4.1. Therapeutic indications

Ifosfamide is a cytotoxic drug for the treatment of malignant disease. As a single agent it has successfully produced objective remissions in a wide range of malignant conditions. Ifosfamide is also frequently used in combination with other cytotoxic drugs, radiotherapy and surgery.

Children and adolescents - see section 5.1-Paediatric population

4.2. Posology and method of administration

Ifosfamide should only be administered when 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 by physicians experienced with this drug.

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

Method of administration

A guide to the dosage regimens used for most indications is given below:

a) 8 - 12 g/m2 equally fractionated as single daily doses over 3 - 5 days every 2 - 4 weeks.

b) 5 - 6 g/m2 (maximum 10 g) given as a 24 hour infusion every 3 – 4 weeks.

The frequency of dosage is determined by the degree of myelosuppression and the time taken to recover adequate bone marrow function. The usual number of courses given is 4, but up to 7 (6 by 24 hour infusion) courses have been given. Re-treatment has been given following relapse.

During or immediately after administration, adequate amounts of fluid should be ingested or infused to force diuresis in order to reduce the risk of urothelial toxicity. See Section 4.4.

For prophylaxis of haemorrhagic cystitis, ifosfamide should be used in combination with mesna.

Use in Patients with Renal Impairment

In patients with renal impairment, particularly in those with severe renal impairment, decreased renal excretion may result in increased plasma levels of ifosfamide and its metabolites. This may result in increased toxicity (e.g., neurotoxicity, nephrotoxicity, haematotoxicity) and should be considered when determining the dosage in such patients. See section 4.3.

Ifosfamide and its metabolites are dialyzable.

Use in Patients with Hepatic Impairment

Hepatic impairment, particularly if severe, may be associated with decreased activation of ifosfamide. This may alter the effectiveness of ifosfamide treatment. Hepatic impairment may increase the formation of a metabolite that is believed to cause or contribute to nephrotoxicity. This should be considered when selecting the dose and interpreting response to the dose selected. See section 4.3.

Use in Paediatric Patients

In children, the dosage and administration should be determined by the tumour type, tumour stage, the general condition of the patient, any previous cytotoxic therapy, and whether chemotherapy or radiotherapy is to be administered concurrently. Clinical trials have involved doses of:

a) 5 g/m2 over 24 hours

b) 9 g/m2 equally fractionated as single daily doses over 5 days

c) 9 g/m2 as a continuous infusion over 72 hours- repeated at three weekly intervals.

Use in Elderly Patients

In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy (See Section 5.2).

Administration:

Ifosfamide is inert until activated by enzymes in the liver. However, safe handling is required, and advice is included under Pharmaceutical Precautions. The dry contents of a vial should be dissolved in Water for Injections as follows:

2 g vial: add 25 ml of Water for Injections

The resultant solution of 8% of ifosfamide should not be injected directly into the vein. The solution may be:

1. diluted to less than a 4% solution in Sodium Chloride 0.9% and injected directly into the vein, with the patient supine.

2. infused in Sodium Chloride 0.9% over 30-120 mins.

3. injected directly into a fast-running infusion,

4. made up in 3 x 1 litres of Sodium Chloride 0.9% and infused over 24 hours. Each litre should be given over eight hours.

See section 6.3 for in-use requirements.

Care should be taken that extravasation does not take place, however, should it occur local tissue damage is unlikely, and no specific measures need be taken. Repeated intravenous injections of large doses of Ifosfamide have resulted in local irritation.

Mesna should be used to prevent urothelial toxicity.

Where Ifosfamide is used as an i.v. bolus, increased dosages of mesna are recommended in children, patients whose urothelium may be damaged from previous therapies and those who are not adequately protected by the standard dose of mesna.

The patient should be well hydrated and maintained in fluid balance, replacement fluids being given as necessary to achieve this. The fluid intake of patients on the intermittent regimen should be at least 2 litres in 24 hours. As Ifosfamide may exert an antidiuretic effect, a diuretic may be necessary to ensure an adequate urinary output.

Urine should be sent for laboratory analysis before, and at the end of, each course of treatment, and the patient should be monitored for output and evidence of proteinuria and haematuria at regular intervals (4-hourly if possible) throughout the treatment period. The patient should be instructed to report any signs or symptoms of cystitis. Ifosfamide should be avoided in patients with cystitis from any cause until it has been treated.

Antiemetics given before, during and after therapy may reduce nausea and vomiting. Oral hygiene is important.

