- Approval Id
- 92d86686093f92f2
- Drug Approval Emc Name
- Ifosfamide Injection 1g
- Drug Name
- Ifosfamide Injection 1g
- Company Address
- Caxton Way, Thetford, Norfolk, IP24 3SE, UK
- Company Website
- https://www.baxterhealthcare.co.uk/
- Company Medical Info Direct Line
- 0800 0260516
- Company Medical Info Email
- Medinfo_uki@baxter.com
- Company Customer Care Direct Line
- 0800 028 9881
- Legal Category
- Prescription only medicine
- Authorisation Holder
- Baxter Healthcare Ltd
Caxton Way,ThetfordNorfolkIP24 3SEUnited Kingdom
- Authorisation Number
- PL 00116/0392
- Authorisation Date
- 15 December 2003
- Instruction Authorisation Holder
- Baxter Healthcare Ltd
Caxton Way,ThetfordNorfolkIP24 3SEUnited Kingdom
- Instruction Authorisation Number
- PL 00116/0392
- Instruction Authorisation Date
- 15 December 2003
- Instruction Composition
- Each vial contains 1g of ifosfamide.
When reconstituted as directed, each milliliter of concentrate contains 80 mg Ifosfamide
- Instruction Dosage Form
- Powder for concentrate for solution for infusion.
White powder.
- Instruction Clinical Particulars
- 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 population4.2 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:
1 g vial: add 12.5 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 infections4.4 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 ST segment 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, another oxazaphosphorine cytotoxic agent 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) | Common |
| Sepsis (septic shock)\\* | 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) | Not known |
| Progressions of underlying malignancies\\* | Not known |
| \*\*BLOOD AND LYMPHATIC SYSTEM DISORDERS\*\* | Myelosuppression | Very common |
| - Leukopenia | Very common |
| - Thrombocytopenia\\* | Very common |
| - Anaemia | Not known |
| - Agranulocytosis | Not known |
| Haematotoxicity\\* | Not known |
| - Haemolytic anaemia | Not known |
| - Methaemoglobinaemia | Not known |
| Febrile bone marrow aplasia | Not known |
| Disseminated intravascular coagulation | Not known |
| Haemolytic uremic syndrome | Not known |
| Neonatal anaemia | Not known |
| \*\*IMMUNE SYSTEM DISORDERS\*\* | Angioedema\\* | Not known |
| Anaphylactic reaction | Not known |
| Immunosuppression | Not known |
| Urticaria | Not known |
| Hypersensitivity reaction | Not known |
| \*\*ENDOCRINE DISORDERS\*\* | Syndrome of inappropriate antidiuretic hormone secretion (SIADH) | Not known |
| \*\*METABOLISM AND NUTRITION DISORDERS\*\* | Decreased Appetite | Common |
| Tumor lysis syndrome | Not known |
| Metabolic acidosis | Not known |
| Hypokalaemia | Not known |
| Hypocalcaemia | Not known |
| Hypophosphataemia | Not known |
| Hyperglycaemia | Not known |
| Polydipsia | Not known |
| \*\*PSYCHIATRIC DISORDERS\*\* | Mutism | Not known |
| Mental status change (includine mania, paranoia, delusion, delirium, catatonia, amnesia, panic attack) | Not known |
| Echolalia | Not known |
| Perseveration | Not known |
| \*\*NERVOUS SYSTEM DISORDERS\*\* | Central nervous system toxicity | Not known |
| - Encephalopathy | Not known |
| - Faecal incontinence | Not known |
| - Status epilepticus\\* (convulsive and nonconvulsive) | Not known |
| - Movement disorder | Not known |
| - Extrapyramidal disorder | Not known |
| - Gait disturbance | Not known |
| - Dysarthria | Not known |
| Peripheral neuropathy | Not known |
| - Hypoesthesia | Not known |
| - Paresthesia | Not known |
| Asterixis | Not known |
| Neuralgia | Not known |
| \*\*EYE DISORDERS\*\* | Visual impairment | Not known |
| Conjunctivitis | Not known |
| Eye irritation | Not known |
| \*\*EAR AND LABYRINTH DISORDERS\*\* | Deafness | Not known |
| Vertigo | Not known |
| Tinnitus | Not known |
| \*\*CARDIAC DISORDERS\*\* | Cardiotoxicity\\* | Uncommon |
