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Revisión médica por Fedorchenko Olga Valeryevna Última actualización de farmacia el 31.03.2022
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Leucemia linfocítica crónica (CLL)
La inyección de Treakisym ™ (clorhidrato de bendamustina) está indicada para el tratamiento de pacientes con leucemia linfocítica crónica. No se ha establecido la eficacia en relación con las terapias de primera línea que no sean clorambucilo.
Linfoma no Hodgkin (NHL)
La inyección de treakisym (clorhidrato de bendamustina) está indicada para el tratamiento de pacientes con linfoma no Hodgkin de células B indolente que ha progresado durante o dentro de los seis meses posteriores al tratamiento con rituximab o un régimen que contiene rituximab.
Instrucciones de dosificación para CLL
Dosis recomendada
La dosis recomendada es de 100 mg / m2 administrado por vía intravenosa durante 10 minutos los días 1 y 2 de un ciclo de 28 días, hasta 6 ciclos.
Retrasos de dosis, modificaciones de dosis y reiniciación de terapia para CLL
La administración de inyección de treakisym (clorhidrato de bendamustina) debe retrasarse en caso de toxicidad hematológica de grado 4 o clínicamente significativa mayor o igual a la toxicidad no hematológica de grado 2. Una vez que la toxicidad no hematológica se ha recuperado a menos o igual que el Grado 1 y / o los recuentos sanguíneos han mejorado [Conteo absoluto de neutrófilos (ANC) mayor o igual a 1 x 109 / L, plaquetas mayores o iguales a 75 x 109 / L], la inyección de treakisym (clorhidrato de bendamustina) puede reiniciarse a discreción del médico tratante. Además, la reducción de la dosis puede estar justificada.
Modificaciones de dosis por toxicidad hematológica: para toxicidad de grado 3 o mayor, reduzca la dosis a 50 mg / m2 en los días 1 y 2 de cada ciclo; Si la toxicidad de grado 3 o mayor se repite, reduzca la dosis a 25 mg / m2 en los días 1 y 2 de cada ciclo.
Modificaciones de dosis para toxicidad no hematológica: para toxicidad clínicamente significativa de Grado 3 o mayor, reduzca la dosis a 50 mg / m2 en los días 1 y 2 de cada ciclo.
La reescalada de dosis en ciclos posteriores puede considerarse a discreción del médico tratante.
Instrucciones de dosificación para NHL
Dosis recomendada
La dosis recomendada es de 120 mg / m2 administrado por vía intravenosa durante 10 minutos los días 1 y 2 de un ciclo de 21 días, hasta 8 ciclos.
Retrasos de dosis, modificaciones de dosis y reiniciación de terapia para NHL
La administración de inyección de treakisym (clorhidrato de bendamustina) debe retrasarse en caso de toxicidad hematológica de grado 4 o clínicamente significativa mayor o igual a la toxicidad no hematológica de grado 2. Una vez que la toxicidad no hematológica se ha recuperado a menos o igual que el Grado 1 y / o los recuentos sanguíneos han mejorado [Conteo absoluto de neutrófilos (ANC) mayor o igual a 1 x 109 / L, plaquetas mayores o iguales a 75 x 109 / L], la inyección de treakisym (clorhidrato de bendamustina) puede reiniciarse a discreción del médico tratante. Además, la reducción de la dosis puede estar justificada.
Modificaciones de dosis por toxicidad hematológica: para toxicidad de grado 4, reduzca la dosis a 90 mg / m2 en los días 1 y 2 de cada ciclo; Si la toxicidad de grado 4 se repite, reduzca la dosis a 60 mg / m2 en los días 1 y 2 de cada ciclo.
Modificaciones de dosis para toxicidad no hematológica: para toxicidad de grado 3 o mayor, reduzca la dosis a 90 mg / m2 en los días 1 y 2 de cada ciclo; Si la toxicidad de grado 3 o mayor se repite, reduzca la dosis a 60 mg / m2 en los días 1 y 2 de cada ciclo.
Preparación para la administración intravenosa
La inyección de treakisym (clorhidrato de bendamustina) es un fármaco citotóxico. Siga los procedimientos especiales de manipulación y eliminación aplicables.1
Treakisym está en un vial de dosis múltiples. A temperatura ambiente, Treakisym es una solución transparente e incolora a amarilla lista para diluir. Almacene Treakisym en las condiciones de almacenamiento refrigerado recomendadas (2-8 ° C o 36-46 ° F). Cuando se refrigera, el contenido puede congelarse parcialmente. Permita que el vial alcance la temperatura ambiente (15-30 ° C o 59-86 ° F) antes de usarlo. Si se observan partículas después de alcanzar la temperatura ambiente, no se debe usar el producto.
Infusión intravenosa
- Retire asépticamente el volumen necesario para la dosis requerida de los 25 mg / m2L solución según la Tabla A a continuación y transfiera inmediatamente la solución a una bolsa de infusión de 50 ml de uno de los siguientes diluyentes:
- 0.9% de inyección de cloruro de sodio, USP; o
- 2.5% Dextrosa / 0.45% Inyección de cloruro de sodio, USP; o
- 5% de inyección de dextrosa, USP .
La concentración final resultante de clorhidrato de bendamustina en la bolsa de infusión debe estar dentro de 1.85 mg / ml - 5.6 mg / ml. Después de la transferencia, mezcle bien el contenido de la bolsa de infusión. La mezcla debe ser una solución transparente e incolora a amarilla.
