CYCLOPHOSPHAMIDE ACCORD 2000 MG POWDER FOR SOLUTION FOR INJECTION/INFUSION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

2   QUALITATIVE AND QUANTITATIVE COMPOSITION

3 PHARMACEUTICAL FORM

Powder for solution for injection/infusion

A white lyophilized powder or cake.

4.1 Therapeutic indications

Cyclophosphamide is used in combination with chemotherapy regimens or alone, depending on the indication. Cyclophosphamide is indicated in the treatment of:

Chronic Lymphocytic Leukemia (CLL)

Acute Lymphocytic Leukemia (ALL)

As conditioning for a bone marrow transplantation, in the treatment of Acute Lymphocytic Leukemia, Chronic myelogenous leukaemia and Acute myelogenous leukaemia in combination with whole body irradiation or busulfan.

Hodgkin’s disease, Non-Hodgkin’s lymphoma and Multiple Myeloma.

Metastatic ovarian and breast, carcinoma

Adjuvant treatment of breast carcinoma

Ewing’s sarcoma

Small cell lung cancer

Advances or metastatic neuroblastoma,

Life-threatening autoimmune diseases: severe progressive forms of lupus nephritis and Wegener’s gra­nulomatosis.

4.2 Posology and method of administration

Cyclophosphamide should only be used by clinicians experienced in the use of cancer chemotherapy.

Cyclophosphamide should only be administered where there are facilities for monitoring of clinical, biochemical and haematological parameters before, during, and after administration and under the supervision of an oncology specialist.

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 or 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 4.4

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

For daily treatment:

3 – 6 mg/kg body weight (= 120 – 240 mg/m2 body surface area), injected intravenously

For the 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

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.

If a busulfan-cyclophosphamide (Bu/Cy) regimen is applied, the first dose of cyclophosphamide must be administered at least 24 hours after the last dose of busulfan (see section 4.4 and 4.5).

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 estimating response to the medicinal product. (See section 4.4).

The dose must be reduced in patients with severe hepatic impairment. A dose reduction of 25% is recommended in patients with serum bilirubin concentrations of 3.1 – 5 mg/100 ml (=0.053–0.086 mmol/l).

Patients with Renal Impairment

In patients with renal impairment, particularly in patients with severe 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 4.4). 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, consistent interval between dialysis cycles and Cyclophosphamide administration should be considered. See section 4.4.

Elderly patients

In elderly patients, monitoring for toxicities and the need for dose adjustment should reflect the higher frequency of decreased hepatic, renal or cardiac function, 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.

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 handling 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 depends on the route of administration to be used.

Infusion:

Intravenous administration should preferably be conducted as an infusion.

If the solution is to be used for IV infusion, Cyclophosphamide is reconstituted by adding sterile water for injection or 0.9% sterile sodium chloride solution or 5% glucose solution.

Reconstituted Cyclophosphamide should be further diluted in the solvents listed in section 6.6.

Direct injection:

If the solution is to be used for direct injection, Cyclophosphamide is reconstituted by adding 0.9% sterile sodium chloride solution. Please note that only Cyclophosphamide reconstituted in 0.9% sterile sodium chloride solution is suitable for bolus injection.

Cyclophosphamide reconstituted in water is hypotonic and should not be injected directly.

For detailed instruction on reconstitution and dilution please refer to section 6.6.

Intravenous use

To reduce the likelihood of adverse reactions that appear to be administration rate-dependent (e.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.

4.3 Contraindications

Cyclophosphamide is contra-indicated in patients with:

hypersensitivity to cyclophosphamide, its metabolites or any of the excipients listed in section 6.1;

acute infections;

bone marrow aplasia or bone marrow depression prior to treatment;

urinary tract infection;

acute urothelial toxicity following cytotoxic chemotherapy or radiation therapy;

urinary outflow obstruction.

breastfeeding (see section 4.6)

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

4.4 Special warnings and precautions for use

WARNINGS

Anaphylactic Reactions, Interaction with Other Alkylating Agents.

Anaphylactic reactions including those with fatal outcomes have been reported in association with cyclophosphamide. Possible interaction with other alkylating agents has been reported.

