacavir and Lamivudine tablets, in combination with other antiretroviral agents, are indicated for the treatment of human immunodeficiency virus type 1 (HIV?1) infection.

Abacavir and Lamivudine tablets, containing two nucleoside analogue HIV-1 reverse transcriptase inhibitors, are indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.

(1)

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Advisory information

contraindications

4 CONTRAINDICATIONS Abacavir and Lamivudine 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)] or lamivudine.

with moderate or severe hepatic impairment [see Use in Specific Populations (8.7)].

•Presence of HLA-B * 5701 allele.

(4) •Prior hypersensitivity reaction to abacavir or lamivudine.

(4) •Moderate or severe hepatic impairment.

(4, 8.7)

Adverse reactions

6 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)].

•Lactic acidosis and severe hepatomegaly with steatosis [see Boxed Warning, Warnings and Precautions (5.2)].

•Exacerbations of hepatitis B [see Boxed Warning, Warnings and Precautions (5.3)].

•Hepatic decompensation in patients co-infected with HIV-1 and Hepatitis C [see Warnings and Precautions (5.4)].

•Immune reconstitution syndrome [see Warnings and Precautions (5.5)].

•Fat redistribution [see Warnings and Precautions (5.6)].

•Myocardial infarction [see Warnings and Precautions (5.7)].

The most commonly reported adverse reactions of at least moderate intensity (incidence greater than 5 %) in an adult HIV-1 clinical trial were drug hypersensitivity, insomnia, depression/depressed mood, headache/migraine, fatigue/malaise, dizziness/vertigo, nausea, and diarrhea.

(6.1) To report SUSPECTED ADVERSE REACTIONS, contact ViiV Healthcare at 1-877-844-8872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience in Adult Subjects 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 and Lamivudine 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 and Lamivudine Tablets Therapy?naive Adults: Treatment?emergent clinical adverse reactions (rated by the investigator as moderate or severe) with greater than or equal to 5 % frequency during therapy with ZIAGEN 600 mg once daily or ZIAGEN 300 mg twice daily, both in combination with lamivudine 300 mg once daily and efavirenz 600 mg once daily, are listed in Table 1.

Table 1.

Treatment?emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades 2-4, Greater than or Equal to 5 % Frequency) in Therapy?naive Adults (CNA30021) through 48 Weeks of Treatment Adverse Event ZIAGEN 600 mg q.d. plus EPIVIR plus Efavirenz (n = 384) ZIAGEN 300 mg b.i.d. plus EPIVIR plus Efavirenz (n = 386) Drug hypersensitivity a, b 9 % 7 % Insomnia 7 % 9 % Depression/Depressed mood 7 % 7 % Headache/Migraine 7 % 6 % Fatigue/Malaise 6 % 8 % Dizziness/Vertigo 6 % 6 % Nausea 5 % 6 % Diarrheaa 5 % 6 % Rash 5 % 5 % Pyrexia 5 % 3 % Abdominal pain/gastritis 4 % 5 % Abnormal dreams 4 % 5 % Anxiety 3 % 5 % aSubjects receiving ZIAGEN 600 mg once daily

experienced a significantly higher incidence of severe drug hypersensitivity reactions and severe diarrhea compared with subjects who received ZIAGEN 300 mg twice daily.

Five percent (5 %) of subjects receiving ZIAGEN 600 mg once daily had severe drug hypersensitivity reactions compared with 2 % of subjects receiving ZIAGEN 300 mg twice daily.

Two percent (2 %) of subjects receiving ZIAGEN 600 mg once daily had severe diarrhea while none of the subjects receiving ZIAGEN 300 mg twice daily had this event.

bCNA30024 was a multi?center, double-blind, controlled trial in which 649 HIV?1?infected, therapy?naive adults were randomized and received either ZIAGEN (300 mg twice daily), EPIVIR (150 mg twice daily), and efavirenz (600 mg once daily); or zidovudine (300 mg twice daily), EPIVIR (150 mg twice daily), and efavirenz (600 mg once daily).

CNA30024 used double?blind ascertainment of suspected hypersensitivity reactions.

During the blinded portion of the trial, suspected hypersensitivity to abacavir was reported by investigators in 9 % of 324 subjects in the abacavir group and 3 % of 325 subjects in the zidovudine group.

Laboratory Abnormalities: Laboratory abnormalities observed in clinical trials of ZIAGEN were anemia, neutropenia, liver function test abnormalities, and elevations of CPK, blood glucose, and triglycerides.

Additional laboratory abnormalities observed in clinical trials of EPIVIR were thrombocytopenia and elevated levels of bilirubin, amylase, and lipase.

