Chemical formula: C₇H₁₅Cl₂N₂O₂P Molecular mass: 261.086 g/mol PubChem compound: 3690
Ifosfamide interacts in the following cases:
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 of ifosfamide with St. John’s Wort.
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 of ifosfamide with corticosteroids.
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.
The immunosuppressive effects of ifosfamide can be expected to reduce the response to vaccination. Use of live vaccines may lead to vaccine induced infection.
In some patients, alcohol may increase ifosfamide-induced nausea and vomiting.
Additive CNS effects may result from a combined effect of ifosfamide and antiemetics.
Concurrent administration of antidiabetic agents, such as sulfonylureas and ifosfamide may enhance the hypoglycaemic effects of the former drugs.
Increased INR (increased international normalized ratio) has been reported in patients receiving ifosfamide and warfarin.
Increased haematotoxicity and/or immunosuppression may result from a combined effect of ifosfamide and ACE inhibitors. ACE inhibitors can cause leukopenia.
Increased nephrotoxicity may result from a combined effect of ifosfamide and aminoglycosides.
Increased cardiotoxicity may result from a combined effect of ifosfamide and anthracyclines.
Increased pulmonary toxicity may result from a combined effect of ifosfamide and G-CSF, GM-CSF (granulocyte colonystimulating factor, granulocyte macrophage colony-stimulating factor).
Additive CNS effects may result from a combined effect of ifosfamide and narcotics.
Additive CNS effects may result from a combined effect of ifosfamide and sedatives.
Additive CNS effects may result from a combined effect of ifosfamide and antihistamines.
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.
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.
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.
Increased nephrotoxicity may result from a combined effect of ifosfamide and acyclovir.
Theoretical interactions of ifosfamide and allopurinol resulting in an increased severity of bone marrow depression.
Increased pulmonary toxicity may result from a combined effect of ifosfamide and amiodarone.
Increased nephrotoxicity may result from a combined effect of ifosfamide and amphotericin B.
Reports suggest increased ifosfamide neurotoxicity in patients receiving antiemetic prophylaxis with aprepitant, which is both an inducer and a moderate inhibitor of CYP 3A4.
An increased risk of developing haemorrhagic cystitis may result from a combined effect of ifosfamide and busulfan.
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 of ifosfamide with carbamazepine.
Increased haematotoxicity and/or immunosuppression may result from a combined effect of ifosfamide and carboplatin.
Increased nephrotoxicity may result from a combined effect of ifosfamide and carboplatin.
Increased haematotoxicity and/or immunosuppression may result from a combined effect of ifosfamide and cisplatin.
Increased nephrotoxicity may result from a combined effect of ifosfamide and cisplatin.
Cisplatin-induced hearing loss can be exacerbated by concurrent ifosfamide therapy.
Increased gastrointestinal toxicity has been reported when ifosfamide was administered before docetaxel infusion.
Formation of the active metabolite of irinotecan may be reduced when irinotecan is administered with ifosfamide.
Increased haematotoxicity and/or immunosuppression may result from a combined effect of ifosfamide and natalizumab.
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 of ifosfamide with phenobarbital.
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 of ifosfamide with phenytoin.
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 of ifosfamide with rifampicin.
Concomitant use of tamoxifen and chemotherapy may increase the risk of thromboembolic complications.
An increased risk of developing haemorrhagic cystitis may result from a combined effect of ifosfamide and irradiation of the bladder.
Administration of ifosfamide can cause CNS toxicity and other neurotoxic effects.
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:
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.
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.
Ifosfamide and its metabolites are dialyzable.
Ifosfamide may interfere with normal wound healing.
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.
Fatal outcome from nephrotoxicity has been documented.
Disorders of renal function (glomerular and tubular) following ifosfamide administration are very common.
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:
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.
Veno-occlusive liver disease has been reported with chemotherapy that included ifosfamide and also is a known complication with another oxazaphosphorine cytotoxic agent.
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.
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.
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.
Potential side-effects on the central nervous system may transiently impair the ability to operate machinery and motor vehicles.
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).
