Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2016 Publisher: Baxter Healthcare Ltd, Caxton Way, Thetford, Norfolk, IP24 3SE, 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.
Cyclophosphamide is contra-indicated during pregnancy. See section 4.4 and 4.6.
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 and significant suppression of immune responses.
Cyclophosphamide-induced myelosuppression can cause leukopenia, neutropenia, thrombocytopenia (associated with a higher risk of bleeding events), and anaemia.
Severe immunosuppression has lead to serious, sometimes fatal, infections. Sepsis and septic shock have also been reported. 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 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 should be used with caution, if at all, in patients with severe impairment of bone marrow function and in patients with severe immunosuppression.
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).
Cyclophosphamide treatment may not be indicated, or should be interrupted, or the dose reduced, in patients who have or who develop a serious infection.
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 normalize, as a rule, after approximately 20 days.
Severe myelosuppression must be expected particularly in patients pretreated with and/or receiving concomitant chemotherapy and/or radiation therapy.
Close haematological monitoring is required for all patients during treatment.
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.
Cystectomy may become necessary due to fibrosis, bleeding, or secondary malignancy.
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.
Past or concomitant radiation or busulfan treatment may increase the risk for cyclophosphamide-induced hemorrhagic cystitis.
Cystitis is, in general, initially abacterial. Secondary bacterial colonization 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.
Cyclophosphamide should be used with caution, if at all, in patients with active urinary tract infections.
Adequate treatment with mesna and/or strong hydration to force dieresis can markedly reduce the frequency and severity of bladder toxicity. It is important to ensure that patients empty the bladder at regular intervals.
Hematuria usually resolves in a few days after cyclophosphamide treatment is stopped, but it may persist.
It is usually necessary to discontinue cyclophosphamide therapy in instances of severe hemorrhagic cystitis.
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 occurred secondary to hemorrhagic myocarditis and myocardial necrosis.
Acute cardiac toxicity has been reported with a single dose of less than 2mg/kg 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 may be increased for example, 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 necessary in patients with risk factors for cardiotoxicity and in patients with 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 late 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 lymphoma, 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.
Veno-occlusive liver disease (VOLD) has been reported in patients receiving cyclophosphamide.
A cytoreductive regimen in preparation for bone marrow transplantation that consists of cyclophosphamide in combination with whole-body irradiation, busulfan, or other agents has been identified (see Section 4.5) as a major risk factor for the development of VOLD. 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 with high-dose cytoreductive therapy include:
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.
Both women and men should wait at least 6 to 12 months after stopping Cyclophosphamide before attempting to conceive or father a child.
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 fertilization 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.
Fertility, 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.
Administration of cyclophosphamide may cause nausea and vomiting.
Current guidelines on the use of antiemetics 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.
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 decreased activation of cyclophosphamide. This may alter the effectiveness of cyclophosphamide treatment and should be considered when selecting the dose and interpreting response to the dose selected.
Patients with adrenal insufficiency may require an increase in corticoid substitution dose when exposed to stress from toxicity due to cytostatics, including cyclophosphamide.
Planned coadministration or sequential administration of other substances or treatments 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:
Ondansetron:
There have been reports of a pharmacokinetic interaction between ondansetron and high-dose cyclophosphamide resulting in decreased cyclophosphamide AUC.
Pharmacodynamic Interactions and Interactions of Unknown Mechanism Affecting the Use of Cyclophosphamide
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
Increase in other toxicities:
A reduced antitumor activity was observed in tumor-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.
Cyclophosphamide metabolism by CYP2B6 may inhibit bupropion metabolism.
Both increased and decreased warfarin effect 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.
Cyclophosphamide treatment causes a marked and persistent inhibition of cholinesterase activity. Prolonged apnea may occur with concurrent depolarizing muscle relaxants (e.g. succinylcholine). If a patient has been treated with cyclophosphamide within 10 days of general anesthesia, the anesthesiologist should be alerted.
Cytotoxic treatment has been reported to impair intestinal absorption of digoxin and β-acetyldigoxin tablets.
The immunosuppressive effects of cyclophosphamide can be expected to reduce the response to vaccination. Use of live vaccines may lead to vaccine-induced infection.
Cytotoxic treatment has been reported to impair intestinal absorption of orally administered verapamil.
