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Revisión médica por Militian Inessa Mesropovna Última actualización de farmacia el 14.03.2022
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Los 20 mejores medicamentos con los mismos ingredientes:
El Торизел está indicado para el tratamiento del carcinoma avanzado de células renales.
Carcinoma avanzado de células renales
La dosis recomendada de Торизел para el carcinoma avanzado de células renales se infunde en 25 mg durante un período de 30 a 60 minutos una vez por semana.
El tratamiento debe continuar hasta que ocurra la progresión de la enfermedad o la toxicidad inaceptable.
Premedicación
Los pacientes deben recibir difenhidramina intravenosa profiláctica de 25 a 50 mg (o antihistamínico similar) aproximadamente 30 minutos antes del inicio de cada dosis de Торизел.
Interrupción / Ajuste de dosis
El Торизел debe mantenerse para el recuento absoluto de neutrófilos (ANC) <1,000 / mm3, recuento de plaquetas <75,000 / mm3, o NCI CTCAE grado 3 o mayores reacciones adversas. Una vez que las toxicidades se hayan resuelto a grado 2 o menos, Торизел puede reiniciarse con la dosis reducida en 5 mg / semana a una dosis no inferior a 15 mg / semana.
Pautas de modificación de dosis
Insuficiencia hepática
Tenga precaución al tratar pacientes con insuficiencia hepática. Si se debe administrar Торизел en pacientes con insuficiencia hepática leve (bilirrubina> 1 - 1.5 × ULN o AST> ULN pero bilirrubina ≤ULN), reduzca la dosis de Торизел a 15 mg / semana. Торизел está contraindicado en pacientes con bilirrubina> 1.5 × ULN .
Inhibidores concomitantes fuertes de CYP3A4
Se debe evitar el uso concomitante de inhibidores potentes de CYP3A4 (p. Ej. ketoconazol, itraconazol, claritromicina, atazanavir, indinavir, nefazodona, nelfinavir, ritonavir, saquinavir, telitromicina y voriconazol). El jugo de toronja también puede aumentar las concentraciones plasmáticas de sirolimus (un metabolito principal de temsirolimus) y debe evitarse. Si los pacientes deben ser administrados conjuntamente con un inhibidor fuerte de CYP3A4, según estudios farmacocinéticos, se debe considerar una reducción de la dosis de Торизел a 12.5 mg / semana. Se predice que esta dosis de Торизел ajustará el AUC al rango observado sin inhibidores. Sin embargo, no hay datos clínicos con este ajuste de dosis en pacientes que reciben inhibidores potentes de CYP3A4. Si se suspende el inhibidor fuerte, se debe permitir un período de lavado de aproximadamente 1 semana antes de que la dosis de Торизел se ajuste nuevamente a la dosis utilizada antes del inicio del inhibidor fuerte de CYP3A4.
Inductores CYP3A4 fuertes concomitantes
Se debe evitar el uso de inductores concomitantes fuertes de CYP3A4 (p. Ej. dexametasona, fenitoína, carbamazepina, rifampicina, rifabutina, rifampacina, fenobarbital). Si los pacientes deben ser administrados conjuntamente con un inductor fuerte de CYP3A4, según estudios farmacocinéticos, se debe considerar un aumento de la dosis de Торизел de 25 mg / semana a 50 mg / semana. Se predice que esta dosis de Торизел ajustará el AUC al rango observado sin inductores. Sin embargo, no hay datos clínicos con este ajuste de dosis en pacientes que reciben inductores potentes de CYP3A4. Si se suspende el inductor fuerte, la dosis de temsirolimus debe devolverse a la dosis utilizada antes del inicio del inductor fuerte de CYP3A4.
Instrucciones para la preparación
El Торизел debe almacenarse bajo refrigeración a 2 ° –8 ° C (36 ° –46 ° F) y protegerse de la luz. Durante el manejo y la preparación de las mezclas, Торизел debe protegerse de la luz excesiva de la habitación y la luz solar. Los productos farmacológicos parenterales deben inspeccionarse visualmente para detectar partículas y decoloración antes de la administración, siempre que la solución y el envase lo permitan.
Para minimizar la exposición del paciente al plastificante DEHP (di-2-etilhexil ftalato), que puede lixiviarse de bolsas o juegos de infusión de PVC, la dilución final de Торизел para perfusión debe almacenarse en botellas (vidrio, polipropileno) o plástico bolsas (polipropileno, poliolefina) y administradas a través de administración revestida de polietileno.
La inyección de Торизел 25 mg / ml debe diluirse con el diluyente suministrado antes de una dilución adicional en la inyección de cloruro de sodio al 0.9%, USP .
Tenga en cuenta que tanto la inyección de Торизел como los viales diluyentes contienen un sobrellenado para garantizar que se pueda retirar el volumen recomendado.
