AHFS Class:

• HIV Integrase Inhibitors 8:18.08.12

Generic Name(s):

• Dolutegravir Sodium

Dolutegravir sodium, an antiretroviral agent, is a human immunodeficiency virus (HIV) integrase strand transfer inhibitor (INSTI).1,200

Treatment of HIV Infection

Dolutegravir sodium is used in conjunction with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults who are antiretroviral-naïve (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-naïve or antiretroviral-experienced but have not previously received an HIV integrase strand transfer inhibitor (INSTI-naïve).1

Dolutegravir is commercially available as a single entity and in various fixed-combination preparations that contain additional antiretrovirals; refer to separate combination product monographs for information related to the specific uses of these products.1,240,247,256

The single entity dolutegravir preparation is used in conjunction with rilpivirine as a complete regimen for the treatment of HIV-1 infection in adults to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable antiretroviral regimen for ≥6 months with no history of treatment failure and no known substitutions associated with resistance to either agent; for more information on dolutegravir/rilpivirine as a complete regimen, refer to the monograph for the fixed-combination dolutegravir/rilpivirine preparation.1,247

Dolutegravir is commonly used as part of a fully suppressive antiretroviral regimen in conjunction with 1 or 2 nucleotide/nucleoside reverse transcriptase inhibitors (NRTIs); consult guidelines for the most current information on recommended regimens.200,201,202 Selection of an initial antiretroviral regimen should be individualized based on factors such as virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance test results, comorbid conditions, access, and cost.200,201,202

Clinical Experience

Antiretroviral-naïve Adults and Adolescents

Efficacy and safety of dolutegravir in antiretroviral-naïve HIV-1-infected adults have been evaluated in phase 3 randomized studies (SPRING-2, SINGLE, FLAMINGO). 1,2,3,4,5,24,33

SPRING-2 is a phase 3, randomized, active-controlled, double-placebo, noninferiority study in antiretroviral-naïve HIV-1-infected adults with baseline plasma HIV-1 RNA levels of 1000 copies/mL or higher.1,2,3 Patients were randomized to receive dolutegravir 50 mg once daily or raltegravir 400 mg twice daily in conjunction with an investigator-selected dual NRTI regimen of either the fixed-combination preparation containing emtricitabine and tenofovir disoproxil fumarate (emtricitabine/tenofovir DF) or fixed-combination preparation containing abacavir and lamivudine (abacavir/lamivudine).1,2,3 Baseline characteristics of the 822 study patients were similar in both treatment groups (median age 36 years, 87% male, 15% non-white, 11% with hepatitis B virus [HBV] and/or hepatitis C virus [HCV] coinfection, 2% Centers for Disease Control and Prevention [CDC] Class C, median baseline plasma HIV-1 RNA level 4.52 or 4.58 log₁₀ copies/mL, median baseline CD4⁺ T-cell count 359 or 362 cells/mm³).1,2 At 96 weeks, 82% of patients in the dolutegravir group and 78% of those in the raltegravir group had plasma HIV-1 RNA levels <50 copies/mL; the median increase in CD4⁺ T-cell count was 276 cells/mm³ in the dolutegravir group and 264 cells/mm³ in the raltegravir group.1

SINGLE is a 96-week randomized, double-blind, active-controlled study in antiretroviral-naïve HIV-1-infected adults evaluating the efficacy and safety of dolutegravir 50 mg once daily in conjunction with abacavir/lamivudine compared with the fixed-combination preparation containing efavirenz, emtricitabine, and tenofovir DF (efavirenz/emtricitabine/tenofovir DF) followed by an open-label phase through week 144.1,4,24 Baseline characteristics of the 833 study patients were similar in both treatment groups (median age 35 years, 16% female, 32% non-white, 7% with HCV coinfection, 4% CDC Class C, 32% with HIV-1 RNA >100,000 copies/mL, 53% with CD4⁺ T-cell count <350 cells/mm³). 1,4,24 At 144 weeks, 71% of patients receiving dolutegravir with abacavir/lamivudine and 63% of those receiving efavirenz/emtricitabine/tenofovir DF achieved plasma HIV-1 RNA levels <50 copies/mL.1,24 The adjusted mean increase in CD4⁺ T-cell count was 378 cells/mm³ in those receiving dolutegravir and abacavir/lamivudine compared with 332 cells/mm³in those receiving efavirenz/emtricitabine/tenofovir DF.1,24

FLAMINGO is an open-label, randomized, noninferiority study in antiretroviral-naïve HIV-1-infected adults that compared the efficacy and safety of dolutegravir 50 mg once daily with that of ritonavir-boosted darunavir when the drugs were given in conjunction with an investigator-selected dual NRTI regimen of abacavir/lamivudine or emtricitabine/tenofovir DF.1,5,33 At baseline, the 484 study patients had a median age of 34 years, 15% were female, 28% were non-white, 25% had plasma HIV-1 RNA levels >100,000 copies/mL, and 35% had CD4⁺ T-cell counts <350 cells/mm³.1,5 At 96 weeks, 80% of patients in the dolutegravir group achieved plasma HIV-1 RNA levels <50 copies/mL compared with 68% in the ritonavir-boosted darunavir group.1,33

Antiretroviral-experienced Adults and Adolescents

The comparative efficacy and safety of dolutegravir in 715 antiretroviral-experienced, INSTI-naïve HIV-1-infected adults was studied in a phase 3, randomized, double-blind, active-controlled, double-placebo study (SAILING).1,6 All enrolled patients had previously received antiretroviral therapy (average duration 77 months of prior therapy) and had infections resistant to at least 2 classes of antiretrovirals (49% had HIV-1 resistant to at least 3 classes of antiretrovirals).6 Patients were randomized to receive dolutegravir 50 mg once daily or raltegravir 400 mg twice daily, each in conjunction with an investigator-selected optimized background antiretroviral regimen (OBR) consisting of ≥1 fully active antiretroviral.1,6 Baseline characteristics were similar in both treatment groups (median age 43 years, 32% female, 50% non-white, 16% with HBV and/or HCV coinfection, 46% CDC Class C, 20% with plasma HIV-1 RNA levels >100,000 copies/mL, 72% with CD4⁺ T-cell counts <350 cells/mm³).1,6 At 48 weeks, 71% of patients in the dolutegravir group and 64% of those in the raltegravir group had plasma HIV-1 RNA levels <50 copies/mL; 1,6 CD4⁺ T-cell counts were increased from baseline in both groups (mean change 162 cells/mm³ in the dolutegravir group and 153 cells/mm³ in the raltegravir group)1,6

