Special Warning : אזהרת שימוש

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 hematopoiesis-stimulating agents (colonystimulating 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 colonystimulating 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.
Close hematologic monitoring is recommended. White blood cell count, platelet count, and hemoglobin levels should be obtained prior to each administration and at appropriate intervals after administration.

Central Nervous System Toxicity, Neurotoxicity
Administration of ifosfamide can cause CNS toxicity and other neurotoxic effects (see Section 4.8).
Ifosfamide neurotoxicity may become manifest within a few hours to a few days after first 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.
Recurrence of CNS toxicity after several uneventful treatment courses has been reported.
CNS toxicity appears to be dose dependent.
Other risk factors that have been demonstrated or discussed in the literature include: – Renal dysfunction, elevated serum creatinine
– Low serum albumin
– Hepatic dysfunction
– Low bilirubin, low hemoglobin levels, decreased white blood cell count – Acidosis, low serum bicarbonate
– Electrolyte imbalances, hyponatremia and inappropriate ADH (vasopressin) secretion, low fluid intake
– Presence of brain metastases, prior CNS disease, brain irradiation – Cerebral sclerosis, peripheral vasculopathy
– Presence of tumour in lower abdomen, bulky abdominal disease
– Poor performance status, advanced age
– Obesity, female gender
– Interactions with other medicines (e.g., aprepitant, CYP 3A4 inhibitors), alcohol, drug abuse, or pretreatment with cisplatin
If encephalopathy develops, administration of ifosfamide should be discontinued.
Publications report both successful and unsuccessful use of methylene blue for the treatment and prophylaxis of ifosfamide-associated encephalopathy.
Due to the potential for additive effects, drugs acting on the CNS (such as antiemetics, sedatives, narcotics, or antihistamines) must be used with particular caution or, if necessary, be discontinued in case of ifosfamide induced encephalopathy.

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.
Hemorrhagic cystitis requiring blood transfusion has been reported with ifosfamide.
The risk of hemorrhagic cystitis is dose-dependent and increased with administration of single high doses compared to fractionated administration.
Hemorrhagic 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.

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. Low serum albumin and hepatic impairment are also considered risk factors for the development of CNS toxicity.
Hepatic impairment may increase the formation of a metabolite that is believed to cause or contribute to CNS toxicity and also contribute to nephrotoxicity.
This should be considered when selecting the dose and interpreting response to the dose selected.

1 vial with 50 ml IFO-cell® 2g contains 4.2 mmol (96.6 mg) sodium.

1 vial with 25 ml of IFO-cell® 5g concentrate for solution for infusion contains 5.95 mmol (136.6 mg) of sodium.

This must be taken into account in patients undergoing a sodium controlled (low-sodium/low- salt) diet.

Effects on Driving

4.7 Effects on ability to drive and use machines
Potential side-effects on the central nervous system may transiently impair the ability to operate machinery and motor vehicles.