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Dolutegravir

Generic name: dolutegravir systemic

Brand names: Tivicay, Tivicay PD

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Tivicay: 10 mg, 25 mg, 50 mg

Pharmacology

Mechanism of Action

Binds to the integrase active site and inhibits the strand transfer step of HIV-1 DNA integration necessary for the HIV replication cycle.

Pharmacokinetics/Pharmacodynamics

Absorption

Food increased the extent of absorption and slowed the rate of absorption of dolutegravir. Low-, moderate-, and high-fat meals increased dolutegravir AUC by 33%, 41%, and 66%, respectively; increased Cmax by 46%, 52%, and 67%, respectively; and prolonged Tmax to 3, 4, and 5 hours from 2 hours under fasted conditions, respectively.

Distribution

Vd/F = ~17.4 L

Metabolism

Primarily metabolized via UGT1A1 with some contribution from CYP3A

Excretion

Feces (53% as unchanged drug); urine (31% as metabolites, <1% as unchanged drug)

Time to Peak

2 to 3 hours

Half-Life Elimination

~14 hours

Protein Binding

≥98.9%

Use: Labeled Indications

HIV-1 infection, treatment: Treatment of HIV-1 infection in combination with other antiretroviral agents in adult and pediatric patients weighing at least 30 kg, or in combination with rilpivirine in adults to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA <50 copies per mL) on a stable antiretroviral regimen for at least 6 months with no history of treatment failure or known substitutions associated with resistance to either antiretroviral agent.

Use: Off Label

HIV-1 nonoccupational postexposure prophylaxisyes

Based on the Centers for Disease Control and Prevention, US Department of Health and Human Services updated guidelines for antiretroviral postexposure prophylaxis after sexual, injection drug use, or other nonoccupational exposure to HIV, dolutegravir (in conjunction with other antiretrovirals) is effective and recommended as postexposure prophylaxis of HIV-1 infection following nonoccupational exposure (nPEP) in individuals exposed to blood, genital secretions, or other potentially infectious body fluids that may contain HIV when that exposure represents a substantial risk for HIV transmission.

Contraindications

Hypersensitivity to dolutegravir or any component of the formulation; concurrent use with dofetilide

Dosage and Administration

Dosing: Adult

HIV-1 infection, treatment: Oral: Note: Must be given in combination with other antiretroviral agents. Dolutegravir is a component of recommended initial regimens for any antiretroviral therapy (ART)-naive adult or adolescent patient (when coadministered with tenofovir plus emtricitabine [or lamivudine]) or for ART-naive adult or adolescent patients who are HLA-B*5701 negative (when coadministered with abacavir plus lamivudine [or emtricitabine]) (HHS [adult] 2017).

Treatment naive or treatment-experienced integrase strand transfer inhibitor (INSTI)-naive: 50 mg once daily

Treatment naive or treatment-experienced INSTI-naive when coadministered with carbamazepine, efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, or rifampin: 50 mg twice daily

INSTI-experienced with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance (Note: Consult prescribing information for details): 50 mg twice daily

Virologically suppressed (HIV-1 RNA <50 copies/mL) patients switching to dolutegravir plus rilpivirine: 50 mg once daily

HIV-1 nonoccupational postexposure prophylaxis (nPEP) (off-label use): Oral: 50 mg once daily for 28 days (in combination with other antiretroviral agents). Initiate therapy within 72 hours of exposure (HHS [nPEP] 2016).

Dosing: Geriatric

Refer to adult dosing; use with caution.

Dosing: Pediatric

HIV-1 infection, treatment: Children and Adolescents weighing ≥30 kg: Note: Use in combination with other antiretroviral agents.

Treatment-naive or treatment-experienced integrase strand transfer inhibitor (INSTI)-naive: Oral:

30 kg to <40 kg: 35 mg once daily

≥40 kg: 50 mg once daily

Treatment-naive or treatment-experienced INSTI-naive when coadministered with carbamazepine, efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir or rifampin: Oral:

30 kg to <40 kg: 35 mg twice daily

≥40 kg: 50 mg twice daily

HIV-1 nonoccupational postexposure prophylaxis (nPEP) (HHS [nPEP] 2016): Adolescents weighing ≥40 kg: Oral: 50 mg once daily for 28 days in combination with other antiretroviral agents. Initiate therapy within 72 hours of exposure.

Administration

Administer without regard to meals. Administer 2 hours before or 6 hours after cation-containing antacids or laxatives, sucralfate, oral supplements containing iron or calcium, or buffered medications. Alternatively, dolutegravir and supplements containing calcium or iron can be taken together with food.

Dietary Considerations

Take 2 hours before or 6 hours after cation-containing antacids or laxatives, sucralfate, oral supplements containing iron or calcium, or buffered medications. Alternatively, dolutegravir and supplements containing calcium or iron can be taken together with food.

