Wirkstoffe & Arzneimittelsicherheit

Wechselwirkungen · Tivicay

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HOS-129190 · Präparat HOS-096689

Dolutegravir is eliminated mainly through metabolism by UGT1A1. Dolutegravir is also a substrate of UGT1A3, UGT1A9, CYP3A4, Pgp, and BCRP; therefore, medicinal products that induce those enzymes may decrease dolutegravir plasma concentration and reduce the therapeutic effect of dolutegravir (see Table 3). Co-administration of dolutegravir and other medicinal products that inhibit these enzymes may increase dolutegravir plasma concentration (see Table 3).

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Wechselwirkungen · Tivicay

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HOS-129191 · Präparat HOS-096689

The absorption of dolutegravir is reduced by certain anti-acid agents (see Table 3).

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Wechselwirkungen · Tivicay

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HOS-129192 · Präparat HOS-096689

Effect of dolutegravir on the pharmacokinetics of other agents

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Wechselwirkungen · Tivicay

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HOS-129193 · Präparat HOS-096689

In vivo, dolutegravir did not have an effect on midazolam, a CYP3A4 probe. Based on in vivo and/or in vitro data, dolutegravir is not expected to affect the pharmacokinetics of medicinal products that are substrates of any major enzyme or transporter such as CYP3A4, CYP2C9 and P-gp (for more information see section 5.2).

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RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): midazolam (HOS-086167)

Wechselwirkungen · Tivicay

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HOS-129194 · Präparat HOS-096689

In vitro, dolutegravir inhibited the renal organic cation transporter 2 (OCT2) and multidrug and toxin extrusion transporter (MATE) 1. In vivo, a 10-14% decrease of creatinine clearance (secretory fraction is dependent on OCT2 and MATE-1 transport) was observed in patients. In vivo, dolutegravir may increase plasma concentrations of medicinal products in which excretion is dependent upon OCT2 and/or MATE-1 (e.g. fampridine [also known as dalfampridine], metformin) (see Table 3).

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RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): creatinine (HOS-086273) dalfampridine (HOS-124191) metformin (HOS-091032)

Wechselwirkungen · Tivicay

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HOS-129195 · Präparat HOS-096689

36 In vitro, dolutegravir inhibited the renal uptake transporters, organic anion transporters (OAT1) and OAT3. Based on the lack of effect on the in vivo pharmacokinetics of the OAT substrate tenofovir, in vivo inhibition of OAT1 is unlikely. Inhibition of OAT3 has not been studied in vivo. Dolutegravir may increase plasma concentrations of medicinal products in which excretion is dependent upon OAT3.

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RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): tenofovir (HOS-088083)

Wechselwirkungen · Tivicay

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HOS-129196 · Präparat HOS-096689

Established and theoretical interactions with selected antiretrovirals and non-antiretroviral medicinal products are listed in Table 3.

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Wechselwirkungen · Tivicay

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HOS-129197 · Präparat HOS-096689

Interaction table Interactions between dolutegravir and co-administered medicinal products are listed in Table 3 (increase is indicated as “↑”, decrease as “↓”, no change as “↔”, area under the concentration versus time curve as “AUC”, maximum observed concentration as “Cmax”, concentration at end of dosing interval as “Cτ”).

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Wechselwirkungen · Tivicay

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HOS-129198 · Präparat HOS-096689

Table 3: Drug Interactions Medicinal products Interaction Recommendations concerning by therapeutic areas Geometric mean change co-administration (%) HIV-1 Antiviral Agents Non-nucleoside Reverse Transcriptase Inhibitors Etravirine without Dolutegravir  Etravirine without boosted protease inhibitors boosted protease AUC  71% decreased plasma dolutegravir concentration. The inhibitors Cmax  52% recommended adult dose of dolutegravir should be Cτ  88% given twice daily when co-administered with etravirine without boosted protease inhibitors. In Etravirine  paediatric patients the weight-based once daily (induction of UGT1A1 and dose should be administered twice daily. CYP3A enzymes) Dolutegravir should not be used with etravirine without co-administration of atazanavir/ritonavir, darunavir/ritonavir or lopinavir/ritonavir in INI- resistant patients (see further below in table). Lopinavir/ritonavir + Dolutegravir  No dose adjustment is necessary. etravirine AUC  11% Cmax  7% Cτ  28% LPV  RTV  Darunavir/ritonavir + Dolutegravir  No dose adjustment is necessary. etravirine AUC  25% Cmax  12% Cτ  36% DRV  RTV  Efavirenz Dolutegravir  The recommended adult dose of dolutegravir AUC  57% should be given twice daily when co-administered Cmax  39% with efavirenz. In paediatric patients the weight- Cτ  75% based once daily dose should be administered twice daily. Efavirenz  (historical In the presence of integrase class resistance controls) alternative combinations that do not include (induction of UGT1A1 and efavirenz should be considered (see section 4.4). CYP3A enzymes) Nevirapine Dolutegravir  The recommended adult dose of dolutegravir (Not studied, a similar should be given twice daily when co-administered reduction in exposure as with nevirapine. In paediatric patients the weight-

