`
`
`
`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`
`
`
`
`Public Health Service
`Food and Drug Administration
`Rockville, MD 20857
`
`
`
`
`NDA 22-088
`
`Wyeth Pharmaceuticals
`Attention: Patricia Johnson
`Director, Regulatory Affairs
`35 CambridgePark Drive
`Cambridge, MA 02140
`
`
`Dear Ms. Johnson:
`
`Please refer to your new drug application (NDA) dated October 5, 2006, received October 5, 2006,
`submitted under 505(b) of the Federal Food, Drug, and Cosmetic Act for TORISEL™ (temsirolimus)
`injection.
`
`We acknowledge receipt of your submissions dated October 18, 2006; November 16, 21, and 22, 2006;
`December 5, and 13, 2006; January 19, and 26, 2007; February 20, 22, and 23, 2007; March 7, and 9,
`2007; April 5, 12, 17, and 30, 2007, and May 4, 2007.
`
`This new drug application provides for the use of TORISEL™ (temsirolimus) injection, for the
`treatment of advanced renal cell carcinoma.
`
`We completed our review of this application, as amended. It is approved, effective on the date of this
`letter, for use as recommended in the agreed-upon labeling text.
`
`Within 21 days of the date of this letter, submit content of labeling [21 CFR 314.50(l)] in structured
`product labeling (SPL) format, as described at http://www.fda.gov/oc/datacouncil/spl.html, that is
`identical in content to the enclosed labeling text. Upon receipt, we will transmit that version to the
`National Library of Medicine for public dissemination. For administrative purposes, please designate
`this submission “SPL for approved NDA 22-088.”
`
`The final printed labeling (FPL) for immediate container and carton labels must be identical to the
`enclosed labeling. Marketing the product with FPL that is not identical to the approved labeling text
`may render the product misbranded and an unapproved new drug.
`
`Please submit an electronic version of the FPL according to the guidance for industry titled Providing
`Regulatory Submissions in Electronic Format - NDA. Alternatively, you may submit 20 paper copies
`of the FPL as soon as it is available but no more than 30 days after it is printed. Individually mount 15
`of the copies on heavy-weight paper or similar material. For administrative purposes, designate this
`submission “FPL for approved NDA 22-088”. Approval of this submission by FDA is not required
`before the labeling is used.
`
`We remind you of your postmarketing study commitments in your submission dated May 24, 2007.
`
`
`West-Ward Exhibit 1088
`TORISEL Approval
`Page 001
`
`

`

`NDA 22-088
`Page 2
`
`These commitments are listed below.
`
`
`1. Submit the completed report and data sets for the thorough QT prolongation evaluation for
`study entitled "A single-dose, single-blind, placebo and moxifloxacin controlled 2- period,
`randomized, crossover, 3rd-period sequential study of the effects of temsirolimus on cardiac
`repolarization in healthy subjects".
`
`
`
`
`Protocol Submission: March 2006
`
`Study Start: March 2006
`
`Final Report Submission: September 2007
`
`
`2. Submit the completed report and datasets for the hepatic impairment study (NCI study
`6813 (3066K1-152-US))
`
`
`
`
`
`Protocol Submission: November 2005
`Study Start: January 2006
`
`
`Final Report Submission: September 2008
`
`
`
`
`Submit clinical protocols to your IND for this product. Submit nonclinical and chemistry,
`manufacturing, and controls protocols and all study final reports to this NDA. In addition, under 21
`CFR 314.81(b)(2)(vii) and 314.81(b)(2)(viii), you should include a status summary of each
`commitment in your annual report to this NDA. The status summary should include expected
`summary completion and final report submission dates, any changes in plans since the last annual
`report, and, for clinical studies, number of patients entered into each study. All submissions, including
`supplements, relating to these postmarketing study commitments must be prominently labeled
`“Postmarketing Study Commitment Protocol”, “Postmarketing Study Commitment Final
`Report”, or “Postmarketing Study Commitment Correspondence.”
`
`We have the following comments and risk management statements regarding CMC.
`
`
`1. As stated in the April 5, 2007 meeting, your proposed Chemistry, Manufacturing
`and Controls (CMC) Regulatory Agreement, submitted as part of the CMC Pilot
`program, was not reviewed and is not part of this approval action. Existing
`regulations and guidances should be followed, as appropriate, for all postapproval
`CMC changes. We remind you that you must comply with the reporting
`requirements for an approved NDA (21 CFR 314.80 and 314.81).
`
`2. We have not completed validation of the regulatory methods. However, we
`expect your continued cooperation to resolve any problems that may be identified
`during this process.
`
`
`We remind you of our agreements that were made in the April 5, 2007 teleconference and in your
`submission dated April 12, 2007. These agreements are listed below:
`
`
`1. You have agreed to investigate the use of a flag label, or a suitable alternative, in
`order to incorporate additional information in the container labels for both the
`diluent and active vials.
`
`2. You have agreed to submit the developed strategy for the above agreement in a
`
`West-Ward Exhibit 1088
`TORISEL Approval
`Page 002
`
`

