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Tivicay

Generic Name: Dolutegravir Sodium
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

Warning(s)

  • Fixed Combinations
  • If using abacavir/dolutegravir/lamivudine (Triumeq), consider that abacavir has been associated with serious and sometimes fatal hypersensitivity reactions.240 Because individuals with human leukocyte antigen (HLA)-B*5701 allele are at high risk for abacavir hypersensitivity reactions, screening for HLA-B*5701 allele recommended prior to initiation of abacavir-containing preparations.240 Discontinue abacavir/dolutegravir/lamivudine as soon as a hypersensitivity reaction is suspected.240 Regardless of patient’s HLA-B*5701 status, permanently discontinue if hypersensitivity cannot be ruled out.240

  • If using abacavir/dolutegravir/lamivudine, consider that lactic acidosis and severe hepatomegaly with steatosis, including fatalities, reported in patients receiving HIV nucleoside reverse transcriptase inhibitors (NRTIs) in conjunction with other antiretrovirals.240

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

Introduction

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

Uses for Tivicay

Treatment of HIV Infection

Treatment of HIV-1 infection in adults, adolescents, and pediatric patients ≥12 years of age;1 2 3 4 5 6 22 23 usually used in conjunction with 2 HIV NRTIs.1 200 201

For initial treatment in antiretroviral-naive adults and adolescents, experts state that dolutegravir in conjunction with tenofovir disoproxil fumarate (tenofovir DF) and emtricitabine (or lamivudine) is a recommended INSTI-based regimen.200 Dolutegravir in conjunction with abacavir and lamivudine (or emtricitabine) also is a recommended INSTI-based regimen for initial treatment, but use only in those who are HLA-B*5701 negative.200

For initial treatment in antiretroviral-naive pediatric patients, experts state that an INSTI-based regimen of dolutegravir in conjunction with 2 NRTIs is an alternative regimen that can be used in those ≥12 years of age weighing ≥40 kg.201

Use of dolutegravir in INSTI-experienced patients should be guided by the number and type of baseline INSTI-resistance substitutions.1 Efficacy of dolutegravir (50 mg twice daily) is reduced in patients who have HIV-1 with an INSTI-resistance Q148 substitution and ≥2 additional INSTI-resistance substitutions (e.g., T66A, L74I/M, E138A/K/T, G140S/A/C, Y143R/C/H, E157Q, G163S/E/K/Q, G193E/R).1

Fixed-combination preparation containing abacavir, dolutegravir, and lamivudine (abacavir/dolutegravir/lamivudine; Triumeq) is used alone or in conjunction with other antiretrovirals in adults ≥18 years of age.240

Do not use abacavir/dolutegravir/lamivudine alone in patients with suspected or confirmed INSTI-resistance substitutions;240 dosage of dolutegravir in the fixed combination insufficient in such patients.240 Do not use abacavir/dolutegravir/lamivudine in patients who have HIV-1 resistant to any of the 3 components of the fixed combination.240

Tivicay Dosage and Administration

Administration

Oral Administration

Dolutegravir (Tivicay): Administer orally once or twice daily without regard to food.1 Use in conjunction with other antiretrovirals.1

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

Administer dolutegravir or abacavir/dolutegravir/lamivudine at least 2 hours before or 6 hours after drugs or other preparations containing polyvalent cations (e.g., cation-containing antacids or laxatives, oral iron supplements, oral calcium supplements, sucralfate, buffered preparations).1 200 240 (See Interactions.)

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, or rifampin).240 When abacavir/dolutegravir/lamivudine and single-entity dolutegravir both indicated, give daily dose of the fixed combination and daily dose of the single-entity 12 hours apart.240

Because antiretrovirals in abacavir/dolutegravir/lamivudine may also be available in single-entity or other fixed-combination preparations, take care to ensure that therapy is not duplicated if used in conjunction with other antiretrovirals.240 (See Use of Fixed Combinations under Cautions.)