Cyclophosphamide is contraindicated in pregnancy (see section 4.3). Cyclophosphamide crosses the placental barrier. Treatment with cyclophosphamide has a genotoxic effect and may cause foetal damage when administered to pregnant women. Both women and men should wait at least 6 to 12 months after stopping Cyclophosphamide before attempting to conceive or father a child.
Malformations have been reported in children born to mothers treated with cyclophosphamide during the first trimester of pregnancy. However, there are also reports of children without malformations born to women exposed during the first trimester.
Exposure to cyclophosphamide in utero may cause miscarriage, foetal growth retardation, and foetotoxic effects manifesting in the newborn, including leukopenia, anaemia, pancytopenia, severe bone marrow hypoplasia, and gastroenteritis.
Animal data suggest that an increased risk of failed pregnancy and malformations may persist after discontinuation of cyclophosphamide as long as oocytes/follicles exist that were exposed to cyclophosphamide during any of their maturation phases. See Section 4.4, Genotoxicity.
If cyclophosphamide is used during pregnancy, or if the patient becomes pregnant while taking this drug or after treatment (see Section 4.4, Genotoxicity), the patient should be apprised of the potential hazard to a foetus.
Cyclophosphamide is passed into the breast milk. Neutropenia, thrombocytopenia, low hemoglobin, and diarrhoea have been reported in children breast fed by women treated with cyclophosphamide. Women must not breastfeed during treatment with cyclophosphamide.
Cyclophosphamide interferes with oogenesis and spermatogenesis. It may cause sterility in both sexes.
Development of sterility appears to depend on the dose of cyclophosphamide, duration of therapy, and the state of gonadal function at the time of treatment.
Cyclophosphamide-induced sterility may be irreversible in some patients.
Sexually active women and men should use effective methods of contraception during these periods of time.
Amenorrhea, transient or permanent, associated with decreased oestrogen and increased gonadotrophin secretion develops in a significant proportion of women treated with cyclophosphamide.
For older women, in particular, amenorrhea may be permanent.
Oligomenorrhea has also been reported in association with cyclophosphamide treatment.
Girls treated with cyclophosphamide during prepubescence generally develop secondary sexual characteristics normally and have regular menses.
Girls treated with cyclophosphamide during prepubescence 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).
Men treated with cyclophosphamide may develop oligospermia or azoospermia, which are normally associated with increased gonadotrophin but normal testosterone secretion.
Sexual potency and libido generally are unimpaired in these patients.
Boys treated with cyclophosphamide during prepubescence may develop secondary sexual characteristics normally, but may have oligospermia or azoospermia.
Some degree of testicular atrophy may occur.
Cyclophosphamide-induced azoospermia is reversible in some patients, though the reversibility may not occur for several years after cessation of therapy.
Patients undergoing treatment with cyclophosphamide may experience undesirable effects (including, e.g., 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.
ADR frequency is based upon the following scale: Very Common (≥1/10); Common (≥1/100 - <1/10), Uncommon (≥1/1,000 - <1/100), Rare (≥1/10,000 - <1/1,000), Very Rare (<1/10,000), Unknown (adverse reactions reported in the post-marketing experience).