The frequencies of treatment?emergent laboratory abnormalities were comparable between treatment groups in CNA30021.

Other Adverse Events: In addition to adverse reactions listed above, other adverse events observed in the expanded access program for abacavir were pancreatitis and increased GGT. 6.2 Clinical Trials Experience in Pediatric Subjects The safety of once-daily compared with twice-daily dosing of abacavir and lamivudine, administered as either single products or as the fixed-dose combination of abacavir and lamivudine, was assessed in the ARROW trial (n = 336).

Primary safety assessment in the ARROW (COL105677) trial was based on Grade 3 and Grade 4 adverse events.

The frequency of Grade 3 and 4 adverse events was similar among subjects randomized to once-daily dosing compared with subjects randomized to twice-daily dosing.

One event of Grade 4 hepatitis in the once-daily cohort was considered as uncertain causality by the investigator and all other Grade 3 or 4 adverse events were considered not related by the investigator.

No additional safety issues were identified in pediatric subjects receiving abacavir and lamivudine once-daily compared with historical data in adults [see Adverse Reactions (6.1)].

6.3 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 and Lamivudine Body as a Whole: Redistribution/accumulation of body fat [see Warnings and Precautions (5.6)].

Digestive: Stomatitis.

Endocrine and Metabolic: Hyperglycemia.

General: Weakness.

Hemic and Lymphatic: Aplastic anemia, anemia (including pure red

cell aplasia and severe anemias

progressing on therapy), lymphadenopathy, splenomegaly.

Hepatic: Lactic acidosis and hepatic steatosis [see Warnings and Precautions (5.2)], posttreatment exacerbations of hepatitis B [see Warnings and Precautions (5.3)].

Hypersensitivity: Sensitization reactions (including anaphylaxis), urticaria.

Musculoskeletal: Muscle weakness, CPK elevation, rhabdomyolysis.

Nervous: Paresthesia, peripheral neuropathy, seizures.

Respiratory: Abnormal breath sounds/wheezing.

Skin: Alopecia, erythema multiforme, Stevens-Johnson syndrome.

Usage information

Dosing and administration

2 DOSAGE AND ADMINISTRATION •Before initiating Abacavir and Lamivudine tablets, screen for the HLA?B * 5701 allele because Abacavir and Lamivudine tablets contain abacavir.

(2.1) •Adults: One tablet orally once daily.

(2.2) •Pediatric patients weighing at least 25 kg: One tablet daily.

(2.3) •Because Abacavir and Lamivudine tablets are a fixed-dose tablet and can not be dose adjusted, Abacavir and Lamivudine tablets are not recommended in patients requiring dosage adjustment or patients with hepatic impairment.

(2.4, 4) 2.1 Screening for HLAB * 5701 Allele prior to Starting Abacavir and Lamivudine Tablets Screen for the HLA?B * 5701 allele prior to initiating therapy with Abacavir and Lamivudine tablets [see Boxed Warning, Warnings and Precautions (5.1)].

2.2 Recommended Dosage for Adult Patients The recommended dosage of Abacavir and Lamivudine tablets for adults is one tablet taken orally once daily, in combination with other antiretroviral agents, with or without food.

2.3 Recommended Dosage for Pediatric Patients The recommended oral dose of Abacavir and Lamivudine tablets for pediatric patients weighing at least 25 kg is one tablet daily in combination with other antiretroviral agents [see Clinical Studies (14.2)].

Before prescribing Abacavir and Lamivudine tablets, pediatric patients should be assessed for the ability to swallow tablets.

2.4 Not Recommended Due to Lack of Dosage Adjustment Because Abacavir and Lamivudine tablets are fixed?dose tablets and can not be dose adjusted, Abacavir and Lamivudine tablets are not recommended for: •patients with creatinine clearance less than 50 mL per minute [see Use in Specific Populations (8.6)].

•patients with mild hepatic impairment.

Abacavir and Lamivudine tablets are contraindicated in patients with moderate or severe hepatic impairment [see Contraindications (4), Use in Specific Populations (8.7)].

Use of EPIVIR® (lamivudine) oral solution or tablets and ZIAGEN® (abacavir) oral solution may be considered.

Use in special populations

8 USE IN SPECIFIC POPULATIONS •Lactation: Breastfeeding not recommended.

(8.2) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Abacavir and Lamivudine tablets during pregnancy.

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

Risk Summary Available data from the Antiretroviral Pregnancy Registry show no difference in the risk of overall major birth defects for abacavir or lamivudine compared with the background rate for major birth defects of 2.7 % in the US reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP).

