Komposition:
Anwendung:
Wird bei der Behandlung verwendet:
Medizinisch geprüft von Oliinyk Elizabeth Ivanovna, Apotheke Zuletzt aktualisiert am 28.03.2022
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Ifosfamide EG is indicated for use in combination with certain other approved antineoplastic agents for third-line chemotherapy of germ cell testicular cancer. It should be used in combination with mesna for prophylaxis of hemorrhagic cystitis.
IFEX is indicated for use in combination with certain other approved antineoplastic agents for third-line chemotherapy of germ cell testicular cancer. It should be used in combination with mesna for prophylaxis of hemorrhagic cystitis.
Ifosfamid EG sollte intravenös in einer Dosis von 1,2 Gramm pro m verabreicht werden2 pro Tag an 5 aufeinander folgenden Tagen. Die Behandlung wird alle 3 Wochen oder nach Wiederherstellung nach hämatologischer Toxizität wiederholt.
Um eine Blasentoxizität zu verhindern, sollte Ifosfamid EG mit einer ausgedehnten Flüssigkeitszufuhr verabreicht werden, die aus mindestens 2 Litern oraler oder intravenöser Flüssigkeit pro Tag besteht. Mesna sollte verwendet werden, um die Inzidenz hämorrhagischer Blasenentzündung zu verringern. Ifosfamid EG sollte als langsame intravenöse Infusion verabreicht werden, die mindestens 30 Minuten dauert. Studien zu Ifosfamid EG bei Patienten mit Leber- oder Nierenfunktionsstörung wurden nicht durchgeführt.
Injektionen werden durch Hinzufügen für die parenterale Verwendung vorbereitet Steriles Wasser zur Injektion USP oder Bakteriostatisches Wasser zur InjektionUSP (Benzylalkohol oder Parabene konserviert), in die Durchstechflasche und Schütteln, um sich aufzulösen. Vor der parenteralen Verabreichung muss der Stoff vollständig aufgelöst werden. Verwenden Sie die unten angegebene Menge an Verdünnungsmitteln, um das Produkt zu bilden:
Dosierungsstärke | Menge an Verdünnungsmittel | Endkonzentration |
1 Gramm | 20 ml | 50 mg pro ml |
3 Gramm | 60 ml | 50 mg pro ml |
Lösungen von Ifosfamid können weiter verdünnt werden, um Konzentrationen von 0,6 bis 20 mg / m zu erreichen2L in den folgenden Flüssigkeiten:
5% Dextrose Injection, USP
0,9% Natriumchlorid-Injektion, USP
Lactated Ringer's Injections, USP
Steriles Wasser zur Injektion, USP
Da für sterile Wassereinbauelemente im Wesentlichen identische Stabilitätsergebnisse erzielt wurden wie für die anderen Vormischungen (5% Dextrose-Injektion, 0,9% Natriumchlorid-Injektion und laktierte Ringer-Injektion), wurden parenterale Glasflaschen mit großem Volumen, VIAFLEX-Beutel oder PAB-Beutel verwendet, die Zwischenkonzentrationen enthalten oder Gemische von Hilfsstoffen (z.Eine 2,5% ige Dextrose-Injektion, eine 0,45% ige Natriumchlorid-Injektion oder 5% Dextrose und eine 0,9% ige Natriumchlorid-Injektion sind ebenfalls akzeptabel.
Konstituierte oder konstituierte und weiter verdünnte Lösungen von Ifosfamid EG sollten gekühlt und innerhalb von 24 Stunden verwendet werden. Benzylalkoholhaltige Lösungen können die Stabilität von Ifosfamid verringern.
Parenterale Arzneimittel sollten vor der Verabreichung visuell auf Partikel und Verfärbungen untersucht werden, wenn Lösung und Behälter dies zulassen.
IFEX sollte intravenös in einer Dosis von 1,2 Gramm pro m verabreicht werden2 pro Tag an 5 aufeinander folgenden Tagen. Die Behandlung wird alle 3 Wochen oder nach Wiederherstellung nach hämatologischer Toxizität wiederholt.
Um eine Blasentoxizität zu verhindern, sollte IFEX mit einer ausgedehnten Flüssigkeitszufuhr verabreicht werden, die aus mindestens 2 Litern oraler oder intravenöser Flüssigkeit pro Tag besteht. Mesna sollte verwendet werden, um die Inzidenz hämorrhagischer Blasenentzündung zu verringern. IFEX sollte als langsame intravenöse Infusion verabreicht werden, die mindestens 30 Minuten dauert. Studien zu IFEX bei Patienten mit Leber- oder Nierenfunktionsstörung wurden nicht durchgeführt.
Injektionen werden durch Hinzufügen für die parenterale Verwendung vorbereitet Steriles Wasser zur Injektion USP oder Bakteriostatisches Wasser zur InjektionUSP (Benzylalkohol oder Parabene konserviert), in die Durchstechflasche und Schütteln, um sich aufzulösen. Vor der parenteralen Verabreichung muss der Stoff vollständig aufgelöst werden. Verwenden Sie die unten angegebene Menge an Verdünnungsmitteln, um das Produkt zu bilden:
Dosierungsstärke | Menge an Verdünnungsmittel | Endkonzentration |
1 Gramm | 20 ml | 50 mg pro ml |
3 Gramm | 60 ml | 50 mg pro ml |
Lösungen von Ifosfamid können weiter verdünnt werden, um Konzentrationen von 0,6 bis 20 mg / m zu erreichen2L in den folgenden Flüssigkeiten:
5% Dextrose Injection, USP
0,9% Natriumchlorid-Injektion, USP
Lactated Ringer's Injections, USP
Steriles Wasser zur Injektion, USP
Da für sterile Wassereinbauelemente im Wesentlichen identische Stabilitätsergebnisse erzielt wurden wie für die anderen Vormischungen (5% Dextrose-Injektion, 0,9% Natriumchlorid-Injektion und laktierte Ringer-Injektion), wurden parenterale Glasflaschen mit großem Volumen, VIAFLEX-Beutel oder PAB-Beutel verwendet, die Zwischenkonzentrationen enthalten oder Gemische von Hilfsstoffen (z.Eine 2,5% ige Dextrose-Injektion, eine 0,45% ige Natriumchlorid-Injektion oder 5% Dextrose und eine 0,9% ige Natriumchlorid-Injektion sind ebenfalls akzeptabel.
