Ifosfamide 40mg/Ml Solution For Infusion
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Ifosfamide 40 mg/ml solution for infusion
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Active ingredient: Ifosfamide
1 vial with 25 ml solution for infusion contains: Ifosfamide 1 g (40 mg/ml)
1 vial with 50 ml solution for infusion contains: Ifosfamide 2 g (40 mg/ml)
For full list of excipients, see 6.1
3 PHARMACEUTICAL FORM
Galenical form and amount of active ingredient per unit dose Solution for infusion: vials containing 1g/25ml and 2g/50ml solution Clear, colourless solution, practically free of foreign particles.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Ifosfamide solution for infusion is to be administered exclusively by physicians with experience in oncology.
Ifosfamide solution for infusion 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 solution for infusion 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 be administered only by physicians experienced with this drug.
Dosage must be individualized. 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.
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 hemorrhagic cystitis, ifosfamide should be used in combination with mesna.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.
Before parenteral administration, the substance must be completely dissolved.
Patients with Renal Impairment
The dose may need to be adjusted to patients with renal impairment (see section 4.4).
Ifosfamide and its metabolites are dialyzable. In patients requiring dialysis, use of a consistent interval between ifosfamide administration and dialysis should be considered.
Elderly
In general, dose selection for elderly patients should be cautious, reflecting the higher frequency of decreased hepatic, renal, or cardiac function, and concomitant disease or other drug therapy.
4.3 Contraindications
Ifosfamide is contraindicated 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 and/or obstructions of the urine flow
• 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 (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 dosedependent 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 haemoglobin 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 haemoglobin levels, decreased white blood cell count
- Acidosis, low serum bicarbonate
- Electrolyte imbalances, hyponatraemia and inappropriate ADH (vasopressin) secretion, water intoxication, 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, younger age
- Obesity, female gender, individual predisposition
- 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.
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 hemorrhagic 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 leukemias, is increased.
Malignancy has also been reported after in utero exposure with another oxazaphosphorine cytotoxic agent.
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.
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 may develop oligospermia or azoospermia.
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.
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, hematotoxicity) 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.
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 colonystimulating 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 hemorrhagic 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
See also aprepitant below.
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
See also aprepitant below.
Aprepitant: Reports suggest increased ifosfamide neurotoxicity in patients receiving antiemetic prophylaxis with aprepitant, which is both an inducer and a moderate inhibitor of CYP 3A4.
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 hemoglobin 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. Ifosfamide may cause transient or permanent amenorrhea in women and oligospermia or azoospermia in boys during pre-pubescence. Men treated with Ifosfamide are informed prior to treatment about the possibility to save and keep in proper condition pre-produced sperm.
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.
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
Ifosfamide can lead to impairment of the ability to drive a vehicle or to operate machinery, directly by inducing encephalopathy and indirectly by inducing nausea and vomiting - particularly in the case of concomitant administration of medical products acting on the CNS or consumption of alcohol.
