Wirkstoffe & Arzneimittelsicherheit

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HOS-086387 · Präparat HOS-083284

Concomitant medicinal product levels increased or decreased 1-Adrenoreceptor Alfuzosin Increased plasma concentrations of alfuzosin Antagonist which may lead to severe hypotension (see section 4.5).

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): alfuzosin (HOS-086139) lead (HOS-085592)

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HOS-086388 · Präparat HOS-083284

35 Analgesics Pethidine, Increased plasma concentrations of propoxyphene norpethidine and propoxyphene. Thereby, increasing the risk of serious respiratory depression or haematologic abnormalities, or other serious adverse effects from these agents. Antianginal Ranolazine Increased plasma concentrations of ranolazine which may increase the potential for serious and/or life-threatening reactions (see section 4.5). Anticancer Neratinib Increased plasma concentrations of neratinib which may increase the potential for serious and/or life-threatening reactions including hepatotoxicity (see section 4.5). Venetoclax Increased plasma concentrations of venetoclax. Increased risk of tumor lysis syndrome at the dose initiation and during the dose-titration phase (see section 4.5). Antiarrhythmics Amiodarone, bepridil, Increased plasma concentrations of amiodarone, dronedarone, bepridil, dronedarone, encainide, flecainide, encainide, flecainide, propafenone, quinidine. Thereby, increasing propafenone, quinidine the risk of arrhythmias or other serious adverse effects from these agents. Antibiotic Fusidic Acid Increased plasma concentrations of fusidic acid and ritonavir. Antihistamines Astemizole, Increased plasma concentrations of astemizole terfenadine and terfenadine. Thereby, increasing the risk of serious arrhythmias from these agents. Anti-gout Colchicine Potential for serious and/or life-threatening reactions in patients with renal and/or hepatic impairment (see sections 4.4 and 4.5). Antipsychotics/ Lurasidone Increased plasma concentrations of lurasidone Neuroleptics which may increase the potential for serious and/or life-threatening reactions (see section 4.5). Clozapine, pimozide Increased plasma concentrations of clozapine and pimozide. Thereby, increasing the risk of serious haematologic abnormalities, or other serious adverse effects from these agents. Quetiapine Increased plasma concentrations of quetiapine which may lead to coma. The concomitant administration with quetiapine is contraindicated (see section 4.5). Ergot Derivatives Dihydroergotamine, Increased plasma concentrations of ergot ergonovine, derivatives leading to acute ergot toxicity, ergotamine, including vasospasm and ischaemia. methylergonovine GI motility agent Cisapride Increased plasma concentrations of cisapride. Thereby, increasing the risk of serious arrhythmias from this agent. Lipid-modifying agents

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): propoxyphene (HOS-086140) quetiapine (HOS-086150) encainide (HOS-086145) methylergonovine (HOS-086155) propafenone (HOS-084530) dronedarone (HOS-086144) cisapride (HOS-085610) fusidic acid (HOS-086146) flecainide (HOS-086203) bepridil (HOS-085612) quinidine (HOS-085593) neratinib (HOS-086142) venetoclax (HOS-086143) lead (HOS-085592) pimozide (HOS-085600) colchicine (HOS-086147) astemizole (HOS-085608) clozapine (HOS-086149) ergotamine (HOS-086154) amiodarone (HOS-085596) terfenadine (HOS-085607) lurasidone (HOS-086148) ranolazine (HOS-086141) ergonovine (HOS-086153) dihydroergotamine (HOS-086152)

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HOS-086389 · Präparat HOS-083284

36  HMG Co-A Reductase Lovastatin, simvastatin Increased plasma concentrations of lovastatin Inhibitors and simvastatin; thereby, increasing the risk of myopathy including rhabdomyolysis (see section 4.5).