Konstituierte oder konstituierte und weiter verdünnte Lösungen von IFEX sollten gekühlt und innerhalb von 24 Stunden verwendet werden. Benzylalkoholhaltige Lösungen können die Stabilität von Ifosfamid verringern.
Parenterale Arzneimittel sollten vor der Verabreichung visuell auf Partikel und Verfärbungen untersucht werden, wenn Lösung und Behälter dies zulassen.
Ifosfamid EG ist bei Patienten mit: kontraindiziert
- Bekannte Überempfindlichkeit gegen die Verabreichung von Ifosfamid.
- Obstruktion des Urinabflusses.
IFEX ist bei Patienten mit: kontraindiziert
- Bekannte Überempfindlichkeit gegen die Verabreichung von Ifosfamid.
- Obstruktion des Urinabflusses.
WARNINGS
Included as part of the "PRECAUTIONS" Section
PRECAUTIONS
Myelosuppression, Immunosuppression, And Infections
Treatment with ifosfamide may cause myelosuppression and significant suppression of immune responses, which can lead to severe infections. Fatal outcomes of ifosfamide-associated myelosuppression have been reported. Ifosfamide-induced myelosuppression can cause leukopenia, neutropenia, thrombocytopenia (associated with a higher risk of bleeding events), and anemia. The nadir of the leukocyte count tends to be reached approximately during the second week after administration. When Ifosfamide EG is given in combination with other chemotherapeutic/hematotoxic agents and/or radiation therapy, severe myelosuppression is frequently observed. The risk of myelosuppression is dosedependent and is increased with administration of a single high dose compared with fractionated administration. The risk of myelosuppression is also increased in patients with reduced renal function.
Severe immunosuppression has led to serious, sometimes fatal, infections. Sepsis and septic shock also have been reported. Infections reported with ifosfamide include pneumonias, as well as other bacterial, fungal, viral, and parasitic infections. Latent infections can be reactivated. In patients treated with ifosfamide, reactivation has been reported for various viral infections. Infections must be treated appropriately. Antimicrobial prophylaxis may be indicated in certain cases of neutropenia at the discretion of the managing physician. In case of neutropenic fever, antibiotics and/or antimycotics must be given. Close hematologic monitoring is recommended. White blood cell (WBC) count, platelet count and hemoglobin should be obtained prior to each administration and at appropriate intervals after administration. Unless clinically essential, Ifosfamide EG should not be given to patients with a WBC count below 2000/μL and/or a platelet count below 50,000/μL.
Ifosfamide EG should be given cautiously, if at all, to patients with presence of an infection, severe immunosuppression or compromised bone marrow reserve, as indicated by leukopenia, granulocytopenia, extensive bone marrow metastases, prior radiation therapy, or prior therapy with other cytotoxic agents.
Central Nervous System Toxicity, Neurotoxicity
Administration of ifosfamide can cause CNS toxicity and other neurotoxic effects. The risk of CNS toxicity and other neurotoxic effects necessitates careful monitoring of the patient. Neurologic manifestations consisting of somnolence, confusion, hallucinations, blurred vision, psychotic behavior, extrapyramidal symptoms, urinary incontinence, seizures, and in some instances, coma, have been reported following Ifosfamide EG therapy. There have also been reports of peripheral neuropathy associated with ifosfamide use.
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. Supportive therapy should be maintained until their complete resolution. Occasionally, recovery has been incomplete. Fatal outcomes of CNS toxicity have been reported. Recurrence of CNS toxicity after several uneventful treatment courses has been reported. If encephalopathy develops, administration of ifosfamide should be discontinued.
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.
Manifestations of CNS toxicity may impair a patient’s ability to operate an automobile or other heavy machinery.
Renal And Urothelial Toxicity And Effects
Ifosfamide is both nephrotoxic and urotoxic. Glomerular and tubular kidney function must be evaluated before commencement of therapy as well as during and after treatment. Monitor urinary sediment regularly for the presence of erythrocytes and other signs of uro/nephrotoxicity.
Monitor serum and urine chemistries, including phosphorus and potassium regularly. Administer appropriate replacement therapy as indicated. Renal parenchymal and tubular necrosis have been reported in patients treated with ifosfamide. Acute tubular necrosis, acute renal failure, and chronic renal failure secondary to ifosfamide therapy have been reported, and fatal outcome from nephrotoxicity has been documented.
Disorders of renal function, (glomerular and tubular) following ifosfamide administration are very common. Manifestations include a decrease in glomerular filtration rate, increased serum creatinine, proteinuria, enzymuria, cylindruria, aminoaciduria, phosphaturia, and glycosuria as well as tubular acidosis. Fanconi syndrome, renal rickets, and growth retardation in children as well as osteomalacia in adults also have been reported. 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 and expected benefits of ifosfamide therapy should be carefully weighed when considering the use of ifosfamide in patients with preexisting renal impairment or reduced nephron reserve.
Urotoxic side effects, especially hemorrhagic cystitis, have been very commonly associated with the use of Ifosfamide EG. These urotoxic effects can be reduced by prophylactic use of mesna.
Hemorrhagic cystitis requiring blood transfusion has been reported with ifosfamide. The risk of hemorrhagic cystitis is dose-dependent and increased with administration of single high doses compared to fractionated administration. Hemorrhagic cystitis after a single dose of ifosfamide has been reported. Past or concomitant radiation of the bladder or busulfan treatment may increase the risk for hemorrhagic cystitis.
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 dieresis in order to reduce the risk of urinary tract toxicity. Obtain a urinalysis prior to each dose of Ifosfamide EG. If microscopic hematuria (greater than 10 RBCs per high power field) is present, then subsequent administration should be withheld until complete resolution. Further administration of Ifosfamide EG should be given with vigorous oral or parenteral hydration.
