` 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
`
`
`
`————————— 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×ULN. (4)
`
`——————— WARNINGS AND PRECAUTIONS ————————
`
`
`
`Hypersensitivity/Infusion Reactions (including some life-threatening and
`
`
`•
`rare fatal reactions) can occur early in the first infusion of TORISEL.
`
`
`Patients should be monitored throughout the infusion. (5.1)
`
`
`
`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)
`
`
`
`•
`
`
`•
`
`
`•
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`1 INDICATIONS AND USAGE
`
`2 DOSAGE AND ADMINISTRATION
`2.1 Advanced Renal Cell Carcinoma
`
`
`2.2 Premedication
`
`2.3 Dosage Interruption/Adjustment
`
`
`2.4 Dose Modification Guidelines
`
`2.5 Instructions for Preparation
`
`2.6 Administration
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Hypersensitivity/Infusion Reactions
`
`5.2 Hepatic Impairment
`
`5.3 Hyperglycemia/Glucose Intolerance
`
`5.4 Infections
`
`
`5.5 Interstitial Lung Disease
`
`5.6 Hyperlipemia
`
`
`5.7 Bowel Perforation
`
`
`5.8 Renal Failure
`
`
`5.9 Wound Healing Complications
`
`
`
`5.10 Intracerebral Hemorrhage
`
`
`5.11 Co-administration with Inducers or Inhibitors of CYP3A
`
`
`
`Metabolism
`
`5.12 Concomitant use of TORISEL with sunitinib
`
`
`
`
`5.13 Vaccinations
`
`
`5.14 Use in Pregnancy
`
`
`5.15 Elderly Patients
`
`5.16 Monitoring Laboratory Tests
`
`
`
`
`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)
`
`
`
`Elderly patients may be more likely to experience certain adverse
`reactions, including diarrhea, edema and pneumonia. (5.15)
`
`
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`——————————— 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: 07/2016
`
`
`6 ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`
`6.2 Post-marketing and Other Clinical Experience
`
`7 DRUG INTERACTIONS
`
`7.1 Agents Inducing CYP3A Metabolism
`
`
`7.2 Agents Inhibiting CYP3A Metabolism
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`8.3 Nursing Mothers
`
`
`8.4 Pediatric Use
`
`
`8.5 Geriatric Use
`
`
`8.6 Renal Impairment
`
`
`8.7 Hepatic Impairment
`
`
`10 OVERDOSAGE
`
`11 DESCRIPTION
`
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`
`12.2 Pharmacodynamics
`
`12.3 Pharmacokinetics
`
`13 NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`14 CLINICAL STUDIES
`
`15 REFERENCES
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`17 PATIENT COUNSELING INFORMATION
`
`* Sections or subsections omitted from the full prescribing
`
`
`
`information are not listed.
`
`
`
`
`
`Reference ID: 3964379
`
`
`
` 1
`
`West-Ward Exhibit 1089
`TORISEL Prescribing Information
`Page 001
`
`

`

`
` 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
`
`
`Warnings and Precautions (5.1)].
`
`
`2.3 Dosage Interruption/Adjustment
`
`
` TORISEL should be held for absolute neutrophil count (ANC) <1,000/mm3, platelet count
`
` <75,000/mm3, or NCI CTCAE grade 3 or greater adverse reactions. Once toxicities have
`
`
`resolved to grade 2 or less, TORISEL may be restarted with the dose reduced by 5 mg/week to a
`
`dose no lower than 15 mg/week.
`
`
`
`2.4 Dose Modification Guidelines
`
`
`
`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×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×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)].
`
`
`
`
`
`Reference ID: 3964379
`
`
`
` 2
`
`
`West-Ward Exhibit 1089
`TORISEL Prescribing Information
`Page 002
`
`

`

`
`
`
`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)].
`
`
`
` 2.5 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).
`
`
`
`
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`
`
`
`
`
`
` • 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.
`
`
`
`Reference ID: 3964379
`
`
`
` 3
`
`
`West-Ward Exhibit 1089
`TORISEL Prescribing Information
`Page 003
`
`

`

`
`
` 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.
`
`2.6 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.
`
`
`Reference ID: 3964379
`
`
`
` 4
`
`
`West-Ward Exhibit 1089
`TORISEL Prescribing Information
`Page 004
`
`

