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Kovalenko Svetlana Olegovna tarafından tıbbi olarak gözden geçirilmiştir, Eczane Son güncelleme: 21.03.2022
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Ifosfamida Glenmark, germ hücresi testis kanserinin üçüncü basamak kemoterapisi için onaylanmış diğer bazı antineoplastik ajanlarla kombinasyon halinde kullanım için endikedir. Hemorajik sistitin profilaksisi için mesna ile kombinasyon halinde kullanılmalıdır.
IFEX, mikrop hücresi testis kanserinin üçüncü basamak kemoterapisi için onaylanmış diğer bazı antineoplastik ajanlarla kombinasyon halinde kullanım için endikedir. Hemorajik sistitin profilaksisi için mesna ile kombinasyon halinde kullanılmalıdır.
Ifosfamida Glenmark, m başına 1.2 gramlık bir dozda intravenöz olarak uygulanmalıdır2 arka arkaya 5 gün boyunca günde. Tedavi her 3 haftada bir veya hematolojik toksisiteden iyileştikten sonra tekrarlanır.
Mesane toksisitesini önlemek için, Ifosfamida Glenmark günde en az 2 litre oral veya intravenöz sıvıdan oluşan geniş hidrasyon ile verilmelidir. Hemorajik sistit insidansını azaltmak için Mesna kullanılmalıdır. Ifosfamida Glenmark, en az 30 dakika süren yavaş bir intravenöz infüzyon olarak uygulanmalıdır. Karaciğer veya böbrek yetmezliği olan hastalarda Ifosfamida Glenmark çalışmaları yapılmamıştır.
Enjeksiyonlar parenteral kullanım için eklenerek hazırlanır Enjeksiyon için Steril Su, USP veya Enjeksiyon için Bakteriyostatik Su, USP (benzil alkol veya parabenler korunmuş), şişeye ve erimesi için çalkalama. Parenteral uygulamadan önce, madde tamamen çözülmelidir. Ürünü oluşturmak için aşağıda gösterilen seyreltici miktarını kullanın:
Dozaj Gücü | Seyreltici miktarı | Son Konsantrasyon |
1 gram | 20 mL | ML başına 50 mg |
3 gram | 60 mL | ML başına 50 mg |
İfosfamid çözeltileri, 0.6 ila 20 mg / m konsantrasyonlara ulaşmak için daha fazla seyreltilebilir2Aşağıdaki sıvılarda L:
% 5 Dekstroz Enjeksiyonu, USP
% 0.9 Sodyum Klorür Enjeksiyonu, USP
Emzikli Zil Enjeksiyonları, USP
Enjeksiyon için Steril Su, USP
Steril Su katkı maddeleri için diğer katkı maddelerinde olduğu gibi esasen aynı stabilite sonuçları elde edildiğinden (% 5 Dekstroz Enjeksiyonu,% 0.9 Sodyum Klorür Enjeksiyonu ve Laktatlı Zil Enjeksiyonu), büyük hacimli parenteral cam şişeler, VIAFLEX torbaları veya PAB torbalarının kullanımı ara konsantrasyonlar veya eksipiyan karışımları (örn.% 2.5 Dekstroz Enjeksiyonu,% 0.45 Sodyum Klorür Enjeksiyonu veya% 5 Dekstroz ve% 0.9 Sodyum Klorür Enjeksiyonu) da kabul edilebilir.
Ifosfamida Glenmark'ın oluşturulmuş veya oluşturulmuş ve daha fazla seyreltilmiş çözeltileri 24 saat içinde soğutulmalı ve kullanılmalıdır. Benzil-alkol içeren çözeltiler ifosfamidin stabilitesini azaltabilir.
Parenteral ilaç ürünleri, çözelti ve kap izin verdiğinde uygulamadan önce partikül madde ve renk değişikliği açısından görsel olarak incelenmelidir.
IFEX, m başına 1.2 gramlık bir dozda intravenöz olarak uygulanmalıdır2 arka arkaya 5 gün boyunca günde. Tedavi her 3 haftada bir veya hematolojik toksisiteden iyileştikten sonra tekrarlanır.