Dosage

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

Abacavir/dolutegravir/lamivudine (Triumeq): Contains abacavir sulfate, dolutegravir sodium, and lamivudine;240 dosages of abacavir and dolutegravir components expressed in terms of the bases.240

A film-coated tablet containing abacavir 600 mg, dolutegravir 50 mg, and lamivudine 300 mg taken in fasted state is bioequivalent to a 50-mg dolutegravir tablet taken simultaneously with a fixed-combination tablet containing abacavir 600 mg and lamivudine 300 mg (abacavir/lamivudine) in fasted state.21 240

Pediatric Patients

Treatment of HIV Infection
Antiretroviral-naive Pediatric Patients
Oral

Dolutegravir (Tivicay) in children and adolescents ≥12 years of age weighing ≥40 kg: 50 mg once daily.1

Dolutegravir in children and adolescents ≥12 years of age weighing ≥40 kg receiving certain UGT1A1 or CYP3A inducers (i.e., efavirenz, ritonavir-boosted fosamprenavir, ritonavir-boosted tipranavir, carbamazepine, rifampin): 50 mg twice daily.1

Antiretroviral-experienced Pediatric Patients
Oral

Dolutegravir (Tivicay) in children and adolescents ≥12 years of age weighing ≥40 kg who are antiretroviral-experienced, INSTI-naive: 50 mg once daily.1

Dolutegravir in children and adolescents ≥12 years of age weighing ≥40 kg who are antiretroviral-experienced, INSTI-naive, and receiving certain UGT1A1 or CYP3A inducers (i.e., efavirenz, ritonavir-boosted fosamprenavir, ritonavir-boosted tipranavir, carbamazepine, rifampin): 50 mg twice daily.1

Dolutegravir: Safety and efficacy not established in INSTI-experienced pediatric patients with documented or clinically suspected resistance to other INSTIs (e.g., elvitegravir, raltegravir).1

Abacavir/dolutegravir/lamivudine (Triumeq): Safety and efficacy not established in pediatric patients.240

Adults

Treatment of HIV Infection
Antiretroviral-naive Adults
Oral

Dolutegravir (Tivicay): 50 mg once daily.1

Dolutegravir in adults receiving certain UGT1A1 or CYP3A inducers (i.e., efavirenz, ritonavir-boosted fosamprenavir, ritonavir-boosted tipranavir, carbamazepine, rifampin): 50 mg twice daily.1

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

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

Antiretroviral-experienced Adults
Oral

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

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

Dolutegravir in antiretroviral-experienced adults receiving certain UGT1A1 or CYP3A inducers (i.e., efavirenz, ritonavir-boosted fosamprenavir, ritonavir-boosted tipranavir, carbamazepine, rifampin): 50 mg twice daily.1

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

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

Special Populations

Hepatic Impairment

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

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

Renal Impairment

Dolutegravir (Tivicay): Dosage adjustments not needed in antiretroviral-naive or antiretroviral-experienced, INSTI-naive patients with mild, moderate, or severe renal impairment;1 dosage adjustments not needed in antiretroviral-experienced, INSTI-experienced patients with mild or moderate renal impairment.1 Use with caution in patients with severe renal impairment who are INSTI-experienced and have certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance.1 10 (See Renal Impairment under Cautions.)

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

Geriatric Patients

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

Cautions for Tivicay

Contraindications

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

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

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

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

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

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

Individuals with HBV or HCV Infection

Increased risk of development or worsening of serum aminotransferase elevations in HIV-infected patients with HBV or HCV coinfection.1 In some cases, elevations in serum aminotransferase concentrations may be consistent with immune reconstitution syndrome or HBV reactivation, particularly in the setting where HBV therapy had been discontinued.1

In patients with underlying hepatic disease such as HBV or HCV infection, perform laboratory monitoring for hepatotoxicity prior to and routinely during dolutegravir or abacavir/dolutegravir/lamivudine treatment.1 240 (See Hepatic Impairment under Cautions.)

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

Use of Fixed Combinations

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

Do not use abacavir/dolutegravir/lamivudine concomitantly with single-entity dolutegravir, unless needed for adjustment of dolutegravir dosage (e.g., when fixed combination used concomitantly with efavirenz, ritonavir-boosted fosamprenavir, ritonavir-boosted tipranavir, or rifampin).240 (See Interactions.)