`

`NDA 22-088
`Page 3
`
`
`Prior Approval supplement.
`
`3. You have agreed to further discussions with the Agency regarding packaging
`technology options available, to ensure the physical connection of the two copackaged
`vials.
`
`
`In addition, submit three copies of the introductory promotional materials that you propose to use for
`this product. Submit all proposed materials in draft or mock-up form, not final print. Send two copies
`of both the promotional materials and the package insert directly to:
`
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Drug Marketing, Advertising, and Communications
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`We remind you that you must comply with reporting requirements for an approved NDA (21 CFR
`314.80 and 314.81).
`
`The MedWatch-to-Manufacturer Program provides manufacturers with copies of serious adverse event
`reports that are received directly by the FDA. New molecular entities and important new biologics
`qualify for inclusion for three years after approval. Your firm is eligible to receive copies of reports for
`this product. To participate in the program, please see the enrollment instructions and program
`description details at www.fda.gov/medwatch/report/mmp.htm.
`
`If you have any questions, call Carl Huntley, Regulatory Project Manager, at (301) 796-1372.
`
`
`
`
`
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Richard Pazdur, M.D.
`Director
`Office of Oncology Drug Products
`Office of New Drugs
`Center for Drug Evaluation and Research
`Food and Drug Administration
`
`
`
`
`
`Enclosure
`
`
`West-Ward Exhibit 1088
`TORISEL Approval
`Page 003
`
`

`

`---------------------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
` /s/
`---------------------
`Richard Pazdur
`5/30/2007 03:06:27 PM
`
`West-Ward Exhibit 1088
`TORISEL Approval
`Page 004
`
`

`

`(cid:131) 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. (5.4)
`(cid:131)
`Bowel perforation may occur. Evaluate fever, abdominal pain, bloody
`stools, and/or acute abdomen promptly. (5.6)
`(cid:131)
`Renal failure, sometimes fatal, has occurred. Monitor renal function at
`baseline and while on TORISEL. (5.7)
`(cid:131) Due to abnormal wound healing, use TORISEL with caution in the
`perioperative period. (5.8)
`(cid:131)
`Live vaccinations and close contact with those who received live
`vaccines should be avoided. (5.12)
`(cid:131) Women of childbearing potential should be advised of the potential
`hazard to the fetus and to avoid becoming pregnant. (5.13)
`
`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 ---------- ----
`(cid:131)
`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)
`(cid:131) Antihistamine pre-treatment is recommended. (2.2)
`(cid:131)
`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 ----------------------
`(cid:131) None. (4)
`
`
`---------------------------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----------------------
`--------------------WARNINGS AND PRECAUTIONS ---------------
`Strong inducers of CYP3A4/5 and inhibitors of CYP3A4 may affect
`(cid:131)
`To treat hypersensitivity reactions stop TORISEL and treat with an
`concentrations of the primary metabolite of TORISEL. If alternatives cannot
`antihistamine. TORISEL may be restarted at physician discretion at a
`be used, dose modifications of TORISEL are recommended. (7.1, 7.2)
`slower rate. (5.1)
`
`
`(cid:131) Hyperglycemia and hyperlipemia are likely and may require treatment.
`See 17 for PATIENT COUNSELING INFORMATION.
`Monitor glucose and lipid profiles. (5.2, 5.5)
`Revision date: 5/2007
`(cid:131)
`Infections may result from immunosuppression. (5.3)
`---------------------------------------------------------------------------------------------------------------------
`FULL PRESCRIBING INFORMATION: CONTENTS [*]
`7
`DRUG INTERACTIONS
`7.1
`Agents Inducing CYP3A Metabolism
`7.2
`Agents Inhibiting CYP3A Metabolism
`7.3
`Interactions with Drugs Metabolized by CYP2D6
`
`1
`
`2
`2.1
`2.2
`2.3
`2.4
`2.5
`
`INDICATIONS AND USAGE
`
`DOSAGE AND ADMINISTRATION
`Advanced Renal Cell Carcinoma
`Premedication
`Dosage Interruption/Adjustment
`Dose Modification Guidelines
`Instructions for Preparation and Administration
`
`3
`
`4
`
`5
`5.1
`5.2
`5.3
`5.4
`5.5
`5.6
`5.7
`5.8
`5.9
`5.10
`
`5.11
`5.12
`5.13
`5.14
`
`6
`6.1
`
`DOSAGE FORMS AND STRENGTHS
`
`CONTRAINDICATIONS
`
`WARNINGS AND PRECAUTIONS
`Hypersensitivity Reactions
`Hyperglycemia/Glucose Intolerance
`Infections
`Interstitial Lung Disease
`Hyperlipemia
`Bowel Perforation
`Renal Failure
`Wound Healing Complications
`Intracerebral Hemorrhage
`Co-administration with Inducers or Inhibitors of
`CYP3A Metabolism
`Concomitant use of TORISEL with sunitinib
`Vaccinations
`Pregnancy
`Monitoring Laboratory Tests
`
`ADVERSE REACTIONS
`Clinical Trials Experience
`
`*Sections or subsections omitted from the full prescribing information are not listed.
`1
`
`8
`8.1
`8.3
`8.4
`8.5
`8.6
`8.7
`
`10
`
`11
`
`12
`12.1
`12.3
`
`13
`13.1
`
`14
`
`15
`
`16
`
`17
`
`USE IN SPECIFIC POPULATIONS
`Pregnancy
`Nursing Mothers
`Pediatric Use
`Geriatric Use
`Renal Impairment
`Hepatic Impairment
`
`OVERDOSAGE
`
`DESCRIPTION
`
`CLINICAL PHARMACOLOGY
`Mechanism of Action
`Pharmacokinetics
`
`NONCLINICAL TOXICOLOGY
`Carcinogenesis, Mutagenesis, Impairment of
`Fertility
`
`CLINICAL STUDIES
`
`REFERENCES
`
`HOW SUPPLIED/STORAGE AND HANDLING
`
`PATIENT COUNSELING INFORMATION
`
`West-Ward Exhibit 1088
`TORISEL Approval
`Page 005
`
`