Mesane toksisitesini önlemek için, IFEX günde en az 2 litre oral veya intravenöz sıvıdan oluşan geniş hidrasyon ile verilmelidir. Hemorajik sistit insidansını azaltmak için Mesna kullanılmalıdır. IFEX, en az 30 dakika süren yavaş bir intravenöz infüzyon olarak uygulanmalıdır. Karaciğer veya böbrek yetmezliği olan hastalarda IFEX çalışmaları yapılmamıştır.
Enjeksiyonlar parenteral kullanım için eklenerek hazırlanır Enjeksiyon için Steril Su, USP veya Enjeksiyon için Bakteriyostatik Su, USP (benzil alkol veya parabenler korunmuş), şişeye ve erimesi için çalkalama. Parenteral uygulamadan önce, madde tamamen çözülmelidir. Ürünü oluşturmak için aşağıda gösterilen seyreltici miktarını kullanın:
Dozaj Gücü | Seyreltici miktarı | Son Konsantrasyon |
1 gram | 20 mL | ML başına 50 mg |
3 gram | 60 mL | ML başına 50 mg |
İfosfamid çözeltileri, 0.6 ila 20 mg / m konsantrasyonlara ulaşmak için daha fazla seyreltilebilir2Aşağıdaki sıvılarda L:
% 5 Dekstroz Enjeksiyonu, USP
% 0.9 Sodyum Klorür Enjeksiyonu, USP
Emzikli Zil Enjeksiyonları, USP
Enjeksiyon için Steril Su, USP
Steril Su katkı maddeleri için diğer katkı maddelerinde olduğu gibi esasen aynı stabilite sonuçları elde edildiğinden (% 5 Dekstroz Enjeksiyonu,% 0.9 Sodyum Klorür Enjeksiyonu ve Laktatlı Zil Enjeksiyonu), büyük hacimli parenteral cam şişeler, VIAFLEX torbaları veya PAB torbalarının kullanımı ara konsantrasyonlar veya eksipiyan karışımları (örn.% 2.5 Dekstroz Enjeksiyonu,% 0.45 Sodyum Klorür Enjeksiyonu veya% 5 Dekstroz ve% 0.9 Sodyum Klorür Enjeksiyonu) da kabul edilebilir.
IFEX'in oluşturulmuş veya oluşturulmuş ve daha fazla seyreltilmiş çözeltileri 24 saat içinde soğutulmalı ve kullanılmalıdır. Benzil-alkol içeren çözeltiler ifosfamidin stabilitesini azaltabilir.
Parenteral ilaç ürünleri, çözelti ve kap izin verdiğinde uygulamadan önce partikül madde ve renk değişikliği açısından görsel olarak incelenmelidir.
Ifosfamida Glenmark is contraindicated in patients with:
- Known hypersensitivity to administration of ifosfamide.
- Urinary outflow obstruction.
IFEX is contraindicated in patients with:
- Known hypersensitivity to administration of ifosfamide.
- Urinary outflow obstruction.
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 Ifosfamida Glenmark 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, Ifosfamida Glenmark should not be given to patients with a WBC count below 2000/μL and/or a platelet count below 50,000/μL.
Ifosfamida Glenmark 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 Ifosfamida Glenmark 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 Ifosfamida Glenmark. 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 Ifosfamida Glenmark. 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 Ifosfamida Glenmark 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
Ifosfamida Glenmark 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.
.
Ifosfamida Glenmark 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. Ifosfamida Glenmark 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
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 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.
Klinik Araştırmalardan Olumsuz Reaksiyonlar
Klinik araştırmalar çok çeşitli durumlardan yapıldığından, bir ilacın klinik çalışmalarında gözlenen advers reaksiyon oranları, başka bir ilacın klinik çalışmalarındaki oranlarla doğrudan karşılaştırılamaz ve klinik uygulamada gözlemlenen oranları yansıtmayabilir. Aşağıdaki advers reaksiyonlar ve frekanslar, toplam 4 ila 12 g / m dozunda monoterapi olarak fraksiyone ifosfamidin uygulanmasıyla klinik deneyimi tanımlayan 30 yayına dayanmaktadır2 kurs başına.