No se ha demostrado que otros diluyentes sean compatibles. La inyección de dextrosa al 5%, USP, ofrece un método de administración libre de sodio para pacientes con ciertas afecciones médicas que requieren una ingesta restringida de sodio.
Tabla A: Volumen (ml) de Treakisym requerido para dilución en 50 ml de solución salina al 0.9%, o 0.45% de solución salina / 2.5% dextrosa o 5% de dextrosa para una dosis dada (mg / m2 ) y área de superficie corporal (m2 )
Área de superficie corporal (m2 ) | Volumen de Treakisym para retirar (ml) | |||||
120 mg / m2 | 100 mg / m2 | 90 mg / m2 | 60 mg / m2 | 50 mg / m2 | 25 mg / m2 | |
1 | 4.8 | 4 | 3.6 | 2.4 | 2 | 1 |
1.1 | 5.3 | 4.4 | 4 | 2.6 | 2.2 | 1.1 |
1.2 | 5.8 | 4.8 | 4.3 | 2.9 | 2.4 | 1.2 |
1.3 | 6.2 | 5.2 | 5.2 | 3.1 | 2.6 | 1.3 |
1.4 | 6.7 | 5.6 | 5 | 3.4 | 2.8 | 1.4 |
1.5 | 7.2 | 6 | 5.4 | 3.6 | 3 | 1.5 |
1.6 | 7.7 | 6.4 | 5.8 | 3.8 | 3.2 | 1.6 |
1.7 | 8.2 | 6.8 | 6.1 | 4.1 | 3.4 | 1.7 |
1.8 | 8.6 | 7.2 | 6.5 | 4.3 | 3.6 | 1.8 |
1.9 | 9.1 | 7.6 | 6.8 | 4.6 | 3.8 | 1.9 |
2 | 9.6 | 8 | 7.2 | 4.8 | 4 | 2 |
2.1 | 10.1 | 8.4 | 7.6 | 5 | 4.2 | 2.1 |
2.2 | 10.6 | 8.8 | 7.9 | 5.3 | 4.4 | 2.2 |
2.3 | 11 | 9.2 | 8.3 | 5.5 | 4.6 | 2.3 |
2.4 | 11,5 | 9.6 | 8.6 | 5.8 | 4.8 | 2.4 |
2.5 | 12 | 10 | 9 | 6 | 5 | 2.5 |
2.6 | 12.5 | 10.4 | 9.4 | 6.2 | 5.2 | 2.6 |
2.7 | 13 | 10.8 | 9.7 | 6.5 | 5.4 | 2.7 |
2.8 | 13.4 | 11,2 | 10.1 | 6.7 | 5.6 | 2.8 |
2.9 | 13,9 | 11,6 | 10.4 | 10.4 | 5.8 | 2.9 |
3 | 14.4 | 12 | 10.8 | 7.2 | 6 | 3 |
Los productos farmacológicos parenterales deben inspeccionarse visualmente para detectar partículas y decoloración antes de la administración siempre que la solución y el contenedor lo permitan. Cualquier solución no utilizada debe desecharse de acuerdo con los procedimientos institucionales para los antineoplásicos.
Estabilidad de mezcla
La inyección de treakisym (clorhidrato de bendamustina) no contiene conservantes antimicrobianos. La mezcla debe prepararse lo más cerca posible del momento de la administración del paciente.
Si se diluye con inyección de cloruro de sodio al 0.9%, USP o inyección de cloruro de sodio al 2.5% / 0.45%, USP, la mezcla final es estable durante 24 horas cuando se almacena refrigerada (2-8 ° C o 36-46 ° F) o durante 6 horas cuando se almacena a temperatura ambiente (15-30 ° C o 6. La administración de la inyección diluida de Treakisym (clorhidrato de bendamustina) debe completarse dentro de este período de tiempo.
En el caso de que se utilice una inyección de dextrosa al 5%, se utiliza USP, la mezcla final es estable durante 24 horas cuando se almacena refrigerada (2-8 ° C o 36-46 ° F) o solo durante 3 horas cuando se almacena a temperatura ambiente (15- 30 ° C o 59-86 ° F) y luz de ambiente. La administración de Treakisym diluido debe completarse dentro de este período de tiempo.
Conserve el vial parcialmente utilizado en el paquete original para protegerlo de la luz y almacene refrigerado (2-8 ° C o 36-46 ° F) si se pretende retirar la dosis adicional del mismo vial.
Estabilidad de viales parcialmente usados (viales perforados con aguja)
Treakisym se suministra en un vial de dosis múltiples. Aunque no contiene ningún conservante antimicrobiano, el treakisimo es bacteriostático. Los viales parcialmente utilizados son estables hasta 28 días cuando se almacenan en su caja original bajo refrigeración (2-8 ° C o 36-46 ° F). No se recomienda cada vial para más de un total de seis (6) retiros de dosis.
Después del primer uso, el vial parcialmente usado debe almacenarse en el refrigerador en la caja original a 2 ° - 8 ° C o 36-46 ° F y luego desecharse después de 28 días.
La inyección de treakisym (clorhidrato de bendamustina) está contraindicada en pacientes con hipersensibilidad conocida (p. Ej., reacciones anafilácticas y anafilactoides) a bendamustina, polietilenglicol 400, propilenglicol o monotioglicerol.
