Abacavir + Lamivudine

Usage

Abacavir + Lamivudine is prescribed for the treatment of Human Immunodeficiency Virus (HIV) infection in adults, adolescents, and children. It is used in combination with other antiretroviral agents. It belongs to the pharmacological classification of nucleoside analog reverse-transcriptase inhibitors (NRTIs). Abacavir and lamivudine interfere with the enzyme reverse transcriptase, which HIV needs to replicate within human cells. By inhibiting this enzyme, they prevent the virus from multiplying and spreading.

Alternate Names

This combination is often referred to as simply “abacavir/lamivudine.” A common brand name for this combination is Kivexa®. Epzicom® is another brand name but contains different strengths of abacavir and lamivudine.

How It Works

Pharmacodynamics: Abacavir and lamivudine are both nucleoside analog reverse-transcriptase inhibitors (NRTIs). They act intracellularly, needing to be phosphorylated to their active triphosphate forms. These active metabolites compete with natural nucleosides, integrating into the viral DNA and acting as chain terminators. This disrupts viral replication by preventing the completion of the DNA chain.

Pharmacokinetics:

• Absorption: Both drugs are well-absorbed orally. Food does not significantly affect the bioavailability of the combined formulation.
• Metabolism: Abacavir is primarily metabolized in the liver by alcohol dehydrogenase and glucuronyl transferase to inactive metabolites. Lamivudine is minimally metabolized.
• Elimination: Abacavir metabolites are excreted primarily in the urine. Lamivudine is predominantly excreted unchanged in the urine by active tubular secretion.

Mode of Action: Both are competitive substrates for HIV-1 reverse transcriptase. Once phosphorylated intracellularly into their active 5’-triphosphate forms, they bind to the active site of the reverse transcriptase, inhibiting the synthesis of viral DNA and acting as chain terminators in the growing DNA strand.

Receptor Binding/Enzyme Inhibition: No specific receptor binding is involved. The primary mechanism is competitive inhibition of HIV-1 reverse transcriptase.

Dosage

Standard Dosage

Adults and Adolescents (≥ 25 kg): One 600mg/300mg tablet once daily.

Children (< 25 kg): Use of the individual components, abacavir and lamivudine, is recommended for children weighing less than 25 kg, as the fixed-dose combination tablet cannot be adjusted. The dose needs to be determined by the physician based on the child’s weight and should be administered as instructed in the individual product information for abacavir and lamivudine.

Special Cases:

• Elderly Patients (≥65 years): Exercise caution and monitor for age-related changes in organ function, potentially requiring dose adjustments.
• Patients with Renal Impairment: Not recommended for patients with creatinine clearance <30 mL/min. Lamivudine dose reduction may be necessary based on creatinine clearance, and in such cases the fixed-dose combination should not be used, and the individual components should be administered based on the patient’s renal function.
• Patients with Hepatic Dysfunction: Not recommended for patients with moderate to severe hepatic impairment. Use with caution in patients with mild hepatic impairment. If a dose adjustment of abacavir is needed, the combined formulation should be avoided.
• Patients with Comorbid Conditions: Consider the specific condition and potential drug interactions. Patients with a history of cardiovascular disease should be closely monitored. Patients co-infected with HBV should be monitored closely for signs of hepatitis exacerbation if therapy is stopped.

Clinical Use Cases

Abacavir/lamivudine is specifically indicated for chronic HIV infection management and not for acute situations like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations such as cardiac arrest.

Dosage Adjustments

Dose adjustments are required for renal and hepatic impairment (as detailed above). No dose adjustments are needed for other comorbid conditions unless they significantly affect renal or liver function.

Side Effects

Common Side Effects

Nausea, vomiting, diarrhea, headache, fatigue, fever, skin rash, hair loss, cough, nasal symptoms, insomnia, muscle pain, joint pain, loss of appetite.

Rare but Serious Side Effects

Hypersensitivity reaction (fever, rash, nausea, vomiting, malaise, respiratory symptoms, abdominal pain), lactic acidosis, liver damage (including hepatitis and liver failure), pancreatitis, changes in body fat distribution, increased risk of myocardial infarction, immune reconstitution inflammatory syndrome (IRIS).

Long-Term Effects

Changes in body fat distribution (lipodystrophy), dyslipidemia, insulin resistance, increased risk of cardiovascular disease.

Adverse Drug Reactions (ADR)

Hypersensitivity reaction to abacavir, lactic acidosis, severe hepatotoxicity, pancreatitis.