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Sistem Organ Sınıfı (SOC) | Olumsuz Reaksiyon | Yüzde (Ratio) |
ENFEKSİYONLAR VE ENFESTASYONLAR | Enfeksiyon | % 9.9 (112/1128) |
KAN VE LİMFATİK SİSTEM BOZUKLUKLARI | Lökopeni (herhangi biri) | -† |
Lökopeni <1 x 103 /UlL | % 43.5 (267/614) | |
Trombositopeni‡ (Herhangi biri) | -§ | |
Trombositopeni, 50 x 103 /UlL | % 4.8 (35/729) | |
Anemi¶ | % 37.9 (202/533) | |
METABOLİZM VE BESLENME BOZUKLUKLARI | Anoreksiya | % 1.1 (15/1317) |
SİNİR SİSTEMİ BOZUKLUKLARI | Merkezi sinir sistemi toksisitesi#, Þ | % 15.4 (154/1001) |
Periferik nöropati | % 0.4 (5/1317) | |
KARDİYAC BOZUKLUKLARI | Kardiyotoksisiteß | % 0.5 (7/1317) |
VASKÜLER BOZUKLUKLAR | İktidarsızlıkà | % 0.3 (4/1317) |
GASTROINTESTINAL BOZUKLUKLAR | Bulantı / Kusma | % 46.8 (443/964) |
İshal | % 0.7 (9/1317) | |
Stomatit | % 0.3 (4/1317) | |
MUTLU BOZUKLUKLAR | Hepatotoksisiteè | % 1.8 (22/1190) |
CİLT VE YÜKSEK DİSKLER DISORDERS | Alopesi | % 89.6 (540/603) |
Dermatit | % 0.08 (1/1317) | |
Papüler döküntü | % 0.08 (1/1317) | |
RENAL VE ÜRETİMLİ BOZUKLUKLAR | Hemorajik sistit | -ð |
Hematüri | ||
- mesna olmadan | % 44.1 (282/640) | |
- mesna ile | % 21.3 (33/155) | |
Makrohematüri | ||
- mesna olmadan | % 11.1 (66/594) | |
- mesna ile | % 5.2 (5/97) | |
Böbrek fonksiyon bozukluğuø | - | |
Böbrek yapısal hasarı | - | |
GENEL BOZUKLUKLAR VE İDARİ SİTE KOŞULLARI | Flebitý | % 2.8 (37/1317) |
Nötropenik ateş£ | % 1.0 (13/1317) | |
Yorgunluk | % 0.3 (4/1317) | |
Malaise | Hesaplanamıyor | |
* Lökopeni için aşağıdaki advers reaksiyon terimleri bildirilmiştir: nötropeni, granülositopeni, lenfopeni ve pansitopeni. Nötropenik ateş için aşağıya bakınız. †Lökopeni frekans kategorisi lökopeni frekansına <3 x 10 dayanmaktadır3 / ìL [4% 2.5 (150/353) tabloda gösterilmemiştir] ve <1 x 103 / ìL; toplanan veriler için ilgili bir yüzde oranı hesaplanamaz ve bu nedenle “Çok yaygın” muhafazakar frekans kategorisi tabloya dahil edilmiştir. ‡ Trombositopeni kanama ile de komplike olabilir. Ölümcül sonuç ile kanama bildirilmiştir. §Trombositopeni sıklığı, trombositopeni <100 x 10 sıklığına dayanır3 / ìL [% 12.2 (24/196) tabloda gösterilmemiştir] ve <50 x 103 / ìL; toplanan verilerden ilgili bir yüzde oranı hesaplanamaz ve bu nedenle “Çok yaygın” konservatif sıklığı tabloya dahil edilmiştir. ¶Anemi olarak bildirilen vakaları ve hemoglobin / hematokritte azalma içerir. #Koma ve ölüm ile ensefalopati bildirilmiştir. ÞMerkezi sinir sistemi toksisitesinin aşağıdaki belirti ve semptomlarla ortaya çıktığı bildirilmiştir: Anormal davranış, İstikrarlı Saldırganlığı etkileyin, Ajitasyon, Anksiyete, Afazi, Asteni, Ataksi, Serebellar sendromu, Serebral fonksiyon