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brand tivicay 50 mg tablet

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Uses

Treatment of HIV Infection

Dolutegravir sodium is used in conjunction with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral-naive (have not previously received antiretroviral therapy) or antiretroviral-experienced (previously treated) adults, adolescents, and children weighing at least 30 kg.

Dolutegravir usually is used in HIV integrase strand transfer inhibitor-based (INSTI-based) regimens that include dolutegravir and 2 HIV nucleoside reverse transcriptase inhibitors (dual NRTIs).

If an INSTI-based regimen of dolutegravir, abacavir, and lamivudine is used for the treatment of HIV-1 infection, a fixed-combination preparation containing all 3 drugs (abacavir/dolutegravir/lamivudine; Triumeq) is commercially available and can be used in adults 18 years of age or older to decrease pill burden and improve adherence. Abacavir/dolutegravir/lamivudine can be used alone as a complete treatment regimen or in conjunction with other antiretrovirals.

The manufacturer of dolutegravir states that use of the drug in HIV INSTI-experienced patients should be guided by the number and type of baseline INSTI-resistance substitutions. Efficacy of dolutegravir (50 mg twice daily) is reduced in patients who have HIV-1 with an INSTI-resistance Q148 substitution plus 2 or more additional INSTI-resistance substitutions (e.g., T66A, L74I/M, E138A/K/T, G140S/A/C, Y143R/C/H, E157Q, G163S/E/K/Q, G193E/R). The manufacturer of abacavir/dolutegravir/lamivudine states that the fixed combination should not be used alone in patients who have HIV-1 with clinically suspected or confirmed INSTI-resistance substitutions since it contains a dolutegravir dosage that is insufficient in such patients. In addition, abacavir/dolutegravir/lamivudine should not be used alone in patients with HIV-1 resistant to any of the 3 components of the fixed combination.

The most appropriate antiretroviral regimen cannot be defined for each clinical scenario, and selection of specific antiretroviral agents for use in multiple-drug regimens should be individualized based on information regarding antiretroviral potency, potential rate of development of resistance, known toxicities, and potential for pharmacokinetic interactions as well as virologic, immunologic, and clinical characteristics of the patient. For information on the general principles and guidelines for use of antiretroviral therapy, including specific recommendations for initial therapy in antiretroviral-naive patients and recommendations for changing antiretroviral regimens,

Antiretroviral-naive Adults and Adolescents

For initial treatment in HIV-infected adults and adolescents, the US Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents states that dolutegravir in conjunction with tenofovir alafenamide and emtricitabine or dolutegravir in conjunction with tenofovir disoproxil fumarate (tenofovir DF) and emtricitabine (or lamivudine) are recommended INSTI-based regimens. These experts also state that dolutegravir in conjunction with abacavir and lamivudine (or emtricitabine) is another recommended INSTI-based regimen for initial treatment in antiretroviral-naive adults and adolescents, but should be used only in patients who are negative for human leukocyte antigen (HLA)-B*5701.

Clinical Experience

Efficacy and safety of dolutegravir in antiretroviral-naive HIV-1-infected adults have been evaluated in phase 3 randomized studies (SPRING-2, SINGLE, FLAMINGO).

SPRING-2 is an ongoing phase 3, randomized, active-controlled, double-placebo, noninferiority study in antiretroviral-naive HIV-1-infected adults with baseline plasma HIV-1 RNA levels of 1000 copies/mL or higher. Patients were randomized to receive dolutegravir 50 mg once daily or raltegravir 400 mg twice daily in conjunction with an investigator-selected dual NRTI regimen of either the fixed-combination preparation containing emtricitabine and tenofovir DF (emtricitabine/tenofovir DF) or fixed-combination preparation containing abacavir and lamivudine (abacavir/lamivudine). Baseline characteristics of the 822 study patients were similar in both treatment groups (median age 36 years, 87% male, 15% non-white, 11% with hepatitis B virus [HBV] and/or hepatitis C virus [HCV] coinfection, 2% Centers for Disease Control and Prevention [CDC] Class C, median baseline plasma HIV-1 RNA level 4.52 or 4.58 log10 copies/mL, median baseline CD4 T-cell count 359 or 362 cells/mm). At 96 weeks, 82% of patients in the dolutegravir group and 78% of those in the raltegravir group had plasma HIV-1 RNA levels less than 50 copies/mL; the median increase in CD4 T-cell count was 276 cells/mm in the dolutegravir group and 264 cells/mm in the raltegravir group.

SINGLE is a 96-week randomized, double-blind, active-controlled study in antiretroviral-naive HIV-1-infected adults evaluating the efficacy and safety of dolutegravir 50 mg once daily in conjunction with abacavir/lamivudine compared with the fixed-combination preparation containing efavirenz, emtricitabine, and tenofovir DF (efavirenz/emtricitabine/tenofovir DF) followed by an open-label phase through week 144. Baseline characteristics of the 833 study patients were similar in both treatment groups (median age 35 years, 16% female, 32% non-white, 7% with HCV coinfection, 4% CDC Class C, median plasma HIV-1 RNA level 4.68 log10 copies/mL, median baseline CD4 T-cell count 338 cells/mm). At 144 weeks, 71% of patients receiving dolutegravir with abacavir/lamivudine and 63% of those receiving efavirenz/emtricitabine/tenofovir DF achieved plasma HIV-1 RNA levels less than 50 copies/mL. The adjusted mean increase in CD4 T-cell count was 378 cells/mm in those receiving dolutegravir and abacavir/lamivudine compared with 332 cells/mm in those receiving efavirenz/emtricitabine/tenofovir DF.

FLAMINGO is an open-label, randomized, noninferiority study in antiretroviral-naive HIV-1-infected adults that compared the efficacy and safety of dolutegravir 50 mg once daily with that of ritonavir-boosted darunavir when the drugs were given in conjunction with an investigator-selected dual NRTI regimen of abacavir/lamivudine or emtricitabine/tenofovir DF. At baseline, the 484 study patients had a median age of 34 years, 15% were female, 28% were non-white, 25% had plasma HIV-1 RNA levels greater than 100,000 copies/mL, and 35% had CD4 T-cell counts less than 350 cells/mm. At 96 weeks, 80% of patients in the dolutegravir group achieved plasma HIV-1 RNA levels less than 50 copies/mL compared with 68% in the ritonavir-boosted darunavir group.

Antiretroviral-experienced Adults

Clinical Experience

The comparative efficacy and safety of dolutegravir in 715 antiretroviral-experienced, INSTI-naive HIV-1-infected adults are being studied in an ongoing phase 3, randomized, double-blind, active-controlled, double-placebo study (SAILING). All enrolled patients had previously received antiretroviral therapy (average duration 77 months of prior therapy) and had infections resistant to at least 2 classes of antiretrovirals (49% had HIV-1 resistant to at least 3 classes of antiretrovirals). Patients were randomized to receive dolutegravir 50 mg once daily or raltegravir 400 mg twice daily, each in conjunction with an investigator-selected optimized background antiretroviral regimen (OBR) consisting of at least 1 fully active antiretroviral. Baseline characteristics were similar in both treatment groups (median age 43 years, 32% female, 50% non-white, 16% with HBV and/or HCV coinfection, 46% CDC Class C, 20% with plasma HIV-1 RNA levels greater than 100,000 copies/mL, 72% with CD4 T-cell counts less than 350 cells/mm). At 48 weeks, 71% of patients in the dolutegravir group and 64% of those in the raltegravir group had plasma HIV-1 RNA levels less than 50 copies/mL; CD4 T-cell counts were increased from baseline in both groups (mean change 162 cells/mm in the dolutegravir group and 153 cells/mm in the raltegravir group).

