Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: Sandoz Limited, Frimley Business Park, Frimley, Camberley, Surrey, GU16 7SR, United Kingdom
Cyclophosphamide is contra-indicated in patients with:
Cyclophosphamide should not be used in the management of non-malignant disease, except for immunosuppression in life-threatening situations.
Anaphylactic reactions including those with fatal outcomes have been reported in association with cyclophosphamide. Possible cross-sensitivity with other alkylating agents has been reported.
Treatment with cyclophosphamide may cause myelosuppression (anaemia, leukopenia, neutropenia and thrombocytopenia) and significant suppression of immune responses, which may result in severe, sometimes fatal, infections, sepsis and septic shock. Infections reported with cyclophosphamide include pneumonias, as well as other bacterial, fungal, viral, protozoal, and parasitic infections.
Latent infections can be reactivated. Reactivation has been reported for various bacterial, fungal, viral, protozoal, and parasitic infections.
Infections occurring during treatment with cyclophosphamide, including neutropenic fever, must be treated appropriately. Antimicrobial prophylaxis may be indicated in certain cases of neutropenia (at the discretion of the managing physician). In case of neutropenic fever, antibiotics and/or antimycotics must be given. Cyclophosphamide must be administered with the necessary caution (or not at all) in patients with severe functional impairment of bone marrow and patients with severe immunosuppression.
Close haematological monitoring is required for all patients during treatment. Haematological parameters must be checked prior to each administration and regularly during treatment. More frequent monitoring may be required if leukocyte counts drop below 3000 cells/microlitre (cells/mm³). Dose adjustment due to myelosuppression is recommended (see section 4.2).
Unless essential, cyclophosphamide should not be administered to patients with a leukocyte count below 2500 cells/microlitre (cells/ mm³) and/or a platelet count below 50,000 cells/microlitre (cells/mm³).
In principle, the fall in the peripheral blood cell and thrombocyte count and the time taken to recover may increase with increasing doses of cyclophosphamide.
The nadirs of the reduction in leukocyte count and thrombocyte count are usually reached in weeks 1 and 2 of treatment. The bone marrow recovers relatively quickly, and the levels of peripheral blood cell counts normalise, as a rule, after approximately 20 days.
Cyclophosphamide treatment may not be indicated, or should be interrupted, or the dose reduced, in patients who have or who develop a serious infection.
Severe myelosuppression must be expected particularly in patients pre-treated with and/or receiving concomitant chemotherapy and/or radiation therapy.
Hemorrhagic cystitis, pyelitis, ureteritis, and haematuria have been reported with cyclophosphamide therapy. Bladder ulceration/necrosis, fibrosis/contracture and secondary cancer may develop. Urotoxicity may mandate interruption of treatment. Cases of urotoxicity with fatal outcomes have been reported.
Urotoxicity can occur with short-term and long-term use of cyclophosphamide. Hemorrhagic cystitis after single doses of cyclophosphamide has been reported. Cystectomy may become necessary due to fibrosis, bleeding, or secondary malignancy. Past or concomitant radiation or busulfan treatment may increase the risk for cyclophosphamide-induced hemorrhagic cystitis. Cystitis is, in general, initially abacterial. Secondary bacterial colonisation may follow.
Before starting treatment, it is necessary to exclude or correct any urinary tract obstructions. See section 4.3.Urinary sediment should be checked regularly for the presence of erythrocytes and other signs of uro/nephrotoxicity. Adequate treatment with mesna and/or strong hydration to force diuresis can markedly reduce the frequency and severity of bladder toxicity. It is important to ensure that patients empty the bladder at regular intervals. Haematuria usually resolves in a few days after cyclophosphamide treatment is stopped, but it may persist. Severe hemorrhagic cystitis usually requires a discontinuation of the treatment with cyclophosphamide.
Cyclophosphamide has also been associated with nephrotoxicity, including renal tubular necrosis.
Hyponatremia associated with increased total body water, acute water intoxication, and a syndrome resembling SIADH (syndrome of inappropriate secretion of antidiuretic hormone) have been reported in association with cyclophosphamide administration. Fatal outcomes have been reported.
Myocarditis and myopericarditis, which may be accompanied by significant pericardial effusion and cardiac tamponade, have been reported with cyclophosphamide therapy and have led to severe, sometimes fatal congestive heart failure. Histopathologic examination has primarily shown hemorrhagic myocarditis. Haemopericardium has been reported secondary to hemorrhagic myocarditis and myocardial necrosis. Acute cardiac toxicity has been reported with single doses as low as 20 mg/kg of cyclophosphamide.
