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Tivicay

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Tivicay

SIDE EFFECTS

The following adverse drug reactions (adverse events assessed as causally related by the investigator or ADRs) are discussed in other sections of the labeling:

  • Hypersensitivity reactions [see WARNINGS AND PRECAUTIONS].
  • Effects on serum liver biochemistries in patients with hepatitis B or C co-infection [see WARNINGS AND PRECAUTIONS].
  • Fat Redistribution [see WARNINGS AND PRECAUTIONS].
  • Immune Reconstitution Syndrome [see WARNINGS AND PRECAUTIONS].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical Trials Experience In Adult Subjects

Treatment-Emergent Adverse Drug Reactions (ADRs)

Treatment-Na´ve Subjects: The safety assessment of TIVICAY in HIV-1-infected treatment-na´ve subjects is based on the analyses of 48-week data from 2 ongoing, international, multicenter, double-blind trials, SPRING-2 (ING113086) and SINGLE (ING114467).

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. 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. The rates of adverse events leading to discontinuation were 2% in subjects receiving TIVICAY 50 mg once daily + EPZICOM and 10% in subjects receiving ATRIPLA once daily.

Treatment-emergent ADRs of moderate to severe intensity observed in ≥ 2% of subjects in either treatment arm 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.

Table 2: Treatment-Emergent Adverse Drug Reactions of at Least Moderate Intensity (Grades 2 to 4) and ≥ 2% Frequency in Treatment-Na´ve Subjects in SPRING-2 and SINGLE Trials (Week 48 Analysis)

System Organ Class/ Preferred Term SPRING-2 SINGLE
TIVICAY 50 mg Once Daily +2 NRTIs
(N = 403)
Raltegravir 400 mg Twice Daily + 2 NRTIs
(N = 405)
TIVICAY 50 mg + EPZICOM Once Daily
(N = 414)
ATRIPLA Once Daily
(N = 419)
Psychiatric
Insomnia < 1% < 1% 3% 2%
Abnormal dreams < 1% < 1% < 1% 2%
Nervous System
Dizziness < 1% < 1% < 1% 5%
Headache < 1% < 1% 2% 2%
Gastrointestinal
Nausea 1% 1% < 1% 3%
Diarrhea < 1% < 1% < 1% 2%
Skin and Subcutaneous Tissue
Rasha 0 < 1% < 1% 6%
Ear and Labyrinth
Vertigo 0 < 1% 0 2%
aIncludes pooled terms: rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and drug eruption.

In addition, Grade 1 insomnia was reported by 1% and < 1% of subjects receiving TIVICAY and raltegravir, respectively, in SPRING-2; whereas in SINGLE the rates were 7% and 3% for TIVICAY and ATRIPLA, respectively. These events were not treatment limiting.

Treatment-Experienced, Integrase Strand Transfer Inhibitor-Na´ve 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 24 weeks, the rates of adverse events leading to discontinuation were 2% 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 ≥ 2% frequency in either treatment group was diarrhea, 1% (5/354) in subjects receiving TIVICAY 50 mg once daily + background regimen and 2% (6/361) 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 3% of subjects at Week 24.

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-Na´ve and Treatment-Experienced Trials

The following ADRs occurred in < 2% of treatment-na´ve 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, upper abdominal pain, vomiting.

General Disorders: Fatigue.

Hepatobiliary Disorders: Hepatitis.

Musculoskeletal Disorders: Myositis.

Renal and Urinary Disorders: Renal impairment.

Skin and Subcutaneous Tissue Disorders: Pruritus.

Laboratory Abnormalities

Treatment-Na´ve Subjects: Selected laboratory abnormalities (Grades 2 to 4) with a worsening grade from baseline and representing the worst-grade toxicity in ≥ 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.