`

`
`FULL PRESCRIBING INFORMATION
`1
`INDICATIONS AND USAGE
`TORISEL is indicated for the treatment of advanced renal cell carcinoma.
`2
`DOSAGE AND ADMINISTRATION
`2.1
`Advanced Renal Cell Carcinoma
`The recommended dose of TORISEL for advanced renal cell carcinoma is 25 mg infused over a
`30-60 minute period once a week.
`Treatment should continue until disease progression or unacceptable toxicity occurs.
`2.2
`Premedication
`Patients should receive prophylactic intravenous diphenhydramine 25 to 50 mg (or similar
`antihistamine) approximately 30 minutes before the start of each dose of TORISEL [see
`Hypersensitivity Reactions (5.1)].
`2.3
`Dosage Interruption/Adjustment
`TORISEL should be held for absolute neutrophil count (ANC) < 1,000/mm3, platelet count <
`75,000/mm3, or NCI CTCAE grade 3 or greater adverse reactions. Once toxicities have resolved
`to grade 2 or less, TORISEL may be restarted with the dose reduced by 5 mg/week to a dose no
`lower than 15 mg/week.
`2.4
`Dose Modification Guidelines
`Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors
`should be avoided (e.g. ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir,
`nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). Grapefruit juice
`may also increase plasma concentrations of sirolimus (a major metabolite of temsirolimus) and
`should be avoided. If patients must be co-administered a strong CYP3A4 inhibitor, based on
`pharmacokinetic studies, a TORISEL dose reduction to 12.5 mg/week should be considered.
`This dose of TORISEL is predicted to adjust the AUC to the range observed without inhibitors.
`However, there are no clinical data with this dose adjustment in patients receiving strong
`CYP3A4 inhibitors. If the strong inhibitor is discontinued, a washout period of approximately 1
`week should be allowed before the TORISEL dose is adjusted back to the dose used prior to
`initiation of the strong CYP3A4 inhibitor. [see Drug Interactions (7.2)]
`
`Concomitant Strong CYP3A4 Inducers: The use of concomitant strong CYP3A4 inducers should
`be avoided (e.g. dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifampacin,
`phenobarbital). If patients must be co-administered a strong CYP3A4 inducer, based on
`pharmacokinetic studies, a TORISEL dose increase from 25 mg/week up to 50 mg/week should
`be considered. This dose of TORISEL is predicted to adjust the AUC to the range observed
`without inducers. However, there are no clinical data with this dose adjustment in patients
`receiving strong CYP3A4 inducers. If the strong inducer is discontinued the temsirolimus dose
`should be returned to the dose used prior to initiation of the strong CYP3A4 inducer. [see Drug
`Interactions (7.1)]
`
`2
`
`West-Ward Exhibit 1088
`TORISEL Approval
`Page 006
`
`