| Arrythmia (including supraventricular and ventricular arrhythmia) | Not known |
| Atrial fibrillation | Not known |
| Premature atrial contractions | Not known |
| Bradycardia | Not known |
| Cardiac arrest\\* | Not known |
| Myocardial infarction | Not known |
| Cardiac failure\\* | Not known |
| Myocardial haemorrhage | Not known |
| Angina pectoris | Not known |
| Cardiomyopathy\\* (including congestive cardiomyopathy) | Not known |
| Electrocardiogram ST-segment abnormal | Not known |
| Electrocardiogram T- wave inversion | Not known |
| Electrocardiogram QRS complex abnormal | Not known |
| \*\*VASCULAR DISORDERS\*\* | Hypotension | Uncommon |
| Pulmonary embolism | Not known |
| Deep vein thrombosis | Not known |
| Capillary leak syndrome | Not known |
| Vasculitis | Not known |
| Hypertension | Not known |
| Flushing | Not known |
| \*\*RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS\*\* | Respiratory failure\\* | Not known |
| Acute respiratory distress syndrome\\* | Not known |
| Pulmonary hypertension | Not known |
| Interstitial lung disease\\* (as manifested by Pulmonary fibrosis) | Not known |
| Pneumonitis\\* | Not known |
| Pulmonary oedema\\* | Not known |
| Pleural effusion | Not known |
| Dyspnea | Not known |
| Hypoxia | Not known |
| Cough | Not known |
| \*\*GASTROINTESTINAL DISORDERS\*\* | Nausea/Vomiting | Very common |
| Diarrhoea | Uncommon |
| Stomatitis | Uncommon |
| Enterocolitis | Not known |
| Pancreatitis | Not known |
| Ileus | Not known |
| Gastrointestinal haemorrhage | Not known |
| Mucosal ulceration | Not known |
| Constipation | Not known |
| Abdominal pain | Not known |
| Salivary hypersecretion | Not known |
| \*\*HEPATOBILIARY DISORDERS\*\* | Hepatotoxicity | Common |
| - Hepatic failure | Not known |
| Veno-occlusive liver disease | Not known |
| Portal vein thrombosis | Not known |
| Cytolytic hepatitis | Not known |
| \*\*SKIN AND SUBCUTANEOUS TISSUE DISORDERS\*\* | Alopecia | Very common |
| 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 |
| Rash | Not known |
| Pruritus | Not known |
| Erythema | Not known |
| Skin hyperpigmentation | Not known |
| Hyperhidrosis | Not known |
| Nail disorder | Not known |
| \*\*MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS\*\* | Rhabdomyolysis | Not known |
| Osteomalacia | Not known |
| Rickets | Not known |
| Growth retardation | Not known |
| Myalgia | Not known |
| Arthralgia | Not known |
| Muscle twitching | Not known |
| \*\*RENAL AND URINARY DISORDERS\*\* | Haemorrhagic cystitis | Very common |
| Haematuria | Very common |
| Renal dysfunction\\* | Very common |
| - Acute renal failure | Very common |
| - Chronic renal failure | Not known |
| - Aminoaciduria | Not known |
| - Phosphaturia | Not known |
| - Fanconi syndrome | Not known |
| - Tubulointerstitial nephritis | Not known |
| Renal structural damage | Not known |
| Nephrogenic diabetes insipidus | Not known |
| Polyuria | Not known |
| Enuresis | Not known |
| Feeling of residual urine | Not known |
| \*\*REPRODUCTIVE SYSTEM AND BREAST DISORDERS\*\* | Infertility | Not known |
| Ovarian failure | Not known |
| Premature menopause | Not known |
| Amenorrhea | Not known |
| Ovulation disorder | Not known |
| Azoospermia | Not known |
| Oligospermia | Not known |
| \*\*CONGENITAL, FAMILIAL AND GENETIC DISORDERS\*\* | Fetal growth retardation | Not known |
| \*\*GENERAL DISORDERS AND ADMINISTRATIVE SITE CONDITIONS\*\* | Phlebitis | Common |
| Fatigue | Uncommon |
| Malaise | Not known |
| Multiorgan failure\\* | Not known |
| General physical deterioration | Not known |
| Injection/Infusion site reactions | Not known |
| Oedema | Not known |
| Pain | Not known |
| Pyrexia | Not known |
| Chills | 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 the 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 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.