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): lopinavir (HOS-086269) atazanavir (HOS-086180) protease (HOS-085623) etravirine (HOS-088088) darunavir (HOS-086181) efavirenz (HOS-087947) nevirapine (HOS-088064) ritonavir (HOS-084521)

Wechselwirkungen · Tivicay

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HOS-129199 · Präparat HOS-096689

37  observed with efavirenz is based once daily dose should be administered expected, due to induction) twice daily. In the presence of integrase class resistance alternative combinations that do not include nevirapine should be considered (see section 4.4). Rilpivirine Dolutegravir  No dose adjustment is necessary. AUC  12% Cmax  13% Cτ  22% Rilpivirine  Nucleoside Reverse Transcriptase Inhibitors Tenofovir Dolutegravir  No dose adjustment is necessary. AUC  1% Cmax  3% Cτ  8% Tenofovir  Protease Inhibitors Atazanavir Dolutegravir  No dose adjustment is necessary. AUC  91% Cmax  50% Tivicay should not be dosed higher than 30 mg Cτ  180% twice daily in combination with atazanavir (see section 5.2) due to lack of data. Atazanavir  (historical controls) (inhibition of UGT1A1 and CYP3A enzymes) Atazanavir/ritonavir Dolutegravir  No dose adjustment is necessary. AUC  62% Cmax  34% Tivicay should not be dosed higher than 30 mg Cτ  121% twice daily in combination with atazanavir (see section 5.2) due to lack of data. Atazanavir  Ritonavir  (inhibition of UGT1A1 and CYP3A enzymes) Tipranavir/ritonavir Dolutegravir  The recommended adult dose of dolutegravir (TPV+RTV) AUC  59% should be given twice daily when co-administered Cmax  47% with tipranavir/ritonavir. In paediatric patients the Cτ  76% weight-based once daily dose should be (induction of UGT1A1 and administered twice daily. CYP3A enzymes) In the presence of integrase class resistance this combination should be avoided (see section 4.4). Fosamprenavir/ Dolutegravir  No dose adjustment is necessary in the absence of ritonavir (FPV+RTV) AUC  35% integrase class resistance. Cmax  24% In the presence of integrase class resistance Cτ  49% alternative combinations that do not include (induction of UGT1A1 and fosamprenavir/ritonavir should be considered. CYP3A enzymes) Darunavir/ritonavir Dolutegravir  No dose adjustment is necessary. AUC  22% Cmax  11% C24  38% (induction of UGT1A1 and CYP3A enzymes)

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): tenofovir (HOS-088083) atazanavir (HOS-086180) protease (HOS-085623) rilpivirine (HOS-088090) darunavir (HOS-086181) efavirenz (HOS-087947) nevirapine (HOS-088064) fosamprenavir (HOS-086182) ritonavir (HOS-084521) tipranavir (HOS-086184)

Wechselwirkungen · Tivicay

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HOS-129200 · Präparat HOS-096689