WARNINGS
Included as part of the "PRECAUTIONS" Section
PRECAUTIONS
Myelosuppression
Bendamustine hydrochloride caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies (see Table 4). Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV).
Treakisym (bendamustine hydrochloride) injection causes myelosuppression. Monitor complete blood counts, including leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs occurred predominantly in the third week of therapy. Myelosuppression may require dose delays and/or subsequent dose reductions if recovery to the recommended values has not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥1 x 109 /L and the platelet count should be ≥ 75 x 109 /L.
Infections
Infection, including pneumonia, sepsis, septic shock, hepatitis and death has occurred in adult and pediatric patients in clinical trials and in postmarketing reports for bendamustine hydrochloride. Patients with myelosuppression following treatment with bendamustine hydrochloride are more susceptible to infections. Advise patients with myelosuppression following Treakisym (bendamustine hydrochloride) injection treatment to contact a physician immediately if they have symptoms or signs of infection.
Patients treated with bendamustine hydrochloride are at risk for reactivation of infections including (but not limited to) hepatitis B, cytomegalovirus, Mycobacterium tuberculosis, and herpes zoster. Patients should undergo appropriate measures (including clinical and laboratory monitoring, prophylaxis, and treatment) for infection and infection reactivation prior to administration.
Anaphylaxis And Infusion Reactions
Infusion reactions to bendamustine hydrochloride have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances, severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experienced Grade 3 or worse allergic-type reactions were not typically rechallenged. Consider measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions. Discontinue Treakisym (bendamustine hydrochloride) injection for patients with Grade 4 infusion reactions. Consider discontinuation for Grade 3 infusion reactions as clinically appropriate considering individual benefits, risks, and supportive care.
Tumor Lysis Syndrome
Tumor lysis syndrome associated with bendamustine hydrochloride has occurred in patients in clinical trials and in postmarketing reports. The onset tends to be within the first treatment cycle of bendamustine hydrochloride and, without intervention, may lead to acute renal failure and death. Preventive measures include vigorous hydration and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of bendamustine hydrochloride therapy. However, there may be an increased risk of severe skin toxicity when bendamustine hydrochloride and allopurinol are administered concomitantly.
Skin Reactions
Fatal and serious skin reactions have been reported with bendamustine hydrochloride injection treatment in clinical trials and postmarketing safety reports, including toxic skin reactions [Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS)], bullous exanthema, and rash. Events occurred when bendamustine hydrochloride injection was given as a single agent and in combination with other anticancer agents or allopurinol.
Where skin reactions occur, they may be progressive and increase in severity with further treatment. Monitor patients with skin reactions closely. If skin reactions are severe or progressive, withhold or discontinue Treakisym (bendamustine hydrochloride) injection.
Hepatotoxicity
Fatal and serious cases of liver injury have been reported with bendamustine hydrochloride injection. Combination therapy, progressive disease or reactivation of hepatitis B were confounding factors in some patients. Most cases were reported within the first three months of starting therapy. Monitor liver chemistry tests prior to and during bendamustine therapy.
Other Malignancies
There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with bendamustine hydrochloride, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with Treakisym (bendamustine hydrochloride) injection therapy has not been determined.
Extravasation Injury
Bendamustine hydrochloride extravasations have been reported in postmarketing resulting in hospitalizations from erythema, marked swelling, and pain. Assure good venous access prior to starting drug infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of Treakisym (bendamustine hydrochloride) injection.
Embryo-Fetal Toxicity
Bendamustine hydrochloride can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Bendamustine was carcinogenic in mice. After intraperitoneal injections at 37.5 mg/m2 /day (12.5 mg/kg/day, the lowest dose tested) and 75 mg/m2 /day (25 mg/kg/day) for four days, peritoneal sarcomas in female AB/jena mice were produced. Oral administration at 187.5 mg/m2 /day (62.5 mg/kg/day, the only dose tested) for four days induced mammary carcinomas and pulmonary adenomas.
Bendamustine is a mutagen and clastogen. In a reverse bacterial mutation assay (Ames assay), bendamustine was shown to increase revertant frequency in the absence and presence of metabolic activation. Bendamustine was clastogenic in human lymphocytes in vitro, and in rat bone marrow cells in vivo (increase in micronucleated polychromatic erythrocytes) from 37.5 mg/m2 , the lowest dose tested.
Impaired spermatogenesis, azoospermia, and total germinal aplasia have been reported in male patients treated with alkylating agents, especially in combination with other drugs. In some instances spermatogenesis may return in patients in remission, but this may occur only several years after intensive chemotherapy has been discontinued. Patients should be warned of the potential risk to their reproductive capacities.
Use In Specific Populations
Pregnancy
Pregnancy Category D
Risk Summary
Bendamustine hydrochloride can cause fetal harm when administered to a pregnant woman. Bendamustine caused malformations in animals, when a single dose was administered to pregnant animals. Advise women to avoid becoming pregnant while receiving Treakisym (bendamustine hydrochloride) injection and for 3 months after therapy has stopped. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to a fetus. Advise men receiving Treakisym (bendamustine hydrochloride) injection to use reliable contraception for the same time period.