An open-label, single-arm, phase 3 study (VIKING-3) evaluated use of dolutegravir and an OBR in 183 antiretroviral-experienced adults with current or prior virologic failure on another INSTI-containing regimen (elvitegravir, raltegravir) and current or historical evidence of resistance to these other INSTIs.1,22 At baseline, most patients had HIV-1 resistant to other antiretroviral classes (79% with resistance to ≥2 NRTIs, 75% with resistance to ≥1 HIV nonnucleoside reverse transcriptase inhibitor [NNRTI], 71% with resistance to ≥2 HIV protease inhibitors [PIs]).1 At baseline, the median age of study patients was 48 years, 23% were female, 29% were non-white, 20% had HBV and/or HCV coinfection, median plasma HIV-1 RNA level was 4.38 log₁₀ copies/mL, median CD4⁺ T-cell count was 140 cells/mm³, and median duration of prior antiretroviral therapy was 13-14 years.1,22 Patients received dolutegravir 50 mg twice daily with their current failing background regimen for 7 days; on day 8, dolutegravir was continued and the background regimen was further optimized if possible.1,22 The mean reduction in plasma HIV-1 RNA level on day 8 (primary efficacy end point) was 1.4 log₁₀ copies/mL.1,22 At 48 weeks after initiation of dolutegravir, 63% of study patients had plasma HIV-1 RNA levels <50 copies/mL and the median increase in CD4⁺ T-cell count was 80 cells/mm³.1 The presence of INSTI-resistance substitutions at baseline affected the 48-week response rate.1 The response rate to the dolutegravir regimen was 74% in those who had HIV-1 without the Q148 resistance substitution present at baseline, but was 61% if the Q148H/R and G140S/A/C substitutions were present at baseline and 29% if the Q148H/R substitution plus 2 or more additional INSTI-resistance substitutions (T66A, L74I/M, E138A/K/T, G140S/A/C, Y143R/C/H, E157Q, G163S/E/K/Q, or G193E/R) were present at baseline.1

In a randomized, double-blind, placebo-controlled, phase 3 study (VIKING-4), antiretroviral-experienced, dolutegravir-naïve adults receiving a failing INSTI-based regimen that included elvitegravir or raltegravir were randomized to receive dolutegravir (50 mg twice daily) or placebo with their previous failing antiretroviral regimen for 7 days, followed by a single-arm, open-label regimen of dolutegravir (50 mg twice daily) in conjunction with an optimized antiretroviral regimen containing ≥1 fully active antiretroviral selected based on baseline resistance data.23 At baseline, all patients had plasma HIV-1 RNA levels of 1000 copies/mL or greater and HIV-1 with INSTI genotypic resistance.23 In addition, most patients had HIV-1 resistant to other antiretroviral classes (63% with resistance to ≥3 NRTIs, 53% with resistance to ≥2 NNRTIs, 67% with resistance to ≥2 PIs).23 The mean reduction in plasma HIV-1 RNA level on day 8 (primary efficacy end point) in those initially randomized to dolutegravir was 1.06 log₁₀ copies/mL.23 At 48 weeks, 40% of all study patients had plasma HIV-1 RNA levels <50 copies/mL and the median increase in CD4⁺ T-cell count was 125 cells/mm³.23 The response rate at 48 weeks was 57% in those with HIV-1 without the Q148 resistance substitution present at baseline, but was only 25% if the Q148 substitution plus ≥1 additional INSTI-resistance substitutions were present at baseline.23

Pediatric Patients

The safety, efficacy, and pharmacokinetic profile of dolutegravir in HIV-1-infected pediatric patients ≥4 weeks of age were evaluated in a phase 1/phase 2, open-label, noncomparative study (IMPAACT P1093).1,34,36,37 Patients were stratified by age into cohort 1 (12 to <18 years of age), cohort 2A (6 to <12 years of age), cohort 3 (2 to <6 years of age), cohort 4 (6 months to <2 years of age), and cohort 5 (4 weeks to <6 months of age).1

Seventy-five pediatric patients received the recommended dolutegravir dosage (based on weight and age) administered either as conventional tablets (Tivicay^®) or tablets for oral suspension (Tivicay^® PD) in conjunction with other antiretrovirals.1 The median age of these patients was 27 months (range: 1 to 214 months), 59% were female, and 68% were Black or African American.1 At baseline, mean plasma HIV-1 RNA level was 4.4 log₁₀ copies/mL, median CD4⁺ T-cell count was 1225 cells/mm³(range: 1-8255), and median CD4⁺ T-cell percentage was 23% (range: 0.3-49%).1 Overall, 33% of these pediatric patients had baseline plasma HIV-1 RNA levels >50,000 copies/mL and 12% had a CDC HIV clinical classification of category C.1 The majority (80%) were treatment-experienced, but all were INSTI-naïve; 44% had previously received at least 1 HIV NNRTI and 76% had previously received at least 1 HIV PI (76%).1

Virologic outcomes are available for the pediatric patients who received the recommended weight-based dolutegravir dosage through week 24 (58 patients) or week 48 (42 patients).1 At week 24, 62% of patients achieved plasma HIV-1 RNA levels <50 copies/mL and 86% achieved plasma HIV-1 RNA levels <400 copies/mL (snapshot algorithm); the median CD4⁺ T-count increase from baseline was 105 cells/mm³.1 At week 48, 69% of patients achieved plasma HIV-1 RNA levels <50 copies/mL and 79% achieved plasma HIV-1 RNA levels <400 copies/mL (snapshot algorithm); the median CD4⁺ T-count increase from baseline was 141 cells/mm³.1

Clinical Perspective

Therapeutic options for the treatment and prevention of HIV infection and recommendations concerning the use of antiretrovirals are continuously evolving.200,201,202 Antiretroviral therapy is recommended for all individuals with HIV regardless of CD4 counts, and should be initiated as soon as possible after diagnosis of HIV and continued indefinitely.200,201,202 The primary goals of antiretroviral therapy are to achieve and maintain durable suppression of HIV viral load (as measured by plasma HIV-1 RNA levels) to a level below which drug-resistance mutations cannot emerge (i.e., below detectable limits), restore and preserve immunologic function, reduce HIV-related morbidity and mortality, improve quality of life, and prevent transmission of HIV.200,202 While the most appropriate antiretroviral regimen cannot be defined for each clinical scenario, the US Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents, HHS Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV, and HHS Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission, have developed comprehensive guidelines that provide information on selection and use of antiretrovirals for the treatment or prevention of HIV infection.200,201,202 Because of the complexity of managing patients with HIV, it is recommended that clinicians with HIV expertise be consulted when needed.200,201,202

The use of combination antiretroviral regimens that generally include 3 drugs from 2 or more drug classes is currently recommended to achieve viral suppression.200,201 In both treatment-naïve adults and children, an initial antiretroviral regimen generally consists of 2 NRTIs administered in combination with a third active antiretroviral drug from 1 of 3 drug classes: an INSTI, an NNRTI, or a PI with a pharmacokinetic enhancer (also known as a booster; the 2 drugs used for this purpose are cobicistat and ritonavir).200,201,202 Selection of an initial antiretroviral regimen should be individualized based on factors such as virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance-test results, comorbid conditions, access, and cost.200,201,202 In patients with comorbid infections (e.g., hepatitis B, tuberculosis), antiretroviral regimen selection should also consider the potential for activity against other present infections and timing of initiation relative to other anti-infective regimens.200

