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

Introduction

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

Uses for Tivicay

Treatment of HIV Infection

Treatment of HIV-1 infection in adults, adolescents, and pediatric patients ≥12 years of age;1 usually used in conjunction with 2 HIV nucleoside reverse transcriptase inhibitors (NRTIs).1

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 that can be used regardless of baseline viral load or CD4+ T-cell count.200 Dolutegravir in conjunction with abacavir and lamivudine (or emtricitabine) also is a recommended INSTI-based regimen for initial treatment that can be used regardless of baseline viral load or CD4+ T-cell count, but use only in those who are human leukocyte antigen (HLA)-B*5701 negative.200

Slideshow: Flashback: FDA Drug Approvals 2013

For initial treatment in antiretroviral-naive pediatric patients, experts state that an INSTI-based regimen of dolutegravir in conjunction with 2 NRTIs can be considered in those ≥12 years of age in special circumstances when preferred or alternative antiretrovirals cannot be used.201

Consider that poor virologic response reported in patients with an INSTI-resistance Q148 substitution and ≥2 additional INSTI-resistance substitutions (e.g., L741/M, E138A/D/K/T, G140A/S, Y143H/R, E157Q, G163E/K/Q/R/S, G193E/R).1

Safety and efficacy not established in pediatric patients <12 years of age.1

Tivicay Dosage and Administration

Administration

Oral Administration

Administer orally once daily without regard to food.1

Administer 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 (See Interactions.)

Dosage

Available as dolutegravir sodium; dosage expressed in terms of dolutegravir.1

Must be used in conjunction with other antiretrovirals.1

Pediatric Patients

Treatment of HIV Infection
Antiretroviral-naive Pediatric Patients
Oral

Children and adolescents ≥12 years of age weighing ≥40 kg: 50 mg once daily.1

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

Antiretroviral-experienced Pediatric Patients
Oral

Children and adolescents ≥12 years of age weighing ≥40 kg who are antiretroviral-experienced but INSTI-naive: 50 mg once daily.1

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

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

Adults

Treatment of HIV Infection
Antiretroviral-naive Adults
Oral

50 mg once daily.1

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

Antiretroviral-experienced Adults
Oral

Antiretroviral-experienced but INSTI-naive: 50 mg once daily.1

Antiretroviral-experienced, INSTI-experienced with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance: 50 mg twice daily.1

Antiretroviral-experienced receiving certain potent UGT1A1 or CYP3A inducers (i.e., efavirenz, ritonavir-boosted fosamprenavir, ritonavir-boosted tipranavir, rifampin): 50 mg twice daily.1

Special Populations

Hepatic Impairment

Dosage adjustments not needed in patients with mild or moderate hepatic impairment (Child-Pugh class A or B).1

Do not use in patients with severe hepatic impairment (Child-Pugh class C).1 (See Hepatic Impairment under Cautions.)

Renal Impairment

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.)

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

Cautions for Tivicay

Contraindications

  • Concomitant use with dofetilide.1 (See Specific Drugs under Interactions.)

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 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 Monitor clinical status, including liver aminotransferases, and initiate appropriate therapy.1

Life-threatening reactions could occur if discontinuance of dolutegravir or other suspect agents is delayed after onset of hypersensitivity reaction.1

Do not use in those with a history of previous hypersensitivity to dolutegravir.1

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 treatment.1 (See Hepatic Impairment under Cautions.)

Fat Redistribution

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

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

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

Specific Populations

Pregnancy

Category B.1

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

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

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

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.1

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

Hepatic Impairment

Not recommended in patients with severe hepatic impairment (Child-Pugh class C); 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

Renal Impairment

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

Mild or moderate renal impairment does not have 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.)

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

Common Adverse Effects

Insomnia; headache; 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 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

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

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

Administer dolutegravir at least 2 hours before or 6 hours after aluminum-, calcium-, or magnesium-containing antacids1 19 200

Antiarrhythmic agents

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

Dofetilide: Concomitant use contraindicated1

Anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin)

Carbamazepine, oxcarbazepine, phenobarbital, phenytoin: Decreased dolutegravir concentrations1

Carbamazepine, oxcarbazepine, phenobarbital, phenytoin: Avoid concomitant use; data insufficient to make dosage recommendations;1 consider alternative anticonvulsant200

Antidiabetic agents

Metformin: Possible increased metformin concentrations1 200

Metformin: Closely monitor patient when starting or stopping concomitant dolutegravir and metformin;200 metformin dosage adjustments may be needed1 200

Antimycobacterial agents (rifabutin, rifampin)

