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Dolutegravir

Class: HIV Integrase Inhibitors
Chemical Name: (4R,12aS)-N-[(2,4-Difluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-7-hydroxy-4-methyl-6,8-dioxo-2H-pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide sodium salt
Molecular Formula: C20H18F2N3NaO5
CAS Number: 1051375-19-9
Brands: Tivicay

Medically reviewed by Drugs.com. Last updated on Oct 5, 2020.

Warning

    Fixed Combination of Abacavir, Dolutegravir, and Lamivudine
  • If using abacavir/dolutegravir/lamivudine (Triumeq), consider that abacavir has been associated with serious and sometimes fatal hypersensitivity reactions, with multiple organ failure or involvement.240 Individuals with the human leukocyte antigen (HLA)-B*5701 allele are at higher risk for abacavir hypersensitivity reactions, although such reactions have occurred in those without the HLA-B*5701 allele.240 Contraindicated in patients who are HLA-B*5701 positive and in those with prior hypersensitivity reaction to abacavir.240 Screen all patients for HLA-B*5701 allele prior to initiation or reinitiation of abacavir/dolutegravir/lamivudine, unless patient has previously documented HLA-B*5701 allele assessment.240 Immediately discontinue abacavir/dolutegravir/lamivudine if hypersensitivity reaction suspected, regardless of HLA-B*5701 status and even when other diagnoses are possible.240 Following a hypersensitivity reaction, never reinitiate abacavir/dolutegravir/lamivudine or any other abacavir-containing preparations because more severe reactions, including death, can occur within hours.240 Similar severe reactions also reported rarely following reintroduction of abacavir-containing preparations in patients with no history of abacavir hypersensitivity.240

  • If using abacavir/dolutegravir/lamivudine, consider that severe, acute exacerbations of HBV reported following discontinuance of lamivudine in HIV-infected patients coinfected with HBV.240 Closely monitor hepatic function with both clinical and laboratory follow-up for at least several months after discontinuance of lamivudine-containing preparations in coinfected patients.240 If appropriate, initiation of HBV treatment may be warranted.240

Introduction

Antiretroviral; HIV integrase strand transfer inhibitor (INSTI).1 200

Uses for Dolutegravir

Treatment of HIV Infection

Treatment of HIV type 1 (HIV-1) infection in adults who are antiretroviral-naive (have not previously received antiretroviral therapy) or antiretroviral-experienced (previously treated) and in pediatric patients ≥4 weeks of age weighing ≥3 kg who are antiretroviral-naive or antiretroviral-experienced but INSTI-naive.1 2 3 4 5 6 22 23 33

For initial treatment in antiretroviral-naive adults and adolescents, experts state that a 3-drug regimen of dolutegravir in conjunction with a tenofovir prodrug (tenofovir alafenamide fumarate [TAF] or tenofovir disoproxil fumarate [TDF]) and emtricitabine or lamivudine is a recommended INSTI-based regimen for most patients.200 These experts state that a 3-drug regimen of dolutegravir in conjunction with abacavir and lamivudine is another INSTI-based regimen recommended for initial treatment in most adults and adolescents, but use only in those who are HLA-B*5701 negative and not coinfected with HBV.200

Fixed combination containing abacavir, dolutegravir, and lamivudine (abacavir/dolutegravir/lamivudine; Triumeq) is used in adults and pediatric patients weighing ≥40 kg;240 can be used alone as a complete treatment regimen or in conjunction with other antiretrovirals.240 Do not use abacavir/dolutegravir/lamivudine alone in patients with suspected or confirmed INSTI-resistance substitutions;240 dosage of dolutegravir in the fixed combination insufficient in such patients.240

Experts state that a 2-drug regimen of dolutegravir and lamivudine is a recommended INSTI-based regimen for initial treatment in most antiretroviral-naive adults and a recommended regimen for initial treatment in adults when abacavir, TAF, and TDF cannot be used or are not optimal; however, do not use in patients with plasma HIV-1 RNA levels >500,000 copies/mL or HBV coinfection and do not use if results of HIV genotypic resistance testing for reverse transcriptase or results of HBV testing not available.200 Single-entity dolutegravir and single-entity lamivudine can be used concomitantly or the commercially available fixed-combination preparation of dolutegravir and lamivudine (dolutegravir/lamivudine; Dovato) can be used.256

In certain virologically suppressed antiretroviral-experienced adults (i.e., those with plasma HIV-1 RNA levels <50 copies/mL on a stable antiretroviral regimen who have no known history of treatment failure and are infected with HIV-1 with no known substitutions associated with resistance to dolutegravir or lamivudine), a 2-drug regimen of dolutegravir and lamivudine can be used to replace the current regimen.256 The commercially available fixed combination (dolutegravir/lamivudine; Dovato) can be used256 as an alternative to single-entity dolutegravir and single-entity lamivudine used concomitantly.200

In certain virologically suppressed antiretroviral-experienced adults (i.e., those with plasma HIV-1 RNA levels <50 copies/mL on a stable antiretroviral regimen for ≥6 months who have no known history of treatment failure and are infected with HIV-1 with no known substitutions associated with resistance to dolutegravir or rilpivirine), a 2-drug regimen of dolutegravir and rilpivirine can be used to replace the current regimen.1 247 Single-entity dolutegravir and single-entity rilpivirine can be used concomitantly1 or the commercially available fixed combination of dolutegravir and rilpivirine (dolutegravir/rilpivirine; Juluca) can be used.247

Most appropriate antiretroviral regimen cannot be defined for every clinical scenario; select regimen based on information regarding antiretroviral potency, potential rate of resistance development, known toxicities, potential for pharmacokinetic interactions, and patient's virologic, immunologic, and clinical characteristics.200 201 202 Guidelines for the management of HIV infection, including specific recommendations for initial treatment in antiretroviral-naive patients and recommendations for changing antiretroviral regimens, are available at [Web].200 201 202

Postexposure Prophylaxis following Nonoccupational Exposure to HIV (nPEP)

Postexposure prophylaxis of HIV infection following nonoccupational exposure (nPEP) in individuals exposed to blood, genital secretions, or other potentially infectious body fluids that might contain HIV when the exposure represents a substantial risk for HIV transmission.198 Used in conjunction with other antiretrovirals.198

When nPEP indicated in adults and adolescents ≥13 years of age with normal renal function, CDC states preferred regimen is either raltegravir or dolutegravir used in conjunction with emtricitabine and tenofovir DF (given as the fixed combination emtricitabine/tenofovir DF).198 Pending further accumulation of data on use of dolutegravir during pregnancy (see Fetal/Neonatal Morbidity and Mortality under Cautions), CDC recommends raltegravir (not dolutegravir) if nPEP is indicated in a pregnant woman early in pregnancy or a woman of childbearing potential who is sexually active or was sexually assaulted and is not on effective birth control.203 The recommended alternative nPEP regimen in adults and adolescents ≥13 years of age is ritonavir-boosted darunavir used in conjunction with emtricitabine/tenofovir DF.198

Consult infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or the National Clinicians’ Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) if nPEP indicated in certain exposed individuals (e.g., pregnant women, children, those with medical conditions such as renal impairment) or if considering a regimen not included in CDC guidelines, source virus is known or likely to be resistant to antiretrovirals, or healthcare provider is inexperienced in prescribing antiretrovirals.198 Do not delay initiation of nPEP while waiting for expert consultation.198

Dolutegravir Dosage and Administration

General

  • Test all HIV-infected individuals for HBV and HCV infection prior to initiation of antiretroviral therapy.200 (See HIV-infected Individuals Coinfected with HBV or HCV under Cautions.)

  • Perform pregnancy testing in all women and adolescents of childbearing potential prior to initiation of dolutegravir.1 240 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Administration

Single-entity dolutegravir: Commercially available as conventional tablets (Tivicay) and as tablets for oral suspension (Tivicay PD).1 Administer orally once or twice daily without regard to food.1 Must be used in conjunction with other antiretrovirals.1

Abacavir/dolutegravir/lamivudine (Triumeq): Administer orally once daily without regard to food.240 Use alone as a complete treatment regimen or use in conjunction with other antiretrovirals.240

Do not use single-entity dolutegravir and abacavir/dolutegravir/lamivudine concomitantly, unless needed for adjustment of dolutegravir dosage (e.g., when fixed combination used concomitantly with efavirenz, ritonavir-boosted fosamprenavir, ritonavir-boosted tipranavir, carbamazepine, or rifampin).240 When abacavir/dolutegravir/lamivudine and single-entity dolutegravir both indicated, give daily dose of the fixed combination and daily dose of the single-entity preparation 12 hours apart.240

Dolutegravir Tablets

Conventional tablets (10, 25, or 50 mg): Use in adults and pediatric patients ≥4 weeks of age weighing >14 kg;1 do not use in pediatric patients weighing 3–14 kg.1

Dolutegravir Tablets for Oral Suspension

Tablets for oral suspension (5 mg): Use in pediatric patients ≥4 weeks of age weighing 3 to <20 kg.1 Although those weighing >14 kg can receive either tablet formulation, the tablets for oral suspension are preferred in those weighing 3 to <20 kg.1

May swallow tablets for oral suspension whole or disperse in drinking water to provide an oral suspension.1 Do not chew, cut, or crush.1

If patient is able to swallow the tablets for oral suspension whole and if more than a single 5-mg tablet is required for the dose, swallow the indicated number of tablets whole one at a time to reduce risk of choking.1

Instructions for preparing oral suspension: Add indicated number of 5-mg tablets for oral suspension to the appropriate volume of clean drinking water in the plastic cup provided by manufacturer.1 To prepare a 5- or 15-mg dose of dolutegravir, place 5 mL of drinking water into the cup and add 1 or 3 tablets for oral suspension, respectively, to the water.1 To prepare a 20-, 25-, or 30-mg dose, place 10 mL of drinking water into the cup and add 4, 5, or 6 tablets for oral suspension, respectively, to the water.1 Gently swirl cup for 1–2 minutes until no lumps remain; oral suspension will appear cloudy.1 Swallow oral suspension within 30 minutes after dispersion.1 For infants who cannot drink from the plastic cup, administer oral suspension using the oral syringe provided by manufacturer.1 To ensure no drug remains in the plastic cup, place additional 5 mL of drinking water into the cup, swirl the cup, and administer to the child directly from the cup or using the oral syringe.1

Abacavir/dolutegravir/lamivudine Tablets

Fixed combination abacavir/dolutegravir/lamivudine: Use in adults and pediatric patients weighing ≥40 kg.240

Dosage

Dolutegravir (Tivicay, Tivicay PD): Available as dolutegravir sodium; dosage expressed in terms of dolutegravir.1

Dolutegravir tablets and dolutegravir tablets for oral suspension are not bioequivalent and are not interchangeable on a mg-per-mg basis.1 If patient is switched from one tablet formulation to the other, must adjust dosage to that recommended for specific formulation now being used.1 (See Pediatric Use under Cautions.)