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 |
Infection* |
Common |
|
Pneumonia |
Not known | |
|
INFESTATIONS |
Sepsis (septic shock )** |
Not known |
|
NEOPLASMS BENIGN, |
Secondary tumors |
Not known |
|
MALIGNANT AND |
-Urinary tract carcinoma |
Not known |
|
UNSPECIFIED (INCL |
-Myelodysplastic syndrome |
Not known |
|
CYCTS AND POLYPS) |
-Acute leukaemia*** |
Not known |
|
-Acute lymphocytic leukemia** |
Not known | |
|
-Lymphoma (Non-Hodgkin’s lymphoma) |
Not known | |
|
-Sarcomas** |
Not known | |
|
-Renal cell carcinoma |
Not known | |
|
-Thyroid cancer |
Not known | |
|
Progressions of underlying malignancies* |
Not known | |
|
BLOOD AND |
Leukopenia1 (any) |
Very |
|
LYMPHATIC SYSTEM |
common | |
|
DISORDERS |
Thrombocytopenia2 (any) |
Very common |
|
Anemia3 |
Very common | |
|
Hematotoxicity** |
Not known | |
|
Myelosuppression **** |
Not known | |
|
Agranulocytosis |
Not known | |
|
Febrile bone marrow aplasia |
Not known | |
|
Disseminated intravascular coagulation Hemolytic |
Not known | |
|
uremic syndrome |
Not known | |
|
Hemolytic anemia |
Not known | |
|
Neonatal anemia |
Not known | |
|
Methaemoglobinaemia |
Not known | |
|
IMMUNE SYSTEM |
Angioedema** |
Not known |
|
DISORDERS |
Anaphylactic reaction, |
Not known |
|
Immunosuppression |
Not known | |
|
Urticaria |
Not known | |
|
Hypersensitivity reaction |
Not known | |
|
ENDOCRINE |
Syndrome of inappropriate antidiuretic hormone |
Not known |
|
DISORDERS |
secretion (SIADH) | |
|
METABOLISM AND |
Decreased Appetite |
Common |
|
NUTRITION |
Tumor lysis syndrome Metabolic acidosis |
Not known |
|
DISORDERS |
Hypokalemia |
Not known |
|
Hypocalcemia |
Not known | |
|
Hypophosphatemia |
Not known | |
|
Hyperglycemia |
Not known | |
|
Polydipsia |
Not known |
|
System Organ Class |
Adverse Reaction |
Frequency |
|
(SOC) |
Category | |
|
PSYCHIATRIC |
Panic attack |
Not known |
|
DISORDERS |
Catatonia |
Not known |
|
Mania |
Not known | |
|
Paranoia |
Not known | |
|
Delusion, |
Not known | |
|
Delirium |
Not known | |
|
Bradyphrenia |
Not known | |
|
Mutism |
Not known | |
|
Mental status change |
Not known | |
|
Echolalia |
Not known | |
|
Logorrhea |
Not known | |
|
Perseveration |
Not known | |
|
Amnesia |
Not known | |
|
NERVOUS SYSTEM |
Neurotoxicity 4,5 |
Not known |
|
DISORDERS |
-Central nervous system toxicity |
Not known |
|
-Peripheral neuropathy |
Not known | |
|
-Dysarthria |
Not known | |
|
-Convulsion** |
Not known | |
|
-Status epilepticus (convulsive and |
Not known | |
|
nonconvulsive) |
Not known | |
|
-Reversible posterior leukoencephalopathy |
Not known | |
|
syndrome |
Not known | |
|
-Leukoencephalopathy |
Not known | |
|
-Extrapyramidal disorder |
Not known | |
|
-Asterixis |
Not known | |
|
-Movement disorder |
Not known | |
|
-Polyneuropathy |
Not known | |
|
-Dysesthesia |
Not known | |
|
-Hypoesthesia |
Not known | |
|
-Paresthesia |
Not known | |
|
-Neuralgia |
Not known | |
|
-Gait disturbance |
Not known | |
|
-Fecal incontinence |
Not known | |
|
EYE DISORDERS |
Vision blurred |
Not known |
|
Visual impairment |
Not known | |
|
Conjunctivitis |
Not known | |
|
Eye irritation |
Not known | |
|
EAR AND LABYRINTH |
Deafness |
Not known |
|
DISORDERS |
Hypoacusis |
Not known |
|
Vertigo |
Not known | |
|
Tinnitus |
Not known |
|
System Organ Class |
Adverse Reaction |
Frequency |
|
(SOC) |
Category | |
|
CARDIAC DISORDERS |
Cardiotoxicity6 |
Uncommon |
|
