The recommended dose of TORISEL for advanced renal cell carcinoma is 25 mg administered as an intravenous infusion over a 30 – 60 minute period once a week.

Treatment should continue until disease progression or unacceptable toxicity occurs.

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)].

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.

TORISEL is a cytotoxic drug. Follow applicable special handling and disposal procedures ¹ .

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note that both the TORISEL injection and diluent vials contain an overfill to ensure the recommended volume can be withdrawn.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

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.

The safety and pharmacokinetics of TORISEL were evaluated in a dose escalation phase 1 study in 110 patients with normal or varying degrees of hepatic impairment. Patients with baseline bilirubin >1.5×ULN experienced greater toxicity than patients with baseline bilirubin ≤1.5×ULN when treated with TORISEL. The overall frequency of ≥ grade 3 adverse reactions and deaths, including deaths due to progressive disease, were greater in patients with baseline bilirubin >1.5×ULN due to increased risk of death [see Contraindications (4)].

Use caution when treating patients with mild hepatic impairment. Concentrations of temsirolimus and its metabolite sirolimus were increased in patients with elevated AST or bilirubin levels. If TORISEL must be given in patients with mild hepatic impairment (bilirubin >1 – 1.5×ULN or AST >ULN but bilirubin ≤ULN), reduce the dose of TORISEL to 15 mg/week [see Dosage and Administration (2.4)].

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.

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)].

Pneumocystis jiroveci pneumonia (PJP), including fatalities, has been reported in patients who received temsirolimus. This may be associated with concomitant use of corticosteroids or other immunosuppressive agents. Prophylaxis of PJP should be considered when concomitant use of corticosteroids or other immunosuppressive agents are required.

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. Opportunistic infections such as PJP should be considered in the differential diagnosis. For patients who require use of corticosteroids, prophylaxis of PJP may be considered.

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.

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.

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.

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

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.

Proteinuria (including cases of nephrotic syndrome) has occurred in patients treated with TORISEL. Monitor urine protein prior to the start of TORISEL therapy and periodically thereafter. Discontinue TORISEL in patients who develop nephrotic syndrome.

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).

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.

Based on findings in animal studies and its mechanism of action, TORISEL can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, daily oral administration of temsirolimus to pregnant animals during organogenesis caused adverse embryo-fetal effects in rats and rabbits at approximately 0.04 and 0.12 times the AUC in patients at the recommended human dose, respectively. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TORISEL and for 3 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with TORISEL and for 3 months after the last dose [see Clinical Pharmacology (12.1) and Use in Specific Populations (8.1 , 8.3) ].

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)].