Animal Data
Single intraperitoneal doses of bendamustine from 210 mg/m2 (70 mg/kg) in mice administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations (exencephaly, cleft palates, accessory rib, and spinal deformities) and decreased fetal body weights. This dose did not appear to be maternally toxic and lower doses were not evaluated. Repeat intraperitoneal dosing in mice on gestation days 7-11 resulted in an increase in resorptions from 75 mg/m2 (25 mg/kg) and an increase in abnormalities from 112.5 mg/m2 (37.5 mg/kg) similar to those seen after a single intraperitoneal administration. Single intraperitoneal doses of bendamustine from 120 mg/m2 (20 mg/kg) in rats administered on gestation days 4, 7, 9, 11, or 13 caused embryo and fetal lethality as indicated by increased resorptions and a decrease in live fetuses. A significant increase in external [effect on tail, head, and herniation of external organs (exomphalos)] and internal (hydronephrosis and hydrocephalus) malformations were seen in dosed rats. There are no adequate and well-controlled studies in pregnant women. 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.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants and tumorigenicity shown for bendamustine 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.
Pediatric Use
The effectiveness of bendamustine hydrochloride in pediatric patients has not been established. Bendamustine hydrochloride was evaluated in a single Phase 1/2 trial in pediatric patients with leukemia. The safety profile for bendamustine hydrochloride in pediatric patients was consistent with that seen in adults, and no new safety signals were identified.
The trial included pediatric patients from 1-19 years of age with relapsed or refractory acute leukemia, including 27 patients with acute lymphocytic leukemia (ALL) and 16 patients with acute myeloid leukemia (AML). Bendamustine hydrochloride was administered as an intravenous infusion over 60 minutes on Days 1 and 2 of each 21-day cycle. Doses of 90 and 120 mg/m2 were evaluated. The Phase 1 portion of the study determined that the recommended Phase 2 dose of bendamustine hydrochloride in pediatric patients was 120 mg/m2.
A total of 32 patients entered the Phase 2 portion of the study at the recommended dose and were evaluated for response. There was no treatment response (CR+ CRp) in any patient at this dose. However, there were 2 patients with ALL who achieved a CR at a dose of 90 mg/m2 in the Phase 1 portion of the study.
In the above-mentioned pediatric trial, the pharmacokinetics of bendamustine hydrochloride at 90 and 120 mg/m2 doses were evaluated in 5 and 38 patients, respectively, aged 1 to 19 years (median age of 10 years).
The geometric mean body surface adjusted clearance of bendamustine was 14.2 L/h/m. The exposures (AUC and C ) to bendamustine in pediatric patients following a 120 mg/m2 intravenous infusion over 60 minutes were similar to those in adult patients following the same 120 mg/m2 dose.
Geriatric Use
In CLL and NHL studies, there were no clinically significant differences in the adverse reaction profile between geriatric (≥ 65 years of age) and younger patients.
Chronic Lymphocytic Leukemia
In the randomized CLL clinical study, 153 patients received bendamustine hydrochloride. The overall response rate for patients younger than 65 years of age was 70% (n=82) for bendamustine hydrochloride and 30% (n=69) for chlorambucil. The overall response rate for patients 65 years or older was 47% (n=71) for bendamustine hydrochloride and 22% (n=79) for chlorambucil. In patients younger than 65 years of age, the median progression-free survival was 19 months in the bendamustine hydrochloride group and 8 months in the chlorambucil group. In patients 65 years or older, the median progression-free survival was 12 months in the bendamustine hydrochloride group and 8 months in the chlorambucil group.
Non-Hodgkin Lymphoma
Efficacy (Overall Response Rate and Duration of Response) was similar in patients < 65 years of age and patients ≥ 65 years. Irrespective of age, all of the 176 patients experienced at least one adverse reaction.
Renal Impairment
No formal studies assessing the impact of renal impairment on the pharmacokinetics of bendamustine have been conducted. Treakisym (bendamustine hydrochloride) injection should be used with caution in patients with mild or moderate renal impairment. Treakisym (bendamustine hydrochloride) injection should not be used in patients with CrCL < 40 mL/min.
Hepatic Impairment
No formal studies assessing the impact of hepatic impairment on the pharmacokinetics of bendamustine have been conducted. Treakisym (bendamustine hydrochloride) injection should be used with caution in patients with mild hepatic impairment. Treakisym (bendamustine hydrochloride) injection should not be used in patients with moderate (AST or ALT 2.5-10 X ULN and total bilirubin 1.5-3 X ULN) or severe (total bilirubin > 3 X ULN) hepatic impairment.
Effect Of Gender
No clinically significant differences between genders were seen in the overall incidences of adverse reactions in CLL or NHL studies.
Chronic Lymphocytic Leukemia
In the randomized CLL clinical study, the overall response rate (ORR) for men (n=97) and women (n=56) in the bendamustine hydrochloride group was 60% and 57%, respectively. The ORR for men (n=90) and women (n=58) in the chlorambucil group was 24% and 28%, respectively. In this study, the median progression-free survival for men was 19 months in the bendamustine hydrochloride treatment group and 6 months in the chlorambucil treatment group. For women, the median progression-free survival was 13 months in the bendamustine hydrochloride treatment group and 8 months in the chlorambucil treatment group.
Non-Hodgkin Lymphoma
The pharmacokinetics of bendamustine were similar in male and female patients with indolent NHL. No clinically-relevant differences between genders were seen in efficacy (Overall Response Rate and Duration of Response).
The following serious adverse reactions have been associated with bendamustine hydrochloride in clinical trials and are discussed in greater detail in other sections of the prescribing information.
