DOLUTEGRAVIR SODIUM
Clinical safety rating: caution
Comprehensive clinical and safety monograph for DOLUTEGRAVIR SODIUM (DOLUTEGRAVIR SODIUM).
Integrase strand transfer inhibitor (INSTI); inhibits HIV-1 integrase, blocking viral DNA integration into host genome.
| Metabolism | Primarily metabolized by UGT1A1 with minor contribution by CYP3A4. |
| Excretion | Primarily (64%) excreted unchanged in feces via biliary secretion; 31% in urine, of which 18.9% is unchanged drug and the rest as glucuronide conjugate (5.1%) and other minor metabolites. Total clearance: 0.56 L/h. |
| Half-life | Terminal elimination half-life is approximately 14 hours (range 11-17 hours) in healthy subjects; supports once-daily dosing. Half-life may be prolonged in severe renal impairment but no dose adjustment required. |
| Protein binding | Approximately 99% bound to human plasma proteins, primarily to albumin. |
| Volume of Distribution | Apparent volume of distribution is 17.4 L (approximately 0.25 L/kg for a 70 kg adult), indicating distribution into tissues beyond plasma water. |
| Bioavailability | Oral bioavailability is not determined due to lack of intravenous formulation; however, absorption is rapid with Tmax of 2-3 hours. Food reduces Cmax by 28% and AUC by 9%, but does not affect clinical efficacy; therefore, can be taken with or without food. |
| Onset of Action | Oral: Onset of virologic suppression begins within 1-2 weeks of therapy; maximal antiviral effect achieved by 4-6 weeks. |
| Duration of Action | Duration of antiviral effect is 24 hours with once-daily dosing, based on trough concentrations exceeding protein-adjusted 90% inhibitory concentration (IC90) for wild-type HIV-1. Clinical duration of suppression sustained with continuous therapy. |
50 mg orally once daily, with or without food. For INSTI-naive patients, 50 mg twice daily when co-administered with potent UDP-glucuronosyltransferase (UGT)1A1 or CYP3A inducers (e.g., efavirenz, nevirapine, tipranavir/ritonavir, rifampin).
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to severe renal impairment (CrCl <30 mL/min). Not studied in dialysis; use with caution. |
| Liver impairment | Child-Pugh Class A: No adjustment. Child-Pugh Class B: Use with caution; no specific dose recommendation. Child-Pugh Class C: Not recommended (no data). |
| Pediatric use | Weight-based dosing: <20 kg: 5 mg/kg once daily; 20 to <40 kg: 35 mg once daily; ≥40 kg: 50 mg once daily. Maximum dose 50 mg. For INSTI-naive adolescents (≥12 years and ≥40 kg): 50 mg once daily. |
| Geriatric use | No specific dose adjustment; limited data in patients >65 years. Monitor renal function due to age-related decline, though no renal dose adjustment required. Consider potential for increased adverse effects due to comorbidities and polypharmacy. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for DOLUTEGRAVIR SODIUM (DOLUTEGRAVIR SODIUM).
| Breastfeeding | Dolutegravir is excreted into human breast milk. The milk-to-plasma ratio (M/P ratio) is approximately 0.022. Infant exposure via breast milk is estimated to be about 2% of the maternal weight-adjusted dose. The American Academy of Pediatrics recommends breastfeeding in HIV-infected women on effective antiretroviral therapy with undetectable viral load. However, due to the potential for adverse effects in the infant, caution is advised. |
| Teratogenic Risk | Dolutegravir is associated with an increased risk of neural tube defects (NTDs) when used at the time of conception and during the first trimester. The absolute risk of NTDs is approximately 0.3% (3 per 1000 pregnancies) based on observed data from the Tsepamo study. For second and third trimester exposure, no increased risk of major malformations has been identified. Overall, the risk is highest with periconceptional use. |
■ FDA Black Box Warning
No FDA boxed warning.
| Serious Effects |
["Hypersensitivity to dolutegravir or any component of the formulation","Co-administration with dofetilide or pilsicainide"]
| Precautions | ["Hypersensitivity reactions (e.g., rash, hepatic toxicity)","Hepatotoxicity in patients with pre-existing liver disease or co-infection with HBV/HCV","Immune reconstitution syndrome","Decreased renal function when co-administered with nephrotoxic agents","Risk of neural tube defects if administered at time of conception or early pregnancy"] |
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| Fetal Monitoring | Monitor maternal complete blood count, renal and hepatic function, and HIV RNA viral load regularly. Fetal ultrasound should be performed at 18-20 weeks of gestation to assess for neural tube defects if dolutegravir was used at conception or during the first trimester. Additionally, monitor for signs of lactic acidosis or hepatotoxicity in the mother. |
| Fertility Effects | Dolutegravir has not been associated with clinically significant effects on male or female fertility in human studies. Preclinical studies showed no adverse effects on fertility or reproductive performance. |