`

`
`
` Compatibilities and Incompatibilities
`
`
`Undiluted TORISEL injection should not be added directly to aqueous infusion solutions. Direct
`
`addition of TORISEL injection to aqueous solutions will result in precipitation of drug. Always
`
`
`combine TORISEL injection with DILUENT for TORISEL before adding to infusion solutions.
`
`
`
`
`It is recommended that TORISEL be administered in 0.9% Sodium Chloride Injection after
`
`combining with diluent. The stability of TORISEL in other infusion solutions has not been
`
`evaluated. Addition of other drugs or nutritional agents to admixtures of TORISEL in 0.9%
`Sodium Chloride Injection has not been evaluated and should be avoided. Temsirolimus is
`
` degraded by both acids and bases, and thus combinations of temsirolimus with agents capable of
`
` modifying solution pH should be avoided.
`
`
`
`3
`DOSAGE FORMS AND STRENGTHS
`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.
`
`
`
`
`4
`
`
`
`
`CONTRAINDICATIONS
`
`
`TORISEL is contraindicated in patients with bilirubin >1.5×ULN [see Warnings and
`
`Precautions (5.2)].
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`5.1 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
`
`
`Reference ID: 3964379
`
`
`
` 5
`
`
`West-Ward Exhibit 1089
`TORISEL Prescribing Information
`Page 005
`
`

`

`
`
`
`
` hypersensitivity to an antihistamine, or patients who cannot receive an antihistamine for other
`
` medical reasons.
`
`If a patient develops a hypersensitivity reaction during the TORISEL infusion, the infusion
` should be stopped and the patient should be observed for at least 30 to 60 minutes (depending on
`
`
` the severity of the reaction). At the discretion of the physician, treatment may be resumed with
` the administration of an H1-receptor antagonist (such as diphenhydramine), if not previously
`
`
`administered [see Dosage and Administration (2.2)], and/or an H2-receptor antagonist (such as
`
`
`
`
`
`
`intravenous famotidine 20 mg or intravenous ranitidine 50 mg) approximately 30 minutes before
`
`
`
`restarting the TORISEL infusion. The infusion may then be resumed at a slower rate (up to
`
`
`60 minutes).
`
`A benefit-risk assessment should be done prior to the continuation of temsirolimus therapy in
`
`patients with severe or life-threatening reactions.
`
`
`
`5.2 Hepatic Impairment
`
`
`
`
`
`The safety and pharmacokinetics of TORISEL were evaluated in a dose escalation phase 1 study
`
`in 110 patients with normal or varying degrees of hepatic impairment. Patients with baseline
`
`
`
`
`bilirubin >1.5×ULN experienced greater toxicity than patients with baseline bilirubin ≤1.5×ULN
`
`when treated with TORISEL. The overall frequency of ≥ grade 3 adverse reactions and deaths,
`
`including deaths due to progressive disease, were greater in patients with baseline bilirubin
`>1.5×ULN due to increased risk of death [see Contraindications (4)].
`
`
`
`
`Use caution when treating patients with mild hepatic impairment. Concentrations of
`
`temsirolimus and its metabolite sirolimus were increased in patients with elevated AST or
`
`
`
`bilirubin levels. If TORISEL must be given in patients with mild hepatic impairment (bilirubin
`
`
`
`>1 – 1.5×ULN or AST >ULN but bilirubin ≤ULN), reduce the dose of TORISEL to 15 mg/week
`[see Dosage and Administration (2.4)].
`
`
`
`5.3 Hyperglycemia/Glucose Intolerance
`
`
`
`
`The use of TORISEL is likely to result in increases in serum glucose. In the phase 3 trial, 89% of
`
`
`patients receiving TORISEL had at least one elevated serum glucose while on treatment, and
`
`26% of patients reported hyperglycemia as an adverse event. This may result in the need for an
`
`increase in the dose of, or initiation of, insulin and/or oral hypoglycemic agent therapy. Serum
`
`glucose should be tested before and during treatment with TORISEL. Patients should be advised
`
`to report excessive thirst or any increase in the volume or frequency of urination.
`
`
`
`5.4 Infections
`
`
`The use of TORISEL may result in immunosuppression. Patients should be carefully observed
`
`for the occurrence of infections, including opportunistic infections [see Adverse Reactions (6.1)].
`
`
`
`
`
`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
`
`
`Reference ID: 3964379
`
`
`
` 6
`
`
`West-Ward Exhibit 1089
`TORISEL Prescribing Information
`Page 006
`
`