`

`
`Instructions for Preparation and Administration
`2.5
`TORISEL must be stored under refrigeration at 2°-8°C (36°-46°F) and protected from light.
`During handling and preparation of admixtures, TORISEL should be protected from excessive
`room light and sunlight. Parenteral drug products should be inspected visually for particulate
`matter and discoloration prior to administration, whenever solution and container permit.
`In order to minimize the patient exposure to the plasticizer DEHP (di-2-ethylhexyl phthalate),
`which may be leached from PVC infusion bags or sets, the final TORISEL dilution for infusion
`should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and
`administered through polyethylene-lined administration sets.
`
`Dilution:
`In preparing the TORISEL administration solution, follow this two-step dilution process in an
`aseptic manner.
`Step 1:
`Inject 1.8 mL of DILUENT for TORISEL into the vial of TORISEL (temsirolimus) injection (25
`mg/ml). The TORISEL (temsirolimus) vial contains an overfill of 0.2 mL (30 mg/1.2 mL). Due
`to the intentional overfill in the TORISEL injection vial, the drug concentration of the resulting
`solution will be 10 mg/mL. A total volume of 3 mL will be obtained including the overfill. Mix
`well by inversion of the vial. Allow sufficient time for air bubbles to subside. This 10 mg/mL
`drug solution/diluent mixture must be further diluted as described in Step 2 below.
`The solution is clear to slightly turbid, colorless to yellow, and free from visual particulates. The
`10 mg/mL drug solution/diluent mixture is stable for up to 24 hours at controlled room
`temperature.
`Step 2:
`Withdraw the required amount of temsirolimus from the 10 mg/mL drug solution/diluent mixture
`prepared in Step 1. Inject rapidly into a 250 mL container (glass, polyolefin, or polyethylene) of
`0.9% sodium chloride injection. Mix the admixture by inversion of the bag or bottle. Avoid
`excessive shaking as this may cause foaming.
`Administration:
`The sodium chloride injection container should be composed of non-DEHP containing
`materials, such as glass, polyolefin or polyethylene, and the administration set should
`consist of non-DEHP tubing to avoid extraction of di-(2-ethylhexyl) phthalate (DEHP).
`TORISEL contains polysorbate 80, which is known to increase the rate of di-(2-
`ethylhexyl) phthalate (DEHP) extraction from PVC.
`An in-line polyethersulfone filter with a pore size of not greater than 5 microns is
`recommended for administration.
`The final diluted solution of TORISEL is intravenously infused over a 30-60 minute
`period once a week. The use of an infusion pump is the preferred method of
`administration to ensure accurate delivery of the drug.
`
`•
`
`•
`
`•
`
`3
`
`West-Ward Exhibit 1088
`TORISEL Approval
`Page 007
`
`