Myelosuppression, Immunosuppression, Infections

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 the use of cyclophosphamide include pneumonias, as well as different 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 decision of the treating physician.

In case of neutropenic fever, antibiotics and/or antimycotics must be prescribed.

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).

Intensity of 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 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.

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.

Urinary Tract and Renal Toxicity

Haemorrhagic cystitis, pyelitis, urethritis, 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.

Haemorrhagic 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 development of cyclophosphamide-induced haemorrhagic 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 any other signs of uro/nephrotoxicity. Appropriate treatment with mesna and/or strong hydration with a forced diuresis can markedly reduce the frequency and severity of bladder toxicity. It is important to ensure that the patient empties the bladder at regular intervals. Haematuria usually resolves in a few days after cyclophosphamide treatment is stopped, but it may persist. Severe haemorrhagic cystitis usually requires a discontinuation of the cyclophosphamide treatment.

Cyclophosphamide treatment has also been associated with nephrotoxicity, including renal tubular necrosis.

Hyponatremia associated with increased total body water, acute water intoxication, and a syndrome of inappropriate secretion of antidiuretic hormone (SIADH) have been reported in association with cyclophosphamide administration. Fatal outcomes have been reported.

Cardiotoxicity, Use in Patients with Cardiac Disease

Myocarditis and myopericarditis accompanied by 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 haemorrhagic myocarditis. Hemopericardium has been developed secondary as a consequence of haemorrhagic 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 with different medicinal agents 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 preexisting cardiac disease.

Pulmonary Toxicity

Pneumonitis and pulmonary fibrosis have been reported 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.

Although the incidence of cyclophosphamide-induced pulmonary toxicity is relatively low, prognosis for affected patients is poor.

Late onset of pneumonitis (greater than 6 months after start of cyclophosphamide administration) appears to be associated with a particularly high mortality. Pneumonitis may develop even several years after treatment with cyclophosphamide.

Acute pulmonary toxicity has been reported after a single cyclophosphami­de dose.

Secondary Malignancies

As with all cytotoxic agents, treatment with cyclophosphamide is associated with the risk of secondary tumours and their precursors as sequelae.

Increased risk of urinary tract cancer as well as the risk of acute leukaemia caused by myelodysplastic alterations exist. Other malignancies reported after use of cyclophosphamide or regimens involving cyclophosphamide include lymphomas, thyroid cancer, and sarcomas.

In some cases, the secondary 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)

Veno-occlusive liver disease has been reported in patients receiving cyclophosphamide.

The most important factor in case of veno-occlusive disease appears to be cytoreductive therapy which is used in preparation for bone marrow transplantation and which includes the combination of cyclophosphamide with whole-body irradiation, busulfan, or other agents (see section 4.5). After cytoreductive therapy, the clinical syndrome develops in 1 to 2 weeks after transplantation and is characterized by sudden weight gain, painful hepatomegaly, ascites, and hyperbilirubi­nemia/jaundice.

However, gradual development of VOLD has also been reported in patients receiving long-term low-dose immunosuppressive doses of cyclophosphamide.

As a complication of VOLD, hepatorenal syndrome or multiorgan failure may develop. Fatal outcome of cyclophosphamide-induced 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).;

Genotoxicity

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 for a period of 6 months following discontinuation of the therapy.

Animal studies show that exposure of oocytes during follicular development phase may result in a decreased rate of implantations and alter viable pregnancies, and increase the risk of malformations.

This effect should be considered when considering fertilisation or pregnancy after discontinuation of cyclophosphamide therapy. The duration of follicular development in humans is not known, but it 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).

Fertility

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).

Impairment of Wound Healing.

Cyclophosphamide may interfere with normal wound healing.

Precautions

Alopecia

Alopecia has been reported, and its incidence increases with increasing doses.

Alopecia may progress to baldness.

The hair can be expected to grow back after treatment 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 antiemetics for prevention and amelioration of nausea and vomiting should definitely be considered.

Alcohol consumption may increase cyclophosphamide -induced nausea and vomiting.

