Dolutegravir (Monograph)

Brand name: Tivicay
Drug 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

Medically reviewed by Drugs.com on Sep 26, 2022. Written by ASHP.

Introduction

Antiretroviral; HIV integrase strand transfer inhibitor (INSTI).

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.

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. 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.

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

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. 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.

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. The commercially available fixed combination (dolutegravir/lamivudine; Dovato) can be used as an alternative to single-entity dolutegravir and single-entity lamivudine used concomitantly.

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. Single-entity dolutegravir and single-entity rilpivirine can be used concomitantly or the commercially available fixed combination of dolutegravir and rilpivirine (dolutegravir/rilpivirine; Juluca) can be used.

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. 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].

Postexposure Prophylaxis following Nonoccupational Exposure to HIV (nPEP)

Postexposure prophylaxis of HIV infection following nonoccupational exposure^{† [off-label]} (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. Used in conjunction with other antiretrovirals.

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). 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. The recommended alternative nPEP regimen in adults and adolescents ≥13 years of age is ritonavir-boosted darunavir used in conjunction with emtricitabine/tenofovir DF.

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. Do not delay initiation of nPEP while waiting for expert consultation.

Dolutegravir Dosage and Administration

General

• Test all HIV-infected individuals for HBV and HCV infection prior to initiation of antiretroviral therapy. (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. (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). Administer orally once or twice daily without regard to food. Must be used in conjunction with other antiretrovirals.

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

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). 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.

Dolutegravir Tablets

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

Dolutegravir Tablets for Oral Suspension

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

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

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.

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. 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. 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. Gently swirl cup for 1–2 minutes until no lumps remain; oral suspension will appear cloudy. Swallow oral suspension within 30 minutes after dispersion. For infants who cannot drink from the plastic cup, administer oral suspension using the oral syringe provided by manufacturer. 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.

Abacavir/dolutegravir/lamivudine Tablets

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

Dosage

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

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

Abacavir/dolutegravir/lamivudine (Triumeq): Contains abacavir sulfate, dolutegravir sodium, and lamivudine; dosages of abacavir and dolutegravir components expressed in terms of the bases. 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.

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). (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. (See Interactions.)

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. (See Interactions.)

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.

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.

Adults

Treatment of HIV-1 Infection

Antiretroviral-naive Adults

Oral

Dolutegravir: 50 mg once daily.

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

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

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.

Antiretroviral-experienced Adults

Oral

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

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

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.

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).

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

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.

Postexposure Prophylaxis following Nonoccupational Exposure to HIV (nPEP)† [off-label]

Oral

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

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.

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

Special Populations

Hepatic Impairment

Dolutegravir: Dosage adjustments not needed in patients with mild or moderate hepatic impairment (Child-Pugh class A or B); do not use in those with severe hepatic impairment (Child-Pugh class C). (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; contraindicated in those with moderate or severe hepatic impairment (Child-Pugh class B or C). (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; dosage adjustments not needed in antiretroviral-experienced, INSTI-experienced patients with mild or moderate renal impairment. 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. (See Renal Impairment under Cautions.)

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

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

Geriatric Patients

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

Cautions for Dolutegravir

Contraindications

• Dolutegravir (Tivicay, Tivicay PD): Previous hypersensitivity reaction to dolutegravir; concomitant use with dofetilide. (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); previous hypersensitivity reaction to dolutegravir or lamivudine; concomitant use with dofetilide; moderate or severe hepatic impairment. Consider contraindications associated with each drug in the fixed combination. (See Use of Fixed Combinations under Cautions.)

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

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

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. Monitor clinical status, including liver aminotransferases, and initiate appropriate therapy.

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

Hepatic Effects

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

HIV-infected patients with HBV or HCV coinfection may be at increased risk for development or worsening of aminotransferase elevations. 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.

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.

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

Monitor for hepatotoxicity.

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.

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. Manufacturer also states initiation of dolutegravir not recommended in women actively trying to become pregnant, unless there is no suitable alternative. (See Pregnancy under Cautions.)

Interactions

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

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.

HIV-infected Individuals Coinfected with HBV or HCV

Increased risk for elevated serum aminotransferase concentrations. (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. (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); this may necessitate further evaluation and treatment.

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

Pharmacogenomics

Dolutegravir metabolized primarily by UGT1A. 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.

Use of Fixed Combinations

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

If abacavir/dolutegravir/lamivudine used, consider that abacavir is associated with serious and sometimes fatal hypersensitivity reactions, including multiple organ failure and anaphylaxis. 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. Review medical history for prior exposure to any abacavir-containing preparation. 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. 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. 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. If hypersensitivity ruled out, manufacturer of abacavir/dolutegravir/lamivudine states that the drug may be reinitiated, but only if medical care is readily accessible. Since it is not possible to determine whether hypersensitivity reaction in patients receiving abacavir/dolutegravir/lamivudine is caused by abacavir or dolutegravir, never reinitiate abacavir-containing or dolutegravir-containing preparations in patients who stopped therapy with abacavir/dolutegravir/lamivudine due to a hypersensitivity reaction.