- Myelosuppression
- Infections
- Anaphylaxis and Infusion Reactions
- Tumor Lysis Syndrome
- Skin Reactions
- Hepatotoxicity
- Other Malignancies
- Extravasation Injury
Adverse Events In Clinical Trials
The data described below reflect exposure to bendamustine hydrochloride in 329 patients who participated in an actively controlled trial (N=153) for the treatment of CLL and two single arm studies (N=176) for the treatment of indolent B cell NHL. Because clinical trials are conducted under 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 practice.
The safety of Treakisym (bendamustine hydrochloride) injection administered IV as a 50 mL admixture over a 10-minute infusion is supported by clinical trials using bendamustine hydrochloride administered IV as a 500 mL admixture over 30-60 minutes infusion time, as well as an open-label, crossover study in 81 ‘end-of-life’ cancer patients treated with Treakisym. In total, safety data from clinical studies are available from over 400 cancer patients exposed to bendamustine hydrochloride at doses in the range used in the treatment of CLL and NHL.
No clinically significant differences in the adverse event profile were noted among bendamustine hydrochloride administered as a 500 mL admixture over standard infusion time (30-60 minutes) and Treakisym administered as a 50 mL admixture in a ‘short-time’ infusion over 10 minutes.
The safety and tolerability of Treakisym was evaluated in an 8-week clinical study of Treakisym in 81 ‘end-of-life’ cancer patients, diagnosed with solid tumors and hematologic malignancies (excluding CLL). The population was 40-82 years of age, 58% females, 84% white, 12.3% Black, 1.2% Asian and 2.5% were classified as ‘other’. Treakisym was administered IV at a 120 mg/m2 dose as a 50 mL admixture over 10 minutes. Patients in the study received Treakisym(50 mL IV, over 10 minutes) or bendamustine hydrochloride (500 mL IV, over 60 minutes) on Days 1 and 2 every 28 days for two consecutive 2-day cycles.
Adverse reactions (any grade) that occurred with a frequency greater than 5% during Treakisym infusion and within one hour post-infusion were nausea (8.2%) and fatigue (5.5%).
Adverse reactions (any grade) that occurred with a frequency greater than 5% within 24 hours of Treakisym were nausea (10.9%) and fatigue (8.2%).
Adverse reactions leading to study withdrawal in 4 patients receiving Treakisym were pyrexia (1.2%), nausea (1.2%), vomiting (1.2%), pneumonia (1.2%) and fatigue (1.2%).
Clinical Trials Experience In CLL
The data described below reflect exposure to bendamustine hydrochloride in 153 patients. Bendamustine hydrochloride was studied in an active-controlled randomized trial. The population was 45-77 years of age, 63% male, 100% white, and had treatment naïve CLL. All patients started the study at a dose of 100 mg/m2 intravenously over 30 minutes on Days 1 and 2 every 28 days.
Adverse reactions were reported according to NCI CTC v.2.0. In the randomized CLL clinical study, non-hematologic adverse reactions (any grade) in the bendamustine hydrochloride group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%).
Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation and stomatitis.
Worsening hypertension was reported in 4 patients treated with bendamustine hydrochloride in the randomized CLL clinical study and in none treated with chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved.
The most frequent adverse reactions leading to study withdrawal for patients receiving bendamustine hydrochloride were hypersensitivity (2%) and pyrexia (1%).
Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in ≥ 5% of patients in either treatment group in the randomized CLL clinical study.
Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients
Number (%) of patients | ||||
Bendamus tine Hydrochloride (N=153) | Chlorambucil (N=143) | |||
System organ class Preferred term | All Grades | Grade 3/4 | All Grades | Grade 3/4 |
Total number of patients with at least 1 adverse reaction | 121 (79) | 52 (34) | 96 (67) | 25 (17) |
Gastrointestinal disorders | ||||
Nausea | 31 (20) | 1 (<1) | 21 (15) | 1 (<1) |
Vomiting | 24 (16) | 1 (<1) | 9 (6) | 0 |
Diarrhea | 14 (9) | 2 (1) | 5 (3) | 0 |
General disorders and administration site conditions | ||||
Pyrexia | 36 (24) | 6 (4) | 8 (6) | 2 (1) |
Fatigue | 14 (9) | 2 (1) | 8 (6) | 0 |
Asthenia | 13 (8) | 0 | 6 (4) | 0 |
Chills | 9 (6) | 0 | 1 (<1) | 0 |
Immune system dis orders | ||||
Hypersensitivity | 7 (5) | 2 (1) | 3 (2) | 0 |
Infections and infestations | ||||
Nasopharyngitis | 10 (7) | 0 | 12 (8) | 0 |
Infection | 9 (6) | 3 (2) | 1 (<1) | 1 (<1) |
Herpes simplex | 5 (3) | 0 | 7 (5) | 0 |
Investigations | ||||
Weight decreased | 11 (7) | 0 | 5 (3) | 0 |
Metabolism and nutrition disorders | ||||
Hyperuricemia | 11 (7) | 3 (2) | 2 (1) | 0 |
Respiratory, thoracic and mediastinal disorders | ||||
Cough | 6 (4) | 1 (<1) | 7 (5) | 1 (<1) |
Skin and subcutaneous tissue disorders | ||||
Rash | 12 (8) | 4 (3) | 7 (5) | 3 (2) |
Pruritus | 8 (5) | 0 | 2 (1) | 0 |
The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL clinical study are described in Table 2. These findings confirm the myelosuppressive effects seen in patients treated with bendamustine hydrochloride. Red blood cell transfusions were administered to 20% of patients receiving bendamustine hydrochloride compared with 6% of patients receiving chlorambucil.
Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received bendamustine hydrochloride or Chlorambucil in the Randomized CLL Clinical Study
Laboratory Abnormality | Bendamus tine Hydrochloride N=150 | Chlorambucil N=141 | ||
All Grades n (%) | Grade 3/4 n (%) | All Grades n (%) | Grade 3/4 n (%) | |
Hemoglobin Decreased | 134 (89) | 20 (13) | 115 (82) | 12 (9) |
Platelets Decreased | 116 (77) | 16 (11) | 110 (78) | 14 (10) |
Leukocytes Decreased | 92 (61) | 42 (28) | 26 (18) | 4 (3) |
Lymphocytes Decreased | 102 (68) | 70 (47) | 27 (19) | 6 (4) |
Neutrophils Decreased | 113 (75) | 65 (43) | 86 (61) | 30 (21) |
In the randomized CLL trial, 34% of patients had bilirubin elevations, some without associated significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with bendamustine hydrochloride may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that significant deterioration does not occur.
Clinical Trials Experience In NHL
The data described below reflect exposure to bendamustine hydrochloride in 176 patients with indolent B-cell NHL treated in two single-arm studies. The population was 31-84 years of age, 60% male, and 40% female. The race distribution was 89% White, 7% Black, 3% Hispanic, 1% other, and <1% Asian.
These patients received bendamustine hydrochloride at a dose of 120 mg/m2 intravenously on Days 1 and 2 for up to eight 21-day cycles.
The adverse reactions occurring in at least 5% of the NHL patients, regardless of severity, are shown in Table 3. The most common non-hematologic adverse reactions (≥30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%) and pyrexia (34%). The most common non-hematologic Grade 3 or 4 adverse reactions (≥5%) were fatigue (11%), febrile neutropenia (6%), and pneumonia, hypokalemia and dehydration, each reported in 5% of patients.
Table 3: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated with bendamustine hydrochloride by System Organ Class and Preferred Term (N=176)
System organ class | Number (%) of patients * | |
Preferred Term | All Grades | Grade 3/4 |
Total number of patients with at least 1 adverse reaction | 176 (100) | 94 (53) |
Cardiac Disorders | ||
Tachycardia | 13 (7) | 0 |
Gastrointestinal disorders | ||
Nausea | 132 (75) | 7 (4) |
Vomiting | 71 (40) | 5 (3) |
Diarrhea | 65 (37) | 6 (3) |
Constipation | 51 (29) | 1 (<1) |
Stomatitis | 27 (15) | 1 (<1) |
Abdominal pain | 22 (13) | 2 (1) |
Dyspepsia | 20 (11) | 0 |
Gastroesophageal reflux disease | 18 (10) | 0 |
Dry mouth | 15 (9) | 1 (<1) |
Abdominal pain upper | 8 (5) | 0 |
Abdominal distension | 8 (5) | 0 |
General disorders and administration site conditions | ||
Fatigue | 101 (57) | 19 (11) |
Pyrexia | 59 (34) | 3 (2) |
Chills | 24 (14) | 0 |
Edema peripheral | 23 (13) | 1 (<1) |
Asthenia | 19 (11) | 4 (2) |
Chest pain | 11 (6) | 1 (<1) |
Infusion site pain | 11 (6) | 0 |
Pain | 10 (6) | 0 |
Catheter site pain | 8 (5) | 0 |
Infections and infestations | ||
Herpes zoster | 18 (10) | 5 (3) |
Upper respiratory tract infection | 18 (10) | 0 |
Urinary tract infection | 17 (10) | 4 (2) |
Sinusitis | 15 (9) | 0 |
Pneumonia | 14 (8) | 9 (5) |
Febrile neutropenia | 11 (6) | 11 (6) |
Oral candidiasis | 11 (6) | 2 (1) |
Nasopharyngitis | 11 (6) | 0 |
Investigations | ||
Weight decreased | 31 (18) | 3 (2) |
Metabolism and nutrition disorders | ||
Anorexia | 40 (23) | 3 (2) |
Dehydration | 24 (14) | 8 (5) |
Decreased appetite | 22 (13) | 1 (<1) |
Hypokalemia | 15 (9) | 9 (5) |
Musculos keletal and connective tissue disorders | ||
Back pain | 25 (14) | 5 (3) |
Arthralgia | 11 (6) | 0 |
Pain in extremity | 8 (5) | 2 (1) |
Bone pain | 8 (5) | 0 |
Nervous system disorders | ||
Headache | 36 (21) | 0 |
Dizziness | 25 (14) | 0 |
Dysgeusia | 13 (7) | 0 |
Psychiatric disorder | ||
Insomnia | 23 (13) | 0 |
Anxiety | 14 (8) | 1 (<1) |
Depression | 10 (6) | 0 |
Respiratory, thoracic and mediastinal disorders | ||
Cough | 38 (22) | 1 (<1) |
Dyspnea | 28 (16) | 3 (2) |
Pharyngolaryngeal pain | 14 (8) | 1 (<1) |
Wheezing | 8 (5) | 0 |
Nasal congestion | 8 (5) | 0 |
Skin and subcutaneous tissue disorders | ||
Rash | 28 (16) | 1 (<1) |
Pruritus | 11 (6) | 0 |
Dry skin | 9 (5) | 0 |
Night sweats | 9 (5) | 0 |
Hyperhidrosis | 8 (5) | 0 |
Vascular disorders | ||
Hypotension | 10 (6) | 2 (1) |
*Patients may have reported more than 1 adverse reaction. NOTE: Patients counted only once in each preferred term category and once in each system organ class category. |
Hematologic toxicities, based on laboratory values and CTC grade, in NHL patients treated in both single arm studies combined are described in Table 4. Clinically important chemistry laboratory values that were new or worsened from baseline and occurred in >1% of patients at grade 3 or 4, in NHL patients treated in both single arm studies combined were hyperglycemia (3%), elevated creatinine (2%), hyponatremia (2%), and hypocalcemia (2%).
