This information is intended for use by health professionals
- Name of the medicinal product
- Qualitative and quantitative composition
a) Ifosfamide for Injection USP 1000mg-Taj Pharma
Each Lyophilized vial contains:
Ifosphamide USP 1000mg
b.1) Each ml contains:
(3 x 2ml Amps)
b) Ifosfamide for Injection USP 2000mg-Taj Pharma
Each Lyophilized vial contains:
Ifosphamide USP 2000mg
c.1) Each ml contains:
(3 x 2ml Amps)
c) Ifosfamide for Injection USP 3000mg-Taj Pharma
Each Lyophilized vial contains:
Ifosphamide USP 3000mg
d.1) Each ml contains:
(3 x 2ml Amps)
Powder for concentrate for solution for infusion.
- 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 population
4.2 Posology and method of administration
Ifosfamide should only be administered when there are facilities for regular monitoring of clinical, biochemical and haematological parameters before, during and after administration and under the direction of a specialist oncology service by physicians experienced with this drug.
Dosage must be individualised. Doses and duration of treatment and/or treatment intervals depend on the therapeutic indication, the scheme of a combination therapy, the patient’s general state of health and organ function, and the results of laboratory monitoring.
In combination with other agents of similar toxicity, a dose reduction or extension of the therapy-free intervals may be necessary.
Method of administration
A guide to the dosage regimens used for most indications is given below:
- a) 8 – 12 g/m² equally fractionated as single daily doses over 3 – 5 days every 2 – 4 weeks.
- b) 5 – 6 g/m² (maximum 10 g) given as a 24 hour infusion every 3 – 4 weeks.
The frequency of dosage is determined by the degree of myelosuppression and the time taken to recover adequate bone marrow function. The usual number of courses given is 4, but up to 7 (6 by 24 hour infusion) courses have been given. Re-treatment has been given following relapse.
During or immediately after administration, adequate amounts of fluid should be ingested or infused to force diuresis in order to reduce the risk of urothelial toxicity. See Section 4.4.
For prophylaxis of haemorrhagic cystitis, ifosfamide should be used in combination with mesna.
Use in Patients with Renal Impairment
In patients with renal impairment, particularly in those with severe renal impairment, decreased renal excretion may result in increased plasma levels of ifosfamide and its metabolites. This may result in increased toxicity (e.g., neurotoxicity, nephrotoxicity, haematotoxicity) and should be considered when determining the dosage in such patients. See section 4.3.
Ifosfamide and its metabolites are dialyzable.
Use in Patients with Hepatic Impairment
Hepatic impairment, particularly if severe, may be associated with decreased activation of ifosfamide. This may alter the effectiveness of ifosfamide treatment. 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. 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).
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:
500 gvial: 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:
- diluted to less than a 4% solution and injected directly into the vein, with the patient supine.
- infused in 5% dextrose-saline or normal saline over 30-120 mins.
- injected directly into a fast-running infusion,
- made up in 3 x 1 litres of dextrose-saline or normal saline and infused over 24 hours. Each litre should be given over eight hours, and should be freshly made up immediately before infusion.
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.
Ifosfamide is contra-indicated in patients with:
- known hypersensitivity to ifosfamide. See section 4.4
- urinary outflow obstruction
- severely impaired bone-marrow function (especially in patients previously treated with cytotoxic agents or radiotherapy)
- inflammation of the urinary bladder (cystitis)
- impaired renal function
- hepatic impairment
- acute infections
4.4 Special warnings and precautions for use
In individual patients, risk factors for ifosfamide toxicities and their sequelae described here and in other sections may constitute contraindications. In such situations, individual assessment of risk and expected benefits is necessary. Adverse reactions, depending on their severity, may require dosage modification or discontinuation of treatment
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 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.
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, low fluid intake
– Presence of brain metastases, prior CNS disease, brain irradiation
– Cerebral sclerosis, peripheral vasculopathy
– Presence of tumour in lower abdomen, bulky abdominal disease
– Poor performance status, advanced age
– Obesity, female gender
– Interactions with other medicines (e.g., aprepitant, CYP 3A4 inhibitors), alcohol, drug abuse, or pretreatment with Ifosphamide
If encephalopathy develops, administration of ifosfamide should be discontinued.
