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Dolutegravir and Lamivudine

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: C20H18F2N3NaO5C8H11N3O3S
CAS Number: 1051375-19-9

Medically reviewed by Drugs.com on Jul 6, 2020. Written by ASHP.

Warning

    HBV Infection
  • Test all HIV-infected patients for presence of HBV prior to initiating fixed combination of dolutegravir and lamivudine (dolutegravir/lamivudine). Emergence of lamivudine-resistant HBV associated with use of lamivudine-containing antiretroviral regimens. If dolutegravir/lamivudine used in patients coinfected with HIV and HBV, consider appropriate treatment for chronic HBV or consider alternative antiretroviral regimen. (See HIV-infected Individuals Coinfected with HBV under Cautions.)

  • Severe, acute exacerbations of HBV infection reported following discontinuance of lamivudine in patients coinfected with HIV and HBV. Monitor hepatic function closely. If appropriate, initiation of HBV treatment may be warranted. (See HIV-infected Individuals Coinfected with HBV under Cautions.)

Introduction

Antiretroviral; fixed combination of dolutegravir and lamivudine (dolutegravir/lamivudine). Dolutegravir is an HIV integrase strand transfer inhibitor (INSTI) and lamivudine is an HIV nucleoside reverse transcriptase inhibitor (NRTI).

Uses for Dolutegravir and Lamivudine

Treatment of HIV Infection

Treatment of HIV type 1 (HIV-1) infection in antiretroviral-naive (have not previously received antiretroviral therapy) adults who have no known substitutions associated with resistance to dolutegravir or lamivudine.

Dolutegravir/lamivudine fixed combination is used alone as a complete regimen for treatment of HIV-1 infection; manufacturer states concomitant use with other antiretrovirals not recommended.

Experts state that a 2-drug regimen of dolutegravir and lamivudine (dolutegravir/lamivudine) is a recommended INSTI-based regimen for initial treatment in most adults and also is a recommended regimen for initial treatment in adults when abacavir, tenofovir alafenamide fumarate (TAF), and tenofovir disoproxil fumarate (TDF) cannot be used or are not optimal. However, these experts state do not use dolutegravir/lamivudine for initial treatment in patients with plasma HIV-1 RNA levels >500,000 copies/mL or with HBV coinfection and do not use if results of HIV genotypic resistance testing for reverse transcriptase or results of HBV testing are not available.

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].

Dolutegravir and Lamivudine Dosage and Administration

General

  • Test for HBV infection prior to initiation of dolutegravir/lamivudine. (See HIV-infected Individuals Coinfected with HBV under Cautions.)

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

Administration

Oral Administration

Administer orally once daily with or without food.

Dosage

Available as fixed-combination tablets containing dolutegravir sodium and lamivudine; dosages expressed in terms of dolutegravir and lamivudine, respectively.

Each fixed-combination tablet contains 50 mg of dolutegravir and 300 mg of lamivudine.

Adults

Treatment of HIV-1 Infection
Antiretroviral-naive Adults
Oral

1 tablet of dolutegravir/lamivudine (dolutegravir 50 mg and lamivudine 300 mg) once daily.

Antiretroviral-naive Adults Receiving Carbamazepine or Rifampin
Oral

1 tablet (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 fixed-combination tablet. (See Specific Drugs under Interactions.)

Special Populations

Hepatic Impairment

Mild or moderate hepatic impairment (Child-Pugh class A or B): Dosage adjustments not needed.

Severe hepatic impairment (Child-Pugh class C): Not recommended. (See Hepatic Impairment under Cautions.)

Renal Impairment

Clcr <50 mL/minute: Not recommended. (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 and Lamivudine

Contraindications

  • Hypersensitivity to dolutegravir or lamivudine.

  • Concomitant use with dofetilide; such use may result in serious and/or life-threatening adverse effects due to possible increased dofetilide plasma concentrations. (See Specific Drugs under Interactions.)

Warnings/Precautions

Warnings

HIV-infected Individuals Coinfected with HBV.

Test all HIV-infected patients for presence of HBV before initiating antiretroviral therapy.

Lamivudine-resistant strains of HBV have emerged in HIV-infected patients coinfected with HBV receiving lamivudine-containing antiretroviral regimens.

