Wirkstoffe & Arzneimittelsicherheit

Wechselwirkungen · Xalkori

XALKORI 200 mg hard capsules XALKORI 250 mg hard capsules XALKORI 20 mg granules in capsules for opening XALKORI 50 mg granules in capsules for opening XALKORI 150 mg granules in capsules for opening · Abschnitt 4.5 · PDF-Seite 15–16

HOS-126283 · Präparat HOS-096239

15 In vitro studies in human hepatocytes indicated that crizotinib may induce pregnane X receptor (PXR)- and constitutive androstane receptor (CAR)-regulated enzymes (e.g., CYP3A4, CYP2B6, CYP2C8, CYP2C9, UGT1A1). However, there was no observed induction in vivo when crizotinib was coadministered with the CYP3A probe substrate midazolam. Caution should be exercised in administering crizotinib in combination with medicinal products that are predominantly metabolised by these enzymes. Of note, the effectiveness of concomitant administration of oral contraceptives may be reduced.

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): midazolam (HOS-086167)

Wechselwirkungen · Xalkori

XALKORI 200 mg hard capsules XALKORI 250 mg hard capsules XALKORI 20 mg granules in capsules for opening XALKORI 50 mg granules in capsules for opening XALKORI 150 mg granules in capsules for opening · Abschnitt 4.5 · PDF-Seite 16

HOS-126284 · Präparat HOS-096239

In vitro studies indicated that crizotinib is a weak inhibitor of uridine diphosphate glucuronosyltransferase (UGT)1A1 and UGT2B7. Therefore, crizotinib may have the potential to increase plasma concentrations of coadministered medicinal products that are metabolised predominantly by UGT1A1 (e.g., raltegravir, irinotecan) or UGT2B7 (e.g., morphine, naloxone).

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): morphine (HOS-086053) naloxone (HOS-109490) raltegravir (HOS-086187) uridine (HOS-085192) irinotecan (HOS-112102)

Wechselwirkungen · Xalkori

XALKORI 200 mg hard capsules XALKORI 250 mg hard capsules XALKORI 20 mg granules in capsules for opening XALKORI 50 mg granules in capsules for opening XALKORI 150 mg granules in capsules for opening · Abschnitt 4.5 · PDF-Seite 16

HOS-126287 · Präparat HOS-096239

Based on an in vitro study, crizotinib is predicted to inhibit intestinal P-gp. Therefore, administration of crizotinib with medicinal products that are substrates of P-gp (e.g., digoxin, dabigatran, colchicine, pravastatin) may increase their therapeutic effect and adverse reactions. Close clinical surveillance is recommended when crizotinib is administered with these medicinal products.

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) dabigatran (HOS-112096) colchicine (HOS-086147) pravastatin (HOS-086306)

Wechselwirkungen · Xalkori

XALKORI 200 mg hard capsules XALKORI 250 mg hard capsules XALKORI 20 mg granules in capsules for opening XALKORI 50 mg granules in capsules for opening XALKORI 150 mg granules in capsules for opening · Abschnitt 4.5 · PDF-Seite 16

HOS-126289 · Präparat HOS-096239

Crizotinib is an inhibitor of OCT1 and OCT2 in vitro. Therefore, crizotinib may have the potential to increase plasma concentrations of coadministered medicinal products that are substrates of OCT1 or OCT2 (e.g., metformin, procainamide).

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): procainamide (HOS-086617) metformin (HOS-091032)

Wechselwirkungen · Xalkori

XALKORI 200 mg hard capsules XALKORI 250 mg hard capsules XALKORI 20 mg granules in capsules for opening XALKORI 50 mg granules in capsules for opening XALKORI 150 mg granules in capsules for opening · Abschnitt 4.5 · PDF-Seite 16

HOS-126290 · Präparat HOS-096239

Pharmacodynamic interactions

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

Wechselwirkungen · Xalkori

XALKORI 200 mg hard capsules XALKORI 250 mg hard capsules XALKORI 20 mg granules in capsules for opening XALKORI 50 mg granules in capsules for opening XALKORI 150 mg granules in capsules for opening · Abschnitt 4.5 · PDF-Seite 16

