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TORISEL(Temsirolimus Injection)

2013-04-08 14:44:38  作者:新特药房  来源:互联网  浏览次数:420  文字大小:【】【】【
简介: 英文药名:TORISEL(Temsirolimus Injection) 中文药名:驮瑞塞尔(坦罗莫司注射剂) 生产厂家:美国惠氏公司(WyethPharmaceuticalsInc) 给药说明一般描述西罗莫司脂化物,一种雷帕霉素靶蛋白(mammal ...

TORISEL - temsirolimus   
Wyeth Pharmaceuticals Company, a subsidiary of Pfizer Inc.
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。


HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use TORISEL® safely and effectively.
See full prescribing information for TORISEL.
TORISEL Kit (temsirolimus) injection, for intravenous infusion only
Initial U.S. Approval: 2007
RECENT MAJOR CHANGES
Dosage and Administration, Dose Modification Guidelines (2.4) 07/2010
Contraindications (4) 07/2010
Warnings and Precautions, Hepatic Impairment (5.2) 07/2010
INDICATIONS AND USAGE
TORISEL® is a kinase inhibitor indicated for the treatment of advanced renal cell carcinoma. (1)
DOSAGE AND ADMINISTRATION
The recommended dose of TORISEL is 25 mg infused over a 30-60 minute period once a week. Treat until disease progression or unacceptable toxicity. (2.1)
Antihistamine pre-treatment is recommended. (2.2)
Dose reduction is required in patients with mild hepatic impairment. (2.4)
TORISEL (temsirolimus) injection vial contents must first be diluted with the enclosed diluent before diluting the resultant solution with 250 mL of 0.9% sodium chloride injection. (2.5)
DOSAGE FORMS AND STRENGTHS
TORISEL injection, 25 mg/mL supplied with DILUENT for TORISEL®. (3)
CONTRAINDICATIONS
TORISEL is contraindicated in patients with bilirubin >1.5 x ULN. (4)
WARNINGS AND PRECAUTIONS
To treat hypersensitivity reactions stop TORISEL and treat with an antihistamine. TORISEL may be restarted at physician discretion at a slower rate. (5.1)
Hepatic Impairment: Use caution when treating patients with mild hepatic impairment and reduce dose. (2.4, 5.2)
Hyperglycemia and hyperlipemia are likely and may require treatment. Monitor glucose and lipid profiles. (5.3, 5.6)
Infections may result from immunosuppression. (5.4)
Monitor for symptoms or radiographic changes of interstitial lung disease (ILD). If ILD is suspected, discontinue TORISEL, and consider use of corticosteroids and/or antibiotics. (5.5)
Bowel perforation may occur. Evaluate fever, abdominal pain, bloody stools, and/or acute abdomen promptly. (5.7)
Renal failure, sometimes fatal, has occurred. Monitor renal function at baseline and while on TORISEL. (5.8)
Due to abnormal wound healing, use TORISEL with caution in the perioperative period. (5.9)
Live vaccinations and close contact with those who received live vaccines should be avoided. (5.13)
Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant. (5.14)
ADVERSE REACTIONS
The most common adverse reactions (incidence ≥ 30%) are rash, asthenia, mucositis, nausea, edema, and anorexia. The most common laboratory abnormalities (incidence ≥30%) are anemia, hyperglycemia, hyperlipemia, hypertriglyceridemia, elevated alkaline phosphatase, elevated serum creatinine, lymphopenia, hypophosphatemia, thrombocytopenia, elevated AST, and leukopenia. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Wyeth Pharmaceuticals Inc. at 1-800-934-5556 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
DRUG INTERACTIONS
Strong inducers of CYP3A4/5 and inhibitors of CYP3A4 may affect concentrations of the primary metabolite of TORISEL. If alternatives cannot be used, dose modifications of TORISEL are recommended. (7.1, 7.2)
See 17 for PATIENT COUNSELING INFORMATION
Revised: 09/2010


FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

TORISEL is indicated for the treatment of advanced renal cell carcinoma.

