Ceplene · 4.6 Fertility, pregnancy and lactation · 1

HOS-094782 · has-adverse-reaction-information · PDF-Seite 7

Summary of the safety profile Adverse reactions were reported to be at least possibly related to IL-2 and Ceplene treatment in almost all patients in studies in AML. 7 The most common adverse reactions experienced by 30% or more of patients receiving IL-2 and Ceplene (listed in descending order of frequency) were: flushing, headache, fatigue, injection site granuloma, pyrexia and injection site erythema. Tabulated list of adverse reactions The adverse reactions considered at least possibly related to the treatment of low-dose IL-2 with Ceplene in AML studies (n=280 for the IL-2 and Ceplene treatment arm) are listed below by body system organ, class and frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as 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), or not known (cannot be estimated from the available data). System organ class Adverse reaction Frequency Infections and infestationsupper respiratory tract Very common infections pneumonia Common Blood and lymphatic system eosinophilia, thrombocytopenia Very common disorders leucopenia, Common neutropenia Metabolism and nutrition anorexia Common disorders Psychiatric disorders insomnia Common Nervous system disorders headache, dizziness, dysgeusia Very common Cardiac disorders tachycardia Very common palpitations Common Vascular disorders flushing, hypotension Very common Respiratory, thoracic, and cough, dyspnoea Very common mediastinal disorders nasal congestion Common Gastrointestinal disorders nausea, dyspepsia, diarrhoea Very common vomiting, abdominal pain Common

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HOS-094778 · has-contraindication-information · PDF-Seite 5

 Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.  Patients with significantly compromised cardiac function, e.g., NYHA Class III/IV.  Patients receiving systemic steroid therapy, clonidine and H2 blocking agents.  Patients who have received an allogenic stem cell transplant.  During pregnancy.  During breast feeding. 5

HOS-094777 · has-indication-information · PDF-Seite 2

Ceplene maintenance therapy is indicated for adult patients with acute myeloid leukaemia (AML) in first remission concomitantly treated with interleukin-2 (IL-2). The efficacy of Ceplene has not been fully demonstrated in patients older than age 60.

HOS-094780 · has-interaction-information · PDF-Seite 6

While posology differs, when Ceplene is used in conjunction with IL-2, physicians should also refer to the Summary of Product Characteristics (SmPC) for IL-2 and observe the respective medicinal product interactions. H2 receptor antagonists with imidazole structures similar to histamine, e.g., cimetidine, systemic steroids and clonidine, must not be used during treatment with Ceplene (see section 4.3). Beta-blockers and other anti-hypertensive agents should be used with caution during treatment with Ceplene. Concurrent administration of medicinal products with cardiotoxicity or blood pressure lowering effects may increase the toxicity of Ceplene. 6 H1 receptor blocking antihistamines or neuroleptics (anti-psychotics) with H1 receptor blocking properties that might decrease efficacy of Ceplene should be avoided. Tricyclic anti-depressants may have H1 and H2 receptor blocking properties and should be avoided. Monoamine oxidase inhibitors, anti-malarial, and anti-trypanosomal active substances may alter the metabolism of Ceplene and should be avoided (see section 4.4). It has been noted that neuromuscular blocking agents, narcotic analgesics, and various contrast media can induce the release of endogenous histamine; therefore in patients undergoing diagnostic or surgical procedures, the additive effect of Ceplene treatment should be considered prior to the procedure (see section 4.4).

HOS-094781 · has-pregnancy-information · PDF-Seite 7

Contraception in males and females Women of childbearing potential and sexually active men must use effective methods of contraception during treatment with Ceplene and IL-2. Pregnancy For Ceplene, no clinical data on exposed pregnancies are available. Animal studies showed reproductive toxicity but only at maternotoxic doses, and did not indicate direct harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). Ceplene in conjunction with IL-2 must not be used during pregnancy. Breast-feeding It is unknown whether histamine is excreted in human breast milk. The excretion of histamine in milk has not been studied in animals, but at maternotoxic doses in rats, offspring showed slight toxicity during early lactation (see section 5.3). Ceplene in conjunction with IL-2 must not be used during breast-feeding. Refer to the IL-2 SmPC for information on pregnancy and breast-feeding with IL-2. Fertility No clinical data are available on the effects of Ceplene on fertility. Animal studies revealed no adverse effects on fertility apart from a slight reduction in implantations and viable foetuses (see section 5.3).

HOS-094779 · has-warning-information · PDF-Seite 6

Ceplene should be administered 1 to 3 minutes after IL-2 administration, and not concomitantly. Rapid subcutaneous injection or injection into a vascular space may result in severe hypotension, tachycardia, or syncope. Treatment with Ceplene in conjunction with IL-2 should be used with caution in patients with poorly compensated cardiac function. Patients with cardiac disease should be evaluated for ventricular ejection fraction and wall function by echocardiography or nuclear medicine stress test and then treated with caution. Patients should be monitored during treatment for possible clinical complications due to hypotension or hypovolaemia. Ceplene should be administered in the clinic under supervision of the physician on day 1 of the initial treatment cycle. Patient monitoring on day 1 should include vital signs, including pulse, blood pressure and respiratory rate. Patient monitoring during subsequent treatment days or cycles should be performed as long as the patient continues to experience significant changes in vital signs during administration of Ceplene. If significant hypotension or related symptoms are observed in subsequent treatment cycles, dose reduction should be initiated and if required, administered in hospital until responses to treatment allow for home administration. Caution should be used for patients with any of the following: symptomatic peripheral arterial disease, past or present peptic or oesophageal ulcer disease with a history of bleeding, clinically significant renal disease and stroke within the last 12 months. Where appropriate, consideration should be made to providing concomitant treatment with a proton pump inhibitor. Patients with clinically significant infection requiring the use of antibiotics, antifungals, or antivirals, or who have completed prior anti-infectious therapy within 14 days of starting treatment should be treated with caution unless the use of antibiotics and antivirals were for prophylaxis purposes. Patients with a prior history of autoimmune disease (including systemic lupus, inflammatory bowel disease, psoriasis and rheumatoid arthritis) should be treated with caution. Monitoring of laboratory test results is recommended including standard haematological and blood chemistry tests. Patients receiving the following medicinal products should be treated with caution (see section 4.5): - Beta-blockers or other anti-hypertensive agents. - H1 blocking agents and neuroleptics (anti-psychotics) with H1

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