HOS-126291 · Präparat HOS-096239

In clinical studies, prolonged QT interval was observed with crizotinib. Therefore, the concomitant use of crizotinib with medicinal products known to prolong QT interval or medicinal products able to induce Torsades de pointes (e.g., class IA [quinidine, disopyramide] or class III [e.g., amiodarone, sotalol, dofetilide, ibutilide], methadone, cisapride, moxifloxacine, antipsychotics, etc.) should be carefully considered. A monitoring of the QT interval should be made in case of combinations of such medicinal products (see sections 4.2 and 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): sotalol (HOS-085597) cisapride (HOS-085610) methadone (HOS-086198) dofetilide (HOS-085598) ibutilide (HOS-085599) quinidine (HOS-085593) disopyramide (HOS-085595) amiodarone (HOS-085596)

Wechselwirkungen · Xalkori

XALKORI 200 mg hard capsules XALKORI 250 mg hard capsules XALKORI 20 mg granules in capsules for opening XALKORI 50 mg granules in capsules for opening XALKORI 150 mg granules in capsules for opening · Abschnitt 4.5 · PDF-Seite 16

HOS-126292 · Präparat HOS-096239

Bradycardia has been reported during clinical studies; therefore, use crizotinib with caution due to the risk of excessive bradycardia when used in combination with other bradycardic agents (e.g., non-dihydropyridine calcium channel blockers such as verapamil and diltiazem, beta-blockers, clonidine, guanfacine, digoxin, mefloquine, anticholinesterases, pilocarpine) (see sections 4.2 and 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): diltiazem (HOS-086288) clonidine (HOS-088594) guanfacine (HOS-126294) pilocarpine (HOS-124781) digoxin (HOS-086172) calcium (HOS-085615) mefloquine (HOS-113850) verapamil (HOS-090602)

Nebenwirkungen · Xalkori

XALKORI 200 mg hard capsules XALKORI 250 mg hard capsules XALKORI 20 mg granules in capsules for opening XALKORI 50 mg granules in capsules for opening XALKORI 150 mg granules in capsules for opening · Abschnitt 4.8 · PDF-Seite 17

HOS-126295 · Präparat HOS-096239

Summary of the safety profile in adult patients with ALK-positive or ROS1-positive advanced NSCLC

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

Nebenwirkungen · Xalkori

XALKORI 200 mg hard capsules XALKORI 250 mg hard capsules XALKORI 20 mg granules in capsules for opening XALKORI 50 mg granules in capsules for opening XALKORI 150 mg granules in capsules for opening · Abschnitt 4.8 · PDF-Seite 17

HOS-126296 · Präparat HOS-096239

The data described below reflect exposure to XALKORI in 1669 patients with ALK-positive advanced NSCLC who participated in 2 randomised Phase 3 studies (Studies 1007 and 1014) and in 2 single-arm studies (Studies 1001 and 1005), and in 53 patients with ROS1-positive advanced NSCLC who participated in single-arm Study 1001, for a total of 1722 patients (see section 5.1). These patients received a starting oral dose of 250 mg taken twice daily continuously. In Study 1014, the median duration of study treatment was 47 weeks for patients in the crizotinib arm (N=171); the median duration of treatment was 23 weeks for patients who crossed over from the chemotherapy arm to receive crizotinib treatment (N=109). In Study 1007, the median duration of study treatment was 48 weeks for patients in the crizotinib arm (N=172). For ALK-positive NSCLC patients in Studies 1001 (N=154) and 1005 (N=1063), the median duration of treatment was 57 and 45 weeks, respectively. For ROS1-positive NSCLC patients in Study 1001 (N=53), the median duration of treatment was 101 weeks.

