Wirkstoffe & Arzneimittelsicherheit

Gegenanzeigen · Kyprolis

Kyprolis 10 mg powder for solution for infusion Kyprolis 30 mg powder for solution for infusion Kyprolis 60 mg powder for solution for infusion · Abschnitt 4.3 · PDF-Seite 10

HOS-131553 · Präparat HOS-097095

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. • Women who are breast-feeding (see section 4.6).

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

Gegenanzeigen · Kyprolis

Kyprolis 10 mg powder for solution for infusion Kyprolis 30 mg powder for solution for infusion Kyprolis 60 mg powder for solution for infusion · Abschnitt 4.3 · PDF-Seite 10

HOS-131554 · Präparat HOS-097095

As Kyprolis is administered in combination with other medicinal products, refer to their summaries of product characteristics for additional contraindications.

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

Wechselwirkungen · Kyprolis

Kyprolis 10 mg powder for solution for infusion Kyprolis 30 mg powder for solution for infusion Kyprolis 60 mg powder for solution for infusion · Abschnitt 4.5 · PDF-Seite 14

HOS-131555 · Präparat HOS-097095

Carfilzomib is primarily metabolised via peptidase and epoxide hydrolase activities, and as a result, the pharmacokinetic profile of carfilzomib is unlikely to be affected by concomitant administration of cytochrome P450 inhibitors and inducers.

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

Wechselwirkungen · Kyprolis

Kyprolis 10 mg powder for solution for infusion Kyprolis 30 mg powder for solution for infusion Kyprolis 60 mg powder for solution for infusion · Abschnitt 4.5 · PDF-Seite 14

HOS-131556 · Präparat HOS-097095

In vitro studies indicated that carfilzomib did not induce human CYP3A4 in cultured human hepatocytes. A clinical study using oral midazolam as a CYP3A probe conducted with carfilzomib at a dose of 27 mg/m2 (2 to 10 minute infusion) demonstrated that the pharmacokinetics of midazolam were unaffected by concomitant carfilzomib administration, indicating that carfilzomib is not expected to inhibit the metabolism of CYP3A4/5 substrates and is not a CYP3A4 inducer in human subjects. No clinical study was conducted with a dose of 56 mg/m2. However, it is unknown whether carfilzomib is an inducer of CYP1A2, 2C8, 2C9, 2C19 and 2B6 at therapeutic concentrations. Caution should be observed when carfilzomib is combined with medicinal products that are substrates of these enzymes, such as oral contraceptives. Effective measures to avoid pregnancy should be taken (see section 4.6, and refer also to the current lenalidomide summary of product characteristics), an alternative method of effective contraception should be used if the patient is using 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): lenalidomide (HOS-117069) midazolam (HOS-086167)

Wechselwirkungen · Kyprolis

Kyprolis 10 mg powder for solution for infusion Kyprolis 30 mg powder for solution for infusion Kyprolis 60 mg powder for solution for infusion · Abschnitt 4.5 · PDF-Seite 14

HOS-131558 · Präparat HOS-097095

Carfilzomib does not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19 and 2D6 in vitro and is therefore not expected to influence exposure of medicinal products that are substrates of these enzymes as a result of inhibition.

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

Wechselwirkungen · Kyprolis

Kyprolis 10 mg powder for solution for infusion Kyprolis 30 mg powder for solution for infusion Kyprolis 60 mg powder for solution for infusion · Abschnitt 4.5 · PDF-Seite 14

HOS-131559 · Präparat HOS-097095

Carfilzomib is a P-glycoprotein (P-gp) but not a BCRP substrate. However, given that Kyprolis is administrated intravenously and is extensively metabolised, the pharmacokinetic profile of carfilzomib is unlikely to be affected by P-gp or BCRP inhibitors or inducers. In vitro, at concentrations (3 µM) lower than those expected at therapeutic doses, carfilzomib inhibits the efflux transport of digoxin, a P-gp substrate, by 25%. Caution should be observed when carfilzomib is combined with substrates of P-gp (e.g. digoxin, colchicine).

