Carmustine medac (previously Carmustine Obvius) · 4.4 Special warnings and precautions for use · 1

HOS-217603 · has-adverse-reaction-information · PDF-Seite 6

Summary of the safety profile The table includes adverse reactions that were presented during treatment with this medicinal product but may not necessarily have a causal relationship with the medicinal product. Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed may not reflect the rates observed in clinical practice. Adverse reactions are generally included if they were reported in more than 1% of patients in the product monograph or pivotal trials, and/or determined to be clinically important. When placebo-controlled trials are available, adverse reactions are included if the incidence is ≥ 5% higher in the treatment group. Tabulated list of adverse reactions The following table includes adverse reactions of carmustine listed by MedDRA system organ class and frequency convention presented in order of decreasing seriousness: 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. MedDRA system organ Frequency Adverse reactions class Infections and infestations Not known Opportunistic infections (including fatal) Neoplasms benign, Common Acute leukaemia, bone marrow malignant and unspecified dysplasia – following long-term use. (including cysts and polyps) Blood and lymphatic system disorders 6  Very Myelosuppression. common Common Anaemia. Nervous system disorders Very Ataxia, dizziness, headache. common Common Encephalopathy (high-dose therapy and dose-limiting). Not known Muscular pain, status epilepticus, seizure, grand mal seizure. Eye disorders Very Ocular toxicities, transient conjunctival common flushing and blurred vision due to retinal haemorrhages. Cardiac disorde

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HOS-217599 · has-contraindication-information · PDF-Seite 4

- Hypersensitivity to the active substance, to other nitrosoureas or to any of the excipients listed in section 6.1. - Severe bone marrow depression. - Severe (end-stage) renal impairment. - Children and adolescents - Breast-feeding.

HOS-217598 · has-indication-information · PDF-Seite 2

Carmustine is indicated in adults in the following malignant neoplasms as a single agent or in combination with other antineoplastic agents and/or other therapeutic measures (radiotherapy, surgery): - Brain tumours (glioblastoma, Brain-stem gliomas, medulloblastoma, astrocytoma and ependymoma), brain metastases - Secondary therapy in non-Hodgkin’s lymphoma and Hodgkin’s disease - Tumours of the gastrointestinal tract, - Malignant melanoma in combination with other antineoplastic medicinal products. - as conditioning treatment prior to autologous haematopoietic progenitor cell transplantation (HPCT) in malignant haematological diseases (Hodgkin’s disease / Non-hodgkin’s lymphoma).

HOS-217601 · has-interaction-information · PDF-Seite 5

Phenytoin and dexamethasone In combination with chemotherapeutic medicinal products reduced activity of antiepileptic medicinal products must be anticipated. Cimetidine Concomitant use with cimetidine leads to delayed, major, suspected, increased carmustine toxic effect (due to the inhibition of carmustine metabolism). Digoxin Concomitant use with digoxin leads to delayed, moderate, suspected, decreased effect of digoxin (due to the decreased digoxin absorption). Melphalan Concomitant use with melphalan leads to increased risk of pulmonary toxicity.

HOS-217602 · has-pregnancy-information · PDF-Seite 5

Women of childbearing potential/Contraception in males and females Women should use effective contraception to avoid becoming pregnant while on treatment and for at least 6 months after treatment. Male patients should be advised to use adequate contraceptive measures while on treatment with carmustine and for at least 6 months after treatment. 5 Pregnancy Carmustine should not be administered to patients who are pregnant. Safe use in pregnancy has not been established and therefore the benefit must be carefully weighed against the risk of toxicity. Carmustine is embryotoxic in rats and rabbits and teratogenic in rats when given in doses equivalent to the human dose (see section 5.3). If Carmustine medac is used during pregnancy, or if the patient becomes pregnant while taking (receiving) Carmustine medac, the patient should be apprised of the potential hazard to the foetus. Breast-feeding It is unknown whether carmustine/metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. Carmustine medac is contraindicated during breast-feeding and up to seven days post-treatment (see section 4.3). Fertility Carmustine may impair male fertility. Males should be advised of potential risk of infertility and to seek fertility/family planning counselling prior to therapy with carmustine .

HOS-217600 · has-warning-information · PDF-Seite 4

Pulmonary toxicity characterised by pulmonary infiltrates and/or fibrosis has been reported to occur with a frequency ranging up to 30%. This may occur within 3 years of therapy and appears to be dose related with cumulative doses of 1,200-1,500 mg/m2 being associated with increased likelihood of lung fibrosis. Risk factors include smoking, the presence of a respiratory condition, pre-existing radiographic abnormalities, sequential or concomitant thoracic irradiation and association with other agents that cause lung damage. Baseline pulmonary function studies and chest X-ray should be conducted along with frequent pulmonary function tests during treatment. Patients with a baseline below 70% of the predicted forced vital capacity (FVC) or carbon monoxide diffusing capacity (DLCO) are particularly at risk. An increased risk for pulmonary toxicities upon treatment with conditioning regimes and HPCT for females has been reported. So far, this increased risk is described for the treatment itself including conditioning regimes without carmustine (e.g. TBI or busulfan-cyclophosphamide) or with carmustine (BEAM: carmustine, etopside, cytarabine and melphalan or CBV: cyclophosphamide, carmustine and etoposide). High-dose therapy with carmustine (especially with 600 mg/m2) prior to haematopoietic stem cell transplantation has been shown to increase the risk for incidence and severity of pulmonary toxicities. Therefore, in patients with other risks for pulmonary toxicities, use of carmustine needs to be weighed against the risks. Upon high-dose therapy with carmustine, the risk and severity for infections, cardiac, hepatic, gastrointestinal, and renal toxicity, diseases of the nervous system and electrolyte abnormalities (hypokalemia, hypomagnesemia and hypophosphatemia) rises. 4 Patients with comorbidities and worse disease status have a higher risk for adverse reactions. This needs to be respected especially for elderly patients. Hepatic and renal function should also be checked prior to treatment and regularly monitored during therapy (see section 4.8). Neutropenic enterocolitis can occur as therapy-related adverse reaction upon treatment with chemotherapeutic agents. Carmustine is carcinogenic in rats and mice at doses less than the recommended human dose based on body surface area (see section 5.3). Bone marrow toxicity is a common and severe toxic adverse reaction of carmustine. Complete blood cou

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