eksikliği, Bilişsel bozukluk, Koma, Karışıklık durumu, Konvülsiyonlar, Kranial sinir disfonksiyonu, Depresyon bilinci durumu, Depresyon, Oryantasyon bozukluğu, Baş dönmesi, Elektroensefalogram anormal, Ensefalopati, Düz etki. Halüsinasyonlar, Baş Ağrısı, Fikir, Uyuşukluk, Bellek bozukluğu, Ruh hali değişikliği, Motor disfonksiyonu, Kas spazmları, Miyoklonus, Beyin sapı reflekslerinin progresif kaybı, Psikotik reaksiyon, Huzursuzluk, Somnolans, Tremor, Üriner inkontinans. ßKardiyotoksisite konjestif kalp yetmezliği, taşikardi, pulmoner ödem olarak bildirilmiştir. Ölümcül sonuç bildirildi. àŞok ve ölümcül sonuca yol açan hipotansiyon bildirilmiştir. èHepatotoksisitenin karaciğer enzimlerinde artış olduğu, yani., serum alanin aminotransferaz, serum aspartat aminotransferaz, alkalin fosfataz, gama-glutamiltransferaz ve laktat dehidrojenaz, artmış bilirubin, sarılık, hepatorenal sendrom. ðHemorajik sistit sıklığı, hematüri sıklığına göre tahmin edilir. Hemorajik sistitin bildirilen semptomları arasında dizüri ve pollakiüri vardı. Ayrıca bakınız Pazarlama Sonrası REKLAM REAKSİYONLARI. øBöbrek fonksiyon bozukluğunun şu şekilde ortaya çıktığı bildirilmiştir: Böbrek yetmezliği (akut böbrek yetmezliği, geri dönüşümsüz böbrek yetmezliği; ölümcül sonuçlar bildirilmiştir), Serum kreatinin artışı, BUN artışı, Kreatinin klerensi azaldı, Metabolik asidoz, Anüri, Oligüri, Glikozüri, Hiponatremi, Ürem, Kreatinin klerensi arttı. Böbrek yapısal hasarının şu şekilde ortaya çıktığı bildirilmiştir: Akut tübüler nekroz, renal parankimal hasar, Enzimuria, Silindirüri, Proteinüri. ýFlebit ve venöz duvarların tahrişi olarak bildirilen vakaları içerir. £Nötropenik ateş sıklığı: Granülositopenik ateş olarak bildirilen vakaları içerir. |
Pazarlama Sonrası Deneyim
MedDRA Sistem Organ Sınıfı (SOC) tarafından listelenen pazarlama sonrası deneyimde, daha sonra mümkünse şiddet sırasına göre Tercih Edilen Terim ile aşağıdaki advers reaksiyonlar bildirilmiştir. Bu reaksiyonlar, belirsiz büyüklükteki bir popülasyondan gönüllü olarak bildirildiğinden, sıklıklarını güvenilir bir şekilde tahmin etmek veya ilaca maruz kalma ile nedensel bir ilişki kurmak her zaman mümkün değildir.
Enfeksiyonlar ve Enfestasyonlar
Aşağıdaki belirtiler, ifosfamidin neden olduğu miyelosupresyon ve immünosupresyon ile ilişkilendirilmiştir: enfeksiyon riski ve şiddeti †, pnömoni †, sepsis ve septik şok (ölümcül sonuçlar dahil) ve ayrıca viral hepatit † dahil olmak üzere gizli enfeksiyonların yeniden aktivasyonu, Pneumocystis jiroveci†, herpes zoster, Strongyloides, progresif multifokal lökoensefalopati † ve diğer viral ve mantar enfeksiyonları.
† Şiddetli immünosupresyon ciddi, bazen ölümcül enfeksiyonlara yol açmıştır.