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

Nebenwirkungen · Xalkori

XALKORI 200 mg hard capsules XALKORI 250 mg hard capsules XALKORI 20 mg granules in capsules for opening XALKORI 50 mg granules in capsules for opening XALKORI 150 mg granules in capsules for opening · Abschnitt 4.8 · PDF-Seite 17

HOS-126297 · Präparat HOS-096239

The most serious adverse reactions in 1722 patients with either ALK-positive or ROS1-positive advanced NSCLC were hepatotoxicity, ILD/pneumonitis, neutropenia and QT interval prolongation (see section 4.4). The most common adverse reactions (≥25%) in patients with either ALK-positive or ROS1-positive NSCLC were vision disorder, nausea, diarrhoea, vomiting, oedema, constipation, elevated transaminases, fatigue, decreased appetite, dizziness and neuropathy.

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

Nebenwirkungen · Xalkori

XALKORI 200 mg hard capsules XALKORI 250 mg hard capsules XALKORI 20 mg granules in capsules for opening XALKORI 50 mg granules in capsules for opening XALKORI 150 mg granules in capsules for opening · Abschnitt 4.8 · PDF-Seite 17

HOS-126298 · Präparat HOS-096239

The most frequent adverse reactions (≥3%, all-causality frequency) associated with dosing interruptions were neutropenia (11%), elevated transaminases (7%), vomiting (5%) and nausea (4%). The most frequent adverse reactions (≥3%, all-causality frequency) associated with dose reductions were elevated transaminases (4%) and neutropenia (3%). All-causality adverse events associated with permanent treatment discontinuation occurred in 302 (18%) patients of which the most frequent (≥1%) were ILD (1%) and elevated transaminases (1%).

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

Nebenwirkungen · Xalkori

XALKORI 200 mg hard capsules XALKORI 250 mg hard capsules XALKORI 20 mg granules in capsules for opening XALKORI 50 mg granules in capsules for opening XALKORI 150 mg granules in capsules for opening · Abschnitt 4.8 · PDF-Seite 17

HOS-126299 · Präparat HOS-096239

Tabulated list of adverse reactions

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

Nebenwirkungen · Xalkori

XALKORI 200 mg hard capsules XALKORI 250 mg hard capsules XALKORI 20 mg granules in capsules for opening XALKORI 50 mg granules in capsules for opening XALKORI 150 mg granules in capsules for opening · Abschnitt 4.8 · PDF-Seite 17

HOS-126300 · Präparat HOS-096239

Table 9 presents adverse reactions reported in 1722 patients with either ALK-positive or ROS1-positive advanced NSCLC who received crizotinib across 2 randomised Phase 3 studies (1007 and 1014) and 2 single-arm clinical studies (1001 and 1005) (see section 5.1).

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

Nebenwirkungen · Xalkori

XALKORI 200 mg hard capsules XALKORI 250 mg hard capsules XALKORI 20 mg granules in capsules for opening XALKORI 50 mg granules in capsules for opening XALKORI 150 mg granules in capsules for opening · Abschnitt 4.8 · PDF-Seite 17–18

HOS-126301 · Präparat HOS-096239

17 The adverse reactions listed in Table 9 are presented by system organ class and frequency categories, defined using the following convention: 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), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects 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 · Xalkori

XALKORI 200 mg hard capsules XALKORI 250 mg hard capsules XALKORI 20 mg granules in capsules for opening XALKORI 50 mg granules in capsules for opening XALKORI 150 mg granules in capsules for opening · Abschnitt 4.8 · PDF-Seite 18