In HIV-infected patients with HBV coinfection, severe acute exacerbations of HBV infection, including liver decompensation and liver failure, reported following discontinuance of lamivudine. Such reactions could occur following discontinuance of dolutegravir/lamivudine.

Some experts state do not use a 2-drug antiretroviral regimen of dolutegravir and lamivudine in patients coinfected with HBV.

Manufacturer states that if a decision is made to use dolutegravir/lamivudine in patients coinfected with HIV-1 and HBV, consider appropriate treatment for chronic HBV infection; alternatively, consider a different antiretroviral regimen.

Closely monitor hepatic function using both clinical and laboratory follow-up for at least several months after dolutegravir/lamivudine is discontinued in patients coinfected with HIV-1 and HBV. If appropriate, initiation of HBV treatment may be warranted, especially in patients with advanced liver disease or cirrhosis.

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions (e.g., rash, constitutional findings, and, sometimes, organ dysfunction including liver injury) reported in patients receiving dolutegravir. These adverse effects reported in <1% of patients receiving dolutegravir in phase 3 clinical trials.

Immediately discontinue dolutegravir/lamivudine if signs or symptoms of hypersensitivity reactions occur (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters or peeling of the skin, oral blisters or lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, difficulty breathing). Monitor clinical status, including aminotransferase concentrations, and initiate appropriate therapy. Delay in stopping dolutegravir/lamivudine treatment or other suspect agents after onset of a hypersensitivity reaction may result in a life-threatening reaction.

Other Warnings and Precautions

Hepatotoxicity

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 serum 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 dolutegravir-containing regimens who had no preexisting hepatic disease or other identifiable risk factors. Drug-induced liver injury leading to liver transplantation has been reported with the fixed combination of abacavir, dolutegravir, and lamivudine (abacavir/dolutegravir/lamivudine).

Monitor for hepatotoxicity during dolutegravir/lamivudine therapy.

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/lamivudine for women at the time of conception through the first trimester of pregnancy. Manufacturer also states initiation of dolutegravir/lamivudine not recommended in women actively trying to become pregnant, unless there is no suitable alternative. (See Pregnancy under Cautions.)

Lactic Acidosis and Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis (sometimes fatal) reported in patients receiving nucleoside analogs, including lamivudine. These cases reported most frequently in women; obesity also may be a risk factor.

If dolutegravir/lamivudine is used in patients with known risk factors for liver disease, closely monitor such patients.

Discontinue dolutegravir/lamivudine in patients who develop clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (e.g., hepatomegaly and steatosis even in the absence of markedly increased serum aminotransferase concentrations).

Interactions

Concomitant use of dolutegravir/lamivudine with certain other drugs may result in known or potentially clinically important drug interactions, some of which may lead to loss of therapeutic effect of dolutegravir/lamivudine and possible development of resistance or may increase plasma concentrations of the concomitant drugs.

Consider potential for drug interactions prior to and during treatment with dolutegravir/lamivudine; review concomitant drugs during dolutegravir/lamivudine therapy and monitor for adverse effects. (See Interactions.)

Immune Reconstitution Syndrome

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

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

Use of Fixed Combinations

Consider cautions, precautions, contraindications, and interactions associated with both components of dolutegravir/lamivudine.

Consider cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) for each drug in the fixed combination.

Specific Populations

Pregnancy

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

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.

Human data regarding use of dolutegravir/lamivudine in pregnant women insufficient to definitively assess a drug-associated risk for birth defects and miscarriage with the fixed combination. Based on prospective reports to the APR regarding use of lamivudine during pregnancy, including >12,000 lamivudine exposures resulting in live births (>5000 exposures during first trimester), there was no difference between overall risk of birth defects for lamivudine compared with background birth defect rate of 2.7% in US reference population.

Perform pregnancy testing in all women of childbearing potential before initiating dolutegravir/lamivudine.

Manufacturer states do not use dolutegravir/lamivudine 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/lamivudine not recommended in women actively trying to become pregnant, unless there is no suitable alternative.

Experts state that a 2-drug regimen of dolutegravir/lamivudine is not recommended in antiretroviral-naive or antiretroviral-experienced pregnant women or women of childbearing potential trying to conceive because data not available regarding use of 2-drug regimens for treatment of HIV-1 infection during pregnancy.