Siga este proceso de dilución en dos pasos de manera aséptica.
Paso 1 :
DILUCIÓN DE INYECCIÓN DE TORNEO 25 MG / ML CON DILUYENTE SUMINISTRADO
- Cada vial de Торизел (temsirolimus) debe mezclarse primero con 1,8 ml del diluyente cerrado. La solución resultante contiene 30 mg / 3 ml (10 mg / ml).
- Mezcle bien por inversión del vial. Permita que disminuya el tiempo suficiente para que las burbujas de aire disminuyan. La solución debe ser transparente a ligeramente turbia, incolora a amarilla clara, esencialmente libre de partículas visuales.
La mezcla concentrado-diluyente es estable por debajo de 25ºC por hasta 24 horas.
Paso 2 :
DILUCIÓN DE MEZCLA DE DILUYENTE CONCENTRADO CON 0.9% DE INYECCIÓN DE CLORURO DE SODIO, USP
- Extraiga con precisión la cantidad requerida de mezcla concentrado-diluyente que contiene temsirolimus 10 mg / ml como se prepara en el Paso 1 del vial (p. Ej., 2.5 ml para una dosis de temsirolimus de 25 mg) y diluir adicionalmente en una bolsa de infusión que contenga 250 ml de inyección de cloruro de sodio al 0.9%, USP .
- Mezcle por inversión de la bolsa o botella, evitando sacudidas excesivas, ya que esto puede causar espuma.
La solución resultante debe inspeccionarse visualmente para detectar partículas y decoloración antes de la administración. La mezcla de Торизел en 0.9% de inyección de cloruro de sodio, USP debe protegerse de la luz excesiva de la habitación y la luz solar.
Administración
- La administración de la solución diluida final debe completarse dentro de las seis horas desde el momento en que Торизел se agrega por primera vez a 0.9% de inyección de cloruro de solución, USP .
- El telón se infunde durante un período de 30 a 60 minutos una vez por semana. El uso de una bomba de infusión es el método preferido de administración para garantizar la entrega precisa del producto.
- Los materiales de administración apropiados deben estar compuestos de vidrio, poliolefina o polietileno para evitar la pérdida excesiva de producto y la extracción de dietilhexilftalato (DEHP). Los materiales de administración deben consistir en tubos sin DEHP, sin cloruro de polivinilo (PVC) con el filtro apropiado. En el caso de que deba usarse un conjunto de administración de PVC, no debe contener DEHP. Se recomienda la administración de un filtro de polietersulfona en línea con un tamaño de poro de no más de 5 micras para evitar la posibilidad de infundir partículas de más de 5 micras. Si el conjunto de administración disponible no tiene un filtro en línea incorporado, se debe agregar un filtro de polietersulfona en el conjunto (es decir,., un filtro final) antes de que la mezcla llegue a la vena del paciente. Se pueden usar diferentes filtros finales, que varían en tamaño de poro de filtro desde 0.2 micras hasta 5 micras. No se recomienda el uso de un filtro en línea y final.
- El Торизел, cuando está diluido, contiene polisorbato 80, que se sabe que aumenta la tasa de extracción de DEHP del PVC. Esto debe considerarse durante la preparación y administración de Торизел, incluido el tiempo de almacenamiento transcurrido cuando está en contacto directo con el PVC después de la constitución.
Compatibilidades e incompatibilidades
La inyección no diluida de Торизел no debe agregarse directamente a soluciones de infusión acuosa. La adición directa de inyección de Торизел a soluciones acuosas dará como resultado la precipitación del fármaco. Combine siempre la inyección de Торизел con DILUENTE para Торизел antes de agregar a las soluciones de infusión. Se recomienda administrar Торизел en inyección de cloruro de sodio al 0.9% después de combinarlo con diluyente. No se ha evaluado la estabilidad de Торизел en otras soluciones de infusión. La adición de otros medicamentos o agentes nutricionales a las mezclas de Торизел en la inyección de cloruro de sodio al 0.9% no se ha evaluado y debe evitarse. El temsirolimus se degrada tanto por ácidos como por bases, y por lo tanto se deben evitar las combinaciones de temsirolimus con agentes capaces de modificar el pH de la solución.
Торизел está contraindicado en pacientes con bilirrubina> 1.5 × ULN .
WARNINGS
Included as part of the "PRECAUTIONS" Section
PRECAUTIONS
Hypersensitivity/Infusion Reactions
Hypersensitivity/infusion reactions, including but not limited to flushing, chest pain, dyspnea, hypotension, apnea, loss of consciousness, hypersensitivity and anaphylaxis, have been associated with the administration of temsirolimus. These reactions can occur very early in the first infusion, but may also occur with subsequent infusions. Patients should be monitored throughout the infusion and appropriate supportive care should be available. Temsirolimus infusion should be interrupted in all patients with severe infusion reactions and appropriate medical therapy administered.