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Dispense 10 mg tablets in the original container; protect from moisture.

Drug Interactions

Aluminum Hydroxide: May decrease the serum concentration of Dolutegravir. Management: Administer dolutegravir at least 2 hours before or 6 hours after oral aluminum hydroxide. Administer the dolutegravir/rilpivirine combination product at least 4 hours before or 6 hours after oral aluminum hydroxide. Consider therapy modification

Calcium Salts: May decrease the serum concentration of Dolutegravir. Management: Administer dolutegravir at least 2 hours before or 6 hours after oral calcium. Administer dolutegravir/rilpivirine at least 4 hours before or 6 hours after oral calcium salts. Alternatively, dolutegravir and oral calcium can be taken together with food. Consider therapy modification

CarBAMazepine: May decrease the serum concentration of Dolutegravir. Management: Increase dolutegravir dose to 50 mg twice daily when used together with carbamazepine. Patients with known or suspected integrase strand inhibitor resistance should use an alternative to carbamazepine when possible. Consider therapy modification

Dofetilide: Dolutegravir may increase the serum concentration of Dofetilide. Avoid combination

Efavirenz: May decrease the serum concentration of Dolutegravir. Management: Increase dolutegravir dose to 50 mg twice daily in adults or children. Consider alternatives to efavirenz for INSTI experienced patients with clinically suspected INSTI resistance or certain INSTI associated resistance substitutions. Consider therapy modification

Etravirine: May decrease the serum concentration of Dolutegravir. Management: Avoid etravirine with dolutegravir unless with atazanavir/ritonavir, darunavir/ritonavir or lopinavir/ritonavir; avoid use with Dovato brand combination. Canada recommends using dolutegravir 50 mg twice daily when with etravirine without a boosted PI. Consider therapy modification

Fosamprenavir: May decrease the serum concentration of Dolutegravir. Specifically, Fosamprenavir/Ritonavir may decrease the serum concentration of Dolutegravir. The individual contributions of Fosamprenavir and Ritonavir to this effect are unknown. Management: Increase dolutegravir to 50 mg twice daily in adults and pediatric patients (12 yrs or older and at least 40 kg). Seek alternatives to fosamprenavir/ritonavir in INSTI-experienced patients with suspected or certain INSTI resistance. Consider therapy modification

Fosphenytoin-Phenytoin: May decrease the serum concentration of Dolutegravir. Avoid combination

Iron Preparations: May decrease the serum concentration of Dolutegravir. Management: Administer dolutegravir at least 2 hours before or 6 hours after oral iron. Administer dolutegravir/rilpivirine at least 4 hours before or 6 hours after oral iron. Alternatively, dolutegravir and oral iron can be taken together with food. Exceptions: Ferric Carboxymaltose; Ferric Derisomaltose; Ferric Gluconate; Ferric Hydroxide Polymaltose Complex; Ferric Pyrophosphate Citrate; Ferumoxytol; Iron Dextran Complex; Iron Sucrose. Consider therapy modification

Magnesium Salts: May decrease the serum concentration of Dolutegravir. Management: Administer dolutegravir at least 2 hours before or 6 hours after oral magnesium salts. Administer the dolutegravir/rilpivirine combination product at least 4 hours before or 6 hours after oral magnesium salts. Consider therapy modification

MetFORMIN: Dolutegravir may increase the serum concentration of MetFORMIN. Management: Consider the risks and benefits of this combination. If combined, limit the daily metformin dose to 1,000 mg when used with dolutegravir. Monitor for increased metformin effects/toxicities (including lactic acidosis) during concomitant use. Consider therapy modification

Multivitamins/Minerals (with ADEK, Folate, Iron): May decrease the serum concentration of Dolutegravir. Management: Administer dolutegravir at least 2 hours before or 6 hours after multivitamins. Administer the dolutegravir/rilpivirine product at least 4 hours before or 6 hours multivitamins. Alternatively, dolutegravir and multivitamins can be taken together with food Consider therapy modification

Multivitamins/Minerals (with AE, No Iron): May decrease the serum concentration of Dolutegravir. Management: Administer dolutegravir at least 2 hours before or 6 hours after multivitamins. Administer the dolutegravir/rilpivirine product at least 4 hours before or 6 hours multivitamins. Alternatively, dolutegravir and multivitamins can be taken together with food Consider therapy modification

Nevirapine: May decrease the serum concentration of Dolutegravir. Avoid combination

Orlistat: May decrease the serum concentration of Antiretroviral Agents. Monitor therapy

OXcarbazepine: May decrease the serum concentration of Dolutegravir. Avoid combination

PHENobarbital: May decrease the serum concentration of Dolutegravir. Avoid combination