Advise women of childbearing potential to consistently use effective contraception during dolutegravir/lamivudine therapy. If a woman is currently receiving dolutegravir/lamivudine and is actively trying to become pregnant or if pregnancy is confirmed in the first trimester, inform the woman of potential risk to an embryo exposed to dolutegravir/lamivudine from time of conception through first trimester of pregnancy. Assess risks and benefits of continuing the drug versus switching to a different antiretroviral regimen and consider switching to a 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.

Lactation

Dolutegravir: Some reports that dolutegravir is distributed into human milk in low concentrations; distributed into milk of lactating rats.

Lamivudine: Distributed into human milk.

Dolutegravir/lamivudine: Not known whether the fixed combination or individual drug components affect human milk production or affect the 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

Safety and efficacy not established in pediatric patients.

Geriatric Use

Experience in patients ≥65 years of age insufficient to determine whether they respond differently than younger adults.

Use with caution in geriatric patients because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.

Hepatic Impairment

Mild or moderate hepatic impairment (Child-Pugh class A or B): Dosage adjustments not needed.

Severe hepatic impairment (Child-Pugh class C): Dolutegravir/lamivudine not studied; not recommended in such patients.

Renal Impairment

Clcr <50 mL/minute: Dolutegravir/lamivudine not recommended because dosage of the components cannot be adjusted individually. Use single-entity dolutegravir and single-entity lamivudine in patients with Clcr <50 mL/minute since reduction of lamivudine dosage required in such patients.

Common Adverse Effects

Headache, diarrhea, nausea, insomnia, fatigue.

Interactions for Dolutegravir and Lamivudine

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

Dolutegravir: Metabolized by UGT1A1; substrate for UGT1A3 and UGT1A9. Does not inhibit UGT1A1 or UGT2B7.

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

Dolutegravir: Inhibits multidrug and toxin extrusion transporter (MATE) 1, renal organic anion transporter (OAT) 1 and OAT3, and renal organic cation transporter (OCT) 2. Does not inhibit bile salt export pump (BSEP), hepatic organic anion transporter polypeptide (OATP) 1B1, OATP1B3, OCT1, or multidrug resistance protein (MRP) 2 or MRP4; not a substrate of OATP1B1 or 1B3.

Lamivudine: Not metabolized by CYP isoenzymes to any clinically important extent.

Lamivudine: Substrate of P-gp transport system and BCRP; does not inhibit P-gp or BCRP.

Lamivudine: Substrate of MATE1, MATE2-K, and OCT2. Does not inhibit MATE1, MATE2-K, OATP1B1/3, OCT1, OCT2, or OCT3.

The following drug interactions are based on studies using the individual components of dolutegravir/lamivudine or are predicted to occur with the fixed combination. When dolutegravir/lamivudine used, consider interactions associated with both drugs in the fixed combination.

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A inducers: Possible decreased dolutegravir plasma concentrations; may lead to decreased therapeutic effects of dolutegravir.

CYP3A inhibitors: Possible increased dolutegravir plasma concentrations.

Drugs Affecting UGT

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

UGT1A1 inhibitors: Possible increased dolutegravir concentrations.

Drugs Affecting or Affected by P-glycoprotein Transport

P-gp inducers: Possible decreased dolutegravir plasma concentrations and decreased therapeutic effects of dolutegravir. Unlikely to affect lamivudine concentrations.

P-gp inhibitors: Possible increased dolutegravir plasma concentrations. Unlikely to affect lamivudine concentrations.

Drugs Affecting or Affected by Breast Cancer Resistance Protein

BCRP inducers: Possible decreased dolutegravir plasma concentrations and decreased therapeutic effects of dolutegravir. Unlikely to affect lamivudine concentrations.

BCRP inhibitors: Possible increased dolutegravir plasma concentrations. Unlikely to affect lamivudine concentrations.

Drugs Affecting or Affected by Multidrug and Toxin Extrusion Transporter

MATE1 and MATE2-K inhibitors: Possible increased lamivudine concentrations.