Neoplazmalar ,, Benign Ve Malign Ve Uuspecified (Kistler ve Polipler Dahil) :
Tedaviye bağlı sekonder malignite *, Akut lösemi * (Akut miyeloid lösemi) *, Akut promiyelositik lösemi *, Akut lenfositik lösemi *, Miyelodisplastik sendrom, Lenfoma (Hodgkin dışı lenfoma), Sarkomlar *, Renal hücreli karsinom, Tiroid kanseri
Kan ve Lenf Sistemi Bozuklukları :
Hematotoksisite *, Kemik iliği yetmezliği, Agranülositoz; Febril kemik iliği aplazisi; Yaygın damar içi pıhtılaşma, Hemolitik üremik sendrom, Hemolitik anemi, Yenidoğan anemisi, Methemoglobinemi
Bağışıklık Sistemi Bozuklukları :
Anjiyoödem *, Anafilaktik reaksiyon, İmmünosupresyon, Ürtiker, Aşırı duyarlılık reaksiyonu
Endokrin Bozuklukları :
Uygunsuz antidiüretik hormon salgısı sendromu (SIADH)Metabolizma ve Beslenme Bozuklukları :
Tümör lizis sendromu, Metabolik asidoz, Hipokalemi, Hipokalsemi, Hipofosfatemi, Hiperglisemi, Polidipsi
Psikiyatrik Bozukluklar:
Panik atak, Kataton, Mania, Paranoya, Delüzyon, Deliryum, Bradyphrenia, Mutizm, Zihinsel durum değişikliği, Echolalia, Logorrhea, Azim, Amnezi
Sinir Sistemi Bozuklukları :
Konvülsiyon *, Durum epileptikus (konvülsif ve konvülsif olmayan), geri dönüşümlü posterior lökoensefalopati sendromu, Lökoensefalopati, Ekstrapiramidal bozukluk, Asterixis, Hareket bozukluğu, Polinöropati, Disestezi, Hipotezi, Nevralji, Yürüyüş rahatsızlığı, Fekal inkontinans, Disyon
Göz Bozuklukları:
Görme bozukluğu, Görme bulanıklığı, Konjonktivit, Göz tahrişi
Kulak ve Labirent Bozuklukları :
Sağırlık, Hipoaküs, Vertigo, Tinnitus
Kardiyak Bozukluklar:
Kardiyotoksisite *, Kardiyak arrest *, Ventriküler fibrilasyon *, Ventriküler taşikardi *, Kardiyojenik şok *, Miyokard enfarktüsü *, Kardiyak yetmezlik *, Demet şube bloğu kaldı, Şube bloğunu sağ paketleyin, Perikardiyal efüzyon, Miyokardiyal kanama, Anjina pektoris, Sol ventrikül yetmezliği, Kardiyomiyopati *, Konjestif kardiyomiyopati, Miyokardit *, Aritmi *, Perikardit, Atriyal fibrilasyon, Atriyal çarpıntı, Bradikardi, Supraventriküler ekstrasistoller, Erken atriyal kasılmalar, Ventriküler ekstrasistoller, Miyokardiyal depresyon, Çarpıntı, Ejeksiyon fraksiyonu azaldı *, Elektrokardiyogram ST segmenti anormal, Elektrokardiyogram T dalgası ters çevirme, Elektrokardiyogram QRS kompleksi anormal
Vasküler Bozukluklar :
Pulmoner emboli, Derin ven trombozu, Kılcal sızıntı sendromu, Vaskülit, Hipertansiyon, Kızarma, Kan basıncı azaldı
Solunum, Torasik ve Mediastinal Bozukluklar:
Solunum yetmezliği *, Akut solunum sıkıntısı sendromu *, Pulmoner hipertansiyon *, Pulmoner fibroz *, Alveolit alerjik, İnterstisyel pnömonit, Pnömonit *, Pulmoner ödem *, Plevral efüzyon, Bronkospazm, Dispne, Hipoksi, Öksürük
Gastrointestinal Hastalıklar :
Kekit, Kolit, Enterokolit, Pankreatit, Ileus, Gastrointestinal kanama, Mukozal ülserasyon, Kabızlık, Karın ağrısı, Tükürük hipersekresyonu
Hepatobiliyer Bozukluklar :
Karaciğer yetmezliği *, Hepatit fulminan *, Veno-oklüzif karaciğer hastalığı, Portal ven trombozu, Sitolitik hepatit, Kolestaz
Deri ve Deri Altı Doku Bozuklukları :
Toksik epidermal nekroliz, Stevens-Johnson sendromu, Palmar-plantar eritrodisestezi sendromu, Radyasyon hatırlama dermatiti, Cilt nekrozu, Yüz şişmesi, Peteşiler, Maküler döküntü, Döküntü, Kaşıntı, Eritem, Cilt hiperpigmentasyonu, Hiperhidroz, tırnak bozukluğu
Kas-İskelet sistemi ve Bağ Doku Bozukluğu:
Rabdomiyoliz, Osteomalazi, Raşitizm, Büyüme geriliği, Miyalji, Artralji, Ekstremitede ağrı, Kas seğirmesi
Böbrek ve İdrar Hastalıkları :
Fanconi sendromu, Tubulointerstisyel nefrit, Nefrojenik diyabet insipidus, Fosfatüri, Aminoasidüri, Poliüri, Enürezis, Artık idrar hissi
Akut ve kronik böbrek yetmezliğinden kaynaklanan ölümcül sonuçlar belgelenmiştir.
