Dolutegravir

Dolutegravir is used for: HIV-1 infection

Oral HIV-1 infection Adult: In combination with other antiretrovirals: In patient without resistance to integrase inhibitors: 50 mg once daily. In patient with resistance, or concomitant use with other medication (e.g. carbamazepine, rifampicin, tipranavir/ritonavir, efavirenz, nevirapine): 50 mg bid. Hepatic impairment Mild-to-moderate hepatic impairment (Child-Pugh A or B): No dosage adjustment required Severe hepatic impairment (Child-Pugh C): Not recommended

Oral HIV-1 infection Child: In patient 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.

Renal impairment Plasma concentrations were decreased in subjects with severe renal impairment No dosage adjustment required for treatment-naïve or treatment-experienced and INSTI-naïve patients with mild, moderate, or severe renal impairment or for INSTI-experienced patients (with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance) with mild or moderate renal impairment Severe renal impairment in for INSTI-experienced patients with resistance: Not recommended; decrease in dolutegravir concentrations may result in loss of therapeutic effect and development of resistance

May be taken with or without food.

Hypersensitivity. Lactation. Concomitant use with dofetilide.

Patient with hepatitis B or C co-infection. Severe renal and hepatic impairment. Children. Pregnancy.

Pregnancy A pregnancy exposure registry monitors pregnancy outcomes in women during pregnancy; healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263 There are insufficient human data on use during pregnancy to inform a drug-associated risk of birth defects and miscarriage; given the limited number of pregnancies exposed to dolutegravir-based regimens reported to APR, no definitive conclusions can be drawn on safety in pregnancy, and continued monitoring is ongoing through the APR In animal reproduction studies, no evidence of adverse developmental outcomes was observed during organogenesis Potential risk of neural tube birth defects Serious cases of neural tube birth defects involving the brain, spine, and spinal cord reported in babies born to women treated with dolutegravir Preliminary results from an ongoing observational study in Botswana found women who had received dolutegravir at the time of becoming pregnant or early in the first trimester appear to be at higher risk for these defects; to date, in this observational study there are no reported cases of babies born with neural tube defects to women starting dolutegravir later in pregnancy Recommendations Patients should not discontinue dolutegravir without consulting a healthcare professional because stopping your medicine can cause the HIV infection to worsen Pregnant women stopping dolutegravir-containing regimen without switching to alternative HIV medicines could cause the amount of virus to increase and spread HIV to your baby Patients taking a dolutegravir-containing regimen at the time of becoming pregnant and during the first trimester of pregnancy, there is a potential risk of neural tube defects; neural tube defects happen early in pregnancy, before many women even know they are pregnant Inform women of childbearing age about the potential risk of neural tube defects when a dolutegravir-containing regimen is used at the time of conception and early in pregnancy; women of childbearing age should consult their healthcare providers about other non-dolutegravir-containing antiretroviral medicine Healthcare providers should weigh the benefits and the risks of dolutegravir when prescribing antiretroviral medicines to women of childbearing age; consider alternative antiretroviral medicines; discuss the relative risks and benefits of appropriate alternative antiretroviral therapies Women of childbearing age who decide to take a dolutegravir-containing regimen should consistently use effective birth control (contraception) while on HIV treatment; women should discuss their healthcare professionals about an effective birth control method to use while taking a dolutegravir-containing regimen Perform pregnancy testing before initiating a dolutegravir-containing regimen in women of childbearing age to exclude pregnancy Lactation The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed infants to avoid risking postnatal transmission of HIV-1 infection; not known whether drug is present in human breast milk, affects human milk production, or has effects on breastfed infant; when administered to lactating rats, dolutegravir was present in milk Because of potential for (1) HIV-1 transmission (in HIV-negative infants), and (2) developing viral resistance (in HIV-positive infants), instruct mothers not to breastfeed if they are receiving drug therapy

May increase plasma concentration of metformin. Decreased plasma concentration with nevirapine, oxcarbazepine, phenobarbital, primidone. Reduced absorption with antacids, laxatives, Fe, Ca or mineral supplements. Potentially Fatal: May increase plasma concentration and increase the risk of adverse effects (e.g. torsade de pointes) of dofetilide.

Side effects of Dolutegravir : >10% Increased cholesterol and triglycerides (up to 17%) 1-10% Increased lipase (1-8%) Hyperglycemia (<1-7%) Increased creatinine kinase (3-4%) Increased AST (2-3%) Insomnia (<1-3%) Increased ALT (2%) Increased bilirubin (<1-2%) Headache (<1-2%) GI disorders (<2%) Fatigue (<2%) Hepatitis (<2%) Myositis (<2%) Renal impairment (<2%) Pruritus (<2%) Nausea (<1-1%) <1% Abnormal dreams Dizziness Diarrhea Rash Vertigo Postmarketing Reports Arthralgia Myalgia Hepatobiliary Disorders Acute liver failure, hepatotoxicity Musculoskeletal Psychiatric Anxiety

Dolutegravir inhibits HIV integrase by binding to its active site and blocking the strand transfer step of retroviral DNA integration, thereby preventing viral replication.