Dolutegravir

Dolutegravir
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]

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Overview

Dolutegravir is a antiviral that is FDA approved for the treatment of HIV-1 infection. Common adverse reactions include {{{adverseReactions}}}.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Dolutegravir in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Dolutegravir in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Treatment-naïve or Treatment-experienced INSTI-naïve

The recommended dose of TIVICAY in pediatric patients aged 12 years and older and weighing at least 40 kg is 50 mg administered orally once daily.

If efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, or rifampin are coadministered, the recommended dose of TIVICAY is 50 mg twice daily.

Safety and efficacy of TIVICAY have not been established in pediatric patients younger than 12 years or weighing less than 40 kg, or in pediatric patients who are INSTI-experienced with documented or clinically suspected resistance to other INSTIs (raltegravir, elvitegravir).

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Dolutegravir in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Dolutegravir in pediatric patients.

Contraindications

TIVICAY is contraindicated in patients:

• With previous hypersensitivity reaction to dolutegravir
• Receiving dofetilide due to the potential for increased dofetilide plasma concentrations and the risk for serious and/or life-threatening events.

Warnings

Hypersensitivity Reactions

Hypersensitivity reactions have been reported and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury. The events were reported in less than 1% of subjects receiving TIVICAY in Phase 3 clinical trials. Discontinue TIVICAY and other suspect agents immediately if signs or symptoms of hypersensitivity reactions develop (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). Clinical status, including liver aminotransferases, should be monitored and appropriate therapy initiated. Delay in stopping treatment with TIVICAY or other suspect agents after the onset of hypersensitivity may result in a life-threatening reaction. TIVICAY is contraindicated in patients who have experienced a previous hypersensitivity reaction to dolutegravir.

Effects on Serum Liver Biochemistries in Patients with Hepatitis B or C Coinfection

Patients with underlying hepatitis B or hepatitis C may be at increased risk for worsening or development of transaminase elevations with use of TIVICAY. In some cases the elevations in transaminases were consistent with immune reconstitution syndrome or hepatitis B reactivation particularly in the setting where anti-hepatitis therapy was withdrawn. Appropriate laboratory testing prior to initiating therapy and monitoring for hepatotoxicity during therapy with TIVICAY are recommended in patients with underlying hepatic disease such as hepatitis B or hepatitis C.

Fat Redistribution

Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including TIVICAY. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [[[PCP]]], or tuberculosis), which may necessitate further evaluation and treatment.

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

Adverse Reactions

Clinical Trials Experience

Treatment‑emergent Adverse Drug Reactions (ADRs)

Treatment-naïve Subjects

The safety assessment of TIVICAY in HIV‑1‑infected treatment-naïve subjects is based on the analyses of 96-week data from 2 international, multicenter, double-blind trials, SPRING-2 (ING113086) and SINGLE (ING114467) and 48-week data from the international, multicenter, open-label FLAMINGO (ING114915) trial.

In SPRING-2, 822 subjects were randomized and received at least 1 dose of either TIVICAY 50 mg once daily or raltegravir 400 mg twice daily, both in combination with fixed-dose dual nucleoside reverse transcriptase inhibitor (NRTI) treatment (either abacavir sulfate and lamivudine [EPZICOM®] or emtricitabine/tenofovir [TRUVADA®]). There were 808 subjects included in the efficacy and safety analyses. Through 96 weeks, the rate of adverse events leading to discontinuation was 2% in both treatment arms.

In SINGLE, 833 subjects were randomized and received at least 1 dose of either TIVICAY 50 mg with fixed-dose abacavir sulfate and lamivudine (EPZICOM) once daily or fixed-dose efavirenz/emtricitabine/tenofovir (ATRIPLA®) once daily. Through 96 weeks, the rates of adverse events leading to discontinuation were 3% in subjects receiving TIVICAY 50 mg once daily + EPZICOM and 12% in subjects receiving ATRIPLA once daily.