Dolutegravir, an INSTI, is commonly used as part of a fully suppressive regimen in conjunction with 1 or 2 NRTIs.200 In the HHS adult and adolescent HIV treatment guideline, dolutegravir is included in various antiretroviral regimens.200 Some of these dolutegravir-containing regimens are listed among recommended initial regimens for most people with HIV, and include the following: dolutegravir/abacavir/lamivudine (only in patients who are negative for human leukocyte antigen (HLA)-B*5701); dolutegravir plus tenofovir DF or tenofovir alafenamide plus lamivudine or emtricitabine; dolutegravir/lamivudine (except in individuals with HIV RNA >500,000 copies/mL, HBV coinfection, or in whom antiretroviral therapy is to be started before the results of HIV genotypic resistance testing for reverse transcriptase or HBV testing are available).200 The 2-drug regimen of dolutegravir/rilpivirine is not recommended for initial therapy because it has not been studied for use in this setting.200

In the HHS pediatric HIV treatment guideline, dolutegravir is included in various antiretroviral regimens.201 Dolutegravir plus 2 NRTIs is a preferred initial regimen for infants and children ≥4 weeks of age weighing ≥3 kg.201

In the HHS perinatal HIV treatment guideline, dolutegravir is included in various antiretroviral regimens.202 Some of these dolutegravir-containing regimens are listed among preferred options, and include the following: dolutegravir/abacavir/lamivudine or dolutegravir plus a preferred dual-NRTI backbone.202

Postexposure Prophylaxis following Nonoccupational Exposure to HIV

Dolutegravir is used in conjunction with other antiretrovirals for 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

Clinical Perspective

When nPEP is indicated following a nonoccupational exposure to HIV, the US Centers for Disease Control and Prevention (CDC) states that the preferred regimen in adults and adolescents 13 years of age or older with normal renal function is either raltegravir or dolutegravir used in conjunction with emtricitabine and tenofovir DF (administered as the fixed combination emtricitabine/tenofovir DF; e.g., Truvada^®).198 The alternative nPEP regimen recommended in these patients is ritonavir-boosted darunavir used in conjunction with emtricitabine/tenofovir DF (e.g., Truvada^®).198

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

General

Pretreatment Screening

• Perform testing for hepatitis B virus (HBV) infection and hepatitis C virus (HCV) infection in all patients with human immunodeficiency virus (HIV) infection prior to initiation of antiretroviral therapy.200

Patient Monitoring

• Monitor for signs and symptoms of hepatotoxicity during treatment with dolutegravir.1

Dispensing and Administration Precautions

• Dolutegravir is commercially available as a single entity and in various fixed-combination preparations that contain additional antiretrovirals.1,240,247,256 Refer to the full prescribing information for information on specific uses, cautions, precautions, contraindications, and drug interactions of the combination products.240,247,256
• Dolutegravir tablets and dolutegravir tablets for oral suspension are not bioequivalent and are not interchangeable on a mg-per-mg basis.1

Administration

Single-entity dolutegravir is commercially available as conventional tablets (Tivicay^®) and as tablets for oral suspension (Tivicay^® PD).1 The single-entity tablets and tablets for oral suspension must be used in conjunction with other antiretrovirals.1

Administer dolutegravir sodium orally once or twice daily without regard to food.1

Do not chew, cut, or crush the tablets for oral suspension.1 Dolutegravir tablets for oral suspension may be either swallowed whole (1 tablet at time if more than a single tablet is required for the dose, to reduce the risk of choking), or dispersed in drinking water to provide an oral suspension.1

To prepare an oral suspension, add the indicated number of 5-mg tablets for oral suspension to the appropriate volume of clean drinking water in the plastic cup provided by the 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 the cup for 1-2 minutes until there are no remaining lumps.1 After full dispersion, administer the oral suspension within 30 minutes of mixing1 For infants who cannot drink from the plastic cup, administer the oral suspension using the oral syringe provided by the manufacturer.1 To ensure that the child receives the full dose, place an 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 For more specific instructions on preparation and administration of dolutegravir oral suspension, consult the manufacturer's instructions for use and labeling.1

Store the conventional tablets at controlled room temperature of 25°C (excursions permitted to 15-30ºC).1

Store the tablets for oral suspension below 30°C.1 Store and dispense in the original bottle, protect from moisture, and keep the bottle tightly closed; do not remove the desiccant.1

Fixed Combinations Containing Dolutegravir

Dolutegravir is also commercially available in the following fixed-combination tablets: abacavir, dolutegravir, and lamivudine (Triumeq^®); dolutegravir and lamivudine (Dovato^®); and dolutegravir and rilpivirine (Juluca^®).240,247,256 See the full prescribing information for administration of each of these combination products.240,247,256

Dosage

Dolutegravir conventional tablets and tablets for oral suspension contain dolutegravir sodium; dosage is 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 The relative bioavailability of dolutegravir tablets for oral suspension is approximately 1.6-fold higher than that of dolutegravir conventional tablets.1 If a patient is switched from one tablet formulation to the other, adjust the dosage to that recommended for the specific formulation now being used.1

Adult Dosage

Treatment of HIV-1 Infection

For the treatment of HIV-1 infection in treatment-naïve, or treatment-experienced but integrase strand transfer inhibitor (INSTI)-naïve individuals, the recommended dosage of dolutegravir is 50 mg once daily.1

For the treatment of HIV-1 infection in treatment-naïve, or treatment-experienced but INSTI-naïve individuals, if dolutegravir is coadministered with certain uridine diphosphate-glucuronosyltransferase (UGT) 1A or cytochrome P-450 (CYP) 3A inducers (i.e., efavirenz, ritonavir-boosted fosamprenavir, ritonavir-boosted tipranavir, carbamazepine, rifampin), the recommended dosage of dolutegravir is 50 mg twice daily.1 Whenever possible, consider alternative regimens that do not contain these inducers.1

For the treatment of HIV-1 infection in virologically suppressed (HIV-1 RNA <50 copies/mL) adults switching to dolutegravir plus rilpivirine, the recommended dosage of dolutegravir is 50 mg once daily.1 Rilpivirine dosage is 25 mg once daily for those switching to dolutegravir plus rilpivirine.1

For the treatment of HIV-1 infection in INSTI-experienced adults who have certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance, the recommended dosage of dolutegravir is 50 mg twice daily.1

Fixed-dose combinations containing abacavir, dolutegravir, and lamivudine (Triumeq^®); dolutegravir and lamivudine (Dovato^®); and dolutegravir and rilpivirine (Juluca^®) are used in the treatment of HIV-1 infection in adults.240,247,256 The usual dosage of dolutegravir is 50 mg in conjunction with other antiretrovirals for treatment of HIV-1 infection; consult the full prescribing information for specific dosage of each of the combination products.240,247,256