Stomatitis

Administration of cyclophosphamide may cause stomatitis (oral mucositis).

Current guidelines on measures for prevention and amelioration of stomatitis should definitely be considered.

Paravenous Administration

The cytostatic effect of cyclophosphamide occurs only 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 locally 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.

Use in 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. See section 4.2.

Use in Patients with Hepatic Impairment

Severe hepatic impairment may inhibit the activation of cyclophosphamide. This may negatively alter the effectiveness of the cyclophosphamide treatment and should be considered when selecting the dose and estimating response to the medicinal product. See section 4.2. Due to the porphyrogenic effect of Cyclophosphamide patients with acute porphyria should be treated with caution.

Use in Adrenalectomised Patients

Patients with adrenal insufficiency may require an additional corticoid dose when exposed to stress from toxicity due to treatment with cytostatics, including cyclophosphamide.

Use in Patients with Diabetes Mellitus

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).

Use in Patients who have recently undergone surgery

In general, cytostatics (among which agents cyclophosphamide) should not be administered to patients who had a surgery less than 10 days ago.

4.5 Interaction with other medicinal products and other forms of interaction

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 medicinal products 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 expected the risks and the benefit.

Patients receiving such combinations must be monitored closely to permit timely intervention if any symptoms of toxicity appear. Patients being treated with cyclophosphamide and agents that reduce its activity should be monitored for a potential reduction of therapeutic effectiveness, and, if needed, the dose should be adjustment.

Interactions affecting the pharmacokinetics of cyclophosphamide and its metabolites

Reduced activation of cyclophosphamide may alter the effectiveness of cyclophosphamide treatment. Substances that delay activation of cyclophosphamide include:

– aprepitant,

– bupropion,

– busulfan: decreased clearance of cyclophosphamide and prolonged elimination half-life has been reported in patients who received high-dose cyclophosphamide less than 24 hours after administration of high-dose busulfan; Increased incidence of hepatic veno-occlusive disease and mucositis has been reported with concomitant administration (see section 4.2 and 4.4).

– Ciprofloxacin: regression of the underlying disease has been reported after administration of Ciprofloxacin, when this medicinal product has been used before the administration of cyclophosphamide (for the correction of the condition prior to bone marrow transplantation);

– Chloramphenicol

– Azole-antimycotics (Fluconazole, Itraconazole):- Azole-antimycotics are known to inhibit cytochrome P450 enzymes. Increased amounts of toxic degradation products of cyclophosphamide have been reported in combination with Itraconazole.

– CYP2B6 and CYP3A4 inhibitors (Nevirapin, Ritonavir): co-administration may reduce the efficacy of cyclophosphamide

– Prasugrel,

– Sulfonamides, e.g. sulfadiazine, sulfamethoxazoel and sulfapyridine

– Thiotepa: a strong inhibition of cyclophosphamide bioactivation in case of chemotherapy including high-dose thiotepa, when thiotepa was administered 1 hour prior to cyclophosphamide.

– Ondansetron: There have been reports of a pharmacokinetic interaction between ondansetron and high-dose cyclophosphamide resulting in decreased cyclophosphami­de AUC.

– Grapefruit (fruit or juice), Rifampicin, St. Johns worth: Co-administration with CYP3A4 Inhibitors or Inducers can reduce the efficacy or increase the toxicity of cyclophosphamide.

 An increase of the concentration of cytotoxic metabolites may occur with:

– Allopurinol: an increase of bone marrow suppression was reported.

– Azathioprine: increased risk of hepatotoxicity (liver necrosis)

– Chloral hydrate,

– Cimetidine,

– Disulfiram,

– Glyceraldehyde,

– Inducers of human hepatic and extrahepatic microsomal enzymes (e.g., cytochrome P450 enzymes): The potential for possible increased activity must be considered in case of prior or planned concomitant treatment with medicinal products known to induce an activity of hepatic and extrahepatic microsomal enzymes such as rifampicin, phenobarbital, carbamazepine, phenytoin, St. John's wort, benzodiazepines and corticosteroids;

– Protease inhibitors: concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites. Use of protease inhibitor-involving treatment regimens was found to be associated with a higher incidence of infections and neutropenia in patients receiving Cyclophosphamide, doxorubicin, and etoposide (CDE) than use of an NNRTI-involving treatment regimen.

