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Dolutegravir

Medically reviewed by Drugs.com. Last updated on Jun 19, 2020.

Pronunciation

(doe loo TEG ra vir)

Index Terms

  • Dolutegravir Sodium
  • S/GSK1349572

Dosage Forms

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

Tablet, Oral:

Tivicay: 10 mg, 25 mg, 50 mg

Tablet Soluble, Oral:

Tivicay PD: 5 mg

Brand Names: U.S.

  • Tivicay
  • Tivicay PD

Pharmacologic Category

  • Antiretroviral, Integrase Inhibitor (Anti-HIV)

Pharmacology

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

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 treatment-naïve or -experienced adult patients and treatment-naïve or -experienced pediatric patients (but integrase strand transfer inhibitor naïve) at least 4 weeks of age and weighing at least 3 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.

Off Label Uses

HIV-1 nonoccupational postexposure prophylaxis

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.

Canadian labeling: Additional contraindications (not in US labeling): Concurrent use with organic cation transporter 2 substrates with narrow therapeutic windows (eg, fampridine).

Dosing: Adult

HIV-1 infection, treatment: Oral: Note: Must be given in combination with other antiretroviral agents.

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).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Geriatric

Refer to adult dosing; use with caution.

Dosing: Pediatric

Note: Dolutegravir tablets (Tivicay) and soluble tablets for oral suspension (Tivicay PD) are not bioequivalent and are not substitutable on a mg per mg basis.

HIV-1 infection, treatment: Note: Use in combination with other antiretroviral (ARV) agents. Gene mutation and ARV resistance patterns should be evaluated (refer to https://www.iasusa.org for more information) when necessary.

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

Infants and Children weighing 3 to <14 kg: Oral:

Soluble tablets for oral suspension (Tivicay PD):

3 to <6 kg: 5 mg once daily.

6 to <10 kg: 15 mg once daily.

10 to <14 kg: 20 mg once daily.

Infants, Children, and Adolescents weighing ≥14 kg: Oral:

Soluble tablets for oral suspension (Tivicay PD): Preferred in patients <20 kg:

14 to <20 kg: 25 mg once daily.

≥20 kg: 30 mg once daily.

Tablets (Tivicay):

14 to <20 kg: 40 mg once daily.

≥20 kg: 50 mg once daily.

INSTI-experienced with any INSTI-associated resistance mutation or clinically suspected INSTI resistance: Limited data available (HHS [pediatric 2020]):

Children and Adolescents weighing ≥40 kg: Oral: Tablets (Tivicay): 50 mg twice daily.

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

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

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 to 50 mg twice/day in adults. Increase weight based dose to twice daily in pediatric patients. See interaction monograph for details. Seek alternative to carbamazepine if suspected INSTI resistance. Consider therapy modification

Dalfampridine: Dolutegravir may increase the serum concentration of Dalfampridine. Management: Consider alternatives to this combination. Carefully weigh the risk of seizures against the benefit of combining dolutegravir with dalfampridine. Non-US labels list this combination as contraindicated. 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 to 50 mg twice/day in adults. Increase weight based dose to twice daily in pediatric patients. See interaction monograph for details. Not recommended with Dovato or Juluca combo products. Seek alternatives if INSTI resistance. 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/day in adults. Increase weight based dose to twice daily in pediatric patients. See interaction monograph for details. Not recommended with Dovato or Juluca combo products. Seek alternatives if 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 alternatives to this combination or use of lower metformin doses. Carefully weigh the risk of metformin toxicities (including lactic acidosis) against the benefit of combining dolutegravir with metformin. 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 to 50 mg twice/day in adults. Increase weight based dose to twice daily in pediatric patients. See interaction monograph for details. Seek alternative to rifampin if suspected INSTI resistance. 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 to 50 mg twice/day in adults. Increase weight based dose to twice daily in pediatric patients. See interaction monograph for details. Not recommended with Dovato or Juluca combo products. Seek alternatives if INSTI resistance. 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

Test Interactions

May inhibit tubular secretion of creatinine without affecting actual renal glomerular function.

Adverse Reactions

Adverse reactions reported with combination therapy.

>10%: Gastrointestinal: Increased serum lipase (2% to 11%)

1% to 10%:

Dermatologic: Pruritus (<2%)

Endocrine & metabolic: Hyperglycemia (≤9%)

Gastrointestinal: Abdominal distress (<2%), abdominal pain (<2%), diarrhea (≤2%), flatulence (<2%), nausea (≤1%), upper abdominal pain (<2%), vomiting (<2%)

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

Hepatic: Hepatitis (<2%), hyperbilirubinemia (≤3%), increased serum alanine aminotransferase (1% to 4%), increased serum aspartate aminotransferase (1% to 5%)

Nervous system: Depression (≤1%), fatigue (≤2%), headache (≤2%), insomnia (≤7%), suicidal ideation (<2%), suicidal tendencies (<2%)

Neuromuscular & skeletal: Increased creatinine phosphokinase in blood specimen (2% to 7%), myositis (<2%)

Renal: Renal insufficiency (<2%)

<1%:

Dermatologic: Skin rash

Hypersensitivity: Hypersensitivity reaction

Nervous system: Abnormal dreams, dizziness

Frequency not defined:

Endocrine & metabolic: Increased HDL cholesterol, increased LDL cholesterol, increased serum cholesterol, increased serum triglycerides

Renal: Increased serum creatinine

Postmarketing:

Endocrine & metabolic: Weight gain

Hepatic: Acute hepatic failure, hepatotoxicity

Immunologic: Immune reconstitution syndrome

Nervous system: Anxiety

Neuromuscular & skeletal: Arthralgia, myalgia

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.

Dosage form specific issues:

• Product interchangeability: Dolutegravir tablets and soluble tablets for oral suspension (Tivicay PD) are not bioequivalent and not interchangeable on a milligram-per-milligram basis. If a patient switches from one formulation to another, adjust dose for the new dosage formulation. Incorrect dosing may result in underdosing, loss of therapeutic effect, and possible development of resistance, or adverse reactions from increased exposure to dolutegravir.

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.

• False elevations in serum creatinine: May inhibit tubular secretion of creatinine without affecting actual renal glomerular function; observed onset was within the first 4 weeks of therapy followed by stability through at least 96 weeks. Use caution when interpreting serum creatinine values in patients with medical conditions or receiving drugs needing to be monitored with estimated CrCl.

Monitoring Parameters

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

Reproductive Considerations

Dolutegravir is recommended as an alternative agent for women living with HIV who are not yet pregnant but are trying to conceive. The potential risk of neural tube defects following in utero exposure should be discussed with the patient.

For males and females living with HIV and planning a pregnancy, maximum viral suppression below the limits of detection with antiretroviral therapy (ART), modification of therapy (if needed), optimization of the woman's health, and a discussion of the potential risks and benefits of ART therapy during pregnancy is recommended prior to conception (HHS [perinatal] 2019).

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. 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.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Headache

• Trouble sleeping

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• 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 an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, 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 limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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