Abacavir/dolutegravir/lamivudine (Triumeq): Contains abacavir sulfate, dolutegravir sodium, and lamivudine;240 dosages of abacavir and dolutegravir components expressed in terms of the bases.240 A fixed-combination tablet containing abacavir 600 mg, dolutegravir 50 mg, and lamivudine 300 mg taken in fasted state is bioequivalent to a 50-mg dolutegravir tablet taken simultaneously with a fixed-combination tablet containing abacavir 600 mg and lamivudine 300 mg (abacavir/lamivudine) in fasted state.21 240

Pediatric Patients

Treatment of HIV-1 Infection
Antiretroviral-naive or Antiretroviral-experienced, INSTI-naive Pediatric Patients
Oral

Single-entity dolutegravir in pediatric patients ≥4 weeks of age weighing ≥3 kg: Dosage is based on weight and depends on specific formulation used (i.e., conventional tablets or tablets for oral suspension).1 (See Table 1 and Table 2.)

If dolutegravir is used concomitantly with certain UGT1A or CYP3A inducers (i.e., efavirenz, ritonavir-boosted fosamprenavir, ritonavir-boosted tipranavir, carbamazepine, rifampin), give the recommended weight-based dose twice daily.1 (See Interactions.)

Table 1. Recommended Dosage of Dolutegravir Tablets for Oral Suspension (Tivicay PD) in Pediatric Patients ≥4 Weeks of Age Weighing ≥3 kg

Weight (kg)

Daily Dose

Number of 5-mg Tablets for Oral Suspension

3 to <6

5 mg once daily

1

6 to <10

15 mg once daily

3

10 to <14

20 mg once daily

4

14 to <20

25 mg once daily

5

≥20

30 mg once daily

6

If dolutegravir is used concomitantly with certain UGT1A or CYP3A inducers (i.e., efavirenz, ritonavir-boosted fosamprenavir, ritonavir-boosted tipranavir, carbamazepine, rifampin), give the recommended weight-based dose twice daily.1 (See Interactions.)

Table 2. Recommended Dosage of Dolutegravir Tablets (Tivicay) in Pediatric Patients ≥4 Weeks of Age Weighing ≥14 kg

Weight (kg)

Daily Dose

Number of 10- or 50-mg Tablets

14 to <20

40 mg once daily

Four 10-mg tablets

≥20

50 mg once daily

One 50-mg tablet

Abacavir/dolutegravir/lamivudine in pediatric patients weighing ≥40 kg: 1 tablet (600 mg of abacavir, 50 mg of dolutegravir, and 300 mg of lamivudine) once daily.240

Abacavir/dolutegravir/lamivudine in pediatric patients weighing ≥40 kg receiving certain drugs (i.e., efavirenz, ritonavir-boosted fosamprenavir, ritonavir-boosted tipranavir, carbamazepine, rifampin): 1 tablet (abacavir 600 mg, dolutegravir 50 mg, and lamivudine 300 mg) once daily and a 50-mg tablet of single-entity dolutegravir once daily given 12 hours after the daily dose of the fixed combination.240

Adults

Treatment of HIV-1 Infection
Antiretroviral-naive Adults
Oral

Dolutegravir: 50 mg once daily.1

Dolutegravir in adults receiving certain UGT1A or CYP3A inducers (i.e., efavirenz, ritonavir-boosted fosamprenavir, ritonavir-boosted tipranavir, carbamazepine, rifampin): 50 mg twice daily.1

Abacavir/dolutegravir/lamivudine: 1 tablet (abacavir 600 mg, dolutegravir 50 mg, and lamivudine 300 mg) once daily.240

Abacavir/dolutegravir/lamivudine in adults receiving certain drugs (i.e., efavirenz, ritonavir-boosted fosamprenavir, ritonavir-boosted tipranavir, carbamazepine, rifampin): 1 tablet (abacavir 600 mg, dolutegravir 50 mg, and lamivudine 300 mg) once daily and a 50-mg tablet of single-entity dolutegravir once daily given 12 hours after the daily dose of the fixed combination.240

Antiretroviral-experienced Adults
Oral

Dolutegravir in antiretroviral-experienced, INSTI-naive adults: 50 mg once daily.1

Dolutegravir in antiretroviral-experienced, INSTI-experienced adults with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance: 50 mg twice daily.1

Dolutegravir in antiretroviral-experienced adults receiving certain UGT1A or CYP3A inducers (i.e., efavirenz, ritonavir-boosted fosamprenavir, ritonavir-boosted tipranavir, carbamazepine, rifampin): 50 mg twice daily.1

Dolutegravir in conjunction with rilpivirine in certain antiretroviral-experienced adults (see Treatment of HIV Infection under Uses): 50 mg once daily with single-entity rilpivirine (25 mg once daily).1

Abacavir/dolutegravir/lamivudine in antiretroviral-experienced adults: 1 tablet (600 mg of abacavir, 50 mg of dolutegravir, and 300 mg of lamivudine) once daily.240 Do not use alone in those with clinically suspected or confirmed INSTI-resistance substitutions.240

Abacavir/dolutegravir/lamivudine in antiretroviral-experienced adults receiving certain drugs (efavirenz, ritonavir-boosted fosamprenavir, ritonavir-boosted tipranavir, carbamazepine, rifampin): 1 tablet (abacavir 600 mg, dolutegravir 50 mg, and lamivudine 300 mg) once daily and a 50-mg tablet of single-entity dolutegravir once daily given 12 hours after the daily dose of the fixed combination.240

Postexposure Prophylaxis following Nonoccupational Exposure to HIV (nPEP)†
Oral

Dolutegravir 50 mg once daily.198 Use in conjunction with 2 NRTIs (see Postexposure Prophylaxis following Nonoccupational Exposure to HIV [nPEP] under Uses).198

Initiate nPEP as soon as possible (within 72 hours) following nonoccupational exposure that represents a substantial risk for HIV transmission and continue for 28 days.198

nPEP not recommended if exposed individual seeks care >72 hours after exposure.198

Special Populations

Hepatic Impairment

Dolutegravir: Dosage adjustments not needed in patients with mild or moderate hepatic impairment (Child-Pugh class A or B);1 do not use in those with severe hepatic impairment (Child-Pugh class C).1 (See Hepatic Impairment under Cautions.)

Abacavir/dolutegravir/lamivudine: Do not use in patients with mild hepatic impairment (Child-Pugh class A) since reduction in abacavir dosage needed in such patients;240 contraindicated in those with moderate or severe hepatic impairment (Child-Pugh class B or C).240 (See Hepatic Impairment under Cautions.)

Renal Impairment

Dolutegravir: Dosage adjustments not needed in antiretroviral-naive or antiretroviral-experienced, INSTI-naive patients with mild, moderate, or severe renal impairment;1 dosage adjustments not needed in antiretroviral-experienced, INSTI-experienced patients with mild or moderate renal impairment.1 Use with caution in patients with severe renal impairment who are INSTI-experienced and have certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance.1 11 (See Renal Impairment under Cautions.)

Dolutegravir: Data insufficient to make specific dosage recommendations for patients requiring dialysis;1 unlikely that the drug would be removed by dialysis to any clinically important extent.11

Abacavir/dolutegravir/lamivudine: Do not use in patients with Clcr <50 mL/minute since reduction in lamivudine dosage needed in such patients.240 (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations;1 use with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.1 (See Geriatric Use under Cautions.)

Cautions for Dolutegravir

Contraindications

  • Dolutegravir (Tivicay, Tivicay PD): Previous hypersensitivity reaction to dolutegravir;1 concomitant use with dofetilide.1 (See Specific Drugs under Interactions.)

  • Abacavir/dolutegravir/lamivudine (Triumeq): HLA-B*5701-positive or previous hypersensitivity reaction to abacavir (regardless of HLA-B*5701 status);240 previous hypersensitivity reaction to dolutegravir or lamivudine;240 concomitant use with dofetilide;240 moderate or severe hepatic impairment.240 Consider contraindications associated with each drug in the fixed combination.240 (See Use of Fixed Combinations under Cautions.)

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions reported.1 Reactions include rash and constitutional findings and, occasionally, organ dysfunction including liver toxicity.1

Immediately discontinue dolutegravir, abacavir/dolutegravir/lamivudine, and any other suspect agents if signs or symptoms of hypersensitivity occur, including (but not limited to) severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters or peeling skin, oral blisters or lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, or difficulty breathing.1 240 Monitor clinical status, including liver aminotransferases, and initiate appropriate therapy.1 240

Life-threatening reactions could occur if discontinuance of dolutegravir, abacavir/dolutegravir/lamivudine, and any other suspect agents is delayed after onset of hypersensitivity reaction.1 240

Hepatic Effects

Adverse hepatic effects reported in patients receiving dolutegravir-containing regimens.1 240

HIV-infected patients with HBV or HCV coinfection may be at increased risk for development or worsening of aminotransferase elevations.1 240 In some patients receiving a dolutegravir-containing regimen, serum aminotransferase elevations were consistent with immune reconstitution syndrome or HBV reactivation, particularly in the setting where HBV therapy had been discontinued.1 240

Cases of hepatic toxicity, including elevated serum liver biochemistries, hepatitis, and acute liver failure, also reported in patients receiving a dolutegravir-containing regimen who had no preexisting hepatic disease or other identifiable risk factors.1 240

Drug-induced liver injury leading to liver transplant reported with abacavir/dolutegravir/lamivudine.1 240

Monitor for hepatotoxicity.1 240

Fetal/Neonatal Morbidity and Mortality

Data from an observational study in Botswana showed an association between dolutegravir and an increased risk of neural tube defects when the drug is administered at the time of conception and during early pregnancy.1 10 202 240

Because there is only a limited understanding of reported types of neural tube defects associated with dolutegravir use and because the date of conception may not be determined with precision, manufacturer states consider an alternative to dolutegravir for women at the time of conception through the first trimester of pregnancy.1 240 Manufacturer also states initiation of dolutegravir not recommended in women actively trying to become pregnant, unless there is no suitable alternative.1 240 (See Pregnancy under Cautions.)

