Lamivudine/Tenofovir disoproxil

Uses

This is used alone or in combination with other antiretroviral agents for the treatment of HIV infection.

Lamivudine/Tenofovir disoproxil is also used to associated treatment for these conditions: Human Immunodeficiency Virus Type 1 (HIV-1) InfectionHepatitis B Chronic Infection, Human Immunodeficiency Virus (HIV) InfectionsHIV Transmission, Human Immunodeficiency Virus (HIV) Infections, Perinatal HIV transmission

How Lamivudine/Tenofovir disoproxil works

Abacavir is a carbocyclic synthetic nucleoside analogue and an antiviral agent. Intracellularly, abacavir is converted by cellular enzymes to the active metabolite carbovir triphosphate, an analogue of deoxyguanosine-5'-triphosphate (dGTP). Carbovir triphosphate inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA. Viral DNA growth is terminated because the incorporated nucleotide lacks a 3'-OH group, which is needed to form the 5′ to 3′ phosphodiester linkage essential for DNA chain elongation.

Lamivudine is a synthetic nucleoside analogue and is phosphorylated intracellularly to its active 5'-triphosphate metabolite, lamivudine triphosphate (L-TP). This nucleoside analogue is incorporated into viral DNA by HIV reverse transcriptase and HBV polymerase, resulting in DNA chain termination.

Zidovudine, a structural analog of thymidine, is a prodrug that must be phosphorylated to its active 5′-triphosphate metabolite, zidovudine triphosphate (ZDV-TP). It inhibits the activity of HIV-1 reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue. It competes with the natural substrate dGTP and incorporates itself into viral DNA. It is also a weak inhibitor of cellular DNA polymerase α and γ.

Dosage

Lamivudine/Tenofovir disoproxil dosage

The recommended oral dose for adults and adolescents is 1 tablet twice daily. This drug is not recommended in adults or adolescents who weigh less than 40 kg because it is a fixed-dose tablet.

May be taken with or without food.

Side Effects

Hypersensitivity reaction, GI disturbance, anorexia, headache, insomnia, muscle disorder, cough, rash, alopecia, fever, fatigue, malaise, severe hepatomegaly.

Toxicity

Some myocardial degeneration has been noticed in rats and mice. The most commonly reported adverse reactions of at least moderate intensity (incidence ≥10%) in adult HIV-1 clinical trials were nausea, headache, malaise and fatigue, nausea and vomiting, and dreams/sleep disorders. Serious hypersensitivity reactions have been associated with abacavir which has been strongly linked to the presence of the HLA-B*57:01 allele. This reaction manifests itself in patients within the first 6 weeks of treatment. Patients should be tested for the presence of this allele as recommended by the U.S Food and Drug Administration (FDA).

The most common reported adverse reactions (incidence ≥15%) in adults were headache, nausea, malaise and fatigue, nasal signs and symptoms, diarrhea, and cough.

Symptoms of overdose include fatigue, headache, nausea, and vomiting. LD₅₀ is 3084 mg/kg (orally in mice).

Precaution

Hypersensitivity Reaction: This combination contains abacavir sulfate, which has been associated with fatal hypersensitivity reactions. Patients developing signs or symptoms of hypersensitivity should discontinue this combination as soon as a hypersensitivity reaction is first suspected, and should seek medical evaluation immediately.

Bone Marrow Suppression: Since this combination contains Zidovudine, it should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count <1,000 cells/mm3 or hemoglobin combination. For HIV-infected individuals and patients with asymptomatic or early HIV disease, periodic blood counts are recommended.

Myopathy: Myopathy and myositis, with pathological changes similar to that produced by HIV disease, have been associated with prolonged use of Zidovudine, and therefore may occur with therapy with this combination.

Post-treatment Exacerbations of Hepatitis:In clinical trials in non-HIV-infected patients treated with lamivudine for chronic hepatitis B (HBV), clinical and laboratory evidence of exacerbations of hepatitis after discontinuation of Lamivudine. Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment.

Interaction

No clinically significant changes to pharmacokinetic parameters were observed for Abacavir, Lamivudine, or Zidovudine when administered together.

Abacavir: Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure.

Lamivudine: Trimethoprim (TMP) 160 mg/sulfamethoxazole (SMX) 800 mg once daily has been shown to increase Lamivudine exposure (AUC). The effect of higher doses of TMP/SMX on Lamivudine pharmacokinetics has not been investigated. Lamivudine and Zalcitabine may inhibit the intracellular phosphorylation of one another. Therefore, use of this combination in combination with zalcitabine is not recommended.

Zidovudine: Coadministration of ganciclovir, interferon-alpha, and other bone marrow suppressive or cytotoxic agents may increase the hematologic toxicity of zidovudine. Concomitant use of zidovudine with stavudine should be avoided since an antagonistic relationship has been demonstrated in vitro. In addition, concomitant use of zidovudine with doxorubicin or ribavirin should be avoided because an antagonistic relationship has also been demonstrated in vitro.