Ifosfamide should be used with caution, if at all, in patients with active urinary tract infections.
Cardiotoxicity
Manifestations of cardiotoxicity reported with ifosfamide treatment 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
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 preexisting cardiac disease.
Pulmonary Toxicity
Interstitial pneumonitis, pulmonary fibrosis, and other forms of pulmonary toxicity have been reported with ifosfamide treatment. Pulmonary toxicity leading to respiratory failure as well as fatal outcome has also been reported. Monitor for signs and symptoms of pulmonary toxicity and treat as clinically indicated.
Secondary Malignancies
Treatment with ifosfamide involves the risk of secondary tumors and their precursors as late sequelae. The risk of myelodysplastic alterations, some progressing to acute leukemias, is increased. Other malignancies reported after use of ifosfamide or regimens with ifosfamide include lymphoma, thyroid cancer, and sarcomas.
The secondary malignancy may develop several years after chemotherapy has been discontinued.
Veno-Occlusive Liver Disease
Veno-occlusive liver disease has been reported with chemotherapy that included ifosfamide.
Pregnancy
Ifosfamide EG can cause fetal harm when administered to a pregnant woman. Fetal growth retardation and neonatal anemia have been reported following exposure to ifosfamide-containing chemotherapy regimens during pregnancy. Ifosfamide is genotoxic and mutagenic in male and female germ cells. Embryotoxic and teratogenic effects have been observed in mice, rats and rabbits at doses 0.05 to 0.075 times the human dose.
Women should not become pregnant and men should not father a child during therapy with ifosfamide. Further, men should not father a child for up to 6 months after the end of therapy. If this drug 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.
Effects On Fertility
Ifosfamide interferes with oogenesis and spermatogenesis. Amenorrhea, azoospermia, and sterility in both sexes have been reported. Development of sterility appears to depend on the dose of ifosfamide, duration of therapy, and state of gonadal function at the time of treatment. Sterility may be irreversible in some patients.
Female Patients
Amenorrhea has been reported in patients treated with ifosfamide. The risk of permanent chemotherapyinduced amenorrhea increases with age. Pediatric patients treated with ifosfamide during prepubescence subsequently may not conceive and those who retain ovarian function after completing treatment are at increased risk of developing premature menopause.
Male Patients
Men treated with ifosfamide may develop oligospermia or azoospermia. Pediatric patients treated with ifosfamide during prepubescence might not develop secondary sexual characteristics normally, but may have oligospermia or azoospermia. Azoospermia may be reversible in some patients, though the reversibility may not occur for several years after cessation of therapy. Sexual function and libido are generally unimpaired in these patients. Some degree of testicular atrophy may occur. Patients treated with ifosfamide have subsequently fathered children.
Anaphylactic/Anaphylactoid Reactions And 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.
Nursing
Ifosfamide is excreted in breast milk. Women must not breastfeed during treatment with ifosfamide.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Ifosfamide has been shown to be carcinogenic in rats when administered by intraperitoneal injection at 6 mg/kg (37 mg/m2 , or about 3% of the daily human dose on a mg/m2 basis) 3 times a week for 52 weeks. Female rats had a significantly higher incidence of uterine leiomyosarcomas and mammary fibroadenomas than vehicle controls.
The mutagenic potential of ifosfamide has been documented in bacterial systems in vitro and mammalian cells in vivo. In vivo, ifosfamide has induced mutagenic effects in mice and Drosophila melanogaster germ cells, and has induced a significant increase in dominant lethal mutations in male mice as well as recessive sex-linked lethal mutations in Drosophila.
Ifosfamide was administered to male and female beagle dogs at doses of 1.00 or 4.64 mg/kg/day (20 or 93 mg/m2 ) orally 6 days a week for 26 weeks. Male dogs at 4.64 mg/kg (about 7.7% of the daily clinical dose on a mg/m2 basis) had testicular atrophy with degeneration of the seminiferous tubular epithelium. In a second study, male and female rats were given 0, 25, 50, or 100 mg/kg (0, 150, 300, or 600 mg/m2 ) ifosfamide intraperitoneally once every 3 weeks for 6 months. Decreased spermatogenesis was observed in most male rats given 100 mg/kg (about half the daily clinical dose on a mg/m2 basis).
Use In Specific Populations
Pregnancy
Pregnancy Category D.
.
Ifosfamide EG can cause fetal harm when administered to a pregnant woman. Fetal growth retardation and neonatal anemia have been reported following exposure to ifosfamide-containing chemotherapy regimens during pregnancy.
Animal studies indicate that ifosfamide is capable of causing gene mutations and chromosomal damage in vivo. In pregnant mice, resorptions increased and anomalies were present at day 19 after a 30 mg/m2 dose of ifosfamide was administered on day 11 of gestation. Embryo-lethal effects were observed in rats following the administration of 54 mg/m2 doses of ifosfamide from the 6th through the 15th day of gestation and embryotoxic effects were apparent after dams received 18 mg/m2 doses over the same dosing period. Ifosfamide is embryotoxic to rabbits receiving 88 mg/m2 /day doses from the 6th through the 18th day after mating. The number of anomalies was also significantly increased over the control group.
Women should not become pregnant and men should not father a child during therapy with ifosfamide. Further, men should not father a child for up to 6 months after the end of therapy. If this drug 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.
Nursing Mothers
Ifosfamide is excreted in breast milk. Because of the potential for serious adverse events and the tumorigenicity shown for ifosfamide in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Women must not breastfeed during treatment with ifosfamide.
Pediatric Use
Safety and effectiveness have not been established in pediatric patients.
Geriatric Use
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.
A study of patients 40 to 71 years of age indicated that elimination half-life appears to increase with advancing age. This apparent increase in half-life appeared to be related to increases in volume of distribution of ifosfamide with age. No significant changes in total plasma clearance or renal or non-renal clearance with age were reported.
