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 eva luated. Addition of other drugs or nutritional agents to admixtures of TORISEL in sodium chloride injection has not been eva luated 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 eva luated 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.

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%).

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