An open-label, single-arm, phase 3 study (VIKING-3) evaluated use of dolutegravir and an OBR in 183 antiretroviral-experienced adults with current or prior virologic failure on another INSTI-containing regimen (elvitegravir, raltegravir) and current or historical evidence of resistance to these other INSTIs. At baseline, most patients had HIV-1 resistant to other antiretroviral classes (79% with resistance to 2 or more NRTIs, 75% with resistance to at least 1 HIV nonnucleoside reverse transcriptase inhibitor [NNRTI], 71% with resistance to 2 or more HIV protease inhibitors [PIs]). At baseline, the median age of study patients was 48 years, 23% were female, 29% were non-white, 20% had HBV and/or HCV coinfection, median plasma HIV-1 RNA level was 4.38 log10 copies/mL, median CD4 T-cell count was 140 cells/mm, and median duration of prior antiretroviral therapy was 13-14 years. Patients received dolutegravir 50 mg twice daily with their current failing background regimen for 7 days; on day 8, dolutegravir was continued and the background regimen was further optimized if possible. The mean reduction in plasma HIV-1 RNA level on day 8 (primary efficacy end point) was 1.4 log10 copies/mL. At 48 weeks after initiation of dolutegravir, 63% of study patients had plasma HIV-1 RNA levels less than 50 copies/mL and the median increase in CD4 T-cell count was 80 cells/mm. The presence of INSTI-resistance substitutions at baseline affected the 48-week response rate. The response rate to the dolutegravir regimen was 74% in those who had HIV-1 without the Q148 resistance substitution present at baseline, but was 61% if the Q148H/R and G140S/A/C substitutions were present at baseline and 29% if the Q148H/R substitution plus 2 additional INSTI-resistance substitutions (T66A, L74I/M, E138A/K/T, G140S/A/C, Y143R/C/H, E157Q, G163S/E/K/Q, or G193E/R) were present at baseline.

In a randomized, double-blind, placebo-controlled, phase 3 study (VIKING-4), antiretroviral-experienced, dolutegravir-naive adults receiving a failing INSTI-based regimen that included elvitegravir or raltegravir were randomized to receive dolutegravir (50 mg twice daily) or placebo with their previous failing antiretroviral regimen for 7 days, followed by a single-arm, open-label regimen of dolutegravir (50 mg twice daily) in conjunction with an optimized antiretroviral regimen containing at least 1 fully active antiretroviral selected based on baseline resistance data. At baseline, all patients had plasma HIV-1 RNA levels of 1000 copies/mL or greater and HIV-1 with INSTI genotypic resistance; in addition, most patients had HIV-1 resistant to other antiretroviral classes (63% with resistance to 3 or more NRTIs, 53% with resistance to 2 or more NNRTIs, 67% with resistance to 2 or more PIs). The mean reduction in plasma HIV-1 RNA level on day 8 (primary efficacy end point) in those initially randomized to dolutegravir was 1.06 log10 copies/mL. At 48 weeks, 40% of all study patients had plasma HIV-1 RNA levels less than 50 copies/mL and the median increase in CD4 T-cell count was 125 cells/mm. The response rate at 48 weeks was 57% in those with HIV-1 without the Q148 resistance substitution present at baseline, but was only 25% if the Q148 substitution plus 1 or more additional INSTI-resistance substitutions were present at baseline.

Pediatric Patients

Dolutegravir is used in conjunction with other antiretrovirals for the treatment of HIV-1 infection in antiretroviral-naive or antiretroviral-experienced adolescents and children weighing 30 kg or more. Safety and efficacy of dolutegravir have not been established in antiretroviral-experienced, INSTI-experienced pediatric patients with documented or clinically suspected resistance to other INSTIs (e.g., elvitegravir, raltegravir).

For initial treatment of HIV-infected pediatric patients, the HHS Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children recommends a regimen that includes a ritonavir-boosted PI, NNRTI, or INSTI in conjunction with 2 NRTIs (dual NRTIs). These experts state that an INSTI-based regimen of dolutegravir and 2 NRTIs is a preferred regimen for initial antiretroviral therapy in pediatric patients 12 years of age or older weighing 40 kg or more.

Safety and efficacy of abacavir/dolutegravir/lamivudine (Triumeq) have not been established in pediatric patients.

For further information on treatment of HIV infection in pediatric patients,

Clinical Experience

The pharmacokinetic profile, safety, and efficacy of dolutegravir in HIV-1-infected pediatric patients have been evaluated in a phase 1/phase 2 open-label, noncomparative study (IMPAACT P1093). Patients were stratified by age into cohort 1 (12 to less than 18 years of age) and cohort 2A (6 to less than 12 years of age). Baseline characteristics of the 46 pediatric patients included mean age 12 years (range 6-17 years), 54% female, 52% black, mean plasma HIV-1 RNA level of 4.6 log10 copies/mL, median CD4 T-cell count of 639 cells/mm, and median CD4 T-cell percentage of 23% (range 1-44%); most had previously received at least 1 NNRTI (50%) or PI (70%). Patients weighing 30 to less than 40 kg received dolutegravir 35 mg once daily in conjunction with an OBR and patients weighing 40 kg or more received dolutegravir 50 mg once daily in conjunction with an OBR. At 24 weeks, 70% of patients in cohort 1 and 61% of patients in cohort 2A achieved plasma HIV-1 RNA levels less than 50 copies/mL. At 48 weeks, 61% of patients in cohort 1 achieved plasma HIV-1 RNA levels less than 50 copies/mL. At 48 weeks, the median increase in CD4 T-cell count in cohort 1 was 84 cells/mm; at 24 weeks, the median increase in CD4 T-cell count in cohort 2A was 209 cells/mm.

Postexposure Prophylaxis following Nonoccupational Exposure to HIV

Dolutegravir is used in conjunction with other antiretrovirals for postexposure prophylaxis of HIV infection following nonoccupational exposure (nPEP) in individuals exposed to blood, genital secretions, or other potentially infectious body fluids that might contain HIV when the exposure represents a substantial risk for HIV transmission.

When nPEP is indicated following a nonoccupational exposure to HIV, the US Centers for Disease Control and Prevention (CDC) states that the preferred regimen in adults and adolescents 13 years of age or older with normal renal function is either raltegravir or dolutegravir used in conjunction with emtricitabine and tenofovir DF (administered as emtricitabine/tenofovir DF; Truvada); the recommended alternative nPEP regimen in these patients is ritonavir-boosted darunavir used in conjunction with emtricitabine/tenofovir DF.

Consultation with an infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or the National Clinicians' Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) is recommended if nPEP is indicated in certain exposed individuals (e.g., pregnant women, children, those with medical conditions such as renal impairment) or if an antiretroviral regimen not included in the CDC guidelines is being considered, the source virus is known or likely to be resistant to antiretrovirals, or the healthcare provider is inexperienced in prescribing antiretrovirals. However, initiation of nPEP should not be delayed while waiting for expert consultation.