`

`
`•
`
`Administration of the final diluted infusion solution should be completed within six hours
`from the time that the drug solution/diluent mixture is added to the sodium chloride
`injection.
`Compatibilities and Incompatibilities
`Undiluted TORISEL injection should not be added directly to aqueous infusion solutions. Direct
`addition of TORISEL injection to aqueous solutions will result in precipitation of drug. Always
`combine TORISEL injection with DILUENT for TORISEL before adding to infusion solutions.
`It is recommended that TORISEL be administered in 0.9% sodium chloride injection after
`combining with diluent. The stability of TORISEL in other infusion solutions has not been
`evaluated. Addition of other drugs or nutritional agents to admixtures of TORISEL in sodium
`chloride injection has not been evaluated and should be avoided. Temsirolimus is degraded by
`both acids and bases, and thus combinations of temsirolimus with agents capable of modifying
`solution pH should be avoided.
`3
`DOSAGE FORMS AND STRENGTHS
`TORISEL (temsirolimus) is supplied as a kit consisting of the following:
`•
`TORISEL (temsirolimus) injection (25 mg/ml). The TORISEL vial includes an overfill of
`0.2 mL.
`DILUENT for TORISEL. The DILUENT vial includes a deliverable volume of 1.8 mL.
`
`•
`
`CONTRAINDICATIONS
`
`4
`None.
`WARNINGS AND PRECAUTIONS
`5
`5.1 Hypersensitivity Reactions
`Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis,
`dyspnea, flushing, and chest pain have been observed with TORISEL.
`TORISEL should be used with caution in persons with known hypersensitivity to temsirolimus
`or its metabolites (including sirolimus), polysorbate 80, or to any other component (including the
`excipients) of TORISEL.
`An H1 antihistamine should be administered to patients before the start of the intravenous
`temsirolimus infusion. TORISEL should be used with caution in patients with known
`hypersensitivity to an antihistamine, or patients who cannot receive an antihistamine for other
`medical reasons.
`If a patient develops a hypersensitivity reaction during the TORISEL infusion, the infusion
`should be stopped and the patient should be observed for at least 30 to 60 minutes (depending on
`the severity of the reaction). At the discretion of the physician, treatment may be resumed with
`the administration of an H1-receptor antagonist (such as diphenhydramine), if not previously
`administered [see Dosage and Administration (2.2)], and/or an H2-receptor antagonist (such as
`intravenous famotidine 20 mg or intravenous ranitidine 50 mg) approximately 30 minutes before
`
`4
`
`West-Ward Exhibit 1088
`TORISEL Approval
`Page 008
`
`

`

`
`restarting the TORISEL infusion. The infusion may then be resumed at a slower rate (up to 60
`minutes).
`5.2 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.
`5.3
`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
`5.4
`Cases of interstitial lung disease, some resulting in death, occurred in patients who received
`TORISEL. Some patients were asymptomatic with infiltrates detected on computed tomography
`scan or chest radiograph. Others presented with symptoms such as dyspnea, cough, hypoxia, and
`fever. Some patients required discontinuation of TORISEL and/or treatment with corticosteroids
`and/or antibiotics, while some patients continued treatment without additional intervention.
`Patients should be advised to report promptly any new or worsening respiratory symptoms.
`
`5.5 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
`5.6
`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.
`5.7
`Renal Failure
`Cases of rapidly progressive and sometimes fatal acute renal failure not clearly related to disease
`progression occurred in patients who received TORISEL. Some of these cases were not
`responsive to dialysis.
`5.8 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
`
`West-Ward Exhibit 1088
`TORISEL Approval
`Page 009
`
`

