CYCLOPHOSPHAMIDE SEACROSS

Cyclophosphamide Seacross should only be used by clinicians experienced in the use of cancer chemotherapy. Cyclophosphamide Seacross should only be administered where there are facilities for regular monitoring of clinical, biochemical and haematological parameters before, during, and after administration and under the direction of a specialist oncology service.

Posology Dosage must be individualised. Doses and duration of treatment and/or treatment intervals depend on the therapeutic indication, the scheme of a combination therapy, the patient’s general state of health and organ function, and the results of laboratory monitoring (in particular, blood cell monitoring).

In combination with other cytostatics of similar toxicity, a dose reduction or extension of the therapy- free intervals may be necessary. Use of haematopoiesis stimulating agents (colony-stimulating factors and erythropoiesis stimulating agents) may be considered to reduce the risk of myelosuppressive complications and/or help facilitate the delivery of the intended dosing.

Prior, during and immediately after the administration, adequate amounts of fluid should be ingested or infused to force diuresis in order to reduce the risk of urinary tract toxicity. Therefore, Cyclophosphamide Seacross should be administered in the morning.

See section

The frequency of adverse reactions reported in the table below are derived from clinical trials and from post marketing experience and are 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.

Organ System Class (SOC) Recommended MedDRA term Frequency Infections and infestations Infections1 Pneumonia2 Sepsis1 Common Uncommon Uncommon Neoplasms, benign and malignant and unspecified (including cysts and polyps) Acute leukaemia3 Myelodysplastic syndrome Secondary malignancies Bladder cancer Ureteric cancer Tumour lysis syndrome Non-Hodgkin’s lymphoma Sarcoma Renal cell carcinoma Renal pelvis cancer Thyroid cancer Neoplasia Rare Rare Rare Rare Rare Very rare Not known Not known Not known Not known Not known Not known Blood and lymphatic system disorders Myelosuppression4 Leukopenia Neutropenia Febrile neutropenia Thrombocytopenia Anaemia Disseminated intravascular coagulation Very common Very common Very common Common Uncommon Uncommon Very rare Very rare Haemolytic uremic syndrome Agranulocytosis Lymphopenia Haemoglobin decreased Not known Not known Not known Immune system disorders Immunosuppression Anaphylactic/Anaphylactoid reaction Hypersensitivity reaction Anaphylactic shock Very common Uncommon Uncommon Very rare Endocrine disorders SIADH (syndrome of inappropriate antidiuretic hormone secretion) Water intoxication Rare Not known Metabolism and nutrition disorders Anorexia Dehydration Hyponatremia Blood glucose increased Blood glucose decreased Uncommon Rare Very rare Not known Not known Psychiatric disorders Confusional state Very rare Nervous system disorders Peripheral neuropathy Polyneuropathy Neuralgia Convulsion Dizziness Dysgeusia Hypogeusia Paresthesia Neurotoxicity5 Reversible posterior leukoencephalopathy Syndrome6 Encephalopathy Uncommon Uncommon Uncommon Rare Rare Very rare Very rare Very rare Not known Not known Not known Eye disorders Blurred vision Visual impairment Conjunctivitis Eye oedema7 Lacrimation increased Rare Rare Very rare Very rare Not known Ear and labyrinth disorders Deafness Tinnitus Hearing impaired Uncommon Not known Not known Cardiac disorders Cardiomyopathy Myocarditis Heart failure8 Tachycardia Ventricular arrhythmia Supraventricular arrhythmia Ventricular fibrillation Angina Myocardial infarction Pericarditis Atrial fibrillation Ventricular tachycardia Uncommon Uncommon Uncommon Uncommon Rare Rare Very rare Very rare Very rare Very rare Very rare Not known Cardiogenic shock Pericardial effusion Bradycardia Palpitations Electrocardiogram QT prolonged Myocardial haemorrhage Cardiac failure congestive Left ventricular failure Left ventricular dysfunction Carditis Ejection fraction decreased Not known Not known Not known Not known Not known Not known Not known Not known Not known Not known Not known Vascular disorders Flushing Haemorrhage Thromboembolism Hypertension Hypotension Pulmonary embolism Venous thrombosis Vasculitis Peripheral ischemia Hot flush Blood pressure decreased Uncommon Rare Very rare Very rare Very rare Not known Not known Not known Not known Not known Not known Respiratory, thoracic and mediastinal disorders8,9 Acute respiratory distress syndrome (ARDS) Chronic pulmonary interstitial fibrosis Pulmonary oedema Bronchospasm Dyspnoea Hypoxia Cough Nasal congestion Oropharyngeal pain Rhinorrhea Sneezing Pulmonary veno-occlusive disease Obliterative bronchiolitis Alveolitis allergic Pneumonitis Pleural effusion Respiratory failure Organizing pneumonia Respiratory distress Pulmonary hypertension Very rare Very rare Very rare Very rare Very rare Very rare Very rare Not known Not known Not known Not known Not known Not known Not known Not known Not known Not known Not known Not known Not known Gastrointestinal disorders Mucosal inflammation Enterocolitis haemorrhagic Acute pancreatitis Ascites Stomatitis Diarrhoea Vomiting Common Very rare Very rare Very rare Very rare Very rare Very rare Constipation Nausea Abdominal pain Parotid gland inflammation Gastrointestinal haemorrhage Cecitis Colitis Enteritis Abdominal discomfort Very rare Very rare Not known Not known Not known Not known Not known Not known Not known Hepatobiliary disorders Hepatic function abnormal Hepatitis Veno-occlusive liver disease Hepatomegaly Jaundice Cholestatic hepatitis Hepatotoxicity10 Cytolytic hepatitis Cholestasis Common Rare Very rare Very rare Very rare Not known Not known Not known Not known Skin and subcutaneous tissue disorders Alopecia11 Rash Dermatitis Nail discolouration Skin discolouration12 Stevens-Johnson syndrome Toxic epidermal necrolysis Radiation erythema Pruritus (including itching due to inflammation) Erythema multiforme Palmar-plantar erythrodysesthesia syndrome (hand- foot syndrome) Urticaria Erythema Facial swelling Hyperhidrosis Toxic skin eruption Blister Nail disorder Very common Rare Rare Rare Rare Very rare Very rare Very rare Very rare Not known Not known Not known Not known Not known Not known Not known Not known Not known Musculoskeletal and connective tissue disorders Rhabdomyolysis Cramps Scleroderma Muscle spasms Myalgia Arthralgia Very rare Very rare Not known Not known Not known Not known Renal and urinary tract disorders Cystitis Microhaematuria Haemorrhagic cystitis Macrohematuria Suburethral haemorrhage Bladder wall oedema Very common Very common Common Common Very rare Very rare Bladder fibrosis and sclerosis Renal impairment Renal failure Blood creatinine increased Renal tubular necrosis Renal tubular disorder Nephropathy toxic Haemorrhagic ureteritis Bladder contracture Nephrogenic diabetes insipidus Atypical urinary bladder epithelial cells Blood urea nitrogen increased Bladder necrosis Very rare Very rare Very rare Very rare Very rare Not known Not known Not known Not known Not known Not known Not known Not known Pregnancy, puerperium and perinatal conditions Premature labour Not known […]