Because antiretrovirals contained in abacavir/dolutegravir/lamivudine may also be available in single-entity or other fixed-combination preparations, take care to ensure that therapy is not duplicated if the fixed combination is used in conjunction with other antiretrovirals.240

Do not use abacavir/dolutegravir/lamivudine concomitantly with any preparation containing abacavir or lamivudine.240

If abacavir/dolutegravir/lamivudine used, consider that abacavir associated with serious and sometimes fatal hypersensitivity reactions.240 Patients with the HLA-B*5701 allele are at high risk for hypersensitivity reactions to abacavir.240 Screen all patients for the HLA-B*5701 allele prior to initiating abacavir/dolutegravir/lamivudine.240 Discontinue the fixed combination as soon as a hypersensitivity reaction is suspected.240 Regardless of the patient's HLA-B*5701 status, permanently discontinue abacavir/dolutegravir/lamivudine if hypersensitivity cannot be ruled out.240 Never restart abacavir/dolutegravir/lamivudine or any other abacavir-containing preparation following a hypersensitivity reaction to abacavir.240

If abacavir/dolutegravir/lamivudine used, consider that lactic acidosis and severe hepatomegaly with steatosis, including fatalities, reported in patients receiving HIV NRTIs alone or in conjunction with other antiretrovirals.240 Discontinue abacavir/dolutegravir/lamivudine if clinical or laboratory findings indicate lactic acidosis or pronounced hepatotoxicity, which may include hepatomegaly and steatosis even in the absence of marked increases in serum aminotransferase concentrations.240

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

If abacavir/dolutegravir/lamivudine used in patients coinfected with HIV and HCV, consider that hepatic decompensation, sometimes fatal, reported in some patients receiving HIV NRTIs (e.g., abacavir, lamivudine) concomitantly with peginterferon alfa (or interferon alfa) with or without ribavirin.109 240 Closely monitor such patients for toxicity, especially hepatic decompensation.109 240 Consider discontinuing abacavir/dolutegravir/lamivudine as medically appropriate.240 Consider dosage reduction or discontinuance of peginterferon alfa (or interferon alfa) and/or ribavirin if worsening clinical toxicities, including hepatic decompensation (e.g., Child-Pugh score >6), occur.109 240

Adipogenic Effects

Redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (“buffalo hump”), peripheral wasting, facial wasting, breast enlargement, and general cushingoid appearance reported in patients receiving antiretroviral therapy.1 240

Mechanisms and long-term consequences unknown; causal relationship not established.1 240

Immune Reconstitution Syndrome

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

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome) 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.1 240

Specific Populations

Pregnancy

Dolutegravir (Tivicay): Category B.1

Abacavir/dolutegravir/lamivudine (Triumeq): Category C.240

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

No adequate and well-controlled studies of dolutegravir or abacavir/dolutegravir/lamivudine in pregnant women;1 240 manufacturer states use during pregnancy only if clearly needed or if potential benefits to the woman outweigh risks to the fetus.1 240

Experts state data insufficient to recommend routine use of dolutegravir for initial treatment in antiretroviral-naive pregnant women.202

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 202

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

Pediatric Use

Dolutegravir (Tivicay): Safety and efficacy not established in pediatric patients <12 years of age or weighing <40 kg;1 safety and efficacy not established in INSTI-experienced pediatric patients who have documented or suspected resistance to other INSTIs (e.g., elvitegravir, raltegravir).1 Safety profile in children and adolescents 12–18 years of age similar to that in adults.1

Abacavir/dolutegravir/lamivudine (Triumeq): Safety and efficacy not established in pediatric patients.240

Geriatric Use

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

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

Hepatic Impairment

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

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

Renal Impairment

Dolutegravir (Tivicay): Use with caution in patients with severe renal impairment who are INSTI-experienced and have documented or suspected INSTI resistance;1 10 dolutegravir plasma concentrations decreased in such patients and may result in loss of therapeutic effects and development of resistance to the drug or other antiretrovirals.1

Dolutegravir: May be used in patients with mild or moderate renal impairment; no clinically important effect on dolutegravir pharmacokinetics.1 10 Dosage adjustments not needed in antiretroviral-naive or antiretroviral-experienced, INSTI-naive patients with mild, moderate, or severe renal impairment.1 10 Dosage adjustments not needed in INSTI-experienced patients with mild or moderate renal impairment.1

Not evaluated in dialysis patients;1 unlikely that renal replacement therapy would have clinically important effect on dolutegravir pharmacokinetics.10 (See Renal Impairment under Dosage and Administration.)