Postexposure Prophylaxis following Nonoccupational Exposure to HIV

For postexposure prophylaxis of HIV infection following nonoccupational exposure (nPEP)† when the exposure represents a substantial risk for HIV transmission, the usual adult dosage of dolutegravir is 50 mg once daily in conjunction with 2 HIV nucleoside reverse transcriptase inhibitors (NRTIs).198

Initiate the nPEP regimen as soon as possible (within 72 hours) following nonoccupational exposure to HIV, and continue the regimen for 28 days.198 If the exposed individual seeks care >72 hours after the exposure, nPEP is not recommended.198

Pediatric Dosage

Dosage is based on weight.1 The tablets for oral suspension are labeled for pediatric patients ≥4 weeks of age weighing ≥3 kg; conventional tablets are labeled for use in pediatric patients ≥4 weeks of age weighing ≥14 kg.1

Treatment of HIV-1 Infection in Pediatric Patients 4 Weeks of Age or Older

Do not use dolutegravir conventional tablets in pediatric patients weighing 3-14 kg.1

For the recommended dosage of dolutegravir tablets for oral suspension for the treatment of HIV-1 infection in pediatric patients 4 weeks of age or older weighing ≥3 kg, who are treatment-naïve or treatment-experienced but INSTI-naïve, see Table 1.1 Dolutegravir tablets for oral suspension are preferred for pediatric patients weighing <20 kg.1

For the recommended dosage of dolutegravir conventional tablets for the treatment of HIV-1 infection in pediatric patients 4 weeks of age or older weighing ≥14 kg, see Table 2.1

The fixed-dose combination containing abacavir, dolutegravir, and lamivudine (Triumeq^®) is used in the treatment of HIV-1 infection in pediatric patients; consult the full prescribing information for specific dosage of this combination product.240

Special Populations

Hepatic Impairment

Dosage adjustment of dolutegravir is not necessary in patients with mild or moderate hepatic impairment (Child-Pugh class A or B).1 Do not use dolutegravir in those with severe hepatic impairment (Child-Pugh class C).1

Renal Impairment

Dosage adjustment of dolutegravir is not necessary in antiretroviral-naïve, or antiretroviral-experienced but INSTI-naïve, patients with mild, moderate, or severe renal impairment.1

Dosage adjustment of dolutegravir is not necessary in INSTI-experienced patients (with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance) with mild or moderate renal impairment.1 However, use dolutegravir with caution in INSTI-experienced patients (with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance) with severe renal impairment1

The manufacturer states that data are insufficient to make specific dolutegravir dosage recommendations for use in patients requiring dialysis; it is unlikely that the drug would be removed by dialysis to any clinically important extent.1,11

Geriatric Patients

The manufacturer makes no specific dosage recommendations in geriatric patients, but recommends caution because of possible age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1

Contraindications

• Previous hypersensitivity reaction to dolutegravir.1
• Concomitant use with dofetilide.1

Warnings/Precautions

Hypersensitivity Reactions

Hypersensitivity reactions were reported in <1% of patients receiving dolutegravir in phase 3 clinical trials.1 Reactions were manifested by rash and constitutional findings and, occasionally, organ dysfunction including liver toxicity.1

If signs or symptoms of hypersensitivity reactions occur, discontinue dolutegravir and any other suspect agents immediately.1 These signs or symptoms include, but are 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 Monitor clinical status, including liver aminotransferases, and initiate appropriate therapy.1

A life-threatening reaction could occur if there is a delay in discontinuing dolutegravir or any other suspect agents after the onset of a hypersensitivity reaction.1

Hepatotoxicity

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

Patients with human immunodeficiency virus (HIV) infection and with hepatitis B virus (HBV) or hepatitis C virus (HCV) coinfection may be at increased risk for development or worsening of aminotransferase elevations.1 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

Cases of hepatic toxicity, including elevated serum liver biochemistries, hepatitis, and acute liver failure, also have been reported in patients receiving a dolutegravir-containing regimen who had no preexisting hepatic disease or other identifiable risk factors.1 Drug-induced liver injury leading to liver transplant has been reported with abacavir/dolutegravir/lamivudine.1 Monitor for hepatoxicity in patients receiving dolutegravir.1

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in HIV-infected patients receiving multiple-drug antiretroviral therapy, including dolutegravir.1 During the initial phase of treatment, HIV-infected patients whose immune systems respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium , M. tuberculosis , cytomegalovirus, Pneumocystis jirovecii ); such responses may necessitate further evaluation and treatment.1

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

Different Formulations Are Not Interchangeable

Dolutegravir conventional tablets and dolutegravir tablets for oral suspension are not bioequivalent and are not interchangeable on a mg-per-mg basis.1 If a pediatric patient is switched from one tablet formulation to the other, adjust the dosage to that recommended for the specific formulation now being used.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

Specific Populations

Pregnancy

The Antiretroviral Pregnancy Registry (APR) monitors pregnancy outcomes in women exposed to dolutegravir during pregnancy.1 Clinicians are encouraged to register patients in the APR by calling 800-258-4263 or visiting [Web].1,202

Data regarding the use of dolutegravir in pregnant women are insufficient to date to definitively assess a drug-associated risk for birth defects and miscarria however, human data from the APR do not indicate an increased birth defect risk.1 Of 1,377 dolutegravir exposures during pregnancy resulting in live births, the prevalence of birth defects was 3.3% following first trimester exposure and 5% following second-/third-trimester exposure.1

There has been a concern regarding the development of neural tube defects in infants exposed to dolutegravir during pregnancy.1 The first interim analysis from an ongoing birth outcome surveillance study in Botswana identified an association between dolutegravir and an increased risk of neural tube defects when dolutegravir was administered at the time of conception and in early pregnancy.1 In a larger subsequent analysis, the prevalence of neural tube defects in infants delivered to individuals taking dolutegravir at conception was 0.11%, which did not differ significantly from that of infants delivered to HIV-positive individuals not administered dolutegravir (0.11%) or to HIV-negative individuals (0.06%).1

Results from an Eswatini birth outcome surveillance study revealed similar outcomes; the prevalence of neural tube defects in infants delivered to individuals taking dolutegravir at conception was 0.08%, which did not differ significantly from that of infants delivered to individuals taking non-dolutegravir-containing regimens (0.22%) or to HIV-negative individuals (0.08%).1

Lactation

Dolutegravir is distributed into human milk.1 It is not known whether dolutegravir affects human milk production or affects the breast-fed infant.1