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 Common Toxicity Criteria for Adverse Events (CTCAE), Version 3.0. n (%)	Grades 3&4 n (%)	All Grades n (%)	Grades 3&4 n (%)
General disorders
Asthenia	106 (51)	23 (11)	127 (64)	52 (26)
EdemaIncludes edema, facial edema, and peripheral edema	73 (35)	7 (3)	21 (11)	1 (1)
Pain	59 (28)	10 (5)	31 (16)	4 (2)
Pyrexia	50 (24)	1 (1)	99 (50)	7 (4)
Weight Loss	39 (19)	3 (1)	50 (25)	4 (2)
Headache	31 (15)	1 (1)	30 (15)	0 (0)
Chest Pain	34 (16)	2 (1)	18 (9)	2 (1)
Chills	17 (8)	1 (1)	59 (30)	3 (2)
Gastrointestinal disorders
MucositisIncludes aphthous stomatitis, glossitis, mouth ulceration, mucositis, and stomatitis	86 (41)	6 (3)	19 (10)	0 (0)
Anorexia	66 (32)	6 (3)	87 (44)	8 (4)
Nausea	77 (37)	5 (2)	82 (41)	9 (5)
Diarrhea	56 (27)	3 (1)	40 (20)	4 (2)
Abdominal Pain	44 (21)	9 (4)	34 (17)	3 (2)
Constipation	42 (20)	0 (0)	36 (18)	1 (1)
Vomiting	40 (19)	4 (2)	57 (29)	5 (3)
Infections
InfectionsIncludes infections not otherwise specified (NOS) and the following infections that occurred infrequently as distinct entities: abscess, bronchitis, cellulitis, herpes simplex, and herpes zoster	42 (20)	6 (3)	19 (10)	4 (2)
Urinary tract infectionIncludes cystitis, dysuria, hematuria, urinary frequency, and urinary tract infection	31 (15)	3 (1)	24 (12)	3 (2)
Pharyngitis	25 (12)	0 (0)	3 (2)	0 (0)
Rhinitis	20 (10)	0 (0)	4 (2)	0 (0)
Musculoskeletal and connective tissue disorders
Back Pain	41 (20)	6 (3)	28 (14)	7 (4)
Arthralgia	37 (18)	2 (1)	29 (15)	2 (1)
Myalgia	16 (8)	1 (1)	29 (15)	2 (1)
Respiratory, thoracic and mediastinal disorders
Dyspnea	58 (28)	18 (9)	48 (24)	11 (6)
Cough	53 (26)	2 (1)	29 (15)	0 (0)
Epistaxis	25 (12)	0 (0)	7 (4)	0 (0)
Skin and subcutaneous tissue disorders
RashIncludes eczema, exfoliative dermatitis, maculopapular rash, pruritic rash, pustular rash, rash (NOS), and vesiculobullous rash	97 (47)	10 (5)	14 (7)	0 (0)
Pruritus	40 (19)	1 (1)	16 (8)	0 (0)
Nail Disorder	28 (14)	0 (0)	1 (1)	0 (0)
Dry Skin	22 (11)	1 (1)	14 (7)	0 (0)
Acne	21 (10)	0 (0)	2 (1)	0 (0)
Nervous system disorders
DysgeusiaIncludes taste loss and taste perversion	41 (20)	0 (0)	17 (9)	0 (0)
Insomnia	24 (12)	1 (1)	30 (15)	0 (0)
Depression	9 (4)	0 (0)	27 (14)	4 (2)

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

Gastrointestinal Disorders – Gastrointestinal hemorrhage (1%), rectal hemorrhage (1%).

Eye Disorders – Conjunctivitis (including lacrimation disorder) (8%).

Immune System – 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 (8%), upper respiratory tract infection (7%), wound infection/post-operative wound infection (1%), sepsis (1%).

General Disorders and Administration Site Conditions - Diabetes mellitus (5%).

Respiratory, Thoracic and Mediastinal Disorders – Pleural effusion (4%).

Vascular – Hypertension (7%), venous thromboembolism (including deep vein thrombosis and pulmonary embolus [including fatal outcomes]) (2%), thrombophlebitis (1%), pericardial effusion (1%).

Nervous System Disorders – Convulsion (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 NCI CTC version 3.0 n (%)	Grades 3&4 n (%)	All Grades n (%)	Grades 3&4 n (%)
Any	208 (100)	162 (78)	195 (98)	144 (72)
Hematology
Hemoglobin Decreased	195 (94)	41 (20)	180 (90)	43 (22)
Lymphocytes DecreasedGrade 1 toxicity may be under-reported for lymphocytes and neutrophils	110 (53)	33 (16)	106 (53)	48 (24)
Neutrophils Decreased	39 (19)	10 (5)	58 (29)	19 (10)
Platelets Decreased	84 (40)	3 (1)	51 (26)	0 (0)
Leukocytes Decreased	67 (32)	1 (1)	93 (47)	11 (6)
Chemistry
Alkaline Phosphatase Increased	141 (68)	7 (3)	111 (56)	13 (7)
AST Increased	79 (38)	5 (2)	103 (52)	14 (7)
Creatinine Increased	119 (57)	7 (3)	97 (49)	2 (1)
Glucose Increased	186 (89)	33 (16)	128 (64)	6 (3)
Phosphorus Decreased	102 (49)	38 (18)	61 (31)	17 (9)
Total Bilirubin Increased	16 (8)	2 (1)	25 (13)	4 (2)
Total Cholesterol Increased	181 (87)	5 (2)	95 (48)	2 (1)
Triglycerides Increased	173 (83)	92 (44)	144 (72)	69 (35)
Potassium Decreased	43 (21)	11 (5)	15 (8)	0 (0)

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: angioedema, rhabdomyolysis, Stevens-Johnson Syndrome, complex regional pain syndrome (reflex sympathetic dystrophy), pancreatitis, cholecystitis, and cholelithiasis.

