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Dolutegravir

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

Brand Names: U.S.

  • Tivicay

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 of HIV-1 infection in combination with other antiretroviral agents in adult and pediatric patients weighing at least 30 kg.

Limitations of use: Use in integrase strand transfer inhibitor (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.

Contraindications

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

Dosing: Adult

HIV-1 treatment: Oral: Note: Must be given in combination with other antiretroviral agents. Dolutegravir is a component of recommended initial regimens for any 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] 2015).

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

Dosing: Geriatric

Refer to adult dosing; use with caution.

Dosing: Pediatric

HIV-1 treatment: Children and Adolescents: Oral:

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

30 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:

30 to <40 kg: 35 mg twice daily

≥40 kg: 50 mg twice daily

Dosing: Renal Impairment

Treatment-naive or treatment-experienced INSTI-naive: Mild, moderate, or severe impairment: No dosage adjustment necessary.

INSTI-experienced with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance:

CrCl ≥30 mL/minute: No dosage adjustment necessary.

CrCl <30 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling; use with caution since the reduction in dolutegravir concentrations may result in loss of therapeutic effect and development of resistance to dolutegravir or other coadministered antiretroviral agents.

ESRD including hemodialysis: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosing: Hepatic Impairment

Mild-to-moderate impairment (Child-Pugh class A or B): No dosage adjustment necessary.

Severe impairment (Child-Pugh class C): Use is not recommended (has not been studied).

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 15°C to 30°C (59°F to 86°F).

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. 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. 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: US recommends avoiding the use of etravirine with dolutegravir unless used with atazanavir/ritonavir, darunavir/ritonavir or lopinavir/ritonavir. Canada recommends increasing dolutegravir to 50 mg twice daily when used 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 Salts: May decrease the serum concentration of Dolutegravir. Management: Administer dolutegravir at least 2 hours before or 6 hours after oral iron. Alternatively, dolutegravir and oral iron can be taken together with food. Exceptions: Ferric Carboxymaltose; 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. Consider therapy modification

MetFORMIN: Dolutegravir may increase the serum concentration of MetFORMIN. Management: Limit the daily metformin dose to 1,000 mg when used together with dolutegravir. Metformin dose adjustments may also be needed upon discontinuation of dolutegravir. Monitor patient response to metformin closely. 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 the dose of a multivitamin that contains polyvalent cations (e.g., calcium, iron, magnesium, selenium, zinc). 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 the dose of a multivitamin that contains polyvalent cations (e.g., calcium, iron, magnesium, selenium, zinc). 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. 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. 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. Consider therapy modification

Adverse Reactions

Adverse reactions reported with combination therapy.

>10%

Endocrine & metabolic: Hyperglycemia (≤14%)

Hepatic: Increased serum ALT (≤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 AST (≤8%), hyperbilirubinemia (≤3%), hepatitis (<2%)

Hypersensitivity: Hypersensitivity reaction (≤1%)

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

Renal: Renal insufficiency (<2%)

<1% (Limited to important or life-threatening): Immune reconstitution syndrome

Warnings/Precautions

Concerns related to adverse effects:

• Fat redistribution: May cause redistribution of fat (eg, buffalo hump, peripheral wasting with increased abdominal girth, cushingoid appearance).

• 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.

• Increased liver function tests: Patients with underlying hepatic disease (such as hepatitis B or C coinfection) may be at increased risk of development or worsening of transaminase elevations; use with caution. Elevation in transaminases may be concurrent with development of immune reconstitution syndrome or hepatitis B reactivation (especially if antihepatitis therapy has been discontinued). Monitor transaminases at baseline and during therapy.

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 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.

Monitoring Parameters

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

Pregnancy Considerations

Adverse events were not observed in animal reproduction studies; data collected by the antiretroviral pregnancy registry is insufficient to evaluate human teratogenic risk. It is not known if dolutegravir crosses the placenta. The HHS Perinatal HIV Guidelines note that due to a lack of data, dolutegravir cannot be recommended in antiretroviral-naive pregnant women; pharmacokinetic data are insufficient to make dosing recommendations during pregnancy.

Combination antiretroviral therapy (cART) therapy is recommended for all HIV-infected pregnant women. The goal of therapy is to keep the viral load below the limit of detection and prevent perinatal transmission. Therapy must be individualized. In general, women who become pregnant on a stable cART regimen may continue that regimen if viral suppression is effective, contraindications for use in pregnancy are not present, and the regimen is well tolerated. For HIV infected couples planning a pregnancy, maximum viral suppression with cART is recommended prior to conception for the HIV-infected partner(s). When HIV is diagnosed during pregnancy in a woman who has never received antiretroviral therapy, cART should be considered as soon as possible after diagnosis to reduce the risk of perinatal transmission. If antiretroviral drug-resistance testing is done, treatment may be started prior to obtaining results, then adjusted accordingly. Monitoring during pregnancy is more frequent than in non-pregnant adults. If cART must be interrupted for <24 hours, stop then restart all medications simultaneously in order to decrease the chance of developing resistance. Long-term follow-up is recommended for all infants exposed to antiretroviral medications; children who develop significant organ system abnormalities (particularly of the CNS or heart) should be evaluated for potential mitochondrial dysfunction.

HIV infected women not planning a pregnancy may use any available type of contraception, considering possible drug interactions and contraindications of the specific method. In addition, consistent use of condoms is also recommended (even during pregnancy) to prevent transmission of HIV or other sexually transmitted diseases.

Health care providers are encouraged to enroll pregnant women exposed to antiretroviral medications as early in pregnancy as possible in the Antiretroviral Pregnancy Registry (1-800-258-4263 or www.APRegistry.com). Health care providers caring for HIV-infected women and their infants may contact the National Perinatal HIV Hotline (888-448-8765) for clinical consultation (HHS [perinatal] 2016).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache or insomnia. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), muscle pain, joint pain, mouth sores, eye irritation, shortness of breath, severe loss of strength and energy, change in body fat, or signs of infection (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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