DOLUTEGRAVIR
Clinical safety rating: caution
Comprehensive clinical and safety monograph for DOLUTEGRAVIR (DOLUTEGRAVIR).
Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral DNA integration, which is essential for HIV replication.
| Metabolism | Dolutegravir is primarily metabolized by UGT1A1, with minor contribution from CYP3A4. It is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). |
| Excretion | Dolutegravir is primarily eliminated via metabolism, with approximately 53% excreted unchanged in feces and 32% in urine. Renal excretion of unchanged drug is minimal (<1%). Biliary excretion contributes to fecal elimination. |
| Half-life | Terminal elimination half-life is approximately 14 hours (range 11-16 hours) following oral administration. This supports once-daily dosing in most patients; however, with concomitant UGT1A1/CYP3A4 inducers (e.g., efavirenz, rifampin), half-life may be reduced, necessitating twice-daily dosing. |
| Protein binding | Dolutegravir is approximately 99% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | Volume of distribution is approximately 17-20 L (0.3-0.4 L/kg in adults), indicating moderate distribution into tissues, including the central nervous system (CSF concentrations are about 0.5-1% of plasma levels). |
| Bioavailability | Oral bioavailability is not well characterized but is at least 70% based on absorption; food increases absorption by up to 40%, but no dose adjustment is required. Absolute bioavailability has not been determined due to lack of an intravenous formulation. |
| Onset of Action | Not applicable for oral route (prophylactic therapy); peak plasma concentrations occur at 2-3 hours after oral administration. Virologic suppression is typically achieved within 4-8 weeks of continuous therapy. |
| Duration of Action | Duration of action is 24 hours with once-daily dosing due to sustained virologic suppression and plasma concentrations above the protein-adjusted 90% inhibitory concentration (IC90) throughout the dosing interval. |
| Molecular Weight | 419.38 |
50 mg orally once daily; for integrase strand transfer inhibitor-naïve patients, 50 mg orally twice daily if coadministered with efavirenz, nevirapine, tipranavir/ritonavir, or rifampin.
| Dosage form | FILM |
| Renal impairment | No dose adjustment required for creatinine clearance ≥30 mL/min; insufficient data for <30 mL/min or hemodialysis; use with caution. |
| Liver impairment | Child-Pugh Class A or B: no adjustment; Child-Pugh Class C: not recommended (no data). |
| Pediatric use | For body weight ≥40 kg: 50 mg once daily; for weight 20 kg to <40 kg: 35 mg once daily; for weight 14 kg to <20 kg: 25 mg once daily; for weight <14 kg: not established. |
| Geriatric use | No specific dose adjustment; monitor renal function and potential for QT prolongation (dolutegravir has minimal risk). |
| 1st trimester | Use is generally avoided due to potential risk of neural tube defects, but if benefit outweighs risk, consider use with folic acid supplementation. |
| 2nd trimester | Can be used if indicated; no increased risk of major malformations in second trimester use. |
| 3rd trimester | Can be used; no evidence of adverse fetal outcomes in third trimester. |
Clinical note
Comprehensive clinical and safety monograph for DOLUTEGRAVIR (DOLUTEGRAVIR).
| Placental transfer | Extensive placental transfer observed; umbilical cord plasma concentrations approximately 84-90% of maternal plasma concentrations. |
| Breastfeeding | Dolutegravir is excreted in human breast milk at low concentrations. Avoid breastfeeding or discontinue drug due to potential for infant toxicity and HIV transmission via breast milk. |
■ FDA Black Box Warning
There is no black box warning for dolutegravir. However, postmarketing cases of hepatotoxicity, including acute liver injury and hepatic failure, have been reported.