Treatment-emergent ADRs of moderate to severe intensity observed in at least 2% of subjects in either treatment arm in SPRING-2 and SINGLE trials are provided in Table 2. Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs.

In addition, Grade 1 insomnia was reported by 1% and less than 1% of subjects receiving TIVICAY and raltegravir, respectively, in SPRING-2; whereas in SINGLE the rates were 7% and 4% for TIVICAY and ATRIPLA, respectively. These events were not treatment limiting.

In a multicenter, open-label trial (FLAMINGO), 243 subjects received TIVICAY 50 mg once daily versus 242 subjects who received darunavir 800 mg/ritonavir 100 mg once daily, both in combination with investigator-selected NRTI background regimen (either EPZICOM or TRUVADA). There were 484 subjects included in the efficacy and safety analyses. Through 48 weeks, the rates of adverse events leading to discontinuation were 2% in subjects receiving TIVICAY and 4% in subjects receiving darunavir/ritonavir. The ADRs observed in FLAMINGO were generally consistent with those seen in SPRING-2 and SINGLE.

Treatment-experienced, Integrase Strand Transfer Inhibitor-naïve Subjects: In an international, multicenter, double-blind trial (ING111762, SAILING), 719 HIV‑1‑infected, antiretroviral treatment-experienced adults were randomized and received either TIVICAY 50 mg once daily or raltegravir 400 mg twice daily with investigator-selected background regimen consisting of up to 2 agents, including at least one fully active agent. At 48 weeks, the rates of adverse events leading to discontinuation were 3% in subjects receiving TIVICAY 50 mg once daily + background regimen and 4% in subjects receiving raltegravir 400 mg twice daily + background regimen.

The only treatment-emergent ADR of moderate to severe intensity with at least 2% frequency in either treatment group was diarrhea, 2% (6 of 354) in subjects receiving TIVICAY 50 mg once daily + background regimen and 1% (5 of 361) in subjects receiving raltegravir 400 mg twice daily + background regimen.

Treatment-experienced, Integrase Strand Transfer Inhibitor-experienced Subjects: In a multicenter, open-label, single-arm trial (ING112574, VIKING-3), 183 HIV‑1‑infected, antiretroviral treatment-experienced adults with virological failure and current or historical evidence of raltegravir and/or elvitegravir resistance received TIVICAY 50 mg twice daily with the current failing background regimen for 7 days and with optimized background therapy from Day 8. The rate of adverse events leading to discontinuation was 4% of subjects at Week 48.

Treatment-emergent ADRs in VIKING-3 were generally similar compared with observations with the 50-mg once-daily dose in adult Phase 3 trials.

Less Common Adverse Reactions Observed in Treatment-naïve and Treatment-experienced Trials

The following ADRs occurred in less than 2% of treatment-naïve or treatment-experienced subjects receiving TIVICAY in a combination regimen in any one trial. These events have been included because of their seriousness and assessment of potential causal relationship.

• Gastrointestinal Disorders: Abdominal pain, abdominal discomfort, flatulence, vomiting.
• General Disorders: Fatigue.
• Hepatobiliary Disorders: Hepatitis.
• Musculoskeletal Disorders: Myositis.
• Psychiatric Disorders: Suicidal ideation, attempt, behavior, or completion. These events were observed primarily in subjects with a pre-existing history of depression or other psychiatric illness.
• Renal and Urinary Disorders: Renal impairment.

Skin and Subcutaneous Tissue Disorders: Pruritus.

Laboratory Abnormalities

Treatment-naïve Subjects: Selected laboratory abnormalities (Grades 2 to 4) with a worsening grade from baseline and representing the worst-grade toxicity in at least 2% of subjects are presented in Table 3. The mean change from baseline observed for selected lipid values is presented in Table 4. Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs.

Laboratory abnormalities observed in the FLAMINGO trial were generally consistent with observations in SPRING-2 and SINGLE. Treatment-experienced, Integrase Strand Transfer Inhibitor-naïve Subjects: Laboratory abnormalities observed in SAILING were generally similar compared with observations seen in the treatment-naïve (SPRING-2 and SINGLE) trials.