Торизел should be used with caution in persons with known hypersensitivity to temsirolimus or its metabolites (including sirolimus), polysorbate 80, or to any other component (including the excipients) of Торизел.
An H1 antihistamine should be administered to patients before the start of the intravenous temsirolimus infusion. Торизел should be used with caution in patients with known hypersensitivity to an antihistamine, or patients who cannot receive an antihistamine for other medical reasons.
If a patient develops a hypersensitivity reaction during the Торизел infusion, the infusion should be stopped and the patient should be observed for at least 30 to 60 minutes (depending on the severity of the reaction). At the discretion of the physician, treatment may be resumed with the administration of an H1-receptor antagonist (such as diphenhydramine), if not previously administered , and/or an H2-receptor antagonist (such as intravenous famotidine 20 mg or intravenous ranitidine 50 mg) approximately 30 minutes before restarting the Торизел infusion. The infusion may then be resumed at a slower rate (up to 60 minutes).
A benefit-risk assessment should be done prior to the continuation of temsirolimus therapy in patients with severe or life-threatening reactions.
Hepatic Impairment
The safety and pharmacokinetics of Торизел were evaluated in a dose escalation phase 1 study in 110 patients with normal or varying degrees of hepatic impairment. Patients with baseline bilirubin >1.5×ULN experienced greater toxicity than patients with baseline bilirubin ≤1.5×ULN when treated with Торизел. The overall frequency of ≥ grade 3 adverse reactions and deaths, including deaths due to progressive disease, were greater in patients with baseline bilirubin >1.5×ULN due to increased risk of death.
Use caution when treating patients with mild hepatic impairment. Concentrations of temsirolimus and its metabolite sirolimus were increased in patients with elevated AST or bilirubin levels. If Торизел must be given in patients with mild hepatic impairment (bilirubin >1 – 1.5×ULN or AST >ULN but bilirubin ≤ULN), reduce the dose of Торизел to 15 mg/week.
Hyperglycemia/Glucose Intolerance
The use of Торизел is likely to result in increases in serum glucose. In the phase 3 trial, 89% of patients receiving Торизел had at least one elevated serum glucose while on treatment, and 26% of patients reported hyperglycemia as an adverse event. This may result in the need for an increase in the dose of, or initiation of, insulin and/or oral hypoglycemic agent therapy. Serum glucose should be tested before and during treatment with Торизел. Patients should be advised to report excessive thirst or any increase in the volume or frequency of urination.
Infections
The use of Торизел may result in immunosuppression. Patients should be carefully observed for the occurrence of infections, including opportunistic infections.
Pneumocystis jiroveci pneumonia (PJP), including fatalities, has been reported in patients who received temsirolimus. This may be associated with concomitant use of corticosteroids or other immunosuppressive agents. Prophylaxis of PJP should be considered when concomitant use of corticosteroids or other immunosuppressive agents are required.
Interstitial Lung Disease
Cases of interstitial lung disease, some resulting in death, occurred in patients who received Торизел. Some patients were asymptomatic, or had minimal symptoms, with infiltrates detected on computed tomography scan or chest radiograph. Others presented with symptoms such as dyspnea, cough, hypoxia, and fever. Some patients required discontinuation of Торизел and/or treatment with corticosteroids and/or antibiotics, while some patients continued treatment without additional intervention. Patients should be advised to report promptly any new or worsening respiratory symptoms.
It is recommended that patients undergo baseline radiographic assessment by lung computed tomography scan or chest radiograph prior to the initiation of Торизел therapy. Follow such assessments periodically, even in the absence of clinical respiratory symptoms.
It is recommended that patients be followed closely for occurrence of clinical respiratory symptoms. If clinically significant respiratory symptoms develop, consider withholding Торизел administration until after recovery of symptoms and improvement of radiographic findings related to pneumonitis. Empiric treatment with corticosteroids and/or antibiotics may be considered. Opportunistic infections such as PJP should be considered in the differential diagnosis. For patients who require use of corticosteroids, prophylaxis of PJP may be considered.
Hyperlipemia
The use of Торизел is likely to result in increases in serum triglycerides and cholesterol. In the phase 3 trial, 87% of patients receiving Торизел had at least one elevated serum cholesterol value and 83% had at least one elevated serum triglyceride value. This may require initiation, or increase in the dose, of lipid-lowering agents. Serum cholesterol and triglycerides should be tested before and during treatment with Торизел.
Bowel Perforation
Cases of fatal bowel perforation occurred in patients who received Торизел. These patients presented with fever, abdominal pain, metabolic acidosis, bloody stools, diarrhea, and/or acute abdomen. Patients should be advised to report promptly any new or worsening abdominal pain or blood in their stools.