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): digoxin (HOS-086172) colchicine (HOS-086147)

Wechselwirkungen · Kyprolis

Kyprolis 10 mg powder for solution for infusion Kyprolis 30 mg powder for solution for infusion Kyprolis 60 mg powder for solution for infusion · Abschnitt 4.5 · PDF-Seite 14

HOS-131560 · Präparat HOS-097095

In vitro, carfilzomib inhibits OATP1B1 with an IC50 = 2.01 µM whereas it is unknown whether carfilzomib may or not inhibit other transporters OATP1B3, OAT1, OAT3, OCT2 and BSEP, at the systemic level. Carfilzomib does not inhibit human UGT2B7 but inhibits human UGT1A1 with an IC50 of 5.5 µM. Nonetheless, considering the fast elimination of carfilzomib, notably a rapid decline in systemic concentration 5 minutes after the end of infusion, the risk of clinically relevant interactions with substrates of OATP1B1 and UGT1A1 is probably low.

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

Nebenwirkungen · Kyprolis

Kyprolis 10 mg powder for solution for infusion Kyprolis 30 mg powder for solution for infusion Kyprolis 60 mg powder for solution for infusion · Abschnitt 4.8 · PDF-Seite 15

HOS-131561 · Präparat HOS-097095

Summary of safety profile

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

Nebenwirkungen · Kyprolis

Kyprolis 10 mg powder for solution for infusion Kyprolis 30 mg powder for solution for infusion Kyprolis 60 mg powder for solution for infusion · Abschnitt 4.8 · PDF-Seite 15

HOS-131562 · Präparat HOS-097095

Serious adverse reactions that may occur during Kyprolis treatment include: cardiac failure, myocardial infarction, cardiac arrest, myocardial ischaemia, interstitial lung disease, pneumonitis, acute respiratory distress syndrome, acute respiratory failure, pulmonary hypertension, dyspnoea, hypertension including hypertensive crises, acute kidney injury, tumour lysis syndrome, infusion related reaction, gastrointestinal haemorrhage, intracranial haemorrhage, pulmonary haemorrhage, thrombocytopenia, hepatic failure, hepatitis B virus reactivation, PRES, thrombotic microangiopathy and TTP/HUS. In clinical studies with Kyprolis, cardiac toxicity and dyspnoea typically occurred early in the course of Kyprolis therapy (see section 4.4). The most common adverse reactions (occurring in > 20% of subjects) were: anaemia, fatigue, thrombocytopenia, nausea, diarrhoea, pyrexia, dyspnoea, respiratory tract infection, cough and neutropenia.

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

Nebenwirkungen · Kyprolis

Kyprolis 10 mg powder for solution for infusion Kyprolis 30 mg powder for solution for infusion Kyprolis 60 mg powder for solution for infusion · Abschnitt 4.8 · PDF-Seite 15–16

HOS-131563 · Präparat HOS-097095

15 Following initial doses of carfilzomib at 20 mg/m2, the dose was increased to 27 mg/m2 in study PX-171-009 and to 56 mg/m2 in study 2011-003 (see section 5.1). A cross-study comparison of the adverse reactions occurring in the Kyprolis and dexamethasone (Kd) arm of study 2011-003 versus the Kyprolis, lenalidomide and dexamethasone (KRd) arm of study PX-171-009 suggest that there may be a potential dose relationship for the following adverse reactions: cardiac failure (Kd 8.2%, KRd 6.4%), dyspnoea (Kd 30.9%, KRd 22.7%), hypertension (Kd 25.9%, KRd 15.8%), and pulmonary hypertension (Kd 1.3%, KRd 0.8%).