Drugs eliminated by MATE1 and MATE2-K: Dolutegravir may increase plasma concentrations of MATE1 substrates.

Drugs Affected by Organic Cation Transporters

Drugs eliminated by OCT2: Dolutegravir may increase plasma concentrations of OCT2 substrates.

Specific Drugs

Drug

Interaction

Comments

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

Dolutegravir not expected to affect α1-adrenergic blocking agent concentrations

Dosage adjustments not needed

β-Adrenergic blocking agents

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

Metoprolol, timolol: Dosage adjustments not needed

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

Decreased dolutegravir concentrations and AUC

Give dolutegravir/lamivudine ≥2 hours before or ≥6 hours after aluminum-, calcium-, or magnesium-containing antacids

Antiarrhythmic agents

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

Disopyramide: Possible increased disopyramide concentrations

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

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

Disopyramide: Monitor for disopyramide-associated adverse effects if used with dolutegravir

Dofetilide: Concomitant use with dolutegravir/lamivudine contraindicated

Anticoagulants

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

Warfarin: Dolutegravir not expected to affect warfarin concentrations

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

Warfarin: Dosage adjustments not needed

Anticonvulsants

Carbamazepine: Decreased dolutegravir concentrations and AUC

Eslicarbazepine: Possible decreased dolutegravir concentrations

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

Oxcarbazepine, phenobarbital, phenytoin: Possible decreased dolutegravir concentrations

Valproic acid: Data not available regarding use with dolutegravir

Carbamazepine: If used with dolutegravir/lamivudine, give 50 mg of single-entity dolutegravir once daily 12 hours after the usual daily dose of dolutegravir/lamivudine

Eslicarbazepine: Some experts state consider alternative anticonvulsant or alternative antiretroviral

Ethosuximide, lamotrigine: Dosage adjustments not needed

Oxcarbazepine, phenobarbital, phenytoin: Avoid concomitant use with dolutegravir/lamivudine; data insufficient to make dosage recommendations

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

Antidiabetic agents

Metformin: Increased metformin concentrations and AUC if used with dolutegravir

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

Metformin: Consider risks and benefits if considering use with dolutegravir/lamivudine; use lowest initial metformin dose and titrate dosage based on glycemic control while monitoring metformin adverse effects; may need to adjust metformin dosage when starting or stopping dolutegravir-containing regimens

Saxagliptin, dapagliflozin/saxagliptin: Dosage adjustments not needed

Antifungals, azoles

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

Itraconazole, posaconazole, voriconazole: Dosage adjustments not needed

Antimycobacterial agents (rifabutin, rifampin, rifapentine)

Rifabutin: No clinically important effect on dolutegravir pharmacokinetics

Rifampin: Decreased dolutegravir concentrations and AUC

Rifapentine: Decreased dolutegravir concentrations expected

Rifabutin: Dosage adjustments not needed

Rifampin: If used with dolutegravir/lamivudine, give 50 mg of single-entity dolutegravir once daily 12 hours after the usual daily dose of dolutegravir/lamivudine

Rifapentine: Concomitant use not recommended

Antiplatelet agents

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

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

Antipsychotic agents

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

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

Benzodiazepines

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

Midazolam: No clinically important effect on midazolam AUC

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

Bosentan

Possible decreased dolutegravir concentrations

Dosage adjustments not needed

Buffered preparations

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

Buffered preparations containing polyvalent cations: Give dolutegravir/lamivudine ≥2 hours before or ≥6 hours after such preparations

Buprenorphine

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

Dosage adjustments not needed

Bupropion

Dolutegravir not expected to affect bupropion concentrations

Dosage adjustments not needed

Buspirone

Dolutegravir not expected to affect buspirone concentrations

Dosage adjustments not needed

Calcifediol

Dolutegravir not expected to affect calcifediol concentrations

Dosage adjustments not needed

Calcium-channel blocking agents

No pharmacokinetic interactions with dolutegravir expected

Dosage adjustments not needed

Calcium supplements

Decreased dolutegravir concentrations when given concomitantly in fasted state

Give dolutegravir/lamivudine ≥2 hours before or ≥6 hours after oral calcium supplements; alternatively, may be given concomitantly if taken with food

