The recommended dose of TORISEL for advanced renal cell carcinoma is 25 mg infused over a 30–60 minute period once a week.

Treatment should continue until disease progression or unacceptable toxicity occurs.

2.2 Premedication

Patients should receive prophylactic intravenous diphenhydramine 25 to 50 mg (or similar antihistamine) approximately 30 minutes before the start of each dose of TORISEL [see Warnings and Precautions (5.1)].

2.3 Dosage Interruption/Adjustment

TORISEL should be held for absolute neutrophil count (ANC) < 1,000/mm3, platelet count < 75,000/mm3, or NCI CTCAE grade 3 or greater adverse reactions. Once toxicities have resolved to grade 2 or less, TORISEL may be restarted with the dose reduced by 5 mg/week to a dose no lower than 15 mg/week.

2.4 Dose Modification Guidelines

TORISEL must be stored under refrigeration at 2°–8°C (36°–46°F) and protected from light. During handling and preparation of admixtures, TORISEL should be protected from excessive room light and sunlight. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

In order to minimize the patient exposure to the plasticizer DEHP (di-2-ethylhexyl phthalate), which may be leached from PVC infusion bags or sets, the final TORISEL dilution for infusion should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.

TORISEL 25 mg/mL injection must be diluted with the supplied diluent before further dilution in 0.9% Sodium Chloride Injection, USP.

 Please note that both the TORISEL injection and diluent vials contain an overfill to ensure the recommended volume can be withdrawn.

Follow this two-step dilution process in an aseptic manner.

•  Administration of the final diluted solution should be completed within six hours from the time that TORISEL is first added to 0.9% Solution Chloride Injection, USP.
•  TORISEL is infused over a 30- to 60-minute period once weekly. The use of an infusion pump is the preferred method of administration to ensure accurate delivery of the product.
•  Appropriate administration materials should be composed of glass, polyolefin, or polyethylene to avoid excessive loss of product and diethylhexylpthalate (DEHP) extraction. The administration materials should consist of non-DEHP, non-polyvinylchloride (PVC) tubing with appropriate filter. In the case when a PVC administration set has to be used, it should not contain DEHP. An in-line polyethersulfone filter with a pore size of not greater than 5 microns is recommended for administration to avoid the possibility of particles bigger than 5 microns being infused. If the administration set available does not have an in-line filter incorporated, a polyethersulfone filter should be added at the set (i.e., an end-filter) before the admixture reaches the vein of the patient. Different end-filters can be used, ranging in filter pore size from 0.2 microns up to 5 microns. The use of both an in-line and end-filter is not recommended.
•  TORISEL, when diluted, contains polysorbate 80, which is known to increase the rate of DEHP extraction from PVC. This should be considered during the preparation and administration of TORISEL, including storage time elapsed when in direct contact with PVC following constitution.

 Compatibilities and Incompatibilities

 Undiluted TORISEL injection should not be added directly to aqueous infusion solutions. Direct addition of TORISEL injection to aqueous solutions will result in precipitation of drug. Always combine TORISEL injection with DILUENT for TORISEL before adding to infusion solutions. It is recommended that TORISEL be administered in 0.9% Sodium Chloride Injection after combining with diluent. The stability of TORISEL in other infusion solutions has not been evaluated. Addition of other drugs or nutritional agents to admixtures of TORISEL in 0.9% Sodium Chloride Injection has not been evaluated and should be avoided. Temsirolimus is degraded by both acids and bases, and thus combinations of temsirolimus with agents capable of modifying solution pH should be avoided.

3 DOSAGE FORMS AND STRENGTHS

 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.

 TORISEL 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 TORISEL.

 An H1 antihistamine should be administered to patients before the start of the intravenous temsirolimus infusion. TORISEL 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 TORISEL 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 [see Dosage and Administration (2.2)], and/or an H2-receptor antagonist (such as intravenous famotidine 20 mg or intravenous ranitidine 50 mg) approximately 30 minutes before restarting the TORISEL 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.

5.2 Hepatic Impairment

The safety and pharmacokinetics of TORISEL 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 TORISEL. 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 [see Contraindications (4)].

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 TORISEL must be given in patients with mild hepatic impairment (bilirubin >1 – 1.5 × ULN or AST >ULN but bilirubin ≤ULN), reduce the dose of TORISEL to 15 mg/week [see Dosage and Administration (2.4)].

5.3 Hyperglycemia/Glucose Intolerance

The use of TORISEL is likely to result in increases in serum glucose. In the phase 3 trial, 89% of patients receiving TORISEL 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 TORISEL. Patients should be advised to report excessive thirst or any increase in the volume or frequency of urination.

5.4 Infections

The use of TORISEL may result in immunosuppression. Patients should be carefully observed for the occurrence of infections, including opportunistic infections [see Adverse Reactions (6.1)].

5.5 Interstitial Lung Disease

 Cases of interstitial lung disease, some resulting in death, occurred in patients who received TORISEL. 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 TORISEL 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 TORISEL 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 TORISEL administration until after recovery of symptoms and improvement of radiographic findings related to pneumonitis. Empiric treatment with corticosteroids and/or antibiotics may be considered.