2 DOSAGE AND ADMINISTRATION

2.1 Advanced Renal Cell Carcinoma

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 Hypersensitivity Reactions (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

 Hepatic Impairment: Use caution when treating patients with hepatic impairment. If TORISEL must be given in patients with mild hepatic impairment (bilirubin >1 – 1.5 x ULN or AST >ULN but bilirubin ≤ULN), reduce the dose of TORISEL to 15 mg/week. TORISEL is contraindicated in patients with bilirubin >1.5 x ULN [ see Contraindications ( 4 ), Warnings and Precautions ( 5.2 ) and Use in Specific Populations ( 8.7 ) ].

Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors should be avoided (e.g. ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). Grapefruit juice may also increase plasma concentrations of sirolimus (a major metabolite of temsirolimus) and should be avoided. If patients must be co-administered a strong CYP3A4 inhibitor, based on pharmacokinetic studies, a TORISEL dose reduction to 12.5 mg/week should be considered. This dose of TORISEL is predicted to adjust the AUC to the range observed without inhibitors. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors. If the strong inhibitor is discontinued, a washout period of approximately 1 week should be allowed before the TORISEL dose is adjusted back to the dose used prior to initiation of the strong CYP3A4 inhibitor [see Drug Interactions (7.2)].

Concomitant Strong CYP3A4 Inducers: The use of concomitant strong CYP3A4 inducers should be avoided (e.g. dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifampacin, phenobarbital). If patients must be co-administered a strong CYP3A4 inducer, based on pharmacokinetic studies, a TORISEL dose increase from 25 mg/week up to 50 mg/week should be considered. This dose of TORISEL is predicted to adjust the AUC to the range observed without inducers. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers. If the strong inducer is discontinued the temsirolimus dose should be returned to the dose used prior to initiation of the strong CYP3A4 inducer [see Drug Interactions (7.1)].

2.5 Instructions for Preparation and Administration

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.

Dilution:

In preparing the TORISEL administration solution, follow this two-step dilution process in an aseptic manner.

Step 1:

Inject 1.8 mL of DILUENT for TORISEL® into the vial of TORISEL (temsirolimus) injection (25 mg/ml). The TORISEL (temsirolimus) vial contains an overfill of 0.2 mL (30 mg/1.2 mL). Due to the intentional overfill in the TORISEL injection vial, the drug concentration of the resulting solution will be 10 mg/mL. A total volume of 3 mL will be obtained including the overfill. Mix well by inversion of the vial. Allow sufficient time for air bubbles to subside. This 10 mg/mL drug solution/diluent mixture must be further diluted as described in Step 2 below.

The solution is clear to slightly turbid, colorless to yellow, and free from visual particulates. The 10 mg/mL drug solution/diluent mixture is stable for up to 24 hours at controlled room temperature.

Step 2:

Withdraw the required amount of temsirolimus from the 10 mg/mL drug solution/diluent mixture prepared in Step 1. Inject rapidly into a 250 mL container (glass, polyolefin, or polyethylene) of 0.9% sodium chloride injection. Mix the admixture by inversion of the bag or bottle. Avoid excessive shaking as this may cause foaming.

Administration:

  • The sodium chloride injection container should be composed of non-DEHP containing materials, such as glass, polyolefin or polyethylene, and the administration set should consist of non-DEHP tubing to avoid extraction of di-(2-ethylhexyl) phthalate (DEHP). TORISEL contains polysorbate 80, which is known to increase the rate of di-(2-ethylhexyl) phthalate (DEHP) extraction from PVC.
  • An in line polyethersulfone filter with a pore size of not greater than 5 microns is recommended for administration.
  • The final diluted solution of TORISEL is intravenously infused over a 30-60 minute period once a week. The use of an infusion pump is the preferred method of administration to ensure accurate delivery of the drug.
  • Administration of the final diluted infusion solution should be completed within six hours from the time that the drug solution/diluent mixture is added to the sodium chloride injection.

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 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

TORISEL (temsirolimus) is supplied as a kit consisting of the following:

   TORISEL (temsirolimus) injection (25 mg/ml). The TORISEL vial includes an overfill of 0.2 mL.