| Serious Effects |
Hypersensitivity to dolutegravir or any component of the formulationConcomitant use with dofetilide
| Precautions | Hepatotoxicity: Cases of hepatic injury, including elevated liver enzymes, hepatitis, and acute hepatic failure, have been reported, particularly in patients with underlying liver disease or coinfections (e.g., hepatitis B or C)., Hypersensitivity reactions: Allergic reactions including rash, fever, and organ dysfunction have occurred; discontinue if signs of severe hypersensitivity develop., Lactic acidosis and severe hepatomegaly with steatosis: Reported with nucleoside analogs (though dolutegravir is not a NRTI, caution in combination therapy)., Immune reconstitution syndrome: Inflammatory response to indolent or residual opportunistic infections may occur during initial treatment., Neural tube defects: Data from an observational study showed a slightly increased risk of neural tube defects in infants born to women exposed to dolutegravir at the time of conception. Advise patients of this risk and discuss contraceptive options., Resistance: Potential for cross-resistance with other integrase strand transfer inhibitors (e.g., raltegravir, elvitegravir) when specific integrase mutations are present. |
Loading safety data…
| Lactation Rating |
| L3 (Moderately Safe) but contraindicated due to HIV transmission risk |
| Teratogenic Risk | Dolutegravir is associated with a higher risk of neural tube defects (NTDs) when used at conception and during the first trimester. The absolute risk is approximately 0.3% (compared to 0.1% background). Limited data in second and third trimesters suggest no increased risk of other major malformations. |
| Fetal Monitoring | Monitor maternal HIV viral load every 2-4 weeks during pregnancy and at delivery. Assess for adverse effects including hepatotoxicity and hypersensitivity. Perform fetal ultrasound at 18-20 weeks to screen for neural tube defects if exposed in first trimester. Monitor infant for hyperbilirubinemia (theoretical risk due to UGT1A1 inhibition). |
| Fertility Effects | No significant adverse effects on male or female fertility have been reported in animal studies or human data. Dolutegravir does not impair spermatogenesis or ovulation. |
| Food/Dietary | Dolutegravir can be taken with or without food. However, if taken with a meal, the absorption is slightly increased, which may be beneficial. Avoid taking dolutegravir with antacids or supplements containing calcium, iron, or magnesium; separate by at least 2 hours (or 6 hours if taken with a meal). Do not take with dofetilide or pilsicainide. No significant interactions with alcohol, but excessive alcohol should be avoided due to hepatotoxicity risk. |
| Clinical Pearls | Dolutegravir is an integrase strand transfer inhibitor (INSTI) used in combination antiretroviral therapy for HIV-1. It has a high barrier to resistance and a low potential for drug-drug interactions compared to other antiretrovirals. Do not co-administer with dofetilide or pilsicainide due to risk of arrhythmias. Contraindicated in patients with known hypersensitivity to dolutegravir. Use in pregnancy: avoid during first trimester due to neural tube defect risk; consider alternative therapy in women of childbearing potential unless effective contraception is used. Monitor for signs of immune reconstitution syndrome. Dolutegravir may cause hepatotoxicity, especially in those with hepatitis B or C co-infection. Administer with or without food; however, antacids and iron or calcium supplements should be separated by at least 2 hours (or 6 hours if taken with a meal) as they reduce absorption. |
| Patient Advice | Take dolutegravir exactly as prescribed every day at the same time, with or without food. · Do not skip doses or stop treatment without consulting your doctor, as this can lead to drug resistance. · If you are pregnant or planning to become pregnant, tell your doctor immediately; dolutegravir may harm an unborn baby during the first trimester. · If you are able to become pregnant, use effective contraception while taking dolutegravir. · Avoid taking antacids, iron supplements, or calcium supplements within 2 hours of dolutegravir (or 6 hours if taken with a meal). · Report symptoms of liver problems: yellowing of skin or eyes, dark urine, light-colored stools, abdominal pain, or unexplained fatigue. · Seek medical help if you experience signs of an allergic reaction: rash, hives, swelling of face/lips/tongue, or difficulty breathing. · Inform your healthcare provider of all medications and supplements you take to avoid interactions. · Dolutegravir does not cure HIV, prevent transmission, or treat opportunistic infections; use safer sex practices and regular monitoring. |