Renal Failure
Cases of rapidly progressive and sometimes fatal acute renal failure not clearly related to disease progression occurred in patients who received Торизел. Some of these cases were not responsive to dialysis.
Wound Healing Complications
Use of Торизел has been associated with abnormal wound healing. Therefore, caution should be exercised with the use of Торизел in the perioperative period.
Intracerebral Hemorrhage
Patients with central nervous system tumors (primary CNS tumor or metastases) and/or receiving anticoagulation therapy may be at an increased risk of developing intracerebral bleeding (including fatal outcomes) while receiving Торизел.
Co-Administration With Inducers Or Inhibitors Of CYP3A Metabolism
Agents Inducing CYP3A Metabolism:
Strong inducers of CYP3A4/5 such as dexamethasone, carbamazepine, phenytoin, phenobarbital, rifampin, rifabutin, and rifampacin may decrease exposure of the active metabolite, sirolimus. If alternative treatment cannot be administered, a dose adjustment should be considered. St. John’s Wort may decrease Торизел plasma concentrations unpredictably. Patients receiving Торизел should not take St. John’s Wort concomitantly.
Agents Inhibiting CYP3A Metabolism:
Strong CYP3A4 inhibitors such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin may increase blood concentrations of the active metabolite sirolimus. If alternative treatments cannot be administered, a dose adjustment should be considered.
Concomitant Use Of Торизел With Sunitinib
The combination of Торизел and sunitinib resulted in dose-limiting toxicity. Dose-limiting toxicities (Grade 3/4 erythematous maculopapular rash, and gout/cellulitis requiring hospitalization) were observed in two out of three patients treated in the first cohort of a phase 1 study at doses of Торизел 15 mg IV per week and sunitinib 25 mg oral per day (Days 1-28 followed by a 2-week rest).
Vaccinations
The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with Торизел. Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.
Use In Pregnancy
There are no adequate and well-controlled studies of Торизел in pregnant women. However, based on its mechanism of action, Торизел may cause fetal harm when administered to a pregnant woman. Temsirolimus administered daily as an oral formulation caused embryo-fetal and intrauterine toxicities in rats and rabbits at human sub-therapeutic exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant throughout treatment and for 3 months after Торизел therapy has stopped.
Men should be counseled regarding the effects of Торизел on the fetus and sperm prior to starting treatment. Men with partners of childbearing potential should use reliable contraception throughout treatment and are recommended to continue this for 3 months after the last dose of Торизел.
Elderly Patients
Based on the results of a phase 3 study, elderly patients may be more likely to experience certain adverse reactions including diarrhea, edema, and pneumonia.
Monitoring Laboratory Tests
In the randomized, phase 3 trial, complete blood counts (CBCs) were checked weekly, and chemistry panels were checked every two weeks. Laboratory monitoring for patients receiving Торизел may need to be performed more or less frequently at the physician’s discretion.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Carcinogenicity studies have not been conducted with temsirolimus. However, sirolimus, the major metabolite of temsirolimus in humans, was carcinogenic in mice and rats. The following effects were reported in mice and/or rats in the carcinogenicity studies conducted with sirolimus: lymphoma, hepatocellular adenoma and carcinoma, and testicular adenoma.
Temsirolimus was not genotoxic in a battery of in vitro (bacterial reverse mutation in Salmonella typhimurium and Escherichia coli, forward mutation in mouse lymphoma cells, and chromosome aberrations in Chinese hamster ovary cells) and in vivo (mouse micronucleus) assays.
In male rats, the following fertility effects were observed: decreased number of pregnancies, decreased sperm concentration and motility, decreased reproductive organ weights, and testicular tubular degeneration. These effects were observed at oral temsirolimus doses ≥3 mg/m2/day (approximately 0.2-fold the human recommended intravenous dose). Fertility was absent at 30 mg/m2/day.
In female rats, an increased incidence of pre-and post-implantation losses occurred at oral doses ≥4.2 mg/m2/day (approximately 0.3-fold the human recommended intravenous dose), resulting in decreased numbers of live fetuses.
Use In Specific Populations
Pregnancy
Pregnancy Category D.
Women of childbearing potential should be advised to avoid becoming pregnant throughout treatment and for 3 months after Торизел therapy has stopped. Temsirolimus can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
Temsirolimus administered daily as an oral formulation caused embryo-fetal and intrauterine toxicities in rats and rabbits at human sub-therapeutic exposures. Embryo-fetal adverse effects in rats consisted of reduced fetal weight and reduced ossifications, and in rabbits included reduced fetal weight, omphalocele, bifurcated sternabrae, notched ribs, and incomplete ossifications.
In rats, the intrauterine and embryo-fetal adverse effects were observed at the oral dose of 2.7 mg/m2/day (approximately 0.04-fold the AUC in patients with cancer at the human recommended dose). In rabbits, the intrauterine and embryo-fetal adverse effects were observed at the oral dose of ≥7.2 mg/m2/day (approximately 0.12-fold the AUC in patients with cancer at the recommended human dose).