Primidone: May decrease the serum concentration of Dolutegravir. Specifically, the Primidone metabolite phenobarbital may decrease Dolutegravir serum concentrations. Avoid combination

RifAMPin: May decrease the serum concentration of Dolutegravir. Management: Increase dolutegravir dose to 50 mg twice daily in adults or children. Consider alternatives to rifampin for INSTI experienced patients with clinically suspected INSTI resistance or certain INSTI associated resistance substitutions. Consider therapy modification

Selenium: May decrease the serum concentration of Dolutegravir. Management: Administer dolutegravir at least 2 hours before or 6 hours after oral selenium. Administer the dolutegravir/rilpivirine combination product at least 4 hours before or 6 hours after oral selenium. Consider therapy modification

St John's Wort: May decrease the serum concentration of Dolutegravir. Avoid combination

Sucralfate: May decrease the serum concentration of Dolutegravir. Management: Administer dolutegravir at least 2 hours before or 6 hours after sucralfate. Administer the dolutegravir/rilpivirine combination product at least 4 hours before or 6 hours after sucralfate. Consider therapy modification

Tipranavir: May decrease the serum concentration of Dolutegravir. Specifically, Tipranavir/Ritonavir may decrease the serum concentration of Dolutegravir. The individual contributions of Tipranavir and Ritonavir to this effect are unknown. Management: Increase dolutegravir dose to 50 mg twice daily in patients receiving tipranavir/ritonavir. Seek alternatives to tipranavir/ritonavir in INSTI experienced patients with suspected INSTI resistance or certain INSTI associated resistance substitutions. Consider therapy modification

Zinc Salts: May decrease the serum concentration of Dolutegravir. Management: Administer dolutegravir at least 2 hours before or 6 hours after oral zinc salts. Administer the dolutegravir/rilpivirine combination product at least 4 hours before or 6 hours after oral zinc salts. Consider therapy modification

Adverse Reactions

Adverse reactions reported with combination therapy.

>10%:

Endocrine & metabolic: Hyperglycemia (≤14%)

Hepatic: Increased serum alanine aminotransferase (≤18%; includes patients with hepatitis B and/or C infections)

1% to 10%:

Central nervous system: Insomnia (≤7%), fatigue (≤2%), headache (≤2%), suicidal ideation (<2%), suicidal tendencies (<2%), depression (≤1%)

Dermatologic: Pruritus (<2%)

Gastrointestinal: Increased serum lipase (2% to 10%), diarrhea (≤2%), abdominal distress (<2%), abdominal pain (<2%), flatulence (<2%), upper abdominal pain (<2%), vomiting (<2%), nausea (≤1%)

Hematologic & oncologic: Neutropenia (3% to 4%; grades 3/4: 2%), leukopenia (2% to 3%)

Hepatic: Increased serum aspartate aminotransferase (≤8%), hyperbilirubinemia (≤3%), hepatitis (<2%)

Hypersensitivity: Hypersensitivity reaction (≤1%)

Neuromuscular & skeletal: Increased creatine phosphokinase (1% to 7%), myositis (<2%)

Renal: Renal insufficiency (<2%)

<1%, postmarketing, and/or case reports: Abnormal dreams, acute hepatic failure, anxiety, arthralgia, dizziness, hepatotoxicity, immune reconstitution syndrome, increased serum creatinine, myalgia, skin rash, weight gain

Warnings/Precautions

Concerns related to adverse effects:

  • Hepatotoxicity: Hepatic adverse events, including elevated serum liver biochemistries, hepatitis, and acute liver failure, have been reported; these events have occurred in patients without underlying hepatic disease or other risk factors. Patients with hepatitis B or C may be at increased risk for worsening or development of increased transaminases; sometimes these increases were consistent with immune reconstitution syndrome or hepatitis B reactivation (particularly when anti-hepatitis therapy was withdrawn). Drug-induced liver injury has been reported with dolutegravir in combination with abacavir and lamivudine. Monitor patients for signs/symptoms of hepatotoxicity.
  • Hypersensitivity reactions: Rash, constitutional findings, and organ dysfunction (eg, liver injury) have been reported. Discontinue immediately if signs of hypersensitivity (eg, severe rash, rash with fever, malaise, fatigue, muscle/joint aches, blistering or peeling of skin, oral blisters/lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, difficulty breathing) occur. Monitor clinical status and liver function tests, and initiate supportive therapy as appropriate. If hypersensitivity occurs, do not reinitiate therapy with dolutegravir.
  • Immune reconstitution syndrome: Patients may develop immune reconstitution syndrome resulting in the occurrence of an inflammatory response to an indolent or residual opportunistic infection during initial HIV treatment or activation of autoimmune disorders (eg, Graves disease, polymyositis, Guillain-Barré syndrome) later in therapy; further evaluation and treatment may be required.

