Flexibility to build a tailored treatment regimen with dolutegravir at the core

Not actual size

TIVICAY—the flexibility to build a regimen with dolutegravir at the core

  • Rapid and sustained efficacy1,6-12
  • High barrier to resistance1,6-12
  • Booster-free dosing1,6-12

Indication and Dosing

TIVICAY is indicated in combination with other antiretroviral medicinal products for the treatment of HIV-infected adults, adolescents and children aged 6 years and over, weighing at least 15kg.1*

 

Naive Patient infected with HIV-1 without documented or clinically suspected resistance to the integrase class. The recommended dose of dolutegravir is 50 mg (one tablet) orally once daily. Tivicay should be administered twice daily in this population when co-adminstered with some medicines (e.g. efavirenz, nevirapine, ritonavir or rifampicin)

 

Patients infected with HIV-1 with resistance to the integrase class The recommended dose of dolutegravir is 50 mg (one tablet) orally twice daily. In the presence of documented resistance that includes Q148 + ≥2 secondary mutations from G140A/C/S, E138A/K/T, L741, modelling suggests that an increased dose may be considered for patients with limited treatment options (less than 2 active agents) due to advanced multi class resistance.1

 

*Must be taken in combination with other antiretroviral agents.

 

TIVICAY is available in 3 tablet strengths (10 mg, 25 mg and 50 mg)

Dosed according to weight of the patients (6 years of age, weighing at least 15kg)*1

Once daily in patients without documented or clinically suspected resistance to the integrase class

 

Convenience beyond once-daily dosing

  • Convenient dosing: No food or time-of-day restrictions; no boosting; few significant DDIs; small tablet size. Small tablet size
  • Convenient dosing: No food or time-of-day restrictions; no boosting; few significant DDIs; small tablet size. Taken with or without food
  • Convenient dosing: No food or time-of-day restrictions; no boosting; few significant DDIs; small tablet size. No time-of-day restrictions
  • Convenient dosing: No food or time-of-day restrictions; no boosting; few significant DDIs; small tablet size. No boosting required
  • Convenient dosing: No food or time-of-day restrictions; no boosting; few significant DDIs; small tablet size. Few clinically significant DDIs1

For further information, please see the Summary of Product Characteristics - SPC

Drug-Drug Interactions 

TIVICAY has few clinically significant drug-drug interactions1-5

HIV-1 Antiviral Agents

NNRTI

Medical Products by therapeutic areas

Interaction Geometric mean change (%)

Recommendations concerning co-administration

Etravirine without boosted protease inhibitors

Dolutegravir ↓

AUC ↓ 71 %

Cmax ↓ 52 %

Cτ ↓ 88 %

Etravirine

(induction of UGT1A1 and CYP3A enzymes)

Etravirine without boosted protease inhibitors decreased plasma dolutegravir concentration. The recommended dose of dolutegravir is 50 mg twice daily when co-administered with etravirine without boosted protease inhibitors.

Dolutegravir should not be used with etravirine without co-administration of atazanavir/ritonavir, darunavir/ritonavir or lopinavir/ritonavir in INI-resistant patients.

Lopinavir/Ritonavir + Etravirine

Dolutegravir

AUC ↑ 11 %

Cmax ↑ 7 %

Cτ ↑ 28 %

LPV

RTV

No dose adjustment is necessary.

Darunavir/Ritonavir + Etravirine

Dolutegravir ↓

AUC ↓ 25 %

Cmax ↓ 12 %

Cτ ↓ 36 %

DRV

RTV

No dose adjustment is necessary.

Efavirenz

Dolutegravir ↓

AUC ↓ 57 %

Cmax ↓ 39 %

Cτ ↓ 75 %

Efavirenz (historical controls)

(induction of UGT1A1 and CYP3A enzymes)

The recommended dose of dolutegravir is 50 mg twice daily when co-administered with efavirenz.

In the presence of integrase class resistance alternative combinations that do not include efavirenz should be considered.

Nevirapine

Dolutegravir ↓

(Not studied, a similar reduction in exposure as observed with efavirenz is expected, due to induction).