Nursing Mothers
It is not known whether Торизел is excreted into human milk, and due to the potential for tumorigenicity shown for sirolimus (active metabolite of Торизел) in animal studies, a decision should be made whether to discontinue nursing or discontinue Торизел, taking into account the importance of the drug to the mother.
Pediatric Use
Limited data are available on the use of temsirolimus in pediatric patients. The effectiveness of temsirolimus in pediatric patients with advanced recurrent/refractory solid tumors has not been established.
Торизел was studied in 71 patients (59 patients ages 1 to 17 years and 12 patients ages 18 to 21 years) with relapsed/refractory solid tumors in a phase 1-2 safety and exploratory pharmacodynamic study.
In phase 1, 19 pediatric patients with advanced recurrent/refractory solid tumors received Торизел at doses ranging from 10 mg/m2 to 150 mg/m2 as a 60-minute intravenous infusion once weekly in three-week cycles.
In phase 2, 52 pediatric patients with recurrent/relapsed neuroblastoma, rhabdomyosarcoma, or high grade glioma received Торизел at a weekly dose of 75 mg/m2. One of 19 patients with neuroblastoma achieved a partial response. There were no objective responses in pediatric patients with recurrent/relapsed rhabdomyosarcoma or high grade glioma.
Adverse reactions associated with Торизел were similar to those observed in adults. The most common adverse reactions (≥20%) in pediatric patients receiving the 75 mg/m2 dose included thrombocytopenia, infections, asthenia/fatigue, fever, pain, leukopenia, rash, anemia, hyperlipidemia, increased cough, stomatitis, anorexia, increased plasma levels of alanine aminotransferase and aspartate aminotransferase, hypercholesterolemia, hyperglycemia, abdominal pain, headache, arthralgia, upper respiratory infection, nausea and vomiting, neutropenia, hypokalemia, and hypophosphatemia.
Pharmacokinetics
In phase 1 of the above mentioned pediatric trial, the single dose and multiple dose total systemic exposure (AUC) of temsirolimus and sirolimus were less than dose-proportional over the dose range of 10 to 150 mg/m2.
In the phase 2 portion, the multiple dose (Day 1, Cycle 2) pharmacokinetics of Торизел 75 mg/m2 were characterized in an additional 35 patients ages 28 days to 21 years (median age of 8 years). The geometric mean body surface adjusted clearance of temsirolimus and sirolimus was 9.45 L/h/m2 and 9.26 L/h/m2, respectively. The mean elimination half-life of temsirolimus and sirolimus was 31 hours and 44 hours, respectively.
The exposure (AUCss) to temsirolimus and sirolimus was approximately 6-fold and 2-fold higher, respectively than the exposure in adult patients receiving a 25 mg intravenous infusion.
Geriatric Use
Clinical studies of Торизел did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. Based on the results of a phase 3 study, elderly patients may be more likely to experience certain adverse reactions including diarrhea, edema, and pneumonia.
Renal Impairment
No clinical studies were conducted with Торизел in patients with decreased renal function. Less than 5% of total radioactivity was excreted in the urine following a 25 mg intravenous dose of [14C]-labeled temsirolimus in healthy subjects. Renal impairment is not expected to markedly influence drug exposure, and no dosage adjustment of Торизел is recommended in patients with renal impairment.
Торизел has not been studied in patients undergoing hemodialysis.
Hepatic Impairment
Торизел was evaluated in a dose escalation phase 1 study in 110 patients with normal or varying degrees of hepatic impairment as defined by AST and bilirubin levels and patients with liver transplant (Table 3). Patients with moderate and severe hepatic impairment had increased rates of adverse reactions and deaths, including deaths due to progressive disease, during the study (Table 3).
Table 3 – Adverse Reactions in Patients with Advanced Malignancies Plus Normal or Impaired Hepatic Function
Hepatic Function* | Торизел Dose Range | Adverse Reactions Grade ≥ 3** n (%) | Death*** n (%) |
Normal (n = 25) | 25 – 175 | 20 (80.0) | 2 (8.0) |
Mild (n = 39) | 10 – 25 | 32 (82.1) | 5 (12.8) |
Moderate (n = 20) | 10 – 25 | 19 (95.0) | 8 (40.0) |
Severe (n = 24) | 7.5 – 15 | 23 (95.8) | 13 (54.2) |
Liver Transplant (n = 2) | 10 | 1 (50.0) | 0 (0) |
*Hepatic Function Groups: normal = bilirubin and AST ≤ULN; mild = bilirubin >1 – 1.5×ULN or AST >ULN but bilirubin ≤ULN; moderate = bilirubin >1.5 – 3×ULN; severe = bilirubin >3×ULN; liver transplant = any bilirubin and AST. **Common Terminology Criteria for Adverse Events, version 3.0, including all causality. ***Includes deaths due to progressive disease and adverse reactions. |
Торизел is contraindicated in patients with bilirubin >1.5×ULN. Use caution when treating patients with mild hepatic impairment. If Торизел must be given in patients with mild hepatic impairment (bilirubin >1-1.5×ULN or AST >ULN but bilirubin ≤ULN), reduce the dose of Торизел to 15 mg/week. Because there is a need for dosage adjustment based upon hepatic function, assessment of AST and bilirubin levels is recommended before initiation of Торизел and periodically thereafter.