Üreme Sistemi ve Meme Bozuklukları :
İnfertilite, Yumurtalık yetmezliği, Erken menopoz, Amenore, Yumurtalık bozukluğu, Yumurtlama bozukluğu, Azoospermi, Oligospermi, spermatogenez bozukluğu, Kan östrojeni azaldı, Kan gonadotropini arttı
Konjonktürel, Ailesel ve Genetik Bozukluklar :
Fetal büyüme geriliği
Genel Bozukluklar ve İdari Site Koşulları :
Çok organ yetmezliği *, Genel fiziksel bozulma, Şişme, iltihaplanma, ağrı, eritem, hassasiyet, kaşıntı dahil olmak üzere Enjeksiyon / İnfüzyon bölgesi reaksiyonları; Göğüs ağrısı, Ödem, Mukozal inflamasyon, Ağrı, Pireksi, Titreme
* Ölümcül sonuçlar dahil
Ifosfamida Glenmark için spesifik bir antidot bilinmemektedir.
Doz aşımı alan hastalar, toksisite gelişimi açısından yakından izlenmelidir. Doz aşımının ciddi sonuçları arasında CNS toksisitesi, nefrotoksisite, miyelosupresyon ve mukozit gibi doza bağlı toksisitelerin belirtileri bulunur.
Doz aşımı yönetimi, herhangi bir eşzamanlı enfeksiyon, miyelosupresyon veya diğer toksisite için uygun son teknoloji tedavi de dahil olmak üzere, hastanın ortaya çıkabilecek herhangi bir toksisite dönemi boyunca sürdürülmesi için genel destekleyici önlemleri içerecektir. Ifosfamid ve ifosfamid metabolitleri diyaliz edilebilir.
Mezna ile sistit profilaksisi, aşırı doz ile ürotoksik etkilerin önlenmesinde veya sınırlandırılmasında yardımcı olabilir.
IFEX için spesifik bir antidot bilinmemektedir.
Doz aşımı alan hastalar, toksisite gelişimi açısından yakından izlenmelidir. Doz aşımının ciddi sonuçları arasında CNS toksisitesi, nefrotoksisite, miyelosupresyon ve mukozit gibi doza bağlı toksisitelerin belirtileri bulunur.
Doz aşımı yönetimi, herhangi bir eşzamanlı enfeksiyon, miyelosupresyon veya diğer toksisite için uygun son teknoloji tedavi de dahil olmak üzere, hastanın ortaya çıkabilecek herhangi bir toksisite dönemi boyunca sürdürülmesi için genel destekleyici önlemleri içerecektir. Ifosfamid ve ifosfamid metabolitleri diyaliz edilebilir.
Mezna ile sistit profilaksisi, aşırı doz ile ürotoksik etkilerin önlenmesinde veya sınırlandırılmasında yardımcı olabilir.
Ifosfamid insanlarda doza bağlı farmakokinetik sergiler. 3.8 ila 5.0 g / m'lik tek dozlarda2 plazma konsantrasyonları iki fazlı olarak bozunur ve ortalama terminal eliminasyon yarılanma ömrü yaklaşık 15 saattir. 1.6 ila 2.4 g / m dozlarında2 / gün, plazma bozunması tek yönlüdür ve terminal eliminasyon yarılanma ömrü yaklaşık 7 saattir.