The HHS perinatal HIV transmission guideline provides updated recommendations on infant feeding.202 The guideline states that patients with HIV should receive evidence-based, patient-centered counseling to support shared decision making about infant feeding.202 During counseling, patients should be informed that feeding with appropriate formula or pasteurized donor human milk from a milk bank eliminates the risk of postnatal HIV transmission to the infant.202 Additionally, achieving and maintaining viral suppression with antiretroviral therapy during pregnancy and postpartum reduces the risk of breastfeeding HIV transmission to <1%, but does not completely eliminate the risk.202 Replacement feeding with formula or banked pasteurized donor milk is recommended when patients with HIV are not on antiretroviral therapy and/or do not have a suppressed viral load during pregnancy (at a minimum throughout the third trimester), as well as at delivery.202

Pediatric Use

Safety and efficacy of dolutegravir have not been established in pediatric patients younger than 4 weeks of age or weighing <3 kg.1 In addition, safety and efficacy of the drug have not been established in pediatric patients who previously received another HIV integrase strand inhibitor (INSTI-experienced) and have HIV-1 with documented or suspected resistance to other HIV INSTIs (e.g., elvitegravir, raltegravir)1

Safety, efficacy, and pharmacokinetics of dolutegravir were evaluated in 75 HIV-1-infected, treatment-naïve or treatment-experienced INSTI-naïve pediatric patients 4 weeks to less than 18 years of age weighing at least 3 kg in an ongoing, open-label, multicenter, dose-finding clinical trial (IMPAACT P1093).1 In addition, pharmacokinetic data were evaluated in 2 weight-based pharmacokinetic substudies in an ongoing open-label, randomized, noninferiority trial evaluating safety, efficacy, and pharmacokinetics of dolutegravir in conjunction with 2 HIV NRTIs in HIV-1-infected pediatric patients younger than 18 years of age (ODYSSEY).1

Effectiveness of dolutegravir observed in pediatric patients in the IMPAACT P1093 trial is comparable to that reported in treatment-experienced adults receiving the drug.1 Overall, safety data for dolutegravir in 75 pediatric patients 4 weeks to less than 18 years of age in the IMPAACT P1093 trial were comparable to those observed in adults receiving the drug.1 Pharmacokinetic parameters for dolutegravir reported in pediatric patients in the IMPAACT P1093 and ODYSSEY trials receiving weight-based dosages of the drug 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 dolutegravir are higher in pediatric patients, the increase is not considered clinically important since the safety profiles are similar in adult and pediatric patients.1

Geriatric Use

Experience in patients ≥65 years of age is insufficient to determine whether they respond differently to dolutegravir than younger adults.1 Use dolutegravir with caution in geriatric patients because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.1

Hepatic Impairment

Do not use dolutegravir in patients with severe hepatic impairment (Child-Pugh class C); pharmacokinetics of the drug have not been evaluated in such patients.1

Pharmacokinetics of dolutegravir in patients with moderate hepatic impairment are similar to those in healthy individuals, and dosage adjustments are not needed when the drug is used in those with mild or moderate hepatic insufficiency (Child-Pugh class A or B).1

In phase 3 trials, the safety profile of dolutegravir in patients with HBV or HCV coinfection was similar to that in patients without HBV or HCV; however, rates of AST and ALT abnormalities were increased in this subset of patients.1 Population analyses using pooled pharmacokinetic data from adult trials indicated no clinically relevant effect of HCV coinfection on the pharmacokinetics of dolutegravir.1 There were limited data on HBV coinfection.1

Renal Impairment

Use dolutegravir with caution in patients with severe renal impairment who are INSTI-experienced and have certain INSTI-associated resistance mutations or clinically suspected INSTI resistance.1,11 Plasma concentrations of dolutegravir are decreased in patients with severe renal impairment, which may result in loss of therapeutic effects and development of resistance to the drug or other antiretrovirals.1,11

Mild or moderate renal impairment does not have a clinically important effect on the pharmacokinetics of dolutegravir.1,11 Therefore, dosage adjustments are not needed when dolutegravir is used in antiretroviral-naïve or antiretroviral-experienced, INSTI-naïve patients with mild, moderate, or severe renal impairment.1,11 Dosage adjustments also are not needed when the drug is used in INSTI-experienced patients with mild or moderate renal impairment.1

Data are insufficient to make specific dosage recommendations for use of dolutegravir in patients requiring dialysis.1 It is unlikely that dialysis would have a clinically important effect on the pharmacokinetics of dolutegravir since the drug is highly bound to plasma proteins.1,11

Dolutegravir has been shown to increase serum creatinine concentrations; however, it does not cause a clinically important change in glomerular filtration rate or renal plasma flow.1 In vivo, dolutegravir inhibits tubular secretion of creatinine by inhibiting renal organic cation transporter (OCT) 2 and, possibly, multidrug and toxin extrusion transporter (MATE) 1.1

Common Adverse Effects

In patients receiving dolutegravir in an adult clinical trial, the most common adverse effects of moderate to severe intensity and incidence ≥2% were insomnia, headache, and fatigue.1

The following drug interactions are based on studies using dolutegravir; refer to the full prescribing information for further details.1 Additional drug interactions exist for fixed-combinations containing abacavir, dolutegravir, and lamivudine (Triumeq^®); dolutegravir and lamivudine (Dovato^®); and dolutegravir and rilpivirine (Juluca^®).240,247,256 When a fixed combination is used, consider the interactions associated with each drug in the fixed combination; see the full prescribing information for drug interactions of each combination product.240,247,256

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Cytochrome P-450 (CYP) isoenzyme 3A plays a minor role in the metabolism of dolutegravir.1,8,9

In vitro studies indicate that dolutegravir does not inhibit CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A and does not induce CYP1A2, 2B6, or 3A4.1

Concomitant use of dolutegravir and drugs that induce CYP3A may decrease dolutegravir plasma concentrations and decrease therapeutic effects of the drug.1 Concomitant use with drugs that inhibit CYP3A may increase dolutegravir plasma concentrations.1

Drugs Affecting or Metabolized by Uridine Diphosphate-glucuronosyltransferases

Dolutegravir is metabolized by uridine diphosphate-glucuronosyltransferase (UGT) 1A1.1,8,9 In vitro studies indicate the drug also is a substrate for UGT1A3 and UGT1A9.1

Dolutegravir does not inhibit UGT1A1 or UGT2B7 in vitro.1

Pharmacokinetic interactions are possible if dolutegravir is used with inducers of UGT1A1, 1A3, or 1A9 (decreased plasma concentrations of dolutegravir and decreased therapeutic effects of the drug) or with inhibitors of these enzymes (increased plasma concentrations of dolutegravir).1

Drugs Affecting or Affected by P-glycoprotein Transport

Dolutegravir is a substrate of the P-glycoprotein (P-gp) transport system in vitro; dolutegravir does not inhibit P-gp-mediated transport in vitro.1

Pharmacokinetic interactions are possible if dolutegravir is used with inducers of P-gp (decreased plasma concentrations of dolutegravir and decreased therapeutic effects of the drug) or with inhibitors of P-gp (increased plasma concentrations of dolutegravir).1