   DILUENT for TORISEL®. The DILUENT vial includes a deliverable volume of 1.8 mL.

4 CONTRAINDICATIONS

 TORISEL is contraindicated in patients with bilirubin >1.5 x ULN [ see Warnings and Precautions ( 5.2 )].

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions

Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, and chest pain have been observed with TORISEL.

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).

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 x ULN experienced greater toxicity than patients with baseline bilirubin ≤1.5 x 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 x ULN. TORISEL is contraindicated in patients with bilirubin >1.5 x 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 x 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 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.

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

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 TORISEL plasma concentrations unpredictably. Patients receiving TORISEL should not take St. John’s Wort concomitantly. [see Dosage and Administration (2.4) and Drug Interactions (7.1)].

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. [see Dosage and Administration (2.4) and Drug Interactions (7.2)].

5.12 Concomitant use of TORISEL with sunitinib

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 Pregnancy

Pregnancy Category D

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 cancer patients 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 cancer patients at the recommended human dose).

Women of childbearing potential should be advised to avoid becoming pregnant throughout treatment and for 3 months after TORISEL 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.

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 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

The following serious adverse reactions have been associated with TORISEL in clinical trials and are discussed in greater detail in other sections of the label [see Warnings and Precautions (5)].

Hypersensitivity Reactions [see Warnings and Precautions (5.1)]

Hyperglycemia/Glucose Intolerance [see Warnings and Precautions (5.3)]

Interstitial Lung Disease [see Warnings and Precautions (5.5)]

Hyperlipemia [see Warnings and Precautions (5.6)]

Bowel Perforation [see Warnings and Precautions (5.7)]

Renal Failure [see Warnings and Precautions (5.8)]

The most common (≥ 30%) adverse reactions observed with TORISEL are rash, asthenia, mucositis, nausea, edema, and anorexia. The most common (≥ 30%) laboratory abnormalities observed with TORISEL are anemia, hyperglycemia, hyperlipemia, hypertriglyceridemia, lymphopenia, elevated alkaline phosphatase, elevated serum creatinine, hypophosphatemia, thrombocytopenia, elevated AST, and leukopenia.

6.1 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, 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.

Table 1 – Adverse Reactions Reported in at Least 10% of Patients Who Received 25 mg IV TORISEL or IFN-α in the Randomized Trial
Adverse Reaction TORISEL 25 mg n=208 IFN-α n=200
All Grades* n (%) Grades 3&4* n (%) All Grades* n (%) Grades 3&4* n (%)
* 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 zoster

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

Any
208 (100) 139 (67) 199 (100) 155 (78)
General disorders
     Asthenia
     Edemaa
     Pain
     Pyrexia
     Weight Loss
     Headache
     Chest Pain
     Chills
106 (51)
  73 (35)
59 (28)
 50 (24)
39 (19)
31 (15)
 34 (16)
    17 (8)
 23 (11)
    7 (3)
  10 (5)
    1 (1)
    3 (1)
    1 (1)
    2 (1)
    1 (1)
127 (64)
  21 (11)
  31 (16)
  99 (50)
  50 (25)
  30 (15)
  18  (9)
  59 (30)
  52 (26)
    1 (1)
    4 (2)
    7 (4)
    4 (2)
    0 (0)
    2 (1)
    3 (2)
Gastrointestinal disorders
     Mucositisb
     Anorexia
     Nausea
     Diarrhea
     Abdominal Pain
     Constipation
     Vomiting
    86 (41)
  66 (32)
  77 (37)
  56 (27)
  44 (21)
  42 (20)
  40 (19)
    6 (3)
    6 (3)
    5 (2)
    3 (1)
    9 (4)
    0 (0)
    4 (2)
  19 (10)
  87 (44)
  82 (41)
  40 (20)
  34 (17)
  36 (18)
  57 (29)
    0 (0)
    8 (4)
    9 (5)
    4 (2)
    3 (2)
    1 (1)
    5 (3)
Infections
     Infectionsc
     Urinary tract infectiond
     Pharyngitis
     Rhinitis

  42 (20)
  31 (15)
  25 (12)
  20 (10)