Following exposure to treatment regimens that included cyclophosphamide, supraventricular arrhythmias (including atrial fibrillation and flutter) as well as ventricular arrhythmias (including severe QT prolongation associated with ventricular tachyarrhythmia) have been reported in patients with and without other signs of cardiotoxicity.
The risk of cyclophosphamide cardiotoxicity as a result of treatment with cyclophosphamide may, for example, be increased following high doses of cyclophosphamide, in patients with advanced age, and in patients with previous radiation treatment of the cardiac region and/or previous or concomitant treatment with other cardiotoxic agents. See section 4.5.
Particular caution is required in patients with risk factors for cardiotoxicity and in patients with a pre-existing cardiac disease.
Pneumonitis and pulmonary fibrosis have been reported during and following treatment with cyclophosphamide. Pulmonary veno-occlusive disease and other forms of pulmonary toxicity have also been reported. Pulmonary toxicity leading to respiratory failure has been reported. While the incidence of cyclophosphamide-associated pulmonary toxicity is low, prognosis for affected patients is poor. Late onset of pneumonitis (greater than 6 months after start of cyclophosphamide) appears to be associated with a particularly high mortality. Pneumonitis may develop even years after treatment with cyclophosphamide. Acute pulmonary toxicity has been reported after a single cyclophosphamide dose.
As with all cytotoxic therapy, treatment with cyclophosphamide involves the risk of secondary tumours and their precursors as sequelae.
The risk of urinary tract cancer as well as the risk of myelodysplastic alterations, partly progressing to acute leukemias, is increased. Other malignancies reported after use of cyclophosphamide or regimens with cyclophosphamide include lymphomas, thyroid cancer, and sarcomas.
In some cases, the second malignancy developed several years after cyclophosphamide treatment had been discontinued. Malignancy has also been reported after in utero exposure.
The risk of bladder cancer can be markedly reduced by hemorrhagic cystitis prophylaxis.
Veno-occlusive liver disease (VOLD) has been reported in patients receiving cyclophosphamide, mainly in patients receiving a cytoreductive regimen in preparation for bone marrow transplantation in combination with whole-body irradiation, busulfan, or other agents (see section 4.5). After cytoreductive therapy, the clinical syndrome typically develops 1 to 2 weeks after transplantation and is characterized by sudden weight gain, painful hepatomegaly, ascites, and hyperbilirubinemia/jaundice. However, VOLD has also been reported to develop gradually in patients receiving long-term low-dose immunosuppressive doses of cyclophosphamide.
As a complication of VOLD, hepatorenal syndrome and multiorgan failure may develop. Fatal outcome of cyclophosphamide-associated VOLD has been reported. Risk factors predisposing a patient to the development of VOLD include pre-existing disturbances of hepatic function, previous radiation therapy of the abdomen, and a low performance score.
VOLD incidence has been reported to reduce, if a time interval of at least 24 hours is observed between the last administration of busulfan and the first administration of cyclophosphamide (see section 4.2 and 4.5).
Cyclophosphamide is genotoxic and mutagenic, both in somatic and in male and female germ cells. Therefore, women should not become pregnant and men should not father a child during therapy with cyclophosphamide.
Women should not become pregnant during the treatment and for a period of 12 months following discontinuation of the therapy.
Men should not father a child during the treatment and for a period of 6 months following discontinuation of the therapy.
Animal data indicate that exposure of oocytes during follicular development may result in a decreased rate of implantations and viable pregnancies, and in an increased risk of malformations. This effect should be considered in case of intended fertilisation or pregnancy after discontinuation of cyclophosphamide therapy. The exact duration of follicular development in humans is not known, but may be longer than 12 months. Sexually active women and men should use effective methods of contraception during these periods of time (see section 4.6).
Cyclophosphamide interferes with oogenesis and spermatogenesis. It may cause sterility in both sexes. Men treated with cyclophosphamide should be informed about sperm preservation prior to treatment (see section 4.6).
Cyclophosphamide may interfere with normal wound healing.
Alopecia has been reported and may occur more commonly with increasing doses. Alopecia may progress to baldness. The hair can be expected to grow back after treatment with the drug or even during continued drug treatment, though it may be different in texture or colour.
Nausea and Vomiting
Administration of cyclophosphamide may cause nausea and vomiting. Current guidelines on the use of anti-emetics for prevention and amelioration of nausea and vomiting should be considered.
Alcohol consumption may increase cyclophosphamide-induced vomiting and nausea.