For additional information on nonoccupational exposure to HIV and recommendations regarding postexposure prophylaxis,

Dosage and Administration

Administration

Dolutegravir sodium is administered orally once or twice daily without regard to food.

Although administration with food increases the extent and decreases the rate of absorption of dolutegravir, this effect is not considered clinically important.

Dolutegravir should be administered at least 2 hours before or 6 hours after drugs and other preparations containing polyvalent cations (e.g., antacids or laxatives containing aluminum, calcium, or magnesium; oral iron supplements; oral calcium supplements; sucralfate; buffered preparations).(See Drug Interactions.)

Single-entity dolutegravir (Tivicay) is commercially available as film-coated tablets. Dolutegravir also is commercially available in fixed-combination, film-coated tablets containing abacavir, dolutegravir, and lamivudine (abacavir/dolutegravir/lamivudine; Triumeq).(See Fixed Combinations Containing Dolutegravir under Dosage and Administration: Administration.)

Dolutegravir is used in conjunction with other antiretrovirals. Single-entity dolutegravir should not be used concomitantly with abacavir/dolutegravir/lamivudine, unless needed for adjustment of dolutegravir dosage (e.g., when the fixed combination is used concomitantly with efavirenz, ritonavir-boosted fosamprenavir, ritonavir-boosted tipranavir, carbamazepine, or rifampin).

Fixed Combinations Containing Dolutegravir

Abacavir/dolutegravir/lamivudine film-coated tablets are administered orally once daily without regard to food.

Abacavir/dolutegravir/lamivudine should be administered at least 2 hours before or 6 hours after drugs and other preparations containing polyvalent cations (e.g., antacids or laxatives containing aluminum, calcium, or magnesium; oral iron supplements; oral calcium supplements; sucralfate; buffered preparations).(See Drug Interactions.)

Abacavir/dolutegravir/lamivudine can be used alone as a complete treatment regimen or used in conjunction with other antiretrovirals.

Abacavir/dolutegravir/lamivudine should not be used concomitantly with single-entity dolutegravir, unless needed for adjustment of dolutegravir dosage (e.g., when the fixed combination is used concomitantly with efavirenz, ritonavir-boosted fosamprenavir, ritonavir-boosted tipranavir, carbamazepine, or rifampin). When abacavir/dolutegravir/lamivudine and single-entity dolutegravir are both indicated, the daily dose of the fixed combination and the daily dose of the single-entity preparation should be administered 12 hours apart.

Because the antiretrovirals contained in abacavir/dolutegravir/lamivudine may also be available in single-entity or other fixed-combination preparations, care should be taken to ensure that therapy is not duplicated if the fixed combination is used in conjunction with other antiretrovirals.(See Precautions Related to Use of Fixed Combinations under Cautions: Precautions and Contraindications.)

Dosage

Single-entity dolutegravir (Tivicay) film-coated tablets contain dolutegravir sodium; dosage is expressed in terms of dolutegravir.

Abacavir/dolutegravir/lamivudine (Triumeq) film-coated tablets contain abacavir sulfate, dolutegravir sodium, and lamivudine; dosages of the abacavir and dolutegravir components are expressed in terms of the bases.

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

Adult Dosage

Treatment of HIV Infection in Antiretroviral-naive Adults

For initial treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral-naive adults, the recommended dosage of dolutegravir (Tivicay) is 50 mg once daily.

If dolutegravir is used in antiretroviral-naive adults receiving concomitant therapy with certain uridine diphosphate-glucuronosyltransferase (UGT) 1A or cytochrome P-450 (CYP) 3A inducers (i.e., efavirenz, ritonavir-boosted fosamprenavir, ritonavir-boosted tipranavir, carbamazepine, rifampin), the drug should be given in a dosage of 50 mg twice daily.(See Drug Interactions.)

When abacavir/dolutegravir/lamivudine (Triumeq) is used for the treatment of HIV-1 infection in antiretroviral-naive adults, the usual dosage is 1 tablet (600 mg of abacavir, 50 mg of dolutegravir, and 300 mg of lamivudine) once daily.

If abacavir/dolutegravir/lamivudine is used in antiretroviral-naive adults receiving concomitant therapy with efavirenz, ritonavir-boosted fosamprenavir, ritonavir-boosted tipranavir, carbamazepine, or rifampin, patients should receive 1 tablet of the fixed combination (600 mg of abacavir, 50 mg of dolutegravir, and 300 mg of lamivudine) once daily and a 50-mg tablet of single-entity dolutegravir given once daily 12 hours after the daily dose of the fixed combination.

Treatment of HIV Infection in Antiretroviral-experienced Adults

For treatment of HIV-1 infection in antiretroviral-experienced adults who have not previously received an HIV integrase strand transfer inhibitor (INSTI-naive), the recommended dosage of dolutegravir (Tivicay) is 50 mg once daily.

For treatment of HIV-1 infection in antiretroviral-experienced, INSTI-experienced adults who have certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance, the recommended dosage of dolutegravir is 50 mg twice daily.

If dolutegravir is used in antiretroviral-experienced adults receiving concomitant therapy with certain UGT1A or CYP3A inducers (i.e., efavirenz, ritonavir-boosted fosamprenavir, ritonavir-boosted tipranavir, carbamazepine, rifampin), the drug should be given in a dosage of 50 mg twice daily. Whenever possible, alternative regimens that do not contain these inducers should be considered when dolutegravir is used in INSTI-experienced patients who have certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance.(See Drug Interactions.)

When abacavir/dolutegravir/lamivudine (Triumeq) is used for the treatment of HIV-1 infection in antiretroviral-experienced adults, the usual dosage is 1 tablet (600 mg of abacavir, 50 mg of dolutegravir, and 300 mg of lamivudine) once daily. The fixed combination should not be used alone in patients who have HIV-1 with clinically suspected or confirmed INSTI-resistance substitutions.

If abacavir/dolutegravir/lamivudine is used in antiretroviral-experienced adults receiving efavirenz, ritonavir-boosted fosamprenavir, ritonavir-boosted tipranavir, carbamazepine, or rifampin, patients should receive 1 tablet of the fixed combination (600 mg of abacavir, 50 mg of dolutegravir, and 300 mg of lamivudine) once daily and a 50-mg tablet of single-entity dolutegravir given once daily 12 hours after the daily dose of the fixed combination.

Postexposure Prophylaxis following Nonoccupational Exposure to HIV

For postexposure prophylaxis of HIV infection following nonoccupational exposure (nPEP) when the exposure represents a substantial risk for HIV transmission, the usual adult dosage of dolutegravir is 50 mg once daily in conjunction with 2 HIV nucleoside reverse transcriptase inhibitors (NRTIs).(See Uses: Postexposure Prophylaxis following Nonoccupational Exposure to HIV.)

The nPEP regimen should be initiated as soon as possible (within 72 hours) following nonoccupational exposure to HIV and continued for 28 days. If the exposed individual seeks care more than 72 hours after the exposure, nPEP is not recommended.

Pediatric Dosage

Treatment of HIV Infection in Antiretroviral-naive Pediatric Patients

For initial treatment of HIV-1 infection in antiretroviral-naive children and adolescents weighing 30 to less than 40 kg, the recommended dosage of dolutegravir (Tivicay) is 35 mg once daily (one 25-mg tablet and one 10-mg tablet once daily).