Colchicine

Dolutegravir not expected to affect colchicine concentrations

Dosage adjustments not needed

Corticosteroids

Betamethasone, budesonide, dexamethasone (systemic): No pharmacokinetic interactions with dolutegravir expected

Prednisone, prednisolone (systemic): Concomitant prednisone does not affect dolutegravir pharmacokinetics; dolutegravir not expected to affect concentrations of prednisone or prednisolone

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

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

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

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

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

Co-trimoxazole

No clinically important effects on lamivudine pharmacokinetics

Dalfampridine

Increased dalfampridine concentrations and increased risk of seizures

Weigh potential benefits of concomitant therapy against risk of seizures

Dolutegravir

No in vitro evidence of antagonistic antiretroviral effects between dolutegravir and lamivudine

Dronabinol

Dolutegravir not expected to affect dronabinol concentrations

Dosage adjustments not needed

Elbasvir and grazoprevir

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

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

Eluxadoline

Dolutegravir not expected to affect eluxadoline concentrations

Dosage adjustments not needed

Eplerenone

Dolutegravir not expected to affect eplerenone concentrations

Dosage adjustments not needed

Ergot alkaloids (dihydroergotamine, ergotamine, methylergonovine)

Dolutegravir not expected to affect concentrations of ergot alkaloids

Dosage adjustments not needed

Estrogens and progestins

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

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

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

Estradiol, estrogen, conjugated estrogens: Dosage adjustments not needed

Drospirenone, medroxyprogesterone, progesterone: Dosage adjustments not needed

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

Fentanyl

Dolutegravir not expected to affect fentanyl concentrations

Dosage adjustments not needed

Flibanserin

Dolutegravir not expected to affect flibanserin concentrations

Dosage adjustments not needed

Glecaprevir and pibrentasvir

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

Glecaprevir/pibrentasvir: Dosage adjustments not needed if used with dolutegravir

Goserelin

Dolutegravir not expected to affect goserelin concentrations

Dosage adjustments not needed

Histamine H2-receptor antagonists

No clinically important effect on dolutegravir concentrations expected

Dosage adjustments not needed

HMG-CoA reductase inhibitors (statins)

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

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

Immunosuppressive agents

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

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

Interferon alfa

No clinically important effects on lamivudine pharmacokinetics

Iron preparations

Possible decreased dolutegravir concentrations when given concomitantly in fasted state

Give dolutegravir/lamivudine ≥2 hours before or ≥6 hours after oral iron; alternatively, may be given concomitantly if taken with food

Ivabradine

Dolutegravir not expected to affect ivabradine concentrations

Dosage adjustments not needed

Lamivudine

No in vitro evidence of antagonistic antiretroviral effects between lamivudine and dolutegravir

Laxatives containing polyvalent cations

Possible decreased dolutegravir absorption and decreased dolutegravir concentrations

Give dolutegravir/lamivudine ≥2 hours before or ≥6 hours after laxatives containing polyvalent cations

Ledipasvir and sofosbuvir

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

Ledipasvir/sofosbuvir: Dosage adjustments not needed if used with dolutegravir

Leuprolide

Dolutegravir not expected to affect leuprolide concentrations

Dosage adjustments not needed

Lofexidine

Dolutegravir not expected to affect lofexidine concentrations

Dosage adjustments not needed

Lomitapide

Dolutegravir not expected to affect lomitapide concentrations

Dosage adjustments not needed

Macrolides

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

Azithromycin, clarithromycin, erythromycin: Dosage adjustments not needed

Magnesium preparations

Possible decreased dolutegravir absorption and decreased dolutegravir concentrations

Give dolutegravir/lamivudine ≥2 hours before or ≥6 hours after magnesium

Methadone

Dolutegravir: No clinically important effect on methadone pharmacokinetics

Dosage adjustments not needed

Multivitamins

Decreased dolutegravir concentrations when given concomitantly in fasted state

Give dolutegravir/lamivudine ≥2 hours before or ≥6 hours after multivitamins; alternatively, may be given concomitantly if taken with food

Nefazodone

Dolutegravir not expected to affect nefazodone concentrations

Dosage adjustments not needed

Phosphodiesterase type 5 (PDE5) inhibitors

Avanafil, sildenafil, tadalafil, vardenafil: Dolutegravir not expected to affect PDE5 inhibitor concentrations

