Dolutegravir


Concise Prescribing Info
Indications/Uses
HIV-1 infection.
Dosage/Direction for Use
Adult : PO In combination with other antiretroviral agents: Patients without documented or clinically suspected resistance to integrase inhibitors: 50 mg once daily. Patients with documented or clinically suspected resistance to integrase inhibitors: 50 mg bid. In combination with rilpivirine to replace current antiretroviral regimen in virologically suppressed (HIV-1 RNA <50 copies/mL) patients: 50 mg once daily.
Dosage Details
Oral
HIV-1 infection
Adult: In combination with other antiretroviral agents: Patients without documented or clinically suspected resistance to integrase inhibitors: 50 mg once daily. Patients with documented or clinically suspected resistance to integrase inhibitors: 50 mg bid, preferably with food. In combination with rilpivirine to replace current antiretroviral regimen in virologically suppressed (HIV-1 RNA <50 copies/mL) patients: 50 mg once daily.
Child: In combination with other antiretroviral agents: Patients without resistance to integrase inhibitors: 6-<12 years 15-<20 kg: 20 mg once daily; 20-<30 kg: 25 mg once daily; 30-<40 kg: 35 mg once daily; ≥40 kg: 50 mg once daily. 12-<18 years ≥40 kg: 50 mg once daily.
Special Patient Group
Patient (without integrase inhibitor resistance) concomitantly taking carbamazepine, rifampicin, efavirenz, nevirapine, tipranavir/ritonavir, fosamprenavir/ritonavir, etravirine (without boosted protease inhibitors), oxcarbazepine, phenytoin, phenobarbital, St. John’s wort: In combination with other antiretroviral agents:
Adult: 50 mg bid.
Child: 6-<12 years 15-<20 kg: 20 mg bid; 20-<30 kg: 25 mg bid; 30-<40 kg: 35 mg bid; ≥40 kg: 50 mg bid. 12-<18 years ≥40 kg: 50 mg bid.

Pharmacogenomics:

Dolutegravir is mainly metabolised via glucuronidation by UGT1A1 enzyme and to a lesser extent by CYP3A enzyme component. UGT1A1 polymorphism may affect the pharmacokinetic response of dolutegravir in certain patients. Individuals with UGT1A1 genotypes that confer poor dolutegravir metabolism are known as poor metabolisers while those with UGT1A1 genotype that confer normal dolutegravir metabolism are known as normal metabolisers.

EMA and FDA-approved drug labels for dolutegravir cited that results from a meta-analysis using pharmacogenomics samples collected in healthy subjects in clinical studies indicate that UGT1A1 poor metabolisers had a 32% lower dolutegravir clearance and a 46% higher dolutegravir exposure as compared with UGT1A1 normal metabolisers. Studies in individuals with HIV infection having UGT1A1 gene polymorphism also showed significant increase in dolutegravir trough concentrations compared to patients with normal allele. However, there is no evidence that common polymorphisms in drug metabolising enzymes alter dolutegravir pharmacokinetics to a clinically meaningful extent. Therefore, dosage adjustments are not necessary based on UGT1A1 polymorphisms.