Interactions

Concomitant use with certain drugs may result in drug interactions.1 May lead to loss of therapeutic effects and possible development of resistance or possible adverse effects from increased exposures of concomitant drugs.1

Consider potential for drug interactions prior to and during treatment with dolutegravir or abacavir/dolutegravir/lamivudine and monitor for adverse effects associated with concomitant drugs.1 240

HIV-infected Individuals Coinfected with HBV or HCV

Increased risk for elevated serum aminotransferase concentrations.1 (See Hepatic Effects under Cautions.)

If abacavir/dolutegravir/lamivudine used in HIV-infected patients coinfected with HBV or HCV, consider that additional precautions apply to these coinfected patients.240 (See Use of Fixed Combinations under Cautions.)

Immune Reconstitution Syndrome

During initial treatment, HIV-infected patients who respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium, M. tuberculosis, cytomegalovirus [CMV], Pneumocystis jirovecii);1 240 this may necessitate further evaluation and treatment.1 240

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome) also reported to occur in the setting of immune reconstitution;1 240 time to onset is more variable and can occur many months after initiation of antiretroviral therapy.1 240

Pharmacogenomics

Dolutegravir metabolized primarily by UGT1A.1 Data from healthy individuals indicate that UGT1A1 genotypes conferring poor dolutegravir metabolism result in 32% lower clearance and 46% higher AUC of the drug compared with genotypes associated with normal UGTA1 metabolism.1

Use of Fixed Combinations

Abacavir/dolutegravir/lamivudine: Consider cautions, precautions, contraindications, and drug interactions associated with each drug in the fixed combination.240 Consider cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) for each drug.240

If abacavir/dolutegravir/lamivudine used, consider that abacavir is associated with serious and sometimes fatal hypersensitivity reactions, including multiple organ failure and anaphylaxis.240 Individuals with the HLA-B*5701 allele are at higher risk for hypersensitivity reactions to abacavir, although such reactions reported in patients without the HLA-B*5701 allele.240 Review medical history for prior exposure to any abacavir-containing preparation.240 Screen all patients for the HLA-B*5701 allele prior to initiating or reinitiating abacavir/dolutegravir/lamivudine, unless patient has documentation of prior HLA-B*5701 allele assessment.240 Immediately discontinue abacavir/dolutegravir/lamivudine if a hypersensitivity reaction is suspected, regardless of patient's HLA-B*5701 status and even when other diagnoses are possible.240 Never restart abacavir/dolutegravir/lamivudine or any other abacavir-containing preparation in a patient who experienced a hypersensitivity reaction to an abacavir-containing preparation since more severe reactions can occur within hours and may include life-threatening hypotension and death.240 If hypersensitivity ruled out, manufacturer of abacavir/dolutegravir/lamivudine states that the drug may be reinitiated, but only if medical care is readily accessible.240 Since it is not possible to determine whether hypersensitivity reaction in patients receiving abacavir/dolutegravir/lamivudine is caused by abacavir or dolutegravir,240 never reinitiate abacavir-containing or dolutegravir-containing preparations in patients who stopped therapy with abacavir/dolutegravir/lamivudine due to a hypersensitivity reaction.240

If abacavir/dolutegravir/lamivudine used, consider that lactic acidosis and severe hepatomegaly with steatosis, including fatalities, reported in patients receiving HIV NRTIs, including abacavir and lamivudine.240 Cases reported most frequently in women; obesity also may be a risk factor.240 Discontinue abacavir/dolutegravir/lamivudine if clinical or laboratory findings indicate lactic acidosis or pronounced hepatotoxicity, which may include hepatomegaly and steatosis even in the absence of marked increases in serum aminotransferase concentrations.240

If abacavir/dolutegravir/lamivudine used, consider that several prospective, observational, epidemiological studies reported an association between use of abacavir and risk of MI.240 However, excess risk of MI in abacavir-treated patients compared with controls not observed in meta-analyses of randomized, controlled clinical trials and there is no established biological mechanism to explain a potential increase in such risk.240 Although available data from observational studies and controlled clinical trials are inconsistent and evidence for a causal relationship between abacavir and risk of MI is inconclusive, consider underlying risk of CHD when prescribing abacavir-containing antiretroviral regimens and take precautions to minimize all modifiable risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, smoking).240

If abacavir/dolutegravir/lamivudine used in patients coinfected with HIV and HBV, consider that severe, acute exacerbations of HBV infection reported following discontinuance of lamivudine in coinfected patients.240 Closely monitor hepatic function (using both clinical and laboratory follow-up) for at least several months after abacavir/dolutegravir/lamivudine discontinued.240 If appropriate, initiation of HBV treatment may be warranted.240 Safety and efficacy of abacavir/dolutegravir/lamivudine not established for treatment of chronic HBV infection.240

Specific Populations

Pregnancy

Antiretroviral Pregnancy Registry at 800-258-4263 or [Web].1 202 240

Dolutegravir crosses placenta;202 results of an ex vivo perfusion model indicate high fetal-to-maternal ratio (0.6).202

Manufacturer states that data regarding use of dolutegravir in pregnant women are insufficient to date to definitively assess a drug-associated risk for birth defects and miscarriage.1 240 No evidence of adverse embryofetal or pre- and post-natal development reported in animal reproduction studies.1 240

Data from an observational birth outcome surveillance study in Botswana (Tsepamo study) showed an increased risk of neural tube defects associated with use of dolutegravir-containing regimens at time of conception and during early pregnancy compared with use of antiretroviral regimens that did not contain dolutegravir.1 10 202 240 From August 2014 through March 2019, 5 cases of neural tube defects (2 cases of myelomeningocele and 1 case each of encephalocele, anencephaly, and iniencephaly) were identified out of 1683 deliveries (0.3%) to women exposed to dolutegravir-containing regimens at time of conception;1 10 202 240 prevalence rate of neural tube defects was 0.1% (15/14,792 deliveries) when the mother was receiving an antiretroviral regimen that did not contain dolutegravir at time of conception and was 0.08% (70/89,372 deliveries) when the mother did not have HIV infection.1 10 202 240

To date, data from the birth outcome surveillance study in Botswana and postmarketing sources including >1000 pregnancy outcomes have not shown evidence of increased risk of adverse birth outcomes from dolutegravir exposures occurring during second and third trimesters of pregnancy.1 240

Manufacturer states do not use dolutegravir during first trimester of pregnancy, but may consider use of the drug during second and third trimesters of pregnancy if expected benefits justify potential risks to the pregnant woman and fetus.1 240 Manufacturer also states initiation of dolutegravir not recommended in women actively trying to become pregnant, unless there is no suitable alternative.1 240

HHS Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission currently states that dolutegravir is a preferred antiretroviral for use in 3-drug antiretroviral regimens for treatment of HIV-1 infection in antiretroviral-naive and previously treated pregnant women (regardless of trimester) and is an alternative antiretroviral for such regimens in women of childbearing potential trying to conceive.202 Based on preliminary results of the Tsepamo study published in 2018, the HHS panel previously stated avoid dolutegravir in women in first trimester of pregnancy and those trying to conceive.202 However, after evaluating additional data that subsequently became available from the Tsepamo study and data from other studies assessing risk of neural tube defects, these experts revised their recommendations regarding use of dolutegravir in pregnant women and those trying to conceive.202 The HHS panel now states that the small increased risk of neural tube defects associated with dolutegravir exposure around the time of conception that was reported in Botswana (a country where food is not routinely fortified with folic acid) should be weighed against the advantages of dolutegravir (e.g., once-daily dosing, generally well tolerated, associated with high rates of rapid and durable virologic suppression [important for prevention of perinatal transmission of HIV], high barrier to drug resistance).202 Although no evidence to date that folic acid supplementation prevents dolutegravir-associated neural tube defects, folic acid is known to prevent neural tube defects in the general population and folic acid supplementation of food is required in many countries in North American, Europe, and Latin America.202 The HHS panel strongly emphasizes the importance of patient counseling to ensure informed decision-making before initiating dolutegravir in pregnant women and women trying to conceive.202 Some panel members prefer avoiding use of the drug in antiretroviral-naive women who are initiating antiretroviral therapy before 6 weeks of gestation.202

Perform pregnancy testing in all women and adolescents of childbearing potential before initiating dolutegravir.1 202 240

Advise all women and adolescents of childbearing potential to consistently use effective contraception during dolutegravir therapy;1 240 advise pregnant women of the potential risk to an embryo exposed to dolutegravir from the time of conception through the first trimester of pregnancy.1 240

Manufacturer states that, if a woman currently receiving dolutegravir is actively trying to become pregnant or if pregnancy is confirmed during first trimester, assess risks and benefits of continuing the drug versus switching to a different antiretroviral regimen that does not contain dolutegravir.1 Benefit-risk assessment should address factors such as feasibility of switching to a different regimen, tolerability, ability to maintain viral suppression, and risk of HIV transmission to the infant versus risk of neural tube defects.1 202 240

HHS panel states that available data about risks and benefits of dolutegravir versus what is known (or not known) about risk of neural tube defects associated with use of other antiretrovirals during pregnancy should be carefully considered for the individual patient.202 These experts state that, in most cases, continuation of dolutegravir in pregnant women receiving a 3-drug antiretroviral regimen is recommended.202 However, because data not available regarding use of 2-drug antiretroviral regimens for treatment of HIV-1 infection during pregnancy, these experts state that 2-drug dolutegravir regimens (dolutegravir/lamivudine, dolutegravir/rilpivirine) are not recommended in women who are pregnant or trying to conceive and such women should be switched to a 3-drug antiretroviral regimen (e.g., switch regimens or add additional antiretrovirals to the 2-drug dolutegravir regimen).202

Clinicians can consult the National Perinatal HIV Hotline at 888-448-8765 for additional guidance on use of dolutegravir and other antiretrovirals in women who are pregnant or planning to become pregnant.202

Lactation

Some reports that dolutegravir distributed into human milk in low concentrations;202 distributed into milk in rats.1 202 240