Publications report both successful and unsuccessful use of methylene blue for the treatment and prophylaxis of ifosfamide-associated encephalopathy.
Due to the potential for additive effects, drugs acting on the CNS (such as antiemetics, sedatives, narcotics, or antihistamines) must be used with particular caution or, if necessary, be discontinued in case of ifosfamide induced encephalopathy.
Renal and Urothelial Toxicity
Ifosfamide is both nephrotoxic and urotoxic.
Glomerular and tubular kidney function must be evaluated and checked before commencement of therapy, as well as during and after treatment.
Close clinical monitoring of serum and urine chemistries, including phosphorus, potassium, and other laboratory parameters appropriate for identifying nephrotoxicity and urothelial toxicity is recommended, see section 4.3.
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.
Ifosfamide administration is associated with urotoxic effects, which can be reduced by prophylactic use of mesna.
Haemorrhagic cystitis requiring blood transfusion has been reported with ifosfamide.
The risk of haemorrhagic cystitis is dose-dependent and increased with administration of single high doses compared to fractionated administration.
Haemorrhagic cystitis after a single dose of ifosfamide has been reported.
Before starting treatment, it is necessary to exclude or correct any urinary tract obstructions.
During or immediately after administration, adequate amounts of fluid should be ingested or infused to force diuresis in order to reduce the risk of urinary tract toxicity.
Ifosfamide should be used with caution, if at all, in patients with active urinary tract infections.
Past or concomitant radiation of the bladder or busulfan treatment may increase the risk for haemorrhagic cystitis.
Cardiotoxicity, Use in Patients With Cardiac Disease
Fatal outcome of ifosfamide-associated cardiotoxicity has been reported.
The risk of developing cardiotoxic effects is dose-dependent. It is increased in patients with prior or concomitant treatment with other cardiotoxic agents or radiation of the cardiac region and, possibly, renal impairment.
Particular caution should be exercised when ifosfamide is used in patients with risk factors for cardiotoxicity and in patients with pre-existing cardiac disease.
Manifestations of cardiotoxicity reported with ifosfamide treatment (see Section 4.8) and include:
– Supraventricular or ventricular arrhythmias, including atrial/supraventricular tachycardia, atrial fibrillation, pulseless ventricular tachycardia
– Decreased QRS voltage and STsegment or T-wave changes
– Toxic cardiomyopathy leading to heart failure with congestion and hypotension
– Pericardial effusion, fibrinous pericarditis, and epicardial fibrosis
Pulmonary toxicity leading to respiratory failure as well as fatal outcome has been reported.Interstitial pneumonitis and pulmonary fibrosis have been reported with ifosfamide treatment.
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.
See section 4.6.
Effects on Fertility
See section 4.6.
Amenorrhea has been reported in patients treated with ifosfamide. In addition, with another oxazaphosphorine cytotoxic agent, oligomenorrhea has been reported, see section 4.6.
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.
The cytotoxic effect of ifosfamide occurs after its activation, which takes place mainly in the liver. Therefore, the risk of tissue injury from accidental paravenous administration is low.
In case of accidental paravenous administration of ifosfamide, the infusion should be stopped immediately, the extravascular ifosfamide solution should be aspirated with the cannula in place, and other measures should be instituted as appropriate.
Use in Patients With Renal Impairment
In patients with renal impairment, particularly in those with severe renal impairment, decreased renal excretion may result in increased plasma levels of ifosfamide and its metabolites. This may result in increased toxicity (e.g., neurotoxicity, nephrotoxicity, haematotoxicity) and should be considered when determining the dosage in such patients.
Use in Patients With Hepatic Impairment
Hepatic impairment, particularly if severe, may be associated with decreased activation of ifosfamide. This may alter the effectiveness of ifosfamide treatment. Low serum albumin and hepatic impairment are also considered risk factors for the development of CNS toxicity. Hepatic impairment may increase the formation of a metabolite that is believed to cause or contribute to CNS toxicity and also contribute to nephrotoxicity.