Common: Infections (including reactivation of latent infections)
Not known: Sepsis (septic shock)*
Not known: 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*
Very common: Myelosuppression, Leukopenia, Thrombocytopenia*
Not known: Anaemia, Agranulocytosis, Haematotoxicity*, Haemolytic anaemia, Methaemoglobinaemia, Febrile bone marrow aplasia, Disseminated intravascular coagulation, Haemolytic uremic syndrome, Neonatal anaemia
Not known: Angioedema*, Anaphylactic reaction, Immunosuppression, Urticaria, Hypersensitivity reaction
Not known: Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
Common: Decreased Appetite
Not known: Tumor lysis syndrome, Metabolic acidosis, Hypokalaemia, Hypocalcaemia, Hypophosphataemia, Hyperglycaemia, Polydipsia
Not known: Mutism, Mental status change (includine mania, paranoia, delusion, delirium, catatonia, amnesia, panic attack), Echolalia, Perseveration
Not known: Central nervous system toxicity, Encephalopathy, Faecal incontinence, Status epilepticus* (convulsive and nonconvulsive), Movement disorder, Extrapyramidal disorder, Gait disturbance, Dysarthria, Peripheral neuropathy, Hypoesthesia, Paresthesia, Asterixis, Neuralgia
Not known: Visual impairment, Conjunctivitis, Eye irritation
Not known: Deafness, Vertigo, Tinnitus
Uncommon: Cardiotoxicity*
Not known: Arrythmia (including supraventricular and ventricular arrhythmia), Atrial fibrillation, Premature atrial contractions, Bradycardia, Cardiac arrest*, Myocardial infarction, Cardiac failure*, Myocardial haemorrhage, Angina pectoris, Cardiomyopathy* (including congestive cardiomyopathy), Electrocardiogram ST-segment abnormal, Electrocardiogram T-wave inversion, Electrocardiogram QRS complex abnormal
Uncommon: Hypotension
Not known: Pulmonary embolism, Deep vein thrombosis, Capillary leak syndrome, Vasculitis, Hypertension, Flushing
Not known: Respiratory failure*, Acute respiratory distress syndrome*, Pulmonary hypertension, Interstitial lung disease* (as manifested by Pulmonary fibrosis), Pneumonitis*, Pulmonary oedema*, Pleural effusion, Dyspnea, Hypoxia, Cough
Very common: Nausea/Vomiting
Uncommon: Diarrhoea, Stomatitis
Not known: Enterocolitis, Pancreatitis, Ileus, Gastrointestinal haemorrhage, Mucosal ulceration, Constipation, Abdominal pain, Salivary hypersecretion
Common: Hepatotoxicity
Not known: Hepatic failure, Veno-occlusive liver disease, Portal vein thrombosis, Cytolytic hepatitis
Very common: Alopecia
Rare: Dermatitis, Papular rash
Not known: Toxic epidermal necrolysis, Stevens-Johnson syndrome, Palmar-plantar erythrodysesthesia syndrome, Radiation recall dermatitis, Skin necrosis, Facial swelling, Rash, Pruritus, Erythema, Skin hyperpigmentation, Hyperhidrosis, Nail disorder
Not known: Rhabdomyolysis, Osteomalacia, Rickets, Growth retardation, Myalgia, Arthralgia, Muscle twitching
Very common: Haemorrhagic cystitis, Haematuria, Renal dysfunction*, Acute renal failure
Not known: Chronic renal failure, Aminoaciduria, Phosphaturia, Fanconi syndrome, Tubulointerstitial nephritis, Renal structural damage, Nephrogenic diabetes insipidus, Polyuria, Enuresis, Feeling of residual urine
Not known: Infertility, Ovarian failure, Premature menopause, Amenorrhea, Ovulation disorder, Azoospermia, Oligospermia
Not known: Fetal growth retardation
Common: Phlebitis
Uncommon: Fatigue
Not known: Malaise, Multiorgan failure*, General physical deterioration, Injection/Infusion site reactions, Oedema, Pain, Pyrexia, Chills
* including fatal outcomes
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