Not known whether dolutegravir affects milk production or affects breast-fed infant.1

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.1 202 240

Pediatric Use

Dolutegravir: Safety and efficacy not established in pediatric patients <4 weeks of age or weighing <3 kg;1 safety and efficacy not established in INSTI-experienced pediatric patients who have documented or suspected resistance to other HIV INSTIs (e.g., elvitegravir, raltegravir).1

Data from a clinical trial in pediatric patients 4 weeks to <18 years of age (IMPAACT P1093) indicate effectiveness and overall safety of dolutegravir in pediatric patients are comparable to those reported in adults receiving the drug.1 Pharmacokinetic parameters for dolutegravir reported in pediatric patients receiving weight-based dosages of the drug in clinical trials (IMPAACT P1093, ODYSSEY) indicate that peak plasma concentrations and AUC are comparable to those in adults receiving 50 mg of dolutegravir once or twice daily.1 Although mean peak plasma concentrations of the drug are higher in pediatric patients, this is not considered clinically important since the safety profile is similar in adult and pediatric patients.1

Dolutegravir conventional tablets (Tivicay) and tablets for oral suspension (Tivicay PD) are not bioequivalent and not interchangeable on a mg-per-mg basis.1 Incorrect dosage of a given formulation may result in under-dosing and loss of therapeutic effect and possible development of resistance or may result in clinically important adverse effects from greater dolutegravir exposure.1 The conventional tablets are labeled for use in pediatric patients ≥4 weeks of age weighing ≥14 kg; tablets for oral suspension are labeled for pediatric patients ≥4 weeks of age weighing ≥3 kg.1 If pediatric patient is switched from one tablet formulation to the other, must adjust dosage to that recommended for the specific formulation now being used.1 (See Pediatric Dosage under Dosage and Administration.)

Abacavir/dolutegravir/lamivudine (Triumeq): Do not use in pediatric patients weighing <40 kg; dosage adjustments cannot be made.240 Safety and efficacy in those weighing ≥40 kg are derived from pediatric trials using the individual components of the fixed combination.240

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently to dolutegravir or abacavir/dolutegravir/lamivudine than younger adults.1 240

Caution advised because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1 240

Hepatic Impairment

Dolutegravir: Should not be used in patients with severe hepatic impairment (Child-Pugh class C);1 pharmacokinetics not evaluated in such patients.1 Pharmacokinetics in patients with moderate hepatic impairment similar to those in healthy individuals; dosage adjustments not needed in those with mild or moderate hepatic insufficiency (Child-Pugh class A or B).1 Risk for further elevations in hepatic enzyme concentrations in patients with HBV or HCV coinfection.1

Abacavir/dolutegravir/lamivudine: Should not be used in patients with mild hepatic impairment (Child-Pugh class A).240 Because decreased abacavir dosage is recommended in those with mild hepatic impairment,200 switch to the single-entity components to allow adjustment of abacavir dosage in such patients.240 Contraindicated in those with moderate or severe hepatic impairment (Child-Pugh class B or C).240

Renal Impairment

Dolutegravir: Use with caution in patients with severe renal impairment who are INSTI-experienced and have documented or suspected INSTI resistance;1 11 dolutegravir plasma concentrations decreased in such patients and may result in loss of therapeutic effects and development of resistance to the drug or other antiretrovirals.1

Dolutegravir: May be used in patients with mild or moderate renal impairment; no clinically important effect on dolutegravir pharmacokinetics.1 11 Dosage adjustments not needed in antiretroviral-naive or antiretroviral-experienced, INSTI-naive patients with mild, moderate, or severe renal impairment.1 11 Dosage adjustments not needed in INSTI-experienced patients with mild or moderate renal impairment.1

Data regarding use of dolutegravir in dialysis patients insufficient to make dosage recommendations;1 unlikely that dialysis would have clinically important effect on pharmacokinetics since the drug is highly bound to plasma protein.11

Dolutegravir increases Scr by inhibiting tubular secretion of creatinine;1 does not cause clinically important change in GFR or renal plasma flow.1

Abacavir/dolutegravir/lamivudine: Do not use if Clcr <50 mL/minute.240 Because lamivudine substantially eliminated by kidneys and decreased lamivudine dosage recommended in those with Clcr <50 mL/minute, switch to the single-entity components to allow adjustment of lamivudine dosage in such patients.240

Common Adverse Effects

Insomnia; headache; fatigue; diarrhea; hyperglycemia; decreased neutrophils; increased serum aminotransferases, total bilirubin, creatine kinase, lipase, and cholesterol.1

Interactions for Dolutegravir

CYP3A plays minor role in dolutegravir metabolism.1 8 9 Dolutegravir does not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A;1 does not induce CYP1A2, 2B6, or 3A4.1

Metabolized by UGT1A1 (see Pharmacogenomics under Cautions); also a substrate for UGT1A3 and UGT1A9.1 Does not inhibit UGT1A1 or UGT2B7.1

Substrate of P-glycoprotein (P-gp) transport system and breast cancer resistance protein (BCRP);1 does not inhibit P-gp-mediated transport or BCRP.1

Inhibits multidrug and toxin extrusion transporter (MATE) 1.1

Inhibits renal organic anion transporter (OAT) 1 and OAT3.1 Does not inhibit organic anion transporter polypeptide (OATP) 1B1 or OATP1B3;1 not a substrate of OATP1B1 or 1B3.1

Inhibits renal organic cation transporter (OCT) 2;1 does not inhibit OCT1.1

Does not inhibit bile salt export pump (BSEP) or multidrug resistance protein (MRP) 2 or MRP4.1

The following drug interactions are based on studies using dolutegravir.1 Drug interaction studies not performed using abacavir/dolutegravir/lamivudine.240 When abacavir/dolutegravir/lamivudine used, consider interactions associated with each drug in the fixed combination.240

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A inducers: Possible decreased dolutegravir plasma concentrations and decreased therapeutic effects.1

CYP3A inhibitors: Possible increased dolutegravir plasma concentrations.1

Drugs Affecting UGT

UGT1A1, 1A3, or 1A9 inducers: Possible decreased dolutegravir plasma concentrations and decreased therapeutic effects.1

UGT1A1 inhibitors: Possible increased dolutegravir plasma concentrations.1

Drugs Affecting P-glycoprotein Transport

P-gp inducers: Possible decreased dolutegravir plasma concentrations.1

P-gp inhibitors: Possible increased dolutegravir plasma concentrations.1

Drugs Affecting Breast Cancer Resistance Protein

BCRP inducers: Possible decreased dolutegravir plasma concentrations.1

BCRP inhibitors: Possible increased dolutegravir plasma concentrations.1

Drugs Affected by Multidrug and Toxin Extrusion Transporter

Drugs eliminated by MATE1: Possible decreased plasma concentrations of these drugs.1

Drugs Affected by Renal Organic Cation Transporters

Drugs eliminated by OCT2: Possible increased plasma concentrations of these drugs.1

Specific Drugs

Drug

Interaction

Comments

Abacavir

No in vitro evidence of antagonistic antiretroviral effects1

Adefovir

No in vitro evidence of antagonistic antiviral effects1

α1-Adrenergic blocking agents (alfuzosin, doxazosin, silodosin, tamsulosin, terazosin)

Dolutegravir not expected to affect α1-adrenergic blocking agent concentrations200

Dosage adjustments not needed200

β-Adrenergic blocking agents

Metoprolol, timolol: Dolutegravir not expected to affect β-adrenergic blocking agent concentrations200

Metoprolol, timolol: Dosage adjustments not needed200

Antacids, aluminum-, calcium-, or magnesium-containing

Decreased dolutegravir concentrations and AUC1 19 200 240

Give dolutegravir or abacavir/dolutegravir/lamivudine ≥2 hours before or ≥6 hours after aluminum-, calcium-, or magnesium-containing antacids1 200 240

Antiarrhythmic agents

Amiodarone, digoxin, dronedarone, flecainide, systemic lidocaine, mexiletine, propafenone, quinidine: Dolutegravir not expected to affect concentrations of these antiarrhythmic agents200

Disopyramide: Possible increased disopyramide concentrations200

Dofetilide: Possible increased dofetilide concentrations and increased risk of serious and/or life-threatening adverse effects1 240

Amiodarone, digoxin, dronedarone, flecainide, systemic lidocaine, mexiletine, propafenone, quinidine: Dosage adjustments not needed200

Disopyramide: Monitor for disopyramide-associated adverse effects200

Dofetilide: Concomitant use with dolutegravir or abacavir/dolutegravir/lamivudine contraindicated1 240

Anticoagulants

Apixaban, betrixaban, dabigatran, edoxaban, rivaroxaban: Dolutegravir not expected to affect concentrations of these anticoagulants200

Warfarin: Dolutegravir not expected to affect warfarin concentrations200

Apixaban, betrixaban, dabigatran, edoxaban, rivaroxaban: Dosage adjustments not needed200

Warfarin: Dosage adjustments not needed200

Anticonvulsants

Carbamazepine: Decreased dolutegravir concentrations and AUC1 30

Eslicarbazepine: Possible decreased dolutegravir concentrations200

Ethosuximide, lamotrigine: Dolutegravir not expected to affect concentrations of these anticonvulsants200

Oxcarbazepine, phenobarbital, phenytoin: Possible decreased dolutegravir concentrations1

Valproic acid: Data not available200

Carbamazepine (adults): In antiretroviral-naive or antiretroviral-experienced, INSTI-naive adults, give dolutegravir dose twice daily;1 consider alternative anticonvulsant in INSTI-experienced adults with documented or suspected INSTI resistance;1 if abacavir/dolutegravir/lamivudine used, give 1 fixed-combination tablet (abacavir 600 mg, dolutegravir 50 mg, and lamivudine 300 mg) once daily and a 50-mg tablet of single-entity dolutegravir once daily 12 hours after the fixed-combination dose240

Carbamazepine (pediatric patients): In antiretroviral-naive or antiretroviral-experienced, INSTI-naive pediatric patients, give weight-based dolutegravir dose twice daily;1 consider alternative anticonvulsant in INSTI-experienced patients with documented or suspected INSTI resistance1

Eslicarbazepine: Some experts state consider alternative anticonvulsant or alternative antiretroviral200

Ethosuximide, lamotrigine: Dosage adjustments not needed200

Oxcarbazepine, phenobarbital, phenytoin: Avoid concomitant use with dolutegravir or abacavir/dolutegravir/lamivudine; data insufficient to make dosage recommendations1 240