The recommended adult dose of dolutegravir is 50 mg twice daily when co-administered with nevirapine.

In paediatric patients the weight-based once daily dose should be administered twice daily. In the presence of integrase class resistance alternative combinations that do not include nevirapine should be considered

Rilpivirine

Dolutegravir

AUC ↑ 12 %

Cmax ↑ 13 %

Cτ ↑ 22 %

Rilpivirin

No dose adjustment is necessary.

HIV-1 Antiviral Agents

NRTI

Medical Products by therapeutic areas

Interaction Geometric mean change (%)

Recommendations concerning co-administration

Tenofovir

Dolutegravir

AUC ↑ 1 %

Cmax ↓ 3 %

Cτ ↓ 8 %

Tenofovir

No dose adjustment is necessary.

HIV-1 Antiviral Agents

Protease Inhibitors

Medical Products by therapeutic areas

Interaction Geometric mean change (%)

Recommendations concerning co-administration

Atazanavir

Dolutegravir ↑

AUC ↑ 91 %

Cmax ↑ 50 %

Cτ ↑ 180 %

Atazanavir (historical controls)

(inhibition of UGT1A1 and CYP3A enzymes)

No dose adjustment is necessary.

Tivicay should not be dosed higher than 50 mg twice daily in combination with atazanavir due to lack of data

Atazanavir/Ritonavir

Dolutegravir ↑

AUC ↑ 62 %

Cmax ↑ 34 %

Cτ ↑ 121 %

Atazanavir

Ritonavir

(inhibition of UGT1A1 and CYP3A enzymes)

No dose adjustment is necessary.

Tivicay should not be dosed higher than 50 mg twice daily in combination with atazanavir due to lack of data

Tipranavir/Ritonavir (TPV+RTV)

Dolutegravir ↓

AUC ↓ 59 %

Cmax ↓ 47 %

Cτ ↓ 76 %

(induction of UGT1A1 and CYP3A enzymes)

The recommended dose of dolutegravir is 50 mg twice daily when co-administered with tipranavir/ritonavir the absence of integrase class resistance.

In the presence of integrase class resistance this combination should be avoided.

Fosamprenavir/Ritonavir (FPV+RTV)

Dolutegravir ↓

AUC ↓ 35 %

Cmax ↓ 24 %

Cτ ↓ 49 %

(induction of UGT1A1 and CYP3A enzymes)

No dose adjustment is necessary in the absence of integrase class resistance.

In the presence of integrase class resistance alternative combinations that do not include fosamprenavir/ritonavir should be considered.

Nelfinavir

Dolutegravir

(Not studied)

No dose adjustment is necessary.

Darunavir/Ritonavir

Dolutegravir ↓

AUC ↓ 22 %

Cmax ↓ 11 %

C24 ↓ 38 %

(induction of UGT1A1 and CYP3A enzymes)

No dose adjustment is necessary.

Lopinavir/Ritonavir

Dolutegravir

AUC ↓ 4 %

Cmax 0 %

C24 ↓ 6 %

No dose adjustment is necessary.

Other Antiviral agents

Medical Products by therapeutic areas

Interaction

Geometric mean change (%)

Recommendations concerning co-administration

Daclatasvir

Dolutegravir

AUC ↑ 33 %

Cmax ↑ 29 %

Cτ ↑ 45 %

Daclatasvir

Daclatasvir did not change dolutegravir plasma concentration to a clinically relevant extent.

Dolutegravir did not change daclatasvir plasma concentration.

No dose adjustment is necessary.

No clinically significant interaction expected.

Elbasvir / Grazoprevir

AUC ↑ 16%

Cmax ↑ 22%

Ctrough 14%

Coadministration of mutliple doses of elbasvir / grazoprevir and dolutegravir had no clinically significant effect on the pharmacokinetics of grazoprevir, elbasvir or dolutegravir.

No dose adjustments are required. (In 12 subjects).

No clinically significant interaction expected.