If dolutegravir is used in antiretroviral-naive children and adolescents weighing 30 to less than 40 kg receiving concomitant therapy with certain UGT1A or CYP3A inducers (i.e., efavirenz, ritonavir-boosted fosamprenavir, ritonavir-boosted tipranavir, carbamazepine, rifampin), the drug should be given in a dosage of 35 mg twice daily (one 25-mg tablet and one 10-mg tablet twice daily).(See Drug Interactions.)

For initial treatment of HIV-1 infection in antiretroviral-naive children and adolescents weighing 40 kg or more, the recommended dosage of dolutegravir is 50 mg once daily.

If dolutegravir is used in antiretroviral-naive children and adolescents weighing 40 kg or more receiving concomitant therapy with certain UGT1A or CYP3A inducers (i.e., efavirenz, ritonavir-boosted fosamprenavir, ritonavir-boosted tipranavir, carbamazepine, rifampin), the drug should be given in a dosage of 50 mg twice daily.(See Drug Interactions.)

Treatment of HIV Infection in Antiretroviral-experienced Pediatric Patients

For treatment of HIV-1 infection in antiretroviral-experienced, INSTI-naive children and adolescents weighing 30 to less than 40 kg, the recommended dosage of dolutegravir (Tivicay) is 35 mg once daily (one 25-mg tablet and one 10-mg tablet once daily).

If dolutegravir is used in antiretroviral-experienced, INSTI-naive children and adolescents weighing 30 to less than 40 kg receiving concomitant therapy with certain UGT1A or CYP3A inducers (i.e., efavirenz, ritonavir-boosted fosamprenavir, ritonavir-boosted tipranavir, carbamazepine, rifampin), the drug should be given in a dosage of 35 mg twice daily (one 25-mg tablet and one 10-mg tablet twice daily).(See Drug Interactions.)

For treatment of HIV-1 infection in antiretroviral-experienced, INSTI-naive children and adolescents weighing 40 kg or more, the recommended dosage of dolutegravir is 50 mg once daily.

If dolutegravir is used in antiretroviral-experienced, INSTI-naive children and adolescents weighing 40 kg or more receiving concomitant therapy with certain UGT1A or CYP3A inducers (i.e., efavirenz, ritonavir-boosted fosamprenavir, ritonavir-boosted tipranavir, carbamazepine, rifampin), the drug should be given in a dosage of 50 mg twice daily.(See Drug Interactions.)

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

Safety and efficacy of abacavir/dolutegravir/lamivudine (Triumeq) have not been established in pediatric patients.

Special Populations

Hepatic Impairment

Dosage adjustment of dolutegravir (Tivicay) is not needed in patients with mild or moderate hepatic impairment (Child-Pugh class A or B). Dolutegravir should not be used in those with severe hepatic impairment (Child-Pugh class C).(See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Abacavir/dolutegravir/lamivudine (Triumeq) should not be used in patients with mild hepatic impairment (Child-Pugh class A) since reduction of abacavir dosage is needed in such patients. The fixed combination is contraindicated in those with moderate or severe hepatic impairment (Child-Pugh class B or C).(See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Renal Impairment

Dosage adjustment of dolutegravir (Tivicay) is not needed in antiretroviral-naive or antiretroviral-experienced, INSTI-naive patients with mild, moderate, or severe renal impairment.

In INSTI-experienced patients, dosage adjustment of dolutegravir is not needed in those with mild or moderate renal impairment. However, dolutegravir should be used with caution in patients with severe renal impairment who are INSTI-experienced and have certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance.(See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

The manufacturer makes no specific dosage recommendations regarding use of dolutegravir in patients requiring dialysis; it is unlikely that any type of renal replacement therapy would have a clinically important effect on the pharmacokinetics of dolutegravir.(See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Abacavir/dolutegravir/lamivudine (Triumeq) should not be used in patients with creatinine clearances less than 50 mL/minute since reduction in lamivudine dosage is needed in such patients.(See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Geriatric Patients

The manufacturer makes no specific dosage recommendations for dolutegravir in geriatric patients, but recommends caution because of possible age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.(See Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

Cautions

Contraindications

Dolutegravir (Tivicay) is contraindicated in patients with a previous hypersensitivity reaction to dolutegravir. The drug also is contraindicated in patients receiving dofetilide.(See Dofetilide under Drug Interactions: Antiarrhythmic Agents.)

The fixed combination containing abacavir, dolutegravir, and lamivudine (abacavir/dolutegravir/lamivudine; Triumeq) is contraindicated in patients who have the human leukocyte antigen (HLA)-B*5701 allele or have had a previous hypersensitivity reaction to abacavir (regardless of HLA-B*5701 status). Abacavir/dolutegravir/lamivudine also is contraindicated in patients with a previous hypersensitivity reaction to dolutegravir or lamivudine, patients receiving dofetilide (see Dofetilide under Drug Interactions: Antiarrhythmic Agents), and patients with moderate or severe hepatic impairment (see Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions). When abacavir/dolutegravir/lamivudine is used, the contraindications associated with each drug in the fixed combination should be considered.(See Precautions Related to Use of Fixed Combinations under Cautions: Warnings/Precautions.)

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions were reported in less than 1% of patients receiving dolutegravir in phase 3 clinical trials. Reactions were manifested by rash and constitutional findings and, occasionally, organ dysfunction including liver toxicity.

If signs or symptoms of hypersensitivity reactions occur, dolutegravir, abacavir/dolutegravir/lamivudine, and any other suspect agents should be discontinued immediately. These signs or symptoms include, but are 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. Clinical status, including liver aminotransferases, should be monitored and appropriate therapy initiated.

A life-threatening reaction could occur if there is a delay in discontinuing dolutegravir, abacavir/dolutegravir/lamivudine, and any other suspect agents after the onset of a hypersensitivity reaction.

Individuals with Hepatitis B Virus or Hepatitis C Virus Infection

Patients with human immunodeficiency virus (HIV) infection and with hepatitis B virus (HBV) or hepatitis C virus (HCV) coinfection may be at increased risk of development or worsening of serum aminotransferase elevations. In some patients receiving dolutegravir, serum aminotransferase elevations were consistent with immune reconstitution syndrome or HBV reactivation, particularly in the setting where HBV therapy had been discontinued.

In patients with underlying hepatic disease such as HBV or HCV infection, laboratory monitoring for hepatotoxicity should be performed prior to and routinely during dolutegravir or abacavir/dolutegravir/lamivudine treatment.(See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

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

Precautions Related to Use of Fixed Combinations

When abacavir/dolutegravir/lamivudine is used, the cautions, precautions, contraindications, and drug interactions associated with each drug in the fixed combination must be considered. Cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) should be considered for each drug. For cautionary information related to and , see Cautions in and in

Abacavir/dolutegravir/lamivudine should not be used concomitantly with single-entity dolutegravir, unless needed for adjustment of dolutegravir dosage (e.g., when the fixed combination is used concomitantly with certain uridine diphosphate-glucuronosyltransferase [UGT] 1A or cytochrome P-450 [CYP] 3A inducers).(See Dosage and Administration: Dosage.)

Abacavir/dolutegravir/lamivudine should not be used concomitantly with any preparation containing abacavir or lamivudine.