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

Proton-pump inhibitors

Omeprazole: No clinically important effect on dolutegravir pharmacokinetics

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

Ranolazine

Dolutegravir not expected to affect ranolazine concentrations

Dosage adjustments not needed

Ribavirin

No clinically important effects on lamivudine pharmacokinetics

Selective β-adrenergic agonists

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

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

Sofosbuvir

Dolutegravir: No clinically important effect on sofosbuvir pharmacokinetics; not expected to affect dolutegravir pharmacokinetics

Dosage adjustments not needed if used with dolutegravir

Sofosbuvir and velpatasvir

Fixed combination of sofosbuvir and velpatasvir (sofosbuvir/velpatasvir): No clinically important effect on dolutegravir pharmacokinetics

Sofosbuvir/velpatasvir: Dosage adjustments not needed if used with dolutegravir

Sofosbuvir, velpatasvir, and voxilaprevir

Fixed combination of sofosbuvir, velpatasvir, and voxilaprevir (sofosbuvir/velpatasvir/voxilaprevir): No pharmacokinetic interactions with dolutegravir expected

Sofosbuvir/velpatasvir/voxilaprevir: Dosage adjustments not needed if used with dolutegravir

Sorbitol

Lamivudine: Decreased lamivudine AUC and plasma concentrations

Sorbitol-containing drugs: Avoid concomitant use with dolutegravir/lamivudine

Spironolactone

Dolutegravir not expected to affect spironolactone concentrations

Dosage adjustments not needed

SSRIs

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

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

St. John's wort (Hypericum perforatum)

Possible decreased dolutegravir concentrations

Avoid concomitant use with dolutegravir/lamivudine; data insufficient to make dosage recommendations

Sucralfate

Possible decreased dolutegravir concentrations

Give dolutegravir/lamivudine ≥2 hours before or ≥6 hours after sucralfate

Suvorexant

Dolutegravir not expected to affect suvorexant concentrations

Dosage adjustments not needed

Testosterone

Dolutegravir not expected to affect testosterone concentrations

Dosage adjustments not needed

Tramadol

Dolutegravir not expected to affect tramadol concentrations

Dosage adjustments not needed

Trazodone

Dolutegravir not expected to affect trazodone concentrations

Dosage adjustments not needed

Tricyclic antidepressants

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

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

Zolpidem

Dolutegravir not expected to affect zolpidem concentrations

Dosage adjustments not needed

Dolutegravir and Lamivudine Pharmacokinetics

Absorption

Bioavailability

Dolutegravir: Absolute bioavailability not established.

Lamivudine: Absolute bioavailability 86%.

Food

High-fat meal does not have clinically important effect on pharmacokinetics of dolutegravir, lamivudine, or fixed combination containing both drugs.

Plasma Concentrations

Dolutegravir: Peak concentrations attained 2–3 hours after an oral dose.

Lamivudine: Peak concentrations attained 1 hour after an oral dose.

Distribution

Extent

Dolutegravir: Crosses placenta. Appears to be distributed into human milk in low concentrations; distributed into milk in rats.

Lamivudine: Crosses placenta. Distributed into human milk.

Plasma Protein Binding

Dolutegravir: Approximately 99%.

Lamivudine: 36%.

Elimination

Metabolism

Dolutegravir: Primarily metabolized by UGT1A1; CYP3A plays only minor role.

Lamivudine: Not metabolized by CYP isoenzymes to any clinically important extent.

Elimination Route

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

Lamivudine: Principally eliminated in urine by active cationic secretion; approximately 71% of a dose eliminated in urine.

Half-life

Dolutegravir: Approximately 14 hours.

Lamivudine: 5–7 hours after a single oral dose.

Stability

Storage

Oral

Tablets

<30°C.

Actions and Spectrum

  • Dolutegravir/lamivudine is a fixed-combination antiretroviral containing dolutegravir and lamivudine.

  • Dolutegravir is an HIV INSTI. The drug binds to the 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).