`

` immunosuppressive agents. Prophylaxis of PJP should be considered when concomitant use of
`
`
`
` corticosteroids or other immunosuppressive agents are required.
`
`
`5.5 Interstitial Lung Disease
`
`
`
`
`
`
`
`
`
`
`Cases of interstitial lung disease, some resulting in death, occurred in patients who received
`
`
`
`
`TORISEL. Some patients were asymptomatic, or had minimal symptoms, with infiltrates
`
`
`detected on computed tomography scan or chest radiograph. Others presented with symptoms
`
`such as dyspnea, cough, hypoxia, and fever. Some patients required discontinuation of TORISEL
`and/or treatment with corticosteroids and/or antibiotics, while some patients continued treatment
`
` without additional intervention. Patients should be advised to report promptly any new or
`
` worsening respiratory symptoms.
`
`
`
`
`It is recommended that patients undergo baseline radiographic assessment by lung computed
`
`tomography scan or chest radiograph prior to the initiation of TORISEL therapy. Follow such
`
`assessments periodically, even in the absence of clinical respiratory symptoms.
`
`
`
`
`It is recommended that patients be followed closely for occurrence of clinical respiratory
`
`
`
`symptoms. If clinically significant respiratory symptoms develop, consider withholding
`
`
`TORISEL administration until after recovery of symptoms and improvement of radiographic
`
`findings related to pneumonitis. Empiric treatment with corticosteroids and/or antibiotics may be
`
`
`considered. 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.
`
`
`
`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.
`
`
`
`Reference ID: 3964379
`
`
`
` 7
`
`
`West-Ward Exhibit 1089
`TORISEL Prescribing Information
`Page 007
`
`

`

`
`
` 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.
`
`
`
`Reference ID: 3964379
`
`
`
` 8
`
`
`West-Ward Exhibit 1089
`TORISEL Prescribing Information
`Page 008
`
`

`

`
`
` 5.14 Use in Pregnancy
`
`
`
`
`
`
` There are no adequate and well-controlled studies of TORISEL in pregnant women. However,
` based on its mechanism of action, TORISEL may cause fetal harm when administered to a
`
`
`
`
` pregnant woman. Temsirolimus administered daily as an oral formulation caused embryo-fetal
`
` and intrauterine toxicities in rats and rabbits at human sub-therapeutic exposures. If this drug is
`
` used during pregnancy or if the patient becomes pregnant while taking the drug, the patient
`should be apprised of the potential hazard to the fetus. Women of childbearing potential should
`be advised to avoid becoming pregnant throughout treatment and for 3 months after TORISEL
`
`therapy has stopped [see Use in Specific Populations (8.1)].
`
`
`
`
`
`
` Men should be counseled regarding the effects of TORISEL on the fetus and sperm prior to
` starting treatment [see Nonclinical Toxicology (13.1)]. Men with partners of childbearing
`
`
`potential should use reliable contraception throughout treatment and are recommended to
`continue this for 3 months after the last dose of TORISEL.
`
`
`5.15 Elderly Patients
`
`
`
`
`Based on the results of a phase 3 study, elderly patients may be more likely to experience certain
`
`
`
`adverse reactions including diarrhea, edema, and pneumonia [see Use in Specific
`
`
`
`Populations (8.5)].
`
`
`
`5.16 Monitoring Laboratory Tests
`
`
`
`In the randomized, phase 3 trial, complete blood counts (CBCs) were checked weekly, and
`
`chemistry panels were checked every two weeks. Laboratory monitoring for patients receiving
`
`
`
`
`TORISEL may need to be performed more or less frequently at the physician’s discretion.
`
`
`6
`
`
`ADVERSE REACTIONS
`
`
`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)]
`
`
`
`
`
`
`• Hepatic Impairment [see Warnings and Precautions (5.2)]
`
`
`
`
`• Hyperglycemia/Glucose Intolerance [see Warnings and Precautions (5.3)]
`
`
`
`
`Infections [see Warnings and Precautions (5.4)]
`
`
`
`
`
`•
`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)]
`
`
`
`
`• Wound Healing Complications [see Warnings and Precautions (5.9)]
`
`
`
`
`
`Intracerebral Hemorrhage [see Warnings and Precautions (5.10)]
`
`
`
`•
`
`
`
`
`Reference ID: 3964379
`
`
`
` 9
`
`
`West-Ward Exhibit 1089
`TORISEL Prescribing Information
`Page 009
`
`

`

`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
`
`
`
`
` TORISEL
`
`
` 25 mg
`
` n = 208
`
`
`
` Grades
`
` 3&4*
`
` n (%)
`
`
` 23 (11)
`
`7 (3)
`
`10 (5)
`
`1 (1)
`
`3 (1)
`
`1 (1)
`
`2 (1)
`
` 1 (1)
`
` 6 (3)
`
` All
`
`
` Grades*
`
` n (%)
`
`
` 106 (51)
`
`73 (35)
`
`59 (28)
`
`50 (24)
`
`39 (19)
`
`31 (15)
`
`34 (16)
`
` 17 (8)
`
` 86 (41)
`
`
`
`
`
`
` Adverse Reaction
`
` General disorders
`
`
` Asthenia
`
` Edemaa
`
`
`
`Pain
`
`
`Pyrexia
`
`
`Weight Loss
`
`
`Headache
`
`
`Chest Pain
`
`
` Chills
` Gastrointestinal disorders
`
` Mucositisb
`
`
`
`
`
`Reference ID: 3964379
`
`
`
` 10
`
`
`
`
`
` All
`
`
` Grades*
`
` n (%)
`
`
` 127 (64)
`
`21 (11)
`
`31 (16)
`
`99 (50)
`
`50 (25)
`
`30 (15)
`
`
`18 (9)
` 59 (30)
`
`
` 19 (10)
`
`
`
` IFN-α
`
`
` n = 200
`
`
` Grades
`
` 3&4*
`
` n (%)
`
`
` 52 (26)
`
`1 (1)
`
`4 (2)
`
`7 (4)
`
`4 (2)
`
`0 (0)
`
`2 (1)
`
` 3 (2)
`
` 0 (0)
`
`
`
`West-Ward Exhibit 1089
`TORISEL Prescribing Information
`Page 0010
`
`