Ifosfamide and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
Use In Patients With Renal Impairment
No formal studies were conducted in patients with renal impairment. Ifosfamide and its metabolites are known to be excreted by the kidneys and may accumulate in plasma with decreased renal function. Patients with renal impairment should be closely monitored for toxicity and dose reduction may be considered. Ifosfamide and its metabolites are dialyzable.
Use In Patients With Hepatic Impairment
No formal studies were conducted in patients with hepatic impairment. Ifosfamide is extensively metabolized in the liver and forms both efficacious and toxic metabolites. Ifosfamide EG should be given cautiously to patients with impaired hepatic function.
WARNINGS
Included as part of the "PRECAUTIONS" Section
PRECAUTIONS
Myelosuppression, Immunosuppression, And Infections
Treatment with ifosfamide may cause myelosuppression and significant suppression of immune responses, which can lead to severe infections. Fatal outcomes of ifosfamide-associated myelosuppression have been reported. Ifosfamide-induced myelosuppression can cause leukopenia, neutropenia, thrombocytopenia (associated with a higher risk of bleeding events), and anemia. The nadir of the leukocyte count tends to be reached approximately during the second week after administration. When IFEX is given in combination with other chemotherapeutic/hematotoxic agents and/or radiation therapy, severe myelosuppression is frequently observed. The risk of myelosuppression is dosedependent and is increased with administration of a single high dose compared with fractionated administration. The risk of myelosuppression is also increased in patients with reduced renal function.
Severe immunosuppression has led to serious, sometimes fatal, infections. Sepsis and septic shock also have been reported. Infections reported with ifosfamide include pneumonias, as well as other bacterial, fungal, viral, and parasitic infections. Latent infections can be reactivated. In patients treated with ifosfamide, reactivation has been reported for various viral infections. Infections must be treated appropriately. Antimicrobial prophylaxis may be indicated in certain cases of neutropenia at the discretion of the managing physician. In case of neutropenic fever, antibiotics and/or antimycotics must be given. Close hematologic monitoring is recommended. White blood cell (WBC) count, platelet count and hemoglobin should be obtained prior to each administration and at appropriate intervals after administration. Unless clinically essential, IFEX should not be given to patients with a WBC count below 2000/μL and/or a platelet count below 50,000/μL.
IFEX should be given cautiously, if at all, to patients with presence of an infection, severe immunosuppression or compromised bone marrow reserve, as indicated by leukopenia, granulocytopenia, extensive bone marrow metastases, prior radiation therapy, or prior therapy with other cytotoxic agents.
Central Nervous System Toxicity, Neurotoxicity
Administration of ifosfamide can cause CNS toxicity and other neurotoxic effects. The risk of CNS toxicity and other neurotoxic effects necessitates careful monitoring of the patient. Neurologic manifestations consisting of somnolence, confusion, hallucinations, blurred vision, psychotic behavior, extrapyramidal symptoms, urinary incontinence, seizures, and in some instances, coma, have been reported following IFEX therapy. There have also been reports of peripheral neuropathy associated with ifosfamide use.
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. Supportive therapy should be maintained until their complete resolution. Occasionally, recovery has been incomplete. Fatal outcomes of CNS toxicity have been reported. Recurrence of CNS toxicity after several uneventful treatment courses has been reported. If encephalopathy develops, administration of ifosfamide should be discontinued.
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.
Manifestations of CNS toxicity may impair a patient’s ability to operate an automobile or other heavy machinery.
Renal And Urothelial Toxicity And Effects
Ifosfamide is both nephrotoxic and urotoxic. Glomerular and tubular kidney function must be evaluated before commencement of therapy as well as during and after treatment. Monitor urinary sediment regularly for the presence of erythrocytes and other signs of uro/nephrotoxicity.
Disorders of renal function, (glomerular and tubular) following ifosfamide administration are very common. Manifestations include a decrease in glomerular filtration rate, increased serum creatinine, proteinuria, enzymuria, cylindruria, aminoaciduria, phosphaturia, and glycosuria as well as tubular acidosis. Fanconi syndrome, renal rickets, and growth retardation in children as well as osteomalacia in adults also have been reported. 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 and expected benefits of ifosfamide therapy should be carefully weighed when considering the use of ifosfamide in patients with preexisting renal impairment or reduced nephron reserve.
Urotoxic side effects, especially hemorrhagic cystitis, have been very commonly associated with the use of IFEX. These urotoxic effects can be reduced by prophylactic use of mesna.
Hemorrhagic cystitis requiring blood transfusion has been reported with ifosfamide. The risk of hemorrhagic cystitis is dose-dependent and increased with administration of single high doses compared to fractionated administration. Hemorrhagic cystitis after a single dose of ifosfamide has been reported. Past or concomitant radiation of the bladder or busulfan treatment may increase the risk for hemorrhagic cystitis.
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 dieresis in order to reduce the risk of urinary tract toxicity. Obtain a urinalysis prior to each dose of IFEX. If microscopic hematuria (greater than 10 RBCs per high power field) is present, then subsequent administration should be withheld until complete resolution. Further administration of IFEX should be given with vigorous oral or parenteral hydration.
Ifosfamide should be used with caution, if at all, in patients with active urinary tract infections.
Cardiotoxicity
Manifestations of cardiotoxicity reported with ifosfamide treatment 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
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 preexisting cardiac disease.
Pulmonary Toxicity
Interstitial pneumonitis, pulmonary fibrosis, and other forms of pulmonary toxicity have been reported with ifosfamide treatment. Pulmonary toxicity leading to respiratory failure as well as fatal outcome has also been reported. Monitor for signs and symptoms of pulmonary toxicity and treat as clinically indicated.
Secondary Malignancies
Treatment with ifosfamide involves the risk of secondary tumors and their precursors as late sequelae. The risk of myelodysplastic alterations, some progressing to acute leukemias, is increased. Other malignancies reported after use of ifosfamide or regimens with ifosfamide include lymphoma, thyroid cancer, and sarcomas.
The secondary malignancy may develop several years after chemotherapy has been discontinued.
Veno-Occlusive Liver Disease
Veno-occlusive liver disease has been reported with chemotherapy that included ifosfamide.