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. Cases reported most frequently in women; obesity also may be a risk factor. 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.

If abacavir/dolutegravir/lamivudine used, consider that several prospective, observational, epidemiological studies reported an association between use of abacavir and risk of MI. 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. 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).

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. Closely monitor hepatic function (using both clinical and laboratory follow-up) for at least several months after abacavir/dolutegravir/lamivudine discontinued. If appropriate, initiation of HBV treatment may be warranted. Safety and efficacy of abacavir/dolutegravir/lamivudine not established for treatment of chronic HBV infection.

Specific Populations

Pregnancy

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

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

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. No evidence of adverse embryofetal or pre- and post-natal development reported in animal reproduction studies.

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. 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; 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.

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.

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. Manufacturer also states initiation of dolutegravir not recommended in women actively trying to become pregnant, unless there is no suitable alternative.

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. 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. 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. 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). 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. 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. Some panel members prefer avoiding use of the drug in antiretroviral-naive women who are initiating antiretroviral therapy before 6 weeks of gestation.

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

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

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. 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.

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. These experts state that, in most cases, continuation of dolutegravir in pregnant women receiving a 3-drug antiretroviral regimen is recommended. 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).

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.

Lactation

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

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

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

Pediatric Use

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

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. 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. 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.

Dolutegravir conventional tablets (Tivicay) and tablets for oral suspension (Tivicay PD) are not bioequivalent and not interchangeable on a mg-per-mg basis. 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. 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. 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. (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. Safety and efficacy in those weighing ≥40 kg are derived from pediatric trials using the individual components of the fixed combination.

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.

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

Hepatic Impairment

Dolutegravir: Should not be used in patients with severe hepatic impairment (Child-Pugh class C); pharmacokinetics not evaluated in such patients. 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). Risk for further elevations in hepatic enzyme concentrations in patients with HBV or HCV coinfection.

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

Renal Impairment

Dolutegravir: Use with caution in patients with severe renal impairment who are INSTI-experienced and have documented or suspected INSTI resistance; 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.

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

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

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

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

Common Adverse Effects

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

Interactions for Dolutegravir

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

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

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

Inhibits multidrug and toxin extrusion transporter (MATE) 1.

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

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

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

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

Drugs Affecting Hepatic Microsomal Enzymes

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

CYP3A inhibitors: Possible increased dolutegravir plasma concentrations.

Drugs Affecting UGT

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

UGT1A1 inhibitors: Possible increased dolutegravir plasma concentrations.

Drugs Affecting P-glycoprotein Transport

P-gp inducers: Possible decreased dolutegravir plasma concentrations.

P-gp inhibitors: Possible increased dolutegravir plasma concentrations.

Drugs Affecting Breast Cancer Resistance Protein

BCRP inducers: Possible decreased dolutegravir plasma concentrations.

BCRP inhibitors: Possible increased dolutegravir plasma concentrations.

Drugs Affected by Multidrug and Toxin Extrusion Transporter

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

Drugs Affected by Renal Organic Cation Transporters

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

Specific Drugs

Dolutegravir Pharmacokinetics

Absorption

Bioavailability

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

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

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.

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; abacavir peak plasma concentrations decreased by 23%; lamivudine exposures not affected.

Distribution

Extent

Dolutegravir distributed into CSF; clinical importance unknown.

Crosses placenta.

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

Plasma Protein Binding

Approximately 99%.

Elimination

Metabolism

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

Elimination Route

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

Half-life

Approximately 14 hours.

Special Populations

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

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

HCV coinfection: No clinically important effect on dolutegravir pharmacokinetics.

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

Severe renal impairment (Cl_cr <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. (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.

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.

Stability

Storage

Oral

Tablets

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

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

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

Actions and Spectrum

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

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

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

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

• 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). However, cross-resistance between dolutegravir and other INSTIs (e.g., elvitegravir and/or raltegravir) reported.

Advice to Patients

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

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

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

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

• 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.

• 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. 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).

• Importance of reading patient information provided by the manufacturer.

• 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. 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.

• 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. The amount of water needed to disperse the tablets depends on the dose (i.e., required number of tablets).

• 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. A double dose should not be taken to make up for a missed dose.

• 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).

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

• 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.

• 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.

• 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. Advise women of childbearing potential of the risks to the fetus if dolutegravir is used at the time of conception through the first trimester. Advise women of childbearing potential taking dolutegravir or abacavir/dolutegravir/lamivudine to consistently use effective contraception during treatment with the drug. (See Pregnancy under Cautions.)

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

• Importance of advising patients of other important precautionary information. (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.

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Frequently asked questions

• What drugs are contained in HIV treatment Juluca?

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