If leucocyte count is below 4,000/mm3 or the platelet count is below 100,000/mm3, treatment with Ifosfamide should be withheld until the blood count returns to normal.

There should be no signs or symptoms of urothelial toxicity or renal or hepatic impairment prior to the start of each course of Ifosfamide.

4.3. Contraindications

Ifosfamide is contra-indicated in patients with:

• known hypersensitivity to ifosfamide. See section 4.4

• urinary outflow obstruction.

• severely impaired bone-marrow function (especially in patients previously treated with cytotoxic agents or radiotherapy)

• inflammation of the urinary bladder (cystitis)

• impaired renal function

• hepatic impairment

• acute infections

4.4. Special warnings and precautions for use

In individual patients, risk factors for ifosfamide toxicities and their sequelae described here and in other sections may constitute contraindications. In such situations, individual assessment of risk and expected benefits is necessary. Adverse reactions, depending on their severity, may require dosage modification or discontinuation of treatment

WARNINGS

Myelosuppression, Immunosuppression, Infections

Treatment with ifosfamide may cause myelosuppression and significant suppression of immune responses, which can lead to severe infections. Fatal outcome of ifosfamide-associated myelosuppression has been reported.

Administration of ifosfamide is normally followed by a reduction in the leukocyte count. The nadir of the leukocyte count tends to be reached approximately during the second week after administration. Subsequently, the leukocyte count rises again.

Severe myelosuppression and immunosuppression must be expected particularly in patients pre-treated with and/or receiving concomitant chemotherapy/haematotoxic agents, immunosuppressants and/or radiation therapy(See Section 4.5).

Where indicated, 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. For information on a potential interaction with G-CSF and GM-CSF (granulocyte colony stimulating factor, granulocyte macrophage colony-stimulating factor) (See section 4.5).

The risk of myelosuppression is dose dependent and is increased with administration of a single high dose compared to fractionated administration.

The risk of myelosuppression is increased in patients with reduced renal function.

Severe immunosuppression has led to serious, sometimes fatal, infections. Infections reported with ifosfamide include pneumonias, as well as other bacterial, fungal, viral, and parasitic infections. Sepsis and septic shock also have been reported.

Latent infections can be reactivated. In patients treated with ifosfamide, reactivation has been reported for various viral infections.

Antimicrobial prophylaxis may be indicated in certain cases of neutropenia at the discretion of the managing physician.

Close haematologic monitoring is recommended. White blood cell count, platelet count, and haemoglobin levels should be obtained prior to each administration and at appropriate intervals after administration.

Encephalopathy and CNS toxicity

Administration of ifosfamide can cause Encephalopathy and other neurotoxic effects

An ifosfamide-induced CNS toxicity may become manifest within a few hours to a few days after administration and in most cases resolves within 48 to 72 hours of ifosfamide discontinuation. Symptoms may persist for longer periods of time. Occasionally, recovery has been incomplete. Fatal outcome of CNS toxicity has been reported. If CNS toxicity develops, administration of ifosfamide should be discontinued.

The symptoms may include the following: confusion, somnolence, coma, hallucination, blurred vision, psychotic behavior, extrapyramidal symptoms, urinary incontinence, and seizures.

CNS toxicity seems to be dose dependent. Risk factors for the development of ifosfamide associated encephalopathy include hypoalbuminaemia, impaired renal function, poor performance status, pelvic disease (e.g. presence of tumour in lower abdomen, bulky abdominal disease), and previous or concomitant nephrotoxic treatments including cisplatin.

Due to the potential for additive effects, drugs acting on the CNS (such as antiemetics, sedatives, narcotics, or antihistamines) or substances (such as alcohol) acting on the CNS must be used with particular caution or, if necessary, be discontinued in case of ifosfamide induced encephalopathy.

Patients treated with ifosfamide should be closely monitored for symptoms of encephalopathies in particular if patients are at increased risk for encephalopathies.

The use of methylene blue may be considered for the treatment and prophylaxis of ifosfamide-associated encephalopathies.

Renal and Urothelial Toxicity

Ifosfamide is both nephrotoxic and urotoxic.

Glomerular and tubular kidney function must be evaluated and checked before commencement of therapy, as well as during and after treatment.

Close clinical monitoring of serum and urine chemistries, including phosphorus, potassium, and other laboratory parameters appropriate for identifying nephrotoxicity and urothelial toxicity is recommended, see section 4.3.

Nephrotoxic Effects

Fatal outcome from nephrotoxicity has been documented.

Disorders of renal function (glomerular and tubular) following ifosfamide administration are very common. (See 4.8).