Treatment-experienced, Integrase Strand Transfer Inhibitor-experienced Subjects

The most common treatment-emergent laboratory abnormalities (greater than 5% for Grades 2 to 4 combined) observed in VIKING-3 at Week 48 were elevated ALT (9%), AST (8%), cholesterol (10%), creatine kinase (6%), hyperglycemia (14%), and lipase (10%). Two percent (4 of 183) of subjects had a Grade 3 to 4 treatment-emergent hematology laboratory abnormality, with neutropenia (2% [3 of 183]) being the most frequently reported.

Hepatitis B and/or Hepatitis C Virus Co-infection

In Phase 3 trials, subjects with hepatitis B and/or hepatitis C virus co-infection were permitted to enroll provided that baseline liver chemistry tests did not exceed 5 times the upper limit of normal. Overall, the safety profile in subjects with hepatitis B and/or hepatitis C virus co-infection was similar to that observed in subjects without hepatitis B or hepatitis C co-infection, although the rates of AST and ALT abnormalities were higher in the subgroup with hepatitis B and/or hepatitis C virus co-infection for all treatment groups. Grades 2 to 4 ALT abnormalities in hepatitis B and/or hepatitis C co-infected compared with HIV mono-infected subjects receiving TIVICAY were observed in 18% vs. 3% with the 50-mg once-daily dose and 13% vs. 8% with the 50-mg twice-daily dose. Liver chemistry elevations consistent with immune reconstitution syndrome were observed in some subjects with hepatitis B and/or hepatitis C at the start of therapy with TIVICAY, particularly in the setting where anti-hepatitis therapy was withdrawn.

Changes in Serum Creatinine

Dolutegravir has been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal glomerular function. Increases in serum creatinine occurred within the first 4 weeks of treatment and remained stable through 48 to 96 weeks. In treatment-naïve subjects, a mean change from baseline of 0.15 mg per dL (range: -0.32 mg per dL to 0.65 mg per dL) was observed after 96 weeks of treatment. Creatinine increases were comparable by background NRTIs and were similar in treatment-experienced subjects.

Clinical Trials Experience in Pediatric Subjects

IMPAACT P1093 is an ongoing multicenter, open-label, non-comparative trial of approximately 160 HIV‑1‑infected pediatric subjects aged 6 weeks to less than 18 years, of which 23 treatment-experienced, INSTI-naïve subjects aged 12 to less than 18 years were enrolled.

The adverse reaction profile was similar to that for adults. Grade 2 ADRs reported in at least 1 subject were rash (n = 1), abdominal pain (n = 1), and diarrhea (n = 1). No Grade 3 or 4 ADRs were reported. The Grade 3 laboratory abnormalities were elevated total bilirubin and lipase reported in 1 subject each. No Grade 4 laboratory abnormalities were reported. The changes in mean serum creatinine were similar to those observed in adults.

Postmarketing Experience

There is limited information regarding Dolutegravir Postmarketing Experience in the drug label.

Drug Interactions

Effect of Dolutegravir on the Pharmacokinetics of Other Agents

In vitro, dolutegravir inhibited the renal organic cation transporters, OCT2 (IC50 = 1.93 µM) and multidrug and toxin extrusion transporter (MATE) 1 (IC50 = 6.34 µM). In vivo, dolutegravir inhibits tubular secretion of creatinine by inhibiting OCT2 and potentially MATE1. Dolutegravir may increase plasma concentrations of drugs eliminated via OCT2 or MATE1 (dofetilide and metformin). In vitro, dolutegravir inhibited the basolateral renal transporters, organic anion transporter (OAT) 1 (IC50 = 2.12 µM) and OAT3 (IC50 = 1.97 µM). However, in vivo, dolutegravir did not alter the plasma concentrations of tenofovir or para-amino hippurate, substrates of OAT1 and OAT3.