Pharmacogenetic testing prior to initiating dolutegravir treatment has not been addressed by currently available references.
Administration
May be taken with or without food.
Contraindications
Hypersensitivity to dolutegravir. Lactation. Concomitant use with dofetilide.
Special Precautions
Patient with hepatitis B or C co-infection; integrase inhibitor resistance Q148 mutation with ≥2 secondary mutations including, but not limited to G140A/C/S, E138A/K/T, or L74I; history of depression or psychiatric illness. Severe renal and hepatic impairment. Children. Pregnancy. UGT1A1 poor metabolisers. Avoid concomitant use with metabolic inducers such as etravirine (without boosted protease inhibitors), efavirenz, nevirapine, tipranavir/ritonavir, fosamprenavir/ritonavir, rifampicin, carbamazepine, and St. John’s wort in patient with integrase inhibitor resistance.
Adverse Reactions
Significant: Hepatotoxicity (e.g. elevated serum liver biochemistry, hepatitis, acute liver failure), immune reconstitution syndrome including autoimmune disorders (e.g. Graves’ disease, polymyositis, Guillain-Barré syndrome), opportunistic infections, osteonecrosis. Rarely, neural tube defects (during early pregnancy).
Gastrointestinal disorders: Diarrhoea, nausea, vomiting, flatulence, abdominal pain and discomfort.
General disorders and administration site conditions: Fatigue.
Investigations: Increased creatine phosphokinase, serum lipase, total bilirubin.
Metabolism and nutrition disorders: Hyperglycaemia.
Nervous system disorders: Headache, dizziness.
Psychiatric disorders: Insomnia, anxiety, depression, abnormal dreams; suicidal ideation or attempt.
Skin and subcutaneous tissue disorders: Rash, pruritus.
Potentially Fatal: Hypersensitivity reactions (e.g. rash, organ dysfunction including liver injury, constitutional findings).
Patient Counseling Information
This drug may cause dizziness, if affected, do not drive or operate machinery. Women of childbearing potential (WOCBP) must use effective contraception throughout treatment.
MonitoringParameters
Perform pregnancy testing in WOCBP prior to initiation of treatment. Assess the risks and benefits of continuing dolutegravir versus switching to another antiretroviral and consider switching to an alternative regimen for WOCBP seeking to become pregnant or with confirmed pregnancy (within the 1st trimester) during treatment. Monitor viral load, CD4 count, lipid profile; LFTs at baseline and periodically during treatment; signs and symptoms of hypersensitivity.
Drug Interactions
Decreased plasma concentrations with etravirine (without boosted protease inhibitors), efavirenz, nevirapine, tipranavir/ritonavir, carbamazepine, oxcarbazepine, phenytoin, phenobarbital, rifampicin. Increased plasma levels of metformin and fampridine. May reduce the absorption of dolutegravir with concomitant use of Mg- or Al-containing antacids, Fe or Ca supplements, including multivitamins; sucralfate. Elevated plasma concentrations with atazanavir.
Potentially Fatal: May increase the plasma concentration of dofetilide thus increasing the risk of serious adverse effects.
Food Interaction
Slowed rate and increased extent of absorption with high-fat meals. May decrease plasma levels of dolutegravir with St. John’s wort.
Action
Description: Dolutegravir is an inhibitor of HIV integrase that binds to integrase active site and blocks the strand transfer step of retroviral DNA integration, thereby preventing the HIV replication cycle.
Pharmacokinetics:
Absorption: Rapidly absorbed from the gastrointestinal tract. Slowed rate and increased extent of absorption with food, particularly high-fat meals. Time to peak plasma concentration: 2-3 hours.
Distribution: Present in male and female genital tract, and CSF. Crosses the placenta and enters breast milk. Volume of distribution: Approx 17.4 L. Plasma protein binding: ≥98.9%.
Metabolism: Metabolised in the liver via glucuronidation primarily by uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), and to a lesser extent by CYP3A isoenzyme.
Excretion: Mainly via faeces (53% as unchanged drug); urine (31% as metabolites, <1% as unchanged drug). Elimination half-life: Approx 14 hours.
Chemical Structure

Click on icon to see table/diagram/image
Storage
Store between 15-30°C. Protect from moisture.
MIMS Class
ATC Classification
J05AX12 - dolutegravir ; Belongs to the class of other antivirals. Used as a direct acting antiviral in the systemic treatment of viral infections.
Disclaimer: This information is independently developed by MIMS based on Dolutegravir from various references and is provided for your reference only. Therapeutic uses, prescribing information and product availability may vary between countries. Please refer to MIMS Product Monographs for specific and locally approved prescribing information. Although great effort has been made to ensure content accuracy, MIMS shall not be held responsible or liable for any claims or damages arising from the use or misuse of the information contained herein, its contents or omissions, or otherwise. Copyright © 2020 MIMS. All rights reserved. Powered by MIMS.com
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