Torisel is indicated for the treatment of advanced renal cell carcinoma.
Torisel Dosage and Administration
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.
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)].
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.
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 Warnings and Precautions (5.11) and 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 Warnings and Precautions (5.11) and Drug Interactions (7.1)].
Instructions for Preparation
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.
Step 1:
DILUTION OF Torisel INJECTION 25 MG/ML WITH SUPPLIED DILUENT
- Each Vial of Torisel (temsirolimus) must first be mixed with 1.8 mL of the enclosed diluent. The resultant solution contains 30 mg/3 mL (10 mg/mL)
- Mix well by inversion of the vial. Allow sufficient time for the air bubbles to subside. The solution should be clear to slightly turbid, colorless to light-yellow solution, essentially free from visual particulates.
The concentrate-diluent mixture is stable below 25ºC for up to 24 hours.
Step 2:
DILUTION OF CONCENTRATE-DILUENT MIXTURE WITH 0.9% SODIUM CHLORIDE INJECTION, USP
- Withdraw precisely the required amount of concentrate-diluent mixture containing temsirolimus 10 mg/mL as prepared in Step 1 from the vial (i.e., 2.5 mL for a temsirolimus dose of 25 mg) and further dilute into an infusion bag containing 250 mL of 0.9% Sodium Chloride Injection, USP
- Mix by inversion of the bag or bottle, avoiding excessive shaking, as this may cause foaming.
The resulting solution should be inspected visually for particulate matter and discoloration prior to administration. The admixture of Torisel in 0.9% Sodium Chloride Injection, USP should be protected from excessive room light and sunlight.
Administration
- 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.
Dosage Forms and Strengths
Torisel® (temsirolimus) is supplied as a kit consisting of the following:
Torisel (temsirolimus) injection (25 mg/mL). The Torisel vial contains temsirolimus at a concentration of 25 mg/mL. The vial contains an overfill of 0.2 mL to ensure the ability to withdraw the recommended dose.
DILUENT for Torisel®. The DILUENT vial includes a deliverable volume of 1.8 mL. This vial contains an overfill in order to ensure that the appropriate volume can be withdrawn.
Contraindications
Torisel is contraindicated in patients with bilirubin >1.5 x ULN [ see Warnings and Precautions ( 5.2 )].
Warnings and Precautions
Hypersensitivity/Infusion Reactions
Hypersensitivity/infusion reactions, including but not limited to flushing, chest pain, dyspnea, hypotension, apnea, loss of consciousness, hypersensitivity and anaphylaxis, have been associated with the administration of temsirolimus. These reactions can occur very early in the first infusion, but may also occur with subsequent infusions. Patients should be monitored throughout the infusion and appropriate supportive care should be available. Temsirolimus infusion should be interrupted in all patients with severe infusion reactions and appropriate medical therapy administered.
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.
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 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 ) ].
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.
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)].
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.
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.
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.
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.
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.
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.
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)].
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).
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.
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.
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)].
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.
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/Infusion 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.
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 (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%).
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) |
Post-marketing and Other Clinical Experience
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.
Drug Interactions
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)].
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)].
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.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category D [see Warnings and Precautions (5.14)].
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.
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).
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.
Pediatric Use
The safety and effectiveness of Torisel in pediatric patients have not been established.
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. 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)].
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.
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.
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.
Torisel 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