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

Nebenwirkungen · Kyprolis

Kyprolis 10 mg powder for solution for infusion Kyprolis 30 mg powder for solution for infusion Kyprolis 60 mg powder for solution for infusion · Abschnitt 4.8 · PDF-Seite 16

HOS-131564 · Präparat HOS-097095

In study 20160275 (see section 5.1), in which the administration of Kyprolis in combination with daratumumab and dexamethasone (KdD) was compared to Kyprolis in combination with dexamethasone (Kd), deaths due to adverse events within 30 days of the last dose of any study treatment occurred in 10% of patients in the KdD arm compared with 5% of patients in the Kd arm. The most common cause of death occurring in patients in the two arms (KdD versus Kd) was infections (5% versus 3%). The risk of fatal treatment-emergent adverse events was higher among subjects ≥ 65 years of age. Serious adverse events were reported in 56% of the patients in the KdD arm and 46% of the patients in the Kd arm. The most common serious adverse events reported in the KdD arm as compared with the Kd arm were anaemia (2% versus 1%), diarrhoea (2% versus 0%), pyrexia (4% versus 2%), pneumonia (12% versus 9%), influenza (4% versus 1%), sepsis (4% versus 1%) and bronchitis (2% versus 0%).

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

Nebenwirkungen · Kyprolis

Kyprolis 10 mg powder for solution for infusion Kyprolis 30 mg powder for solution for infusion Kyprolis 60 mg powder for solution for infusion · Abschnitt 4.8 · PDF-Seite 16

HOS-131565 · Präparat HOS-097095

Tabulated list of adverse reactions

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

Nebenwirkungen · Kyprolis

Kyprolis 10 mg powder for solution for infusion Kyprolis 30 mg powder for solution for infusion Kyprolis 60 mg powder for solution for infusion · Abschnitt 4.8 · PDF-Seite 16

HOS-131566 · Präparat HOS-097095

Adverse reactions are presented below by system organ class and frequency category (see table 6). Frequency categories were determined from the crude incidence rate reported for each adverse reaction in a dataset of pooled clinical studies (n = 3 878). Within each system organ class and frequency category, adverse reactions are presented in order of decreasing seriousness.

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

Nebenwirkungen · Kyprolis

Kyprolis 10 mg powder for solution for infusion Kyprolis 30 mg powder for solution for infusion Kyprolis 60 mg powder for solution for infusion · Abschnitt 4.8 · PDF-Seite 16

HOS-131567 · Präparat HOS-097095

Table 6. Tabulated list of adverse reactions

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

Nebenwirkungen · Kyprolis

Kyprolis 10 mg powder for solution for infusion Kyprolis 30 mg powder for solution for infusion Kyprolis 60 mg powder for solution for infusion · Abschnitt 4.8 · PDF-Seite 16

HOS-131568 · Präparat HOS-097095

MedDRA system Very common Common Uncommon Rare organ class (≥ 1/10) (≥ 1/100 to < 1/10) (≥ 1/1 000 to < 1/100) (≥ 1/10 000 to < 1/1 000) Infections and Pneumonia Sepsis Clostridium difficile infestations Respiratory tract Lung infection colitis infection Influenza Cytomegalovirus Herpes zoster* infection Urinary tract infection Hepatitis B virus Bronchitis reactivation Gastroenteritis Viral infection Nasopharyngitis Rhinitis Immune system Drug hypersensitivity disorders Blood and Thrombocytopenia Febrile neutropenia HUS Thrombotic lymphatic system Neutropenia TTP microangiopathy disorders Anaemia Lymphopenia Leukopenia Metabolism and Hypokalaemia Dehydration Tumour lysis nutrition disorders Decreased appetite Hyperkalaemia syndrome Hypomagnesaemia Hyponatraemia Hypercalcaemia Hypocalcaemia Hypophosphataemia Hyperuricaemia Hypoalbuminaemia Hyperglycaemia

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

Nebenwirkungen · Kyprolis

Kyprolis 10 mg powder for solution for infusion Kyprolis 30 mg powder for solution for infusion Kyprolis 60 mg powder for solution for infusion · Abschnitt 4.8 · PDF-Seite 16–17

