4.1. Therapeutic indications

Cyclophosphamide may be used alone or in combination with other chemotherapeutic agents, depending on the indication. Cyclophosphamide Seacross is indicated in the treatment of:

• Chronic Lymphocytic Leukaemia (CLL),

• Acute Lymphocytic Leukaemia (ALL),

• As conditioning for a bone marrow transplantation, in the treatment of Acute Lymphoblastic Leukaemia, Chronic Myelogenous Leukaemia and Acute Myelogenous Leukaemia in combination with whole body irradiation or busulfan,

• Hodgkin's lymphoma, Non-Hodgkin's lymphoma and Multiple Myeloma,

• Metastatic ovarian and breast, carcinoma,

• Adjuvant treatment of breast carcinoma,

• Ewing's sarcoma,

• Small cell lung cancer,

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

Posology

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

In combination with other cytostatics of similar toxicity, a dose reduction or extension of the therapy- free intervals may be necessary.

Use of haematopoiesis stimulating agents (colony-stimulating factors and erythropoiesis stimulating agents) may be considered to reduce the risk of myelosuppressive complications and/or help facilitate the delivery of the intended dosing.

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

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.

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 interpreting response to the dose selected. (See section 4.4). The dose must be reduced in patients with severe hepatic impairment.

Patients with Renal Impairment

In patients with renal impairment, particularly in patients with severe renal impairment, decreased renal excretion may result in increased plasma levels of cyclophosphamide and its metabolites. This may result in increased toxicity and should be considered when determining the dosage in such patients. (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, use of a consistent interval between cyclophosphamide administration and dialysis should be considered. See section 4.4.

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 Seacross containing cyclophosphamide depends on the route of administration to be used.

Infusion:

If the solution is to be used for intravenous infusion, Cyclophosphamide Seacross (containing cyclophosphamide) is reconstituted by adding sterile water for injection or sodium chloride 9 mg/mL (0.9%) solution for injection.

Reconstituted Cyclophosphamide Seacross should be further diluted in 5% glucose or sodium chloride 9 mg/mL (0.9%) solution for infusion prior to infusion.

Direct injection:

If the solution is to be used for direct injection, Cyclophosphamide Seacross (containing cyclophosphamide) is reconstituted by adding sodium chloride 9 mg/mL (0.9%) solution for injection.

Please note that only Cyclophosphamide Seacross reconstituted in sodium chloride 9 mg/mL (0.9%) solution for injection is suitable for bolus injection.

Cyclophosphamide Seacross (containing cyclophosphamide) reconstituted in water is hypotonic and should not be injected directly.

Intravenous use

Intravenous administration should preferably be conducted as an infusion.

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.

For instructions on reconstitution and dilution of Cyclophosphamide Seacross before administration, see section 6.6.

4.3. Contraindications

Cyclophosphamide Seacross is contra-indicated in patients with:

• hypersensitivity to cyclophosphamide, any of its metabolites

• acute infections;

• bone marrow aplasia or bone marrow depression prior to treatment,

• urinary tract infection;

• acute urothelial toxicity from 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, Cross-sensitivity with Other Alkylating Agents

Anaphylactic reactions including those with fatal outcomes have been reported in association with cyclophosphamide. Possible cross-sensitivity 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 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 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

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.

Cardiotoxicity, Use in Patients with Cardiac Disease

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.

Pulmonary Toxicity

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.

Secondary Malignancies

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

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).

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 6 months following discontinuation of the therapy.

Men should not father a child during the treatment and for a period of 3 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 malfor-mations. 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 (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 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

Administraton 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.

Stomatitis

Administration of cyclophosphamide may cause stomatitis (oral mucositis). Current guidelines on measures for pre-vention and amelioration of stomatitis should be considered.

Paravenous Administration

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.

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 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 Cyclophosphamide patients with acute porphyria should be treated with caution.

Use in Adrenalectomised Patients

Patients with adrenal insufficiency may require an increase in corticoid substitution dose when exposed to stress from toxicity due to 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 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.

Interactions negatively 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 elimination of cyclophosphamide and prolonged half-life has been reported in patients who received high-dose cyclophosphamide less than 24 hours after 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: when administered prior to treatment with cyclophosphamide (used for conditioning prior to bone marrow transplant), ciprofloxacin may cause regression of the underlying disease.

- 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, sulfamethoxazole and sulfapyridine.

- Thiotepa: a strong inhibition of cyclophosphamide bioactivation by thiotepa in high-dose chemotherapy regimens has been reported 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

- Protease inhibitors: concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites. Use of protease inhibitor-based 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-based regimen. Increased incidence of mucositis is reported in combined therapy of cyclophosphamide (CDE) and saquinavir.

