Abacavir and Lamivudine Tablets USP

Abacavir and Lamivudine Tablets USP

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Abacavir and Lamivudine Tablets USP

Abacavir and lamivudine tablets USP contain the following 2 synthetic nucleoside analogues: abacavir (ZIAGEN , also a component of TRIZIVIR ) and lamivudine, USP (also known as EPIVIR or 3TC) with inhibitory activity against HIV-1.

Abacavir and lamivudine tablets USP are for oral administration. Each yellow, film-coated tablet contains the active ingredients 600 mg of abacavir as abacavir sulfate, USP and 300 mg of lamivudine, USP, and the inactive ingredients FD&C yellow #6, hypromellose, iron oxide yellow, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, and titanium dioxide.

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

Abacavir sulfate, USP is a white to off-white solid with a solubility of approximately 77 mg/mL in distilled water at 25°C.

In vivo, abacavir sulfate, USP dissociates to its free base, abacavir. Dosages are expressed in terms of abacavir.

Lamivudine, USP: The chemical name of lamivudine, USP is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)- (1H)-pyrimidin-2-one. Lamivudine, USP is the (-)enantiomer of a dideoxy analogue of cytidine. Lamivudine, USP has also been referred to as (-)2′,3′-dideoxy, 3′-thiacytidine. It has a molecular formula of (C8H11N3O3S and molecular weight of 229.3.

Lamivudine, USP is a white to off-white crystalline solid with a solubility of approximately 70 mg/mL in water at 20°C.

Indications and usage

Mechanism of Action

Abacavir: Abacavir is a carbocyclic synthetic nucleoside analogue. Abacavir is converted by cellular enzymes to the active metabolite, carbovir triphosphate (CBV-TP), an analogue of deoxyguanosine-5′- triphosphate (dGTP). CBV-TP inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA.

Lamivudine: Lamivudine is a synthetic nucleoside analogue. Intracellularly lamivudine is phosphorylated to its active 5′-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of RT via DNA chain termination after incorporation of the nucleotide analogue.

Dosage and administration

  • Screen for the HLA-B*5701 allele prior to initiating therapy with abacavir and lamivudine tablets.

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.

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

Not Recommended Due to Lack of Dosage Adjustment

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

  1. patients with creatinine clearance less than 50 mL per minute.
  2. patients with mild hepatic impairment. Abacavir and lamivudine tablets are contraindicated in patients with moderate or severe hepatic impairment

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

Contraindications

Abacavir and lamivudine tablets are contraindicated in patients:

  1. who have the HLA-B*5701 allele.
  2. with prior hypersensitivity reaction to abacavir or lamivudine.
  3. with moderate or severe hepatic impairment

Warnings and precautions

Hypers ensitivity Reactions:

Serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, a component of abacavir and lamivudine 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. 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.

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. See full prescribing information for ZIAGEN (abacavir) and EPIVIR (lamivudine). Treatment with abacavir and lamivudine 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).

Post-treatment 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 lamivudinecontaining 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 and lamivudine tablets should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. See full prescribing information for EPIVIR® (lamivudine). Discontinuation of abacavir and lamivudine 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).

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including abacavir and lamivudine 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

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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.

Fat Redistribution: Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Myocardial Infarction

In a published prospective, observational, epidemiological trial designed to investigate the rate of myocardial infarction (MI) in patients on combination antiretroviral therapy, the use of abacavir within the previous 6 months was correlated with an increased risk of MI. In a sponsor-conducted pooled analysis of clinical trials, no excess risk of MI was observed in abacavir-treated subjects as compared with control subjects. In totality, the available data from the observational cohort and from clinical trials are 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).

Adverse reactions

The most commonly reported adverse reactions of at least moderate intensity (incidence greater than 5%) in an adult HIV1 clinical trial were drug hypersensitivity, insomnia, depression/depressed mood, headache/migraine, fatigue/malaise, dizziness/vertigo, nausea, and diarrhea.

Drug interactions

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. 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.

Use in specific populations

Pregnancy: 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. Lamivudine has been shown to cross the placenta,

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. Abacavir and lamivudine are present in human milk. There is no information on the effects of abacavir and lamivudine 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) serious adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving abacavir and lamivudine tablets.

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 abacavir and lamivudine tablets.

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

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.

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 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 50 mL per min, then the individual components should be used.

Patients with Impaired Hepatic Function: Abacavir and lamivudine tablets are 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.

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.

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: 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.

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