Drugs Affecting or Affected by Bile Salt Export Pump

Dolutegravir does not inhibit the bile salt export pump (BSEP) in vitro; pharmacokinetic interactions with drugs that are substrates of BSEP are not expected.1

Drugs Affecting or Affected by Breast Cancer Resistance Protein

Dolutegravir is a substrate of breast cancer resistance protein (BCRP) in vitro.1

Pharmacokinetic interactions are possible if dolutegravir is used with inducers of BCRP (decreased plasma concentrations of dolutegravir and decreased therapeutic effects of the drug)1 or with inhibitors of BCRP (increased plasma concentrations of dolutegravir).1

Dolutegravir does not inhibit BCRP in vitro; pharmacokinetic interactions with drugs that are substrates for BCRP are not expected.1

Drugs Affecting or Affected by Multidrug and Toxin Extrusion Transporter

Dolutegravir inhibits multidrug and toxin extrusion transporter (MATE) 1 in vitro.1

Concomitant use of dolutegravir may increase plasma concentrations of drugs eliminated by MATE1 (e.g., dofetilide, metformin).1

Drugs Affecting or Affected by Multidrug Resistance Protein

Dolutegravir does not inhibit multidrug resistance protein (MRP) 2 or MRP4 in vitro; pharmacokinetic interactions with drugs that are substrates for these transporters are not expected.1

Drugs Affecting or Affected by Organic Anion Transporters

In vitro, dolutegravir inhibits renal organic anion transporter (OAT) 1 and OAT3.1 In vivo, dolutegravir does not alter plasma concentrations of OAT1 or OAT3 substrates (e.g., tenofovir, aminohippurate).1

Dolutegravir does not inhibit organic anion transporter polypeptide (OATP) 1B1 or OATP1B3 in vitro; pharmacokinetic interactions with drugs that are substrates for these transporters are not expected.1 Dolutegravir is not a substrate of OATP1B1 or 1B3 in vitro.1

Drugs Affecting or Affected by Organic Cation Transporters

In vitro, dolutegravir inhibits renal organic cation transporter (OCT) 2. 1 Therefore, dolutegravir may increase plasma concentrations of drugs eliminated by OCT2 (e.g., dalfampridine, dofetilide, metformin).1

Dolutegravir does not inhibit OCT1 in vitro; pharmacokinetic interactions with drugs that are substrates for this transporter are not expected.1

Anticonvulsants

Carbamazepine

Concomitant use of carbamazepine (300 mg twice daily) and dolutegravir (50 mg once daily) decreases peak plasma concentrations and AUC of dolutegravir.1,30

If carbamazepine is used concomitantly with dolutegravir in adults who are antiretroviral-naïve or antiretroviral-experienced but have not previously received an HIV integrase strand transfer inhibitor (INSTI-naïve), administer the recommended dolutegravir dose twice daily.1,30 If carbamazepine is used concomitantly with dolutegravir in antiretroviral-naïve or antiretroviral-experienced pediatric patients, administer the recommended weight-based dolutegravir dose twice daily.1 Whenever possible, use an alternative anticonvulsant in patients receiving dolutegravir who are INSTI-experienced and have HIV-1 with documented or suspected INSTI resistance.1

Oxcarbazepine, Phenobarbital, and Phenytoin

Oxcarbazepine, phenobarbital, and phenytoin induce metabolism of dolutegravir and may cause decreased plasma concentrations of dolutegravir.1

Avoid concomitant use of oxcarbazepine, phenobarbital, or phenytoin and dolutegravir since data are insufficient to make dosage recommendations.1

Antidiabetic Agents

Metformin

Concomitant use of metformin hydrochloride (500 mg twice daily) and dolutegravir (50 mg once or twice daily) increases peak plasma concentrations and AUC of metformin.1,31

If concomitant use of metformin and dolutegravir is being considered, assess the benefits and risks.1 Some experts state that, if metformin is initiated in patients receiving dolutegravir, the lowest metformin dosage should be used initially and dosage of the antidiabetic agent should be titrated to achieve glycemic control while monitoring for metformin-associated adverse effects.200 Metformin dosage may need to be adjusted when initiating or discontinuing dolutegravir.200

Antimycobacterial Agents

Rifampin

Concomitant use of rifampin and dolutegravir decreases plasma concentrations and AUC of dolutegravir.1,200

If rifampin is used concurrently with dolutegravir in adults who are antiretroviral-naïve or antiretroviral-experienced but INSTI-naïve, administer the recommended dolutegravir dose twice daily.1 If rifampin is used concurrently with dolutegravir in antiretroviral-naïve or antiretroviral-experienced pediatric patients, administer the recommended weight-based dolutegravir dose twice daily.1 Whenever possible, consider an alternative to rifampin in patients receiving dolutegravir who are INSTI-experienced and have HIV-1 with documented or suspected INSTI resistance.1,200

Antiretroviral Agents

Efavirenz

Concomitant use of efavirenz and dolutegravir decreases plasma concentrations and AUC of dolutegravir.1,26,200

If efavirenz is used concurrently with dolutegravir in adults who are antiretroviral-naïve or antiretroviral-experienced but INSTI-naïve, increase dolutegravir dosage to 50 mg twice daily.1 If efavirenz is used concurrently with dolutegravir in antiretroviral-naïve or antiretroviral-experienced pediatric patients, increase dolutegravir dosage by giving the recommended weight-based dolutegravir dosage twice daily.1 Whenever possible, consider an alternative to efavirenz that is not a metabolic inducer in patients receiving dolutegravir who are INSTI-experienced and have HIV-1 with documented or suspected INSTI resistance.1,200

Etravirine

Concomitant use of etravirine and dolutegravir results in substantially decreased plasma concentrations and AUC of dolutegravir.1 The effect on dolutegravir pharmacokinetics is mitigated if ritonavir-boosted darunavir or the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) is used concomitantly with etravirine and dolutegravir and is expected to be mitigated if ritonavir-boosted atazanavir is used concomitantly with etravirine and dolutegravir.1

Do not use etravirine concomitantly with dolutegravir unless ritonavir-boosted atazanavir, ritonavir-boosted darunavir, or lopinavir/ritonavir is included in the regimen.1,200

If etravirine is used concomitantly with dolutegravir in adults who are antiretroviral-naïve or antiretroviral-experienced without INSTI resistance, some experts state that dolutegravir should be given in a dosage of 50 mg once daily and ritonavir-boosted atazanavir, ritonavir-boosted darunavir, or lopinavir/ritonavir should also be included in the regimen.200 If etravirine is used concomitantly with dolutegravir in adults with known or suspected INSTI resistance, these experts state that dolutegravir should be given in a dosage of 50 mg twice daily and ritonavir-boosted atazanavir, ritonavir-boosted darunavir, or lopinavir/ritonavir should also be included in the regimen.200

Nevirapine

Concomitant use of nevirapine and dolutegravir may decrease dolutegravir plasma concentrations and AUC.1,200