Abacavir produced fetal malformations and other embryonic and fetal toxicities in rats at 35 times the human exposure at the recommended clinical dose.

Lamivudine produced embryonic toxicity in rabbits at a dose that produced similar human exposures to the recommended clinical dose.

The relevance of animal findings to human pregnancy registry data is not known.

Data Human Data: Abacavir: Based on prospective reports from the Antiretroviral Pregnancy Registry of over 2,000 exposures to abacavir during pregnancy resulting in live births (including over 900 exposed in the first trimester), there was no difference between abacavir and overall birth defects compared with the background birth defect rate of 2.7 % in the US reference population of the MACDP.

The prevalence of defects in the first trimester was 3.0 % (95 % CI: 2.0 % to 4.4 %).

Lamivudine: Based on prospective reports from the Antiretroviral Pregnancy Registry of over 11,000 exposures to lamivudine during pregnancy resulting in live births (including over 4,300 exposed in the first trimester), there was no difference between lamivudine and overall birth defects compared with the background birth defect rate of 2.7 % in the U.S. reference population of the MACDP.

The prevalence of defects in the first trimester was 3.1 % (95 % CI: 2.6 % to 3.7 %).

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 pharmacokinetics in pregnant women were similar to those seen in non-pregnant adults and in postpartum women.

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.

Amniotic fluid concentrations of lamivudine were typically 2 times greater than maternal serum levels and ranged from 1.2 to 2.5 mcg per mL (150 mg twice daily) and 2.1 to 5.2 mcg per mL (300 mg twice daily).

Animal Data: 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.

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 The dosing recommendations in this population are based on the safety and efficacy established in a controlled trial conducted using either the combination of EPIVIR and ZIAGEN or the fixed-dose combination abacavir and lamivudine tablet [see Dosage and Administration (2.3), Adverse Reactions (6.2), Clinical Studies (14.2)].

In pediatric patients weighing less than 25 kg, use of abacavir and lamivudine as single products is recommended to achieve appropriate dosing.

8.5 Geriatric Use Clinical trials of abacavir and lamivudine 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 and Lamivudine tablets in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Dosage and Administration (2.4), Use in Specific Populations (8.6, 8.7)].

8.6 Patients with Impaired Renal Function Abacavir and Lamivudine tablets are not recommended for patients with creatinine clearance less than 50 mL per min because Abacavir and Lamivudine tablets are fixed-dose combination tablets and the dosage of the individual components can not be adjusted.

If a dose reduction of lamivudine, a component of Abacavir and Lamivudine tablets, is required for patients with creatinine clearance less than 50 mL per min, then the individual components should be used [see Clinical Pharmacology (12.3)].

8.7 Patients with Impaired Hepatic Function Abacavir and Lamivudine tablets are fixed-dose combination tablets and the dosage of the individual components can not be adjusted.

If a dose reduction of abacavir, a component of Abacavir and Lamivudine tablets, 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 and Lamivudine tablets are contraindicated in these patients [see Contraindications (4)].

Interactions

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

(7.1) 7.1 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.

More information

Category Value
Authorisation number NDA021652
Agency product number 2T8Q726O95
Orphan designation No
Product NDC 66993-482
Date Last Revised 29-02-2016
Type HUMAN PRESCRIPTION DRUG
Marketing authorisation holder Prasco Laboratories
Warnings

WARNING:

HYPERSENSITIVITY REACTIONS, 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 and Lamivudine 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 and Lamivudine 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 and Lamivudine tablets or reinitiation of therapy with Abacavir and Lamivudine tablets, unless patients have a previously documented HLA?

B * 5701 allele assessment.

Discontinue Abacavir and Lamivudine 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 and Lamivudine tablets, NEVER restart Abacavir and Lamivudine 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)].

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 and

Lamivudine tablets if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur [see Warnings and Precautions (5.2)].

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, which is a component of Abacavir and Lamivudine tablets.

Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue Abacavir and Lamivudine 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 (5.3)].

WARNING:

HYPERSENSITIVITY REACTIONS, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY, and 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 and Lamivudine tablets are contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B * 5701-positive patients.

(4) Discontinue Abacavir and Lamivudine tablets as soon as a hypersensitivity reaction is suspected.

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

(5.1) • Following a hypersensitivity reaction to Abacavir and Lamivudine tablets, NEVER restart Abacavir and Lamivudine tablets or any other abacavir-containing product.

(5.1) 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.

(5.2) 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 and Lamivudine tablets.

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

(5.3)

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