The following serious adverse reactions have been associated with Торизел in clinical trials and are discussed in greater detail in other sections of the label.
- Hypersensitivity/Infusion Reactions
- Hepatic Impairment
- Hyperglycemia/Glucose Intolerance
- Infections
- Interstitial Lung Disease
- Hyperlipemia
- Bowel Perforation
- Renal Failure
- Wound Healing Complications
- Intracerebral Hemorrhage
The most common (≥30%) adverse reactions observed with Торизел are rash, asthenia, mucositis, nausea, edema, and anorexia. The most common (≥30%) laboratory abnormalities observed with Торизел are anemia, hyperglycemia, hyperlipemia, hypertriglyceridemia, lymphopenia, elevated alkaline phosphatase, elevated serum creatinine, hypophosphatemia, thrombocytopenia, elevated AST, and leukopenia.
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.
In the phase 3 randomized, open-label study of interferon alfa (IFN-α) alone, Торизел alone, and Торизел and IFN-α, a total of 616 patients were treated. Two hundred patients received IFN-α weekly, 208 received Торизел 25 mg weekly, and 208 patients received a combination of Торизел and IFN-α weekly.
Treatment with the combination of Торизел 15 mg and IFN-α was associated with an increased incidence of multiple adverse reactions and did not result in a significant increase in overall survival when compared with IFN-α alone.
Table 1 shows the percentage of patients experiencing treatment emergent adverse reactions. Reactions reported in at least 10% of patients who received Торизел 25 mg alone or IFN-α alone are listed. Table 2 shows the percentage of patients experiencing selected laboratory abnormalities. Data for the same adverse reactions and laboratory abnormalities in the IFN-α alone arm are shown for comparison:
Table 1 – Adverse Reactions Reported in at Least 10% of Patients Who Received 25 mg IV Торизел or IFN-α in the Randomized Trial
Adverse Reaction | Торизел 25 mg n = 208 | IFN-α n = 200 | ||
All Grades* n (%) | Grades 3&4* n (%) | All Grades* n (%) | Grades 3&4* n (%) | |
General disorders | ||||
Asthenia | 106 (51) | 23 (11) | 127 (64) | 52 (26) |
Edemaa | 73 (35) | 7 (3) | 21 (11) | 1 (1) |
Pain | 59 (28) | 10 (5) | 31 (16) | 4 (2) |
Pyrexia | 50 (24) | 1 (1) | 99 (50) | 7 (4) |
Weight Loss | 39 (19) | 3 (1) | 50 (25) | 4 (2) |
Headache | 31 (15) | 1 (1) | 30 (15) | 0 (0) |
Chest Pain | 34 (16) | 2 (1) | 18 (9) | 2 (1) |
Chills | 17 (8) | 1 (1) | 59 (30) | 3 (2) |
Gastrointestinal disorders | ||||
Mucositisb | 86 (41) | 6 (3) | 19 (10) | 0 (0) |
Anorexia | 66 (32) | 6 (3) | 87 (44) | 8 (4) |
Nausea | 77 (37) | 5 (2) | 82 (41) | 9 (5) |
Diarrhea | 56 (27) | 3 (1) | 40 (20) | 4 (2) |
Abdominal Pain | 44 (21) | 9 (4) | 34 (17) | 3 (2) |
Constipation | 42 (20) | 0 (0) | 36 (18) | 1 (1) |
Vomiting | 40 (19) | 4 (2) | 57 (29) | 5 (3) |
Infections | ||||
Infectionsc | 42 (20) | 6 (3) | 19 (10) | 4 (2) |
Urinary tract infectiond | 31 (15) | 3 (1) | 24 (12) | 3 (2) |
Pharyngitis | 25 (12) | 0 (0) | 3 (2) | 0 (0) |
Rhinitis | 20 (10) | 0 (0) | 4 (2) | 0 (0) |
Musculoskeletal and connective tissue disorders | ||||
Back Pain | 41 (20) | 6 (3) | 28 (14) | 7 (4) |
Arthralgia | 37 (18) | 2 (1) | 29 (15) | 2 (1) |
Myalgia | 16 (8) | 1 (1) | 29 (15) | 2 (1) |
Respiratory, thoracic and mediastinal disorders | ||||
Dyspnea | 58 (28) | 18 (9) | 48 (24) | 11 (6) |
Cough | 53 (26) | 2 (1) | 29 (15) | 0 (0) |
Epistaxis | 25 (12) | 0 (0) | 7 (4) | 0 (0) |
Skin and subcutaneous tissue disorders | ||||
Rashe | 97 (47) | 10 (5) | 14 (7) | 0 (0) |
Pruritus | 40 (19) | 1 (1) | 16 (8) | 0 (0) |