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

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

Common Adverse Effects

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

Interactions for Tivicay

CYP3A plays minor role in dolutegravir metabolism.1 8 9 The drug does not inhibit CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A and does not induce CYP1A2, 2B6, or 3A4.1

Dolutegravir is a substrate of P-glycoprotein (P-gp);1 does not inhibit P-gp-mediated transport.1

Substrate of breast cancer resistance protein (BCRP);1 does not inhibit BCRP.1

Inhibits multidrug and toxin extrusion transporter (MATE) 1;1 may increase concentrations of drugs eliminated by MATE1.1

Inhibits the renal organic cation transporter (OCT) 2;1 may increase concentrations of drugs eliminated by OCT2.1 Does not inhibit OCT1.1

Inhibits organic anion transporter (OAT) 1 and OAT3;1 no in vivo evidence of increased concentrations of OAT1 or OAT3 substrates.1

Does not inhibit bile salt export pump (BSEP), multidrug resistance protein (MRP) 2 or MRP4, or organic anion transporter polypeptide (OATP) 1B1 or OATP1B3;1 not expected to affect pharmacokinetics of drugs that are substrates of these transporters.1

Metabolized by UGT1A1 and is a substrate for UGT1A3 and UGT1A9.1 Does not inhibit UGT1A1 or UGT2B7.1

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

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

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

CYP3A inhibitors: Possible increased dolutegravir concentrations.1

Drugs Affecting or Metabolized by Uridine Diphosphate-glucuronosyltransferases

UGT1A1 inducers: Possible decreased dolutegravir concentrations and decreased therapeutic effects.1

UGT1A1 inhibitors: Possible increased dolutegravir concentrations.1

Drugs Affecting P-glycoprotein Transport

P-gp inducers: Possible decreased dolutegravir concentrations.1

P-gp inhibitors: Possible increased dolutegravir concentrations.1

Drugs Affecting Breast Cancer Resistance Protein

BCRP inducers: Possible decreased dolutegravir concentrations.1

BCRP inhibitors: Possible increased dolutegravir concentrations.1

Specific Drugs

Drug

Interaction

Comments

Abacavir

No in vitro evidence of antagonistic antiretroviral effects1

Adefovir

No in vitro evidence of antagonistic antiviral effects1

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

Decreased dolutegravir concentrations and AUC1 19 200 240

Administer dolutegravir or abacavir/dolutegravir/lamivudine at least 2 hours before or 6 hours after aluminum-, calcium-, or magnesium-containing antacids1 200 240

Antiarrhythmic agents (dofetilide)

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

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

Anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin)

Carbamazepine: Decreased dolutegravir concentrations and AUC1

Oxcarbazepine, phenobarbital, phenytoin: Decreased dolutegravir concentrations1

Carbamazepine: In antiretroviral-naive or antiretroviral-experienced, INSTI-naive patients, use dolutegravir 50 mg twice daily;1 consider alternative anticonvulsant in INSTI-experienced patients with documented or suspected INSTI resistance;1 avoid concomitant use with abacavir/dolutegravir/lamivudine since data insufficient to make dosage recommendations240

Oxcarbazepine, phenobarbital, phenytoin: Avoid concomitant use with dolutegravir or abacavir/dolutegravir/lamivudine since data insufficient to make dosage recommendations;1 240 consider alternative anticonvulsant200

Antidiabetic agents (metformin)

Metformin: Increased metformin concentrations and AUC1 200

Metformin: Adjustment of metformin dosage may be needed if used with dolutegravir or abacavir/dolutegravir/lamivudine;1 200 240 monitor blood glucose concentrations when initiated or discontinued in patient receiving metformin and do not exceed metformin hydrochloride dosage of 1 g daily during concomitant therapy;1 experts state use low metformin dosage if initiated in patient receiving dolutegravir and titrate dosage to achieve glycemic control and minimize adverse GI effects200

Antimycobacterial agents (rifabutin, rifampin, rifapentine)

Rifabutin: No clinically important effects on dolutegravir pharmacokinetics1 200

Rifampin: Decreased dolutegravir concentrations and AUC1 200

Rifapentine: Decreased dolutegravir concentrations expected200

Rifabutin: Dosage adjustments not needed200

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

Rifapentine: Experts state do not use concomitantly with dolutegravir200

Atazanavir

Ritonavir-boosted atazanavir or unboosted atazanavir: Increased dolutegravir concentrations and AUC; no effects on atazanavir pharmacokinetics1 200

Cobicistat-boosted atazanavir: Data not available200

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Dosage adjustments not needed200

Buffered preparations

Buffered preparations containing polyvalent cations: Possible decreased dolutegravir concentrations1

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

Calcium supplements

Possible decreased dolutegravir concentrations when used concomitantly in the fasted state1