Table 4: Incidence of Hematology Laboratory Abnormalities in Patients Who Received bendamustine hydrochloride in the NHL Studies
Hematology Variable | Percent of Patients | |
All Grades | Grade 3/4 | |
Lymphocytes Decreased | 99 | 94 |
Leukocytes Decreased | 94 | 56 |
Hemoglobin Decreased | 88 | 11 |
Neutrophils Decreased | 86 | 60 |
Platelets Decreased | 86 | 25 |
In both studies, serious adverse reactions, regardless of causality, were reported in 37% of patients receiving bendamustine hydrochloride. The most common serious adverse reactions occurring in ≥5% of patients were febrile neutropenia and pneumonia. Other important serious adverse reactions reported in clinical trials and/or postmarketing experience were acute renal failure, cardiac failure, hypersensitivity, skin reactions, pulmonary fibrosis, and myelodysplastic syndrome.
Serious drug-related adverse reactions reported in clinical trials included myelosuppression, infection, pneumonia, tumor lysis syndrome and infusion reactions. Adverse reactions occurring less frequently but possibly related to bendamustine hydrochloride treatment were hemolysis, dysgeusia/taste disorder, atypical pneumonia, sepsis, herpes zoster, erythema, dermatitis, and skin necrosis.
Post-Marketing Experience
The following adverse reactions have been identified during post-approval use of bendamustine hydrochloride. 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.
Blood and lymphatic systems disorders: Pancytopenia.
Cardiovascular disorders: Atrial fibrillation, congestive heart failure (some fatal), myocardial infarction (some fatal), palpitation.
General disorders and administration site conditions: Injection site reactions (including phlebitis, pruritus, irritation, pain, swelling), infusion site reactions (including phlebitis, pruritus, irritation, pain, swelling).
Immune system disorders: Anaphylaxis.
Infections and infestations: Pneumocystis jiroveci pneumonia.
Respiratory, thoracic and mediastinal disorders: Pneumonitis.
Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome, Toxic epidermal necrolysis, DRESS (Drug reaction with eosinophilia and systemic symptoms)..
La DL intravenosa del clorhidrato de bendamustina es de 240 mg / m2 en el ratón y la rata. Las toxicidades incluyeron sedación, temblor, ataxia, convulsiones y dificultad respiratoria.
En toda la experiencia clínica, la dosis única máxima informada recibida fue de 280 mg / m2 Tres de los cuatro pacientes tratados con esta dosis mostraron cambios en el ECG considerados limitantes de la dosis a los 7 y 21 días después de la dosificación. Estos cambios incluyeron prolongación del intervalo QT (un paciente), taquicardia sinusal (un paciente), desviaciones de las ondas ST y T (dos pacientes) y bloqueo fascicular anterior izquierdo (un paciente). Las enzimas cardíacas y las fracciones de eyección permanecieron normales en todos los pacientes.
No se conoce ningún antídoto específico para la sobredosis de clorhidrato de bendamustina. El manejo de la sobredosis debe incluir medidas generales de apoyo, incluido el monitoreo de parámetros hematológicos y ECG.
Based on the pharmacokinetics/pharmacodynamics analyses of data from adult NHL patients, nausea increased with increasing bendamustine Cmax.
Cardiac Electrophysiology
The effect of bendamustine on the QTc interval was evaluated in 53 patients with indolent NHL and mantle cell lymphoma on Day 1 of Cycle 1 after administration of rituximab at 375 mg/m2 intravenous infusion followed by a 30-minute intravenous infusion of bendamustine at 90 mg/m2 /day. No mean changes greater than 20 milliseconds were detected up to one hour post infusion. The potential for delayed effects on the QT interval after one hour was not evaluated.
Absorción
En un estudio de farmacocinética realizado en pacientes con cáncer (N = 60), una dosis intravenosa única de inyección de Treakisym (clorhidrato de bendamustina) (120 mg / m2 ; administrado como una infusión de 10 minutos), resultó en una concentración plasmática máxima más alta (Cmáx) y una exposición sistémica equivalente (AUC), en comparación con una dosis única de Treanda® (clorhidrato de bendamustina) (120 mg / m2 ) infundido durante 60 minutos. La Cmáx media alcanzada fue de 35 μg / ml (rango de 6 a 49 μg / ml), que ocurre típicamente al final de la infusión.
Distribución
In vitro, la unión de bendamustina a proteínas plasmáticas séricas humanas varió del 94-96% y fue independiente de la concentración de 1-50 μg / ml. Los datos sugieren que no es probable que la bendamustina se desplace o se desplace por fármacos altamente unidos a proteínas. Las relaciones de concentración de sangre a plasma en la sangre humana oscilaron entre 0,84 y 0,86 en un rango de concentración de 10 a 100 μg / ml, lo que indica que la bendamustina se distribuye libremente en los glóbulos rojos humanos.