In vitro, dolutegravir did not inhibit (IC50 greater than 50 μM) the following: cytochrome P450 (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, uridine diphosphate (UDP)-glucuronosyl transferase 1A1 (UGT1A1), UGT2B7, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), bile salt export pump (BSEP), organic anion transporter polypeptide (OATP)1B1, OATP1B3, OCT1, multidrug resistance protein (MRP)2, or MRP4. In vitro, dolutegravir did not induce CYP1A2, CYP2B6, or CYP3A4. Based on these data and the results of drug interaction trials, dolutegravir is not expected to affect the pharmacokinetics of drugs that are substrates of these enzymes or transporters.

In drug interaction trials, dolutegravir did not have a clinically relevant effect on the pharmacokinetics of the following drugs: tenofovir, methadone, midazolam, rilpivirine, and oral contraceptives containing norgestimate and ethinyl estradiol. Using cross-study comparisons to historical pharmacokinetic data for each interacting drug, dolutegravir did not appear to affect the pharmacokinetics of the following drugs: atazanavir, darunavir, efavirenz, etravirine, fosamprenavir, lopinavir, ritonavir, boceprevir, and telaprevir.

Effect of Other Agents on the Pharmacokinetics of Dolutegravir

Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A. Dolutegravir is also a substrate of UGT1A3, UGT1A9, BCRP, and P-gp in vitro. Drugs that induce those enzymes and transporters may decrease dolutegravir plasma concentration and reduce the therapeutic effect of dolutegravir. Coadministration of dolutegravir and other drugs that inhibit these enzymes may increase dolutegravir plasma concentration.

Etravirine significantly reduced plasma concentrations of dolutegravir, but the effect of etravirine was mitigated by coadministration of lopinavir/ritonavir or darunavir/ritonavir, and is expected to be mitigated by atazanavir/ritonavir. Darunavir/ritonavir, lopinavir/ritonavir, rilpivirine, tenofovir, boceprevir, telaprevir, prednisone, rifabutin, and omeprazole had no clinically significant effect on the pharmacokinetics of dolutegravir.

Established and Other Potentially Significant Drug Interactions

Table 5 provides clinical recommendations as a result of drug interactions with TIVICAY. These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): There is no FDA guidance on usage of Dolutegravir in women who are pregnant.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dolutegravir in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Dolutegravir during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Dolutegravir in women who are nursing.

Pediatric Use

There is no FDA guidance on the use of Dolutegravir in pediatric settings.

Geriatic Use

There is no FDA guidance on the use of Dolutegravir in geriatric settings.

Gender

There is no FDA guidance on the use of Dolutegravir with respect to specific gender populations.

Race

There is no FDA guidance on the use of Dolutegravir with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Dolutegravir in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Dolutegravir in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Dolutegravir in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Dolutegravir in patients who are immunocompromised.

Administration and Monitoring

Administration

There is limited information regarding Dolutegravir Administration in the drug label.

Monitoring

There is limited information regarding Dolutegravir Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Dolutegravir and IV administrations.

Overdosage

There is limited information regarding Dolutegravir overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

There is limited information regarding Dolutegravir Pharmacology in the drug label.

Mechanism of Action

There is limited information regarding Dolutegravir Mechanism of Action in the drug label.

Structure

There is limited information regarding Dolutegravir Structure in the drug label.

Pharmacodynamics

There is limited information regarding Dolutegravir Pharmacodynamics in the drug label.

Pharmacokinetics

There is limited information regarding Dolutegravir Pharmacokinetics in the drug label.

Nonclinical Toxicology

There is limited information regarding Dolutegravir Nonclinical Toxicology in the drug label.

Clinical Studies

There is limited information regarding Dolutegravir Clinical Studies in the drug label.

How Supplied

There is limited information regarding Dolutegravir How Supplied in the drug label.

Storage

There is limited information regarding Dolutegravir Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Dolutegravir Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Dolutegravir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Dolutegravir Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Dolutegravir Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.