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

Co-administration of TORISEL with rifampin, a potent CYP3A4/5 inducer, had no significant effect on temsirolimus C_max (maximum concentration) and AUC (area under the concentration versus the time curve) after intravenous administration, but decreased sirolimus C_max 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)].

Co-administration of TORISEL with ketoconazole, a potent CYP3A4 inhibitor, had no significant effect on temsirolimus C_max or AUC; however, sirolimus AUC increased 3.1-fold, and C_max 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)].

Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with ramipril and/or amlodipine. Monitor patients for signs and symptoms of angioedema when temsirolimus is given concomitantly with angiotensin converting enzyme (ACE) inhibitors (e.g., ramipril) or calcium channel blockers (CCB) (e.g., amlodipine).

Limited data are available on the use of temsirolimus in pediatric patients. The effectiveness of temsirolimus in pediatric patients with advanced recurrent/refractory solid tumors has not been established.

TORISEL was studied in 71 patients (59 patients ages 1 to 17 years and 12 patients ages 18 to 21 years) with relapsed/refractory solid tumors in a phase 1–2 safety and exploratory pharmacodynamic study.

In phase 1, 19 pediatric patients with advanced recurrent/refractory solid tumors received TORISEL at doses ranging from 10 mg/m² to 150 mg/m² as a 60-minute intravenous infusion once weekly in three-week cycles.

In phase 2, 52 pediatric patients with recurrent/relapsed neuroblastoma, rhabdomyosarcoma, or high grade glioma received TORISEL at a weekly dose of 75 mg/m². One of 19 patients with neuroblastoma achieved a partial response. There were no objective responses in pediatric patients with recurrent/relapsed rhabdomyosarcoma or high grade glioma.

Adverse reactions associated with TORISEL were similar to those observed in adults. The most common adverse reactions (≥20%) in pediatric patients receiving the 75 mg/m² dose included thrombocytopenia, infections, asthenia/fatigue, fever, pain, leukopenia, rash, anemia, hyperlipidemia, increased cough, stomatitis, anorexia, increased plasma levels of alanine aminotransferase and aspartate aminotransferase, hypercholesterolemia, hyperglycemia, abdominal pain, headache, arthralgia, upper respiratory infection, nausea and vomiting, neutropenia, hypokalemia, and hypophosphatemia.

Clinical studies of TORISEL did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. Based on the results of a phase 3 study, elderly patients may be more likely to experience certain adverse reactions including diarrhea, edema, and pneumonia [see Warnings and Precautions (5.16)].

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.

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 Hepatic Function Groups: normal = bilirubin and AST ≤ULN; mild = bilirubin >1 – 1.5×ULN or AST >ULN but bilirubin ≤ULN; moderate = bilirubin >1.5 – 3×ULN; severe = bilirubin >3×ULN; liver transplant = any bilirubin and AST.	TORISEL Dose Range	Adverse Reactions Grade ≥ 3 Common Terminology Criteria for Adverse Events, version 3.0, including all causality. n (%)	Death Includes deaths due to progressive disease and adverse reactions. 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×ULN [see Contraindications (4), and Warnings and Precautions (5.2)]. Use caution when treating patients with mild hepatic impairment. If TORISEL must be given in patients with mild hepatic impairment (bilirubin >1–1.5×ULN or AST >ULN but bilirubin ≤ULN), reduce the dose of TORISEL to 15 mg/week [see Dosage and Administration (2.4)]. Because there is a need for dosage adjustment based upon hepatic function, assessment of AST and bilirubin levels is recommended before initiation of TORISEL and periodically thereafter.

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.

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

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 a fertility study in male rats, decreased number of pregnancies, decreased sperm concentration and motility, decreased reproductive organ weights, and testicular tubular degeneration were observed. 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 a fertility study 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.