    6 (3)
    3 (1)
    0 (0)
    0 (0)

  19 (10)
  24 (12)
    3 (2)
    4 (2)

    4 (2)
    3 (2)
    0 (0)
    0 (0)
Musculoskeletal and connective tissue disorders
     Back Pain
     Arthralgia
     Myalgia


  41 (20)
  37 (18)
  16 (8)


    6 (3)
    2 (1)
    1 (1)


  28 (14)
  29 (15)
  29 (15)


    7 (4)
    2 (1)
    2 (1)
Respiratory, thoracic and mediastinal disorders
     Dyspnea
     Cough
     Epistaxis


  58 (28)
  53 (26)
  25 (12)


  18 (9)
    2 (1)
    0 (0)


  48 (24)
  29 (15)
    7 (4)


  11 (6)
    0 (0)
    0 (0)
Skin and subcutaneous tissue disorders
     Rashe
     Pruritus
     Nail Disorder
     Dry Skin
     Acne

  97 (47)
  40 (19)
  28 (14)
  22 (11)
  21 (10)

  10 (5)
    1 (1)
    0 (0)
    1 (1)
    0 (0)

  14 (7)
  16 (8)
    1 (1)
  14 (7)
    2 (1)

    0 (0)
    0 (0)
    0 (0)
    0 (0)
    0 (0)
Nervous system disorders
     Dysgeusiaf
     Insomnia
     Depression

  41 (20)
  24 (12)
         9 (4)

    0 (0)
    1 (1)
    0 (0)

  17 (9)
  30 (15)
  27 (14)

    0 (0)
    0 (0)
    4 (2)

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 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) occurred in 5 patients (2%); thrombophlebitis occurred in 2 patients (1%).

Table 2 – Incidence of Selected Laboratory Abnormalities in Patients Who Received 25 mg IV TORISEL or IFN-α in the Randomized Trial
Laboratory Abnormality TORISEL 25 mg n=208 IFN-α n=200
All Grades* n (%) Grades 3&4* n (%) All Grades* n (%) Grades 3&4* n (%)
*NCI CTC version 3.0

**Grade 1 toxicity may be under-reported for lymphocytes and neutrophils


Any
208 (100) 162 (78) 195 (98) 144 (72)
Hematology
      Hemoglobin Decreased
      Lymphocytes Decreased**
      Neutrophils Decreased**
      Platelets Decreased
      Leukocytes Decreased

195 (94)
110 (53)
39 (19)
84 (40)
67 (32)

41 (20)
33 (16)
10 (5)
3 (1)
1 (1)

180 (90)
106 (53)
58 (29)
51 (26)
93 (47)

43 (22)
48 (24)
19 (10)
0 (0)
11 (6)
Chemistry
   Alkaline Phosphatase Increased
   AST Increased
   Creatinine Increased
   Glucose Increased
   Phosphorus Decreased
   Total Bilirubin Increased
   Total Cholesterol Increased
   Triglycerides Increased
   Potassium Decreased

141 (68)
79 (38)
119 (57)
186 (89)
102 (49)
16 (8)
181 (87)
173 (83)
43 (21)

7 (3)
5 (2)
7 (3)
33 (16)
38 (18)
2 (1)
5 (2)
92 (44)
11 (5)

111 (56)
103 (52)
97 (49)
128 (64)
61 (31)
25 (13)
95 (48)
144 (72)
15 (8)

13 (7)
14 (7)
2 (1)
6 (3)
17 (9)
4 (2)
2 (1)
69 (35)
0 (0)

6.2 Post-marketing and Other Clinical Experience

The following adverse reactions have been identified during postapproval use of TORISEL. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to readily estimate their frequency or establish a causal relationship to drug exposure.

There have been reports of rhabdomyolysis in patients who received TORISEL.

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

Pregnancy Category D [see Warnings and Precautions (5.14)].

8.3 Nursing Mothers

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

The safety and effectiveness of TORISEL in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of TORISEL did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects.

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).