- Instruction Pharmacology
- 5.1 Pharmacodynamic properties
Ifosfamide is an antineoplastic, a cytotoxic alkylating agent. It is a prodrug and shows no in vitro cytotoxic activity until activated by microsomal enzymes. The cytotoxic activity of Ifosfamide (alkylation of the nucleophilic centres in the cells) is associated with the activated oxazaphosphorine ring hydroxylated at the C4 atom which interacts with DNA-DNA cross linking. This activity manifests itself by blocking the late S and early G2 phases of the cell cycle.
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'ssarcoma (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 hypophosphataemia 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
Ifosfamide is rapidly absorbed from the site of administration, activation of Ifosfamide is primarily in the liver by microsomal mixed function oxidases. Elimination of metabolised Ifosfamide is primarily via the kidneys. The serum half-life ranges between 4 - 8 hours depending on the dose and dosage regimen. Over 80% of a single dose of ifosfamide was excreted in the urine within 24 hours. Approximately 80% of the dose was excreted as parent compound. Significant quantities of unchanged ifosfamide were found in the cerebrospinal fluid consistent with the high lipid solubility of the drug.5.3 Preclinical safety data
Not relevant
- Instruction Pharmaceutical Particulars
- 6.1 List of excipients
None6.2 Incompatibilities
Benzyl alcohol-containing solutions can reduce the stability of ifosfamide.6.3 Shelf life
Five years.
\*\*After dilution\*\*
Chemical and physical in use stability has been demonstrated for 17 hours at 25ºC in Sodium Chloride 0.9%.
In circumstances where the diluted solution cannot be used immediately, chemical and physical in-use stability has been demonstrated with storage at refrigerated conditions for a number of days with additional storage at 25ºC for the durations indicated in the table below:
| | |
| --- | --- |
| \*\*Storage at 2ºC to 8ºC\*\* \*\*(days)\*\* | \*\*Subsequent in-use shelf-life at 25ºC\*\* \*\*(hours)\*\* |
| 0 | 17 h |
| 1 | 16 h |
| 7 | 13 h |
From a microbiological point of view, the infusion solution should be administered immediately, in use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 ºC to 8 ºC, unless reconstitution/dilution has been taken place in controlled and validated aseptic condition.6.4 Special precautions for storage
Do not store above 25ºC.
Keep container in outer carton.6.5 Nature and contents of container
Type I or Type III clear glass injection vial with bromobutyl rubber closure and beading cap. Vials are packed singly in a cardboard box.
Vials are packed with or without a protective plastic overwrap. Protective plastic overwrap does not come into contact with the medicinal product and provides additional transport protection, which increases the safety for the medical and pharmaceutical personnel.6.6 Special precautions for disposal and other handling
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.
Before parenteral administration, the substance must be completely dissolved.
The following protective recommendations are advised during handling due to the toxic nature of the substance:
Reconstitution and administration must be undertaken only by trained personnel. Pregnant staff and breastfeeding mothers should be excluded.
Protective clothing, goggles, masks and disposable PVC or latex gloves should be worn.