HOS-126302 · Präparat HOS-096239

Table 9. Adverse reactions reported in crizotinib clinical studies of NSCLC (N=1722) System organ class Very common Common Uncommon Blood and lymphatic Neutropaeniaa (22%) system disorders Anaemiab (15%) Leukopeniac (15%) Metabolism and Decreased appetite Hypophosphataemia (6%) nutrition disorders (30%) Nervous system Neuropathyd (25%) disorders Dysgeusia (21%) Eye disorders Vision disordere (63%) Cardiac disorders Dizzinessf (26%) Cardiac failureh (1%) g Bradycardia (13%) Electrocardiogram QT prolonged (4%) Syncope (3%) Respiratory, thoracic Interstitial lung diseasei and mediastinal (3%) disorders Gastrointestinal Vomiting (51%) Oesophagitisk (2%) Gastrointestinal disorders Diarrhoea (54%) Dyspepsia (8%) perforationl Nausea (57%) (<1%) Constipation (43%) Abdominal painj (21%) Hepatobiliary Elevated Blood alkaline Hepatic failure disorders transaminasesm (32%) phosphatase increased (<1%) (7%) Skin and Rash (13%) Photosensitivity subcutaneous tissue (<1%) disorders Renal and urinary Renal cystn (3%) Acute renal disorders Blood creatinine failure (<1%) o increased (8%) Renal failure (<1%) General disorders Oedemap (47%) and administration Fatigue (30%) site conditions Investigations Blood testosterone Blood creatine decreasedq (2%) phosphokinase increased (<1%)* Event terms that represent the same medical concept or condition were grouped together and reported as a single adverse drug reaction in Table 9. Terms actually reported in the study up to the data cutoff date and contributing to the relevant adverse drug reaction are indicated in parentheses, as listed below. * Creatine phosphokinase was not a standard laboratory test in the crizotinib clinical trials. a. Neutropaenia (Febrile neutropaenia, Neutropaenia, Neutrophil count decreased). b. Anaemia (Anaemia, Haemoglobin decreased, Hypochromic anaemia). c. Leukopenia (Leukopenia, White blood cell count decreased). d. Neuropathy (Burning sensation, Dysaesthesia, Formication, Gait disturbance, Hyperaesthesia, Hypoaesthesia, Hypotonia, Motor dysfunction, Muscle atrophy, Muscular weakness, Neuralgia, Neuritis, Neuropathy peripheral, Neurotoxicity, Paraesthesia, Peripheral motor neuropathy, Peripheral sensorimotor neuropathy,

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

Nebenwirkungen · Xalkori

XALKORI 200 mg hard capsules XALKORI 250 mg hard capsules XALKORI 20 mg granules in capsules for opening XALKORI 50 mg granules in capsules for opening XALKORI 150 mg granules in capsules for opening · Abschnitt 4.8 · PDF-Seite 18–19

HOS-126303 · Präparat HOS-096239

18  Peripheral sensory neuropathy, Peroneal nerve palsy, Polyneuropathy, Sensory disturbance, Skin burning sensation). e. Vision disorder (Diplopia, Halo vision, Photophobia, Photopsia, Vision blurred, Visual acuity reduced, Visual brightness, Visual impairment, Visual perseveration, Vitreous floaters). f. Dizziness (Balance disorder, Dizziness, Dizziness postural, Presyncope). g. Bradycardia (Bradycardia, Heart rate decreased, Sinus bradycardia). h. Cardiac failure (Cardiac failure, Cardiac failure congestive, Ejection fraction decreased, Left ventricular failure, Pulmonary oedema). Across clinical studies (n=1722), 19 (1.1%) patients treated with crizotinib had any grade cardiac failure, 8 (0.5%) patients had Grade 3 or 4, and 3 (0.2%) patients had fatal outcome. i. Interstitial lung disease (Acute respiratory distress syndrome, Alveolitis, Interstitial lung disease, Pneumonitis). j. Abdominal pain (Abdominal discomfort, Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness). k. Oesophagitis (Oesophagitis, Oesophageal ulcer). l. Gastrointestinal perforation (Gastrointestinal perforation, Intestinal perforation, Large intestine perforation). m. Elevated transaminases (Alanine aminotransferase increased, Aspartate aminotransferase increased, Gamma-glutamyltransferase increased, Hepatic enzyme increased, Hepatic function abnormal, Liver function test abnormal, Transaminases increased). n. Renal cyst (Renal abscess, Renal cyst, Renal cyst haemorrhage, Renal cyst infection). o. Blood creatinine increased (blood creatinine increased, creatinine renal clearance decreased). p. Oedema (Face oedema, Generalised oedema, Local swelling, Localised oedema, Oedema, Oedema peripheral, Periorbital oedema). q. Blood testosterone decreased (Blood testosterone decreased, Hypogonadism, Secondary hypogonadism).