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

- Dabrafenib

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

- ACE inhibitors: ACE inhibitors can cause leukopenia.

- Natalizumab

- Paclitaxel: Increased hematotoxicity 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 cytotoxic chemotherapy that includes cyclophosphamide and G-CSF or GMCSF.

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

- Amphotericin B

- Indomethacin: acute water intoxication has been reported with concomitant use of indomethacin.

Other interactions

• Alcohol

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.

• 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 cyclophosphamide and metronidazole. Causal association is unclear.

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

• Tamoxifen

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

Interactions Affecting the Pharmacokinetics and/or Actions of Other Drugs

• Bupropion

Cyclophosphamide metabolism by CYP2B6 may inhibit bupropion metabolism.

• Coumarins

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

• 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 result in an increased incidence 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 pseudocholinesterase level. If a patient has been treated with cyclophosphamide within 10 days of general anaesthesia, the anaesthesiologist should be alerted.

• Digoxin, β- acetyldigoxin

Impaired absorption of digoxin and β-acetyldigoxin tablets have been reported during a concomitant cytotoxic treatment

• Vaccines

The immunosuppressive effects of cyclophosphamide can be expected to reduce the response to vaccination. Use of live vaccines may lead to vaccine-induced infection.

• Verapamil

Impaired intestinal absorption of orally administered verapamil has been reported.

• Sulfonylurea derivatives

Blood sugar levels 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 6 months following discontinuation of the therapy.

Men should not father a child during the treatment and for a period of 3 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.

Breastfeeding

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 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.

4.8. Undesirable effects

The frequency of adverse reactions reported in the table below are derived from clinical trials and from post marketing experience and are defined using the following convention: very common (≥1/10), common (≥ 1/100 to <1/10), uncommon (≥ 1/1,000 to <1/100), rare (≥ 1/10,000 to <1/1,000), very rare (< 1/10,000) not known.

Organ System Class (SOC)

Recommended MedDRA term

Frequency

Infections and infestations

Infections1

Pneumonia2

Sepsis1

Common

Uncommon

Uncommon

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

Acute leukaemia3

Myelodysplastic syndrome

Secondary malignancies

Bladder cancer

Ureteric cancer

Tumour lysis syndrome

Non-Hodgkin's lymphoma

Sarcoma

Renal cell carcinoma

Renal pelvis cancer

Thyroid cancer

Neoplasia

Rare

Rare

Rare

Rare

Rare

Very rare

Not known

Not known

Not known

Not known

Not known

Not known

Blood and lymphatic system disorders

Myelosuppression4

Leukopenia

Neutropenia

Febrile neutropenia

Thrombocytopenia

Anaemia

Disseminated intravascular coagulation

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)

Water intoxication

Rare

Not known

Metabolism and nutrition disorders

Anorexia

Dehydration

Hyponatremia

Blood glucose increased

Blood glucose decreased

Uncommon

Rare

Very rare

Not known

Not known

Psychiatric disorders

Confusional state

Very rare

Nervous system disorders

Peripheral neuropathy

Polyneuropathy

Neuralgia

Convulsion

Dizziness

Dysgeusia

Hypogeusia

Paresthesia

Neurotoxicity5

Reversible posterior leukoencephalopathy Syndrome6

Encephalopathy

Uncommon

Uncommon

Uncommon

Rare

Rare

Very rare

Very rare

Very rare

Not known

Not known

Not known

Eye disorders

Blurred vision

Visual impairment

Conjunctivitis

Eye oedema7

Lacrimation increased

Rare

Rare

Very rare

Very rare

Not known

Ear and labyrinth disorders

Deafness

Tinnitus

Hearing impaired

Uncommon

Not known

Not known

Cardiac disorders

Cardiomyopathy

Myocarditis

Heart failure8

Tachycardia

Ventricular arrhythmia

Supraventricular arrhythmia

Ventricular fibrillation

Angina

Myocardial infarction

Pericarditis

Atrial fibrillation

Ventricular tachycardia

Cardiogenic shock

Pericardial effusion

Bradycardia

Palpitations

Electrocardiogram QT prolonged

Myocardial haemorrhage

Cardiac failure congestive

Left ventricular failure

Left ventricular dysfunction

Carditis

Ejection fraction decreased

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

Not known

Not known

Not known

Not known

Not known

Not known

Vascular disorders

Flushing

Haemorrhage

Thromboembolism

Hypertension

Hypotension

Pulmonary embolism

Venous thrombosis

Vasculitis

Peripheral ischemia

Hot flush

Blood pressure decreased

Uncommon

Rare

Very rare

Very rare

Very rare

Not known

Not known

Not known

Not known

Not known

Not known

Respiratory, thoracic and mediastinal disorders8,9

Acute respiratory distress syndrome (ARDS)