This should be considered when selecting the dose and interpreting response to the dose selected.
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.
Increased cardiotoxicity may result from a combined effect of ifosfamide and, for example:
– Irradiation of the cardiac region
Increased pulmonary toxicity may result from a combined effect of ifosfamide and, for example:
– 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:
– Amphotericin B
An increased risk of developing haemorrhagic cystitis may result from a combined effect of ifosfamide and, for example:
– Irradiation of the bladder
Additive CNS effects may result from a combined effect of ifosfamide and, for example:
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:
– 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:
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.
Ifosphamide: Ifosphamide-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
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.
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).
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.
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.
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.
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
Potential side-effects on the central nervous system may transiently impair the ability to operate machinery and motor vehicles.
4.8 Undesirable effects
The adverse reactions and frequencies below are based on publications describing clinical experience with fractionated administration of ifosfamide as monotherapy with a total dose of 4 to 12 g/m2 per course.
ADR frequency is based upon the following scale: Very common (≥1/10); Common (≥1/100 – <1/10), Uncommon (≥1/1,000 – <1/100), Rare (≥1/10,000 – <1/1,000), Very rare (<1/10,000), Not known (adverse reactions reported in the post-marketing experience).
|System Organ Class (SOC)||Adverse Reaction||Frequency Category|
|INFECTIONS AND INFESTATIONS||Infections (including reactivation of latent infections)
Sepsis (septic shock)*
|NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYCTS AND POLYPS)||Secondary tumors*
(including Urinary tract carcinoma, Myelodysplastic syndrome, Acute leukaemia, Acute lymphocytic leukaemia, Lymphoma [Non-Hodgkin’s lymphoma], Sarcomas, Renal cell carcinoma, Thyroid cancer)
Progressions of underlying malignancies*
|BLOOD AND LYMPHATIC SYSTEM DISORDERS||Myelosuppression
– Haemolytic anaemia
Febrile bone marrow aplasia
Disseminated intravascular coagulation
Haemolytic uremic syndrome
|IMMUNE SYSTEM DISORDERS||Angioedema*
|ENDOCRINE DISORDERS||Syndrome of inappropriate antidiuretic hormone secretion (SIADH)||Not known|
|METABOLISM AND NUTRITION DISORDERS||Decreased Appetite
Tumor lysis syndrome
Mental status change (includine mania, paranoia, delusion, delirium, catatonia, amnesia, panic attack)
|NERVOUS SYSTEM DISORDERS||Central nervous system toxicity
– Faecal incontinence
– Status epilepticus* (convulsive and nonconvulsive)
– Movement disorder
– Extrapyramidal disorder
– Gait disturbance
|EYE DISORDERS||Visual impairment
|EAR AND LABYRINTH DISORDERS||Deafness
Arrythmia (including supraventricular and ventricular arrhythmia)
Premature atrial contractions
Cardiomyopathy* (including congestive cardiomyopathy )
Electrocardiogram ST-segment abnormal
Electrocardiogram T- wave inversion
Electrocardiogram QRS complex abnormal
Deep vein thrombosis
Capillary leak syndrome
|RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS||Respiratory failure*
Acute respiratory distress syndrome*
Interstitial lung disease* (as manifested by Pulmonary fibrosis)
– Hepatic failure
Veno-occlusive liver disease
Portal vein thrombosis
|SKIN AND SUBCUTANEOUS TISSUE DISORDERS||Alopecia
Toxic epidermal necrolysis
Palmar-plantar erythrodysesthesia syndrome
Radiation recall dermatitis
|MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS||Rhabdomyolysis
|RENAL AND URINARY DISORDERS||Haemorrhagic cystitis
– Acute renal failure
– Chronic renal failure
– Fanconi syndrome
– Tubulointerstitial nephritis
Renal structural damage
Nephrogenic diabetes insipidus
Feeling of residual urine
|REPRODUCTIVE SYSTEM AND BREAST DISORDERS||Infertility
|CONGENITAL, FAMILIAL AND GENETIC DISORDERS||Fetal growth retardation||Not known|
|GENERAL DISORDERS AND ADMINISTRATIVE SITE CONDITIONS||Phlebitis
General physical deterioration
Injection/Infusion site reactions
* 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.