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): lovastatin (HOS-086157) simvastatin (HOS-086158)

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HOS-086390 · Präparat HOS-083284

Microsomal Lomitapide Increased plasma concentrations of lomitapide triglyceride transfer (see section 4.5). protein (MTTP) inhibitor PDE5 inhibitor Avanafil Increased plasma concentrations of avanafil (see section 4.4. and 4.5). Sildenafil Contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) only. Increased plasma concentrations of sildenafil. Thereby, increasing the potential for sildenafil- associated adverse events (which include hypotension and syncope). See section 4.4 and section 4.5 for co-administration of sildenafil in patients with erectile dysfunction. Vardenafil Increased plasma concentrations of vardenafil (see section 4.4. and 4.5). Sedatives/hypnotics Clorazepate, diazepam, Increased plasma concentrations of clorazepate, estazolam, flurazepam, diazepam, estazolam, flurazepam, oral oral midazolam and midazolam and triazolam. Thereby, increasing triazolam the risk of extreme sedation and respiratory depression from these agents. (For caution on parenterally administered midazolam, see section 4.5.). Ritonavir medicinal product level decreased Herbal Preparation St. John’s Wort Herbal preparations containing St John’s wort (Hypericum perforatum) due to the risk of decreased plasma concentrations and reduced clinical effects of ritonavir (see section 4.5).

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): estazolam (HOS-086165) lomitapide (HOS-086160) clorazepate (HOS-086164) diazepam (HOS-085904) avanafil (HOS-086161) sildenafil (HOS-086162) triazolam (HOS-086168) flurazepam (HOS-086166) midazolam (HOS-086167) vardenafil (HOS-086163)

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HOS-086170 · Präparat HOS-083284

Ritonavir has a high affinity for several cytochrome P450 (CYP) isoforms and may inhibit oxidation with the following ranked order: CYP3A4 > CYP2D6. Co-administration of ritonavir and medicinal products primarily metabolised by CYP3A may result in increased plasma concentrations of the other medicinal product, which could increase or prolong its therapeutic and adverse effects. For selected 9 medicinal products (e.g. alprazolam) the inhibitory effects of ritonavir on CYP3A4 may decrease over time. Ritonavir also has a high affinity for P-glycoprotein and may inhibit this transporter. The inhibitory effect of ritonavir (with or without other protease inhibitors) on P-gp activity may decrease over time (e.g. digoxin and fexofenadine-see table “Ritonavir effects on non-antiretroviral medicinal products” below). Ritonavir may induce glucuronidation and oxidation by CYP1A2, CYP2C8, CYP2C9 and CYP2C19 thereby increasing the biotransformation of some medicinal products metabolised by these pathways, and may result in decreased systemic exposure to such medicinal products, which could decease or shorten their therapeutic effect.

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): protease (HOS-085623) alprazolam (HOS-086171) digoxin (HOS-086172)

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HOS-086173 · Präparat HOS-083284

Important information regarding medicinal product interactions when ritonavir is used as a pharmacokinetic enhancer is also contained in the SmPC of the co-administered protease inhibitor.

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): protease (HOS-085623)

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HOS-086174 · Präparat HOS-083284

Medicinal products that affect ritonavir levels

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

Wechselwirkungen · Norvir

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HOS-086175 · Präparat HOS-083284

Serum levels of ritonavir can be reduced by concomitant use of herbal preparations containing St John’s wort (Hypericum perforatum). This is due to the induction of medicinal product metabolising enzymes by St John’s wort. Herbal preparations containing St John’s wort must not be used in combination with ritonavir. If a patient is already taking St John’s wort, St John’s wort should be stopped and if possible check viral levels. Ritonavir levels may increase on stopping St John’s wort. The dose of ritonavir may need adjusting. The inducing effect may persist for at least 2 weeks after cessation of treatment with St John’s wort (see section 4.3).

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

Wechselwirkungen · Norvir

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HOS-086176 · Präparat HOS-083284

Serum levels of ritonavir may be affected by select co-administered medicinal products (e.g. phenytoin and rifampicin). These interactions are noted in the medicinal product interaction tables below.