Table 3 – Adverse Reactions in Patients With Advanced Malignancies Plus Normal or Impaired Hepatic Function
* Hepatic Function Groups: normal = bilirubin and AST ≤ULN; mild = bilirubin >1 – 1.5 x ULN or AST >ULN but bilirubin ≤ULN; moderate = bilirubin >1.5 - 3 x ULN; severe = bilirubin >3 x 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.

Hepatic Function* TORISEL 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)

TORISEL is contraindicated in patients with bilirubin >1.5 x 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 x 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

There is no specific treatment for TORISEL intravenous overdose. TORISEL 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 TORISEL greater than 25 mg.

11 DESCRIPTION

Temsirolimus, an inhibitor of mTOR, is an antineoplastic agent.

Temsirolimus is a white to off-white powder with a molecular formula of C56H87NO16 and a molecular weight of 1030.30. It is non-hygroscopic. Temsirolimus is practically insoluble in water and soluble in alcohol. It has no ionizable functional groups, and its solubility is independent of pH.

The chemical name of temsirolimus is (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone 4′-[2,2-bis(hydroxymethyl)propionate]; or Rapamycin, 42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate].

TORISEL (temsirolimus) injection, 25 mg/mL, is a clear, colorless to light yellow, non-aqueous, ethanolic, sterile solution. TORISEL (temsirolimus) injection requires two dilutions prior to intravenous infusion. TORISEL (temsirolimus) injection should be diluted only with the supplied DILUENT for TORISEL®.

DILUENT for TORISEL® is a sterile, non-aqueous solution that is supplied with TORISEL injection, as a kit.

TORISEL (temsirolimus) injection, 25 mg/mL:

Active ingredient: temsirolimus (25 mg/mL)

Inactive ingredients: dehydrated alcohol (39.5% w/v), dl-alpha-tocopherol (0.075% w/v), propylene glycol (50.3% w/v), and anhydrous citric acid (0.0025% w/v).

DILUENT for TORISEL®

Inactive ingredients: polysorbate 80 (40.0% w/v), polyethylene glycol 400 (42.8% w/v) and dehydrated alcohol (19.9% w/v).

After the TORISEL (temsirolimus) injection vial has been diluted with DILUENT for TORISEL®, in accordance with the instructions in section 2.5, the solution contains 35.2% alcohol.

TORISEL (temsirolimus) injection and DILUENT for TORISEL® are filled in clear glass vials with butyl rubber stoppers.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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, 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 175 mg 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

Absorption

Following administration of a single 25 mg dose of TORISEL in patients with cancer, mean temsirolimus Cmax in whole blood was 585 ng/mL (coefficient of variation, CV =14%), and mean AUC in blood was 1627 ng•h/mL (CV=26%). Typically Cmax occurred at the end of infusion. Over the dose range of 1 mg to 25 mg, temsirolimus exposure increased in a less than dose proportional manner while sirolimus exposure increased proportionally with dose. Following a single 25 mg intravenous dose in patients with cancer, sirolimus AUC was 2.7-fold that of temsirolimus AUC, due principally to the longer half-life of sirolimus.

Distribution

Following a single 25 mg intravenous dose, mean steady-state volume of distribution of temsirolimus in whole blood of patients with cancer was 172 liters. Both temsirolimus and sirolimus are extensively partitioned into formed blood elements.

Metabolism

Cytochrome P450 3A4 is the major isozyme responsible for the formation of five temsirolimus metabolites. Sirolimus, an active metabolite of temsirolimus, is the principal metabolite in humans following intravenous treatment. The remainder of the metabolites account for less than 10% of radioactivity in the plasma. In human liver microsomes temsirolimus was an inhibitor of CYP2D6 and 3A4. However, there was no effect observed in vivo when temsirolimus was administered with desipramine (a CYP2D6 substrate), and no effect is anticipated with substrates of CYP3A4 metabolism.

Elimination

Elimination is primarily via the feces. After a single IV dose of [14C]-temsirolimus approximately 82% of total radioactivity was eliminated within 14 days, with 4.6% and 78% of the administered radioactivity recovered in the urine and feces, respectively. Following a single 25 mg dose of TORISEL in patients with cancer, temsirolimus mean (CV) systemic clearance was 16.2 (22%) L/h. Temsirolimus exhibits a bi-exponential decline in whole blood concentrations and the mean half-lives of temsirolimus and sirolimus were 17.3 hr and 54.6 hr, respectively.