Development of a syndrome resembling SIADH (syndrome of inappropriate antidiuretic hormone secretion) has been reported with ifosfamide.

Tubular damage may become apparent during therapy, months or even years after cessation of treatment.

Glomerular or tubular dysfunction may resolve with time, remain stable, or progress over a period of months or years, even after completion of ifosfamide treatment.

The risk of developing clinical manifestations of nephrotoxicity is increased with, for example:

– large cumulative doses of ifosfamide

– pre-existing renal impairment

– prior or concurrent treatment with potentially nephrotoxic agents

– younger age in children

– reduced nephron reserve as in patients with renal tumours and those having undergone renal radiation or unilateral nephrectomy.

Urothelial Effects

Ifosfamide administration is associated with urotoxic effects, which can be reduced by prophylactic use of mesna.

Haemorrhagic cystitis requiring blood transfusion has been reported with ifosfamide.

The risk of haemorrhagic cystitis is dose-dependent and increased with administration of single high doses compared to fractionated administration.

Haemorrhagic cystitis after a single dose of ifosfamide has been reported.

Before starting treatment, it is necessary to exclude or correct any urinary tract obstructions.

During or immediately after administration, adequate amounts of fluid should be ingested or infused to force diuresis in order to reduce the risk of urinary tract toxicity.

Ifosfamide should be used with caution, if at all, in patients with active urinary tract infections.

Past or concomitant radiation of the bladder or busulfan treatment may increase the risk for haemorrhagic cystitis.

Cardiotoxicity, Use in Patients with Cardiac Disease

Fatal outcome of ifosfamide-associated cardiotoxicity has been reported.

The risk of developing cardiotoxic effects is dose-dependent. It is increased in patients with prior or concomitant treatment with other cardiotoxic agents or radiation of the cardiac region and, possibly, renal impairment.

Particular caution should be exercised when ifosfamide is used in patients with risk factors for cardiotoxicity and in patients with pre-existing cardiac disease.

Manifestations of cardiotoxicity reported with ifosfamide treatment (see Section 4.8) and include:

– Supraventricular or ventricular arrhythmias, including atrial/supraventricular tachycardia, atrial fibrillation, pulseless ventricular tachycardia

– Decreased QRS voltage and STsegment or T-wave changes

– Toxic cardiomyopathy leading to heart failure with congestion and hypotension

– Pericardial effusion, fibrinous pericarditis, and epicardial fibrosis

Pulmonary Toxicity

Pulmonary toxicity leading to respiratory failure as well as fatal outcome has been reported.Interstitial pneumonitis and pulmonary fibrosis have been reported with ifosfamide treatment.

Secondary Malignancies

As with all cytotoxic therapy, treatment with ifosfamide involves the risk of secondary tumours and their precursors. The secondary malignancy may develop several years after chemotherapy has been discontinued.

The risk of myelodysplastic alterations, some progressing to acute leukaemias, is increased.

Veno-occlusive Liver Disease

Veno-occlusive liver disease has been reported with chemotherapy that included ifosfamide and also is a known complication with another oxazaphosphorine cytotoxic agent.

Genotoxicity

See section 4.6

Effects on Fertility

See section 4.6.

Female Patients

Amenorrhea has been reported in patients treated with ifosfamide. In addition, with another oxazaphosphorine cytotoxic agent, oligomenorrhea has been reported, see section 4.6.

The risk of permanent chemotherapy-induced amenorrhea is increased in older women.

Male Patients

Men treated with ifosfamide may develop oligospermia or azoospermia, see section 4.6.

Anaphylactic/Anaphylactoid Reactions, Cross-sensitivity

Anaphylactic/anaphylactoid reactions have been reported in association with ifosfamide.

Cross-sensitivity between oxazaphosphorine cytotoxic agents has been reported.

Impairment of Wound Healing

Ifosfamide may interfere with normal wound healing.

Paravenous Administration

The cytotoxic effect of ifosfamide 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 ifosfamide, the infusion should be stopped immediately, the extravascular ifosfamide solution should be aspirated with the cannula in place, and other measures should be instituted as appropriate.

Use in Patients with Renal Impairment

In patients with renal impairment, particularly in those with severe renal impairment, decreased renal excretion may result in increased plasma levels of ifosfamide and its metabolites. This may result in increased toxicity (e.g., neurotoxicity, nephrotoxicity, haematotoxicity) and should be considered when determining the dosage in such patients.