Increased incidence of mucositis is reported in combined therapy of cyclophosphamide (CDE) and saquinavir.

– Dabrafenib

Pharmacokinetic Interactions and Interactions of Unknown Mechanism Affecting the Use of

Cyclophosphamide Concomitant 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

– ACE inhibitors: ACE inhibitors may cause leukopenia;

– Natalizumab;

– Paclitaxel: increased hemotoxicity has been reported when cyclophosphamide was administered after paclitaxel infusion;

– Thiazide diuretics (e.g. hydrochlorothi­azide): An increase of bone marrow suppression was reported.

– Zidovudine

– Clozapine

Increased cardiotoxicity may result from a combined effect of cyclophosphamide and, for example

– Anthracyclines;

– Mitomycin Cytarabine;

– Pentostatin;

– Radiation therapy of the cardiac region or a whole-body irradiation in combination with high doses of cyclophosphamide;

– Trastuzumab.

Increased pulmonary toxicity may result from a combined effect of cyclophosphamide and, for example

– amiodarone;

– G-CSF, GM-CSF (granulocyte colony-stimulating factor, granulocyte macrophage colony-stimulating factor): reports suggest an increased risk of pulmonary toxicity in patients treated with chemotherapy with cytotoxic agents, including cyclophosphamide, and G-CSF or GM-CSF.

Increased nephrotoxicity may result from a combined effect of cyclophosphamide and, for example

– Amphotericin B;

– indomethacin: acute water intoxication has been reported following concomitant use of indomethacin.

Other interactions

Alcohol

A reduced antitumor activity was observed in tumour-bearing animals during ethanol (alcohol) consumption and concomitant low-dose cyclophosphamide medication.

In some patients, alcohol may increase cyclophosphamide-induced vomiting and nausea.

Etanercept

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.

Metronidazole

Acute encephalopathy has been reported in a patient receiving concomitant cyclophosphamide and metronidazole. Causal association is unclear.

In animal studies, the combination of cyclophosphamide with metronidazole was associated with increased cyclophosphamide toxicity.

Tamoxifen

Concomitant use of chemotherapy and tamoxifen may increase the risk of thromboembolic complications.

Interactions Affecting the Pharmacokinetics and/or Actions of Other Medicinal Products

Bupropion

Cyclophosphamide metabolism by CYP3B6 may inhibit bupropion metabolism.

Coumarin

Both increased and decreased warfarin effects have been reported in patients receiving cyclophosphamide and warfarin.

Cyclosporine

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 stimulate the development of graft versus host disease (GVHD).

Depolarising muscle relaxants

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 pseudo cholinesterase level. If a patient has been treated with cyclophosphamide within 10 days of general anaesthesia, the anaesthesiologist should be alerted.

Digoxin, P-acetyldigoxin. Cytotoxic treatment is reported to impair absorption of digoxin and P-acetyldigoxin tablets.

Vaccines

Since cyclophosphamide has an immunosuppressive activity, reduced response to vaccines can be expected; vaccine-induced infection is possible when live virus vaccines are administered.

Verapamil

Cytotoxic treatment is reported to impair the intestinal absorption of orally administered verapamil.

Sulfonylurea derivatives

Blood sugar level may drop, if cyclophosphamide and sulfonylurea derivatives are used concomitantly.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

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).

Contraception in males and females

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.

Pregnancy

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.

Breast-feeding

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).

Fertility

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 prepubescence, 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.

4.7 Effects on ability to drive and use machines

Patients may experience undesirable effects during the treatment with cyclophosphamide (including nausea, vomiting, dizziness, blurred vision, visual impairment) which could affect the ability to drive or use machines. The decision if the patient is allowed to drive or operate machinery should be made by the doctor on an individual basis.

4.8 Undesirable effects

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

The frequency of adverse reactions is 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.