Nail Disorder | 28 (14) | 0 (0) | 1 (1) | 0 (0) |
Dry Skin | 22 (11) | 1 (1) | 14 (7) | 0 (0) |
Acne | 21 (10) | 0 (0) | 2 (1) | 0 (0) |
Nervous system disorders | ||||
Dysgeusiaf | 41 (20) | 0 (0) | 17 (9) | 0 (0) |
Insomnia | 24 (12) | 1 (1) | 30 (15) | 0 (0) |
Depression | 9 (4) | 0 (0) | 27 (14) | 4 (2) |
* Common Toxicity Criteria for Adverse Events (CTCAE), Version 3.0. a Includes edema, facial edema, and peripheral edema b Includes aphthous stomatitis, glossitis, mouth ulceration, mucositis, and stomatitis c Includes infections not otherwise specified (NOS) and the following infections that occurred infrequently as distinct entities: abscess, bronchitis, cellulitis, herpes simplex, and herpes zosterd d Includes cystitis, dysuria, hematuria, urinary frequency, and urinary tract infection e Includes eczema, exfoliative dermatitis, maculopapular rash, pruritic rash, pustular rash, rash (NOS), and vesiculobullous rash f Includes taste loss and taste perversion |
The following selected adverse reactions were reported less frequently (<10%).
Gastrointestinal Disorders – Gastrointestinal hemorrhage (1%), rectal hemorrhage (1%).
Eye Disorders – Conjunctivitis (including lacrimation disorder) (8%).
Immune System – Angioneurotic edema-type reactions (including delayed reactions occurring two months following initiation of therapy) have been observed in some patients who received Торизел and ACE inhibitors concomitantly.
Infections – Pneumonia (8%), upper respiratory tract infection (7%), wound infection/postoperative wound infection (1%), sepsis (1%).
General Disorders and Administration Site Conditions -Diabetes mellitus (5%).
Respiratory, Thoracic and Mediastinal Disorders – Pleural effusion (4%).
Vascular – Hypertension (7%), venous thromboembolism (including deep vein thrombosis and pulmonary embolus [including fatal outcomes]) (2%), thrombophlebitis (1%), pericardial effusion (1%).
Nervous System Disorders – Convulsion (1%).
Table 2 – Incidence of Selected Laboratory Abnormalities in Patients Who Received 25 mg IV Торизел or IFN-α in the Randomized Trial
Laboratory Abnormality | Торизел 25 mg n = 208 | IFN-α n = 200 | ||
All Grades* n (%) | Grades 3&4* n (%) | All Grades* n (%) | Grades 3&4* n (%) | |
Any | 208 (100) | 162 (78) | 195 (98) | 144 (72) |
Hematology | ||||
Hemoglobin Decreased | 195 (94) | 41 (20) | 180 (90) | 43 (22) |
Lymphocytes Decreased** | 110 (53) | 33 (16) | 106 (53) | 48 (24) |
Neutrophils Decreased** | 39 (19) | 10 (5) | 58 (29) | 19 (10) |
Platelets Decreased | 84 (40) | 3 (1) | 51 (26) | 0 (0) |
Leukocytes Decreased | 67 (32) | 1 (1) | 93 (47) | 11 (6) |
Chemistry | ||||
Alkaline Phosphatase Increased | 141 (68) | 7 (3) | 111 (56) | 13 (7) |
AST Increased | 79 (38) | 5 (2) | 103 (52) | 14 (7) |
Creatinine Increased | 119 (57) | 7 (3) | 97 (49) | 2 (1) |
Glucose Increased | 186 (89) | 33 (16) | 128 (64) | 6 (3) |
Phosphorus Decreased | 102 (49) | 38 (18) | 61 (31) | 17 (9) |
Total Bilirubin Increased | 16 (8) | 2 (1) | 25 (13) | 4 (2) |
Total Cholesterol Increased | 181 (87) | 5 (2) | 95 (48) | 2 (1) |
Triglycerides Increased | 173 (83) | 92 (44) | 144 (72) | 69 (35) |
Potassium Decreased | 43 (21) | 11 (5) | 15 (8) | 0 (0) |
*NCI CTC version 3.0 **Grade 1 toxicity may be under-reported for lymphocytes and neutrophils |
Post-Marketing And Other Clinical Experience
The following adverse reactions have been identified during post approval use of Торизел. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to readily estimate their frequency or establish a causal relationship to drug exposure.