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.
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 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
- Pharmaceutical particulars
6.1 List of excipients
Benzyl alcohol-containing solutions can reduce the stability of ifosfamide.
6.3 Shelf life
The reconstituted solution should be used immediately. The product does not contain a preservative, therefore microbial stability cannot be guaranteed. When prepared under strict aseptic conditions, ifosfamide is, as a 4% solution, however, chemically stable for 7 days at room temperature with Water for Injections, 0.9% saline, dextrose/saline and dextrose solutions. Ifosfamide and mesna when prepared under strict aseptic conditions at the recommended dilutions are chemically stable with:
(i) 0.9% saline and dextrose/saline solution for one week at room temp.
(ii) Water for Injections for one week under refrigeration.
(iii) 5% dextrose solution for 24 hours at room temperature, and
(iv) 0.9% saline solution for 28 days at room temperature.
6.4 Special precautions for storage
Do not store above 25°C.
Keep container in outer carton.
6.5 Nature and contents of container
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.
Manufactured in India By:
TAJ PHARMACEUTICALS LIMITED
at SURVEY NO.188/1 TO 189/1,190/1 TO 4,
ATHIYAWAD, DABHEL, DAMAN- 396210 (INDIA)
Ifosfamide for Injection USP 1000 mg-Taj Pharma
Package leaflet: Information for the user
Read all of this leaflet carefully before you start using this medicine because it contains important information for you.
- Keep this leaflet. You may need to read it
- If you have further questions, ask your doctor, pharmacist or
- This medicine has been prescribed for you Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor, pharmacist or This includes any possible side effects not listed in this leaflet. See section 4.
What is in this leaflet:
- What Ifosphamide Injection is and what it is used for
- What you need to know before you use Ifosphamide Injection
- How to use Ifosphamide Injection
- Possible side effects
- How to store Ifosphamide Injection
- Contents of the pack and other information
- What Ifosphamide Injection is and what it is used for
Ifosphamide forms part of a group of medicines called cytostatics, which are used in the treatment of cancer. Ifosphamide can be used alone but more commonly Ifosphamide is used in combination with other cytostatics.
What is it used for?
Ifosphamide can destroy cells in your body that may cause certain types of cancer (tumour of testis, tumour of ovary, tumour of the bladder, head and neck epithelial tumour, lung cancer and for cervical cancer in combination with radiotherapy).
Your doctor will be able to provide you with more information
2. What you need to know before you use Ifosphamide Injection
Do not take Ifosphamide if:
- you are allergic to Ifosphamide or to any of the other ingredients of this medicine (listed in section 6
- you are allergic (hypersensitive) to any other medicine that contains platina compounds
- you have kidney problems (renal dysfunction)
- you suffer from dehydration
- you suffer from severe suppression of bone marrow functionality, symptoms may be: extreme tiredness, easy bruising or bleeding, occurrence of infections
- your hearing is impaired
- you suffer from nervous disorders caused by Ifosphamide
- you are breast-feeding
- combined with live vaccines, including yellow fever
- combined with phenytoin in prophylactic use (see “Other medicines and Cisplaitn” below).
Warnings and precautions
Your doctor will carry out tests in order to determine the levels of calcium, sodium, potassium and magnesium in your blood, as well as to check your blood picture and your liver and kidney functionality and neurological function.
- Ifosphamide should only be administered under the strict supervision of a specialist doctor experienced in administrating
- Your hearing will be tested prior to each treatment with
- If you suffer from a nervous disorder not caused by
- If you have had radiation therapy to your head
- If you suffer from an infection. Please consult your
- If you intend to have children (see Pregnancy, breast-feeding and fertility
- Tell your doctor if the above applies to you before this medicine is
- With spillage of Ifosphamide the contaminated skin must immediately be washed with water and soap. If Ifosphamide is injected outside the blood vessels the administration must be stopped immediately. Infiltration of Ifosphamide in the skin can result in tissue damage (cellulitis, fibrosis and necrosis).