Administration of cyclophosphamide may cause stomatitis (oral mucositis). Current guidelines on measures for prevention and amelioration of stomatitis should be considered.
The cytostatic effect of cyclophosphamide occurs after its activation, which takes place mainly in the liver. Therefore, the risk of tissue injury from accidental paravenous administration is low.
In case of accidental paravenous administration of cyclophosphamide, the infusion should be stopped immediately, the extravascular cyclophosphamide solution should be aspirated with the cannula in place, and other measures should be instituted as appropriate. The area should subsequently be rinsed with physiological saline solution, and the arm or leg should rest.
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. See section 4.2.
Severe hepatic impairment may be associated with a decreased effect of cyclophosphamide. This may negatively alter the effectiveness of cyclophosphamide treatment and should be considered when selecting the dose and interpreting response to the dose selected. See section 4.2. Due to the porphyrogenic effect of Cycolphosphamide patients with acute porphyria should be treated with caution.
Patients with adrenal insufficiency may require an increase in corticoid substitution dose when exposed to stress from toxicity due to cytostatics, including cyclophosphamide.
Caution is also advised in is patients with diabetes mellitus, since cyclophosphamide may interact with insulin and other hypoglycaemic agents (also see section 4.5).
In general, cytostatics (among which agents cyclophosphamide) should not be administered to patients who had a surgery less than 10 days ago.
Cyclophosphamide is inactive, but is metabolised in the liver, mainly by CYP2A6, 2B6, 2C9, 2C19 and 3A4, into two active metabolites.
Planned co-administration or sequential administration of other substances or treatments with cyclophosphamide that could increase the likelihood or severity of toxic effects (by means of pharmacodynamic or pharmacokinetic interactions) requires careful individual assessment of the expected benefit and the risks.
Patients receiving such combinations must be monitored closely for signs of toxicity to permit timely intervention. Patients being treated with cyclophosphamide and agents that reduce its activation should be monitored for a potential reduction of therapeutic effectiveness and the need for dose adjustment.
Reduced activation of cyclophosphamide may alter the effectiveness of cyclophosphamide treatment.
Substances that delay activation of cyclophosphamide include:
An increase of the concentration of cytotoxic metabolites may occur with:
Combined or sequential use of cyclophosphamide and other agents with similar toxicities can cause combined (increased) toxic effects.
Increased hematotoxicity and/or immunosuppression may result from a combined effect of cyclophosphamide and, for example:
Increased cardiotoxicity may result from a combined effect of cyclophosphamide and, for example:
Increased pulmonary toxicity may result from a combined effect of cyclophosphamide and, for example:
Increased nephrotoxicity may result from a combined effect of cyclophosphamide and, for example:
A reduced antitumor activity was observed in tumour-bearing animals during ethanol (alcohol) consumption and concomitant oral low-dose cyclophosphamide medication. In some patients, alcohol may increase cyclophosphamide-induced vomiting and nausea.
In patients with Wegener’s granulomatosis, the addition of etanercept to standard treatment, including cyclophosphamide, was associated with a higher incidence of non-cutaneous solid malignancies.
Acute encephalopathy has been reported in a patient receiving cyclophosphamide and metronidazole. Causal association is unclear.
In an animal study, the combination of cyclophosphamide with metronidazole was associated with increased cyclophosphamide toxicity.
Concomitant use of tamoxifen and chemotherapy may increase the risk of thromboembolic complications.
Interactions Affecting the Pharmacokinetics and/or Actions of Other Drugs
Cyclophosphamide metabolism by CYP2B6 may inhibit bupropion metabolism.
Both increased and decreased warfarin effects have been reported in patients receiving warfarin and cyclophosphamide.
Lower serum concentrations of cyclosporine have been observed in patients receiving a combination of cyclophosphamide and cyclosporine than in patients receiving only cyclosporine. This interaction may result in an increased incidence of graft versus host disease (GVHD).
Cyclophosphamide treatment causes a marked and persistent inhibition of cholinesterase activity. Prolonged apnoea may occur with concurrent depolarizing muscle relaxants (e.g. succinylcholine, suxamethonium) as a result of a decreased pseudocholinesterase level. If a patient has been treated with cyclophosphamide within 10 days of general anaesthesia, the anaesthesiologist should be alerted.
Impaired absorption of digoxin and β-acetyldigoxin tablets have been reported during a concomitant cytotoxic treatment
The immunosuppressive effects of cyclophosphamide can be expected to reduce the response to vaccination. Use of live vaccines may lead to vaccine-induced infection.
Impaired intestinal absorption of orally administered verapamil has been reported.