`

`
`
` Table 1 – Adverse Reactions Reported in at Least 10% of Patients Who Received 25 mg IV
`
`
`
`
` TORISEL or IFN-α in the Randomized Trial
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` TORISEL
`
`
` 25 mg
`
` n = 208
`
`
`
`
` 66 (32)
` 6 (3)
`
` 5 (2)
`
` 77 (37)
`
` 56 (27)
`
` 3 (1)
`
` 44 (21)
`
` 9 (4)
`
` 42 (20)
`
` 0 (0)
`
` 40 (19)
`
` 4 (2)
`
`
`
` IFN-α
`
`
`
`
` n = 200
`
` 8 (4)
`
` 87 (44)
`
` 9 (5)
`
` 82 (41)
`
` 4 (2)
`
` 40 (20)
`
` 3 (2)
`
` 34 (17)
`
` 1 (1)
`
` 36 (18)
`
` 5 (3)
`
` 57 (29)
`
`
` 42 (20)
`
`31 (15)
`
`25 (12)
`
` 20 (10)
`
`
` 41 (20)
`
` 37 (18)
`
` 16 (8)
`
`
` 58 (28)
`
` 53 (26)
`
` 25 (12)
`
`
` 97 (47)
`
` 40 (19)
`
` 28 (14)
`
` 22 (11)
`
` 21 (10)
`
`
` 6 (3)
`
`3 (1)
`
`0 (0)
`
` 0 (0)
`
`
` 6 (3)
`
` 2 (1)
`
` 1 (1)
`
`
` 18 (9)
`
` 2 (1)
`
` 0 (0)
`
`
` 10 (5)
`
` 1 (1)
`
` 0 (0)
`
` 1 (1)
`
` 0 (0)
`
`
` 19 (10)
`
`24 (12)
`
`3 (2)
`
` 4 (2)
`
`
` 28 (14)
`
` 29 (15)
`
` 29 (15)
`
`
` 48 (24)
`
` 29 (15)
`
` 7 (4)
`
`
` 14 (7)
`
` 16 (8)
` 1 (1)
`
` 14 (7)
`
`
` 2 (1)
`
`
` 17 (9)
` 30 (15)
`
`
` 27 (14)
`
`
` 4 (2)
`
`3 (2)
`
`0 (0)
`
` 0 (0)
`
`
` 7 (4)
`
` 2 (1)
`
` 2 (1)
`
`
` 11 (6)
`
` 0 (0)
`
` 0 (0)
`
`
` 0 (0)
`
` 0 (0)
`
` 0 (0)
`
` 0 (0)
`
` 0 (0)
`
`
` 0 (0)
`
` 0 (0)
`
` 4 (2)
`
` Adverse Reaction
`
`
` Anorexia
`
` Nausea
`
`
` Diarrhea
`
`
` Abdominal Pain
`
`
` Constipation
`
` Vomiting
`
` Infections
`
`
` Infectionsc
`
` Urinary tract infectiond
`
`
`
`Pharyngitis
`
`
` Rhinitis
` Musculoskeletal and connective tissue disorders
`
`
` Back Pain
`
`
` Arthralgia
`
`
` Myalgia
` Respiratory, thoracic and mediastinal disorders
`
`
` Dyspnea
`
`
` Cough
`
`
` Epistaxis
` Skin and subcutaneous tissue disorders
`
` Rashe
`
`
`
` Pruritus
`
` Nail Disorder
`
`
` Dry Skin
`
`
`
` Acne
` Nervous system disorders
`
` Dysgeusiaf
`
` 41 (20)
`
`
` 0 (0)
`
` 24 (12)
`
`
` Insomnia
`
` 1 (1)
`
`
`
` Depression
` 9 (4)
`
` 0 (0)
` * Common Toxicity Criteria for Adverse Events (CTCAE), Version 3.0.
`
`
` a Includes edema, facial edema, and peripheral edema