Administer dolutegravir or abacavir/dolutegravir/lamivudine at least 2 hours before or 6 hours after oral calcium supplements;1 200 240 alternatively, may be used concomitantly if taken with food1 200 240

Corticosteroids

Prednisone: No clinically important effects on dolutegravir pharmacokinetics1 8

Darunavir

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

Cobicistat-boosted darunavir: Clinically important interactions with dolutegravir not expected 237

Ritonavir-boosted or cobicistat-boosted darunavir: Dosage adjustments not needed200

Efavirenz

Decreased dolutegravir concentrations and AUC;1 200 effect on efavirenz pharmacokinetics unlikely1

No in vitro evidence of antagonistic antiretroviral effects1

Dolutegravir: In antiretroviral-naive or antiretroviral-experienced, INSTI-naive patients, use dolutegravir 50 mg twice daily;1 200 in INSTI-experienced patients with documented or suspected INSTI resistance, consider alternative to efavirenz whenever possible1 200

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

Enfuvirtide

No in vitro evidence of antagonistic antiretroviral effects1

Etravirine

Substantially decreased dolutegravir concentrations and AUC;1 200 no apparent effects on etravirine pharmacokinetics1

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

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

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

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

Estrogens/progestins

Oral contraceptives containing ethinyl estradiol and norgestimate: No effect on pharmacokinetics of ethinyl estradiol or norgestimate1

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

Fosamprenavir

Ritonavir-boosted fosamprenavir: Decreased dolutegravir concentrations and AUC;1 200 effect on fosamprenavir pharmacokinetics unlikely1

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

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

Iron preparations

Possible decreased dolutegravir concentrations when used concomitantly in the fasted state1

Administer dolutegravir or abacavir/dolutegravir/lamivudine at least 2 hours before or 6 hours after oral iron;1 200 240 alternatively, may be used concomitantly if taken with food1 200 240

Laxatives containing polyvalent cations

Possible decreased dolutegravir concentrations1

Administer dolutegravir or abacavir/dolutegravir/lamivudine at least 2 hours before or 6 hours after laxatives containing polyvalent cations1 200 240

Ledipasvir

Fixed combination of ledipasvir and sofosbuvir (ledipasvir/sofosbuvir): Some experts state may be used concomitantly with dolutegravir200

Lopinavir/ritonavir

No clinically important effects on dolutegravir or lopinavir pharmacokinetics1 200

No in vitro evidence of antagonistic antiretroviral effects1

Once-daily or twice-daily lopinavir/ritonavir: Dosage adjustments not needed200

Maraviroc

No in vitro evidence of antagonistic antiretroviral effects1

Methadone

No clinically important effect on methadone pharmacokinetics1 200

Dosage adjustments not needed200

Midazolam

No clinically important effect on midazolam pharmacokinetics1 18 200

Dosage adjustments not needed200

Multivitamins

Decreased dolutegravir concentrations1

Administer dolutegravir or abacavir/dolutegravir/lamivudine at least 2 hours before or 6 hours after multivitamins containing calcium or iron;1 200 240 alternatively, may be used concomitantly if taken with food1 240

Nevirapine

Decreased dolutegravir concentrations1 200

No in vitro evidence of antagonistic antiretroviral effects1

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

Proton-pump inhibitors

Omeprazole: No clinically important effect on dolutegravir pharmacokinetics1 19

Proton-pump inhibitors: Dosage adjustments not needed200

Raltegravir

No in vitro evidence of antagonistic antiretroviral effects1

Ribavirin

No in vitro evidence of antagonistic antiviral effects1

Rilpivirine

No clinically important effect on rilpivirine or dolutegravir pharmacokinetics1 200

Dosage adjustments not needed200

Ritonavir

Effect on ritonavir pharmacokinetics unlikely1

St. John's wort

Decreased dolutegravir concentrations1

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

Saquinavir

Ritonavir-boosted saquinavir: Experts state dosage adjustments not necessary200

Simeprevir

Some experts state may be used concomitantly with dolutegravir200

Sofosbuvir

Clinically important interactions unlikely200

Dosage adjustments not needed200

Stavudine

No in vitro evidence of antagonistic antiretroviral effects1

Sucralfate

Decreased dolutegravir concentrations1

Administer dolutegravir or abacavir/dolutegravir/lamivudine at least 2 hours before or 6 hours after sucralfate1 200 240