Pregnancy
IFEX can cause fetal harm when administered to a pregnant woman. Fetal growth retardation and neonatal anemia have been reported following exposure to ifosfamide-containing chemotherapy regimens during pregnancy. Ifosfamide is genotoxic and mutagenic in male and female germ cells. Embryotoxic and teratogenic effects have been observed in mice, rats and rabbits at doses 0.05 to 0.075 times the human dose.
Women should not become pregnant and men should not father a child during therapy with ifosfamide. Further, men should not father a child for up to 6 months after the end of therapy. If this drug 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.
Effects On Fertility
Ifosfamide interferes with oogenesis and spermatogenesis. Amenorrhea, azoospermia, and sterility in both sexes have been reported. Development of sterility appears to depend on the dose of ifosfamide, duration of therapy, and state of gonadal function at the time of treatment. Sterility may be irreversible in some patients.
Female Patients
Amenorrhea has been reported in patients treated with ifosfamide. The risk of permanent chemotherapyinduced amenorrhea increases with age. Pediatric patients treated with ifosfamide during prepubescence subsequently may not conceive and those who retain ovarian function after completing treatment are at increased risk of developing premature menopause.
Male Patients
Men treated with ifosfamide may develop oligospermia or azoospermia. Pediatric patients treated with ifosfamide during prepubescence might not develop secondary sexual characteristics normally, but may have oligospermia or azoospermia. Azoospermia may be reversible in some patients, though the reversibility may not occur for several years after cessation of therapy. Sexual function and libido are generally unimpaired in these patients. Some degree of testicular atrophy may occur. Patients treated with ifosfamide have subsequently fathered children.
Anaphylactic/Anaphylactoid Reactions And 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.
Nursing
Ifosfamide is excreted in breast milk. Women must not breastfeed during treatment with ifosfamide.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Ifosfamide has been shown to be carcinogenic in rats when administered by intraperitoneal injection at 6 mg/kg (37 mg/m2 , or about 3% of the daily human dose on a mg/m2 basis) 3 times a week for 52 weeks. Female rats had a significantly higher incidence of uterine leiomyosarcomas and mammary fibroadenomas than vehicle controls.
The mutagenic potential of ifosfamide has been documented in bacterial systems in vitro and mammalian cells in vivo. In vivo, ifosfamide has induced mutagenic effects in mice and Drosophila melanogaster germ cells, and has induced a significant increase in dominant lethal mutations in male mice as well as recessive sex-linked lethal mutations in Drosophila.
Ifosfamide was administered to male and female beagle dogs at doses of 1.00 or 4.64 mg/kg/day (20 or 93 mg/m2 ) orally 6 days a week for 26 weeks. Male dogs at 4.64 mg/kg (about 7.7% of the daily clinical dose on a mg/m2 basis) had testicular atrophy with degeneration of the seminiferous tubular epithelium. In a second study, male and female rats were given 0, 25, 50, or 100 mg/kg (0, 150, 300, or 600 mg/m2 ) ifosfamide intraperitoneally once every 3 weeks for 6 months. Decreased spermatogenesis was observed in most male rats given 100 mg/kg (about half the daily clinical dose on a mg/m2 basis).
Use In Specific Populations
Pregnancy
Pregnancy Category D.
.
IFEX can cause fetal harm when administered to a pregnant woman. Fetal growth retardation and neonatal anemia have been reported following exposure to ifosfamide-containing chemotherapy regimens during pregnancy.
Animal studies indicate that ifosfamide is capable of causing gene mutations and chromosomal damage in vivo. In pregnant mice, resorptions increased and anomalies were present at day 19 after a 30 mg/m2 dose of ifosfamide was administered on day 11 of gestation. Embryo-lethal effects were observed in rats following the administration of 54 mg/m2 doses of ifosfamide from the 6th through the 15th day of gestation and embryotoxic effects were apparent after dams received 18 mg/m2 doses over the same dosing period. Ifosfamide is embryotoxic to rabbits receiving 88 mg/m2 /day doses from the 6th through the 18th day after mating. The number of anomalies was also significantly increased over the control group.
Women should not become pregnant and men should not father a child during therapy with ifosfamide. Further, men should not father a child for up to 6 months after the end of therapy. If this drug 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.
Nursing Mothers
Ifosfamide is excreted in breast milk. Because of the potential for serious adverse events and the tumorigenicity shown for ifosfamide in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Women must not breastfeed during treatment with ifosfamide.
Pediatric Use
Safety and effectiveness have not been established in pediatric patients.
Geriatric Use
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.
A study of patients 40 to 71 years of age indicated that elimination half-life appears to increase with advancing age. This apparent increase in half-life appeared to be related to increases in volume of distribution of ifosfamide with age. No significant changes in total plasma clearance or renal or non-renal clearance with age were reported.
Ifosfamide and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
Use In Patients With Renal Impairment
No formal studies were conducted in patients with renal impairment. Ifosfamide and its metabolites are known to be excreted by the kidneys and may accumulate in plasma with decreased renal function. Patients with renal impairment should be closely monitored for toxicity and dose reduction may be considered. Ifosfamide and its metabolites are dialyzable.
Use In Patients With Hepatic Impairment
No formal studies were conducted in patients with hepatic impairment. Ifosfamide is extensively metabolized in the liver and forms both efficacious and toxic metabolites. IFEX should be given cautiously to patients with impaired hepatic function.
Adverse Reactions From Clinical Trials
Because clinical trials are conducted from widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The adverse reactions and frequencies below are based on 30 publications describing clinical experience with fractionated administration of ifosfamide as monotherapy with a total dose of 4 to 12 g/m2 per course.