Rifabutin: No clinically important effect on dolutegravir pharmacokinetics1

Rifampin: Decreased dolutegravir concentrations and AUC1 200

Rifabutin: Dosage adjustments not needed200

Rifampin: In 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

Rifapentine: Concomitant use not recommended200

Atazanavir

Atazanavir or ritonavir-boosted atazanavir: Increased dolutegravir concentrations and AUC;200 effect not considered clinically important1 17

Dosage adjustments not needed200

Boceprevir

No clinically important effect on dolutegravir pharmacokinetics1 200

Dosage adjustments not needed200

Buffered preparations

Buffered preparations containing polyvalent cations: Possible decreased dolutegravir concentrations1

Buffered preparations containing polyvalent cations: Administer dolutegravir at least 2 hours before or 6 hours after such preparations1

Calcium supplements

Decreased dolutegravir concentrations when used concomitantly in the fasted state1

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

Corticosteroids

Prednisone: No clinically important effect on dolutegravir pharmacokinetics1 8

Darunavir

Ritonavir-boosted darunavir: Decreased dolutegravir concentrations and AUC;200 effect not considered clinically important1

Once-daily or twice-daily ritonavir-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

In 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

Enfuvirtide

No in vitro evidence of antagonistic antiretroviral effects1

Etravirine

Substantially decreased dolutegravir concentrations and AUC;1 200 no apparent effect 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 concomitantly unless ritonavir-boosted atazanavir, ritonavir-boosted darunavir, or lopinavir/ritonavir also included in the regimen1 200

INSTI-naive 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 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 possible1 200

Iron preparations

Decreased dolutegravir concentrations when used concomitantly in the fasted state1

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

Laxatives containing polyvalent cations

Possible decreased dolutegravir concentrations1

Administer dolutegravir at least 2 hours before or 6 hours after laxatives containing polyvalent cations1 200

Lopinavir/ritonavir

No clinically important effect 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 at least 2 hours before or 6 hours after multivitamins containing calcium or iron;1 200 alternatively, may be used concomitantly if taken with food1

Nevirapine

Decreased dolutegravir concentrations1 200

No in vitro evidence of antagonistic antiretroviral effects1

Do not use concomitantly;1 200 data insufficient to make dosage recommendations1

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 use1

Stavudine

No in vitro evidence of antagonistic antiretroviral effects1

Sucralfate

Decreased dolutegravir concentrations1

Administer dolutegravir at least 2 hours before or 6 hours after sucralfate1 200

Telaprevir

Increased dolutegravir concentrations and AUC;1 200 no apparent effect on telaprevir pharmacokinetics1

Dosage adjustments not needed200

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 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 possible1 200

Tivicay Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability not established.1

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

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

Distribution

Extent

Distributed into CSF; clinical importance unknown.1

Crosses placenta in animals.1 202

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

Plasma Protein Binding

≥98.9%.1

Elimination

Metabolism

Metabolized primarily by UGT1A1; CYP3A plays minor role.1

Elimination Route

Excreted in feces (53%) and urine (31%).1

Half-life

Approximately 14 hours.1

Special Populations

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

Severe hepatic impairment: Pharmacokinetics not studied.1

HCV coinfection: No clinically important effect on pharmacokinetics.1

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

Severe renal impairment (Clcr <30 mL/minute): AUC decreased by 40%; 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 similar to HIV-1-infected adults receiving dolutegravir 50 mg once daily.1

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1

Actions

  • 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 nucleoside reverse transcriptase inhibitors (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, some HIV-1 resistant to elvitegravir and/or raltegravir also are resistant to dolutegravir.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

  • Importance of using in conjunction with other antiretrovirals—not for monotherapy.1

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

  • 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

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

  • If a dose 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 If a missed dose 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 A double dose should not be taken to make up for a missed dose.1

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

  • Advise patients that severe and potentially life-threatening rash has been reported.1 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

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

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

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

Preparations

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

Dolutegravir Sodium

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

50 mg (of dolutegravir)

Tivicay

Viiv

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions October 30, 2014. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. ViiV Healthcare. TIVICAY (dolutegravir) prescribing information. Research Triangle Park, NC; 2014 May.

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; :. [PubMed 24096683]

11. Panel on Antiretroviral Guidelines for Adults and Adolescents, US Department of Health and Human Services (HHS). Recommendation on integrase inhibitor use in antiretroviral treatment-naive HIV-infected individuals from the HHS Panel on Antiretroviral Guidelines for Adults and Adolescents (October 30, 2013). Updates may be available at HHS AIDS Information (AIDSinfo) website.

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.

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 (May 1, 2014). 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 (February 12, 2014). 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 (March 28, 2014). Updates may be available at HHS AIDS Information (AIDSinfo) website.

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