ABACAVIR AND LAMIVUDINE_- abacavir and lamivudine_tablet, film coated

Abacavir and lamivudine tablets is an antiretroviral agent with activity against HIV-1 [see Microbiology ( 12. 4 Pharmacokinetics in Adults max Abacavir: Lamivudine: 24,ss The pharmacokinetic properties of abacavir and lamivudine in fasting subjects are summarized in Table 2. Pharmacokinetic Parametersa for Abacavir and Lamivudine in Adults Parameter Abacavir Lamivudine Oral bioavailability (%) 86 +/-25 n = 6 86 +/-16 n = 12 Apparent volume of distribution (L/kg) 0. 4 n = 20 Systemic clearance (L/h/kg) 0. 06 n = 20 Renal clearance (L/h/kg) 0. 008 n = 6 0. 06 n = 20 Elimination half-life (h) 1. 32 n = 20 13 to 19 b a b Effect of Food on Absorption of Abacavir and Lamivudine Tablets last max max Specific Populations Patients with Renal Impairment: Patients with Hepatic Impairment: Pregnant Women: Lamivudine: Pediatric Patients: Abacavir and Lamivudine: [see Dosage and Administration ( 2. 2 Geriatric Patients: Male and Female Patients: Racial Groups: Drug Interaction Studies Effect of Abacavir and Lamivudine on the Pharmacokinetics of Other Agents: Riociguat: Coadministration of a single dose of riociguat (0. 5 mg) to HIV-1en dashinfected subjects receiving fixed-dose abacavir/dolutegravir/lamivudine is reported to increase riociguat AUC(infinity) compared with riociguat AUC(infinity) reported in healthy subjects due to CYP1A1 inhibition by abacavir. The exact magnitude of increase in riociguat exposure has not been fully characterized based on findings from two studies [see Drug Interactions ( 7. 3 Effect of Other Agents on the Pharmacokinetics of Abacavir or Lamivudine: Lamivudine is a substrate of MATE1, MATE2-K, and OCT2 in vitro. Trimethoprim (an inhibitor of these drug transporters) has been shown to increase lamivudine plasma concentrations. This interaction is not considered clinically significant as no dose adjustment of lamivudine is needed. Lamivudine is a substrate of P-gp and BCRP; however, considering its absolute bioavailability (87%), it is unlikely that these transporters play a significant role in the absorption of lamivudine. Therefore, coadministration of drugs that are inhibitors of these efflux transporters is unlikely to affect the disposition and elimination of lamivudine. Abacavir: Lamivudine and/or Zidovudine: Lamivudine: Zidovudine: Other Interactions Ethanol: Interferon Alfa: Methadone: [see Drug Interactions ( 7 Ribavirin: Sorbitol (Excipient): Table 3. Effect of Coadministered Drugs on Abacavir or Lamivudine Coadministered Drug and Dose Drug and Dose n Concentrations of Abacavir or Lamivudine Concentration of Coadministered Drug AUC Variability Ethanol Abacavir Single 600 mg 24 up arrow41% 90% CI: 35% to 48% left-right arrow a Nelfinavir Lamivudine Single 150 mg 11 up arrow10% 95% CI: 1% to 20% left-right arrow Trimethoprim 160 mg/ Sulfamethoxazole 800 mg daily x 5 days Lamivudine Single 300 mg 14 up arrow43% 90% CI: 32% to 55% left-right arrow up arrow = Increase; left-right arrow = No significant change; AUC = Area under the concentration versus time curve; CI = Confidence interval. a Mechanism of Action Abacavir: Lamivudine: Antiviral Activity Abacavir: IIIB Lamivudine: 50 50 The combination of abacavir and lamivudine has demonstrated antiviral activity in cell culture against non-subtype B isolates and HIV-2 isolates with equivalent antiviral activity as for subtype B isolates. Neither abacavir, nor lamivudine, were antagonistic to all tested anti-HIV agents. See full prescribing information for ZIAGEN (abacavir) and EPIVIR (lamivudine). Ribavirin, used in the treatment of HCV infection, decreased the anti-HIV-1 potency of abacavir/lamivudine reproducibly by 2-to 6-fold in cell culture. Resistance Cross-Resistance.

Abacavir and lamivudine tablets, in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. Abacavir and lamivudine tablets, a combination of abacavir and lamivudine, both nucleoside analogue HIV-1 reverse transcriptase inhibitors, is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.

Before initiating abacavir and lamivudine tablets, screen for the HLA-B*5701 allele because abacavir and lamivudine tablets contains abacavir. 4 4 Screen for the HLA-B*5701 allele prior to initiating therapy with abacavir and lamivudine tablets [see Boxed Warning, Warnings and Precautions ( 5. 1 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. 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 Because abacavir and lamivudine tablets is a fixed-dose tablet and cannot be dose adjusted, abacavir and lamivudine tablets is not recommended for: patients with creatinine clearance less than 30 mL per minute [see Use in Specific Populations ( 8. [see Contraindications ( 4 ), Use in Specific Populations ( 8. Use of EPIVIR (lamivudine) oral solution or tablets and ZIAGEN (abacavir) oral solution may be considered.