Ombitasvir / Paritaprevir/r + Dasabuvir

Dolutegravir ↑ 22-38%

Coadministration of ombitasvir / paritaprevir / ritonavir + dasabuvir and doutegravir had no clinically significant effect on the pharamcokinetics of ombitasvir, paritaprevoe, ritonavir, dasabuvir or dolutegravir.

No dose adjustment is required.

(In 12 HIV/HCV-negative subjects).

No clinically significant interaction expected.

Ribavirin

Coadministration has not been studied

Based on metabolism and clearance a clinically significant interaction is unlikely.

Simeprevir

Coadministration has not been studied

Based on metabolism and clearance a clinically significant interaction is unlikely.

Sofosbuvir

Coadministration has not been studied

Based on metabolism and clearance a clinically significant interaction is unlikely.

Medical Products by therapeutic areas

Interaction

Geometric mean change (%)

Recommendations concerning co-administration

Dofetilide

Dofetilide ↑

(Not studied, potential increase via inhibition of OCT2 transporter)

Dolutegravir and dofetilide co-administration is contraindicated due to potential life-threatening toxicity caused by high dofetilide concentrations.

Medical Products by therapeutic areas

Interaction

Geometric mean change (%)

Recommendations concerning co-administration

Carbamazepine

Dolutegravir ↓

AUC ↓ 49 %

Cmax ↓ 33 %

Cτ ↓ 73 %

The recommended adult dose of dolutegravir is 50 mg twice daily when co-administered with carbamazepine. In paediatric patients the weight-based once daily dose should be administered twice daily.

Alternatives to carbamazepine should be used where possible for INI resistant patients.

Oxcarbazepine

Phenytoin

Phenobarbital

Dolutegravir ↓

(Not studied, decrease expected due to induction of UGT1A1 and CYP3A enzymes, a similar reduction in exposure as observed with carbamazepine is expected)

The recommended adult dose of dolutegravir is 50 mg twice daily when co-administered with these metabolic inducers. In paediatric patients the weight-based once daily dose should be administered twice daily.

Alternative combinations that do not include these metabolic inducers should be used where possible in INI-resistant patients.

Medical Products by therapeutic areas

Interaction

Geometric mean change (%)

Recommendations concerning co-administration

Ketoconazole

Fluconazole

Itraconazole

Posaconazole

Voriconazole

Dolutegravir

(Not studied)

No dose adjustment is necessary. Based on data from other CYP3A4 inhibitors, a marked increase is not expected.

Medical Products by therapeutic areas

Interaction

Geometric mean change (%)

Recommendations concerning co-administration

St. John's wort

Dolutegravir ↓

(Not studied, decrease expected due to induction of UGT1A1 and CYP3A enzymes, a similar reduction in exposure as observed with carbamazepine is expected)

The recommended adult dose of dolutegravir is 50 mg twice daily when co-administered with St. John's wort. In paediatric patients the weight-based once daily dose should be administered twice daily.

Alternative combinations that do not include St. John's wort should be used where possible in INI-resistant patients.

Medical Products by therapeutic areas

Interaction

Geometric mean change (%)

Recommendations concerning co-administration

Magnesium/

aluminium-containing antacid

Dolutegravir ↓

AUC ↓ 74 %

Cmax ↓ 72 %

(Complex binding to polyvalent ions)

Magnesium/ aluminium-containing antacid should be taken well separated in time from the administration of dolutegravir (minimum 2 hours after or 6 hours before).

Calcium supplements

Dolutegravir ↓

AUC ↓ 39 %

Cmax ↓ 37 %

C24 ↓ 39 %

(Complex binding to polyvalent ions)

Calcium supplements, iron supplements or multivitamins should be taken well separated in time from the administration of dolutegravir (minimum 2 hours after or 6 hours before).