Use in Patients with Hepatic Impairment

Hepatic impairment, particularly if severe, may be associated with decreased activation of ifosfamide. This may alter the effectiveness of ifosfamide treatment.

This should be considered when selecting the dose and interpreting response to the dose selected.

4.5. Interaction with other medicinal products and other forms of interaction

Planned co administration 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 ifosfamide and agents that reduce its activation should be monitored for a potential reduction of therapeutic effectiveness and the need for dose adjustment.

Increased haematotoxicity and/or immunosuppression may result from a combined effect of ifosfamide and, for example:

– ACE inhibitors: ACE inhibitors can cause leukopenia.

– Carboplatin

– Cisplatin

– Natalizumab

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

– Anthracyclines

– Irradiation of the cardiac region

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

– Amiodarone

– G-CSF, GM-CSF (granulocyte colony stimulating factor, granulocyte macrophage colony-stimulating factor)

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

– Acyclovir

– Aminoglycosides

– Amphotericin B

– Carboplatin

– Cisplatin

An increased risk of developing haemorrhagic cystitis may result from a combined effect of ifosfamide and, for example:

– Busulfan

– Irradiation of the bladder

Additive CNS effects may result from a combined effect of ifosfamide and, for example:

– Antiemetics

– Antihistamines

– Narcotics

– Sedatives

Inducers of human hepatic and extrahepatic microsomal enzymes (e.g.,cytochrome P450 enzymes):

The potential for increased formation of metabolites responsible for cytotoxicity and other toxicities (depending on the enzymes induced) must be considered in case of prior or concomitant treatment with, for example:

– Carbamazepine

– Corticosteroids

– Rifampin

– Phenobarbital

– Phenytoin

– St. John's Wort

Inhibitors of CYP 3A4: Reduced activation and metabolism of ifosfamide may alter the effectiveness of ifosfamide treatment. Inhibition of CYP 3A4 can also lead to increased formation of an ifosfamide metabolite associated with CNS and nephrotoxicity. CYP 3A4 inhibitors include:

– Ketoconazole

– Fluconazole

– Itraconazole

– Sorafenib

Docetaxel: Increased gastrointestinal toxicity has been reported when ifosfamide was administered before docetaxel infusion.

Coumarin derivatives: Increased INR (increased international normalized ratio) has been reported in patients receiving ifosfamide and warfarin.

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

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

Cisplatin: Cisplatin-induced hearing loss can be exacerbated by concurrent ifosfamide therapy (see also interactions above).

Irinotecan: Formation of the active metabolite of irinotecan may be reduced when irinotecan is administered with ifosfamide.

Alcohol: In some patients, alcohol may increase ifosfamide-induced nausea and vomiting.

Concurrent administration of antidiabetic agents, such as sulfonylureas and ifosfamide may enhance the hypoglycaemic effects of the former drugs.

Theoretical interactions of ifosfamide and allopurinol resulting in an increased severity of bone marrow depression.

4.6. Fertility, pregnancy and lactation

Pregnancy

The administration of ifosfamide during organogenesis has been shown to have a fetotoxic effect in mice, rats, and rabbits and therefore may cause fetal damage when administered to pregnant women.

There are only very limited data available on the use of ifosfamide during pregnancy in humans. Fetal growth retardation and neonatal anaemia have been reported following exposure to ifosfamide-containing chemotherapy regimens during pregnancy. Multiple congenital deviations have been reported after use during the first trimester of pregnancy. Animal data generated with cyclophosphamide, another oxazaphosphorine cytotoxic agent suggest that an increased risk of failed pregnancy and malformations may persist after discontinuation of the agent as long as oocytes/follicles exist that were exposed to the agent during any of their maturation phases.

In addition, exposure to cyclophosphamide has been reported to cause miscarriage, malformations (following exposure during the first trimester), and neonatal effects, including leukopenia, pancytopenia, severe bone marrow hypoplasia, and gastroenteritis.

Based on the results of animal studies, human case reports and the substance's mechanism of action, the use of Ifosfamide during pregnancy, particularly in the first trimester, is advised against.

In every individual case, the benefits of the treatment will have to be weighed against possible risks for the fetus.

If ifosfamide is used during pregnancy, or if the patient becomes pregnant while taking this drug or after treatment, the patient should be apprised of the potential hazard to a fetus.

Breast-feeding

Ifosfamide is passed into the breast milk and may cause neutropenia, thrombocytopenia, low haemoglobin concentrations and diarrhea in children. Ifosfamide is contra-indicated for breast-feeding (see section 4.3).