The following adverse reactions are discussed in other sections of the labeling: [see Boxed Warning, Warnings and Precautions ( 5. [see Boxed Warning, Warnings and Precautions ( 5. [see Warnings and Precautions ( 5. 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. 1 To report SUSPECTED ADVERSE REACTIONS, contact Macleods Pharma USA, Inc. , at 1-888-943-3210 or or 1-855-926-3384 FDA at 1-800-FDA-1088 or www. gov/medwatch 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 [see Boxed Warning, Warnings and Precautions ( 5. 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 Therapy-Naive Adults: 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. plus EPIVIR plus Efavirenz (n = 384) ZIAGEN 300 mg b. plus EPIVIR plus Efavirenz (n = 386) Drug hypersensitivity a,b a a b Laboratory Abnormalities: Other Adverse Events: The safety of once-daily compared with twice-daily dosing of abacavir and lamivudine, administered as either single products or as abacavir and lamivudine tablets, 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 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 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. Abacavir and Lamivudine Body as a Whole: Digestive: Endocrine and Metabolic: General: Hemic and Lymphatic: Hepatic: [see Warnings and Precautions ( 5. 3 )], [see Warnings and Precautions ( 5. Hypersensitivity: Musculoskeletal: Nervous: Respiratory: Skin:.

Abacavir and lamivudine tablets is contraindicated in patients: [see Warnings and Precautions ( 5. [see Warnings and Precautions ( 5. 1 )] [see Use in Specific Populations ( 8. Presence of HLA-B*5701 allele.

Lactation: Women infected with HIV should be instructed not to breastfeed due to potential for HIV transmission. 2 Pregnancy Exposure Registry Risk Summary max (see Data). Data [see Clinical Pharmacology ( 12. 3 Lamivudine: Animal Data: Lamivudine: Risk Summary 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 abacavir and lamivudine tablets [see Dosage and Administration ( 2. 2 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. 7 Abacavir and lamivudine tablets is not recommended for patients with creatinine clearance less than 30 mL per min because abacavir and lamivudine tablets is a fixed-dose combination and the dosage of the individual components cannot be adjusted. If a dose reduction of lamivudine, a component of abacavir and lamivudine tablets, is required for patients with creatinine clearance less than 30 mL per min, then the individual components should be used [see Clinical Pharmacology ( 12. 3 Patients with a creatinine clearance between 30 and 49 mL per min receiving abacavir and lamivudine tablets may experience a 1. 3-fold higher lamivudine exposure (AUC) than patients with a creatinine clearance >=50 mL per min. There are no safety data from randomized, controlled trials comparing abacavir and lamivudine tablets to the individual components in patients with a creatinine clearance between 30 and 49 mL per min who received dose-adjusted lamivudine. In the original lamivudine registrational trials in combination with zidovudine, higher lamivudine exposures were associated with higher rates of hematologic toxicities (neutropenia and anemia), although discontinuations due to neutropenia or anemia each occurred in <1% of subjects. Patients with a sustained creatinine clearance between 30 and 49 mL per min who receive abacavir and lamivudine tablets should be monitored for hematologic toxicities. If new or worsening neutropenia or anemia develop, dose adjustment of lamivudine, per lamivudine prescribing information, is recommended. If lamivudine dose adjustment is indicated, abacavir and lamivudine tablets should be discontinued and the individual components should be used to construct the treatment regimen. Abacavir and lamivudine tablets 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 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 [see Contraindications ( 4.

Methadone: An increased methadone dose may be required in a small number of patients. 2 Riociguat: The riociguat dose may need to be reduced. 3 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. 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 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.

