Usage
- This fixed-dose combination medication is prescribed for the treatment of Human Immunodeficiency Virus type 1 (HIV-1) infection in adults and children weighing at least 35 kg. It is also used as pre-exposure prophylaxis (PrEP) to reduce the risk of HIV infection in individuals at high risk.
- Pharmacological classification: Antiretroviral, Nucleoside/Nucleotide Reverse Transcriptase Inhibitor (NRTI), Integrase Strand Transfer Inhibitor (INSTI).
- Mechanism of action: This combination targets two different stages of the HIV-1 replication cycle. Tenofovir disoproxil fumarate and lamivudine are NRTIs that inhibit reverse transcriptase, thus blocking the conversion of viral RNA into DNA. Dolutegravir is an INSTI, preventing the integration of viral DNA into the host cell’s genome.
Alternate Names
- While the generic name is Dolutegravir + Lamivudine + Tenofovir disoproxil fumarate, this combination is often referred to by its components.
- A common brand name is Triumeq.
How It Works
- Pharmacodynamics: The combination of drugs works synergistically to suppress HIV-1 replication by inhibiting different stages of the viral life cycle. Lamivudine and Tenofovir DF, as NRTIs, compete with natural nucleosides for incorporation into viral DNA. Dolutegravir, an INSTI, blocks integrase, an HIV enzyme crucial for viral replication. The combined action powerfully inhibits viral replication and lowers the viral load.
- Pharmacokinetics: All three drugs are absorbed orally. Tenofovir disoproxil fumarate is a prodrug which is metabolized to the active form, tenofovir. Lamivudine is primarily renally excreted, while Tenofovir is eliminated both renally and by metabolism. Dolutegravir is predominantly metabolized through uridine 5’-diphospho-glucuronosyltransferase (UGT)1A1 with renal excretion playing a minor role.
- Mode of action: Dolutegravir exerts its activity via binding to the active site of HIV integrase, inhibiting strand transfer. Tenofovir and lamivudine, following intracellular phosphorylation to their active moieties, inhibit HIV reverse transcriptase through chain termination.
- Elimination pathways: Lamivudine and Tenofovir disoproxil fumarate are primarily renally cleared. Dolutegravir undergoes glucuronidation via UGT1A1, with renal excretion playing a secondary role. It’s important to note that some drug interactions may affect these pathways.
Dosage
Standard Dosage
Adults:
One tablet containing Dolutegravir 50 mg/ Lamivudine 300 mg/ Tenofovir disoproxil fumarate 300 mg orally once daily, with or without food.
Children:
For children weighing at least 35 kg, the adult dose is appropriate. For children weighing less than 35 kg, the individual components of this combination must be dosed separately based on weight and guidelines specific for each drug.
Special Cases:
- Elderly Patients: No dose adjustment is generally needed unless significant renal impairment is present.
- Patients with Renal Impairment: Dose adjustment is usually required for creatinine clearance less than 50 ml/min for Tenofovir disoproxil fumarate and Lamivudine, and for those with severe impairment (CrCl<30 ml/min) or on dialysis with Dolutegravir. Refer to individual drug guidelines.
- Patients with Hepatic Dysfunction: Caution is advised in patients with hepatic impairment. Dosage adjustment might be necessary, especially for dolutegravir in severe hepatic dysfunction.
- Patients with Comorbid Conditions: Dosage modifications may be required based on coexisting conditions and concomitant medications.
Clinical Use Cases
This combination is specifically for HIV treatment and pre-exposure prophylaxis (PrEP), therefore dosage in settings such as intubation, surgical procedures, mechanical ventilation, ICU use, and other acute situations is not applicable. Other antiretrovirals might be utilized in these contexts, if needed, to maintain viral suppression.
Dosage Adjustments
Refer to individual component guidelines (Dolutegravir, Lamivudine, Tenofovir disoproxil fumarate) for specific dose adjustments for renal/hepatic dysfunction, other metabolic conditions, and other drug interactions.
Side Effects
Common Side Effects
Nausea, diarrhea, headache, fatigue, insomnia, and rash.
Rare but Serious Side Effects
Lactic acidosis, severe hepatomegaly with steatosis, immune reconstitution inflammatory syndrome, new-onset or worsening renal impairment, decreased bone mineral density, and hypersensitivity reactions.
Long-Term Effects
Changes in body fat distribution, dyslipidemia, hyperglycemia, and increased risk of cardiovascular disease with long term Tenofovir use. Regular monitoring is essential.