Valproic acid: Some experts recommend monitoring valproic acid concentrations and virologic response if used with dolutegravir200

Antidiabetic agents

Metformin: Increased metformin concentrations and AUC1 31 200

Saxagliptin or fixed combination of dapagliflozin and saxagliptin (dapagliflozin/saxagliptin): Dolutegravir not expected to affect concentrations of these antidiabetic agents200

Metformin: Assess risks and benefits if considering use with dolutegravir or abacavir/dolutegravir/lamivudine;1 31 240 use lowest initial metformin dosage and titrate dosage based on glycemic control while monitoring metformin adverse effects;200 may need to adjust metformin dosage when starting or stopping dolutegravir

Saxagliptin, dapagliflozin/saxagliptin: Dosage adjustments not needed200

Antifungals, azoles

Itraconazole, posaconazole, voriconazole: Pharmacokinetic interactions not expected if used with dolutegravir 200

Itraconazole, posaconazole, voriconazole: Dosage adjustments not needed200

Antimycobacterial agents (rifabutin, rifampin, rifapentine)

Rifabutin: No clinically important effect on dolutegravir pharmacokinetics1 200

Rifampin: Decreased dolutegravir concentrations and AUC1 200

Rifapentine: Decreased dolutegravir concentrations expected200

Rifabutin: Dosage adjustments not needed200

Rifampin (adults): In antiretroviral-naive or antiretroviral-experienced, INSTI-naive adults, give dolutegravir dose twice daily;1 200 consider alternative to rifampin (e.g., rifabutin) in INSTI-experienced adults with documented or suspected INSTI resistance;1 200 if abacavir/dolutegravir/lamivudine used, give 1 fixed-combination tablet (abacavir 600 mg, dolutegravir 50 mg, and lamivudine 300 mg) once daily and give a 50-mg tablet of single-entity dolutegravir once daily 12 hours after the fixed-combination dose240

Rifampin (pediatric patients): In antiretroviral-naive or antiretroviral-experienced, INSTI-naive pediatric patients, give weight-based dolutegravir dose twice daily;1 consider alternative to rifampin (e.g., rifabutin) in INSTI-experienced patients with documented or suspected INSTI resistance1

Rifapentine: Concomitant use not recommended200

Antiplatelet agents

Clopidogrel, prasugrel, ticagrelor, vorapaxar: Dolutegravir not expected to affect concentrations of these antiplatelet agents200

Clopidogrel, prasugrel, ticagrelor, vorapaxar: Dosage adjustments not needed200

Antipsychotic agents

Aripiprazole, brexpiprazole, cariprazine, iloperidone, lurasidone, pimavanserin, pimozide, quetiapine, ziprasidone: Dolutegravir not expected to affect concentrations of these antipsychotic agents200

Aripiprazole, brexpiprazole, cariprazine, iloperidone, lurasidone, pimavanserin, pimozide, quetiapine, ziprasidone: Dosage adjustments not needed200

Atazanavir

Ritonavir-boosted atazanavir or unboosted atazanavir: Increased dolutegravir concentrations and AUC200

Cobicistat-boosted atazanavir: Data not available200

Cobicistat-boosted, ritonavir-boosted, or unboosted atazanavir: Dosage adjustments not needed1 200

Benzodiazepines

Clonazepam, clorazepate, diazepam, estazolam, flurazepam: Dolutegravir not expected to affect concentrations of these benzodiazepines200

Midazolam: No clinically important effect on midazolam AUC1 18 200

Clonazepam, clorazepate, diazepam, estazolam, flurazepam, midazolam: Dosage adjustments not needed200

Bosentan

Possible decreased dolutegravir concentrations200

Dosage adjustments not needed200

Buffered preparations

Buffered preparations containing polyvalent cations: Possible decreased dolutegravir absorption and decreased dolutegravir concentrations1

Buffered preparations containing polyvalent cations: Give dolutegravir or abacavir/dolutegravir/lamivudine ≥2 hours before or ≥6 hours after such preparations;1 200 240

Buprenorphine

Buprenorphine (buccal, sublingual, subdermal implant): Dolutegravir not expected to affect buprenorphine or norbuprenorphine concentrations200

Dosage adjustments not needed200

Bupropion

Dolutegravir not expected to affect bupropion concentrations200

Dosage adjustments not needed200

Buspirone

Dolutegravir not expected to affect buspirone concentrations200

Dosage adjustments not needed200

Calcifediol

Dolutegravir not expected to affect calcifediol concentrations200

Dosage adjustments not needed200

Calcium-channel blocking agents

No pharmacokinetic interactions with dolutegravir expected200

Dosage adjustments not needed200

Calcium supplements

Decreased dolutegravir concentrations when given concomitantly in fasted state1 28

Give dolutegravir or abacavir/dolutegravir/lamivudine ≥2 hours before or ≥6 hours after oral calcium supplements;1 28 200 240 alternatively, may be given concomitantly if taken with food1 28 200 240

Colchicine

Dolutegravir not expected to affect colchicine concentrations200

Dosage adjustments not needed200

Corticosteroids

Betamethasone, budesonide, dexamethasone, prednisone, prednisolone (systemic): No pharmacokinetic interactions with dolutegravir expected200

Budesonide, ciclesonide, fluticasone, mometasone (orally inhaled or intranasal): Dolutegravir not expected to affect concentrations of these corticosteroids200

Betamethasone, methylprednisolone, prednisolone, triamcinolone (intra-articular, epidural, intraorbital): Dolutegravir not expected to affect concentrations of these corticosteroids200

Betamethasone, budesonide, dexamethasone, prednisone, prednisolone (systemic): Dosage adjustments not needed200

Budesonide, ciclesonide, fluticasone, mometasone (orally inhaled or intranasal): Dosage adjustments not needed200

Betamethasone, methylprednisolone, prednisolone, triamcinolone (intra-articular, epidural, intraorbital): Dosage adjustments not needed200

Dalfampridine

Increased dalfampridine concentrations and increased risk of seizures1

Weigh potential benefits of concomitant use against risk of seizures1

Darunavir

Ritonavir-boosted darunavir: Decreased dolutegravir concentrations and AUC; no effects on darunavir pharmacokinetics1 200

Cobicistat-boosted darunavir: Clinically important interactions not expected 200

Cobicistat-boosted or ritonavir-boosted darunavir: Dosage adjustments not needed1 200

Dronabinol

Dolutegravir not expected to affect dronabinol concentrations200

Dosage adjustments not needed200

Efavirenz

Decreased dolutegravir concentrations and AUC1 26 200

No in vitro evidence of antagonistic antiretroviral effects1

Dolutegravir (adults): In antiretroviral-naive or antiretroviral-experienced, INSTI-naive adults, give dolutegravir dose twice daily;1 200 in INSTI-experienced adults with documented or suspected INSTI resistance, consider alternative to efavirenz whenever possible1 200

Dolutegravir (pediatric patients): In antiretroviral-naive or antiretroviral-experienced, INSTI-naive pediatric patients, give weight-based dolutegravir dose twice daily;1 in INSTI-experienced pediatric patients with documented or suspected INSTI resistance, consider alternative to efavirenz whenever possible1

Abacavir/dolutegravir/lamivudine (adults): Give 1 fixed-combination tablet (abacavir 600 mg, dolutegravir 50 mg, and lamivudine 300 mg) once daily and give a 50-mg tablet of single-entity dolutegravir once daily 12 hours after the fixed-combination dose240

Elbasvir and grazoprevir

No clinically important pharmacokinetic interactions between dolutegravir and grazoprevir with or without elbasvir1 177

Fixed combination of elbasvir and grazoprevir (elbasvir/grazoprevir): Dosage adjustments not needed if used with dolutegravir1 177

Eluxadoline

Dolutegravir not expected to affect eluxadoline concentrations200

Dosage adjustments not needed200

Enfuvirtide

No in vitro evidence of antagonistic antiretroviral effects1

Eplerenone

Dolutegravir not expected to affect eplerenone concentrations200

Dosage adjustments not needed200

Ergot alkaloids (dihydroergotamine, ergotamine, methylergonovine)

Dolutegravir not expected to affect concentrations of ergot alkaloids200

Dosage adjustments not needed200

Estrogens and progestins

Estradiol, estrogen, conjugated estrogens: Dolutegravir not expected to affect concentrations of these estrogens200

Drospirenone, medroxyprogesterone, progesterone: Dolutegravir not expected to affect concentrations of these hormones200

Oral contraceptives containing ethinyl estradiol and norgestimate: Dolutegravir has no effect on pharmacokinetics of ethinyl estradiol or norgestimate1 29

Estradiol, estrogen, conjugated estrogens: Dosage adjustments not needed200

Drospirenone, medroxyprogesterone, progesterone: Dosage adjustments not needed200

Oral contraceptives containing ethinyl estradiol and norgestimate: Dosage adjustments not needed200

Etravirine

Substantially decreased dolutegravir concentrations and AUC1 200

Effect on dolutegravir pharmacokinetics is mitigated if etravirine and dolutegravir used concomitantly with lopinavir/ritonavir or ritonavir-boosted darunavir;1 200 effect expected to be mitigated if etravirine and dolutegravir used concomitantly with ritonavir-boosted atazanavir1 200

Do not use etravirine and dolutegravir or abacavir/dolutegravir/lamivudine concomitantly unless ritonavir-boosted atazanavir, ritonavir-boosted darunavir, or lopinavir/ritonavir also included in the regimen1 200 240

In antiretroviral-naive or antiretroviral-experienced, INSTI-naive patients without INSTI resistance: Use dolutegravir 50 mg once daily with etravirine and with ritonavir-boosted atazanavir, ritonavir-boosted darunavir, or lopinavir/ritonavir200

INSTI-experienced with documented or suspected INSTI resistance: Use dolutegravir 50 mg twice daily with etravirine and with ritonavir-boosted atazanavir, ritonavir-boosted darunavir, or lopinavir/ritonavir200

Fentanyl

Dolutegravir not expected to affect fentanyl concentrations200

Dosage adjustments not needed200

Flibanserin

Dolutegravir not expected to affect flibanserin concentrations200

Dosage adjustments not needed200

Fosamprenavir

Ritonavir-boosted fosamprenavir: Decreased dolutegravir concentrations and AUC;1 27 effect on fosamprenavir pharmacokinetics unlikely1 27