-Arrythmia |
Not known | |
|
Ventricular arrhythmia |
Not known | |
|
Ventricular fibrillation** |
Not known | |
|
Ventricular tachycardia** |
Not known | |
|
Ventricular extrasystoles |
Not known | |
|
- Supraventricular arrhythmia |
Not known | |
|
Atrial fibrillation |
Not known | |
|
- Atrial flutter |
Not known | |
|
Supraventricular extrasystoles |
Not known | |
|
Premature atrial contractions |
Not known | |
|
- Bradycardia |
Not known | |
|
Cardiac arrest** |
Not known | |
|
Myocardial infarction |
Not known | |
|
Cardiogenic shock** |
Not known | |
|
Cardiac failure** |
Not known | |
|
Bundle branch block left |
Not known | |
|
Bundle branch block right |
Not known | |
|
Pericardial effusion |
Not known | |
|
Myocardial hemorrhage |
Not known | |
|
Angina pectoris |
Not known | |
|
Left ventricular failure |
Not known | |
|
Cardiomyopathy** |
Not known | |
|
Congestive cardiomyopathy |
Not known | |
|
Myocarditis** |
Not known | |
|
Pericarditis |
Not known | |
|
Myocardial depression |
Not known | |
|
Palpitations |
Not known | |
|
Ejection fraction decreased** |
Not known | |
|
Electrocardiogram ST-segment abnormal |
Not known | |
|
Electrocardiogram T- wave inversion |
Not known | |
|
Electrocardiogram QRS complex abnormal |
Not known | |
|
VASCULAR |
Hypotension7 |
Uncommon |
|
DISORDERS |
Pulmonary embolism |
Not known |
|
Deep vein thrombosis |
Not known | |
|
Capillary leak syndrome |
Not known | |
|
Vasculitis |
Not known | |
|
Hypertension |
Not known | |
|
Flushing |
Not known | |
|
Blood pressure decreased |
Not known |
|
System Organ Class (SOC) |
Adverse Reaction |
Frequency Category |
|
RESPIRATORY, |
Respiratory failure** |
Not known |
|
THORACIC, AND |
Acute respiratory distress syndrome** Pulmonary |
Not known |
|
MEDIASTINAL |
hypertension** |
Not known |
|
DISORDERS |
Interstitial lung disease** (as manifested by |
Not known |
|
Pulmonary fibrosis ) |
Not known | |
|
Alveolitis allergic, |
Not known | |
|
Interstitial pneumonitis |
Not known | |
|
Pneumonitis** |
Not known | |
|
Pulmonary edema** |
Not known | |
|
Pleural effusion |
Not known | |
|
Bronchospasm |
Not known | |
|
Dyspnea |
Not known | |
|
Hypoxia |
Not known | |
|
Cough |
Not known | |
|
GASTROINTESTINAL |
Nausea/Vomiting |
Very |
|
DISORDERS |
common | |
|
Diarrhea |
Uncommon | |
|
Stomatitis |
Uncommon | |
|
Cecitis |
Not known | |
|
Colitis |
Not known | |
|
Enterocolitis |
Not known | |
|
Pancreatitis |
Not known | |
|
Ileus |
Not known | |
|
Gastrointestinal hemorrhage |
Not known | |
|
Mucosal ulceration |
Not known | |
|
Constipation |
Not known | |
|
Abdominal pain |
Not known | |
|
Salivary hypersecretion |
Not known | |
|
HEPATOBILIARY |
Hepatotoxicity8 |
Common |
|
DISORDERS |
Hepatic failure** |
Not known |
|
Hepatitis fulminant** |
Not known | |
|
Veno-occlusive liver disease |
Not known | |
|
Portal vein thrombosis |
Not known | |
|
Cytolytic hepatitis |
Not known | |
|
Cholestasis |
Not known |
|
System Organ Class (SOC) |
Adverse Reaction |
Frequency Category |
|
SKIN AND |
Alopecia |
Very |
|
SUBCUTANEOUS |
common | |
|
TISSUE DISORDERS |
Dermatitis |
Rare |
|
Papular rash |
Rare | |
|
Toxic epidermal necrolysis |
Not known | |
|
Stevens-Johnson syndrome |
Not known | |
|
Palmar-plantar erythrodysesthesia syndrome |
Not known | |
|
Radiation recall dermatitis |
Not known | |
|
Skin necrosis |
Not known | |
|
Facial swelling |
Not known | |
|
Petechiae |
Not known | |