Iron supplements

Dolutegravir ↓

AUC ↓ 54 %

Cmax ↓ 57 %

C24 ↓ 56 %

(Complex binding to polyvalent ions)

Multivitamin

Dolutegravir ↓

AUC ↓ 33 %

Cmax ↓ 35 %

C24 ↓ 32 %

(Complex binding to polyvalent ions)

Medical Products by therapeutic areas

Interaction

Geometric mean change (%)

Recommendations concerning co-administration

Prednisone

Dolutegravir

AUC ↑ 11 %

Cmax ↑ 6 %

Cτ ↑ 17 %

No dose adjustment is necessary.

Medical Products by therapeutic areas

Interaction

Geometric mean change (%)

Recommendations concerning co-administration

Metformin

Metformin ↑

When co-administered with dolutegravir 50mg once daily:

Metformin

AUC ↑ 79 %

Cmax ↑ 66 %

When co-administered with dolutegravir 50mg twice daily:

Metformin

AUC ↑ 145 %

Cmax ↑ 111 %

A dose adjustment of metformin should be considered when starting and stopping coadministration of dolutegravir with metformin, to maintain glycaemic control.

In patients with moderate renal impairment a dose adjustment of metformin should be considered when coadministered with dolutegravir, because of the increased risk for lactic acidosis in patients with moderate renal impairment due to increased metformin concentration.

Medical Products by therapeutic areas

Interaction

Geometric mean change (%)

Recommendations concerning co-administration

Rifampicin

Dolutegravir ↓

AUC ↓ 54 %

Cmax ↓ 43 %

Cτ ↓ 72 %

(induction of UGT1A1 and CYP3A enzymes)

The recommended dose of dolutegravir is 50 mg twice daily when co-administered with rifampicin in the absence of integrase class resistance.

In the presence of integrase class resistance this combination should be avoided.

Rifabutin

Dolutegravir

AUC ↓ 5 %

Cmax ↑ 16 %

Cτ ↓ 30 %

(induction of UGT1A1 and CYP3A enzymes)

No dose adjustment is necessary.

Medical Products by therapeutic areas

Interaction

Geometric mean change (%)

Recommendations concerning co-administration

Ethinyl estradiol (EE) and Norelgestromin (NGMN)

Dolutegravir

EE

AUC ↑ 3 %

Cmax ↓ 1 %

NGMN

AUC ↓ 2 %

Cmax ↓ 11 %

Dolutegravir had no pharmacodynamic effect on Luteinizing Hormone (LH), Follicle Stimulating Hormone (FSH) and progesterone.

No dose adjustment of oral contraceptives is necessary when co-administered with dolutegravir.

Medical Products by therapeutic areas

Interaction

Geometric mean change (%)

Recommendations concerning co-administration

Methadone

Dolutegravir

Methadone

AUC ↓ 2 %

Cmax 0 %

Cτ ↓ 1 %

No dose adjustment is necessary of either agent.

For a more comprehensive list of interactions, please see the Liverpool Drug-Drug Interaction Tables.

 

 

For further information, please see the Summary of Product Characteristics - SPC

Safety and Tolerability

TIVICAY is generally well tolerated with few discontinuations1,6-12

Only 2% discontinuation rates due to adverse events across 3 large treatment-naïve studies at 48 weeks6,7,9 

Fewer treatment-related adverse events in SINGLE* and FLAMINGO and comparable rates in SPRING-213

In Single dolutegravir showed superiority vs. Atripla®  at Weeks 48, 96 and 144 in treatment-naïve adults (TRIUMEQ* QD vs Atripla®  QD (N=833))2,6,12
More details on SINGLE 

In FLAMINGO dolutegravir showed superiority vs. darunavir/r at Weeks 48 and 96 in treatment-naïve adults (DTG 50 mg + 2 NRTIs QD vs. DRV/r 800 mg/100 mg QD (N=484))5,6,9,10
More details on FLAMINGO 

In SPRING 2 dolutegravir showed comparable efficacy vs. raltegravir at weeks 48 and 96 in treatment-naïve adults (DTG 50mg QD + 2 NRTIs vs. RAL 400mg BD + 2 NRTIs (N=822))3,4,7,8
More details on SPRING 2 

 

