Wirkstoffe & Arzneimittelsicherheit

Gegenanzeigen · Javlor

Javlor 25 mg/mL concentrate for solution for infusion · Abschnitt 4.3 · PDF-Seite 5

HOS-209957 · Präparat HOS-154415

Hypersensitivity to the active substance or other vinca alkaloids. Recent (within 2 weeks) or current severe infection. Baseline ANC < 1 500/mm3 for the first administration, baseline ANC < 1 000/mm3 for subsequent administrations (see section 4.4). Platelets < 100 000/mm3(see section 4.4). Breast-feeding (see section 4.6).

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Wechselwirkungen · Javlor

Javlor 25 mg/mL concentrate for solution for infusion · Abschnitt 4.5 · PDF-Seite 7

HOS-209958 · Präparat HOS-154415

In vitro studies showed that vinflunine had neither inducing effects on CYP1A2, CYP2B6 or CYP3A4 activity nor inhibition effects on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4.

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Wechselwirkungen · Javlor

Javlor 25 mg/mL concentrate for solution for infusion · Abschnitt 4.5 · PDF-Seite 7

HOS-209959 · Präparat HOS-154415

In vitro studies showed that vinflunine is a Pgp-substrate like other vinca alkaloids, but with a lower affinity. Therefore, risks of clinically significant interactions should be unlikely. No pharmacokinetic interaction was observed in patients when vinflunine was combined with either cisplatin, carboplatin, capecitabine or gemcitabine. No pharmacokinetic interaction was observed in patients when vinflunine was combined with doxorubicin. However, this combination was associated with a particularly high risk of haematological toxicity.

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RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): gemcitabine (HOS-113530) cisplatin (HOS-086022) carboplatin (HOS-084540) capecitabine (HOS-090904) doxorubicin (HOS-084538)

Wechselwirkungen · Javlor

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HOS-209965 · Präparat HOS-154415

A phase I study evaluating the effect of ketoconazole treatment (a potent CYP3A4 inhibitor) on vinflunine pharmacokinetics indicated that co-administration of ketoconazole (400 mg orally once daily for 8 days) resulted in a 30% and 50% increase in blood exposures to vinflunine and its metabolite 4Odeacetyl-vinflunine (DVFL), respectively.

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RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): ketoconazole (HOS-084513)

Wechselwirkungen · Javlor

Javlor 25 mg/mL concentrate for solution for infusion · Abschnitt 4.5 · PDF-Seite 7

HOS-209967 · Präparat HOS-154415

Therefore the concomitant use of vinflunine and potent CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole and grapefruit juice) or inducers (such as rifampicin and Hypericum perforatum (St John’s wort)) should be avoided since they may increase or decrease vinflunine and DVFL concentrations (see section 4.4 and 5.2).

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): ketoconazole (HOS-084513) grapefruit juice (HOS-088787) itraconazole (HOS-084516) ritonavir (HOS-084521)

Wechselwirkungen · Javlor

Javlor 25 mg/mL concentrate for solution for infusion · Abschnitt 4.5 · PDF-Seite 7

HOS-209971 · Präparat HOS-154415

The concomitant use of vinflunine with others QT/QTc interval prolonging medicinal products should be avoided (see section 4.4).

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Wechselwirkungen · Javlor

Javlor 25 mg/mL concentrate for solution for infusion · Abschnitt 4.5 · PDF-Seite 7

HOS-209972 · Präparat HOS-154415

A pharmacokinetic interaction between vinflunine and pegylated/liposomal doxorubicin was observed, resulting in a 15% to 30% apparent increase in vinflunine exposure and a 2 to 3-fold apparent decrease of doxorubicin AUC, whereas for doxorubicinol, the concentrations of the metabolite were not affected. According to an in vitro study, such changes could be related to adsorption of vinflunine on the liposomes and a modified blood distribution of both compounds. Therefore, caution should be excercised when this type of combination is used.

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RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): doxorubicin (HOS-084538)

Wechselwirkungen · Javlor

Javlor 25 mg/mL concentrate for solution for infusion · Abschnitt 4.5 · PDF-Seite 7

HOS-209973 · Präparat HOS-154415

A possible interaction with paclitaxel and docetaxel (CYP3 substrates) has been suggested from an in vitro study (slight inhibition of vinflunine metabolism). No specific clinical studies of vinflunine in combination with these compounds have been carried out yet.

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RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): docetaxel (HOS-084505) paclitaxel (HOS-087959)

Wechselwirkungen · Javlor

Javlor 25 mg/mL concentrate for solution for infusion · Abschnitt 4.5 · PDF-Seite 7

HOS-209976 · Präparat HOS-154415

The concomitant use of opioids could enhance the risk of constipation.