4. It is within the responsibility of the physician to decide on the use of Cyclophosphamide according to the operative treatment guidelines.

The doses below can be regarded as general guidelines:

Hematologic and solid tumours a. For daily treatment: 3 – 6 mg/kg body weight (= 120 – 240 mg/m2 body surface area), injected intravenously, b. For intermittent treatment: 10 – 15 mg/kg body weight (= 400 – 600 mg/m2 body surface area), injected intravenously, with therapy-free intervals of 2 to 5 days.

c. For high-dose- intermittent treatment: 20 – 40 mg/kg body weight (= 800 – 1600 mg/m2 body surface area), injected intravenously, with therapy-free intervals of 21 to 28 days. As preparation for a bone marrow transplantation 2 days 60 mg/kg or 4 days 50 mg/kg body weight injected intravenously.

5). Autoimmune diseases Per month 500 – 1000 mg/m2 body surface area. Patients with Hepatic Impairment Severe hepatic impairment may be associated with a decreased activation of cyclophosphamide. This may alter the effectiveness of the cyclophosphamide treatment and should be considered when selecting the dose and interpreting response to the dose selected.

4). The dose must be reduced in patients with severe hepatic impairment. Patients with Renal Impairment In patients with renal impairment, particularly in patients with severe renal impairment, decreased renal excretion may result in increased plasma levels of cyclophosphamide and its metabolites.

This may result in increased toxicity and should be considered when determining the dosage in such patients. 4). A dose reduction of 50% for a glomerular filtration rate below 10 mL/minute is recommended. Cyclophosphamide and its metabolites are dialyzable, although there may be differences in clearance depending upon the dialysis system being used.

6) Cyclophosphamide should not be used in the management of non-malignant disease, except for immunosuppression in life-threatening situations