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System Organ Class (SOC) | Adverse Reaction | Percentage (Ratio) |
INFECTIONS AND INFESTATIONS | Infection | 9.9% (112/1128) |
BLOOD AND LYMPHATIC SYSTEM DISORDERS | Leukopenia (any) | -† |
Leukopenia <1 x 103 /μL | 43.5% (267/614) | |
Thrombocytopenia‡ (any) | -§ | |
Thrombocytopenia, 50 x 103 /μL | 4.8% (35/729) | |
Anemia¶ | 37.9% (202/533) | |
METABOLISM AND NUTRITION DISORDERS | Anorexia | 1.1% (15/1317) |
NERVOUS SYSTEM DISORDERS | Central nervous system toxicity#,Þ | 15.4% (154/1001) |
Peripheral neuropathy | 0.4% (5/1317) | |
CARDIAC DISORDERS | Cardiotoxicityß | 0.5% (7/1317) |
VASCULAR DISORDERS | Hypotentionà | 0.3% (4/1317) |
GASTROINTESTINAL DISORDERS | Nausea/Vomiting | 46.8% (443/964) |
Diarrhea | 0.7% (9/1317) | |
Stomatitis | 0.3% (4/1317) | |
HEPATOBILIARY DISORDERS | Hepatotoxicityè | 1.8% (22/1190) |
SKIN AND SUBCUTANEOUS TISSUES DISORDERS | Alopecia | 89.6% (540/603) |
Dermatitis | 0.08% (1/1317) | |
Papular rash | 0.08% (1/1317) | |
RENAL AND URINARY DISORDERS | Hemorrhagic cystitis | -ð |
Hematuria | ||
- without mesna | 44.1% (282/640) | |
- with mesna | 21.3% (33/155) | |
Macrohematuria | ||
- without mesna | 11.1% (66/594) | |
- with mesna | 5.2% (5/97) | |
Renal dysfunctionø | - | |
Renal structural damage | - | |
GENERAL DISORDERS AND ADMINISTRATIVE SITE CONDITIONS | Phlebitisý | 2.8% (37/1317) |
Neutropenic fever£ | 1.0% (13/1317) | |
Fatigue | 0.3% (4/1317) | |
Malaise | Unable to calculate | |
*The following adverse reaction terms have been reported for leukopenia: neutropenia, granulocytopenia, lymphopenia, and pancytopenia. For neutropenic fever, see below. †The frequency category of leukopenia is based on the frequency of leukopenia <3 x 103 /ìL [4 2.5% (150/353) not shown in table] and <1 x 103 /ìL; a relevant percentage ratio cannot be calculated for the pooled data and thus the conservative frequency category of “Very common” was included in the table. ‡ Thrombocytopenia may also be complicated by bleeding. Bleeding with fatal outcome has been reported. §Frequency of thrombocytopenia is based on the frequency of thrombocytopenia <100 x 103 /ìL [12.2% (24 /196) not shown in table] and <50 x 103 /ìL; a relevant percentage ratio cannot be calculated from the pooled data and thus the conservative frequency of “Very common” was included in the table. ¶Includes cases reported as anemia and decrease in hemoglobin/hematocrit. #Encephalopathy with coma and death has been reported. ÞCentral nervous system toxicity was reported to be manifested by the following signs and symptoms: Abnormal behavior, Affect lability Aggression, Agitation, Anxiety, Aphasia, Asthenia, Ataxia, Cerebellar syndrome, Cerebral function deficiency, Cognitive disorder, Coma, Confusional state, Convulsions, Cranial nerve dysfunction, Depressed state of consciousness, Depression, Disorientation, Dizziness, Electroencephalogram abnormal, Encephalopathy, Flat affect. Hallucinations, Headache, Ideation, Lethargy, Memory impairment, Mood change, Motor dysfunction, Muscle spasms, Myoclonus, Progressive loss of brainstem reflexes, Psychotic reaction, Restlessness, Somnolence, Tremor, Urinary incontinence. ßCardiotoxicity was reported as congestive heart failure, tachycardia, pulmonary edema. Fatal outcome has been reported. àHypotension leading to shock and fatal outcome has been reported. èHepatotoxicity was reported as increases in liver enzymes, i.e., serum alanine aminotransferase, serum aspartate aminotransferase, alkaline phosphatase, gamma-glutamyltransferase and lactate dehydrogenase, increased bilirubin, jaundice, hepatorenal syndrome. ðFrequency of hemorrhagic cystitis is estimated based on the frequency of hematuria. Reported symptoms of hemorrhagic cystitis included dysuria and pollakiuria. See also Post-Marketing ADVERSE REACTIONS. øRenal dysfunction was reported to be manifested as: Renal failure (including acute renal failure, irreversible renal failure; fatal outcomes have been reported), Serum creatinine increased, BUN increased, Creatinine clearance decreased, Metabolic acidosis, Anuria, Oliguria, Glycosuria, Hyponatremia, Uremia, Creatinine clearance increased. Renal structural damage was reported to be manifested as: Acute tubular necrosis, renal parenchymal damage, Enzymuria, Cylindruria, Proteinuria. ýIncludes cases reported as phlebitis and irritation of the venous walls. £Frequency of neutropenic fever: Includes cases reported as granulocytopenic fever. |
Postmarketing Experience
The following adverse reactions have been reported in the post-marketing experience, listed by MedDRA System Organ Class (SOC), then by Preferred Term in order of severity, where feasible. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Infections And Infestations
The following manifestations have been associated with myelosuppression and immunosuppression caused by ifosfamide: increased risk for and severity of infections†, pneumonias†, sepsis and septic shock (including fatal outcomes), as well as reactivation of latent infections, including viral hepatitis†, Pneumocystis jiroveci†, herpes zoster, Strongyloides, progressive multifocal leukoencephalopathy†, and other viral and fungal infections.
† Severe immunosuppression has led to serious, sometimes fatal, infections.