Disease-related concerns:

  • Hepatic impairment: Not recommended for use in patients with severe hepatic impairment (has not been studied).
  • Renal impairment: Use with caution in integrase strand transfer inhibitor (INSTI)-experienced patients with severe renal impairment; decreases in dolutegravir concentrations were observed and may result in loss of therapeutic effect and development of resistance to dolutegravir or other coadministered antiretroviral agents.

Concurrent drug therapy issues:

  • Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

  • Appropriate use: Use in INSTI-experienced patients should be guided by the number and type of baseline INSTI substitutions. Efficacy with 50 mg twice daily is reduced in patients with an INSTI-resistance Q148 substitution plus 2 or more additional INSTI-resistance substitutions, including T66A, L74I/M, E138A/K/T, G140S/A/C, Y143R/C/H, E157Q, G163S/E/K/Q, or G193E/R.

Monitoring Parameters

Viral load, CD4 count, lipid profile; liver aminotransferases (baseline and during therapy); monitor for hypersensitivity.

Pregnancy

Pregnancy Considerations

Dolutegravir has a high level of transfer across the human placenta.

A small but significant increase in neural tube defects (NTDs) was observed following maternal use of dolutegravir in a study conducted in Botswana. The risk of NTDs was increased in women who became pregnant while taking dolutegravir, but not in women who started dolutegravir during pregnancy. Data from the study, completed in an area without routine folate fortification via food, may not predict the risk in the United States. It is not known if folic acid supplementation would decrease the risk of NTDs in women taking dolutegravir; however, daily folic acid is recommended for all women who are pregnant or who might conceive.

Maternal antiretroviral therapy (ART) may be associated with adverse pregnancy outcomes including preterm delivery, stillbirth, low birth weight, and small for gestational age infants. Actual risks may be influenced by maternal factors such as disease severity, gestational age at initiation of therapy, and specific ART regimen; therefore, close fetal monitoring is recommended. Because there is clear benefit to appropriate treatment, maternal ART should not be withheld due to concerns for adverse neonatal outcomes. Long-term follow-up is recommended for all infants exposed to antiretroviral medications; children without HIV but who were exposed to ART in utero and develop significant organ system abnormalities of unknown etiology (particularly of the CNS or heart) should be evaluated for potential mitochondrial dysfunction.

The Health and Human Services (HHS) Perinatal HIV Guidelines consider dolutegravir a preferred integrase strand transfer inhibitor (INSTI) for pregnant females living with HIV who are antiretroviral-naive, who have had ART therapy in the past but are restarting, and who require a new ART regimen (due to poor tolerance or poor virologic response of current regimen). In addition, females who become pregnant while taking dolutegravir may continue if viral suppression is effective and the regimen is well tolerated. Dolutegravir is also a preferred component of an initial regimen when acute HIV infection is detected during pregnancy. The HHS Perinatal HIV Guidelines consider dolutegravir in combination with abacavir and lamivudine to be a preferred INSTI regimen for initial therapy in antiretroviral-naive pregnant females. Dolutegravir is recommended as an alternative agent for women who are not yet pregnant but are trying to conceive. INSTIs can rapidly suppress viral load. A regimen with dolutegravir may be useful when drug interactions or the potential for preterm delivery with protease inhibitors are a concern. In addition, use of dolutegravir may be beneficial in women living with HIV who are not on ART and present for care late in pregnancy, as a fourth drug in women with high viral loads, or as part of a new regimen for a woman experiencing virologic failure on ART. The potential risk of NTDs following in utero exposure should be discussed with the patient. Pharmacokinetics of dolutegravir may be altered, but dosing adjustments are not needed during pregnancy.

In general, ART is recommended for all pregnant females living with HIV to keep the viral load below the limit of detection and reduce the risk of perinatal transmission. Therapy should be individualized following a discussion of the potential risks and benefits of treatment during pregnancy. Monitoring of pregnant females is more frequent than in nonpregnant adults. ART should be continued postpartum for all females living with HIV and can be modified after delivery.

Health care providers are encouraged to enroll pregnant females exposed to antiretroviral medications as early in pregnancy as possible in the Antiretroviral Pregnancy Registry (1-800-258-4263 or http://www.APRegistry.com). Health care providers caring for pregnant females living with HIV and their infants may contact the National Perinatal HIV Hotline (1-888-448-8765) for clinical consultation (HHS [perinatal] 2019).

Patient Education

What is this drug used for?

  • It is used to treat HIV infection.

Frequently reported side effects of this drug

  • Headache
  • Trouble sleeping

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

  • Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.
  • Muscle pain
  • Joint pain
  • Mouth sores
  • Eye irritation
  • Shortness of breath
  • Severe loss of strength and energy
  • Infection
  • Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Source: Wolters Kluwer Health. Last updated January 31, 2020.