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

If abacavir/dolutegravir/lamivudine is used, clinicians should consider that abacavir has been associated with serious and sometimes fatal hypersensitivity reactions, including multiorgan failure and anaphylaxis. Individuals with the HLA-B*5701 allele are at higher risk for abacavir hypersensitivity reactions, although such reactions have occurred in those without the HLA-B*5701 allele. Abacavir/dolutegravir/lamivudine is contraindicated in patients who have the HLA-B*5701 allele and in patients who have had a previous hypersensitivity reaction to abacavir or abacavir-containing preparations. Prior to initiating abacavir/dolutegravir/lamivudine, the patient's medical history should be reviewed for prior exposure to any abacavir-containing preparation. All patients should be screened for the HLA-B*5701 allele prior to initiation or reinitiation of abacavir/dolutegravir/lamivudine, unless there is documentation of a previous HLA-B*5701 allele assessment. Abacavir/dolutegravir/lamivudine should be discontinued immediately if a hypersensitivity reaction is suspected, regardless of the patient's HLA-B*5701 status and even when other diagnoses are possible. Abacavir-containing preparations, including abacavir/dolutegravir/lamivudine, should never be restarted in a patient who experienced a hypersensitivity reaction since more severe reactions can occur within hours and may include life-threatening hypotension and death. If hypersensitivity is ruled out, the manufacturer of abacavir/dolutegravir/lamivudine states that the drug may be reinitiated, but only if medical care is readily accessible. There have been rare reports of life-threatening reactions within hours after reinitiation of abacavir-containing preparations in patients who discontinued abacavir for reasons other than hypersensitivity. Since it is not possible to determine whether a hypersensitivity reaction in patients receiving abacavir/dolutegravir/lamivudine is caused by abacavir or dolutegravir, abacavir-containing and dolutegravir-containing preparations should never be reinitiated in patients who stopped therapy with abacavir/dolutegravir/lamivudine because of a hypersensitivity reaction.

If abacavir/dolutegravir/lamivudine is used, clinicians should consider that lactic acidosis and severe hepatomegaly with steatosis, including fatalities, have been reported in patients receiving HIV nucleoside reverse transcriptase inhibitors (NRTIs) alone or in conjunction with other antiretrovirals. Abacavir/dolutegravir/lamivudine should be discontinued in patients with clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity, which may include hepatomegaly and steatosis even in the absence of marked increases in serum aminotransferase concentrations.

If abacavir/dolutegravir/lamivudine is used in HIV-infected patients coinfected with HBV, clinicians should consider that severe, acute exacerbations of HBV infection have been reported following discontinuance of lamivudine in patients coinfected with HIV and HBV. Hepatic function should be closely monitored with clinical and laboratory follow-up for at least several months after abacavir/dolutegravir/lamivudine is discontinued in HIV-infected patients coinfected with HBV and, if appropriate, initiation of HBV treatment may be warranted. Safety and efficacy of abacavir/dolutegravir/lamivudine have not been established for treatment of chronic HBV infection.

Adipogenic Effects

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

The mechanisms and long-term consequences of fat redistribution are unknown; a causal relationship has not been established.

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in HIV-infected patients receiving multiple-drug antiretroviral therapy, including dolutegravir. 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, M. tuberculosis, cytomegalovirus [CMV], Pneumocystis jirovecii [formerly P. carinii], varicella-zoster virus [VZV]); such responses may necessitate further evaluation and treatment.

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barre 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 antiretroviral therapy.

Specific Populations

Pregnancy

Antiretroviral Pregnancy Registry at 800-258-4263 or http://apregistry.com.

There are insufficient human data to assess the risk of birth defects and miscarriage if dolutegravir is used during pregnancy.

There are no adequate and well-controlled studies of abacavir/dolutegravir/lamivudine in pregnant women, and the manufacturer states that the fixed combination should be used during pregnancy only if potential benefits to the woman justify potential risks to the fetus.

The US Department of Health and Human Services (HHS) Panel on Treatment of HIV-infected Pregnant Women and Prevention of Perinatal Transmission states that, because only limited data are available regarding use of dolutegravir during pregnancy, the drug is not recommended for initial treatment in antiretroviral-naive pregnant women.

Dolutegravir crosses the placenta in animals; it is not known whether the drug crosses the placenta in humans.

Lactation

Dolutegravir is distributed into milk in rats. It is not known whether the drug is distributed into human milk, affects human milk production, or affects the breast-fed infant.

Because of the risk of adverse effects in the infant and the risk of HIV transmission, HIV-infected women should not breast-feed infants.

Pediatric Use

Safety and efficacy of dolutegravir (Tivicay) have not been established in pediatric patients weighing less than 30 kg. In addition, safety and efficacy of the drug have not been established in pediatric patients who previously received another HIV integrase strand inhibitor (INSTI-experienced) and have HIV-1 with documented or suspected resistance to other INSTIs (e.g., elvitegravir, raltegravir). The safety profile of dolutegravir in children and adolescents 6 to less than 18 years of age is similar to that in adults.

Safety and efficacy of abacavir/dolutegravir/lamivudine (Triumeq) have not been established in pediatric patients.

Geriatric Use

Experience in patients 65 years of age and older is insufficient to determine whether they respond differently to dolutegravir (Tivicay) or abacavir/dolutegravir/lamivudine (Triumeq) than younger adults.

Dolutegravir and abacavir/dolutegravir/lamivudine should be used 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

Dolutegravir (Tivicay) should not be used in patients with severe hepatic impairment (Child-Pugh class C); pharmacokinetics of the drug have not been evaluated in such patients.

Pharmacokinetics of dolutegravir in patients with moderate hepatic impairment are similar to those in healthy individuals, and dosage adjustments are not needed when the drug is used in those with mild or moderate hepatic insufficiency (Child-Pugh class A or B).

In phase 3 trials, the safety profile of dolutegravir in patients with HBV or HCV coinfection was similar to that in patients without HBV or HCV; however, rates of AST and ALT abnormalities were increased in this subset of patients.

Abacavir/dolutegravir/lamivudine (Triumeq) should not be used in adults with mild hepatic impairment (Child-Pugh class A). Because decreased abacavir dosage is recommended in patients with mild hepatic impairment, abacavir/dolutegravir/lamivudine should be switched to the single-entity components to allow adjustment of abacavir dosage in such patients. Abacavir/dolutegravir/lamivudine is contraindicated in adults with moderate or severe hepatic impairment (Child-Pugh class B or C).

Renal Impairment

Dolutegravir (Tivicay) should be used with caution in patients with severe renal impairment who are INSTI-experienced and have certain INSTI-associated resistance mutations or clinically suspected INSTI resistance. Plasma concentrations of dolutegravir are decreased in patients with severe renal impairment, which may result in loss of therapeutic effects and development of resistance to the drug or other antiretrovirals.

Mild or moderate renal impairment does not have a clinically important effect on the pharmacokinetics of dolutegravir. Therefore, dosage adjustments are not needed when dolutegravir is used in antiretroviral-naive or antiretroviral-experienced, INSTI-naive patients with mild, moderate, or severe renal impairment. Dosage adjustments also are not needed when the drug is used in INSTI-experienced patients with mild or moderate renal impairment.

Dolutegravir has not been evaluated in patients requiring dialysis. Although there are no specific dosage recommendations for use of dolutegravir in this subset of patients, it is unlikely that any type of renal replacement therapy would have a clinically important effect on the pharmacokinetics of dolutegravir since the drug is highly bound to plasma proteins.