Tenofovir

No clinically important effect on tenofovir or dolutegravir pharmacokinetics1

Dosage adjustments not needed200

Tipranavir

Ritonavir-boosted tipranavir: Decreased dolutegravir concentrations and AUC1 200

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

Tivicay Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability of dolutegravir not established.1

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

Food

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

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

Distribution

Extent

Dolutegravir distributed into CSF;1 clinical importance unknown.1

Crosses placenta in animals.1 202

Distributed into milk in rats;1 202 not known whether distributed into human milk.1 202

Plasma Protein Binding

≥98.9%.1

Elimination

Metabolism

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

Elimination Route

Dolutegravir excreted in feces (53%) and urine (31%).1

Half-life

Approximately 14 hours.1

Special Populations

Moderate hepatic impairment: No clinically important effect on dolutegravir pharmacokinetics.1

Severe hepatic impairment: Dolutegravir pharmacokinetics not studied.1

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

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

Severe renal impairment (Clcr <30 mL/minute): Dolutegravir AUC decreased by 40%;1 peak plasma concentration decreased by 23%.1 (See Renal Impairment under Cautions.)

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

HIV-1-infected children and adolescents 12 to <18 years of age: Pharmacokinetic profile of dolutegravir similar to HIV-1-infected adults receiving dolutegravir 50 mg once daily.1

Stability

Storage

Oral

Tablets

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

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

Actions and Spectrum

  • Dolutegravir binds to active site of HIV integrase and blocks strand transfer step of retroviral DNA integration, which is essential for HIV replication.1

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

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

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

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

Advice to Patients

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

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

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

  • Antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications associated with HIV disease may still occur.1 240 Sustained decreases in plasma HIV RNA have been associated with reduced risk of progression to AIDS and death.1 240

  • Advise patients that effective antiretroviral regimens can decrease HIV concentrations in blood and genital secretions and strict adherence to such regimens in conjunction with risk-reduction measures may decrease, but cannot absolutely eliminate, the risk of secondary transmission of HIV to others.200 Importance of continuing to practice safer sex (e.g., using latex or polyurethane condoms to minimize sexual contact with body fluids), never sharing personal items that can have blood or body fluids on them (e.g., toothbrushes, razor blades), and never reusing or sharing needles.1 200 240

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

  • If a dose of dolutegravir or abacavir/dolutegravir/lamivudine is missed and remembered ≥4 hours before the next scheduled time, the dose should be taken as soon as it is remembered and the next dose taken at the regularly scheduled time.1 240 If a missed dose of dolutegravir or abacavir/dolutegravir/lamivudine is remembered within 4 hours before the next dose is due, the dose should be skipped and the next dose taken at the regularly scheduled time.1 240 A double dose should not be taken to make up for a missed dose.1 240

  • Importance of informing clinician if unusual symptoms develop or known symptoms persist or worsen.1 240

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

  • Advise patients that dolutegravir or abacavir/dolutegravir/lamivudine should not be used concomitantly with dofetilide.1 240 Concomitant use may result in potentially life-threatening adverse effects.1 240

  • Redistribution/accumulation of body fat may occur with antiretroviral therapy, with as yet unknown long-term health effects.1 240

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal products, and any concomitant illnesses.1 240

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 240 Advise HIV-infected women not to breast-feed.1 240

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

Preparations

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

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

Dolutegravir Sodium

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

50 mg (of dolutegravir)

Tivicay

ViiV

Dolutegravir Sodium Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

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

Triumeq

ViiV

AHFS DI Essentials. © Copyright, 2004-2016, Selected Revisions March 2, 2016. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. ViiV Healthcare. Tivicay (dolutegravir) tablets prescribing information. Research Triangle Park, NC; 2015 Aug.

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. [PubMed 23306000]

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. [PubMed 24074642]

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. [PubMed 24195548]

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 resultsfrom 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. [PubMed 23830355]

7. Song IH, Borland J, Chen S et al. Effect of food on the pharmacokinetics of the integrase inhibitor dolutegravir. Antimicrob Agents Chemother. 2012; 56:1627-9. [PubMed 22183173]

8. Song IH, Borland J, Chen S et al. Effect of prednisone on the pharmacokinetics of the integrase inhibitor dolutegravir. Antimicrob Agents Chemother. 2013; 57:4394-7. [PubMed 23817375]

9. Castellino S, Moss L, Wagner D et al. Metabolism, excretion, and mass balance of the HIV-1 integrase inhibitor dolutegravir in humans. Antimicrob Agents Chemother. 2013; 57:3536-46. [PubMed 23669385]

10. Weller S, Borland J, Chen S et al. Pharmacokinetics of dolutegravir in HIV-seronegative subjects with severe renal impairment. Eur J Clin Pharmacol. 2013; :.