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): phenytoin (HOS-084531)

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HOS-086177 · Präparat HOS-083284

Medicinal product that are affected by the use of ritonavir

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

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HOS-086178 · Präparat HOS-083284

Interactions between ritonavir and protease inhibitors, antiretroviral agents other than protease inhibitors and other non-antiretroviral medicinal products are listed in the tables below. This list is not intended to be inclusive or comprehensive. Individual SmPCs should be consulted.

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): protease (HOS-085623)

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HOS-086179 · Präparat HOS-083284

Medicinal Product Interactions – Ritonavir with Protease Inhibitors Co-administered Dose of Co- Dose of Medicinal Product AUC Cmin Medicinal Product administered NORVIR Assessed Medicinal (mg) Product (mg) Atazanavir 300 q24h 100 q24h Atazanavir ↑ 86% ↑ 11 fold 1 Atazanavir ↑ 2 fold ↑ 3-7 fold Ritonavir increases the serum levels of atazanavir as a result of CYP3A4 inhibition. Clinical trials confirmed the safety and efficacy of 300 mg atazanavir once daily with ritonavir 100 mg once daily in treatment experienced patients. For further information, physicians should refer to the SmPC for atazanavir. Darunavir 600, single 100 q12h Darunavir ↑ 14 fold Ritonavir increases the serum levels of darunavir as a result of CYP3A inhibition. Darunavir must be given with ritonavir to ensure its therapeutic effect. Ritonavir doses higher than 100 mg twice daily have not been studied with darunavir. For further information, refer to the SmPC for darunavir. Fosamprenavir 700 q12h 100 q12h Amprenavir ↑ 2.4 ↑ 11 fold fold Ritonavir increases the serum levels of amprenavir (from fosamprenavir) as a result of CYP3A4 inhibition. Fosamprenavir must be given with ritonavir to ensure its therapeutic effect. Clinical trials confirmed the safety and efficacy of fosamprenavir 700 mg twice daily with ritonavir 100 mg twice daily. Ritonavir doses higher than 100 mg twice daily 10  have not been studied with fosamprenavir. For further information, physicians should refer to the SmPC for fosamprenavir. Indinavir 800 100 q12h Indinavir2 ↑ 178% ND q12h Ritonavir ↑ 72% ND Ritonavir increases the serum levels of indinavir as a result of CYP3A4 inhibition. Appropriate doses for this combination, with respect to efficacy and safety, have not been established. Minimal benefit of ritonavir-mediated pharmacokinetic enhancement is achieved with doses higher than 100 mg twice daily. In cases of co-administration of ritonavir (100 mg twice daily) and indinavir (800 mg twice daily) caution is warranted as the risk of nephrolithiasis may be increased. Nelfinavir 1250 100 q12h Nelfinavir ↑ ND q12h 20to39% Ritonavir increases the serum levels of nelfinavir as a result of CYP3A4 inhibition. Appropriate doses for this combination, with respect to efficacy and safety, have not been established. Minimal benefit of ritonavir-mediated pharmacokinetic enhancement is achieved with doses higher than 100 mg twice daily. Tipranavir 500 200 q12h Tipranavir ↑ 11 fold ↑ 29 fold q12h Ritonavir ↓ 40% ND Ritonavir increases the serum levels of tipranavir as a result of CYP3A inhibition. Tipranavir must be given with low dose ritonavir to ensure its therapeutic effect. Doses of ritonavir less than 200 mg twice daily should not be used with tipranavir as they might alter the efficacy of the combination. For further information, physicians should refer to the SmPC for tipranavir. ND: Not determined. 1. Based on cross-study comparison to 400 mg atazanavir once daily alone. 2. Based on cross-study comparison to 800 mg indinavir three times daily alone.