Contraindications

Hypersensitivity to abacavir or lamivudine, HLA-B*5701 positivity (due to increased risk of hypersensitivity to abacavir), moderate to severe hepatic impairment, concurrent use of drugs with narrow therapeutic indexes that are substrates of organic cation transporter (OCT) 2.

Drug Interactions

Alcohol (may increase risk of pancreatitis and other adverse effects).

Methadone (abacavir may reduce methadone levels).

Co-trimoxazole (lamivudine levels may be increased).

Sorbitol (additive gastrointestinal side effects with lamivudine).

Pregnancy and Breastfeeding

Not recommended during pregnancy unless the potential benefit outweighs the risk to the fetus. Breastfeeding is not recommended due to potential HIV transmission to the infant and possible adverse effects in the nursing infant.

Drug Profile Summary

• Mechanism of Action: Nucleoside reverse-transcriptase inhibitor (NRTI). Inhibits viral DNA synthesis by acting as a chain terminator.

• Side Effects: Common: Nausea, vomiting, diarrhea, headache, fatigue. Serious: Hypersensitivity, lactic acidosis, liver damage, pancreatitis.

• Contraindications: Hypersensitivity, HLA-B*5701 positivity, moderate/severe hepatic impairment, concomitant use of drugs with narrow therapeutic indexes that are OCT2 substrates.

• Drug Interactions: Alcohol, methadone, co-trimoxazole, sorbitol.

• Pregnancy & Breastfeeding: Not recommended.

• Dosage: Adults/adolescents (≥25 kg): 600mg/300mg once daily. Children: Use individual components.

• Monitoring Parameters: HIV viral load, CD4 cell count, liver function tests, renal function tests, signs of hypersensitivity, serum lipids, blood glucose.

Popular Combinations

Commonly used in combination with other antiretrovirals as part of a highly active antiretroviral therapy (HAART) regimen, such as with dolutegravir (Triumeq) or other NRTIs, NNRTIs, and protease inhibitors or integrase inhibitors. Combinations are chosen to maximize viral suppression and minimize the development of drug resistance.

Precautions

Screen all patients for HLA-B*5701 allele before starting abacavir.

Monitor for signs and symptoms of hypersensitivity reaction to abacavir, particularly during the first six weeks of treatment.

Monitor liver function tests regularly, especially in patients with pre-existing liver disease.

Monitor for signs of lactic acidosis, especially in pregnant women and obese patients.

Avoid alcohol consumption due to potential for increased risk of pancreatitis and other adverse effects.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Abacavir + Lamivudine?

A: One 600mg/300mg tablet once daily for adults and adolescents ≥25kg. For children <25kg, use individual components, adjusting the dose according to weight and referring to the individual product information.

Q2: What is the most serious side effect associated with Abacavir + Lamivudine?

A: A hypersensitivity reaction to abacavir, which can be fatal. This typically presents with fever, rash, and at least one other symptom such as gastrointestinal or respiratory issues.

Q3: Should Abacavir + Lamivudine be used in pregnant women?

A: It is not recommended during pregnancy unless the potential benefit outweighs the potential risk to the fetus. Close monitoring is necessary if it is used.

Q4: What should be done if a patient develops a suspected hypersensitivity reaction?

A: Discontinue Abacavir + Lamivudine immediately and permanently. Never rechallenge the patient with abacavir or any abacavir-containing product.

Q5: Can Abacavir + Lamivudine be used in patients with renal impairment?

A: It is not recommended for patients with creatinine clearance <30 mL/min. Dose adjustments of lamivudine might be necessary for patients with creatinine clearance between 30 and 50 mL/min, therefore the single pill containing the fixed dose combination of abacavir and lamivudine is not appropriate for this subset of patients. The individual components should be used, and the physician should consult the individual product information.

Q6: What is the role of HLA-B*5701 testing?

A: All patients must be screened for the HLA-B*5701 allele before starting abacavir. Patients who are positive for this allele have a significantly increased risk of developing a hypersensitivity reaction and should not receive abacavir.

Q7: Can Abacavir + Lamivudine be used as monotherapy for HIV?

A: No, it should always be used as part of a combination antiretroviral regimen.

Q8: What are the key monitoring parameters during treatment?

A: HIV viral load, CD4 cell count, liver function tests, and renal function. It is also crucial to monitor for signs and symptoms of hypersensitivity reaction, especially in the first six weeks of treatment.

Q9: What patient education is crucial when prescribing this medication?

A: Educate patients about the signs and symptoms of a hypersensitivity reaction and the importance of immediate discontinuation if these occur. Emphasize the importance of adherence to the prescribed regimen to prevent the development of drug resistance. Discuss potential side effects, drug interactions, and the need for regular monitoring. Advise against breastfeeding.