Please consult your doctor, even if these statements were applicable to you at any time in the past.
Other medicines and Ifosphamide
Please note that these statements may also apply to products used some time ago or at some time in the future. Tell your doctor or pharmacist if you are taking, or have recently taken, or might take any other medicine –
- Simultaneous use of medicines that inhibit the bone marrow function or radiation can potentiate the adverse effects of Ifosphamide on the bone
- Ifosphamide toxicity may increase when administered simultaneously with other cytostatics (medicine for cancer treatment), such as bleomycin and
- Agents to treat high blood pressure (antihypertensives containing furosemide, hydralazine, diazoxide, and propranolol) may increase the toxic effect of Ifosphamide on kidneys.
- Ifosphamide toxicity may severely affect the kidneys when administered simultaneously with agents that may cause side effects in the kidneys, such as those for the prevention/ treatment of certain infections (antibiotics: cephalosporins, aminoglycosides, and/or amphotericin B) and contrast
- Ifosphamide toxicity may affect hearing faculties when administered simultaneously with agents that may have a side effect on hearing faculties, such as
- If you use agents to treat gout during your treatment with Ifosphamide, then the dosage of such agents may need to be adjusted (e.g. allopurinol, colchicine, probenecid and/or sulfinpyrazone).
- Administration of drugs that elevate your rate of bodily urine excretion (loop diuretics) combined with Ifosphamide (Ifosphamide dose: more than 60mg/m², urine secretion: less than 500 ml per 24 hours) may result in toxic effects on kidneys and
- The first signs of hearing damage (dizziness and/or tinnitus) may remain hidden when – during your treatment with Ifosphamide – you are also being administered agents to treat hypersensitivity (antihistamines, such as buclizine, cyclizine, loxapine, meclozine, phenothiazines, thioxanthenes and/or trimethobenzamides).
- Ifosphamide given in combination with ifosphamide may result in hearing
- The effects of treatment with Ifosphamide can be reduced through simultaneous administration of pyridoxine and hexamethylmelamine.
- Ifosphamide given in combination with bleomycin and vinblastine may result in paleness or blue coloration of the fingers and/or toes (Raynaud’s phenomenon).
- Administration of Ifosphamide prior to treatment with paclitaxel or in combination with docetaxel may result in severe nerve
- The combined use of Ifosphamide with bleomycin and etoposide may decrease lithium levels in the Therefore, lithium levels should be checked on a regular basis.
- Ifosphamide reduces the effects of phenytoin on the treatment of
- Penicillamine may reduce the effectiveness of
- Ifosphamide may have an adverse impact on the effectivity of agents preventing coagulation (anticoagulants). Therefore, coagulation should be checked more often during combined
- Concomitant use of Ifosphamide with ciclosporin can weaken the immune system, with the risk of increased production of white blood cells (lymphocytes)
- You should not receive any vaccinations containing live viruses within three months after the end of treatment with
- When undergoing treatment with Ifosphamide, you should not receive yellow fever vaccinations (also see “Do not take Ifosphamide”).
Pregnancy, breast-feeding and fertility
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.
Ifosphamide must not be used during pregnancy unless clearly indicated by your doctor.
You must use effective contraception during and at least 6 months after treatment with Ifosphamide. You must not breastfeed while you are treated with Ifosphamide.
Male patients treated with Ifosphamide are advised not to father a child during treatment and for up to 6 months after treatment. Further, men are advised to seek counseling on sperm preservation before starting treatment.
Driving and using machines
Ifosphamide may cause side effects such as feeling sleepy and/or vomiting. If you suffer from either of these conditions, then you should not operate any machines that require your full attention.
Ifosphamide injection contains sodium
Ifosphamide contains 3.5 mg sodium per ml. This should be considered if you have to keep to a low sodium diet
3. How to use Ifosphamide Injection
Dosage and method of administration
Ifosphamide should only be given by a specialist in cancer treatment.