  • Lamivudine is an HIV NRTI. Prodrug that is inactive until converted intracellularly to an active 5′-triphosphate metabolite (lamivudine triphosphate). After conversion, acts as a reverse transcriptase inhibitor via DNA chain termination after incorporation of the nucleotide analogue. Active against HIV-1; also active against HBV.

  • HIV-1 resistant to dolutegravir produced in vitro and have emerged in HIV-infected patients receiving the drug; amino acid substitution G118R confers tenfold decrease in in vitro susceptibility to dolutegravir. HIV-1 resistant to lamivudine produced in vitro and have emerged in HIV-infected patients receiving lamivudine-containing regimens; HIV-1 resistance to lamivudine often involves amino acid substitutions M184V or M184I.

  • In a phase 3 clinical study evaluating 2-drug regimen of dolutegravir and lamivudine in antiretroviral-naive adults, treatment-emergent INSTI- or NRTI-resistance substitutions not reported in any patients at 48 or 96 weeks. In preliminary studies evaluating 2-drug regimen of dolutegravir and lamivudine for switch therapy in previously treated HIV-1-infected adults, emergence of dolutegravir resistance-associated mutations not reported; presence of M184V lamivudine resistance-associated mutation was not a predictor of virological failure.

  • Cross-resistance occurs among HIV INSTIs (e.g., dolutegravir, elvitegravir, raltegravir). Cross-resistance also occurs among HIV NRTIs (e.g., abacavir, emtricitabine, lamivudine, zidovudine).

  • No in vitro evidence of antagonistic anti-HIV effects between dolutegravir and lamivudine.

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.

  • 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 acquired immunodeficiency syndrome (AIDS) and death.

  • Advise patients that effective antiretroviral regimens can decrease HIV levels 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., reusing or sharing needles).

  • Importance of reading patient information provided by the manufacturer.

  • Advise patients to take dolutegravir/lamivudine once every day at a regularly scheduled time with or without food. Dolutegravir/lamivudine is used alone as a complete regimen for treatment of HIV-1 infection.

  • If a dose of dolutegravir/lamivudine is missed, it should be taken as soon as it is remembered. Advise patients not to double their next dose and not to take more than the prescribed dose.

  • Inform patients that testing for HBV infection is recommended before antiretroviral therapy is initiated. Advise patients that emergence of lamivudine-resistant HBV has been reported in HIV-infected patients coinfected with HBV receiving lamivudine-containing antiretroviral regimens. Also advise patients that severe acute exacerbations of HBV infection have been reported following discontinuance of lamivudine in HIV-infected patients coinfected with HBV and may occur with dolutegravir/lamivudine. Importance of patients with HIV and HBV coinfection discussing with their healthcare provider whether additional treatment for chronic HBV is warranted.

  • Importance of immediately discontinuing dolutegravir/lamivudine 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 right side below ribs). Advise patients that close monitoring and appropriate laboratory testing and treatment may be required if a hypersensitivity reaction occurs.

  • Inform patients that hepatotoxicity has been reported in patients receiving the components of dolutegravir/lamivudine, and that monitoring for hepatotoxicity is recommended.

  • Inform patients that some HIV drugs, including dolutegravir/lamivudine, can cause a rare, but serious condition called lactic acidosis with liver enlargement (hepatomegaly).

  • Advise patients that signs and symptoms of inflammation from other previous infections may occur soon after initiation of antiretroviral therapy in some HIV-infected individuals. Importance of immediately informing clinicians 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, become pregnant, or if pregnancy is suspected during treatment with dolutegravir/lamivudine. Advise women of childbearing potential of the risks to the fetus if dolutegravir/lamivudine is used at the time of conception through the first trimester. Inform women of childbearing potential about the need for pregnancy testing before initiation of dolutegravir/lamivudine and counsel them that alternative antiretroviral regimens should be considered at the time of conception through the first trimester. Advise women of childbearing potential taking dolutegravir/lamivudine to consistently use effective contraception during dolutegravir/lamivudine treatment. (See Pregnancy under Cautions.)

  • Importance of women informing clinicians if they plan to breast-feed. 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.

Dolutegravir Sodium and Lamivudine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

50 mg (of dolutegravir) and Lamivudine 300 mg

Dovato

ViiV

AHFS DI Essentials™. © Copyright 2022, Selected Revisions July 6, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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