|
Rash |
Not known | |
|
-Macular rash |
Not known | |
|
Pruritus |
Not known | |
|
Erythema |
Not known | |
|
Skin hyperpigmentation |
Not known | |
|
Hyperhidrosis |
Not known | |
|
Nail disorder |
Not known | |
|
MUSCULOSKELETAL |
Rhabdomyolysis Osteomalacia Rickets |
Not known |
|
AND CONNECTIVE |
Not known | |
|
TISSUE DISORDERS |
Not known Not known | |
|
Growth retardation |
Not known | |
|
Myalgia |
Not known | |
|
Arthralgia |
Not known | |
|
Pain in extremity |
Not known | |
|
Muscle twitching |
Not known | |
|
RENAL AND URINARY |
Hemorrhagic cystitis |
Very |
|
DISORDERS |
common | |
|
Hematuria |
Very common | |
|
Macrohematuria |
Very common | |
|
Renal dysfunction10 |
Very common | |
|
Renal structural damage |
Very common | |
|
Fanconi syndrome |
Not known | |
|
Tubulointerstitial nephritis |
Not known | |
|
Nephrogenic diabetes insipidus |
Not known | |
|
Phosphaturia |
Not known | |
|
Aminoaciduria |
Not known | |
|
Polyuria |
Not known | |
|
Enuresis |
Not known | |
|
Feeling of residual urine |
Not known | |
|
Acute renal failure** |
Not known | |
|
Chronic renal failure** |
Not known |
|
System Organ Class (SOC) |
Adverse Reaction |
Frequency Category |
|
REPRODUCTIVE |
Infertility |
Not known |
|
SYSTEM AND BREAST |
Ovarian failure |
Not known |
|
DISORDERS |
Premature menopause |
Not known |
|
Amenorrhea |
Not known | |
|
Ovulation disorder |
Not known | |
|
Azoospermia |
Not known | |
|
Oligospermia |
Not known | |
|
Blood estrogen decreased |
Not known | |
|
Blood gonadotrophin increased |
Not known | |
|
CONGENITAL, FAMILIAL AND GENETIC DISORDERS |
Fetal growth retardation |
Not known |
|
GENERAL |
Phlebitis11 |
Common |
|
DISORDERS AND |
Neutropenic fever12 |
Common |
|
ADMINISTRATIVE |
Fatigue |
Uncommon |
|
SITE CONDITIONS |
Malaise |
Not known |
|
Not known | ||
|
General physical deterioration |
Not known | |
|
Injection/Infusion site reactions4 |
Not known | |
|
Chest pain |
Not known | |
|
Edema |
Not known | |
|
Mucosal inflammation |
Not known | |
|
Pain |
Not known | |
|
Pyrexia |
Not known | |
|
Chills |
Not known | |
|
* including as we |
ll as reactivation of latent infections, including viral hepatitis, | |
Pneumocystis jiroveci, herpes zoster, Strongyloides, progressive multifocal leukoencephalopathy, and other viral and fungal infections
1 The following adverse reaction terms have been reported for leukopenia: neutropenia,
granulocytopenia, lymphopenia, and pancytopenia. For neutropenic fever, see point 12 below.
2
Thrombocytopenia may also be complicated by bleeding. Bleeding with fatal outcome has been reported.
3
Includes cases reported as anemia and decrease in hemoglobin/hematocrit.
4
Encephalopathy with coma and death has been reported.
5
Central nervous system toxicity was reported to be manifested by the following signs and symptoms: Abnormal behavior, Affect lability, Aggression, Agitation, Anxiety, Aphasia, Asthenia, Ataxia, Cerebellar syndrome, Cerebral function deficiency, Cognitive disorder, Coma, Confusional state, Cranial nerve dysfunction, Depressed state of consciousness, Depression, Disorientation, Dizziness, Electroencephalogram abnormal, Encephalopathy, Flat affect, Hallucinations, Headache, Ideation, Lethargy, Memory impairment, Mood change, Motor dysfunction, Muscle spasms, Myoclonus, Progressive loss of brainstem reflexes, Psychotic reaction, Restlessness, Somnolence, Tremor, Urinary incontinence.