Volume of Distribution

• 0.86 ± 0.15 L/kg [IV administration]

Apparent volume of distribution, IV administration = 1.3 ± 0.4 L/kg. Volume of distribution was independent of dose and did not correlate with body weight.

Apparent volume of distribution, HIV-infected patients, IV administration = 1.6 ± 0.6 L/kg

Elimination Route

Rapid and extensive after oral administration (83% bioavailability, tablet). When a 300 mg tablet is given twice daily to subjects, the peak plasma concentration (Cmax) was 3.0 ± 0.89 mcg/mL and the area under the curve (AUC 0-12 hours) was 6.02 ± 1.73 mcg•hr/mL.

Lamivudine was rapidly absorbed after oral administration in HIV-infected patients. Absolute bioavailability in 12 adult patients was 86% ± 16% (mean ± SD) for the 150-mg tablet and 87% ± 13% for the oral solution. The peak serum lamivudine concentration (Cmax) was 1.5 ± 0.5 mcg/mL when an oral dose of 2 mg/kg twice a day was given to HIV-1 patients. When given with food, absorption is slower, compared to the fasted state.

Rapid and nearly complete absorption from the gastrointestinal tract following oral administration; however, because of first-pass metabolism, systemic bioavailability of zidovudine capsules and solution is approximately 65% (range, 52 to 75%). Bioavailability in neonates up to 14 days of age is approximately 89%, and it decreases to approximately 61% and 65% in neonates over 14 days of age and children 3 months to 12 years, respectively. Administration with a high-fat meal may decrease the rate and extent of absorption.

Half Life

1.54 ± 0.63 hours

5 to 7 hours (healthy or HBV-infected patients)

Elimination half life, HIV-infected patients, IV administration = 1.1 hours (range of 0.5 - 2.9 hours)

Clearance

• 0.80 ± 0.24 L/hr/kg [asymptomatic, HIV-1-infected adult patients receiving single (IV dose of 150 mg]

• Renal clearance = 199.7 ± 56.9 mL/min [300 mg oral dose, healthy subjects]
• Renal clearance = 280.4 ± 75.2 mL/min [single IV dose, HIV-1-infected patients]
• Total clearance = 398.5 ± 69.1 mL/min [HIV-1-infected patients]

• 0.65 +/- 0.29 L/hr/kg [HIV-infected, Birth to 14 Days of Age]
• 1.14 +/- 0.24 L/hr/kg [HIV-infected, 14 Days to 3 Months of Age]
• 1.85 +/- 0.47 L/hr/kg [HIV-infected, 3 Months to 12 Years of Age]. The transporters, ABCB1, ABCC4, ABCC5, and ABCG2 are involved with the clearance of zidovudine.

Elimination Route

Elimination of abacavir was quantified in a mass balance study following administration of a 600-mg dose of 14C-abacavir: 99% of the radioactivity was recovered, 1.2% was excreted in the urine as abacavir, 30% as the 5′-carboxylic acid metabolite, 36% as the 5′-glucuronide metabolite, and 15% as unidentified minor metabolites in the urine. Fecal elimination accounted for 16% of the dose. Renal excretion of unchanged abacavir is a minor route of elimination in humans.

The majority of lamivudine is eliminated unchanged in urine by active organic cationic secretion. 5.2% ± 1.4% (mean ± SD) of the dose was excreted as the trans-sulfoxide metabolite in the urine. Lamivudine is excreted in human breast milk and into the milk of lactating rats.

As in adult patients, the major route of elimination was by metabolism to GZDV. After intravenous dosing, about 29% of the dose was excreted in the urine unchanged and about 45% of the dose was excreted as GZDV.

Pregnancy & Breastfeeding use

Pregnancy Category C. There are no adequate and well-controlled studies of abacavir / Lamivudine / Zidovudine in pregnant women. This drug should be used during pregnancy only if the potential benefits outweigh the risks.

The Centers for Disease Control and Prevention recommend that HIVinfected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV infection.

Zidovudine is excreted in breast milk; abacavir and lamivudine are secreted into the milk of lactating rats. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving this combination.

Contraindication

Contraindicated in patients with previously demonstrated hypersensitivity to any of the components of the product.

Special Warning

This combination is not intended for use in pediatric patients. This combination tablet should not be administered to adolescents who weigh less than 40 kg because it is a fixed-dose tablet that cannot be adjusted for this patient population.

Acute Overdose

Symptoms: Vomiting, CNS effects (e.g. fatigue, dizziness, drowsiness, lethargy, confusion), haematologic effects (e.g. anaemia, decreased Hb). Bone marrow hypoplasia, mild ataxia, tonic-clonic seizure and increased serum concentration of AST and ALT may also occur. Management: Supportive and symptomatic treatment. Induce emesis and admin activated charcoal to prevent further absorption of unrecovered drug.

Storage Condition

Store at a dry and cool place. Protect from light and moisture. Keep the medicine out of the reach of children.

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