Dolutegravir has been shown to increase serum creatinine concentrations; however, it does not cause a clinically important change in glomerular filtration rate or renal plasma flow. Dolutegravir inhibits tubular secretion of creatinine by inhibiting renal organic cation transporter (OCT) 2 and, possibly, multidrug and toxin extrusion transporter (MATE) 1.(See Drug Interactions.)

Abacavir/dolutegravir/lamivudine (Triumeq) should not be used in adults with creatinine clearances less than 50 mL/minute. Because lamivudine is substantially eliminated by the kidneys and decreased lamivudine dosage is recommended in patients with creatinine clearances less than 50 mL/minute, abacavir/dolutegravir/lamivudine should be switched to the single-entity components to allow adjustment of lamivudine dosage in such patients.

Common Adverse Effects

Adverse effects reported in 2% or more of patients receiving dolutegravir include insomnia, headache, fatigue, diarrhea, hyperglycemia, decreased neutrophil count, and increased serum concentrations of aminotransferases, total bilirubin, creatine kinase, lipase, and cholesterol.

Drug Interactions

The following drug interactions are based on studies using dolutegravir. Drug interaction studies have not been performed to date using the fixed combination containing abacavir, dolutegravir, and lamivudine (abacavir/dolutegravir/lamivudine). When abacavir/dolutegravir/lamivudine is used, interactions associated with each drug in the fixed combination should be considered.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Cytochrome P-450 (CYP) isoenzyme 3A plays a minor role in the metabolism of dolutegravir. Concomitant use with drugs that induce CYP3A may decrease dolutegravir plasma concentrations and decrease therapeutic effects of the drug. Concomitant use with drugs that inhibit CYP3A may increase dolutegravir plasma concentrations.

In vitro studies indicate that dolutegravir does not inhibit CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A. Dolutegravir does not induce CYP1A2, 2B6, or 3A4.

Drugs Affecting or Metabolized by Uridine Diphosphate-glucuronosyltransferases

Dolutegravir is metabolized by uridine diphosphate-glucuronosyltransferase (UGT) 1A1 and is a substrate for UGT1A3 and UGT1A9. Pharmacokinetic interactions are possible with inducers of these enzymes (decreased plasma concentrations of dolutegravir) or inhibitors of these enzymes (increased plasma concentrations of dolutegravir). Concomitant use with drugs that induce UGT1A1 may decrease dolutegravir plasma concentrations and decrease therapeutic effects of the drug.

Dolutegravir does not inhibit UGT1A1 or UGT2B7. Therefore, dolutegravir is not expected to affect the pharmacokinetics of drugs that are substrates for these enzymes.

Drugs Affecting or Affected by P-glycoprotein Transport

Dolutegravir is a substrate of the P-glycoprotein (P-gp) transport system. Pharmacokinetic interactions are possible with inducers of P-gp (decreased plasma concentrations of dolutegravir) or inhibitors of P-gp (increased plasma concentrations of dolutegravir).

Dolutegravir does not inhibit P-gp-mediated transport; pharmacokinetic interactions are unlikely with drugs that are P-gp substrates.

Drugs Affecting or Affected by Bile Salt Export Pump

In vitro, dolutegravir does not inhibit the bile salt export pump (BSEP). Dolutegravir is not expected to affect the pharmacokinetics of drugs that are substrates of BSEP.

Drugs Affecting or Affected by Breast Cancer Resistance Protein

Dolutegravir is a substrate of breast cancer resistance protein (BCRP). Pharmacokinetic interactions are possible with inducers of BCRP (decreased plasma concentrations of dolutegravir) or inhibitors of BCRP (increased plasma concentrations of dolutegravir).

In vitro, dolutegravir does not inhibit BCRP; pharmacokinetic interactions are unlikely with drugs that are substrates for BCRP.

Drugs Affecting or Affected by Multidrug and Toxin Extrusion Transporter

In vitro, dolutegravir inhibits multidrug and toxin extrusion transporter (MATE) 1. Therefore, dolutegravir may increase plasma concentrations of drugs eliminated by MATE1 (e.g., dofetilide, metformin).

Drugs Affecting or Affected by Multidrug Resistance Protein

In vitro, dolutegravir does not inhibit multidrug resistance protein (MRP) 2 or MRP4. Dolutegravir is not expected to affect the pharmacokinetics of drugs that are substrates for these transporters.

Drugs Affecting or Affected by Renal Organic Anion Transporters

In vitro, dolutegravir inhibits renal organic anion transporter (OAT) 1 and OAT3. In vivo, dolutegravir does not alter plasma concentrations of OAT1 or OAT3 substrates (e.g., tenofovir, aminohippurate).

In vitro, dolutegravir does not inhibit organic anion transporter polypeptide (OATP) 1B1 or OATP1B3. Dolutegravir is not expected to affect the pharmacokinetics of drugs that are substrates for these transporters. Dolutegravir is not a substrate of OATP1B1 or 1B3.

Drugs Affecting or Affected by Renal Organic Cation Transporters

In vitro, dolutegravir inhibits renal organic cation transporter (OCT) 2. Therefore, dolutegravir may increase plasma concentrations of drugs eliminated by OCT2 (e.g., dofetilide, metformin).

In vitro, dolutegravir does not inhibit OCT1. Dolutegravir is not expected to affect the pharmacokinetics of drugs that are substrates for this transporter.

Drugs that Increase Gastric pH

Antacids

Antacids containing aluminum, calcium, or magnesium decrease peak plasma concentrations and area under the plasma concentration-time curve (AUC) of dolutegravir.

Dolutegravir and abacavir/dolutegravir/lamivudine should be administered at least 2 hours before or 6 hours after antacids containing polyvalent cations (e.g., aluminum, calcium, magnesium).

Proton-pump Inhibitors

Omeprazole

Omeprazole does not have a clinically important effect on the pharmacokinetics of dolutegravir.

Dosage adjustments are not needed if dolutegravir is used concomitantly with a proton-pump inhibitor.

Sucralfate

Sucralfate may decrease plasma concentrations of dolutegravir.

Dolutegravir and abacavir/dolutegravir/lamivudine should be administered at least 2 hours before or 6 hours after sucralfate.

Antiarrhythmic Agents

Dofetilide

Concomitant use of dofetilide and dolutegravir or abacavir/dolutegravir/lamivudine may increase dofetilide plasma concentrations and increase the risk of serious and/or life-threatening adverse effects.

Concomitant use of dofetilide and dolutegravir or abacavir/dolutegravir/lamivudine is contraindicated.

Anticonvulsants

Carbamazepine

Concomitant use of carbamazepine (300 mg twice daily) and dolutegravir (50 mg once daily) decreases peak plasma concentrations and AUC of dolutegravir.

If carbamazepine is used concomitantly with dolutegravir in adults or pediatric patients weighing 40 kg or more who are antiretroviral-naive or antiretroviral-experienced but have not previously received an HIV integrase strand transfer inhibitor (INSTI-naive), dolutegravir should be given in a dosage of 50 mg twice daily. If carbamazepine is used concomitantly with dolutegravir in pediatric patients weighing 30 to less than 40 kg who are antiretroviral-naive or antiretroviral-experienced but INSTI-naive, dolutegravir should be given in a dosage of 35 mg twice daily.(See Dosage and Administration: Dosage.) An alternative anticonvulsant should be considered in patients receiving dolutegravir who are INSTI-experienced and have HIV-1 with documented or suspected INSTI resistance.