Fertility

Ifosfamide interferes with oogenesis and spermatogenesis. It may cause sterility in both sexes.

Development of sterility appears to depend on the dose of ifosfamide, duration of therapy, and state of gonadal function at the time of treatment.

Ifosfamide may cause transient or permanent amenorrhea in women and oligospermia or azoospermia in men.

Female Patients

Women treated with ifosfamide should be informed prior to treatment about the possibility to save and preserve their eggs.

The risk of permanent chemotherapy-induced amenorrhea is increased in older women.

Girls treated with ifosfamide during prepubescence may develop secondary sexual characteristics normally and have regular menses.

Girls treated with ifosfamide during prepubescence subsequently have conceived.

Girls who have retained ovarian function after completing treatment are at increased risk of developing premature menopause.

Male Patients

Men treated with Ifosfamide should be informed prior to treatment about the possibility to save pre-produced sperm kept in proper conditions.

Sexual function and libido generally are unimpaired in these patients.

Boys treated with ifosfamide during prepubescence may develop secondary sexual characteristics normally, but may have oligospermia or azoospermia.

Some degree of testicular atrophy may occur.

Azoospermia may be reversible in some patients, though the reversibility may not occur for several years after cessation of therapy.

Men treated with ifosfamide have subsequently fathered children.

Genotoxicity

Ifosfamide is genotoxic and mutagenic in male and female germ cells. Therefore, women should not become pregnant, and men should not father a child during therapy with ifosfamide.

Women treated with ifosfamide should take contraceptive measures for at least 1 year after discontinuation of ifosfamide therapy.

Men should not father a child for up to 6 months after the end of therapy.

Sexually active women and men should use effective methods of contraception during these periods of time.

4.7. Effects on ability to drive and use machines

Manifestations of CNS toxicity may impair a patient's ability to operate an automobile or other heavy machinery. See Section 4.4.

4.8. Undesirable effects

The adverse reactions and frequencies below are based on publications describing clinical experience with fractionated administration of ifosfamide as monotherapy with a total dose of 4 to 12 g/m2 per course.

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), Not known (adverse reactions reported in the post-marketing experience).

System Organ Class (SOC)

Adverse Reaction

Frequency Category

INFECTIONS AND INFESTATIONS

Infections (including reactivation of latent infections)

Sepsis (septic shock)*

Common

Not known

NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYCTS AND POLYPS)

Secondary tumors*

(including Urinary tract carcinoma, Myelodysplastic syndrome, Acute leukaemia, Acute lymphocytic leukaemia, Lymphoma [Non-Hodgkin's lymphoma], Sarcomas, Renal cell carcinoma, Thyroid cancer)

Progressions of underlying malignancies*

Not known

Not known

BLOOD AND LYMPHATIC SYSTEM DISORDERS

Myelosuppression

- Leukopenia

- Thrombocytopenia*

- Anaemia

- Agranulocytosis

Haematotoxicity*

- Haemolytic anaemia

- Methaemoglobinaemia

Febrile bone marrow aplasia

Disseminated intravascular coagulation

Haemolytic uremic syndrome

Neonatal anaemia

Very common

Very common

Very common

Not known

Not known

Not known

Not known

Not known

Not known

Not known

Not known

Not known

IMMUNE SYSTEM DISORDERS

Angioedema*

Anaphylactic reaction

Immunosuppression

Urticaria

Hypersensitivity reaction

Not known

Not known

Not known

Not known

Not known

ENDOCRINE DISORDERS

Syndrome of inappropriate antidiuretic hormone secretion (SIADH)

Not known

METABOLISM AND NUTRITION DISORDERS

Decreased Appetite

Tumor lysis syndrome

Metabolic acidosis

Hypokalaemia

Hypocalcaemia

Hypophosphataemia

Hyperglycaemia

Polydipsia

Common

Not known

Not known

Not known

Not known

Not known

Not known

Not known

PSYCHIATRIC DISORDERS

Mutism

Mental status change (includine mania, paranoia, delusion, delirium, catatonia, amnesia, panic attack)

Echolalia

Perseveration

Not known

Not known

Not known

Not known

NERVOUS SYSTEM DISORDERS

Central nervous system toxicity

- Encephalopathy

- Faecal incontinence

- Status epilepticus* (convulsive and nonconvulsive)