Blood sugar levels may drop, if cyclophosphamide and sulfonylurea derivatives are used concomitantly.
Girls treated with cyclophosphamide during pre-pubescence generally develop secondary sexual characteristics normally and have regular menses.
Girls treated with cyclophosphamide during pre-pubescence subsequently have conceived.
Girls treated with cyclophosphamide who have retained ovarian function after completing treatment are at increased risk of developing premature menopause (cessation of menses before age of 40 years).
Women should not become pregnant during the treatment and for a period of 12 months following discontinuation of the therapy.
Men should not father a child during the treatment and for a period of 6 months following discontinuation of the therapy.
Sexually active women and men should use effective methods of contraception during these periods of time.
There are very limited data from the use of cyclophosphamide in pregnant women. There are reports of serious multiple congenital aberrations after use during the first trimester.
Animal studies have shown teratogenicity and other reproduction toxicity (see section 5.3).
Considering the data from human case reports, animal studies and the mechanism of action of cyclophosphamide, its use during pregnancy, in particular during the first trimester, is not recommended.
In each individual case the potential benefit of the treatment should be weighed against the potential risk for the foetus.
Cyclophosphamide is excreted into the breast milk and can cause neutropenia, thrombocytopenia, low haemoglobin, and diarrhoea in children. Cyclophosphamide is contraindicated during breastfeeding (see section 4.3).
Cyclophosphamide interferes with oogenesis and spermatogenesis. It may cause sterility in both sexes. In women cyclophosphamide may cause transient or permanent amenorrhea, and in boys treated with cyclophosphamide during pre-pubescence, oligospermia or azoospermia. Men treated with cyclophosphamide may develop oligospermia or azoospermia. Prior to treatment of men with cyclophosphamide, they should be informed of the possibility to store and keep viable sperm collected before treatment.
Patients undergoing treatment with cyclophosphamide may experience undesirable effects (including nausea, vomiting, dizziness, blurred vision, visual impairment) which could affect the ability to drive or use machines. The decision to drive or operate machinery should be made on an individual basis.
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.
Common: Infections1
Uncommon: Pneumonia2, Sepsis1
Rare: Acute leukaemia3, Myelodysplastic syndrome, Secondary malignancies, Bladder cancer, Ureteric cancer
Very rare: Tumour lysis syndrome
Not known: Non-Hodgkin’s lymphoma, Sarcoma, Renal cell carcinoma, Renal pelvis cancer, Thyroid cancer
Very common: Myelosuppression4, Leukopenia, Neutropenia
Common: Febrile neutropenia
Uncommon: Thrombocytopenia, Anaemia
Very rare: Disseminated intravascular coagulation, Haemolytic uremic syndrome
Not known: Agranulocytosis, Lymphopenia, Haemoglobin decreased
Very common: Immunosuppression
Uncommon: Anaphylactic/Anaphylactoid reaction, Hypersensitivity reaction
Very rare: Anaphylactic shock
Rare: SIADH (syndrome of inappropriate antidiuretic hormone secretion)
Uncommon: Anorexia
Rare: Dehydration
Very rare: Hyponatremia
Not known: Blood glucose increased, Blood glucose decreased
Very rare: Confusional state
Uncommon: Peripheral neuropathy, Polyneuropathy, Neuralgia
Rare: Convulsion, Dizziness
Very rare: Dysgeusia, Hypogeusia, Paresthesia
Not known: Neurotoxicity5, Reversible posterior leukoencephalopathy Syndrome6, Encephalopathy
Rare: Blurred vision, Visual impairment
Very rare: Conjunctivitis, Eye oedema7
Not known: Lacrimation increased
Uncommon: Deafness
Not known: Tinnitus
Uncommon: Cardiomyopathy, Myocarditis, Heart failure8, Tachycardia
Rare: Ventricular arrhythmia, Supraventricular arrhythmia
Very rare: Ventricular fibrillation, Angina, Myocardial infarction, Pericarditis, Atrial fibrillation
Not known: Ventricular tachycardia, Cardiogenic shock, Pericardial effusion, Bradycardia, Palpitations, Electrocardiogram QT prolonged
Uncommon: Flushing
Rare: Haemorrhage
Very rare: Thromboembolism, Hypertension, Hypotension
Not known: Pulmonary embolism, Venous thrombosis, Vasculitis, Peripheral ischemia