6
Cardiotoxicity was reported as congestive heart failure, tachycardia, pulmonary edema. Fatal outcome has been reported.
7
Hypotension leading to shock and fatal outcome has been reported.
8
Hepatotoxicity was reported as increases in liver enzymes, i.e., serum alanine aminotransferase, serum aspartate aminotransferase, alkaline phosphatase, gamma-glutamyltransferase and lactate dehydrogenase, increased bilirubin, jaundice, hepatorenal syndrome.
9
Frequency of hemorrhagic cystitis is estimated based on the frequency of hematuria. Reported symptoms of hemorrhagic cystitis included dysuria and pollakiuria.
10Renal dysfunction was reported to be manifested as: Renal failure (including acute renal failure, irreversible renal failure; fatal outcomes have been reported), Serum creatinine increased, BUN increased, Creatinine clearance decreased, Metabolic acidosis, Anuria, Oliguria, Glycosuria, Hyponatremia, Uremia, Creatinine clearance increased. Renal structural damage was reported to be manifested as: Acute tubular necrosis, Renal parenchymal damage, Enzymuria, Cylindruria, Proteinuria.
11 Includes cases reported as phlebitis and irritation of the venous walls.
12 Frequency of neutropenic fever: Includes cases reported as granulocytopenic fever.
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.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
ATC Code: L01AA06
Ifosfamide is a cytostatic agent of the group of oxazaphosphorines. Chemically, it is related to the nitrogen-mustard and it is a synthetic analogue of cyclophosphamide.
Ifosfamide is inactive in vitro and is in vivo preferably activated in the liver by microsomal enzymes to 4-hydroxy-ifosfamide, which is in equilibrium with aldoifosfamide, its tautomer. Aldoifosfamide disintegrates spontaneously into acrolein and the alkylating metabolite isofosfamide-mustard. Acrolein is blamed for the urotoxic effects of ifosfamide.
The cytotoxic effect of ifosfamide is due to interaction between its alkylating metabolites and the DNA. The preferred point of attack is the phosphodiester bridges of the DNA. Alkylation results in strand fracture and cross-linking of the DNA.
In the cell cycle the passage through the G2 phase is slowed down. The cytotoxic effect is not specific to the phase of the cell cycle; however it is specific to the cell cycle.
Cross-resistance, mainly with structurally related cytostatic agents such as cyclophosphamide, but also with other alkylating agents, cannot be ruled out. On the other hand, it has been found that tumours being resistant to cyclophosphamide or which recur after cyclophosphamide therapy often still respond to treatment with ifosfamide.
Paediatric population Ewing’s sarcoma
In a randomized controlled trial, 518 patients (87% under 17 years of age) with Ewing’s Sarcoma, primitive neuroectodermal tumour of bone or primitive sarcoma of bone were randomized to ifosfamide/etoposide alternating with standard treatment, or to standard treatment alone. In those with no metastases at baseline, there was a statistically significant improvement in 5 year survival for those receiving ifosfamide /etoposide (69%) compared to those on standard treatment alone (54%). Overall survival at 5 years was 72% in the ifosfamide/etoposide group compared to 61% in the standard treatment group. Similar toxicities were observed in both treatment arms. In those with metastases at baseline, there was no difference in 5 year event-free survival or 5 year overall survival between treatment groups.
In a randomized comparative study of ifosfamide (VAIA regimen) and cyclophosphamide (VACA regimen) in 155 patients with standard risk Ewing’s sarcoma (83% under 19 years of age), no difference in event free survival or overall survival was demonstrated. Less toxicity was demonstrated for the ifosfamide regimen.
Other paediatric cancers
Ifosfamide has been widely investigated in uncontrolled prospective exploratory studies in children. Various dosage schedules and regimens, in combination with other antitumour agents, have been used. The following paediatric cancers have been investigated: rhabdomyosarcoma, nonrhabdomyosarcoma soft tissue sarcoma, germ cell tumours, osteosarcoma, non-Hodgkins lymphoma, Hodgkins Lymphoma , acute lymphoblastic leukaemia, neuroblastoma, Wilms tumour, and malignant CNS tumours.