The concentrate is diluted with a sodium chloride solution that contains glucose. Ifosphamide is only given by injection into a vein (an intravenous infusion).
Supportive equipment should be available to control anaphylactic reactions. Ifosphamide should not come into contact with any materials that contain aluminium.
The recommended dosage of Ifosphamide depends on your well-being, the anticipated effects of the treatment, and whether or not Ifosphamide is given on its own (monotherapy) or in combination with other agents (combination chemotherapy).
The following dosages are recommended:
- A single dosage of 50 to 120 mg/m² body surface, every 3 to 4
- 15 to 20 mg/m² per day over a 5-day period, every 3 to 4 weeks
Ifosphamide in combination with other chemotherapeutical agents (combination chemotherapy):
- 20 mg/m² or more, once every 3 to 4
For treatment of cervical cancer Ifosphamide is used in combination with radiotherapy. A typical dose is 40 mg/m² weekly for 6 weeks.
In order to avoid, or reduce, kidney problems, you are advised to drink copious amounts of water for a period of 24 hours following treatment with Ifosphamide.
If you take more Ifosphamide than you should
Your doctor will ensure that the correct dose for your condition is given. In case of overdose, you may experience increased side effects. Your doctor may give you symptomatic treatment for these side effects. If you think you received too much Ifosphamide, immediately contact your doctor.
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse
4. Possible side effects
Like all medicines, this medicine can cause side effects, although not everybody gets them
If you experience any side effect it is important that you inform your doctor before your next treatment.
Tell your doctor immediately, if you notice any of the following:
- persistent or severe diarrhoea or vomiting
- stomatitis/mucositis (sore lips or mouth ulcer)
- swelling of the face, lips mouth or throat
- unexplained respiratory symptoms such as non-productive cough, difficulty in breathing or crackles
- difficulty in swallowing
- numbness or tingling in your fingers or toes
- extreme tiredness
- abnormal bruising or bleeding
- signs of infection, such as sore throat and high temperature
- sensation of discomfort close to or at the injection site during the
The following side effects may occur:
Very common (may affect more than 1 in 10 people)
Blood and lymphatic system: suppression of the bone marrow characterised by a severe decrease of white blood cells, which makes infections more likely (leukopenia), reduction in blood platelets, which increases the risk of bruising and bleeding (thrombocytopenia), as well as reduction in red blood cells, which can make the skin pale and cause weakness or breathlessness (anaemia).
Nutrition and metabolism: reduced level of electrolytes (sodium)
Gastrointestinal tract: loss of appetite (anorexia), nausea, vomiting, diarrhoea.
Kidneys and urinary tracts: excessive uric acid levels (hyperuricaemia) in the blood (e.g. gout).
General symptoms: fever.
Common (may affect up to 1 in 10 people) Infections: blood-poisoning (sepsis).
Heart: arrhythmia, including reduced heartbeat (bradycardia), accelerated heartbeat (tachycardia).
Blood vessels: inflammation of a vein (phlebitis) at injection site.
Respiratory disorders: difficulty of breathing (dyspnoea), inflammation of the lungs (pneumonia) and respiratory failure.
Uncommon (may affect up to 1 in 100 people)
Immune system: hypersensitivity reactions, including rash, eczema with severe itching and lump formation (urticaria), redness and inflammation of the skin (erythema) or itching (pruritus), (anaphylactoid reactions) with symptoms such as swelling of the face and fever, low blood pressure (hypotension), accelerated heartbeat (tachycardia), breathing difficulties (dyspnoea), distress as a result of muscle cramps in the airways (bronchospasms) Hearing: damage to the ear (ototoxicity)
Nutrition and metabolism: reduced level of electrolytes (Magnesium)
Gastrointestinal tract: metallic setting on the gums.
Skin: loss of hair (alopecia).
Reproductive system and breasts: dysfunctional spermatogenesis and ovulation, and painful breast growth in men (gynaecomastia).