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): indinavir (HOS-084518) atazanavir (HOS-086180) nelfinavir (HOS-084520) protease (HOS-085623) amprenavir (HOS-086183) darunavir (HOS-086181) fosamprenavir (HOS-086182) tipranavir (HOS-086184)

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HOS-086185 · Präparat HOS-083284

Medicinal product interactions – Ritonavir with antiretroviral agents other than protease inhibitors Co- Dose of Co- Dose of Medicinal Product AUC Cmin administered administered NORVIR (mg) Assessed Medicinal Medicinal Product Product (mg) Maraviroc 100 q12h 100 q12h Maraviroc ↑161% ↑28% Ritonavir increases the serum levels of maraviroc as a result of CYP3A inhibition. Maraviroc may be given with ritonavir to increase the maraviroc exposure. For further information, refer to the SmPC for maraviroc. Raltegravir 400 single 100 q12h Raltegravir ↓ 16% ↓ 1% Co-adminsitration of ritonavir and raltegravir results in a minor reduction in raltegravir levels

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): protease (HOS-085623) maraviroc (HOS-086186) raltegravir (HOS-086187)

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HOS-086188 · Präparat HOS-083284

11  Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products Co-administered Medicinal Products Dose of Co- Dose of Effect on Co- Effect on Co- administered NORVIR (mg) administered administered Medicinal Products Medicinal Medicinal Products (mg) Products Cmax AUC

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

Wechselwirkungen · Norvir

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HOS-086189 · Präparat HOS-083284

Alpha1 -Adrenoreceptor Antagonist Alfuzosin Ritonavir co-administration is likely to result in increased plasma concentrations of alfuzosin and is therefore contraindicated (see section 4.3).

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): alfuzosin (HOS-086139)

Wechselwirkungen · Norvir

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HOS-086190 · Präparat HOS-083284

Amphetamine Derivatives Amphetamine Ritonavir dosed as an antiretroviral agent is likely to inhibit CYP2D6 and as a result is expected to increase concentrations of amphetamine and its derivatives. Careful monitoring of therapeutic and adverse effects is recommended when these medicines are concomitantly administered with antiretroviral doses of ritonavir (see section 4.4).

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): amphetamine (HOS-086191)

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HOS-086192 · Präparat HOS-083284

Analgesics Buprenorphine 16 q24h 100 q12h ↑ 57% ↑ 77% Norbuprenorphine ↑ 33% ↑ 108% Glucuronide metabolites   The increases of plasma levels of buprenorphine and its active metabolite did not lead to clinically significant pharmacodynamic changes in a population of opioid tolerant patients. Adjustment to the dose of buprenorphine or ritonavir may therefore not be necessary when the two are dosed together. When ritonavir is used in combination with another protease inhibitor and buprenorphine, the SmPC of the co-administered protease inhibitor should be reviewed for specific dosing information.

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): protease (HOS-085623) buprenorphine (HOS-086193) lead (HOS-085592)

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HOS-086194 · Präparat HOS-083284

Pethidine, propoxyphene Ritonavir co-administration is likely to result in increased plasma concentrations of norpethidine and propoxyphene and is therefore contraindicated (see section 4.3).

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): propoxyphene (HOS-086140)

Wechselwirkungen · Norvir

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HOS-086195 · Präparat HOS-083284

Fentanyl Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent inhibits CYP3A4 and as a result is expected to increase the plasma concentrations of fentanyl. Careful monitoring of therapeutic and adverse effects (including respiratory depression) is recommended when fentanyl is concomitantly administered with ritonavir.

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): fentanyl (HOS-086196)

Wechselwirkungen · Norvir

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HOS-086197 · Präparat HOS-083284

Methadone1 5, single dose 500 q12h, ↓ 36% ↓ 38% Increased methadone dose may be necessary when concomitantly administered with ritonavir dosed as an antiretroviral agent or as a pharmacokinetic enhancer due to induction of glucuronidation. Dose adjustment should be considered based on the patient’s clinical response to methadone therapy.

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): methadone (HOS-086198)