Adverse Drug Reactions (ADR)
Hepatotoxicity, renal impairment, lactic acidosis, pancreatitis, Stevens-Johnson syndrome, and severe skin reactions are serious ADRs requiring immediate medical attention.
Contraindications
Hypersensitivity to any component of the medication. Coadministration with Dofetilide.
Drug Interactions
- Many drug interactions can occur with this medication. Some important ones include:
- Dolutegravir: Interactions with certain antacids, calcium supplements, polyvalent cations like iron or magnesium, buffered medications, and other inducers/inhibitors of UGT1A1 can alter Dolutegravir levels.
- Lamivudine: Coadministration with Trimethoprim containing medications can increase Lamivudine plasma concentrations.
- Tenofovir disoproxil fumarate: Concurrent use with nephrotoxic drugs may increase the risk of renal toxicity. Didanosine and atazanavir/ritonavir can interact with Tenofovir.
- Always review concomitant medication lists for potential interactions with this combination therapy.
Pregnancy and Breastfeeding
- Dolutegravir, lamivudine, and tenofovir disoproxil fumarate can be used during pregnancy. Data suggests the combination is generally safe, however, neural tube defects have been reported with Dolutegravir use in the first trimester. The benefits of therapy for HIV-positive pregnant women often outweigh the potential risks.
- Lamivudine and tenofovir are present in human breast milk. Data suggests that the presence of dolutegravir in human milk is minimal, and there are no reported adverse effects in breastfed infants. A decision about breastfeeding should consider the risk of postnatal HIV transmission vs the benefits of breastfeeding.
Drug Profile Summary
- Mechanism of Action: Inhibits HIV reverse transcriptase (lamivudine and tenofovir disoproxil fumarate) and integrase (dolutegravir).
- Side Effects: Nausea, diarrhea, headache, insomnia, rash; rarely, lactic acidosis, hepatic steatosis, renal impairment, and hypersensitivity.
- Contraindications: Hypersensitivity to any component; Coadministration with Dofetilide.
- Drug Interactions: Multiple drug interactions exist, including medications such as efavirenz, rifampicin, antacids, calcium supplements, and nephrotoxic drugs.
- Pregnancy & Breastfeeding: Can be used with caution during pregnancy and breastfeeding. Monitor infant for any adverse effects.
- Dosage: One tablet (50 mg/300 mg/300 mg) once daily. Dose adjustments required in patients with renal impairment and certain other medical conditions.
- Monitoring Parameters: Renal function (serum creatinine, creatinine clearance, urine protein), hepatic function, HIV viral load, CD4+ cell count, serum lipids, and bone mineral density.
Popular Combinations
This medication itself represents a popular and recommended combination. Individual components may be used in other combinations based on resistance patterns or other patient factors.
Precautions
- General Precautions: Assess renal and hepatic function before and during treatment. Screen for HBV infection prior to initiation.
- Specific Populations: Caution in pregnancy (especially first trimester), breastfeeding (consider risk/benefit), and in patients with renal/hepatic impairment. Dosage adjustments needed in these populations.
- Lifestyle Considerations: Advise patients on adherence to therapy and potential drug interactions with alcohol and other medications.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Dolutegravir + Lamivudine + Tenofovir disoproxil fumarate?
A: One tablet (50 mg/300 mg/300 mg) once daily for adults and children weighing at least 35 kg.
Q2: What are the common side effects?
A: Common side effects include nausea, diarrhea, headache, fatigue, insomnia, and skin rash.
Q3: What are the major drug interactions?
A: This combination has numerous drug interactions. Key interactions include medications such as efavirenz, rifampicin, some antacids, calcium supplements, iron supplements, and nephrotoxic drugs. Always check for potential interactions.
Q4: Can this medication be used in pregnant or breastfeeding women?
A: It can be used with caution. Consult current treatment guidelines and weigh the benefits and risks. Monitor closely.
Q5: How should renal impairment be managed when using this combination?
A: Dose adjustments are necessary based on the degree of renal impairment. Refer to the specific guidelines for lamivudine and tenofovir.
Q6: What monitoring parameters are important for patients on this medication?
A: Monitor renal and hepatic function, HIV viral load, CD4 count, bone density, and lipid levels.
Q7: What should be done if a patient misses a dose?
A: Take the missed dose as soon as possible unless the next dose is within 4 hours. Do not double the next dose.
Q8: Is there a risk of lactic acidosis with this medication?
A: Yes, though rare, there’s a potential risk of lactic acidosis, especially in patients with risk factors.
Q9: What are the key contraindications for this drug?
A: Contraindications include hypersensitivity to any of the components and co-administration with dofetilide.
