CYCLOPHOSPHAMIDE

Cyclophosphamide should only be used by clinicians experienced in the use of cancer chemotherapy. Cyclophosphamide 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 hematopoiesis 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 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 Infections 1 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 Rare Rare Rare Rare Rare Very rare Not known Not known Not known Not known Thyroid cancer Not known Blood and lymphatic system disorders Myelosuppression4 Leukopenia Neutropenia Febrile neutropenia Thrombocytopenia Anaemia Disseminated intravascular coagulation Haemolytic uremic syndrome Agranulocytosis Lymphopenia Haemoglobin decreased Very common Very common Very common Common Uncommon Uncommon Very rare Very rare 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) Rare 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 Rare Visual impairment Conjunctivitis Eye oedema 7 Lacrimation increased Rare Very rare Very rare Not known Ear and labyrinth disorders Deafness Tinnitus Uncommon Not known Cardiac disorders Cardiomyopathy Myocarditis Heart failure 8 Tachycardia Ventricular arrhythmia Supraventricular arrhythmia Ventricular fibrillation Angina Myocardial infarction Pericarditis Atrial fibrillation Ventricular tachycardia Cardiogenic shock Pericardial effusion Bradycardia Palpitations Electrocardiogram QT prolonged Uncommon Uncommon Uncommon Uncommon Rare Rare Very rare Very rare Very rare Very rare Very rare 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 Uncommon Rare Very rare Very rare Very rare Not known Not known Not known Not known Respiratory, thoracic and mediastinal disorders 89 Acute respiratory distress syndrome (ARDS) Chronic pulmonary interstitial fibrosis, Pulmonary oedema Bronchospasm Dyspnoea Very rare Very rare Very rare Very rare Very rare Hypoxia Cough Nasal congestion Oropharyngeal pain Rhino rhea Sneezing Pulmonary veno-occlusive disease Obliterative bronchiolitis Alveolitis allergic Pneumonitis Pleural effusion Very rare Very rare 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 Constipation Nausea Abdominal pain Parotid gland inflammation Gastrointestinal haemorrhage Cecitis Colitis Enteritis Common Very rare 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 Hepatobiliary disorders Hepatic function abnormal Hepatitis Veno-occlusive liver disease Hepatomegaly Jaundice Cholestatic hepatitis Hepatotoxicity 10 Common Rare Very rare Very rare Very rare Not known Not known Skin and subcutaneous tissue disorders Alopecia 11 Rash Dermatitis Nail discolouration Very common Rare Rare Rare Skin discolouration 12 Stevens-Johnson syndrome Toxic epidermal necrolysis Radiation erythaema Pruritus (including itching due to inflammation) Erythaema multiforme Palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome) Urticaria Erythaema Facial swelling Hyperhidrosis Rare Very rare Very rare Very rare Very rare 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 Bladder fibrosis and sclerosis Renal impairment Blood creatinine increased Renal tubular necrosis Renal tubular disorder Nephropathy toxic Hemorrhagic ureteritis Bladder contracture Nephrogenic diabetes insipidus Atypical urinary bladder epithelial cells Blood urea nitrogen increased Very common Very common Common Common 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 Pregnancy, puerperium and Premature labour Not known perinatal conditions Reproductive system and breast disorders Impairment of spermatogenesis Ovulation disorder (rarely irreversible) Amenorrhea 13 Azoospermia/asperima 13 Oligospermia 13 Infertility Ovarian Failure Oligomenorrhoe Testicular atrophy Common Uncommon Rare Rare Rare Not known Not known Not known Not known Congenital, familial and genetic disorders Intra-uterine death Foetal malformation Foetal growth retardation Foetal damage Carcinogenic effect on offspring Not known Not known Not known Not known Not known General disorders and administrative site conditions Fever Chills Asthenia Malaise Chest pain Headache Multiorgan failure Injection/infusion site reactions […]

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. 086 mmol/l). 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.

In patients requiring dialysis, use of a consistent interval between cyclophosphamide administration and dialysis should be considered. 4. Elderly In elderly patients, monitoring for toxicities and the need for dose adjustment should reflect the higher frequency of decreased hepatic, renal, cardiac, or other organ function, and concomitant diseases or other drug therapy in this population.

Paediatric population Cyclophosphamide has been administered to children. The safety profile of cyclophosphamide in paediatric patients is similar to that of the adult population. Dose modification due to myelosuppression A leukocyte and platelet count should be regularly performed during treatment with cyclophosphamide.

It is recommended to adjust the dose, if required, if signs of myelosuppression become evident. Please refer to the table below. Urinary sediment should also be checked regularly for the presence of erythrocytes. Leukocyte count/μl Platelet count /μl Dosage > 4000 > 100 000 100% of the planned dose 2500 – 4000 50 000 – 100 000 50 % of the planned dose < 2500 < 50 000 Omit until values normalise or decide individually In combination therapy further dose reductions may have to be considered.

Method of administration Cyclophosphamide is inert until activated by enzymes in the liver. However, as with all cytotoxic agents, it is recommended that reconstitution should be performed by trained personnel, in a designated area.

Precaution to be taken before manipulating or administering the product Those handling the preparation should wear protective gloves. Care should be taken to avoid splashing material into the eyes. The material should not be handled by women who are pregnant or who are breast-feeding.

The choice of solvent for reconstituting Cyclophosphamide containing cyclophosphamide depends on the route of administration to be used. 9% sterile sodium chloride solution. 9% sodium chloride solution prior to infusion. 9% sterile sodium chloride solution.

9% sterile sodium chloride solution is suitable for bolus injection. Cyclophosphamide (containing cyclophosphamide) reconstituted in water is hypotonic and should not be injected directly. 6. Intravenous use Intravenous administration should preferably be conducted as an infusion.

g. facial swelling, headache, nasal congestion, scalp burning), cyclophosphamide should be injected or infused very slowly. Duration of the infusion (ranging from 30 minutes to 2 hours) should be appropriate for the volume and type of carrier fluid to be infused.

Before intravenous use, the substance must be completely dissolved. Drug products for intravenous use must be inspected visually for particulate matter and discolouration prior to administration whenever solution and container permit.

6) Cyclophosphamide should not be used in the […]

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