En un estudio de balance de masa, los niveles de radiactividad plasmática se mantuvieron durante un período de tiempo mayor que las concentraciones plasmáticas de bendamustina, γ hidroxibendamustina (M3) y N desmetilbendamustina (M4). Esto sugiere que hay materiales derivados de bendamustina (detectados a través del radiomarcador), que se eliminan rápidamente y tienen una vida media más larga que la bendamustina y sus metabolitos activos. El volumen medio de distribución en estado estacionario (Vss) de bendamustina fue de aproximadamente 20-25 L. El volumen de distribución en estado estacionario para la radiactividad total fue de aproximadamente 50 L, lo que indica que ni la bendamustina ni la radiactividad total se distribuyen ampliamente en los tejidos.
Metabolismo
In vitro los datos indican que la bendamustina se metaboliza principalmente a través de la hidrólisis a metabolitos monohidroxi (HP1) y dihidroxibendamustina (HP2) con baja actividad citotóxica. In vitro, los estudios indican que dos metabolitos menores activos, M3 y M4, se forman principalmente a través de CYP1A2. Sin embargo, las concentraciones de estos metabolitos en plasma son 1/10th y 1/100th el del compuesto original, respectivamente, lo que sugiere que la actividad citotóxica se debe principalmente a la bendamustina.
Los resultados de un estudio de balance de masa humana confirman que la bendamustina se metaboliza ampliamente a través de vías hidrolíticas, oxidativas y conjugativas. In vitro Los estudios que utilizan microsomas hepáticos humanos indican que la bendamustina no inhibe CYP1A2, 2C9 / 10, 2D6, 2E1 o 3A4 / 5. La bendamustina no indujo el metabolismo de las enzimas CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1 o CYP3A4 / 5 en cultivos primarios de hepatocitos humanos.
Eliminación
Recuperación media de la radiactividad total en pacientes con cáncer después de la infusión intravenosa de [14C] el clorhidrato de bendamustina fue aproximadamente el 76% de la dosis. Aproximadamente el 50% de la dosis se recuperó en la orina y aproximadamente el 25% de la dosis se recuperó en las heces. La excreción urinaria se confirmó como una vía relativamente menor de eliminación de bendamustina, con aproximadamente el 3.3% de la dosis recuperada en la orina como progenitor. Menos del 1% de la dosis se recuperó en la orina como M3 y M4, y menos del 5% de la dosis se recuperó en la orina como HP2.
Después de una dosis única de 120 mg / m2 bendamustina IV durante 1 hora, la t½ intermedia del compuesto original es de aproximadamente 40 minutos. La t½ media de eliminación terminal aparente de M3 y M4 es de aproximadamente 3 horas y 30 minutos respectivamente. Se espera poca o ninguna acumulación en plasma para la bendamustina administrada en los días 1 y 2 de un ciclo de 28 días. El aclaramiento de bendamustina en humanos es de aproximadamente 700 ml / minuto.
Deterioro renal
En un análisis farmacocinético poblacional de bendamustina en pacientes que reciben 120 mg / m2 , no hubo un efecto significativo de la insuficiencia renal (CrCL 40 - 80 ml / min, N = 31) sobre la farmacocinética de bendamustina. La bendamustina no se ha estudiado en pacientes con CrCL <40 ml / min.
Sin embargo, estos resultados son limitados y, por lo tanto, la bendamustina debe usarse con precaución en pacientes con insuficiencia renal leve o moderada. La bendamustina no debe usarse en pacientes con CrCL <40 ml / min.
Insuficiencia hepática
En un análisis farmacocinético poblacional de bendamustina en pacientes que reciben 120 mg / m2 , no hubo un efecto significativo de la insuficiencia hepática leve (bilirrubina total ≤ ULN, AST ≥ ULN a 2.5 x ULN y / o ALP ≥ ULN a 5 x ULN, N = 26) sobre la farmacocinética de bendamustina. La bendamustina no se ha estudiado en pacientes con insuficiencia hepática moderada o grave.
Sin embargo, estos resultados son limitados y, por lo tanto, la bendamustina debe usarse con precaución en pacientes con insuficiencia hepática leve. La bendamustina no debe usarse en pacientes con insuficiencia hepática moderada (AST o ALT 2.5 - 10 x ULN y bilirrubina total 1.5 - 3 x ULN) o grave (bilirrubina total> 3 x ULN).
Efecto de la edad
La exposición a bendamustina (medida por AUC y Cmax) se ha estudiado en pacientes de 31 a 84 años. La farmacocinética de bendamustina (AUC y Cmax) no fue significativamente diferente entre pacientes menores o mayores que / iguales a 65 años de edad.
Efecto del género
La farmacocinética de bendamustina fue similar en pacientes masculinos y femeninos.
Efecto de la raza
No se ha establecido el efecto de la raza sobre la seguridad y / o eficacia del clorhidrato de bendamustina. Según una comparación entre estudios, los sujetos japoneses (n = 6) tenían exposiciones promedio que eran un 40% más altas que los sujetos no japoneses que recibían la misma dosis. No se ha establecido la importancia de esta diferencia en la seguridad y eficacia del clorhidrato de bendamustina en sujetos japoneses.