Neoplasms,, Benign And Malignant And Uuspecified (Incl Cysts And Polyps):
As treatment-related secondary malignancy*, Acute leukemia* (Acute myeloid leukemia)*, Acute promyelocytic leukemia*, Acute lymphocytic leukemia*, Myelodysplastic syndrome, Lymphoma (Non- Hodgkin’s lymphoma), Sarcomas*, Renal cell carcinoma, Thyroid cancer
Blood And Lymphatic System Disorders:
Hematotoxicity*, Myelosuppression manifested as Bone marrow failure, Agranulocytosis; Febrile bone marrow aplasia; Disseminated intravascular coagulation, Hemolytic uremic syndrome, Hemolytic anemia, Neonatal anemia, Methemoglobinemia
Immune System Disorders:
Angioedema*, Anaphylactic reaction, Immunosuppression, Urticaria, Hypersensitivity reaction
Endocrine Disorders:
Syndrome of inappropriate antidiuretic hormone secretion (SIADH)Metabolism And Nutrition Disorders:
Tumor lysis syndrome, Metabolic acidosis, Hypokalemia, Hypocalcemia, Hypophosphatemia, Hyperglycemia, Polydipsia
Psychiatric Disorders:
Panic attack, Catatonia, Mania, Paranoia, Delusion, Delirium, Bradyphrenia, Mutism, Mental status change, Echolalia, Logorrhea, Perseveration, Amnesia
Nervous System Disorders:
Convulsion*, Status epilepticus (convulsive and nonconvulsive), reversible posterior leukoencephalopathy syndrome, Leukoencephalopathy, Extrapyramidal disorder, Asterixis, Movement disorder, Polyneuropathy, Dysesthesia, Hypothesia, Paresthesia, Neuralgia, Gait disturbance, Fecal incontinence, Dysarthria
Eye Disorders:
Visual impairment, Vision blurred, Conjunctivitis, Eye irritation
Ear And Labyrinth Disorders:
Deafness, Hypoacusis, Vertigo, Tinnitus
Cardiac Disorders:
Cardiotoxicity*, Cardiac arrest*, Ventricular fibrillation*, Ventricular tachycardia*, Cardiogenic shock*, Myocardial infarction*, Cardiac failure*, Bundle branch block left, Bundle branch block right, Pericardial effusion, Myocardial hemorrhage, Angina pectoris, Left ventricular failure, Cardiomyopathy*, Congestive cardiomyopathy, Myocarditis*, Arrhythmia*, Pericarditis, Atrial fibrillation, Atrial flutter, Bradycardia, Supraventricular extrasystoles, Premature atrial contractions, Ventricular extrasystoles, Myocardial depression, Palpitations, Ejection fraction decreased*, Electrocardiogram ST-segment abnormal, Electrocardiogram T-wave inversion, Electrocardiogram QRS complex abnormal
Vascular Disorders:
Pulmonary embolism, Deep vein thrombosis, Capillary leak syndrome, Vasculitis, Hypertension, Flushing, Blood pressure decreased
Respiratory, Thoracic, And Mediastinal Disorders:
Respiratory failure*, Acute respiratory distress syndrome*, Pulmonary hypertension*, Interstitial lung disease* as manifested by Pulmonary fibrosis*, Alveolitis allergic, Interstitial pneumonitis, Pneumonitis*, Pulmonary edema*, Pleural effusion, Bronchospasm, Dyspnea, Hypoxia, Cough
Gastrointestinal Disorders:
Cecitis, Colitis, Enterocolitis, Pancreatitis, Ileus, Gastrointestinal hemorrhage, Mucosal ulceration, Constipation, Abdominal pain, Salivary hypersecretion
Hepatobiliary Disorders:
Hepatic failure*, Hepatitis fulminant*, Veno-occlusive liver disease, Portal vein thrombosis, Cytolytic hepatitis, Cholestasis
Skin And Subcutaneous Tissue Disorders:
Toxic epidermal necrolysis, Stevens-Johnson syndrome, Palmar-plantar erythrodysesthesia syndrome, Radiation recall dermatitis, Skin necrosis, Facial swelling, Petechiae, Macular rash, Rash, Pruritus, Erythema, Skin hyperpigmentation, Hyperhidrosis, nail disorder
Musculoskeletal And Connective Tissue Disorder:
Rhabdomyolysis, Osteomalacia, Rickets, Growth retardation, Myalgia, Arthralgia, Pain in extremity, Muscle twitching
Renal And Urinary Disorders:
Fanconi syndrome, Tubulointerstitial nephritis, Nephrogenic diabetes insipidus, Phosphaturia, Aminoaciduria, Polyuria, Enuresis, Feeling of residual urine
Fatal outcomes from acute and chronic renal failure have been documented.
Reproductive System And Breast Disorders:
Infertility, Ovarian failure, Premature menopause, Amenorrhea, Ovarian disorder, Ovulation disorder, Azoospermia, Oligospermia, Impairment of spermatogenesis, Blood estrogen decreased, Blood gonadotrophin increased
Congential, Familial And Genetic Disorders:
Fetal growth retardation
General Disorders And Administrative Site Conditions:
Multi-organ failure*, General physical deterioration, Injection/Infusion site reactions including swelling, inflammation, pain, erythema, tenderness, pruritus; Chest pain, Edema, Mucosal inflammation, Pain, Pyrexia, Chills
* Including fatal outcomes
Es ist kein spezifisches Gegenmittel für Ifosfamid EG bekannt.
Patienten, die eine Überdosierung erhalten, sollten engmaschig auf die Entwicklung von Toxizitäten überwacht werden. Schwerwiegende Folgen einer Überdosierung sind Manifestationen dosisabhängiger Toxizitäten wie ZNS-Toxizität, Nephrotoxizität, Myelosuppression und Mukositis.
Das Management einer Überdosierung würde allgemeine unterstützende Maßnahmen zur Aufrechterhaltung des Patienten durch eine mögliche Toxizitätsperiode umfassen, einschließlich einer angemessenen Behandlung nach dem Stand der Technik für gleichzeitige Infektionen, Myelosuppression oder andere Toxizität. Ifosfamid- und Ifosfamid-Metaboliten sind dialyzierbar.
Eine Blasenentzündungsprophylaxe mit Mesna kann hilfreich sein, um urotoxische Wirkungen bei Überdosierung zu verhindern oder zu begrenzen.
Es ist kein spezifisches Gegenmittel für IFEX bekannt.
