Leitlinien & Arzneimittelsicherheit

HOS-154422 · has-adverse-reaction-information · PDF-Seite 8

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. 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. 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 H

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HOS-154418 · has-contraindication-information · PDF-Seite 5

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).

HOS-154417 · has-indication-information · PDF-Seite 2

Javlor is indicated in monotherapy for the treatment of adult patients with advanced or metastatic transitional cell carcinoma of the urothelial tract after failure of a prior platinum-containing regimen. Efficacy and safety of vinflunine have not been studied in patients with performance status ≥ 2.

HOS-154420 · has-interaction-information · PDF-Seite 7

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. 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. 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. 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). The concomitant use of vinflunine with others QT/QTc interval prolonging medicinal products should be avoided (see section 4.4). 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. 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. The concomitant use of opioids could enhance the risk of constipation. 7

HOS-154421 · has-pregnancy-information · PDF-Seite 8

Contraception in males and females Due to the genotoxic potential of vinflunine (see section 5.3), both male and female patients should take adequate and effective contraceptive measures during treatment and up to 4 months after the discontinuation of the therapy for men and 7 months after the discontinuation of therapy for women. Pregnancy There are no data available on the use of vinflunine in pregnant women. Studies in animals have shown embryotoxicity and teratogenicity (see section 5.3). On the basis of the results of animal studies and the pharmacological action of the medicinal product, there is a potential risk of embryonic and foetal abnormalities. Vinflunine should therefore not be used during pregnancy, unless it is strictly necessary. If pregnancy occurs during treatment, the patient should be informed about the risk for the unborn child and be monitored carefully. The possibility of genetic counselling should be considered. Genetic counselling is also recommended for patients wishing to have children after therapy. Women of child-bearing potential Women of child-bearing potential must use effective contraception during treatment and for 7 months after treatment. Breast-feeding It is unknown whether vinflunine or its metabolites are excreted in human milk. Due to the possible very harmful effects on the infants, breast-feeding during treatment with vinflunine is contraindicated (see section 4.3). Fertility Advice on conservation of sperm should be sought prior to treatment because of the possibility of irreversible infertility due to therapy with vinflunine.

HOS-154419 · has-warning-information · PDF-Seite 5

Hematological toxicity Neutropenia, leucopenia, anaemia and thrombocytopenia are frequent adverse reactions of vinflunine. Adequate monitoring of complete blood counts should be conducted to verify the ANC, platelet and haemoglobin values before each vinflunine infusion (see section 4.3). Initiation of vinflunine is contraindicated in subjects with baseline ANC < 1 500/mm3 or platelets < 100 000/mm3. For subsequent administrations, vinflunine is contraindicated in subjects with baseline ANC < 1 000/mm3 or platelets < 100 000/mm3. The recommended dose should be reduced in patients with haematological toxicity (see section 4.2). Gastrointestinal disorders Grade ≥ 3 constipation occurred in 15.3% of treated patients. NCI CTC Grade 3 constipation is defined as an obstipation requiring manual evacuation or enema, Grade 4 constipation as an obstruction or toxic megacolon. Constipation is reversible and can be prevented by special dietary measures such as oral hydration and fibre intake, and by administration of laxatives such as stimulant 5 laxatives or faecal softners from day 1 to day 5 or 7 of the treatment cycle. Patients at high risk of constipation (concomitant treatment with opiates, peritoneal carcinomas, abdominal masses, prior major abdominal surgery) should be medicated with an osmotic laxative from day 1 to day 7 administered once a day in the morning before breakfast. In case of Grade 2 constipation, defined as requiring laxatives, for 5 days or more or Grade ≥ 3 of any duration, the dose of vinflunine should be adjusted (see section 4.2). In case of any Grade ≥ 3 gastrointestinal toxicity (except vomiting or nausea) or of mucositis (Grade 2 for 5 days or more or Grade ≥ 3 of any duration) dose adjustment is required. Grade 2 is defined as “moderate”, Grade 3 as “severe” and Grade 4 as “life-threatening” (see Table 2 in section 4.2). Cardiac disorders Few QT interval prolongations have been observed after the administration of vinflunine. This effect may lead to an increased risk of ventricular arrhythmias although no ventricular arrhythmias were observed with vinflunine. Nevertheless, vinflunine should be used with caution in patients with increase of the proarrhythmic risk (e.g. congestive heart failure, known history of QT interval prolongation, hypokalaemia) (see section 4.8). The concomitant use of two or more QT/QTc interval prolonging substances is not recommended (see section 4.5). Spec

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