No in vitro evidence of antagonistic antiretroviral effects with amprenavir (active metabolite of fosamprenavir)1

Ritonavir-boosted fosamprenavir (adults): In antiretroviral-naive or antiretroviral-experienced, INSTI-naive adults, give dolutegravir dose twice daily;1 in INSTI-experienced adults with documented or suspected INSTI resistance, consider alternative to ritonavir-boosted fosamprenavir whenever possible;1 if abacavir/dolutegravir/lamivudine used, give 1 fixed-combination tablet (abacavir 600 mg, dolutegravir 50 mg, and lamivudine 300 mg) once daily and give a 50-mg tablet of single-entity dolutegravir once daily 12 hours after the fixed-combination dose240

Ritonavir-boosted fosamprenavir (pediatric patients): In antiretroviral-naive or antiretroviral-experienced, INSTI-naive pediatric patients, give weight-based dolutegravir dose twice daily;1 in INSTI-experienced pediatric patients with documented or suspected INSTI resistance, consider alternative to ritonavir-boosted fosamprenavir whenever possible1

Glecaprevir and pibrentasvir

Fixed combination of glecaprevir and pibrentasvir (glecaprevir/pibrentasvir): No clinically important pharmacokinetic interactions with dolutegravir200

Glecaprevir/pibrentasvir: Dosage adjustments not needed200

Goserelin

Dolutegravir not expected to affect goserelin concentrations200

Dosage adjustments not needed200

Histamine H2-receptor antagonists

No clinically important effect on dolutegravir concentrations expected200

Dosage adjustments not needed200

HMG-CoA reductase inhibitors (statins)

Atorvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin: Dolutegravir not expected to affect concentrations of these statins200

Atorvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin: Dosage adjustments not needed200

Immunosuppressive agents

Cyclosporine, everolimus, sirolimus, tacrolimus: Dolutegravir not expected to affect concentrations of these immunosuppressive agents200

Cyclosporine, everolimus, sirolimus, tacrolimus: Dosage adjustments not needed200

Iron preparations

Possible decreased dolutegravir concentrations when given concomitantly in fasted state1 28

Give dolutegravir or abacavir/dolutegravir/lamivudine ≥2 hours before or ≥6 hours after oral iron;1 28 200 240 alternatively, may be given concomitantly if taken with food1 28 200 240

Ivabradine

Dolutegravir not expected to affect ivabradine concentrations200

Dosage adjustments not needed200

Laxatives containing polyvalent cations

Possible decreased dolutegravir absorption and decreased dolutegravir concentrations1

Give dolutegravir or abacavir/dolutegravir/lamivudine ≥2 hours before or ≥6 hours after laxatives containing polyvalent cations1 200 240

Ledipasvir and sofosbuvir

Fixed combination of ledipasvir and sofosbuvir (ledipasvir/sofosbuvir): No effect on dolutegravir pharmacokinetics181 200

Ledipasvir/sofosbuvir: Dosage adjustments not needed200

Leuprolide

Dolutegravir not expected to affect leuprolide concentrations200

Dosage adjustments not needed200

Lofexidine

Dolutegravir not expected to affect lofexidine concentrations200

Dosage adjustments not needed200

Lomitapide

Dolutegravir not expected to affect lomitapide concentrations200

Dosage adjustments not needed200

Lopinavir/ritonavir

No clinically important effects on dolutegravir pharmacokinetics1 200

No in vitro evidence of antagonistic antiretroviral effects1

Dosage adjustments not needed200

Macrolides

Azithromycin, clarithromycin, erythromycin: Dolutegravir not expected to affect macrolide concentrations200

Azithromycin, clarithromycin, erythromycin: Dosage adjustments not needed200

Magnesium preparations

Possible decreased dolutegravir absorption and decreased dolutegravir concentrations1

Give dolutegravir or abacavir/dolutegravir/lamivudine ≥2 hours before or ≥6 hours after magnesium1

Maraviroc

No in vitro evidence of antagonistic antiretroviral effects1

Methadone

No clinically important effect on methadone pharmacokinetics1 200

Dosage adjustments not needed1 200

Multivitamins

Possible decreased dolutegravir concentrations1

Give dolutegravir or abacavir/dolutegravir/lamivudine ≥2 hours before or ≥6 hours after multivitamins containing calcium or iron;1 200 240 alternatively, may be given concomitantly if taken with food1 240

Nefazodone

Dolutegravir not expected to affect nefazodone concentrations200

Dosage adjustments not needed200

Nevirapine

Decreased dolutegravir concentrations and AUC1 200

No in vitro evidence of antagonistic antiretroviral effects1

Manufacturer states do not use concomitantly with dolutegravir or abacavir/dolutegravir/lamivudine;1 200 240 data insufficient to make dosage recommendations1 240

Experts state dosage adjustments not needed200

Phosphodiesterase type 5 (PDE5) inhibitors

Avanafil, sildenafil, tadalafil, vardenafil: Dolutegravir not expected to affect concentrations of these PDE5 inhibitors200

Avanafil, sildenafil, tadalafil, vardenafil: Dosage adjustments not needed200

Proton-pump inhibitors

Omeprazole: No clinically important effect on dolutegravir pharmacokinetics1 19

Omeprazole or other proton-pump inhibitors: Dosage adjustments not needed200

Raltegravir

No in vitro evidence of antagonistic antiretroviral effects1

Ranolazine

Dolutegravir not expected to affect ranolazine concentrations200

Dosage adjustments not needed200

Ribavirin

No in vitro evidence of antagonistic antiviral effects1

Rilpivirine

No clinically important effect on rilpivirine or dolutegravir pharmacokinetics1 200

Dosage adjustments not needed200

Ritonavir

Effect on ritonavir pharmacokinetics unlikely1

Selective β-adrenergic agonists

Arformoterol, formoterol, indacaterol, olodaterol, salmeterol (orally inhaled): Dolutegravir not expected to affect concentrations of the β-adrenergic agonist200

Arformoterol, formoterol, indacaterol, olodaterol, salmeterol (orally inhaled): Dosage adjustments not needed200

Sofosbuvir

No clinically important effect on sofosbuvir pharmacokinetics;1 not expected to affect dolutegravir pharmacokinetics200

Dosage adjustments not needed200

Sofosbuvir and velpatasvir

Fixed combination of sofosbuvir and velpatasvir (sofosbuvir/velpatasvir): No clinically important pharmacokinetic interactions with dolutegravir176

Sofosbuvir/velpatasvir: Dosage adjustments not needed1

Sofosbuvir, velpatasvir, and voxilaprevir

Fixed combination of sofosbuvir, velpatasvir, and voxilaprevir (sofosbuvir/velpatasvir/voxilaprevir): Clinically important pharmacokinetic interactions with dolutegravir not expected200

Sofosbuvir/velpatasvir/voxilaprevir: Dosage adjustments not needed200

Spironolactone

Dolutegravir not expected to affect spironolactone concentrations200

Dosage adjustments not needed200

SSRIs

Citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline: No pharmacokinetic interactions with dolutegravir expected200

Citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline: Dosage adjustments not needed200

Stavudine

No in vitro evidence of antagonistic antiretroviral effects1

St. John's wort (Hypericum perforatum)

Possible decreased dolutegravir concentrations1

Avoid concomitant use with dolutegravir or abacavir/dolutegravir/lamivudine1 240

Sucralfate

Possible decreased dolutegravir concentrations1

Give dolutegravir or abacavir/dolutegravir/lamivudine ≥2 hours before or ≥6 hours after sucralfate1 200 240

Suvorexant

Dolutegravir not expected to affect suvorexant concentrations200

Dosage adjustments not needed200

Tenofovir

Tenofovir alafenamide fumarate (TAF) or tenofovir disoproxil fumarate (TDF): No clinically important effect on tenofovir or dolutegravir pharmacokinetics1 200

TAF or TDF: Dosage adjustments not needed200

Testosterone

Dolutegravir not expected to affect testosterone concentrations200

Dosage adjustments not needed200

Tipranavir

Ritonavir-boosted tipranavir: Decreased dolutegravir concentrations and AUC1 26 200

Ritonavir-boosted tipranavir (adults): In antiretroviral-naive or antiretroviral-experienced, INSTI-naive adults, give dolutegravir dose twice daily;1 200 in INSTI-experienced adults with documented or suspected INSTI resistance, consider alternative to ritonavir-boosted tipranavir whenever possible;1 200 if abacavir/dolutegravir/lamivudine used, give 1 fixed-combination tablet (abacavir 600 mg, dolutegravir 50 mg, and lamivudine 300 mg) once daily and give a 50-mg tablet of single-entity dolutegravir once daily 12 hours after the fixed-combination dose240

Ritonavir-boosted tipranavir (pediatric patients): In antiretroviral-naive or antiretroviral-experienced, INSTI-naive pediatric patients, give weight-based dolutegravir dose twice daily;1 in INSTI-experienced pediatric patients with documented or suspected INSTI resistance, consider alternative to ritonavir-boosted tipranavir whenever possible1

Tramadol

Dolutegravir not expected to affect tramadol concentrations200

Dosage adjustments not needed200

Trazodone

Dolutegravir not expected to affect trazodone concentrations200

Dosage adjustments not needed200

Tricyclic antidepressants

Amitriptyline, desipramine, doxepin, imipramine, nortriptyline: Dolutegravir not expected to affect concentrations of these tricyclic antidepressants

Amitriptyline, desipramine, doxepin, imipramine, nortriptyline: Dosage adjustments not needed200

Zolpidem

Dolutegravir not expected to affect zolpidem concentrations200

Dosage adjustments not needed200

Dolutegravir Pharmacokinetics

Absorption

Bioavailability

Dolutegravir (Tivicay): Following 50 mg orally once or twice daily, peak plasma concentrations occur 2–3 hours after a dose.1 Steady state achieved within approximately 5 days with once-daily dosing.1

Dolutegravir tablets (Tivicay) and dolutegravir tablets for oral suspension (Tivicay PD) are not bioequivalent;1 relative bioavailability of the tablets for oral suspension is approximately 1.6-fold higher than that of the conventional tablets.1

Food

Dolutegravir (Tivicay): Administration with high-fat meal increases AUC by 66%, increases peak concentrations by 67%, and prolongs time to peak concentrations from 2 hours to 5 hours compared with administration in fasting state.1