Patienten, die eine Überdosierung erhalten, sollten engmaschig auf die Entwicklung von Toxizitäten überwacht werden. Schwerwiegende Folgen einer Überdosierung sind Manifestationen dosisabhängiger Toxizitäten wie ZNS-Toxizität, Nephrotoxizität, Myelosuppression und Mukositis.
Das Management einer Überdosierung würde allgemeine unterstützende Maßnahmen zur Aufrechterhaltung des Patienten durch eine mögliche Toxizitätsperiode umfassen, einschließlich einer angemessenen Behandlung nach dem Stand der Technik für gleichzeitige Infektionen, Myelosuppression oder andere Toxizität. Ifosfamid- und Ifosfamid-Metaboliten sind dialyzierbar.
Eine Blasenentzündungsprophylaxe mit Mesna kann hilfreich sein, um urotoxische Wirkungen bei Überdosierung zu verhindern oder zu begrenzen.
Ifosfamid zeigt beim Menschen eine dosisabhängige Pharmakokinetik. Bei Einzeldosen von 3,8 bis 5,0 g / m2 Die Plasmakonzentrationen sinken zweiphasig und die mittlere terminale Eliminationshalbwertszeit beträgt etwa 15 Stunden. Bei Dosen von 1,6 bis 2,4 g / m2 / Tag, der Plasma-Zerfall ist monoexponentiell und die terminale Eliminationshalbwertszeit beträgt ca. 7 Stunden.
Ifosfamid zeigt beim Menschen eine zeitabhängige Pharmakokinetik. Nach intravenöser Verabreichung von 1,5 g / m2 über 0,5 Stunden einmal täglich für 5 Tage bis 15 Patienten mit neoplastischer Erkrankung, Eine Abnahme der mittleren Eliminationshalbwertszeit von 7,2 Stunden am Tag 1 auf 4,6 Stunden am Tag 5 trat mit einer gleichzeitigen Erhöhung der mittleren Clearance von 66 ml / min am Tag 1 auf 115 ml / min am Tag 5 auf. Das Verteilungsvolumen an Tag 5 hat sich im Vergleich zu Tag 1 nicht wesentlich verändert.
Verteilung
Das Ifosfamid-Verteilungsvolumen (Vd) entspricht in etwa dem gesamten Körperwasservolumen, was darauf hindeutet, dass die Verteilung mit minimaler Gewebebindung erfolgt. Nach intravenöser Verabreichung von 1,5 g / m2 über 0,5 Stunden einmal täglich für 5 Tage bis zu 15 Patienten mit neoplastischer Erkrankung, die mittlere Vd von Ifosfamid betrug 0,64 l / kg am Tag 1 und 0,72 l / kg am Tag 5. Ifosfamid zeigt wenig Plasmaproteinbindung. Ifosfamid und seine aktiven Metaboliten sind weitgehend an rote Blutkörperchen gebunden. Ifosfamid ist kein Substrat für P-Glykoprotein.
Stoffwechsel
Ifosfamid wird beim Menschen über zwei Stoffwechselwege weitgehend metabolisiert: Ringoxidation ("Aktivierung") zur Bildung des aktiven Metaboliten, 4-Hydroxy-ifosfamid und Seitenkettenoxidation zur Bildung der inaktiven Metaboliten 3-Dechlorethylifosfamid oder 2-Dechlorethylifosfamid mit Freisetzung des toxischen Metaboliten Chloracetaldehyd. Kleine Mengen (nmol / ml) von Ifosfamidsenf und 4-Hydroxyifosfamid sind im menschlichen Plasma nachweisbar. Der Metabolismus von Ifosfamid ist für die Erzeugung der biologisch aktiven Spezies erforderlich, und obwohl der Metabolismus umfangreich ist, ist er auch bei Patienten sehr unterschiedlich.
Ausscheidung
Nach Verabreichung von Dosen von 5 g / m2 von 14C-markiertes Ifosfamid, von 70% bis 86% der dosierten Radioaktivität, wurde im Urin als Metaboliten gewonnen, wobei etwa 61% der Dosis als Ausgangsverbindung ausgeschieden wurden. Bei Dosen von 1,6 bis 2,4 g / m2 Innerhalb von 72 Stunden wurden nur 12% bis 18% der Dosis als unverändertes Arzneimittel in den Urin ausgeschieden. Zwei verschiedene dechlorethylierte Derivate von Ifosfamid, 4-Carboxyifosfamid, Thiodiacetic Acid und Cysteinkonjugaten von Chloressigsäure wurden als die wichtigsten Harnstoffaboliten von Ifosfamid beim Menschen identifiziert, und es sind nur geringe Mengen an 4-Hydroxyifosfamid und Acrolein vorhanden.
Pädiatrie
Die Populations-PK-Analyse wurde an Plasmadaten von 32 pädiatrischen Patienten mit verschiedenen bösartigen Erkrankungen im Alter zwischen 1 und 18 Jahren durchgeführt. Die Patienten erhielten insgesamt 45 Ifosfamid-Kurse in Dosen von 1,2, 2,0 und 3,0 g / m2 intravenös über 1 oder 3 Stunden an 1, 2 oder 3 Tagen verabreicht. Die mittleren Schätzungen der Standardfehlerpopulation für die anfängliche Clearance und das Verteilungsvolumen von Ifosfamid betrugen 2,4 ± 0,33 l / h / m und 21 ± 1,6 l / m2 mit einer interindividuellen Variabilität von 43% bzw. 32%.
Wirkung des Alters
Eine Studie mit 20 Patienten zwischen 40 und 71 Jahren, die 1,5 g / m erhalten2 von ifosfamid täglich für 3 oder 5 Tage zeigte an, dass die Eliminationshalbwertszeit mit dem Alter zuzunehmen scheint. Der Anstieg der Eliminationshalbwertszeit schien mit dem Anstieg des Ifosfamid-Verteilungsvolumens mit dem Alter in Zusammenhang zu stehen. Es wurden keine signifikanten Änderungen der gesamten Plasma-Clearance oder der renalen Clearance mit dem Alter berichtet.