A designated area should be defined for reconstitution (preferably under a laminar-airflow system). The work surface should be protected by a disposable, plastic backed absorbent paper. Accidental contact with the skin or eyes should be treated immediately by copious lavage with water. Soap and water should then be used on non-mucous membranes. Spillage should be removed by dry or moist disposable towels.
Care must be taken in the disposal of all waste material (syringes, needles and disposable towels etc.) Used items should be placed in appropriate secure containers in readiness for destruction in an appropriate high-temperature incinerator with an after-burner.
- Instruction Content
- ## Composition
Each vial contains 1g of ifosfamide.
When reconstituted as directed, each milliliter of concentrate contains 80 mg Ifosfamide
## Pharmaceutical Form
Powder for concentrate for solution for infusion.
White powder.
## Clinical Particulars
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 population4.2 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:
1 g vial: add 12.5 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 infections4.4 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 ST segment 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, another oxazaphosphorine cytotoxic agent 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) | Common |
| Sepsis (septic shock)\\* | 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) | Not known |
| Progressions of underlying malignancies\\* | Not known |
| \*\*BLOOD AND LYMPHATIC SYSTEM DISORDERS\*\* | Myelosuppression | Very common |
| - Leukopenia | Very common |
| - Thrombocytopenia\\* | Very common |
| - Anaemia | Not known |
| - Agranulocytosis | Not known |
| Haematotoxicity\\* | Not known |
| - Haemolytic anaemia | Not known |
| - Methaemoglobinaemia | Not known |
| Febrile bone marrow aplasia | Not known |
| Disseminated intravascular coagulation | Not known |
| Haemolytic uremic syndrome | Not known |
| Neonatal anaemia | Not known |
| \*\*IMMUNE SYSTEM DISORDERS\*\* | Angioedema\\* | Not known |
| Anaphylactic reaction | Not known |
| Immunosuppression | Not known |
| Urticaria | Not known |
| Hypersensitivity reaction | Not known |
| \*\*ENDOCRINE DISORDERS\*\* | Syndrome of inappropriate antidiuretic hormone secretion (SIADH) | Not known |
| \*\*METABOLISM AND NUTRITION DISORDERS\*\* | Decreased Appetite | Common |
| Tumor lysis syndrome | Not known |
| Metabolic acidosis | Not known |
| Hypokalaemia | Not known |
| Hypocalcaemia | Not known |
| Hypophosphataemia | Not known |
| Hyperglycaemia | Not known |
| Polydipsia | Not known |
| \*\*PSYCHIATRIC DISORDERS\*\* | Mutism | Not known |
| Mental status change (includine mania, paranoia, delusion, delirium, catatonia, amnesia, panic attack) | Not known |
| Echolalia | Not known |
| Perseveration | Not known |
| \*\*NERVOUS SYSTEM DISORDERS\*\* | Central nervous system toxicity | Not known |
| - Encephalopathy | Not known |
| - Faecal incontinence | Not known |
| - Status epilepticus\\* (convulsive and nonconvulsive) | Not known |
| - Movement disorder | Not known |
| - Extrapyramidal disorder | Not known |
| - Gait disturbance | Not known |
| - Dysarthria | Not known |
| Peripheral neuropathy | Not known |
| - Hypoesthesia | Not known |
| - Paresthesia | Not known |
| Asterixis | Not known |
| Neuralgia | Not known |
| \*\*EYE DISORDERS\*\* | Visual impairment | Not known |
| Conjunctivitis | Not known |
| Eye irritation | Not known |
| \*\*EAR AND LABYRINTH DISORDERS\*\* | Deafness | Not known |
| Vertigo | Not known |
| Tinnitus | Not known |
| \*\*CARDIAC DISORDERS\*\* | Cardiotoxicity\\* | Uncommon |
| Arrythmia (including supraventricular and ventricular arrhythmia) | Not known |
| Atrial fibrillation | Not known |