Favourable partial responses, complete responses and survival rates have been documented.
A variety of dosage schedules and regimens of ifosfamide in combination with other antitumor agents, are used. The prescriber should refer to chemotherapy regimens for specific tumour type in choosing a specific dosage, mode of administration and schedules.
Usually the doses of ifosfamide in pediatric tumors range from 0.8 to 3 g/m2/day for 2-5 days for a total dose of 4-12 g/m2 for chemotherapy course.
Fractionated administration of ifosfamide is performed as intravenous infusion over a period ranging between 30 minutes and 2 hours, depending on the infusion volume or recommendations of protocol:
Uroprotection with mesna is mandatory during ifosfamide administration with a dose equivalent to 80-120 % of ifosfamide. It is recommended to prolong Mesna infusion to 12-48 hours after the end of ifosfamide infusion. 20 % of the whole Mesna dose should be given as i.v start bolus. Hyperhydration with at least 3000 ml/m2 is required during ifosfamide infusion and for 24-48 hours after the end of ifosfamide administration.
Under treatment with ifosfamide, especially in case of long-term treatment, sufficient diuresis and regular control of renal function will be required. Children 5 years of age or younger may be more susceptible to ifosfamide-induced renal toxicity than older children or adults. Severe nephrotoxicity leading to Fanconi’s syndrome has been reported. Progressive tubular damage resulting in potentially debilitating hypophosphatemia and rickets has been reported rarely but should be taken into consideration.
Paediatric data from randomized controlled clinical studies are limited.
5.2 Pharmacokinetic properties
Absorption
After intravenous administration, ifosfamide is detectable in organs and tissues after a few minutes. There is a linear relationship between the plasma concentrations reached and the administered dose of ifosfamide.
Distribution
Ifosfamide and its metabolites distribute in the body among tissues and the organs, including the brain. The distribution volume comes to 0.5 -0.8 l/kg. The plasma halflife of ifosfamide is between 4 and 7 hours.
Unchanged ifosfamide may cross the blood-brain barrier. In children, metabolites of ifosfamide were also detected in the cerebrospinal fluid, whereas this is still under controversial discussion for adults.
There are no confirmed data about passage of ifosfamide through the placenta or excretion into breast milk. Because of the teratogenicity of the substance which was confirmed in animal experiments and the structural resemblance with cyclophosphamide it must be expected that ifosfamide also passes the placenta and is excreted into breast milk.
Ifosfamide is bound to about 20% to plasma protein.
Metabolism
Within a few minutes, metabolisation of ifosfamide starts.
Ifosfamide is hydroxylated to active 4-hydroxy-ifosfamide. The process is mainly catalysed by the cytochrome P450 isoenzyme CYP3A4. By ring opening reaction, 4-hydroxy-ifosfamide is transformed into active aldoifosfamide. Further decomposition of aldoifosfamide proceeds by cleavage of acrolein to active isophosphoramide-mustard. Moreover, ifosfamide is being deactivated to 25 - 60% by dealkylation of the chloroethyl side chains. This seems to be catalysed by CYP2B6. Alternatively, aldoifosfamide can be oxidized to the inactive carboxyifosfamide.
Metabolism of ifosfamide is characterized by a wide inter-individual variability.
Elimination
Ifosfamide and its metabolites are mainly eliminated via the kidneys. At a fractionated dose of
1.6 - 2.4 g/m2 body surface/day on three consecutive days, 57% of the dose administered, and at a high single dose of 3.8 - 5 g/m2 body surface, 80% of the dose administered was eliminated in form of metabolites or unchanged ifosfamide within 72 hours. The unmetabolised excreted amount came to 15% and 53%, respectively, for the above-mentioned doses.
Renal clearance is 6 - 22 ml/min.
Pharmacokinetics in special clinical situations/populations Children
The pharmacokinetic properties of ifosfamide seen in children do not vary essentially from the ones observed in adults, with a shorter elimination half-life period and where it seems that renal elimination of ifosfamide and its metabolites might be slightly higher.