*In studies supporting TRIUMEQ, DTG 50 mg + ABC 600 mg/3TC 300 mg were used.1

Bioequivalence has been demonstrated.1

In the UK, Atripla® is not licensed for initial use in treatment-naïve patients. Atripla® is a registered trademark of Bristol-Myers Squibb & Gilead Sciences, LLC

For further information, please see the Summary of Product Characteristics - SPC

References

  1. TIVICAY Summary of Product Characteristics, July 2017.
  2. Fantauzzi A, Turriziani O, Mezzaroma I. Potential benefit of dolutegravir once daily: efficacy and safety. HIV/AIDS (Auckl). 2013;5:29-40.
  3. Teixeira R, Nascimento Y, Crespo D. Safety aspects of protease inhibitors for chronic hepatitis C: adverse events and drug-to-drug interactions. Braz J Infect Dis. 2013;17(2):194-204.
  4. Patel P, Song I, Borland J, et al. Pharmacokinetics of the HIV integrase inhibitor S/GSK1349572 co-administered with acid-reducing agents and multivitamins in healthy volunteers. J Antimicrob Chemother. 2011;66(7):1567-1572.
  5. Zong, J, Borland J, Jerva F, et al. The effect of dolutegravir on the pharmacokinetics of metformin in healthy subjects. J Int AIDS Soc. 2014;17(Suppl 3):19584.
  6. Walmsley S, Antela A, Clumeck N, et al; for the SINGLE Investigators. Dolutegravir plus abacavir–lamivudine for the treatment of HIV-1 infection. N Engl J Med. 2013;369(19):1807-1818.
  7. Raffi F, Rachlis A, Stellbrink H-J, et al; on behalf of the SPRING-2 Study Group. Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study. Lancet. 2013;381(9868):735-743.
  8. Raffi F, Jaeger H, Quiros-Roldan E, et al; on behalf of the extended SPRING-2 Study Group. Once-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naïve adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomised, double-blind, non-inferiority trial. Lancet Infect Dis. 2013;13(11):927-935.
  9. Clotet B, Feinberg J, van Lunzen J, et al; on behalf of the ING114915 Study Team. Once-daily dolutegravir versus darunavir plus ritonavir in antiretroviral-naive adults with HIV-1 infection (FLAMINGO): 48 week results from the randomised open-label phase 3b study. Lancet. 2014;383(9936):2222-2231.
  10. Molina J-M, Clotet B, van Lunzen J, et al; on behalf of the FLAMINGO Study Team. Once-daily dolutegravir versus darunavir plus ritonavir for treatment-naive adults with HIV-1 infection (FLAMINGO): 96 week results from a randomised, open-label, phase 3b study. Lancet HIV. 2015;2(4):e127-e136.
  11. Cahn P, Pozniak AL, Mingrone H, et al; on behalf of the extended SAILING Study Team. Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study. Lancet. 2013;382(9893):700-708.
  12. Walmsley S, Baumgarten A, Berenguer J, et al. Dolutegravir plus abacavir/lamivudine for the treatment of HIV-1 infection in antiretroviral therapy-naive patients: week 96 and week 144 results from the SINGLE randomized clinical trial. J Acquir Immune Defic Syndr. 2015;70(5):515-519.
  13. Fantauzzi A, Turriziani O, Mezzaroma I. Potential benefit of dolutegravir once daily: efficacy and safety. HIV/AIDS (Auckl). 2013;5:29-40.
  14. Curtis L, Nichols G, Stainsby C, et al. dolutegravir: clinical and laboratory safety in integrase inhibitor–naive patients. HIV Clin Trials. 2014;15(5):199-208.
  15. Orrell C, Hagins D, Belonosova E, et al. Superior efficacy of dolutegravir/abacavir/lamivudine FDC compared with ritonavir-boosted atazanavir plus tenofovir disoproxil fumarate/emtricitabine FDC in treatment-naïve women with HIV-1 infection: ARIA Study. Presented at: Annual International AIDS Conference; July 18-22, 2016; Durban, South Africa. Abstract THAB0205LB

UK/DTGP/0023/16(2) |December 2017