| Premature atrial contractions | Not known |
| Bradycardia | Not known |
| Cardiac arrest\\* | Not known |
| Myocardial infarction | Not known |
| Cardiac failure\\* | Not known |
| Myocardial haemorrhage | Not known |
| Angina pectoris | Not known |
| Cardiomyopathy\\* (including congestive cardiomyopathy) | Not known |
| Electrocardiogram ST-segment abnormal | Not known |
| Electrocardiogram T- wave inversion | Not known |
| Electrocardiogram QRS complex abnormal | Not known |
| \*\*VASCULAR DISORDERS\*\* | Hypotension | Uncommon |
| Pulmonary embolism | Not known |
| Deep vein thrombosis | Not known |
| Capillary leak syndrome | Not known |
| Vasculitis | Not known |
| Hypertension | Not known |
| Flushing | Not known |
| \*\*RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS\*\* | Respiratory failure\\* | Not known |
| Acute respiratory distress syndrome\\* | Not known |
| Pulmonary hypertension | Not known |
| Interstitial lung disease\\* (as manifested by Pulmonary fibrosis) | Not known |
| Pneumonitis\\* | Not known |
| Pulmonary oedema\\* | Not known |
| Pleural effusion | Not known |
| Dyspnea | Not known |
| Hypoxia | Not known |
| Cough | Not known |
| \*\*GASTROINTESTINAL DISORDERS\*\* | Nausea/Vomiting | Very common |
| Diarrhoea | Uncommon |
| Stomatitis | Uncommon |
| Enterocolitis | Not known |
| Pancreatitis | Not known |
| Ileus | Not known |
| Gastrointestinal haemorrhage | Not known |
| Mucosal ulceration | Not known |
| Constipation | Not known |
| Abdominal pain | Not known |
| Salivary hypersecretion | Not known |
| \*\*HEPATOBILIARY DISORDERS\*\* | Hepatotoxicity | Common |
| - Hepatic failure | Not known |
| Veno-occlusive liver disease | Not known |
| Portal vein thrombosis | Not known |
| Cytolytic hepatitis | Not known |
| \*\*SKIN AND SUBCUTANEOUS TISSUE DISORDERS\*\* | Alopecia | Very common |
| 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 |
| Rash | Not known |
| Pruritus | Not known |
| Erythema | Not known |
| Skin hyperpigmentation | Not known |
| Hyperhidrosis | Not known |
| Nail disorder | Not known |
| \*\*MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS\*\* | Rhabdomyolysis | Not known |
| Osteomalacia | Not known |
| Rickets | Not known |
| Growth retardation | Not known |
| Myalgia | Not known |
| Arthralgia | Not known |
| Muscle twitching | Not known |
| \*\*RENAL AND URINARY DISORDERS\*\* | Haemorrhagic cystitis | Very common |
| Haematuria | Very common |
| Renal dysfunction\\* | Very common |
| - Acute renal failure | Very common |
| - Chronic renal failure | Not known |
| - Aminoaciduria | Not known |
| - Phosphaturia | Not known |
| - Fanconi syndrome | Not known |
| - Tubulointerstitial nephritis | Not known |
| Renal structural damage | Not known |
| Nephrogenic diabetes insipidus | Not known |
| Polyuria | Not known |
| Enuresis | Not known |
| Feeling of residual urine | Not known |
| \*\*REPRODUCTIVE SYSTEM AND BREAST DISORDERS\*\* | Infertility | Not known |
| Ovarian failure | Not known |
| Premature menopause | Not known |
| Amenorrhea | Not known |
| Ovulation disorder | Not known |
| Azoospermia | Not known |
| Oligospermia | Not known |
| \*\*CONGENITAL, FAMILIAL AND GENETIC DISORDERS\*\* | Fetal growth retardation | Not known |
| \*\*GENERAL DISORDERS AND ADMINISTRATIVE SITE CONDITIONS\*\* | Phlebitis | Common |
| Fatigue | Uncommon |
| Malaise | Not known |
| Multiorgan failure\\* | Not known |
| General physical deterioration | Not known |
| Injection/Infusion site reactions | Not known |
| Oedema | Not known |
| Pain | Not known |
| Pyrexia | Not known |
| Chills | 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 the 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 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.