Table 3: Selected Laboratory Abnormalities (Grades 2 to 4) in Treatment-Na´ve Subjects in SPRING-2 and SINGLE Trials (Week 48 Analysis)

Laboratory Parameter Preferred Term SPRING-2 SINGLE
TIVICAY 50 mg Once Daily +2 NRTIs
(N = 403)
Raltegravir 400 mg Twice Daily + 2NRTIs
(N = 405)
TIVICAY 50 mg +EPZICOM Once Daily
(N = 414)
ATRIPLA Once Daily
(N = 419)
ALT
  Grade 2 ( > 2.5-5.0 x ULN) 2% 3% 2% 5%
  Grade 3 to 4 ( > 5.0 x ULN) 2% 1% < 1% < 1%
AST
  Grade 2 ( > 2.5-5.0 x ULN) 3% 3% 2% 3%
  Grade 3 to 4 ( > 5.0 x ULN) 2% 2% 0 2%
Total Bilirubin
  Grade 2 (1.6-2.5 x ULN) 2% 2% < 1% 0
  Grade 3 to 4 ( > 2.5 x ULN) < 1% < 1% < 1% 0
Creatine kinase
  Grade 2 (6.0-9.9 x ULN) 1% 3% 3% 1%
  Grade 3 to 4 ( ≥ 10.0 x ULN) 4% 3% 3% 4%
Hyperglycemia
  Grade 2 (126-250 mg/dL) 5% 5% 7% 4%
  Grade 3 ( > 251 mg/dL) < 1% 1% 1% < 1%
Lipase
  Grade 2 ( > 15-3.0 x ULN) 5% 6% 8% 7%
  Grade 3 to 4 ( > 3.0 x ULN) 1% 3% 3% 2%
Total neutrophils
  Grade 2 (0.75-0.99 x 109) 3% 3% 2% 4%
  Grade 3 to 4 ( < 0.75 x 109) 2% 1% 2% 3%
ULN = Upper limit of normal.

Table 4: Mean Change From Baseline in Fasted Lipid Values in Treatment-Na´ve Subjects in SPRING-2 and SINGLE Trials (Week 48 Analysis)

Laboratory Parameter Preferred Term SPRING-2 SINGLE
TIVICAY 50 mg Once Daily + 2 NRTIs
(N = 403)
Raltegravir 400 mg Twice Daily + 2 NRTIs
(N = 405)
TIVICAY 50 mg + EPZICOM Once Daily
(N = 414)
ATRIPLA Once Daily
(N = 419)
Cholesterol (mg/dL) 6.7 8.3 17.1 24.0
HDL cholesterol (mg/dL) 2.8 2.6 5.2 7.9
LDL cholesterol (mg/dL) 2.7 2.8 8.5 13.1
Triglycerides (mg/dL) 7.7 9.8 17.7 18.6
aSubjects on lipid-lowering agents at baseline were excluded from these analyses (19 subjects in each arm in SPRING-2, and in SINGLE: TIVICAY n = 27 and ATRIPLA n = 26). Forty-nine subjects initiated a lipid-lowering agent post-baseline; their last fasted on-treatment values (prior to starting the agent) were used regardless if they discontinued the agent (SPRING-2: TIVICAY n = 5, raltegravir n = 8; SINGLE: TIVICAY n = 19 and ATRIPLA: n = 17).

Treatment-Experienced, Integrase Strand Transfer Inhibitor-Na´ve Subjects: Laboratory abnormalities observed in SAILING were generally similar compared with observations seen in the treatment-na´ve (SPRING-2 and SINGLE) trials.

Treatment-Experienced, Integrase Strand Transfer Inhibitor-Experienced Subjects: The most common treatment-emergent laboratory abnormalities ( > 5% for Grades 2 to 4 combined) were elevated ALT (8%), AST (6%), cholesterol (8%), hyperglycemia (12%), and lipase (8%). Two percent (3/183) of subjects had a Grade 3 to 4, treatment-emergent hematology laboratory abnormality, with neutropenia (1% [2/183]) being the most frequently reported.