Elderly and obese patients
In case of elderly and/or obese patients, serum half-life period of ifosfamide is prolonged.
Renal impairment
No formal studies were conducted in patients with impaired renal function. However, due to the fact that renal clearance of ifosfamide is low, it is not expected that a slightly impaired renal function will have any influence on the pharmacokinetic properties of ifosfamide. In case of renal failure, neurotoxicity of ifosfamide may be increased because of impaired renal elimination. Therefore, dose reduction is recommended in these patients.
Hepatic impairment
Ifosfamide is mainly metabolised in the liver. Impaired hepatic function may slow down metabolism of ifosfamide. Hepatic failure led to complete blockage of ifosfamide metabolism and thus excretion took place exclusively in form of ifosfamide.
5.3 Preclinical safety data
Acute toxicity
Following intraperitoneal administration, LD50 values are ranging between 520 and 760 mg/kg in mice and between 150 and 300 mg/kg in rats. Repeated intravenous administration of doses of 100 mg/kg or more caused signs of toxicity in rats.
Chronic toxicity
Corresponding to the clinical side effects, studies concerning chronic toxicity tests did result in damage to the lymphohematopoietic system, the gastrointestinal tract, the urinary bladder, the kidneys, the liver and the gonads.
Mutagenic and carcinogenic potential
Being an alkylating agent, ifosfamide belongs to the genotoxic substances and possesses the corresponding mutagenic potential. In long-term studies in rats and mice, ifosfamide proved to have a carcinogenic effect.
Reproductive toxicity
Ifosfamide has embryotoxic and teratogenic effects. Teratogenic effects were observed in three animal species (mice, rats, rabbits) at doses between 3 and 7.5 mg/kg.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Sodium chloride
Sodium monohydrogen phosphate dodecahydrate Sodium dihydrogen phosphate dehydrate
Phosphoric acid Water for injections
6.2 Incompatibilities
Benzyl alcohol-containing solutions can reduce the stability of ifosfamide.
6.3 Shelf life
18 months
6.4 Special precautions for storage
Store between +2°C and +8°C.
Do not use Ifosfamide solution for infusion after the expiry date indicated on the package.
Store in the original packaging.
6.5 Nature and contents of container
Ifosfamide solution for infusion in a pack containing 1 vial of 25ml or 50ml solution for infusion (40mg/ml).
6.6 Special precautions for disposal
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.
Before parenteral administration, the substance must be completely dissolved.
When handling Ifosfamide solution for infusion, the safety regulations concerning handling of cytostatic agents must be observed.
Any unused product or waste material should be disposed of in accordance with local requirements.
Preparation of the infusion solution
For the purpose of infusion, it is recommended to dilute Ifosfamide solution for infusion with a 0.9%-conc. NaCl solution. The following can be used as a guideline: Dilution to 250 ml for an infusion over a period of 30 - 60 minutes and dilution to 500 ml for an infusion administered over one to two hours. For continuous 24-hours infusion with high doses of Ifosfamide solution for infusion, it is recommended to dilute the total dose (e.g. 5 g/m2) in three litres of 0.9%-conc. NaCl solution.
For the diluted solutions, a chemical and physical stability of 24 hours at 25°C was demonstrated.
For microbiological reasons, it is recommended to use the diluted solutions immediately after their preparation. In case they will not be used immediately, the user will be responsible to observe the instructions given concerning shelf life and storage requirements; however, 24 hours at 2 - 8°C should not be exceeded.
7 MARKETING AUTHORISATION HOLDER
Baxter Healthcare Limited
Caxton Way
Thetford
Norfolk
IP24 3SE
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 00116/0421
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
18/12/2006
10 DATE OF REVISION OF THE TEXT
04/07/2013
including fatal outcomes
including acute myeloid leukemia, acute promyelocytic leukemia , acute lymphocytic leukemia*
Myelosuppression manifested as Bone marrow failure
including swelling, inflammation, pain, erythema, tenderness, pruritus