OVERDOSAGE
There is no known specific treatment for overdose with abacavir and lamivudine tablets. If overdose occurs, the patient should be monitored, and standard supportive treatment applied as required. Abacavir: Lamivudine:
NONCLINICAL TOXICOLOGY
Carcinogenicity Abacavir: Lamivudine: Mutagenicity Abacavir: Lamivudine: Impairment of Fertility Abacavir: Lamivudine: max 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.
CLINICAL STUDIES
One abacavir and lamivudine tablets tablet given once daily is an alternative regimen to EPIVIR tablets 300 mg once daily plus ZIAGEN tablets 2 x 300 mg once daily as a component of antiretroviral therapy. Therapy-Naive Adults Table 4. Outcomes of Randomized Treatment through Week 48 (CNA30021) Outcome ZIAGEN 600 mg q. plus EPIVIR plus Efavirenz (n = 384) ZIAGEN 300 mg b. plus EPIVIR plus Efavirenz (n = 386) Responder a b c 64% (71%) 65% (72%) a b c After 48 weeks of therapy, the median CD4+ cell count increases from baseline were 188 cells per mm3 in the group receiving ZIAGEN 600 mg once daily and 200 cells per mm3 in the group receiving ZIAGEN 300 mg twice daily. Through Week 48, 6 subjects (2%) in the group receiving ZIAGEN 600 mg once daily (4 CDC classification C events and 2 deaths) and 10 subjects (3%) in the group receiving ZIAGEN 300 mg twice daily (7 CDC classification C events and 3 deaths) experienced clinical disease progression. None of the deaths were attributed to trial medications. ARROW (COL105677) was a 5-year, randomized, multicenter trial which evaluated multiple aspects of clinical management of HIV-1 infection in pediatric subjects. HIV-1en dashinfected, treatment-naïve subjects aged 3 months to 17 years were enrolled and treated with a first-line regimen containing abacavir and lamivudine, dosed twice daily according to World Health Organization recommendations. After a minimum of 36 weeks of treatment, subjects were given the option to participate in Randomization 3 of the ARROW trial, comparing the safety and efficacy of once-daily dosing with twice-daily dosing of abacavir and lamivudine, in combination with a third antiretroviral drug, for an additional 96 weeks. Virologic suppression was not a requirement for participation at baseline for Randomization 3. At baseline for Randomization 3 (following a minimum of 36 weeks of twice-daily treatment), 75% of subjects in the twice-daily cohort were virologically suppressed, compared with 71% of subjects in the once-daily cohort. Virologic Outcome of Randomized Treatment at Week 96 a Outcome Abacavir plus Lamivudine Twice-Daily Dosing (n = 333) Abacavir plus Lamivudine Once-Daily Dosing (n = 336) HIV-1 RNA <80 copies/mL b HIV-1 RNA >=80 copies/mL c No virologic data d 70% 67% a b c d.
MEDGUIDE SECTION
Abacavir and Lamivudine Tablets,USP What is the most important information I should know about abacavir and lamivudine tablets? If you get a symptom from 2 or more of the following groups while taking abacavir and lamivudine tablets, call your healthcare provider right away to find out if you should stop taking abacavir and lamivudine tablets Symptom(s) Group 1 Fever Group 2 Rash Group 3 Nausea, vomiting, diarrhea, abdominal (stomach area) pain Group 4 Generally ill feeling, extreme tiredness, or achiness Group 5 Shortness of breath, cough, sore throat A list of these symptoms is on the Warning Card your pharmacist gives you. Carry this Warning Card with you at all times. within hours life-threatening symptoms low blood pressure or death. If your healthcare provider tells you that you can take abacavir and lamivudine tablets again, start taking it when you are around medical help or people who can call a healthcare provider if you need one. If you stop taking abacavir and lamivudine tablets, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your liver function and monitor your HBV infection. It may be necessary to give you a medicine to treat HBV. Tell your healthcare provider about any new or unusual symptoms you may have after you stop taking abacavir and lamivudine tablets. Resistant HBV. For more information about side effects, see “What are the possible side effects of abacavir and lamivudine tablets?” What is Abacavir and lamivudine tablets? Abacavir and lamivudine tablets is a prescription medicine used with other HIV-1 medicines to treat HIV-1 infection. Do not take abacavir and lamivudine tablets if you: have a certain type of gene variation called the HLA-B*5701 allele. Your healthcare provider will test you for this before prescribing treatment with abacavir and lamivudine tablets. Before you take abacavir and lamivudine tablets tell your healthcare provider about all of your medical conditions, including if you: Pregnancy Registry. Do not breastfeed if you take abacavir and lamivudine tablets. Tell your healthcare provider about all the medicines you take, Some medicines interact with abacavir and lamivudine tablets. Keep a list of your medicines to show your healthcare provider and pharmacist when you get a new medicine. Do not start taking a new medicine without telling your healthcare provider. How should I take abacavir and lamivudine tablets? exactly as your healthcare provider tells you to take it. What are the possible side effects of abacavir and lamivudine tablets? Abacavir and lamivudine tablets can cause serious side effects including: Call your healthcare provider right away if you get any of the following symptoms that could be signs of lactic acidosis: o feel very weak or tired Severe liver problems. Call your healthcare provider right away if you get any of the following signs or symptoms of liver problems: o your skin or the white part of your eyes turns yellow (jaundice) You may be more likely to get lactic acidosis or serious liver problems if you are female or very overweight (obese). Heart attack. The most common side effects of abacavir and lamivudine tablets include: Tell your healthcare provider if you have any side effect that bothers you or that does not go away. How should I store abacavir and lamivudine tablets? Keep abacavir and lamivudine tablets and all medicines out of the reach of children. General information for safe and effective use of abacavir and lamivudine tablets. What are the ingredients in abacavir and lamivudine tablets? Active ingredients: abacavir and lamivudine Manufactured for Manufactured by: All trademarks are the property of their respective owners. This Medication Guide has been approved by the U.S. Food and Drug Administration. Medication Guide available at: www.macleodspharma.com/usa Revised: 02/2025

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ABACAVIR AND LAMIVUDINE_- abacavir and lamivudine_tablet, film coated Product manual source documgent