The manufacturer states that concomitant use of nevirapine and dolutegravir should be avoided since data are insufficient to make dosage recommendations.1

Rilpivirine

Concomitant use of rilpivirine and dolutegravir does not have a clinically important effect on the pharmacokinetics of either drug.1,200

Dosage adjustments are not needed if rilpivirine and dolutegravir are used concomitantly. 1,200

HIV Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

There is no in vitro evidence of antagonistic antiretroviral effects between dolutegravir and abacavir.1

Tenofovir

Concomitant use of tenofovir alafenamide fumarate (TAF) or tenofovir disoproxil fumarate (tenofovir DF) and dolutegravir does not have a clinically important effect on the pharmacokinetics of the tenofovir prodrug or dolutegravir.1,200 Dosage adjustments are not needed if TAF or TDF is used concomitantly with dolutegravir.1,200

HIV Protease Inhibitors (PIs)

There is no in vitro evidence of antagonistic antiretroviral effects between dolutegravir and amprenavir (active metabolite of fosamprenavir) or lopinavir.1

Darunavir

Concomitant use of dolutegravir and ritonavir-boosted darunavir decreases peak plasma concentrations and AUC of dolutegravir, but does not appear to affect the pharmacokinetics of darunavir. 1,200 Clinically important drug interactions are not expected if cobicistat-boosted darunavir is used concomitantly with once-daily dolutegravir.200

Dosage adjustments are not needed if dolutegravir is used concomitantly with cobicistat-boosted 200 or ritonavir-boosted darunavir.1,200

Fosamprenavir

Concomitant use of ritonavir-boosted fosamprenavir and dolutegravir decreases plasma concentrations and AUC of dolutegravir,1,27 but does not appear to affect the pharmacokinetics of fosamprenavir or ritonavir.27

If ritonavir-boosted fosamprenavir is used concomitantly with dolutegravir in adults who are antiretroviral-naïve or antiretroviral-experienced but INSTI-naïve, administer the recommended dose of dolutegravir twice daily.1 If ritonavir-boosted fosamprenavir is used concomitantly with dolutegravir in antiretroviral-naïve or antiretroviral-experienced pediatric patients, administer the recommended weight-based dolutegravir dose twice daily.1 Whenever possible, use an alternative to ritonavir-boosted fosamprenavir that is not a metabolic inducer in patients receiving dolutegravir who are INSTI-experienced and have HIV-1 with documented or suspected INSTI resistance.1

Lopinavir

Concomitant use of lopinavir/ritonavir (lopinavir 400 mg/ritonavir 100 mg twice daily) and dolutegravir (30 mg once daily) does not have a clinically important effect on the pharmacokinetics of dolutegravir.1

Tipranavir

Concomitant use of ritonavir-boosted tipranavir and dolutegravir decreases peak plasma concentrations and AUC of dolutegravir.1,26,200

If ritonavir-boosted tipranavir is used concomitantly with dolutegravir in adults who are antiretroviral-naïve or antiretroviral-experienced but INSTI-naïve, administer the recommended dose of dolutegravir twice daily.1,26,200 If ritonavir-boosted tipranavir is used concomitantly with dolutegravir in antiretroviral-naïve or antiretroviral-experienced pediatric patients, administer the recommended weight-based dolutegravir dose twice daily.1 Whenever possible, use an alternative to ritonavir-boosted tipranavir that is not a metabolic inducer in patients receiving dolutegravir who are INSTI-experienced and have HIV-1 with documented or suspected INSTI resistance.1,200

Benzodiazepines

Dolutegravir does not have a clinically important effect on the AUC of midazolam.1,18,200 Concomitant use of dolutegravir with other benzodiazepines (e.g., clonazepam, clorazepate, diazepam, estazolam, flurazepam) is not expected to affect concentrations of the benzodiazepine.200 Dosage adjustments are not needed if dolutegravir is used concomitantly with any of these benzodiazepines.200

Calcium, Iron, Multivitamins, and Other Preparations Containing Polyvalent Cations

Calcium, Iron, and Multivitamins

Oral calcium supplements, oral iron preparations, or other oral supplements containing calcium or iron (e.g., multivitamins) may decrease plasma concentrations of dolutegravir when used concomitantly in the fasted state.1,19,28

Under fasting conditions, administer dolutegravir at least 2 hours before or 6 hours after oral supplements containing calcium or iron.1,28,200 If dolutegravir is administered with food, the drugs can be taken concomitantly with oral supplements containing calcium or iron.1,28,200

Preparations Containing Polyvalent Cations

Concomitant use of dolutegravir and drugs containing polyvalent cations (e.g., magnesium, aluminum, laxatives, buffered preparations) may decrease absorption and plasma concentrations of dolutegravir when used concomitantly in the fasted state.1,19,28

Administer dolutegravir at least 2 hours before or 6 hours after drugs or preparations containing polyvalent cations.1,28,200

Cardiac Drugs

Antiarrhythmic Agents

Dofetilide

Concomitant use of dofetilide and dolutegravir may increase dofetilide plasma concentrations and increase the risk of serious and/or life-threatening adverse effects.1

Concomitant use of dofetilide and dolutegravir is contraindicated.1

Corticosteroids

Prednisone

Concomitant use of prednisone (60 mg once daily with taper) and dolutegravir (50 mg once daily) does not have a clinically important effect on the pharmacokinetics of dolutegravir.1

Dalfampridine

Concomitant use of dalfampridine and dolutegravir may result in increased dalfampridine concentrations and may increase the risk of seizures.1 Weigh the potential benefits of concomitant use of dalfampridine and dolutegravir against the risk of seizures.1

Estrogens and Progestins

Ethinyl Estradiol and Norgestimate

Dolutegravir does not have a clinically important effect on the pharmacokinetics of hormonal contraceptives containing ethinyl estradiol or norgestimate.1,29,200

Dosage adjustments are not needed if oral contraceptives containing ethinyl estradiol and norgestimate are used in patients receiving dolutegravir.1,200

GI Drugs

Antacids

Antacids containing aluminum, calcium, or magnesium decrease peak plasma concentrations and AUC of dolutegravir.1 19,200

Administer dolutegravir at least 2 hours before or 6 hours after antacids containing polyvalent cations (e.g., aluminum, calcium, magnesium).1 200

Proton-pump Inhibitors

Concomitant use of omeprazole (40 mg once daily) and dolutegravir (single 50-mg dose) does not have a clinically important effect on the pharmacokinetics of dolutegravir.1 19

Sucralfate

Sucralfate may decrease plasma concentrations of dolutegravir.1,200

Administer dolutegravir at least 2 hours before or 6 hours after sucralfate.1,200

HCV Antivirals

HCV Polymerase Inhibitors

Sofosbuvir and Velpatasvir

No clinically important pharmacokinetic interactions were observed when the fixed combination of sofosbuvir and velpatasvir (sofosbuvir/velpatasvir) was used concomitantly with dolutegravir.176