5.6 Hyperlipemia

The use of TORISEL is likely to result in increases in serum triglycerides and cholesterol. In the phase 3 trial, 87% of patients receiving TORISEL 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 TORISEL.

5.7 Bowel Perforation

Cases of fatal bowel perforation occurred in patients who received TORISEL. 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.

5.8 Renal Failure

Cases of rapidly progressive and sometimes fatal acute renal failure not clearly related to disease progression occurred in patients who received TORISEL. Some of these cases were not responsive to dialysis.

5.9 Wound Healing Complications

Use of TORISEL has been associated with abnormal wound healing. Therefore, caution should be exercised with the use of TORISEL in the perioperative period.

5.10 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 TORISEL.

5.11 Co-administration with Inducers or Inhibitors of CYP3A Metabolism

The combination of TORISEL 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 TORISEL 15 mg IV per week and sunitinib 25 mg oral per day (Days 1–28 followed by a 2-week rest).

5.13 Vaccinations

The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with TORISEL. Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.

5.14 Use in Pregnancy

There are no adequate and well-controlled studies of TORISEL in pregnant women. However, based on its mechanism of action, TORISEL 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 TORISEL therapy has stopped. [see Use in Specific Populations (8.1)]

Men should be counseled regarding the effects of TORISEL on the fetus and sperm prior to starting treatment [see Nonclinical Toxicology (13.1)]. 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 TORISEL.

5.15 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 [see Use in Specific Populations (8.5)].

5.16 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 TORISEL may need to be performed more or less frequently at the physician's discretion.

6 ADVERSE REACTIONS

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, TORISEL alone, and TORISEL and IFN-α, a total of 616 patients were treated. Two hundred patients received IFN-α weekly, 208 received TORISEL 25 mg weekly, and 208 patients received a combination of TORISEL and IFN-α weekly [see Clinical Studies (14)].

Treatment with the combination of TORISEL 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 TORISEL 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.

The following selected adverse reactions were reported less frequently (<10%).

Gastrointestinal Disorders – Fatal bowel perforation occurred in 1 patient (1%).

Eye Disorders - Conjunctivitis (including lacrimation disorder) occurred in 15 patients (7%).

Immune System - Allergic/Hypersensitivity reactions occurred in 18 patients (9%).

Angioneurotic edema-type reactions (including delayed reactions occurring two months following initiation of therapy) have been observed in some patients who received TORISEL and ACE inhibitors concomitantly.

Infections - Pneumonia occurred in 17 patients (8%); upper respiratory tract infection occurred in 14 patients (7%).

General Disorders and Administration Site Conditions - Impaired wound healing occurred in 3 patients (1%).

Respiratory, Thoracic and Mediastinal Disorders – Interstitial lung disease occurred in 5 patients (2%), including rare fatalities.

Vascular - Hypertension occurred in 14 patients (7%); venous thromboembolism (including deep vein thrombosis and pulmonary embolus [including fatal outcomes]) occurred in 5 patients (2%); thrombophlebitis occurred in 2 patients (1%).

The following adverse reactions have been identified during post approval use of TORISEL. 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: pleural effusion, hemodynamically significant pericardial effusions requiring intervention, convulsions, rhabdomyolysis, Stevens-Johnson Syndrome, and complex regional pain syndrome (reflex sympathetic dystrophy).

There are also postmarketing reports of temsirolimus extravasations resulting in swelling, pain, warmth, and erythema.

7 DRUG INTERACTIONS

7.1 Agents Inducing CYP3A Metabolism

Co-administration of TORISEL with rifampin, a potent CYP3A4/5 inducer, had no significant effect on temsirolimus Cmax (maximum concentration) and AUC (area under the concentration versus the time curve) after intravenous administration, but decreased sirolimus Cmax by 65% and AUC by 56% compared to TORISEL treatment alone. If alternative treatment cannot be administered, a dose adjustment should be considered [see Dosage and Administration (2.4)].

7.2 Agents Inhibiting CYP3A Metabolism

Co-administration of TORISEL with ketoconazole, a potent CYP3A4 inhibitor, had no significant effect on temsirolimus Cmax or AUC; however, sirolimus AUC increased 3.1-fold, and Cmax increased 2.2-fold compared to TORISEL alone. If alternative treatment cannot be administered, a dose adjustment should be considered. [see Dosage and Administration (2.4)].

7.3 Interactions with Drugs Metabolized by CYP2D6

The concentration of desipramine, a CYP2D6 substrate, was unaffected when 25 mg of TORISEL was co-administered. No clinically significant effect is anticipated when temsirolimus is co-administered with agents that are metabolized by CYP2D6 or CYP3A4.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects

It is not known whether TORISEL is excreted into human milk, and due to the potential for tumorigenicity shown for sirolimus (active metabolite of TORISEL) in animal studies, a decision should be made whether to discontinue nursing or discontinue TORISEL, taking into account the importance of the drug to the mother.

8.4 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.

TORISEL 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 TORISEL 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 TORISEL 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 TORISEL 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.

Clinical studies of TORISEL 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 [see Warnings and Precautions (5.15)].