Abacavir/dolutegravir/lamivudine (Triumeq): Administration with high-fat meal increases dolutegravir peak plasma concentrations and AUC by 37 and 48%, respectively, compared with administration in fasting state;240 abacavir peak plasma concentrations decreased by 23%;240 lamivudine exposures not affected.240

Distribution

Extent

Dolutegravir distributed into CSF;1 32 clinical importance unknown.1

Crosses placenta.202

Appears to be distributed into human milk in low concentrations;202 distributed into milk in rats.1

Plasma Protein Binding

Approximately 99%.1

Elimination

Metabolism

Dolutegravir primarily metabolized by UGT1A1;1 CYP3A plays only minor role.1

Elimination Route

Dolutegravir excreted in feces (64% of a dose; 53% as unchanged drug) and urine (31% of a dose; <1% as unchanged drug).1

Half-life

Approximately 14 hours.1

Special Populations

Moderate hepatic impairment (Child-Pugh class B): No clinically important effect on dolutegravir pharmacokinetics.1

Severe hepatic impairment (Child-Pugh class C): Dolutegravir pharmacokinetics not evaluated.1

HCV coinfection: No clinically important effect on dolutegravir pharmacokinetics.1

Mild to moderate renal impairment: No clinically important effect on dolutegravir pharmacokinetics.1

Severe renal impairment (Clcr <30 mL/minute): Dolutegravir AUC, peak plasma concentrations, and plasma concentrations measured 24 hours after dosing are 40, 23, and 43% lower, respectively, compared with healthy individuals.1 (See Renal Impairment under Cautions.)

HIV-1-infected pediatric patients 4 weeks to <18 years of age: Peak plasma concentrations and AUC reported with weight-based dosages are comparable to those in adults receiving dolutegravir 50 mg once or twice daily.1

Polymorphism in UGT1A1: Genotypes of UGT1A1 conferring poor dolutegravir metabolism result in 32% lower clearance and 46% higher AUC compared with genotypes associated with normal UGTIA1 metabolism.1

Stability

Storage

Oral

Tablets

Dolutegravir tablets (Tivicay): 25°C (may be exposed to 15–30°C).1

Dolutegravir tablets for oral suspension (Tivicay PD): <30°C.1 Store and dispense in original bottle; do not remove desiccant; protect from moisture.1

Abacavir/dolutegravir/lamivudine (Triumeq): 25°C (may be exposed to 15–30°C).240 Store and dispense in original package; do not remove desiccant; protect from moisture.240

Actions and Spectrum

  • Dolutegravir is an HIV INSTI.1 200 Binds to active site of HIV integrase and blocks the strand transfer step of retroviral DNA integration, which is essential for HIV replication.4 1

  • Active against HIV-1;1 also has in vitro activity against HIV type 2 (HIV-2).1 20 25 200 Not active against HCV.20

  • Has been active against HIV-1 resistant to HIV NRTIs, HIV nonnucleoside reverse transcriptase inhibitors (NNRTIs), or HIV protease inhibitors (PIs).1

  • HIV-1 resistant to dolutegravir have been produced in vitro and have emerged during dolutegravir therapy.1 12 13

  • Appears to have a different resistance profile than other HIV INSTIs and has been active in vitro against some HIV-1 resistant to other INSTIs (e.g., elvitegravir, raltegravir).1 12 13 14 15 16 However, cross-resistance between dolutegravir and other INSTIs (e.g., elvitegravir and/or raltegravir) reported.1 12 15 16

Advice to Patients

  • Critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician.1 200 Importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.1 200 240

  • Importance of using single-entity dolutegravir (Tivicay, Tivicay PD) in conjunction with other antiretrovirals—not for monotherapy.1

  • Abacavir/dolutegravir/lamivudine (Triumeq) may be used alone as a complete regimen for treatment of HIV-1 infection or in conjunction with other antiretrovirals.240

  • Antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications associated with HIV disease may still occur.200

  • Advise patients that early initiation of antiretroviral therapy and sustained decreases in plasma HIV RNA have been associated with reduced risk of progression to AIDS and death.200

  • Advise patients that effective antiretroviral regimens can decrease HIV concentrations in blood and genital secretions and strict adherence to such regimens in conjunction with risk-reduction measures may decrease, but cannot absolutely eliminate, the risk of secondary transmission of HIV to others.200 Importance of continuing to practice safer sex (e.g., using latex or polyurethane condoms to minimize sexual contact with body fluids) and reducing high-risk behaviors (e.g., never reusing or sharing needles).200

  • Importance of reading patient information provided by the manufacturer.1 240

  • Inform patients and/or caregivers that dolutegravir tablets and dolutegravir tablets for oral suspension are not bioequivalent and are not interchangeable; advise that dosage must be adjusted if a switch is made from one formulation to the other.1 To avoid dosage errors from using the wrong formulation of dolutegravir, strongly advise patients and/or caregivers to visually inspect the tablets to verify that they were given the correct formulation each time the prescription is filled.1

  • If the tablets for oral suspension are used, inform patients and/or caregivers that the tablets may be swallowed whole or dispersed in drinking water and should not be chewed, cut, or crushed. 1 The amount of water needed to disperse the tablets depends on the dose (i.e., required number of tablets).1

  • Advise patients and/or caregivers that if a dose of dolutegravir or abacavir/dolutegravir/lamivudine is missed, it should be taken as soon as it is remembered and the next dose taken at the regularly scheduled time.1 240 A double dose should not be taken to make up for a missed dose.1 240

  • Importance of immediately discontinuing dolutegravir and other suspect agents and seeking medical attention if rash occurs and is associated with fever, generally ill feeling, extreme tiredness, muscle or joint aches, breathing difficulty, blisters or peeling skin, oral blisters or lesions, eye inflammation, swelling of the face, eyes, lips, or mouth, and/or signs and symptoms of liver problems (e.g., yellowing of skin or whites of the eyes, dark or tea-colored urine, pale stools/bowel movements, nausea, vomiting, loss of appetite, or pain, aching, or sensitivity on the right side below ribs).1 240

  • Advise patients that hepatotoxicity has been reported in patients receiving dolutegravir and that monitoring for hepatotoxicity recommended.1 240

  • Advise patients that signs and symptoms of inflammation from previous infection may occur soon after initiation of antiretroviral therapy; importance of immediately informing clinician if any signs or symptoms of infection occur.1 240

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements (e.g., St. John's wort), as well as any concomitant illnesses.1 240

  • Importance of women informing their clinicians if they plan to become pregnant or if pregnancy occurs or is suspected during treatment with dolutegravir or abacavir/dolutegravir/lamivudine.1 240 Advise women of childbearing potential of the risks to the fetus if dolutegravir is used at the time of conception through the first trimester.1 240 Advise women of childbearing potential taking dolutegravir or abacavir/dolutegravir/lamivudine to consistently use effective contraception during treatment with the drug.1 240 (See Pregnancy under Cautions.)

  • Importance of women informing clinicians if they plan to breast-feed.1 240 (See Pregnancy under Cautions.) Advise HIV-infected women not to breast-feed.1 240

  • Importance of advising patients of other important precautionary information.1 240 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Dolutegravir Sodium

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

10 mg (of dolutegravir)

Tivicay

ViiV

25 mg (of dolutegravir)

Tivicay

ViiV

50 mg (of dolutegravir)

Tivicay

ViiV

Tablets, for oral suspension

5 mg (of dolutegravir)

Tivicay PD

ViiV

Dolutegravir Sodium Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

50 mg (of dolutegravir) with Abacavir Sulfate 600 mg (of abacavir) and Lamivudine 300 mg

Triumeq

ViiV

50 mg (of dolutegravir) with Lamivudine 300 mg

Dovato

Viiv

50 mg (of dolutegravir) with Rilpivirine Hydrochloride 25 mg (of rilpivirine)

Juluca

ViiV

AHFS DI Essentials™. © Copyright 2021, Selected Revisions October 5, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. ViiV Healthcare. Tivicay (dolutegravir) tablets and tablets for oral suspension prescribing information. Research Triangle Park, NC; 2020 Jun.

2. Raffi F, Rachlis A, Stellbrink HJ et al. Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study. Lancet. 2013; 381:735-43. http://www.ncbi.nlm.nih.gov/pubmed/23306000?dopt=AbstractPlus

3. Raffi F, Jaeger H, Quiros-Roldan E et al. Once-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomised, double-blind, non-inferiority trial. Lancet Infect Dis. 2013; 13:927-35. http://www.ncbi.nlm.nih.gov/pubmed/24074642?dopt=AbstractPlus

4. Walmsley SL, Antela A, Clumeck N et al. Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection. N Engl J Med. 2013; 369:1807-18. http://www.ncbi.nlm.nih.gov/pubmed/24195548?dopt=AbstractPlus

5. Feinberg J, Clotet B, Khuong-Josses MA, et al. Once-daily dolutegravir (DTG) is superior to darunavir/ritonavir (DRV/r) in antiretroviral-naive adults: 48 week results from FLAMINGO (ING114915). Paper presented at: 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy; Sep 10–13, 2013; Denver CO. http://www.natap.org/2013/ICAAC/ICAAC_24.htm

6. Cahn P, Pozniak AL, Mingrone H et al. Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study. Lancet. 2013; 382:700-8. http://www.ncbi.nlm.nih.gov/pubmed/23830355?dopt=AbstractPlus

7. Song IH, Borland J, Chen S et al. Effect of food on the pharmacokinetics of the integrase inhibitor dolutegravir. Antimicrob Agents Chemother. 2012; 56:1627-9. http://www.ncbi.nlm.nih.gov/pubmed/22183173?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3294934&blobtype=pdf

8. Song IH, Borland J, Chen S et al. Effect of prednisone on the pharmacokinetics of the integrase inhibitor dolutegravir. Antimicrob Agents Chemother. 2013; 57:4394-7. http://www.ncbi.nlm.nih.gov/pubmed/23817375?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3754328&blobtype=pdf

9. Castellino S, Moss L, Wagner D et al. Metabolism, excretion, and mass balance of the HIV-1 integrase inhibitor dolutegravir in humans. Antimicrob Agents Chemother. 2013; 57:3536-46. http://www.ncbi.nlm.nih.gov/pubmed/23669385?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3719771&blobtype=pdf