Very rare: Acute respiratory distress syndrome (ARDS) Chronic pulmonary interstitial fibrosis, Pulmonary oedema, Bronchospasm, Dyspnoea, Hypoxia, Cough
Not known: Nasal congestion, Oropharyngeal pain, Rhino rhea, Sneezing, Pulmonary veno-occlusive disease, Obliterative bronchiolitis, Alveolitis allergic, Pneumonitis, Pleural effusion
Common: Mucosal inflammation
Very rare: Enterocolitis haemorrhagic, Acute pancreatitis, Ascites, Stomatitis, Diarrhoea, Vomiting, Constipation, Nausea
Not known: Abdominal pain, Parotid gland inflammation, Gastrointestinal haemorrhage, Cecitis, Colitis, Enteritis
Common: Hepatic function abnormal
Rare: Hepatitis
Very rare: Veno-occlusive liver disease, Hepatomegaly, Jaundice
Not known: Cholestatic hepatitis, Hepatotoxicity10
Very common: Alopecia11
Rare: Rash, Dermatitis, Nail discolouration, Skin discolouration12
Very rare: Stevens-Johnson syndrome, Toxic epidermal necrolysis, Radiation erythaema, Pruritus (including itching due to inflammation)
Not known: Erythaema multiforme, Palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome), Urticaria, Erythaema, Facial swelling, Hyperhidrosis
Very rare: Rhabdomyolysis, Cramps
Not known: Scleroderma, Muscle spasms, Myalgia, Arthralgia
Very common: Cystitis, Microhaematuria
__Common:__Haemorrhagic cystitis, Macrohematuria
Very rare: Suburethral haemorrhage, Bladder wall oedema, Bladder fibrosis and sclerosis, Renal impairment, Blood creatinine increased, Renal tubular necrosis
Not known: Renal tubular disorder, Nephropathy toxic, Hemorrhagic ureteritis, Bladder contracture, Nephrogenic diabetes insipidus, Atypical urinary bladder epithelial cells, Blood urea nitrogen increased
Not known: Premature labour
Common: Impairment of spermatogenesis
Uncommon: Ovulation disorder (rarely irreversible)
Rare: Amenorrhea13, Azoospermia/asperima13, Oligospermia13
Not known: Infertility, Ovarian Failure, Oligomenorrhoe, Testicular atrophy
Not known: Intra-uterine death, Foetal malformation, Foetal growth retardation, Foetal damage, Carcinogenic effect on offspring
Very common: Fever
Common: Chills, Asthenia, Malaise
Rare: Chest pain
Very rare Headache, Multiorgan failure, Injection/infusion site reactions (thrombosis, necrosis, phlebitis, inflammation, pain, swelling, erythaema)
Uncommon: Blood lactate dehydrogenase increased, C-reactive protein increased, ECG changes, Decreased LVEF, Lower levels of female sex hormones
Very rare: Weight gain
Not known: Blood oestrogen level decreased, Blood gonadotropin level increased
1 An increased risk for and severity of pneumonias (including fatal outcomes), other bacterial, fungal, viral, protozoal, and parasitic infections; reactivation of latent infections, including viral hepatitis, tuberculosis, JC virus with progressive multifocal leukoencephalopathy (including fatal outcomes), pneumocystis jiroveci, herpes zoster, strongyloides, sepsis and septic shock (including fatal outcomes).
2 including fatal outcomes
3 including acute myeloid leukemia, acute promyelocytic leukemia
4 manifested as Bone marrow failure, Pancytopenia, Neutropaenia, Agranulocytosis, Granulocytopenia,Thrombocytopaenia (complicated by bleeding), Leukopenia, Anaemia
5 manifested as myelopathy, peripheral neuropathy, polyneuropathy,neuralgia, dysesthesia, hypoesthesia, paresthesia, tremor, dysgeusia, hypogeusia,parosmia.
6 manifested as headache, altered mental functioning, seizures and abnormal vision from blurriness to vision loss
7 Observed in connection with an allergic reaction
8 Including fatal outcomes
9 While the incidence of cyclophosphamide-associated pulmonary toxicity is low, prognosis for affected patients is poor.
10 Hepatic failure, Hepatic encephalopathy, Ascites, Hepatomegaly, Jaundice, Blood bilirubin increased, Hepatic enzymes increased (ASAT, ALAT, ALP, gamma-GT)
11 May progress to baldness
12 Of the palms and heels
13 Persistent
Certain complication such as thromboembolisms, disseminated intravascular coagulation, and haemolytic uremic syndrome may occur as a result of the underlying disorders, but the frequency of these complications may increase due to chemotherapy with Cyclophosphamide.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme (www.mhra.gov.uk/yellowcard).
Not applicable.
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