Infections and infestations

Common      : Infections1

Uncommon    : Pneumonia2, sepsis1

Neoplasms, benign and malignant and unspecified (including cysts and polyps)

Rare           : Acute leukemia3, 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

Blood and lymphatic system disorders

Immune system disorders

Very common : Immunosuppression

Uncommon : Anaphylactic/ Anaphylactoid reaction, hypersensitivity reaction

Very rare : Anaphylactic shock

Endocrine disorders

Rare : SIADH (syndrome of inappropriate antidiuretic hormone secretion)

Not known : Water intoxication

Metabolism and nutrition disorders

Psychiatric disorders

Nervous system disorders

Ear and labyrinth disorders

Cardiac disorders

Vascular disorders

Respiratory, thoracic and mediastinal disorders8 9

Very rare : Acute respiratory distress syndrome (ARDS), chronic pulmonary interstitial fibrosis,

Gastrointestinal disorders

Hepatobiliary disorders

Skin and subcutaneous tissue disorders

Musculoskeletal and connective tissue disorders

Renal and urinary tract disorders

Very common : Cystitis, microhaematuria

Pregnancy, puerperium and perinatal conditions

Not known : Premature labour

Reproductive system and breast disorders

Congenital, familial and genetic disorders

General disorders and administrative site conditions

1An 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).

2including fatal outcomes

3including acute myeloid leukemia, acute promyelocytic leukemia

4manifested as Bone marrow failure, Pancytopenia, Neutropaenia, Agranulocytosis, Granulocytopenia, Thrombocytopaenia (complicated by bleeding), Leukopenia, Anaemia 5manifested as myelopathy, peripheral neuropathy, polyneuropathy,ne­uralgia, dysesthesia, hypoesthesia, paresthesia, tremor, dysgeusia, hypogeusia,pa­rosmia.

6manifested as headache, altered mental functioning, seizures and abnormal vision from blurriness to vision loss

7Observed in connection with an allergic reaction

8Including fatal outcomes

9While the incidence of cyclophosphamide-associated pulmonary toxicity is low, prognosis for affected patients is poor.

10Hepatic failure, Hepatic encephalopathy, Ascites, Hepatomegaly, Jaundice, Blood bilirubin increased, Hepatic enzymes increased (ASAT, ALAT, ALP, gamma-GT)

11May progress to baldness

12Of the palms and heels

13Persistent

Remark:

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 of suspected adverse reactions

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 to via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Serious consequences of overdosage include manifestations of dose dependent toxicities such as myelosuppression, urotoxicity, cardiotoxicity (including cardiac failure), veno occlusive hepatic disease, and stomatitis. See section 4.4.

In case of an overdose, patients should be closely monitored for the development of toxicities, and hematotoxicity in particular.

There is no specific antidote for an over dosage of cyclophosphamide.

Cyclophosphamide and its metabolites are dialyzable. Therefore, rapid haemodialysis is indicated when treating any suicidal or accidental overdose or intoxication.

Overdosage should be managed with supportive measures, including appropriate, state-of-the-art treatment for any concurrent infection, myelosuppression, or other toxicity, should it occur. Cystitis prophylaxis with mesna can help to prevent or limit urotoxic effects in case of cyclophosphamide overdosage.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic and Immunomodulating Agents; Antineoplastic agents. Alkylating agents. Nitrogen mustard analogues;

ATC code: L01AA01

Cyclophosphamide has been demonstrated to have a cytostatic effect in many tumour types.

Cyclophosphamide engages probably to the S-or G2-phase of the cell cycle.

It remains to be shown whether the cytostatic effect is entirely dependent on the alkylation of DNA or other mechanisms such as inhibition of chromatin transformation processes or inhibition of DNA polymerases play a role. The metabolite acrolein has no antineoplastic activity, but is responsible for the adverse urotoxic effect.

The immunosuppressive effect of cyclophosphamide is based on the fact that cyclophosphamide has an inhibitory effect on B-cells, CD4 + T-cells and to a lesser extent on CD8 ±T-cells. In addition, it is assumed that cyclophosphamide has an inhibitory effect on the suppressor that regulate the IgG2 class of antibodies. Cross-resistance, especially with structurally related cytotoxic agents, e.g. ifosfamide, as well as other alkylating agents, cannot be excluded.