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Nebenwirkungen · Javlor

Javlor 25 mg/mL concentrate for solution for infusion · Abschnitt 4.8 · PDF-Seite 8

HOS-209977 · Präparat HOS-154415

Summary of the safety profile The most frequent treatment-related adverse reactions reported in the two phase II and one phase III trials in patients with transitional cell carcinoma of the urothelium (450 patients treated with vinflunine) were haematological disorders, mainly neutropenia and anaemia; gastrointestinal disorders, especially constipation, anorexia, nausea, stomatitis/mucositis, vomiting, abdominal pain and diarrhoea, and general disorders such as asthenia/fatigue.

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Nebenwirkungen · Javlor

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HOS-209978 · Präparat HOS-154415

Tabulated list of adverse reactions Adverse reactions are listed below by System Organ Class, frequency and grade of severity (NCI CTC version 2.0). Frequency of adverse reactions is 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, adverse reactions are presented in order of decreasing seriousness.

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Nebenwirkungen · Javlor

Javlor 25 mg/mL concentrate for solution for infusion · Abschnitt 4.8 · PDF-Seite 8–10

HOS-209979 · Präparat HOS-154415

8  Table 4 Adverse reactions observed in patients with transitional cell carcinoma of the urothelium treated with vinflunine System Organ Class Frequency Adverse Reactions Worst NCI Grade per patient (%) All grades Grade 3-4 Infections and infestations Common Neutropenic infection 2.4 2.4 Infections (viral, bacterial, 7.6 3.6 fungal) Uncommon Neutropenic sepsis 0.2 0.2 Neoplasm benign, Uncommon Tumour pain 0.2 0.2 malignant and unspecified Blood and lymphatic Very common Neutropenia 79.6 54.6 system disorders Leucopenia 84.5 45.2 Anaemia 92.8 17.3 Thrombocytopenia 53.5 4.9 Common Febrile neutropenia 6.7 6.7 Immune system disorders Common Hypersensitivity 1.3 0.2 Endocrine disorders Uncommon Syndrome of Inappropriate Antidiuretic Hormone 0.4 b 0.4 b Secretion (SIADH) a Metabolism and nutrition Very common Hyponatraemia 39.8 11.7 disorders Decreased appetite 34.2 2.7 Common Dehydration 4.4 2.0 Psychiatric disorders Common Insomnia 5.1 0.2 Nervous system disorders Very common Peripheral sensory 11.3 0.9 neuropathy Common Syncope 1.1 1.1 Headache 6.2 0.7 Dizziness 5.3 0.4 Neuralgia 4.4 0.4 Dysgeusia 3.3 0 Neuropathy 1.3 0 Uncommon Peripheral motor neuropathy 0.4 0 Rare Posterior Reversible 0.03b 0.03b Encephalopathy Syndromea Eye disorders Uncommon Visual disturbance 0.4 0 Ear and Labyrinth Common Ear pain 1.1 0 disorders Uncommon Vertigo 0.9 0.4 Tinnitus 0.9 0 Cardiac disorders Common Tachycardia 1.8 0.2 Uncommon Myocardial ischaemia 0.7 0.7 Myocardial infarction 0.2 0.2 Vascular disorders Common Hypertension 3.1 1.6 Venous thrombosisc 3.6 0.4 Phlebitis 2.4 0 Hypotension 1.1 0.2 Respiratory, thoracic and Common Dyspnoea 4.2 0.4 mediastinal disorders Cough 2.2 0 Uncommon Acute respiratory distress 0.2 0.2 syndrome Pharyngolaryngeal pain 0.9 0 Gastrointestinal disorders Very common Constipation 54.9 15.1 Abdominal pain 21.6 4.7 9  Vomiting 27.3 2.9 Nausea 40.9 2.9 Stomatitis 27.1 2.7 Diarrhoea 12.9 0.9 Common Ileus 2.7 2.2 Dysphagia 2.0 0.4 Buccal disorders 4.0 0.2 Dyspepsia 5.1 0.2 Uncommon Odynophagia 0.4 0.2 Gastric disorders 0.8 0 Oesophagitis 0.4 0.2 Gingival disorders 0.7 0 Skin and subcutaneous Very common Alopecia 28.9 NA tissue disorders Common Rash 1.8 0 Urticaria 1.1 0 Pruritus 1.1 0 Hyperhidrosis 1.1 0 Uncommon Dry skin 0.9 0 Erythema 0.4 0 Musculoskeletal and Very common Myalgia 16.7 3.1 connective tissue Common Muscular weakness 1.8 0.7 disorders Arthralgia 7.1 0.4 Back pain 4.9 0.4 Pain in jaw 5.6 0 Pain in extremity 2.4 0 Bone pain 2.9 0 Musculoskeletal pain 2.7 0.2 Renal and urinary Uncommon Renal failure 0.2 0.2 disorders General disorders and Very common Asthenia/Fatigue 55.3 15.8 administration site Injection site reaction 26.4 0.4 conditions Pyrexia 11.7 0.4 Common Chest pain 4.7 0.9 Chills 2.2 0.2 Pain 3.1 0.2 Oedema 1.1 0 Uncommon Extravasation 0.7 0 Investigations Very common Weight decreased 24.0 0.4 Uncommon Transaminases increased 0.4 0 Weight increased 0.2 0 a adverse reactions reported from post-marketing experience b frequency calculated on the basis of non-TCCU clinical trial c include: phlebitis (2.4%), deep vein thrombosis (0.4%), superficial phlebitis (0.2%), thrombophlebitis (0.2%) and superficial thrombophlebitis (0.2%)