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

Nebenwirkungen · Xalkori

XALKORI 200 mg hard capsules XALKORI 250 mg hard capsules XALKORI 20 mg granules in capsules for opening XALKORI 50 mg granules in capsules for opening XALKORI 150 mg granules in capsules for opening · Abschnitt 4.8 · PDF-Seite 19

HOS-126304 · Präparat HOS-096239

Summary of the safety profile in paediatric patients

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

Nebenwirkungen · Xalkori

XALKORI 200 mg hard capsules XALKORI 250 mg hard capsules XALKORI 20 mg granules in capsules for opening XALKORI 50 mg granules in capsules for opening XALKORI 150 mg granules in capsules for opening · Abschnitt 4.8 · PDF-Seite 19

HOS-126305 · Präparat HOS-096239

The safety analysis population for 110 paediatric patients with all tumour types (ages 1 to <18 years), which included 41 patients with relapsed or refractory systemic ALK-positive ALCL or with unresectable, recurrent, or refractory ALK-positive IMT is based on patients who received crizotinib from 2 single-arm studies, Study 0912 (n=36) and Study 1013 (n=5). In Study 0912, patients received crizotinib at a starting dose of 100 mg/m2, 130 mg/m2, 165 mg/m2, 215 mg/m2, 280 mg/m2, or 365 mg/m2 twice daily. In Study 1013, crizotinib was administered at a starting dose of 250 mg twice daily. There was a total population of 25 paediatric patients with ALK-positive ALCL from 3 to <18 years of age and 16 paediatric patients with ALK-positive IMT from 2 to <18 years of age. Experience on the use of crizotinib in paediatric patients in the different subgroups (age, gender and race) is limited and does not allow for definitive conclusions to be made. The safety profiles were consistent across the subgroups of age, gender and race, although there were slight differences in adverse reactions frequencies within each subgroup. The most frequent adverse reactions (≥80%) reported in all subgroups (age, gender and race) were elevated transaminases, vomiting, neutropenia, nausea, diarrhoea and leukopenia. The most frequent serious adverse reaction (90%) was neutropenia.

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

Nebenwirkungen · Xalkori

XALKORI 200 mg hard capsules XALKORI 250 mg hard capsules XALKORI 20 mg granules in capsules for opening XALKORI 50 mg granules in capsules for opening XALKORI 150 mg granules in capsules for opening · Abschnitt 4.8 · PDF-Seite 19

HOS-126306 · Präparat HOS-096239

The median duration of treatment for paediatric patients with all tumour types was 2.8 months. Permanent discontinuation from treatment due to an adverse event occurred in 11 (10%) patients. Dosing interruptions and dose reductions occurred in 47 (43%) and 15 (14%), respectively. The most frequent adverse reactions (>60%) were elevated transaminases, vomiting, neutropenia, nausea, diarrhoea and leukopenia. The most frequent Grade 3 or 4 adverse reactions (≥40%) was neutropenia.

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

Nebenwirkungen · Xalkori

XALKORI 200 mg hard capsules XALKORI 250 mg hard capsules XALKORI 20 mg granules in capsules for opening XALKORI 50 mg granules in capsules for opening XALKORI 150 mg granules in capsules for opening · Abschnitt 4.8 · PDF-Seite 19

HOS-126307 · Präparat HOS-096239

The median duration of treatment for paediatric patients with ALK-positive ALCL was 5.1 months. Permanent discontinuation from treatment due to an adverse event occurred in 1 patient (4%). Eleven of 25 (44%) patients with ALK-positive ALCL permanently discontinued crizotinib treatment due to subsequently having a haematopoietic stem cell transplant (HSCT). Dosing interruptions and dose reductions occurred in 17 (68%) and 4 (16%) patients, respectively. The most frequent adverse reactions (≥80%) were diarrhoea, vomiting, elevated transaminases, neutropenia, leukopenia and nausea. The most frequent Grade 3 or 4 adverse reactions (≥40%) were neutropenia, leukopenia and lymphopenia.

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