Hepatitis B and/or Hepatitis C Virus Co-infection: In Phase 3 trials, subjects with hepatitis B and/or 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 C virus co-infection was similar to that observed in subjects without hepatitis B or C co-infection, although the rates of AST and ALT abnormalities were higher in the subgroup with hepatitis B and/or C virus co-infection for all treatment groups. Grades 2 to 4 ALT abnormalities in hepatitis B and/or C co-infected compared with HIV mono-infected subjects receiving TIVICAY were observed in 16% vs. 2% with the 50-mg once-daily dose and 8% vs. 7% 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 C at the start of therapy with TIVICAY, particularly in the setting where anti-hepatitis therapy was withdrawn [see WARNINGS AND PRECAUTIONS].

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 [see CLINICAL PHARMACOLOGY]. Increases in serum creatinine occurred within the first 4 weeks of treatment and remained stable through 24 to 48 weeks. In treatment-na´ve subjects, a mean change from baseline of 0.11 mg/dL (range: -0.60 mg/dL to 0.62 mg/dL) was observed after 48 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 multi-center, 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-na´ve subjects aged 12 to less than 18 years were enrolled [see Use in Specific Populations, Clinical Studies].

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.

Read the Tivicay (doutegravir 50mg tablets) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

Refer to Table 5 for established and other potentially significant drug-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, Table 5) [see CONTRAINDICATIONS].

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 paraaminohippurate, substrates of OAT1 and OAT3.

In vitro, dolutegravir did not inhibit (IC50 > 50 μM) the following: cytochrome P450 (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, 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, 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. (Table 5) [see DRUG INTERACTIONS, CLINICAL PHARMACOLOGY].

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. [See DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY]

Table 5: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interactions [see DOSAGE AND ADMINISTRATION]

Concomitant Drug Class: Drug Name Effect on Concentration of Dolutegravir and/or Concomitant Drug Clinical Comment
HIV-1 Antiviral Agents
Non-nucleoside reverse transcriptase inhibitor: Etravirinea ↓Dolutegravir TIVICAY should not be used with etravirine without coadministration of atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir.
Non-nucleoside reverse transcriptase inhibitor: Efavirenza ↓Dolutegravir A dose adjustment of TIVICAY to 50 mg twice daily is recommended in treatment-naive or treatment-experienced, INSTI-naive patients.
Alternative combinations that do not include metabolic inducers should be considered where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance.b
Non-nucleoside reverse transcriptase inhibitor: Nevirapine ↓Dolutegravir Coadministration with nevirapine should be avoided because there are insufficient data to make dosing recommendations.
Protease Inhibitor: Fosamprenavir/ritonavira Tipranavir/ritonavira ↓Dolutegravir A dose adjustment of TIVICAY to 50 mg twice daily is recommended in treatment-naive or treatment-experienced, INSTI-naive patients.
Alternative combinations that do not include metabolic inducers should be considered where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance.
Other Agents
Oxcarbazepine Phenytoin Phenobarbital Carbamazepine St. John’s wort (Hypericum perforatum) ↓Dolutegravir Coadministration with these metabolic inducers should be avoided because there are insufficient data to make dosing recommendations.
Medications containing polyvalent cations (e.g., Mg or Al) Cation-containing antacidsa or laxatives Sucralfate Buffered medications ↓Dolutegravir TIVICAY should be administered 2 hours before or 6 hours after taking medications containing polyvalent cations.
Oral calcium or iron supplements, including multivitamins containing calcium or irona ↓Dolutegravir TIVICAY should be administered 2 hours before or 6 hours after taking supplements containing calcium or iron. Alternatively, TIVICAY and supplements containing calcium or iron can be taken together with food.
Metformin ↑Metformin Metformin dose reductions may be considered when coadministered with TIVICAY.
Rifampina ↓Dolutegravir A dose adjustment of TIVICAY to 50 mg twice daily is recommended in treatment-naive or treatment-experienced, INSTI-naive patients.
Alternatives to rifampin should be used where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance.b
aSee CLINICAL PHARMACOLOGY Table 9 for magnitude of interaction.
bThe lower dolutegravir exposures observed in INSTI-experienced patients (with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance [see Microbiology]) upon coadministration with potent inducers may result in loss of therapeutic effect and development of resistance to TIVICAY or other coadministered antiretroviral agents.

Last reviewed on RxList: 6/2/2014
This monograph has been modified to include the generic and brand name in many instances.

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