Effects of Age and Gender

In population pharmacokinetic-based data analyses, no relationship was apparent between drug exposure and patient age or gender.

13 NONCLINICAL TOXICOLOGY

13.1 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.

14 CLINICAL STUDIES

A phase 3, multi-center, three-arm, randomized, open-label study was conducted in previously untreated patients with advanced renal cell carcinoma (clear cell and non-clear cell histologies). The objectives were to compare Overall Survival (OS), Progression-Free Survival (PFS), Objective Response Rate (ORR), and safety in patients receiving IFN-α to those receiving TORISEL or TORISEL plus IFN-α. Patients in this study had 3 or more of 6 pre-selected prognostic risk factors (less than one year from time of initial RCC diagnosis to randomization, Karnofsky performance status of 60 or 70, hemoglobin less than the lower limit of normal, corrected calcium of greater than 10 mg/dL, lactate dehydrogenase > 1.5 times the upper limit of normal, more than one metastatic organ site). Patients were stratified for prior nephrectomy status within three geographic regions and were randomly assigned (1:1:1) to receive IFN-α alone (n=207), TORISEL alone (25 mg weekly; n=209), or the combination arm (n=210).

The ITT population for this interim analysis included 626 patients. Demographics were comparable between the three treatment arms with regard to age, gender, and race. The mean age of all groups was 59 years (range 23-86). Sixty-nine percent were male and 31% were female. The racial distribution for all groups was 91% White, 4% Black, 2% Asian, and 3% other. Sixty-seven percent of patients had a history of prior nephrectomy.

The median duration of treatment in the TORISEL arm was 17 weeks (range 1-126 weeks). The median duration of treatment on the IFN arm was 8 weeks (range 1-124 weeks).

There was a statistically significant improvement in OS (time from randomization to death) in the TORISEL 25 mg arm compared to IFN-α. The combination of TORISEL 15 mg and IFN-α did not result in a significant increase in overall survival when compared with IFN-α alone. Figure 1 is a Kaplan-Meier plot of OS in this study. The evaluations of PFS (time from randomization to disease progression or death) and ORR, were based on blinded independent radiologic assessment of tumor response. Efficacy results are summarized in Table 4.

Table 4 – Summary of Efficacy Results of TORISEL vs. IFN-α
Parameter TORISEL
n = 209
IFN-α
n = 207
P-valuea Hazard Ratio (95% CI)b
CI = confidence interval; NA = not applicable

* A comparison is considered statistically significant if the p-value is <0.0159 (O'Brien-Fleming boundary at 446 deaths).

** Not adjusted for multiple comparisons.

a. Based on log-rank test stratified by prior nephrectomy and region.

b. Based on Cox proportional hazard model stratified by prior nephrectomy and region.

c. Based on Cochran-Mantel-Haenszel test stratified by prior nephrectomy and region.

Median Overall Survival
Months (95% CI)
10.9 (8.6, 12.7) 7.3 (6.1, 8.8) 0.0078* 0.73 (0.58, 0.92)
Median Progression-Free Survival
Months (95% CI)
5.5 (3.9, 7.0) 3.1 (2.2, 3.8) 0.0001** 0.66 (0.53, 0.81)
Overall Response Rate
% (95% CI)
8.6 (4.8, 12.4) 4.8 (1.9, 7.8) 0.1232**c NA
 

Figure 1: Kaplan-Meier Curves for Overall Survival – TORISEL vs. IFN

15 REFERENCES

  1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165.
  2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html
  3. American Society of Health-System Pharmacists. (2006) ASHP Guidelines on Handling Hazardous Drugs. Am J Health‑syst Pharm. 2006;63:1172-1193.
  4. Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society.

16 HOW SUPPLIED/STORAGE AND HANDLING

NDC 0008-1179-01 TORISEL® (temsirolimus) injection, 25 mg/mL.

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.

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