5.2 Pharmacokinetic properties

Cyclophosphamide is administered as an inactive prodrug that is activated in the liver.

Absorption

Cyclophosphamide is quickly and almost completely absorbed from parenteral sites.

Distribution

Less than 20% of cyclophosphamide is bound to plasma proteins. The protein binding of the metabolites of cyclophosphamide is higher but less than 70%. To what extent the active metabolites protein bound, is not known.

Cyclophosphamide is about in the cerebrospinal fluid and the mother's milk. Cyclophosphamide and metabolites can pass through the placenta.

Metabolism

Cyclophosphamide is activated in the liver to the active metabolites 4-hydroxy-cyclophosphamide and aldofosfamide (tautomeric form of 4-hydroxy-cyclophosphamide) through phase I metabolism by cytochrome P450 (CYP) enzymes. Different CYP isozymes contribute to the bioactivation of cyclophosphamide, including CYP2A6, 2B6, 2C9, 2C19 and 3A4, with 2B6 displaying the highest 4-hydroxylase activity. Detoxification is done mainly through glutathione-S-transferases

(GSTA1, GSTP1) and alcohol dehydrogenase (ALDH1, ALDH3). Two to four hours after administration of cyclophosphamide, the plasma concentrations of the active metabolites are maximal, after which a rapid decrease of plasma concentrations takes place.

Elimination

The plasma half-life of cyclophosphamide is about 4 to 8 hours in adults and children. The plasma half-lives of the active metabolites are not known.

Following high-dose IV administration within the framework of allogeneic bone marrow transplantation, the plasma concentration of pure cyclophosphamide follows linear first- order kinetics. Compared with conventional cyclophosphamide therapy, there is an increase in inactive metabolites, indicating saturation of activating enzyme systems, but not of the stages of metabolism leading to inactive metabolites. During the course of high-dose cyclophosphamide therapy over several days, there is a decrease in the areas under the plasma concentration-time curve of the parent compound, probably due to auto-induction of microsomal metabolism activity.

Cyclophosphamide and its metabolites are primarily excreted by the kidneys.

5.3 Preclinical safety data

Acute toxicity

The acute toxicity of cyclophosphamide is relatively low. This was demonstrated in studies on mice, guinea pigs, rabbits and dogs.

Chronic toxicity

Chronic administration of toxic doses led to hepatic lesions manifested as fatty degeneration followed by necrosis. The intestinal mucosa was not affected. The threshold for hepatotoxic effects was 100 mg/kg in the rabbit and 10 mg/kg in the dog.

Mutagenicity and carcinogenicity

The mutagenic effects of cyclophosphamide have been demonstrated in various in-vitro and in-vivo tests. Chromosome aberrations following administration of cyclophosphamide have also been observed in humans. The carcinogenic effects of cyclophosphamide have been demonstrated in animal studies on rats and mice.

Teratogenicity

The teratogenic effects of cyclophosphamide have been demonstrated in various animals (mice, rats, rabbits, rhesus monkeys and dogs). Cyclophosphamide can cause skeletal, tissue as well as other malformations.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Mannitol (E421)

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life

18 months.

Chemical and physical in-use stability of reconstituted solution (concentration 20 mg/ml) & diluted solution (concentration 2 mg/mL) has been demonstrated for 48 hours at 2°C – 8°C.

From a microbiological point of view, the medicinal product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C – 8°C, unless reconstitution/di­lution has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

Store in a refrigerator (2°C – 8°C).

For storage condition after reconstitution of Cyclophosphamide see section 6.3.

6.5 Nature and contents of container

Cyclophosphamide is filled in a 100 mL clear type I glass vial stoppered with grey Westar silicon rubber stopper and an aluminium flip-off seal.

Pack of 1 vial

6.6 Special precautions for disposal

7   MARKETING AUTHORISATION HOLDER

8   MARKETING AUTHORISATION NUMBER(S)