The following adverse reactions have been observed in patients receiving temsirolimus: rhabdomyolysis, Stevens-Johnson Syndrome, complex regional pain syndrome (reflex sympathetic dystrophy), pancreatitis, cholecystitis, and cholelithiasis.
There are also post-marketing reports of temsirolimus extravasations resulting in swelling, pain, warmth, and erythema.
There is no specific treatment for Торизел intravenous overdose. Торизел has been administered to patients with cancer in phase 1 and 2 trials with repeated intravenous doses as high as 220 mg/m2. The risk of several serious adverse events, including thrombosis, bowel perforation, interstitial lung disease (ILD), seizure, and psychosis, is increased with doses of Торизел greater than 25 mg.
Efectos sobre el electrocardiograma
No se observaron cambios QT clínicamente relevantes a la dosis recomendada para Торизел. En un estudio cruzado aleatorizado, de una sola persiana, 58 sujetos sanos recibieron Торизел 25 mg, placebo y una dosis oral única de moxifloxacina 400 mg. No se estudió una dosis supraterapéutica de Торизел en este ensayo QT aleatorizado. La mayor diferencia entre el IC del 90% del límite superior del límite superior para la diferencia media entre Торизел y el intervalo QT corregido con placebo fue inferior a 10 ms. En un ensayo diferente en 69 pacientes con neoplasia hematológica, se estudiaron dosis de Торизел de hasta 175 mg. Ningún paciente con un QTcF normal al inicio del estudio tuvo un aumento en QTcF> 60 ms. Además, no hubo pacientes con un intervalo QTcF mayor a 500 ms.
Absorción
Después de la administración de una dosis única de 25 mg de Торизел en pacientes con cáncer, la Cmáx de temsirolimus media en sangre completa fue de 585 ng / ml (coeficiente de variación, CV = 14%) y el AUC medio en sangre fue de 1627 ng • h / ml ( CV = 26%). Por lo general, la Cmáx ocurrió al final de la infusión. En el rango de dosis de 1 mg a 25 mg, la exposición a temsirolimus aumentó de manera menos que la dosis proporcional, mientras que la exposición a sirolimus aumentó proporcionalmente con la dosis. Después de una dosis intravenosa única de 25 mg en pacientes con cáncer, el AUC de sirolimus fue 2.7 veces mayor que el AUC de temsirolimus, debido principalmente a la vida media más larga de sirolimus.
Distribución
Después de una dosis intravenosa única de 25 mg, el volumen medio de distribución de temsirolimus en estado estacionario en sangre completa de pacientes con cáncer fue de 172 litros. Tanto temsirolimus como sirolimus se dividen ampliamente en elementos sanguíneos formados.
Metabolismo
El citocromo P450 3A4 es la isoenzima principal responsable de la formación de cinco metabolitos de temsirolimus. Sirolimus, un metabolito activo de temsirolimus, es el metabolito principal en humanos después del tratamiento intravenoso. El resto de los metabolitos representan menos del 10% de la radiactividad en el plasma. En microsomas hepáticos humanos, temsirolimus fue un inhibidor de CYP2D6 y 3A4. Sin embargo, no se observó ningún efecto in vivo cuando se administró temsirolimus con desipramina (un sustrato CYP2D6), y no se anticipa ningún efecto con sustratos del metabolismo de CYP3A4.
Eliminación
La eliminación es principalmente a través de las heces. Después de una dosis intravenosa única de [14C] -temsirolimus, aproximadamente el 82% de la radiactividad total se eliminó en 14 días, con el 4,6% y el 78% de la radiactividad administrada recuperada en la orina y las heces, respectivamente. Después de una dosis única de 25 mg de Торизел en pacientes con cáncer, el aclaramiento sistémico medio de temsirolimus (CV) fue de 16.2 (22%) L / h. Temsirolimus exhibe una disminución bi-exponencial en las concentraciones de sangre completa y la vida media de temsirolimus y sirolimus fue de 17.3 horas y 54.6 horas, respectivamente.
Sistemas de transporte de drogas -P-glicoproteína
Temsirolimus es un sustrato de la glucoproteína P transportadora de eflujo (Pgp) in vitro Si Торизел se administra con medicamentos que inhiben la Pgp, es probable que aumenten las concentraciones de temsirolimus y se debe tener precaución.
In vitro, temsirolimus inhibió la Pgp humana (IC50 valor de 2 μM). Si Торизел se administra con medicamentos que son sustratos de Pgp, es probable que aumenten las concentraciones del fármaco sustrato y se debe tener precaución.
Efectos de la edad y el género
En los análisis de datos basados en farmacocinética de la población, no se observó relación entre la exposición al fármaco y la edad o el sexo del paciente.