12. Deanda F, Hightower KE, Nolte RT et al. Dolutegravir Interactions with HIV-1 Integrase-DNA: Structural Rationale for Drug Resistance and Dissociation Kinetics. PLoS One. 2013; 8:e77448. [PubMed 24146996]

13. Mesplède T, Quashie PK, Osman N et al. Viral fitness cost prevents HIV-1 from evading dolutegravir drug pressure. Retrovirology. 2013; 10:22. [PubMed 23432922]

14. Canducci F, Ceresola ER, Saita D et al. In vitro phenotypes to elvitegravir and dolutegravir in primary macrophages and lymphocytes of clonal recombinant viral variants selected in patients failing raltegravir. J Antimicrob Chemother. 2013; 68:2525-32. [PubMed 23798668]

15. Abram ME, Hluhanich RM, Goodman DD et al. Impact of primary elvitegravir resistance-associated mutations in HIV-1 integrase on drug susceptibility and viral replication fitness. Antimicrob Agents Chemother. 2013; 57:2654-63. [PubMed 23529738]

16. Underwood MR, Johns BA, Sato A et al. The activity of the integrase inhibitor dolutegravir against HIV-1 variants isolated from raltegravir-treated adults. J Acquir Immune Defic Syndr. 2012; 61:297-301. [PubMed 22878423]

17. Song I, Borland J, Chen S et al. Effect of atazanavir and atazanavir/ritonavir on the pharmacokinetics of the next-generation HIV integrase inhibitor, S/GSK1349572. Br J Clin Pharmacol. 2011; 72:103-8. [PubMed 21342217]

18. Min S, Song I, Borland J et al. Pharmacokinetics and safety of S/GSK1349572, a next-generation HIV integrase inhibitor, in healthy volunteers. Antimicrob Agents Chemother. 2010; 54:254-8. [PubMed 19884365]

19. Patel P, Song I, Borland J et al. Pharmacokinetics of the HIV integrase inhibitor S/GSK1349572 co-administered with acid-reducing agents and multivitamins in healthy volunteers. J Antimicrob Chemother. 2011; 66:1567-72. [PubMed 21493648]

20. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 204790Orig1s000: Microbioogy review(s). From FDA website.

21. Weller S, Chen S, Borland J et al. Bioequivalence of a dolutegravir, abacavir, and lamivudine fixed-dose combination tablet and the effect of food. J Acquir Immune Defic Syndr. 2014; 66:393-8. [PubMed 24798770]

22. Castagna A, Maggiolo F, Penco G et al. Dolutegravir in antiretroviral-experienced patients with raltegravir- and/or elvitegravir-resistant HIV-1: 24-week results of the phase III VIKING-3 study. J Infect Dis. 2014; 210:354-62. [PubMed 24446523]

23. Akil B, Blick G, Hagins DP et al. Dolutegravir versus placebo in subjects harbouring HIV-1 with integrase inhibitor resistance associated substitutions: 48-week results from VIKING-4, a randomized study. Antivir Ther. 2015; 20:343-8. [PubMed 25321146]

109. Genentech USA, Inc. Pegasys (peginterferon alfa-2a) injection for subcutaneous use prescribing information. South San Francisco, CA; 2015 Mar.

200. Panel on Antiretroviral Guidelines for Adults and Adolescents, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (April 8, 2015). Updates may be available at HHS AIDS Information (AIDSinfo) website.

201. Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in pediatric HIV infection (April 27, 2015). Updates may be available at HHS AIDS Information (AIDSinfo) website.

202. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, US Department of Health and Human Services (HHS). Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States (August 6, 2015). Updates may be available at HHS AIDS Information (AIDSinfo) website.

237. Janssen Therapeutics. Prezcobix (darunavir/cobicistat) tablets prescribing information. Titusville, NJ; 2015 Jan.

240. ViiV Healthcare. Triumeq (abacavir, dolutegravir, lamivudine) tablets prescribing information. Research Triangle Park, NC; 2014 Aug.

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