Common: Infections1
Uncommon: Pneumonia2, Sepsis1
Not Known: Septic shock
Rare: Acute leukemia3, Myelodysplastic syndrome, Secondary tumours, Bladder cancer
Not known: Tumour lysis syndrome
Very common: Myelosuppression4, Haemolytic uraemic syndrome
Very rare: Disseminated intravascular coagulation (DIC)
Not known: Lymphopenia
Very common: Immunosuppression
Very rare: Anaphylactic/Anaphylactoid reaction
Uncommon: Hypersensitivity reaction
Rare: SIADH
Uncommon: Anorexia
Rare: Dehydration
Very rare: Hyponatraemia, Fluid retention
Not known: Blood glucose changes (increase or decrease)
Very rare: Confusion
Rare: Dizziness
Very rare: Convulsion
Unknown: Neurotoxicity5, Encephalopathy
Very rare: Conjunctivitis, Eye Oedema
Rare: Visual impairment
Not known: Lacrimation increased
Not known: Deafness, Tinnitus
Not known: Ventricular fibrillation, Ventricular tachycardia, Cardiogenic shock, Pericardial effusion, Myocardial infarction, Cardiac failure, Cardiomyopathy, Myocarditis, Pericarditis, Electrocardiogram QT prolonged, Arrhythmias6
Uncommon: Flushing
Not known: Pulmonary embolism, Venous thrombosis, Vasculitis, Peripheral ischaemia
Not known: Pulmonary veno-occlusive disease, Acute respiratory distress syndrome (ARDS), Interstitial Lung Diseases7, Pulmonary hypertension, Pulmonary oedema, Bronchospasm, Dyspnea, Hypoxia, Cough, Nasal congestion, Rhinorrhea, Oropharyngeal pain, Not known
Very rare: Enterocolitis haemorrhagic, Acute pancreatitis, Mucosal ulceration, Stomatitis, Diarrhoea, Vomiting, Constipation, Nausea
Unknown: Gastrointestinal Haemorrhage, Colitis, Enteritis, Cecitis, Abdominal pain, Parotid gland inflammation
Common: Hepatic function abnormal
Not known: Veno-occlusive disorder, Hepatitis, Cholestasis, Hepatotoxicity8
Very common: Alopecia
Rare: Rash, Dermatitis, Discoloration of the palms, fingernails, soles
Very rare: Toxic epidermal necrolysis, Stevens Johnson syndrome
Not known: Erythema multiforme, Palmar-plantar erythrodysaesthesia, Radiation recall dermatitis, Erythema in irradiated area, Pruritus (including inflammatory itching), Erythema, Urticaria, Blisters, Facial swelling, Hyperhidrosis
Not known: Rhabdomyolysis, Scleroderma, Muscle spasms, Myalgia, Arthralgia
Very common: Cystitis, Microhematuria
Common: Haemorrhagic cystitis, Macrohematuria
Very rare: Suburethral bleeding, Oedema of the bladder wall, Interstitial inflammation, fibrosis, and sclerosis of bladder, Renal failure, Blood creatinine increased
Unknown: Renal tubular necrosis, Renal tubular disorder, Nephropathy toxic, Hemorrhagic ureteritis, Cystitis ulcerative, 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
Rare: Amenorrhoea9, Azoospermia9, Oligospermia9
Unknown: Infertility, Ovarian Failure, Oligomenorrhoea, Testicular atrophy, Blood oestrogen decreased, Blood gonadotrophin increased
Not known: Intra-uterine death, Fetal malformation, Fetal growth retardation, Fetal toxicity (including myelosuppression/gastroenteritis)
Very common: Fever
Common: Asthenia, Mucosal inflammation
Rare: Chest pain
Very Rare: Headache
Not known: Injection/infusion site reactions10, Multiorgan failure, Oedema, Influenza-like illness, General physical deterioration
Not known: Blood lactate hydrogenase increased, C-reactive protein increased
1 including other bacterial, fungal, viral, protozoal, parasitic, reactivation of latent infections, including viral hepatitis, tuberculosis, JC virus with progressive multifocal leucoencephalopathy (including fatal outcomes), Pneumocystis jiroveci, herpes zoster, Strongyloides
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 reversible posterior leukoencephalopathy syndrome, myelopathy, peripheral neuropathy, polyneuropathy,neuralgia, dysesthesia, hypoesthesia, paresthesia, tremor, dysgeusia, hypogeusia,parosmia.
6 manifested as Atrial fibrillation,Supraventricular arrhythmia ,Ventricular arrhythmia, Bradycardia, Tachycardia,Palpitation
7 manifested by pulmonary fibrosis, obliterative bronchiolitis, organizing pneumonia, alveolitis allergic, pneumonitis
8 Hepatic failure, Hepatic encephalopathy, Ascites, Hepatomegaly, Jaundice, Blood bilirubin increased, Hepatic enzymes increased (ASAT, ALAT, ALP, gamma-GT)
9 persistent
10 manifested by thrombosis, necrosis, phlebitis, inflammation, pain, swelling, erythema.
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:
Malta: ADR reporting, Website: www.medicines authority.gov.mt/adrportal
UK: Yellow card scheme, Website: www.mhra.gov.uk/yellowcard
Not applicable.
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