## Pharmacological Properties
5.1 Pharmacodynamic properties
Ifosfamide is an antineoplastic, a cytotoxic alkylating agent. It is a prodrug and shows no in vitro cytotoxic activity until activated by microsomal enzymes. The cytotoxic activity of Ifosfamide (alkylation of the nucleophilic centres in the cells) is associated with the activated oxazaphosphorine ring hydroxylated at the C4 atom which interacts with DNA-DNA cross linking. This activity manifests itself by blocking the late S and early G2 phases of the cell cycle.
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'ssarcoma (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 hypophosphataemia 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
Ifosfamide is rapidly absorbed from the site of administration, activation of Ifosfamide is primarily in the liver by microsomal mixed function oxidases. Elimination of metabolised Ifosfamide is primarily via the kidneys. The serum half-life ranges between 4 - 8 hours depending on the dose and dosage regimen. Over 80% of a single dose of ifosfamide was excreted in the urine within 24 hours. Approximately 80% of the dose was excreted as parent compound. Significant quantities of unchanged ifosfamide were found in the cerebrospinal fluid consistent with the high lipid solubility of the drug.5.3 Preclinical safety data
Not relevant
## Pharmaceutical Particulars
6.1 List of excipients
None6.2 Incompatibilities
Benzyl alcohol-containing solutions can reduce the stability of ifosfamide.6.3 Shelf life
Five years.
\*\*After dilution\*\*
Chemical and physical in use stability has been demonstrated for 17 hours at 25ºC in Sodium Chloride 0.9%.
In circumstances where the diluted solution cannot be used immediately, chemical and physical in-use stability has been demonstrated with storage at refrigerated conditions for a number of days with additional storage at 25ºC for the durations indicated in the table below:
| | |
| --- | --- |
| \*\*Storage at 2ºC to 8ºC\*\* \*\*(days)\*\* | \*\*Subsequent in-use shelf-life at 25ºC\*\* \*\*(hours)\*\* |
| 0 | 17 h |
| 1 | 16 h |
| 7 | 13 h |
From a microbiological point of view, the infusion solution should be administered immediately, in use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 ºC to 8 ºC, unless reconstitution/dilution has been taken place in controlled and validated aseptic condition.6.4 Special precautions for storage
Do not store above 25ºC.
Keep container in outer carton.6.5 Nature and contents of container
Type I or Type III clear glass injection vial with bromobutyl rubber closure and beading cap. Vials are packed singly in a cardboard box.
Vials are packed with or without a protective plastic overwrap. Protective plastic overwrap does not come into contact with the medicinal product and provides additional transport protection, which increases the safety for the medical and pharmaceutical personnel.6.6 Special precautions for disposal and other handling
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.
Before parenteral administration, the substance must be completely dissolved.
The following protective recommendations are advised during handling due to the toxic nature of the substance:
Reconstitution and administration must be undertaken only by trained personnel. Pregnant staff and breastfeeding mothers should be excluded.
Protective clothing, goggles, masks and disposable PVC or latex gloves should be worn.
A designated area should be defined for reconstitution (preferably under a laminar-airflow system). The work surface should be protected by a disposable, plastic backed absorbent paper. Accidental contact with the skin or eyes should be treated immediately by copious lavage with water. Soap and water should then be used on non-mucous membranes. Spillage should be removed by dry or moist disposable towels.
Care must be taken in the disposal of all waste material (syringes, needles and disposable towels etc.) Used items should be placed in appropriate secure containers in readiness for destruction in an appropriate high-temperature incinerator with an after-burner.
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