Rare (may affect up to 1 in 1,000 people)
Immune system: severe hypersensitivity (anaphylactic reactions) with low blood pressure (hypotension), accelerated heartbeat (tachycardia), breathing difficulties (dyspnoea), distress as a result of muscle cramps in the airways (bronchospasms), swelling of the face and fever; suppression of the immune system (immunosuppression).
Nervous system: loss of certain types of brain function, including brain dysfunction characterised by spasms and reduced levels of consciousness (encephalopathy), peripheral neuropathy of the sensory nerves (bilateral, sensory neuropathy), characterised by tickling, itching or tingling without cause and sometimes characterised by a loss of taste, touch, sight, sudden shooting pains from the neck through the back into the legs when bending forwards, attacks (seizures)..
Hearing: unable to hold normal conversation, loss of hearing (in particular among children and elderly patients).
Heart: increased blood pressure levels, coronary artery disease and heart attacks.
Liver and bile: reduced albumin (protein) levels in blood
Gastrointestinal tract: inflammation of mucous membranes of the mouth (stomatitis)
General: Ifosphamide, like other similar medicines, increases the risk of leukaemia (acute leukaemia).
Very rare (may affect up to 1 in 10,000 people)
Nutrition and metabolism: increased iron levels in the blood.
Heart: heart(cardiac) arrest.
Not known (frequency cannot be estimated from the available data)
Blood and lymphatic system:, haemolytic anaemia
Hormones: insufficient production of the vasopressin hormone in the brain (SIADH), blood amylase (enzyme) increased.
Nutrition and metabolism: reduced level of electrolytes (calcium, phosphate, potassium) in the blood with muscle cramping and/or changes in an electrocardiogram (ECG). Excessive cholesterol levels in the blood.
Nervous system: spinal disease, brain dysfunction (confusion, slurred speech, sometimes blindness, memory loss, and paralysis);stroke, loss of taste (ageusia), as well as closure of the carotid artery.
General symptoms: weakness (asthenia), malaise, dehydration, swelling (oedema), pain,redness and inflammation of the skin (erythema, skin ulcer)at the area of injection
Kidneys and urinary tracts: kidney dysfunction, such as failure to produce urine (anuria) and urine poisoning of the blood (uraemia)
Musculo skeletal: muscle spasms
Skin and dermis: hair loss, rash
Liver and bile: liver dysfunction, liver enzymes increased, bilirubin increased.
Gastrointestinal tract: loss of appetite (anorexia), nausea, vomiting, diarrhoea, hiccups.
Blood vessels: blood flow dysfunction, e.g. in the brain, but also in the fingers and toes (Raynaud’s syndrome), Thrombotic microangiopathy combined with haemolytic uraemic syndrome.
Heart: cardiac disorder
Hearing and balance function: loss of hearing combined with tinnitus (ringing in ears)
Eyes: blurred vision, difficulties in colour perception and eye movement dysfunction. swelling (papilloedema), inflammation of the eye nerve combined with pain and reduced nerve function (optic neuritis), blindness as a result of brain dysfunction.
Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet.
5. How to store Ifosphamide Injection
Keep this medicine out of sight and reach of children.
Keep the vial in the outer carton (to avoid exposure of Ifosphamide to light).
Concentrate for solution for infusion 1 mg/ml
Keep container in the outer carton in order to protect from light. Do not refrigerate or freeze.
Do not use this medicine after the expiry date which is stated on the vial and the outer carton after ‘exp’. The expiry date refers to the last day of that month. Do not use this medicine if you notice visible signs of deterioration.
All materials that have been used for the preparation and administration, or which have been in contact with Ifosphamide in any way, must be disposed of according to local cytotoxic guidelines
If you find the solution cloudy or a deposit that does not dissolve is noticed, the bottle should be discarded.
6. Contents of the pack and other information
What Ifosphamide Injection contains:
Ifosphamide Injection contains the active ingredient Ifosphamide.
Each 20 ml of solution contains 10 milligram (mg) of Ifosphamide.
- Manufactured in India By:
TAJ PHARMACEUTICALS LIMITED
at SURVEY NO.188/1 TO 189/1,190/1 TO 4,
ATHIYAWAD, DABHEL, DAMAN- 396210 (INDIA).