HOS-131569 · Präparat HOS-097095

16 MedDRA system Very common Common Uncommon Rare organ class (≥ 1/10) (≥ 1/100 to < 1/10) (≥ 1/1 000 to < 1/100) (≥ 1/10 000 to < 1/1 000) Psychiatric Insomnia Anxiety disorders Confusional state Nervous system Dizziness Paraesthesia Intracranial disorders Peripheral neuropathy Hypoaesthesia haemorrhage Headache Cerebrovascular accident PRES Eye disorders Cataract Blurred vision Ear and labyrinth Tinnitus disorders Cardiac disorders Cardiac failure Cardiac arrest Myocardial infarction Cardiomyopathy Atrial fibrillation Myocardial ischaemia Tachycardia Pericarditis Ejection fraction Pericardial effusion decreased Ventricular Palpitations tachycardia Vascular disorders Hypertension Deep vein thrombosis Hypertensive crisis Hypertensive Hypotension Haemorrhage emergency Flushing Respiratory, Dyspnoea Pulmonary embolism ARDS thoracic, and Cough Pulmonary oedema Acute respiratory mediastinal Epistaxis failure disorders Oropharyngeal pain Pulmonary Dysphonia haemorrhage Wheezing Interstitial lung Pulmonary hypertension disease Pneumonitis Gastrointestinal Vomiting Gastrointestinal Gastrointestinal disorders Diarrhoea haemorrhage perforation Constipation Dyspepsia Pancreatitis acute Abdominal pain Toothache Nausea Hepatobiliary Increased alanine Hepatic failure disorders aminotransferase Cholestasis Increased aspartate aminotransferase Gamma- glutamyltransferase increased Hyperbilirubinaemia Skin and Rash Angioedema subcutaneous Pruritus tissue disorders Erythema Hyperhidrosis Musculoskeletal Back pain Musculoskeletal pain and connective Arthralgia Musculoskeletal chest tissue disorders Pain in extremity pain Muscle spasms Bone pain Myalgia Muscular weakness Renal and urinary Increased blood Acute kidney injury disorders creatinine Renal failure Renal impairment Decreased creatinine renal clearance

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

Nebenwirkungen · Kyprolis

Kyprolis 10 mg powder for solution for infusion Kyprolis 30 mg powder for solution for infusion Kyprolis 60 mg powder for solution for infusion · Abschnitt 4.8 · PDF-Seite 17–18

HOS-131570 · Präparat HOS-097095

17 MedDRA system Very common Common Uncommon Rare organ class (≥ 1/10) (≥ 1/100 to < 1/10) (≥ 1/1 000 to < 1/100) (≥ 1/10 000 to < 1/1 000) General disorders Pyrexia Chest pain Multi-organ and administration Peripheral oedema Pain dysfunction syndrome site conditions Asthenia Infusion site reactions Fatigue Influenza like illness Chills Malaise Investigations Increased c-reactive protein Increased blood uric acid Injury, poisoning Infusion related reaction and procedural complications * Frequency is calculated based on data from clinical studies in which most patients used prophylaxis

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

Nebenwirkungen · Kyprolis

Kyprolis 10 mg powder for solution for infusion Kyprolis 30 mg powder for solution for infusion Kyprolis 60 mg powder for solution for infusion · Abschnitt 4.8 · PDF-Seite 18

HOS-131571 · Präparat HOS-097095

Description of selected adverse reactions

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

Nebenwirkungen · Kyprolis

Kyprolis 10 mg powder for solution for infusion Kyprolis 30 mg powder for solution for infusion Kyprolis 60 mg powder for solution for infusion · Abschnitt 4.8 · PDF-Seite 18

HOS-131572 · Präparat HOS-097095

Cardiac failure, myocardial infarction and myocardial ischaemia

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

Nebenwirkungen · Kyprolis

Kyprolis 10 mg powder for solution for infusion Kyprolis 30 mg powder for solution for infusion Kyprolis 60 mg powder for solution for infusion · Abschnitt 4.8 · PDF-Seite 18

HOS-131573 · Präparat HOS-097095

In clinical studies with Kyprolis, cardiac failure was reported in approximately 5% of subjects (approximately 3% of subjects had grade ≥ 3 events), myocardial infarction was reported in approximately 1% of subjects (approximately 1% of subjects had grade ≥ 3 events) and myocardial ischaemia was reported in < 1% of subjects (< 1% of subjects had grade ≥ 3 events). These events typically occurred early in the course of Kyprolis therapy (< 5 cycles).

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