10. Zash R, Holmes L, Diseko M et al. Neural-Tube Defects and Antiretroviral Treatment Regimens in Botswana. N Engl J Med. 2019; 381:827-840. http://www.ncbi.nlm.nih.gov/pubmed/31329379?dopt=AbstractPlus

11. Weller S, Borland J, Chen S et al. Pharmacokinetics of dolutegravir in HIV-seronegative subjects with severe renal impairment. Eur J Clin Pharmacol. 2013; :. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3889630&blobtype=pdf

12. Deanda F, Hightower KE, Nolte RT et al. Dolutegravir Interactions with HIV-1 Integrase-DNA: Structural Rationale for Drug Resistance and Dissociation Kinetics. PLoS One. 2013; 8:e77448. http://www.ncbi.nlm.nih.gov/pubmed/24146996?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3797783&blobtype=pdf

13. Mesplède T, Quashie PK, Osman N et al. Viral fitness cost prevents HIV-1 from evading dolutegravir drug pressure. Retrovirology. 2013; 10:22. http://www.ncbi.nlm.nih.gov/pubmed/23432922?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3598531&blobtype=pdf

14. Canducci F, Ceresola ER, Saita D et al. In vitro phenotypes to elvitegravir and dolutegravir in primary macrophages and lymphocytes of clonal recombinant viral variants selected in patients failing raltegravir. J Antimicrob Chemother. 2013; 68:2525-32. http://www.ncbi.nlm.nih.gov/pubmed/23798668?dopt=AbstractPlus

15. Abram ME, Hluhanich RM, Goodman DD et al. Impact of primary elvitegravir resistance-associated mutations in HIV-1 integrase on drug susceptibility and viral replication fitness. Antimicrob Agents Chemother. 2013; 57:2654-63. http://www.ncbi.nlm.nih.gov/pubmed/23529738?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3716146&blobtype=pdf

16. Underwood MR, Johns BA, Sato A et al. The activity of the integrase inhibitor dolutegravir against HIV-1 variants isolated from raltegravir-treated adults. J Acquir Immune Defic Syndr. 2012; 61:297-301. http://www.ncbi.nlm.nih.gov/pubmed/22878423?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3804312&blobtype=pdf

17. Song I, Borland J, Chen S et al. Effect of atazanavir and atazanavir/ritonavir on the pharmacokinetics of the next-generation HIV integrase inhibitor, S/GSK1349572. Br J Clin Pharmacol. 2011; 72:103-8. http://www.ncbi.nlm.nih.gov/pubmed/21342217?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3141191&blobtype=pdf

18. Min S, Song I, Borland J et al. Pharmacokinetics and safety of S/GSK1349572, a next-generation HIV integrase inhibitor, in healthy volunteers. Antimicrob Agents Chemother. 2010; 54:254-8. http://www.ncbi.nlm.nih.gov/pubmed/19884365?dopt=AbstractPlus

19. Patel P, Song I, Borland J et al. Pharmacokinetics of the HIV integrase inhibitor S/GSK1349572 co-administered with acid-reducing agents and multivitamins in healthy volunteers. J Antimicrob Chemother. 2011; 66:1567-72. http://www.ncbi.nlm.nih.gov/pubmed/21493648?dopt=AbstractPlus

20. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 204790Orig1s000: Microbiology review(s). From FDA website. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204790Orig1s000MicroR.pdf

21. Weller S, Chen S, Borland J et al. Bioequivalence of a dolutegravir, abacavir, and lamivudine fixed-dose combination tablet and the effect of food. J Acquir Immune Defic Syndr. 2014; 66:393-8. http://www.ncbi.nlm.nih.gov/pubmed/24798770?dopt=AbstractPlus

22. Castagna A, Maggiolo F, Penco G et al. Dolutegravir in antiretroviral-experienced patients with raltegravir- and/or elvitegravir-resistant HIV-1: 24-week results of the phase III VIKING-3 study. J Infect Dis. 2014; 210:354-62. http://www.ncbi.nlm.nih.gov/pubmed/24446523?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=4091579&blobtype=pdf

23. Akil B, Blick G, Hagins DP et al. Dolutegravir versus placebo in subjects harbouring HIV-1 with integrase inhibitor resistance associated substitutions: 48-week results from VIKING-4, a randomized study. Antivir Ther. 2015; 20:343-8. http://www.ncbi.nlm.nih.gov/pubmed/25321146?dopt=AbstractPlus

24. Walmsley S, Baumgarten A, Berenguer J et al. Brief Report: Dolutegravir Plus Abacavir/Lamivudine for the Treatment of HIV-1 Infection in Antiretroviral Therapy-Naive Patients: Week 96 and Week 144 Results From the SINGLE Randomized Clinical Trial. J Acquir Immune Defic Syndr. 2015; 70:515-9. http://www.ncbi.nlm.nih.gov/pubmed/26262777?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=4645960&blobtype=pdf

25. Smith RA, Raugi DN, Pan C et al. In vitro activity of dolutegravir against wild-type and integrase inhibitor-resistant HIV-2. Retrovirology. 2015; 12:10. http://www.ncbi.nlm.nih.gov/pubmed/25808007?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=4328052&blobtype=pdf

26. Song I, Borland J, Chen S et al. Effects of enzyme inducers efavirenz and tipranavir/ritonavir on the pharmacokinetics of the HIV integrase inhibitor dolutegravir. Eur J Clin Pharmacol. 2014; 70:1173-9. http://www.ncbi.nlm.nih.gov/pubmed/25146692?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=4158172&blobtype=pdf

27. Song I, Borland J, Chen S et al. Effect of fosamprenavir-ritonavir on the pharmacokinetics of dolutegravir in healthy subjects. Antimicrob Agents Chemother. 2014; 58:6696-700. http://www.ncbi.nlm.nih.gov/pubmed/25155604?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=4249430&blobtype=pdf

28. Song I, Borland J, Arya N et al. Pharmacokinetics of dolutegravir when administered with mineral supplements in healthy adult subjects. J Clin Pharmacol. 2015; 55:490-6. http://www.ncbi.nlm.nih.gov/pubmed/25449994?dopt=AbstractPlus

29. Song IH, Borland J, Chen S et al. Dolutegravir Has No Effect on the Pharmacokinetics of Oral Contraceptives With Norgestimate and Ethinyl Estradiol. Ann Pharmacother. 2015; 49:784-9. http://www.ncbi.nlm.nih.gov/pubmed/25862012?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=4472613&blobtype=pdf

30. Song I, Weller S, Patel J et al. Effect of carbamazepine on dolutegravir pharmacokinetics and dosing recommendation. Eur J Clin Pharmacol. 2016; 72:665-70. http://www.ncbi.nlm.nih.gov/pubmed/26898568?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=4865535&blobtype=pdf

31. Song IH, Zong J, Borland J et al. The Effect of Dolutegravir on the Pharmacokinetics of Metformin in Healthy Subjects. J Acquir Immune Defic Syndr. 2016; 72:400-7. http://www.ncbi.nlm.nih.gov/pubmed/26974526?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=4935531&blobtype=pdf

32. Letendre SL, Mills AM, Tashima KT et al. ING116070: a study of the pharmacokinetics and antiviral activity of dolutegravir in cerebrospinal fluid in HIV-1-infected, antiretroviral therapy-naive subjects. Clin Infect Dis. 2014; 59:1032-7. http://www.ncbi.nlm.nih.gov/pubmed/24944232?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=4166983&blobtype=pdf

33. Molina JM, Clotet B, van Lunzen J et al. Once-daily dolutegravir versus darunavir plus ritonavir for treatment-naive adults with HIV-1 infection (FLAMINGO): 96 week results from a randomised, open-label, phase 3b study. Lancet HIV. 2015; 2:e127-36. http://www.ncbi.nlm.nih.gov/pubmed/26424673?dopt=AbstractPlus

35. US Food and Drug Administration. FDA drug safety communication: FDA to evaluate potential risk of neural tube birth defects with HIV medicine dolutegravir (Juluca, Tivicay, Triumeq). 2018 May 18. From FDA website. https://www.fda.gov/downloads/Drugs/DrugSafety/UCM608127.pdf

176. Gilead Sciences. Epclusa (sofosbuvir and velpatasvir) tablets prescribing information. Foster City, CA; 2019 Nov.

177. Merck & Co., Inc. Zepatier (elbasvir and grazoprevir) tablets prescribing information. Whitehouse Station, NJ; 2018 Jun.

181. Gilead Sciences. Harvoni (ledipasvir and sofosbuvir) tablets and oral pellets prescribing information. Foster City, CA; 2019 Nov.

198. Centers for Disease Control and Prevention. Updated guidelines for antiretroviral postexposure prophylaxis after sexual, injection drug use, or other nonoccupational exposure to HIV – United States, 2016. From HHS AIDS Information (AIDSinfo) website. http://www.aidsinfo.nih.gov

200. Panel on Antiretroviral Guidelines for Adults and Adolescents, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in adults and adolescents Living with HIV. Accessed 2020 Apr 20. Updates may be available at HHS AIDS Information (AIDSinfo) website. http://www.aidsinfo.nih.gov

201. Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in pediatric HIV infection. Accessed 2020 Apr 20. Updates may be available at HHS AIDS Information (AIDSinfo) website. http://www.aidsinfo.nih.gov

202. Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission, US Department of Health and Human Services (HHS). Recommendations for the use of antiretroviral drugs in women with HIV infection and interventions to reduce perinatal HIV transmission in the United States. Accessed 2020 Apr 20. Updates may be available at HHS AIDS Information (AIDSinfo) website. http://www.aidsinfo.nih.gov

203. US Centers for Disease Control and Prevention. Interim statement regarding potential fetal harm from exposure to dolutegravir – implications for HIV post-exposure prophylaxis (PEP). From CDC website. Accessed 2020 Jun 25. https://www.cdc.gov/hiv/risk/pep/index.html

240. ViiV Healthcare. Triumeq (abacavir, dolutegravir, lamivudine) tablets prescribing information. Research Triangle Park, NC; 2020 Mar.

247. ViiV Healthcare. Juluca (dolutegravir and rilpivirine) tablets prescribing information. Research Triangle Park, NC; 2019 Oct.

256. ViiV Healthcare. Dovato (dolutegravir and lamivudine) tablets prescribing information. Research Triangle Park, NC; 2020 Aug.

Frequently asked questions