dolutegravir (Rx)

>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

Contraindications

Documented hypersensitivity

Coadministration with dofetilide due to the potential for increased dofetilide plasma concentrations and the risk for serious and/or life-threatening events

Cautions

Hypersensitivity reactions reported; characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury (see Contraindications)

Hepatic adverse events reported; patients with underlying hepatitis B or C may be at increased risk for worsening or development of transaminase elevations; in some cases, transaminase elevations were consistent with immune reconstitution syndrome or hepatitis B reactivation particularly in the setting where antihepatitis therapy was withdrawn

Hepatic toxicity, including elevated serum liver biochemistries, hepatitis, and acute liver failure reported without pre-existing hepatic disease or other identifiable risk factors; drug-induced liver injury leading to liver transplant reported; monitoring for hepatotoxicity recommended

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy; may develop an inflammatory response to indolent or residual opportunistic infections (eg, Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia [PCP], or tuberculosis) or autoimmune disorders (eg, Graves disease, polymyositis, and Guillain-Barré syndrome)

Dosage forms (ie, tablets and tablets for oral suspension) are not bioequivalent and are not interchangeable on a mg-per-mg basis; if a pediatric patient switches from one formulation to the other, the dose must be adjusted for the new dosage formulation; incorrect dosing of a given formulation may result in underdosing and loss of therapeutic effect and possible resistance or clinically significant adverse reactions from greater exposure of dolutegravir

Dosage forms are not interchangeable on a milligram per milligram basis; dose must be adjusted for new dosage formulation; incorrect dosing may lead to loss of therapeutic effect when underdosing and clinically significant adverse reactions when overdosing

Potential risk of neural tube birth defects (see Pregnancy)

Drug interaction overview

• Coadministration with certain drugs may result in known or potentially significant drug interactions, some of which may lead to loss of therapeutic effect and possible resistance, or significant adverse reactions of other from increase systemic exposure
• Inducers of UGT1A1 and CYP3A (eg, oxcarbazepine, phenytoin, phenobarbital, carbamazepine, St John’s wort, rifampin) decrease dolutegravir
• Coadministration with medications containing polyvalent cations decrease dolutegravir systemic exposure; give dolutegravir 2 hr before or 6 hr after polyvalent cations (eg, antacids, laxatives, sucralfate, iron supplements, calcium supplements, buffered medications)
• Dolutegravir may increase plasma concentrations of drugs eliminated via OCT2 or MATE1 (dofetilide and metformin)

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

Initiation of therapy is not recommended in individuals actively trying to become pregnant unless there is no suitable alternative; a benefit-risk assessment should consider factors such as feasibility of switching, tolerability, ability to maintain viral suppression, and risk of transmission to infant against risk of neural tube defects

In adolescents and adults of childbearing potential currently receiving therapy who are actively trying to become pregnant, or if pregnancy is confirmed in the first trimester, assess risks and benefits of continuing therapy versus switching to another antiretroviral regimen and consider switching to an alternative regimen

Advise pregnant adolescents and adults of potential risk to embryo exposed to drug from time of conception through first trimester of pregnancy; a benefit-risk assessment should consider factors such as feasibility of switching, tolerability, ability to maintain viral suppression, and risk of transmission to infant against risk of neural tube defects

Perform pregnancy testing in adolescents and adults of childbearing potential before initiation of therapy

In animal reproduction studies, no evidence of adverse developmental outcomes was observed during organogenesis

Contraception

• In adolescents and adults of childbearing potential currently receiving therapy who are actively trying to become pregnant, or if pregnancy is confirmed in first trimester, assess risks and benefits of continuing treatment versus switching to another antiretroviral regimen and consider switching to an alternative regimen
• Counsel adolescents and adults of childbearing potential who are taking drug to consistently use effective contraception

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
• Data from a birth outcome surveillance study has identified an increased risk of neural tube defects when therapy is administered at time of conception compared with non- dolutegravir-containing antiretroviral regimens
• As defects related to closure of neural tube occur from conception through the first 6 weeks of gestation, embryos exposed to dolutegravir from the time of conception through first 6 weeks of gestation are at potential risk
• In addition, 2 of birth defects (encephalocele and iniencephaly), which have been observed with therapy, although often termed neural tube defects, may occur post-neural tube closure, the time period of which may be later than 6 weeks of gestation, but within the first trimester

• 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

It is 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

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Integrase strand transfer inhibitor (INSTI); inhibits catalytic activity of HIV-1 integrase, an HIV encoded enzyme required for viral replication

Absorption

Peak plasma time: 2-3 hr

Peak plasma concentration: 3.67-4.15 mcg/mL

AUC 53.6-75.1 mcg•h/mL

Distribution

Protein bound: ≥98.9%

Vd: 17.4 L; 4-232 ng/mL (CSF)

Metabolism

Metabolized by UGT1A1 with some contribution from CYP3A

Elimination

Half-life: 14 hr

Clearance: 1 L/hr

Excretion: 53% feces (unchanged); 31% urine (as ether glucuronide, benzylic carbon, or N-dealkylation product); <1% urine (unchanged)

Oral Administration

May take with or without food

Dosage forms (ie, tablets and tablets for oral suspension) are not bioequivalent and are not interchangeable on a mg-per-mg basis

Tablets for oral suspension

• Do not chew, cut, or crush
• Swallow tablets for oral suspension whole (if >1 tablet required, swallow 1 tablet at a time to reduce choking risk), or
• Fully disperse tablets for oral suspension in 5 mL of drinking water (if using 1-3 tablets for oral suspension) or 10 mL (if using 4-6 tablets for oral suspension) in the supplied cup; swirl suspension so that no lumps remain; after full dispersion, administer oral suspension within 30 minutes of mixing