8.6 Renal Impairment

No clinical studies were conducted with TORISEL 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 TORISEL is recommended in patients with renal impairment.

TORISEL has not been studied in patients undergoing hemodialysis.

8.7 Hepatic Impairment

TORISEL 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).

TORISEL is contraindicated in patients with bilirubin >1.5 × ULN [see Contraindications (4), and Warnings and Precautions (5.2)]. Use caution when treating patients with mild hepatic impairment. If TORISEL must be given in patients with mild hepatic impairment (bilirubin >1 – 1.5 × ULN or AST >ULN but bilirubin ≤ULN), reduce the dose of TORISEL to 15 mg/week [see Dosage and Administration (2.4)]. Because there is a need for dosage adjustment based upon hepatic function, assessment of AST and bilirubin levels is recommended before initiation of TORISEL and periodically thereafter.

10 OVERDOSAGE

Temsirolimus is an inhibitor of mTOR (mammalian target of rapamycin). Temsirolimus binds to an intracellular protein (FKBP-12), and the protein-drug complex inhibits the activity of mTOR that controls cell division. Inhibition of mTOR activity resulted in a G1 growth arrest in treated tumor cells. When mTOR was inhibited, its ability to phosphorylate p70S6k and S6 ribosomal protein, which are downstream of mTOR in the PI3 kinase/AKT pathway was blocked. In in vitro studies using renal cell carcinoma cell lines, temsirolimus inhibited the activity of mTOR and resulted in reduced levels of the hypoxia-inducible factors HIF-1 and HIF-2 alpha, and the vascular endothelial growth factor.

12.2 Pharmacodynamics

Effects on Electrocardiogram There were no clinically relevant QT changes observed at the recommended dose for TORISEL. In a randomized, single-blinded, crossover study, 58 healthy subjects received TORISEL 25 mg, placebo, and a single oral dose of moxifloxacin 400 mg. A supratherapeutic TORISEL dose was not studied in this randomized QT trial. The largest difference between the upper bound 2-sided 90% CI for the mean difference between TORISEL and placebo-corrected QT interval was less than 10 ms. In a different trial in 69 patients with a hematologic malignancy, TORISEL doses up to 175mg were studied. No patient with a normal QTcF at baseline had an increase in QTcF >60 ms. Additionally, there were no patients with a QTcF interval greater than 500 ms.

12.3 Pharmacokinetics

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.

14 CLINICAL STUDIES

Each kit is supplied in a single carton containing one single-use vial of 25 mg/mL of temsirolimus and one DILUENT vial which includes a deliverable volume of 1.8 mL, and must be stored at 2°–8° C (36°–46° F). Protect from light.

靶向治疗肾癌药物Torisel上市
坦罗莫司（Temsirolimus,CCI-779）是一种特异性mTOR抑制剂。在Ⅲ期临床研究中对晚期肾细胞癌具有良好的疗效,延长总生存期至10.9个月。其主要不良反应包括代谢失调（高血脂、高血糖）、黏膜炎、皮疹和肺炎等。2007年5月美国FDA批准坦罗莫司用于难治性晚期肾细胞癌的一线治疗,具有广泛的应用前景。
美国FDA已经批准Torisel（Temsirolimus）上市用于治疗进行肾细胞癌（RCC）。Torisel是第一个治疗肾癌的靶向治疗药物，将在今年7月正式上市。
肾细胞癌占全部肾肿瘤的85%。美国癌症协会预计今年将有新诊断肾癌51190例，其中40%在诊断时已经是晚期或发展阶段。Torisel是唯一上市的特异抑制mTOR激酶的药物，mTOR激酶是调节细胞增值、生长和细胞存活重要的蛋白质。在体外研究中发现，Torisel抑制mTOR激酶后导致一定的血管生长因子如血管内皮生长因子的水平下降，进而阻止新生血管的发展。作为上市后安全监测措施，惠氏将提供2套完整的数据，其一已经完成，另一个关于肝细胞毒的实验即将开始。Torisel也是目前唯一能够显著延长患者生存期的药物。惠氏为Torisel进行了包括626名患者的III期临床研究，共分为三组。Torisel单独一组，Torisel和alpha干扰素混合组以及alpha干扰素单独一组。结果显示，Torisel比alpha干扰素显著延长患者生存率达49%（10.9个月对7.3个月）；在次级评价指标上，Torisel比alpha干扰素显著延长患者的无进展（病情不进一步恶化）生存期（5.5个月对3.1个月）。Torisel和alpha干扰素组合使用没有显示更好的作用。
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产地国家: 美国
原产地英文商品名:
Torisel （25MG/MLvial+1.8MLdiluent)/Kit
原产地英文药品名:
Temsirolimus
原产地英文化合物名称:
Antineoplastic (mTOR kinase inhibitor)
中文参考商品译名:
Torisel (25毫克/毫升瓶+1.8毫升稀释液)/套盒
中文参考药品译名:
Temsirolimus
中文参考化合物名称:
Antineoplastic (mTOR kinase inhibitor)
生产厂家中文参考译名:
美国惠氏公司
生产厂家英文名:
Wyeth Pharmaceuticals Inc