- Movement disorder

- Extrapyramidal disorder

- Gait disturbance

- Dysarthria

Peripheral neuropathy

- Hypoesthesia

- Paresthesia

Asterixis

Neuralgia

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

EYE DISORDERS

Visual impairment

Conjunctivitis

Eye irritation

Not known

Not known

Not known

EAR AND LABYRINTH DISORDERS

Deafness

Vertigo

Tinnitus

Not known

Not known

Not known

CARDIAC DISORDERS

Cardiotoxicity*

Arrythmia (including supraventricular and ventricular arrhythmia)

Atrial fibrillation

Premature atrial contractions

Bradycardia

Cardiac arrest*

Myocardial infarction

Cardiac failure*

Myocardial haemorrhage

Angina pectoris

Cardiomyopathy* (including congestive cardiomyopathy)

Electrocardiogram ST-segment abnormal

Electrocardiogram T- wave inversion

Electrocardiogram QRS complex abnormal

Uncommon

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

VASCULAR DISORDERS

Hypotension

Pulmonary embolism

Deep vein thrombosis

Capillary leak syndrome

Vasculitis

Hypertension

Flushing

Uncommon

Not known

Not known

Not known

Not known

Not known

Not known

RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS

Respiratory failure*

Acute respiratory distress syndrome*

Pulmonary hypertension

Interstitial lung disease* (as manifested by Pulmonary fibrosis)

Pneumonitis*

Pulmonary oedema*

Pleural effusion

Dyspnea

Hypoxia

Cough

Not known

Not known

Not known

Not known

Not known

Not known

Not known

Not known

Not known

Not known

GASTROINTESTINAL DISORDERS

Nausea/Vomiting

Diarrhoea

Stomatitis

Enterocolitis

Pancreatitis

Ileus

Gastrointestinal haemorrhage

Mucosal ulceration

Constipation

Abdominal pain

Salivary hypersecretion

Very common

Uncommon

Uncommon

Not known

Not known

Not known

Not known

Not known

Not known

Not known

Not known

HEPATOBILIARY DISORDERS

Hepatotoxicity

- Hepatic failure

Veno-occlusive liver disease

Portal vein thrombosis

Cytolytic hepatitis

Common

Not known

Not known

Not known

Not known

SKIN AND SUBCUTANEOUS TISSUE DISORDERS

Alopecia

Dermatitis

Papular rash

Toxic epidermal necrolysis

Stevens-Johnson syndrome

Palmar-plantar erythrodysesthesia syndrome

Radiation recall dermatitis

Skin necrosis

Facial swelling

Rash

Pruritus

Erythema

Skin hyperpigmentation

Hyperhidrosis

Nail disorder

Very common

Rare

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

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS

Rhabdomyolysis

Osteomalacia

Rickets

Growth retardation

Myalgia

Arthralgia

Muscle twitching

Not known

Not known

Not known

Not known

Not known

Not known

Not known

RENAL AND URINARY DISORDERS

Haemorrhagic cystitis

Haematuria

Renal dysfunction*

- Acute renal failure

- Chronic renal failure

- Aminoaciduria

- Phosphaturia

- Fanconi syndrome

- Tubulointerstitial nephritis

Renal structural damage

Nephrogenic diabetes insipidus

Polyuria

Enuresis

Feeling of residual urine

Very common

Very common

Very common

Very common

Not known

Not known

Not known

Not known

Not known

Not known

Not known

Not known

Not known

Not known

REPRODUCTIVE SYSTEM AND BREAST DISORDERS

Infertility

Ovarian failure

Premature menopause

Amenorrhea

Ovulation disorder

Azoospermia

Oligospermia

Not known

Not known

Not known

Not known

Not known

Not known

Not known

CONGENITAL, FAMILIAL AND GENETIC DISORDERS

Fetal growth retardation

Not known

GENERAL DISORDERS AND ADMINISTRATIVE SITE CONDITIONS

Phlebitis

Fatigue

Malaise

Multiorgan failure*

General physical deterioration

Injection/Infusion site reactions

Oedema

Pain

Pyrexia

Chills

Common

Uncommon

Not known

Not known

Not known

Not known

Not known

Not known

Not known

Not known

* including fatal outcomes

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 theYellow 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 CNS toxicity, nephrotoxicity, myelosuppression, and mucositis. See Section 4.4.

Patients who received an overdose should be closely monitored for the development of toxicities.

No specific antidote for ifosfamide is known.

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.

Ifosfamide as well as ifosfamide metabolites are dialyzable. Consider haemodialysis in cases of severe overdose presenting early, particularly in patients with renal impairment.

Cystitis prophylaxis with mesna may be helpful in preventing or limiting urotoxic effects with overdose.