Ifosfamid insanlarda zamana bağlı farmakokinetik sergiler. 1.5 g / m intravenöz uygulamayı takiben2 neoplastik hastalığı olan 15 hastaya 5 gün boyunca günde bir kez 0.5 saatten fazla, medyan eliminasyon yarılanma ömründe 1. günde 7.2 saatten 5. günde 4.6 saate bir azalma meydana geldi ve medyan klerensinde 1. günde 66 mL / dk'dan 5. günde 115 mL / dk'ya eşzamanlı bir artış meydana geldi. 5. günde 1. güne kıyasla dağılım hacminde önemli bir değişiklik olmamıştır.
Dağıtım
Ifosfamid dağılım hacmi (Vd) toplam vücut suyu hacmine yaklaşır, bu da dağılımın minimum doku bağlanmasıyla gerçekleştiğini gösterir. 1.5 g / m intravenöz uygulamayı takiben2 neoplastik hastalığı olan 15 hastaya 5 gün boyunca günde bir kez 0.5 saatten fazla, ifosfamidin medyan Vd'si 1. günde 0.64 L / kg ve 5. günde 0.72 L / kg idi. Ifosfamid az plazma proteinlerine bağlanma gösterir. Ifosfamid ve aktif metabolitleri kırmızı kan hücreleri tarafından yoğun bir şekilde bağlanır. Ifosfamid, P-glikoprotein için bir substrat değildir.
Metabolizma
Ifosfamid insanlarda iki metabolik yolla yoğun bir şekilde metabolize edilir: aktif metaboliti oluşturmak için halka oksidasyonu ("aktivasyon"), aktif olmayan metabolitleri oluşturmak için 4-hidroksi-ifosfamid ve yan zincir oksidasyonu, 3-dekloro-etilifosfamid veya 2-dekloroetilifosfamid toksik metabolit, kloroasetaldehitin serbest bırakılması ile. İnsan plazmasında küçük miktarlarda (nmol / mL) ifosfamid hardalı ve 4-hidroksifosfamid tespit edilebilir. Biyolojik olarak aktif türlerin üretimi için ifosfamidin metabolizması gereklidir ve metabolizma geniş olmakla birlikte hastalar arasında da oldukça değişkendir.
Boşaltım
5 g / m'lik dozların uygulanmasından sonra2 nın-nin 14Dozlanan radyoaktivitenin% 70 ila% 86'sı C etiketli ifosfamid, idrarda metabolit olarak geri kazanıldı ve dozun yaklaşık% 61'i ana bileşik olarak atıldı. 1.6 ila 2.4 g / m dozlarında2 dozun sadece% 12 ila% 18'i 72 saat içinde değişmemiş ilaç olarak idrarla atılmıştır. İnsanlarda ifosfamidin ana idrar metabolitleri olarak iki farklı kloroetillenmiş ifosfamid, 4- karboksifosfamid, tiyodiyasetik asit ve kloroasetik asidin sistein konjügatları tanımlanmıştır ve sadece az miktarda 4-hidroksifosfamid ve akrolein mevcuttur.
Pediatri
Nüfus PK analizi, 32 pediatrik hastanın 1 ila 18 yaşları arasındaki çeşitli malign hastalıklardan alınan plazma verileri üzerinde gerçekleştirilmiştir. Hastalara 1.2, 2.0 ve 3.0 g / m dozlarında toplam 45 ders ifosfamid verildi2 1, 2 veya 3 günde 1 veya 3 saat boyunca intravenöz olarak verilir. İfosfamidin başlangıç klerensi ve dağılım hacmi için ortalama ± standart hata popülasyonu tahminleri 2.4 ± 0.33 L / s / m ve 21 ± 1.6 L / m idi2 bireyler arası değişkenliği sırasıyla% 43 ve% 32'dir.
Yaşın Etkisi
40 ila 71 yaşları arasındaki 20 hastanın 1.5 g / m aldığı bir çalışma2 3 veya 5 gün boyunca günlük ifosfamid, eliminasyon yarılanma ömrünün yaşla birlikte arttığı görülmüştür. Eliminasyon yarılanma ömrü artışının, yaşla birlikte ifosfamid dağılım hacmindeki artışla ilişkili olduğu görülmüştür. Toplam plazma klerensi veya yaşla birlikte böbrek klerensinde önemli bir değişiklik bildirilmemiştir.