Chronic pulmonary interstitial fibrosis

Pulmonary oedema

Bronchospasm

Dyspnoea

Hypoxia

Cough

Nasal congestion

Oropharyngeal pain

Rhinorrhea

Sneezing

Pulmonary veno-occlusive disease

Obliterative bronchiolitis

Alveolitis allergic

Pneumonitis

Pleural effusion

Respiratory failure

Organizing pneumonia

Respiratory distress

Pulmonary hypertension

Very rare

Very rare

Very rare

Very rare

Very rare

Very rare

Very rare

Not known

Not known

Not known

Not known

Not known

Not known

Not known

Not known

Not known

Not known

Not known

Not known

Not known

Gastrointestinal disorders

Mucosal inflammation

Enterocolitis haemorrhagic

Acute pancreatitis

Ascites

Stomatitis

Diarrhoea

Vomiting

Constipation

Nausea

Abdominal pain

Parotid gland inflammation

Gastrointestinal haemorrhage

Cecitis

Colitis

Enteritis

Abdominal discomfort

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

Not known

Hepatobiliary disorders

Hepatic function abnormal

Hepatitis

Veno-occlusive liver disease

Hepatomegaly

Jaundice

Cholestatic hepatitis

Hepatotoxicity10

Cytolytic hepatitis

Cholestasis

Common

Rare

Very rare

Very rare

Very rare

Not known

Not known

Not known

Not known

Skin and subcutaneous tissue disorders

Alopecia11

Rash

Dermatitis

Nail discolouration

Skin discolouration12

Stevens-Johnson syndrome

Toxic epidermal necrolysis

Radiation erythema

Pruritus (including itching due to inflammation)

Erythema multiforme

Palmar-plantar erythrodysesthesia syndrome (hand- foot syndrome)

Urticaria

Erythema

Facial swelling

Hyperhidrosis

Toxic skin eruption

Blister

Nail disorder

Very common

Rare

Rare

Rare

Rare

Very rare

Very rare

Very rare

Very rare

Not known

Not known

Not known

Not known

Not known

Not known

Not known

Not known

Not known

Musculoskeletal and connective tissue disorders

Rhabdomyolysis

Cramps

Scleroderma

Muscle spasms

Myalgia

Arthralgia

Very rare

Very rare

Not known

Not known

Not known

Not known

Renal and urinary tract disorders

Cystitis

Microhaematuria

Haemorrhagic cystitis

Macrohematuria

Suburethral haemorrhage

Bladder wall oedema

Bladder fibrosis and sclerosis

Renal impairment

Renal failure

Blood creatinine increased

Renal tubular necrosis

Renal tubular disorder

Nephropathy toxic

Haemorrhagic ureteritis

Bladder contracture

Nephrogenic diabetes insipidus

Atypical urinary bladder epithelial cells

Blood urea nitrogen increased

Bladder necrosis

Very common

Very common

Common

Common

Very rare

Very rare

Very rare

Very rare

Very rare

Very rare

Very rare

Not known

Not known

Not known

Not known

Not known

Not known

Not known

Not known

Pregnancy, puerperium and perinatal conditions

Premature labour

Not known

Reproductive system and breast disorders

Impairment of spermatogenesis

Ovulation disorder (rarely irreversible)

Amenorrhea 13

Azoospermia/asperima 13

Oligospermia 13

Infertility

Ovarian Failure

Oligomenorrhea

Testicular atrophy

Ovarian disorder

Blood oestrogen decreased

Blood gonadotrophin increased

Common

Uncommon

Rare

Rare

Rare

Not known

Not known

Not known

Not known

Not known

Not known

Not known

Congenital, familial and geneticdisorders

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 (thrombosis, necrosis, phlebitis, inflammation, pain, swelling, erythema)

General physical deterioration

Influenza-like illness

Pyrexia

Oedema

Pain

Fatigue

Very common

Common

Common

Common

Rare

Very rare

Very rare

Very rare

Not known

Not known

Not known

Not known

Not known

Not known

Investigations

Blood lactate dehydrogenase increased

C-reactive protein increased

ECG changes

Decreased LVEF

Weight gain

Lower levels of female sex hormones

Blood oestrogen level decreased

Blood gonadotropin level increased

Uncommon

Uncommon

Uncommon

Uncommon

Very rare

Uncommon

Not known

Not known

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 leukaemia, acute promyelocytic leukaemia

4. manifested as Bone marrow failure, Pancytopenia, Neutropenia, 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

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 Seacross.

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 via the national reporting system listed in Yellow Card Scheme – Website: 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.

Patients who received an overdose should be closely monitored for the development of toxicities, and hematotoxicity in particular.

There is no specific antidote for an overdosage 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 reduce urotoxic effects in case of cyclophosphamide overdosage.