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 2º–8º C (36º–46º F). Protect from light.

TORISEL is a cytotoxic drug. Follow applicable special handling and disposal procedures¹.

Allergic (Hypersensitivity/Infusion) Reactions

Patients should be informed of the possibility of serious allergic reactions, including anaphylaxis (including life threatening and fatal reactions), despite premedication with antihistamines, and to immediately report any facial swelling or difficulty breathing [see Warnings and Precautions (5.1)].

Increased Blood Glucose Levels

Patients are likely to experience increased blood glucose levels while taking TORISEL. This may result in the need for initiation of, or increase in the dose of, insulin and/or hypoglycemic agents. Patients should be directed to report any excessive thirst or frequency of urination to their physician [see Warnings and Precautions (5.3)].

Infections

Patients should be informed that they may be more susceptible to infections while being treated with TORISEL [see Warnings and Precautions (5.4)].

Interstitial Lung Disease

Patients should be warned of the possibility of developing interstitial lung disease, a chronic inflammation of the lungs, which may rarely result in death [see Warnings and Precautions (5.5)]. Patients, including those who are taking or have taken corticosteroids or immunosuppressive agents, should be directed to report promptly any new or worsening respiratory symptoms to their physician.

Increased Blood Triglycerides and/or Cholesterol

Patients are likely to experience elevated triglycerides and/or cholesterol during TORISEL treatment. This may require initiation of, or increase in the dose of, lipid-lowering agents [see Warnings and Precautions (5.6)].

Bowel Perforation

Patients should be warned of the possibility of bowel perforation. Patients should be directed to report promptly any new or worsening abdominal pain or blood in their stools [see Warnings and Precautions (5.7)].

Renal Failure

Patients should be informed of the risk of renal failure [see Warnings and Precautions (5.8)].

Wound Healing Complications

Patients should be advised of the possibility of abnormal wound healing if they have surgery within a few weeks of initiating therapy or during therapy [see Warnings and Precautions (5.9)].

Intracerebral Bleeding

Patients with CNS tumors and/or receiving anticoagulants should be informed of the increased risk of developing intracerebral bleeding (including fatal outcomes) while on TORISEL [see Warnings and Precautions (5.10)].

Proteinuria and Nephrotic Syndrome

Advise patients that treatment with TORISEL may require monitoring for proteinuria and nephrotic syndrome and to contact their health care provider for signs and symptoms of nephrotic syndrome [see Warnings and Precautions (5.11)].

Medications that can interfere with TORISEL

Some medicines can interfere with the breakdown or metabolism of TORISEL. In particular, patients should be directed to inform their physician if they are taking any of the following: Protease inhibitors, anti-epileptic medicines including carbamazepine, phenytoin, and barbiturates, St. John's Wort, rifampicin, rifabutin, nefazodone or selective serotonin re-uptake inhibitors used to treat depression, antibiotics or antifungal medicines used to treat infections [see Warnings and Precautions (5.12)].

Vaccinations

Patients should be advised that vaccinations may be less effective while being treated with TORISEL. In addition, the use of live vaccines, and close contact with those who have received live vaccines, while on TORISEL should be avoided [see Warnings and Precautions (5.14)].

Embryo-Fetal Toxicity

Advise pregnant women and females of reproductive potential that TORISEL can cause fetal harm. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.15) and Use in Specific Populations (8.1)].

Advise females of reproductive potential to use effective contraception during treatment with TORISEL and for 3 months after receiving the last dose [see Use in Specific Populations (8.3)].

Advise males with female partners of reproductive potential to use effective contraception during treatment with TORISEL and for 3 months after receiving the last dose [see Use in Specific Populations (8.3)].

Lactation

Advise lactating women not to breastfeed during treatment with TORISEL and for 3 weeks after the last dose [see Use in Specific Populations (8.2)].

Infertility

Advise patients that male and female fertility may be compromised by treatment with TORISEL [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)].

Elderly Patients

Elderly patients should be advised that they may be more likely to experience certain adverse reactions including diarrhea, edema, and pneumonia [see Warnings and Precautions (5.16)].