If abacavir/dolutegravir/lamivudine is used concomitantly with carbamazepine, adults should receive 1 tablet of the fixed combination (600 mg of abacavir, 50 mg of dolutegravir, and 300 mg of lamivudine) once daily and a 50-mg tablet of single-entity dolutegravir given once daily 12 hours after the daily dose of the fixed combination.

Oxcarbazepine, Phenobarbital, and Phenytoin

Oxcarbazepine, phenobarbital, and phenytoin induce metabolism of dolutegravir and cause decreased plasma concentrations of dolutegravir.

Concomitant use of oxcarbazepine, phenobarbital, or phenytoin and dolutegravir or abacavir/dolutegravir/lamivudine should be avoided since data are insufficient to make dosage recommendations. An alternative anticonvulsant should be considered.

Antidiabetic Agents

Metformin

Concomitant use of metformin hydrochloride (500 mg twice daily) and dolutegravir (50 mg twice daily) increases peak plasma concentrations and AUC of metformin.

If dolutegravir or abacavir/dolutegravir/lamivudine is initiated or discontinued in patients receiving metformin, blood glucose concentrations should be monitored; metformin hydrochloride dosage should not exceed 1 g daily during concomitant therapy. Some experts state that, if metformin is initiated in a patient receiving dolutegravir, a low metformin dosage should be used and dosage of the antidiabetic agent titrated to achieve glycemic control and minimize adverse GI effects.

Antimycobacterial Agents

Rifabutin

Rifabutin does not have a clinically important effect on the pharmacokinetics of dolutegravir. Dosage adjustments are not needed if the drugs are used concomitantly.

Rifampin

Concomitant use of rifampin and dolutegravir decreases plasma concentrations and AUC of dolutegravir.

If rifampin is used concurrently with dolutegravir in adults or pediatric patients weighing 40 kg or more who are antiretroviral-naive or antiretroviral-experienced but INSTI-naive, dolutegravir should be given in a dosage of 50 mg twice daily. If rifampin is used concurrently with dolutegravir in pediatric patients weighing 30 to less than 40 kg who are antiretroviral-naive or antiretroviral-experienced but INSTI-naive, dolutegravir should be given in a dosage of 35 mg twice daily. An alternative to rifampin (e.g., rifabutin) should be considered in patients receiving dolutegravir who are INSTI-experienced and have HIV-1 with documented or suspected INSTI resistance.

If abacavir/dolutegravir/lamivudine is used concurrently with rifampin, adults should receive 1 tablet of the fixed combination (600 mg of abacavir, 50 mg of dolutegravir, and 300 mg of lamivudine) once daily and a 50-mg tablet of single-entity dolutegravir given once daily 12 hours after the daily dose of the fixed combination.(See Dosage and Administration: Dosage.)

Rifapentine

Clinically important decreases in dolutegravir plasma concentrations are expected if the drug is used concomitantly with rifapentine. Some experts state that dolutegravir and rifapentine should not be used concomitantly.

Antiretroviral Agents

HIV Entry and Fusion Inhibitors

There is no in vitro evidence of antagonistic antiretroviral effects between dolutegravir and enfuvirtide or maraviroc.

HIV Integrase Inhibitors (INSTIs)

There is no in vitro evidence of antagonistic antiretroviral effects between dolutegravir and raltegravir.

HIV Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

There is no in vitro evidence of antagonistic antiretroviral effects between dolutegravir and efavirenz or nevirapine.

Efavirenz

Concomitant use of efavirenz and dolutegravir decreases plasma concentrations and AUC of dolutegravir, but does not appear to affect the pharmacokinetics of efavirenz.

If efavirenz is used concurrently with dolutegravir in adults or pediatric patients weighing 40 kg or more who are antiretroviral-naive or antiretroviral-experienced but INSTI-naive, dolutegravir should be given in a dosage of 50 mg twice daily. If efavirenz is used concurrently with dolutegravir in pediatric patients weighing 30 to less than 40 kg who are antiretroviral-naive or antiretroviral-experienced but INSTI-naive, dolutegravir should be given in a dosage of 35 mg twice daily. Whenever possible, an alternative to efavirenz that is not a metabolic inducer should be considered when dolutegravir is used in INSTI-experienced patients who have HIV-1 with documented or suspected INSTI resistance.

If abacavir/dolutegravir/lamivudine is used concurrently with efavirenz, adults should receive 1 tablet of the fixed combination (600 mg of abacavir, 50 mg of dolutegravir, and 300 mg of lamivudine) once daily and a 50-mg tablet of single-entity dolutegravir given once daily 12 hours after the daily dose of the fixed combination.(See Dosage and Administration: Dosage.)

Etravirine

Concomitant use of etravirine and dolutegravir results in substantially decreased plasma concentrations and AUC of dolutegravir, but does not appear to affect the pharmacokinetics of etravirine. The effect on dolutegravir pharmacokinetics is mitigated if ritonavir-boosted darunavir or the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) is used concomitantly with etravirine and dolutegravir and is expected to be mitigated if ritonavir-boosted atazanavir is used concomitantly with etravirine and dolutegravir.

Etravirine should not be used concomitantly with dolutegravir or abacavir/dolutegravir/lamivudine unless ritonavir-boosted atazanavir, ritonavir-boosted darunavir, or lopinavir/ritonavir is included in the regimen. However, concomitant use of etravirine and ritonavir-boosted atazanavir is not usually recommended.

If etravirine is used concomitantly with dolutegravir in patients who are antiretroviral-naive or antiretroviral-experienced without INSTI resistance, some experts state that dolutegravir should be given in a dosage of 50 mg once daily and ritonavir-boosted atazanavir, ritonavir-boosted darunavir, or lopinavir/ritonavir should also be included in the regimen.(See Dosage and Administration: Dosage.)

Nevirapine

Concomitant use of nevirapine and dolutegravir may decrease dolutegravir plasma concentrations.

Nevirapine should not be used concomitantly with dolutegravir or abacavir/dolutegravir/lamivudine; data are insufficient to make dosage recommendations.

Rilpivirine

Concomitant use of rilpivirine and dolutegravir does not have a clinically important effect on the pharmacokinetics of either drug.

Dosage adjustments are not needed if rilpivirine and dolutegravir are used concomitantly.

HIV Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

There is no in vitro evidence of antagonistic antiretroviral effects between dolutegravir and abacavir or stavudine.

Tenofovir

Concomitant use of tenofovir disoproxil fumarate (tenofovir DF) and dolutegravir does not have a clinically important effect on the pharmacokinetics of either drug.

Dosage adjustments are not needed if tenofovir DF and dolutegravir are used concomitantly.

HIV Protease Inhibitors (PIs)

There is no in vitro evidence of antagonistic antiretroviral effects between dolutegravir and amprenavir (active metabolite of fosamprenavir) or lopinavir.

Atazanavir

Concomitant use of dolutegravir and ritonavir-boosted or unboosted atazanavir results in increased dolutegravir plasma concentrations and AUC, but does not appear to affect the pharmacokinetics of atazanavir. Data are not available regarding concomitant use of dolutegravir and cobicistat-boosted atazanavir.