38 Lopinavir/ritonavir Dolutegravir  No dose adjustment is necessary. AUC  4% Cmax  0% C24  6% Other Antiviral agents Daclatasvir Dolutegravir  Daclatasvir did not change dolutegravir plasma AUC  33% concentration to a clinically relevant extent. Cmax  29% Dolutegravir did not change daclatasvir plasma C  45% concentration. No dose adjustment is necessary. Daclatasvir  Other agents Potassium channel blocker Fampridine (also Fampridine  Co-administration of dolutegravir has the potential known as to cause seizures due to increased fampridine dalfampridine) plasma concentration via inhibition of OCT2 transporter; co-administration has not been studied. Fampridine co-administration with dolutegravir is contraindicated. Anticonvulsants Carbamazepine Dolutegravir  The recommended adult dose of dolutegravir AUC  49% should be given twice daily when co-administered Cmax  33% with carbamazepine. In paediatric patients the C  73% weight-based once daily dose should be administered twice daily. Alternatives to carbamazepine should be used where possible for INI resistant patients. Oxcarbazepine Dolutegravir  The recommended adult dose of dolutegravir Phenytoin (Not studied, decrease should be given twice daily when co-administered Phenobarbital expected due to induction of with these metabolic inducers. In paediatric UGT1A1 and CYP3A patients the weight-based once daily dose should enzymes, a similar reduction be administered twice daily. Alternative in exposure as observed combinations that do not include these metabolic with carbamazepine is inducers should be used where possible in INI- expected) resistant patients. Azole anti-fungal agents Ketoconazole Dolutegravir  No dose adjustment is necessary. Based on data Fluconazole (Not studied) from other CYP3A4 inhibitors, a marked increase Itraconazole is not expected. Posaconazole Voriconazole Herbal products St. John’s wort Dolutegravir  The recommended adult dose of dolutegravir (Not studied, decrease should be given twice daily when co-administered expected due to induction of with St. John’s wort. In paediatric patients the UGT1A1 and CYP3A weight-based once daily dose should be enzymes, a similar reduction administered twice daily. Alternative combinations in exposure as observed that do not include St. John’s wort should be used with carbamazepine is where possible in INI-resistant patients. expected) Antacids and supplements Magnesium/ Dolutegravir  Magnesium/ aluminium-containing antacid should aluminium-containing AUC  74% be taken well separated in time from the antacid Cmax  72% administration of dolutegravir (minimum 2 hours (Complex binding to after or 6 hours before). polyvalent ions)

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): lopinavir (HOS-086269) daclatasvir (HOS-119742) phenobarbital (HOS-085617) ketoconazole (HOS-084513) carbamazepine (HOS-085618) voriconazole (HOS-084524) itraconazole (HOS-084516) dalfampridine (HOS-124191) fluconazole (HOS-087945) oxcarbazepine (HOS-110224) ritonavir (HOS-084521) potassium (HOS-086929) magnesium (HOS-085165) phenytoin (HOS-084531) posaconazole (HOS-085622)

Wechselwirkungen · Tivicay

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HOS-129201 · Präparat HOS-096689

39 Calcium supplements Dolutegravir  - When taken with food, Tivicay and supplements (fasted intake) AUC  39% or multivitamins containing calcium, iron or Cmax  37% magnesium can be taken at the same time. C24  39% - If Tivicay is taken in a fasted state, such (Complex binding to supplements should be taken a minimum 2 hours polyvalent ions) after or 6 hours before the intake of Tivicay. Iron supplements Dolutegravir  (fasted intake) AUC  54% The stated reductions in dolutegravir exposure Cmax  57% were observed with the intake of dolutegravir and C24  56% these supplements during fasted conditions. In fed (Complex binding to state, the changes in exposure following intake polyvalent ions) together with calcium or iron supplements were Multivitamin Dolutegravir  modified by the food effect, resulting in an (containing calcium, AUC  33% exposure similar to that obtained with dolutegravir iron and magnesium) Cmax  35% administered in the fasted state. (fasted intake) C24  32% (Complex binding to polyvalent ions) Corticosteroids Prednisone Dolutegravir  No dose adjustment is necessary. AUC  11% Cmax  6% Cτ  17% Antidiabetics Metformin Metformin  A dose adjustment of metformin should be When co-administered with considered when starting and stopping dolutegravir 50mg film- coadministration of dolutegravir with metformin, coated tablets once daily: to maintain glycaemic control. In patients with Metformin moderate renal impairment a dose adjustment of AUC  79% metformin should be considered when Cmax  66% coadministered with dolutegravir, because of the When co-administered with increased risk for lactic acidosis in patients with dolutegravir 50mg film- moderate renal impairment due to increased coated tablets twice daily: metformin concentration (section 4.4). Metformin AUC  145 % Cmax  111% Antimycobacterials Rifampicin Dolutegravir  The recommended adult dose of dolutegravir AUC  54% should be given twice daily when co-administered Cmax  43% with rifampicin in the absence of integrase class Cτ 72% resistance. In paediatric patients the weight-based (induction of UGT1A1 and once daily dose should be administered twice CYP3A enzymes) daily. In the presence of integrase class resistance this combination should be avoided (see section 4.4). Rifabutin Dolutegravir  No dose adjustment is necessary. AUC  5% Cmax  16% Cτ  30% (induction of UGT1A1 and CYP3A enzymes) Oral contraceptives