`

`Intracerebral Hemorrhage
`
`
`5.9
`
`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.
`5.10 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)].
`
`5.11 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).
`5.12 Vaccinations
`The use of live vaccines and close contact with those who have received live vaccines should be
`avoided during treatment with TORISEL. Examples of live vaccines are: intranasal influenza,
`measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.
`
`5.13 Pregnancy
`Pregnancy Category D
`Temsirolimus administered daily as an oral formulation caused embryo-fetal and intrauterine
`toxicities in rats and rabbits at human sub-therapeutic exposures. Embryo-fetal adverse effects in
`rats consisted of reduced fetal weight and reduced ossifications, and in rabbits included reduced
`fetal weight, omphalocele, bifurcated sternabrae, notched ribs, and incomplete ossifications.
`In rats, the intrauterine and embryo-fetal adverse effects were observed at the oral dose of 2.7
`mg/m2/day (approximately 0.04-fold the AUC in cancer patients at the human recommended
`dose). In rabbits, the intrauterine and embryo-fetal adverse effects were observed at the oral
`
`6
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`West-Ward Exhibit 1088
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`dose of ≥7.2 mg/m2/day (approximately 0.12-fold the AUC in cancer patients at the
`recommended human dose).
`Women of childbearing potential should be advised to avoid becoming pregnant throughout
`treatment and for 3 months after TORISEL therapy has stopped. Temsirolimus can cause fetal
`harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the
`patient becomes pregnant while taking this drug, the patient should be apprised of the potential
`hazard to the fetus.
`Men should be counseled regarding the effects of TORISEL on the fetus and sperm prior to
`starting treatment [see Nonclinical Toxicology (13.1)]. Men with partners of childbearing
`potential should use reliable contraception throughout treatment and are recommended to
`continue this for 3 months after the last dose of TORISEL.
`5.14 Monitoring Laboratory Tests
`In the randomized, phase 3 trial, complete blood counts (CBCs) were checked weekly, and
`chemistry panels were checked every two weeks. Laboratory monitoring for patients receiving
`TORISEL may need to be performed more or less frequently at the physician’s discretion.
`6
`ADVERSE REACTIONS
`The following serious adverse reactions have been associated with TORISEL in clinical trials
`and are discussed in greater detail in other sections of the label [see Warnings and Precautions
`(5)].
`Hypersensitivity Reactions [see Warnings and Precautions (5.1)]
`Hyperglycemia/Glucose Intolerance [see Warnings and Precautions (5.2)]
`Interstitial Lung Disease [see Warnings and Precautions (5.4)]
`Hyperlipemia [see Warnings and Precautions (5.5)]
`Bowel Perforation [see Warnings and Precautions (5.6)]
`Renal Failure (see Warnings and Precautions (5.7)]
`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)].
`
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`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
`
`IFN-α
`
`n=200
`
`All
`Grades*
`n (%)
`
`199 (100)
`
`127 (64)
`21 (11)
`31 (16)
`99 (50)
`50 (25)
`30 (15)
`18 (9)
`59 (30)
`
`19 (10)
`87 (44)
`82 (41)
`40 (20)
`34 (17)
`36 (18)
`57 (29)
`
`19 (10)
`24 (12)
`3 (2)
`4 (2)
`
`
`28 (14)
`29 (15)
`
`Grades
`3&4*
`n (%)
`
`155 (78)
`
`52 (26)
`1 (1)
`4 (2)
`7 (4)
`4 (2)
`0 (0)
`2 (1)
`3 (2)
`
`0 (0)
`8 (4)
`9 (5)
`4 (2)
`3 (2)
`1 (1)
`5 (3)
`
`4 (2)
`3 (2)
`0 (0)
`0 (0)
`
`
`7 (4)
`2 (1)
`
`Adverse Reaction
`
`
`Any
`General disorders
`Asthenia
`Edemaa
`Pain
`Pyrexia
`Weight Loss
`Headache
`Chest Pain
`Chills
`Gastrointestinal disorders
`Mucositisb
`Anorexia
`Nausea
`Diarrhea
`Abdominal Pain
`Constipation
`Vomiting
`Infections
`Infectionsc
`Urinary tract infectiond
`Pharyngitis
`Rhinitis
`Musculoskeletal and
`connective tissue disorders
`Back Pain
`Arthralgia
`
`Grades
`3&4*
`n (%)
`
`139 (67)
`
`23 (11)
`7 (3)
`10 (5)
`1 (1)
`3 (1)
`1 (1)
`2 (1)
`1(1)
`
`6 (3)
`6 (3)
`5 (2)
`3 (1)
`9 (4)
`0 (0)
`4 (2)
`
`6 (3)
`3 (1)
`0 (0)
`0 (0)
`
`
`6 (3)
`2 (1)
`
`All
`Grades*
`n (%)
`
`208 (100)
`
`106 (51)
`73 (35)
`59 (28)
`50 (24)
`39 (19)
`31 (15)
`34 (16)
`17 (8)
`
`86 (41)
`66 (32)
`77 (37)
`56 (27)
`44 (21)
`42 (20)
`40 (19)
`
`42 (20)
`31 (15)
`25 (12)
`20 (10)
`
`
`41 (20)
`37 (18)
`
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`Adverse Reaction
`
`
`Any
`
`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
`Insomnia
`Depression
`
` *
`
`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
`
`IFN-α
`
`n=200
`
`All
`Grades*
`n (%)
`
`208 (100)
`16 (8)
`
`
`58 (28)
`53 (26)
`25 (12)
`
`
`97 (47)
`40 (19)
`28 (14)
`22 (11)
`21 (10)
`
`41 (20)
`24 (12)
`9 (4)
`
`Grades
`3&4*
`n (%)
`
`139 (67)
`1 (1)
`
`
`18 (9)
`2 (1)
`0 (0)
`
`
`10 (5)
`1 (1)
`0 (0)
`1 (1)
`0 (0)
`
`0 (0)
`1 (1)
`0 (0)
`
`All
`Grades*
`n (%)
`
`199 (100)
`29 (15)
`
`
`48 (24)
`29 (15)
`7 (4)
`
`
`14 (7)
`16 (8)
`1 (1)
`14 (7)
`2 (1)
`
`17 (9)
`30 (15)
`27 (14)
`
`Grades
`3&4*
`n (%)
`
`155 (78)
`2 (1)
`
`
`11 (6)
`0 (0)
`0 (0)
`
`
`0(0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`
`0 (0)
`0 (0)
`4 (2)
`
` Common Terminology 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