Dosage adjustments are not needed if sofosbuvir/velpatasvir and dolutegravir are used concomitantly.1

HCV Replication Complex Inhibitors

Elbasvir and Grazoprevir

Concomitant use of dolutegravir and the fixed combination of elbasvir and grazoprevir (elbasvir/grazoprevir) does not result in clinically important changes in the pharmacokinetics of dolutegravir.1

Dosage adjustments are not needed if elbasvir/grazoprevir and dolutegravir are used concomitantly.1

Nucleoside and Nucleotide Antivirals

There is no in vitro evidence of antagonistic antiviral effects between dolutegravir and adefovir or ribavirin.1

Opiate Agonists and Partial Agonists

Methadone

Dolutegravir does not have a clinically important effect on the pharmacokinetics of methadone; dosage adjustments are not needed if methadone and dolutegravir are used concomitantly.1,200

St. John's Wort

St. John's wort ( Hypericum perforatum ) induces metabolism of dolutegravir and may cause decreased plasma concentrations of dolutegravir.1

Avoid concomitant use of St. John's wort with dolutegravir.1

Description

Dolutegravir sodium, an antiretroviral agent, is a human immunodeficiency virus (HIV) integrase strand transfer inhibitor (INSTI).1,200 Dolutegravir binds to the active site of HIV integrase and blocks the strand transfer step of retroviral DNA integration, which is essential for HIV replication.1 The drug is active against HIV type 1 (HIV-1) and also has in vitro activity against HIV type 2 (HIV-2).1,20,25,200 Dolutegravir is not active against hepatitis C virus (HCV).20

Dolutegravir-resistant HIV-1 has been produced in vitro and has emerged during dolutegravir therapy.1,12,13 In initial clinical studies in antiretroviral-naïve patients, dolutegravir treatment was not associated with emergence of INSTI resistance.1,2,3,4,13 Treatment-emergent INSTI resistance has been reported when dolutegravir was used in clinical studies in antiretroviral-experienced patients who had not previously received an INSTI (INSTI-naïve) or patients who had previously received an INSTI (INSTI-experienced), including some patients with historical genotypic evidence of INSTI-resistance substitutions or phenotypic evidence of resistance to other INSTIs (elvitegravir, raltegravir).1 In some studies, treatment-emergent INSTI resistance was reported less frequently in those who received dolutegravir than those who received raltegravir,6 and it has been suggested that dolutegravir may possess a higher barrier to resistance than elvitegravir and raltegravir.12,13 Evidence of dolutegravir resistance substitutions has been reported in clinical studies of patients with confirmed virologic failure.1

Although there is some evidence that dolutegravir has a different resistance profile than other HIV INSTIs and has been active in vitro against some HIV-1 strains resistant to other INSTIs (e.g., elvitegravir, raltegravir),1,12,13,14,15,16 cross-resistance between dolutegravir and other INSTIs (e.g., elvitegravir and/or raltegravir) has been reported.1,12,15,16 Dolutegravir has been active against HIV-1 resistant to HIV nucleoside reverse transcriptase inhibitors (NRTIs), HIV nonnucleoside reverse transcriptase inhibitors (NNRTIs), or HIV protease inhibitors (PIs).12

Following oral administration of 50 mg of dolutegravir as conventional tablets once or twice daily, peak plasma concentrations of the drug are attained 1-3 hours after a dose; steady state is achieved within approximately 5 days when a once-daily regimen is used.1 Although studies using dolutegravir tablets indicate that food increases the extent and decreases the rate of oral absorption of the drug,1,7 dolutegravir may be taken with or without food.1 Dolutegravir tablets and dolutegravir tablets for oral suspension are not bioequivalent; the relative bioavailability of dolutegravir tablets for oral suspension is approximately 1.6-fold higher than that of dolutegravir conventional tablets.1 Studies in HIV-1-infected pediatric patients 4 weeks to less than 18 years of age indicate that peak plasma concentrations and AUC reported with weight-based dolutegravir dosages of the tablets for oral suspension or conventional tablets are comparable to those in adults receiving 50 mg of the drug once or twice daily.1

In vitro studies indicate that dolutegravir is approximately 99% bound to plasma proteins.1 Dolutegravir is distributed into cerebrospinal fluid;1,32 the clinical importance of this is unknown.1 Dolutegravir is metabolized primarily by uridine diphosphate-glucuronosyltransferase (UGT) 1A1; cytochrome P-450 (CYP) isoenzyme 3A plays only a minor role in metabolism of the drug.1 Results of a meta-analysis of healthy individuals indicate that those with UGT1A1 genotypes that confer poor dolutegravir metabolism have a 32% lower clearance of dolutegravir and a 46% higher area under the plasma concentration-time curve (AUC) of the drug compared with those with genotypes associated with normal metabolism via UGT1A1.1 Following a single oral dose, 53% is excreted as unchanged drug in the feces and 31% is eliminated in urine (<1% as unchanged drug).1 Dolutegravir has a terminal half-life of approximately 14 hours.1

Advice to Patients

• Inform patients of the critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician.200 Advise patients that it is important to take the antiretroviral regimen as prescribed, and to not alter or discontinue the antiretroviral regimen without consulting clinician.1,200
• Inform patients and/or caregivers that dolutegravir tablets and dolutegravir tablets for oral suspension are not bioequivalent and are not interchangeable on a mg-per-mg basis and 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 Inform patients that the amount of water needed to disperse the tablets depends on the dose (i.e., required number of tablets).1 Instruct patients to refer to the instructions for use regarding preparation and administration of the tablets for oral suspension.1
• Advise patients and/or caregivers that if a dose of dolutegravir is missed, it should be taken as soon as it is remembered and the next dose taken at the regularly scheduled time.1 Advise patients that a double dose should not be taken to make up for a missed dose.1
• Advise patients to immediately discontinue dolutegravir and other suspect agents and seek 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 right side below ribs).1
• Advise patients that hepatotoxicity has been reported in patients receiving dolutegravir and that monitoring for hepatotoxicity is recommended.1
• Advise patients that signs and symptoms of inflammation from previous infections may occur soon after initiation of antiretroviral therapy in some individuals.1 Advise patients to immediately inform their clinician if any signs or symptoms of infection occur.1
• Advise women to inform their clinician if they plan to become or are pregnant.1 Advise patients that there is a pregnancy registry to monitor fetal outcomes in those exposed to dolutegravir during pregnancy.1
• Advise women to inform their clinician if they plan to breast-feed.1
• Advise patients to inform their clinician 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
• Advise patients of other important precautionary information.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Only references cited for selected revisions after 1984 are available electronically.

1. ViiV Healthcare. Tivicay® (dolutegravir) tablets and tablets for oral suspension prescribing information. Durham, NC; 2024 Apr.

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.

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.

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.

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.

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.

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