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): rifabutin (HOS-086262) calcium (HOS-085615) iron (HOS-085656) magnesium (HOS-085165) prednisone (HOS-084526) metformin (HOS-091032)

Wechselwirkungen · Tivicay

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HOS-129202 · Präparat HOS-096689

40  Ethinyl estradiol (EE) Dolutegravir  Dolutegravir had no pharmacodynamic effect on and Norelgestromin EE  Luteinizing Hormone (LH), Follicle Stimulating (NGMN) AUC  3% Hormone (FSH) and progesterone. No dose Cmax  1% adjustment of oral contraceptives is necessary when co-administered with dolutegravir. NGMN  AUC  2% Cmax  11% Analgesics Methadone Dolutegravir  No dose adjustment is necessary of either agent. Methadone  AUC  2% Cmax  0% C  1%

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RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): progesterone (HOS-090753) methadone (HOS-086198) norelgestromin (HOS-110295) ethinyl estradiol (HOS-088135) luteinizing hormone (HOS-090752)

Wechselwirkungen · Tivicay

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HOS-129203 · Präparat HOS-096689

Paediatric population

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Wechselwirkungen · Tivicay

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HOS-129204 · Präparat HOS-096689

Interaction studies have only been performed in adults.

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Nebenwirkungen · Tivicay

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HOS-129173 · Präparat HOS-096689

Summary of the safety profile

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Nebenwirkungen · Tivicay

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HOS-129174 · Präparat HOS-096689

The most severe adverse reaction, seen in an individual patient, was a hypersensitivity reaction that included rash and severe liver effects (see section 4.4). The most commonly seen treatment emergent adverse reactions were nausea (13%), diarrhoea (18%) and headache (13%).

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Nebenwirkungen · Tivicay

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HOS-129175 · Präparat HOS-096689

Tabulated list of adverse reactions

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Nebenwirkungen · Tivicay

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HOS-129176 · Präparat HOS-096689

The adverse reactions considered at least possibly related to dolutegravir are listed by body system, organ class and absolute frequency. Frequencies are defined as very common (1/10), common (1/100 to <1/10), uncommon (1/1,000 to <1/100), rare (1/10,000 to <1/1,000), very rare (<1/10,000), and not known (cannot be estimated from the available data).

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Nebenwirkungen · Tivicay

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HOS-129177 · Präparat HOS-096689

12 Table 4 Adverse Reactions Blood and lymphatic Not known Sideroblastic anaemia1 system disorders Immune system Uncommon Hypersensitivity (see section 4.4) disorders Uncommon Immune Reconstitution Syndrome (see section 4.4)2 Psychiatric disorders Common Insomnia Common Abnormal dreams Common Depression Common Anxiety Uncommon Panic attack Uncommon Suicidal ideation*, suicide attempt* *particularly in patients with a pre-existing history of depression or psychiatric illness. Rare Completed suicide* *particularly in patients with a pre-existing history of depression or psychiatric illness. Nervous system Very common Headache disorders Common Dizziness Gastrointestinal Very common Nausea disorders Very common Diarrhoea Common Vomiting Common Flatulence Common Upper abdominal pain Common Abdominal pain Common Abdominal discomfort Hepatobiliary Common Alanine aminotransferase (ALT) and/or Aspartate disorders aminotransferase (AST) elevations Uncommon Hepatitis Rare Acute hepatic failure, increased bilirubin3 Skin and Common Rash subcutaneous tissue Common Pruritus disorders Musculoskeletal and Uncommon Arthralgia connective tissue Uncommon Myalgia disorders General disorders Common Fatigue and administration site conditions Investigations Common Creatine phosphokinase (CPK) elevations, weight increased 1 reversible sideroblastic anaemia has been reported with dolutegravir-containing regimens. The contribution of dolutegravir in these cases is unclear. 2 see below under Description of selected adverse reactions. 3 in combination with increased transaminases.

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