Some experts state that dosage adjustments are not necessary if dolutegravir is used concomitantly with ritonavir-boosted atazanavir, cobicistat-boosted atazanavir, or unboosted atazanavir.

Darunavir

Concomitant use of dolutegravir and ritonavir-boosted darunavir decreases peak plasma concentrations and AUC of dolutegravir, but does not appear to affect the pharmacokinetics of darunavir. Clinically important drug interactions are not expected if cobicistat-boosted darunavir is used concomitantly with dolutegravir.

Dosage adjustments are not necessary if dolutegravir is used concomitantly with ritonavir-boosted darunavir or cobicistat-boosted darunavir.

Fosamprenavir

Concomitant use of ritonavir-boosted fosamprenavir and dolutegravir decreases plasma concentrations and AUC of dolutegravir, but does not appear to affect the pharmacokinetics of fosamprenavir or ritonavir.

If ritonavir-boosted fosamprenavir is used concomitantly with dolutegravir in adults or pediatric patients weighing 40 kg or more who are antiretroviral-naive or antiretroviral-experienced but INSTI-naive, dolutegravir should be given in a dosage of 50 mg twice daily. If ritonavir-boosted fosamprenavir is used concomitantly with dolutegravir in pediatric patients weighing 30 to less than 40 kg who are antiretroviral-naive or antiretroviral-experienced but INSTI-naive, dolutegravir should be given in a dosage of 35 mg twice daily. Whenever possible, an alternative to ritonavir-boosted fosamprenavir that is not a metabolic inducer should be considered when dolutegravir is used in INSTI-experienced patients who have HIV-1 with documented or suspected INSTI resistance.

If abacavir/dolutegravir/lamivudine is used concomitantly with ritonavir-boosted fosamprenavir, adults should receive 1 tablet of the fixed combination (600 mg of abacavir, 50 mg of dolutegravir, and 300 mg of lamivudine) once daily and a 50-mg tablet of single-entity dolutegravir given once daily 12 hours after the daily dose of the fixed combination.(See Dosage and Administration: Dosage.)

Lopinavir

Concomitant use of lopinavir/ritonavir (lopinavir 400 mg/ritonavir 100 mg twice daily) and dolutegravir (30 mg once daily) does not have a clinically important effect on the pharmacokinetics of dolutegravir or lopinavir.

Dosage adjustments are not necessary if dolutegravir is used concomitantly with a once- or twice-daily regimen of lopinavir/ritonavir.

Saquinavir

Some experts state that dosage adjustments are not necessary if dolutegravir is used concomitantly with ritonavir-boosted saquinavir.

Tipranavir

Concomitant use of ritonavir-boosted tipranavir and dolutegravir decreases peak plasma concentrations and AUC of dolutegravir.

If ritonavir-boosted tipranavir is used concomitantly with dolutegravir in adults or pediatric patients weighing 40 kg or more who are antiretroviral-naive or antiretroviral-experienced but INSTI-naive, dolutegravir should be given in a dosage of 50 mg twice daily. If ritonavir-boosted tipranavir is used concomitantly with dolutegravir in pediatric patients weighing 30 to less than 40 kg who are antiretroviral-naive or antiretroviral-experienced but INSTI-naive, dolutegravir should be given in a dosage of 35 mg twice daily. Whenever possible, an alternative to ritonavir-boosted tipranavir that is not a metabolic inducer should be considered when dolutegravir is used in INSTI-experienced patients who have HIV-1 with documented or suspected INSTI resistance.

If abacavir/dolutegravir/lamivudine is used concomitantly with ritonavir-boosted tipranavir, adults should receive 1 tablet of the fixed combination (600 mg of abacavir, 50 mg of dolutegravir, and 300 mg of lamivudine) once daily and a 50-mg tablet of single-entity dolutegravir given once daily 12 hours after the daily dose of the fixed combination.(See Dosage and Administration: Dosage.)

Benzodiazepines

Midazolam

Dolutegravir does not have a clinically important effect on the pharmacokinetics of midazolam. Dosage adjustments are not needed if midazolam is used concomitantly with dolutegravir.

Calcium, Iron, Multivitamins, and Other Preparations Containing Polyvalent Cations

Oral calcium supplements, oral iron preparations, other oral supplements containing calcium or iron (e.g., multivitamins), and laxatives or other preparations containing polyvalent cations may decrease plasma concentrations of dolutegravir when used concomitantly in the fasted state.

Dolutegravir or abacavir/dolutegravir/lamivudine should be administered at least 2 hours before or 6 hours after oral supplements containing calcium or iron or preparations (e.g., laxatives, buffered preparations) containing polyvalent cations. Alternatively, if dolutegravir or abacavir/dolutegravir/lamivudine is administered with food, the drugs can be used concomitantly with oral supplements containing calcium or iron.

Corticosteroids

Prednisone

Prednisone does not have a clinically important effect on the pharmacokinetics of dolutegravir.

Estrogens and Progestins

Dolutegravir does not have a clinically important effect on the pharmacokinetics of oral contraceptives containing norgestimate and ethinyl estradiol. Dosage adjustments are not needed if oral contraceptives are used in patients receiving dolutegravir.

HCV Antivirals

HCV Polymerase Inhibitors

Sofosbuvir

Concomitant use of sofosbuvir and dolutegravir is not expected to have clinically important effects on dolutegravir or sofosbuvir pharmacokinetics.

Dosage adjustments are not needed if sofosbuvir and dolutegravir are used concomitantly.

Sofosbuvir and Velpatasvir

No clinically important pharmacokinetic interactions were observed when the fixed combination of sofosbuvir and velpatasvir (sofosbuvir/velpatasvir) was used concomitantly with dolutegravir.

HCV Protease Inhibitors

Simeprevir

No clinically important interactions are expected if simeprevir is used concomitantly with dolutegravir.

Some experts state that simeprevir and dolutegravir can be used concomitantly.

HCV Replication Complex Inhibitors

Daclatasvir

Concomitant use of daclatasvir and dolutegravir does not have a clinically important effect on the pharmacokinetics of either drug.

Elbasvir and Grazoprevir

Concomitant use of dolutegravir and the fixed combination of elbasvir and grazoprevir (elbasvir/grazoprevir) does not result in clinically important changes in the pharmacokinetics of elbasvir, grazoprevir, or dolutegravir.

Dosage adjustments are not needed if elbasvir/grazoprevir is used concomitantly with dolutegravir.

Ledipasvir and Sofosbuvir

Concomitant use of the fixed combination of ledipasvir and sofosbuvir (ledipasvir/sofosbuvir) and dolutegravir is not expected to result in clinically important pharmacokinetic interactions.

Some experts state that ledipasvir/sofosbuvir and dolutegravir can be used concomitantly.

Nucleoside and Nucleotide Antivirals

There is no in vitro evidence of antagonistic antiviral effects between dolutegravir and adefovir or ribavirin.

Opiates and Opiate Partial Agonists

Methadone

Dolutegravir does not have a clinically important effect on the pharmacokinetics of methadone. Dosage adjustments are not needed if methadone and dolutegravir are used concomitantly.

St. John's Wort

St. John's wort (Hypericum perforatum) induces metabolism of dolutegravir and causes decreased plasma concentrations of dolutegravir. Concomitant use of St. John's wort with dolutegravir or abacavir/dolutegravir/lamivudine should be avoided.

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