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Nebenwirkungen · Javlor

Javlor 25 mg/mL concentrate for solution for infusion · Abschnitt 4.8 · PDF-Seite 10

HOS-209980 · Präparat HOS-154415

Adverse reactions in all indications Adverse reactions occurring in patients with transitional cell carcinoma of the urothelium and in patients with other disease than this indication and potentially severe or adverse reactions that are a class effect of the vinca alkaloids are described below:

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Nebenwirkungen · Javlor

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HOS-209981 · Präparat HOS-154415

Blood and lymphatic system disorders Grade 3/4 neutropenia was observed in 43.8% of patients. Severe anaemia and thrombocytopenia were less common (respectively 8.8 and 3.1%). Febrile neutropenia defined as ANC < 1 000/mm3 and fever ≥ 38.5 °C of unknown origin without clinically microbiologically documented infection (NCI

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Nebenwirkungen · Javlor

Javlor 25 mg/mL concentrate for solution for infusion · Abschnitt 4.8 · PDF-Seite 10–11

HOS-209982 · Präparat HOS-154415

10 CTC version 2.0) was observed in 5.2% of patients. Infection with Grade 3/4 neutropenia was observed in 2.8% of patients. Overall 8 patients (0.6% of the treated population) died from infection as a complication occurring during neutropenia.

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Nebenwirkungen · Javlor

Javlor 25 mg/mL concentrate for solution for infusion · Abschnitt 4.8 · PDF-Seite 11

HOS-209983 · Präparat HOS-154415

Gastrointestinal disorders Constipation is a class effect of the vinca alkaloids: 11.8% of patients experienced severe constipation during treatment with vinflunine. Grade 3/4 ileus reported in 1.9% of patients was reversible when managed by medical care. Constipation is managed by medical care (see section 4.4).

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Nebenwirkungen · Javlor

Javlor 25 mg/mL concentrate for solution for infusion · Abschnitt 4.8 · PDF-Seite 11

HOS-209984 · Präparat HOS-154415

Nervous system disorders Sensory peripheral neuropathy is a class effect of the vinca alkaloids. Grade 3 was experienced by 0.6% patients. All resolved during the study. Rare cases of Posterior Reversible Encephalopathy Syndrome have been reported (see section 4.4).

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Nebenwirkungen · Javlor

Javlor 25 mg/mL concentrate for solution for infusion · Abschnitt 4.8 · PDF-Seite 11

HOS-209985 · Präparat HOS-154415

Cardiovascular disorders Cardiac effects are a known class effect of the vinca alkaloids. Myocardial infarction or ischaemia were experienced by 0.5% of the patients and most of them had a pre-existing cardiovascular disease or risk factors. One patient died after myocardial infarction and another one due to a cardiopulmonary arrest. Few QT interval prolongations have been observed after the administration of vinflunine.

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Nebenwirkungen · Javlor

Javlor 25 mg/mL concentrate for solution for infusion · Abschnitt 4.8 · PDF-Seite 11

HOS-209986 · Präparat HOS-154415

Respiratory, thoracic and mediastinal disorders Dyspnoea occurred in 3.2% of the patients but was rarely severe (Grade 3/4: 1.2%). Bronchospam was reported in one patient treated with vinflunine for a different setting from the indication.

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Nebenwirkungen · Javlor

Javlor 25 mg/mL concentrate for solution for infusion · Abschnitt 4.8 · PDF-Seite 11

HOS-209987 · Präparat HOS-154415

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

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