Temsirolimus

RECENT MAJOR CHANGES Warnings and Precautions, Proteinuria and Nephrotic Syndrome ( 5.11 ) 3/2018 Warnings and Precautions, Embryo-Fetal Toxicity ( 5.15 ) 3/2018

1 INDICATIONS AND USAGE Temsirolimus injection is indicated for the treatment of advanced renal cell carcinoma. Temsirolimus injection is a kinase inhibitor indicated for the treatment of advanced renal cell carcinoma. ( 1 )

2 DOSAGE AND ADMINISTRATION The recommended dose of Temsirolimus injection is 25 mg administered as an intravenous infusion 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 ) 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 ) 2.1 Advanced Renal Cell Carcinoma The recommended dose of Temsirolimus injection 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. 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 Temsirolimus injection [see Warnings and Precautions ( 5.1 )] . 2.3 Dosage Interruption/Adjustment Temsirolimus injection should be held for absolute neutrophil count (ANC) 1 - 1.5xULN or AST >ULN but bilirubin ≤ULN), reduce the dose of Temsirolimus injection to 15 mg/week. Temsirolimus injection 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 Temsirolimus injection dose reduction to 12.5 mg/week should be considered. This dose of Temsirolimus injection 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 Temsirolimus injection dose is adjusted back to the dose used prior to initiation of the strong CYP3A4 inhibitor [see Warnings and Precautions ( 5.12 ) and Drug Interactions ( 7.2 )] . Concomitant Strong CYP3A4 Inducers : The use of concomitant strong CYP3A4 inducers should be avoided (e.g. dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifampacin, phenobarbital). If patients must be co-administered a strong CYP3A4 inducer, based on pharmacokinetic studies, a Temsirolimus injection dose increase from 25 mg/week up to 50 mg/week should be considered. This dose of Temsirolimus injection 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 ( 5.12 ) and Drug Interactions ( 7.1 )]. 2.5 Instructions for Preparation Temsirolimus injection is a cytotoxic drug. Follow applicable special handling and disposal procedures 1 . Temsirolimus injection must be stored under refrigeration at 2° to 8°C (36°–46°F) and protected from light. During handling and preparation of admixtures, Temsirolimus injection 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), whic …

3 DOSAGE FORMS AND STRENGTHS Temsirolimus injection is supplied as a kit consisting of the following: Temsirolimus injection (25 mg/mL). The temsirolimus injection 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 temsirolimus injection. 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. Temsirolimus injection, 25 mg/mL supplied with DILUENT for temsirolimus injection. ( 3 )

4 CONTRAINDICATIONS Temsirolimus injection is contraindicated in patients with bilirubin >1.5 x ULN [ see Warnings and Precautions ( 5.2 )]. Temsirolimus injection is contraindicated in patients with bilirubin >1.5 x ULN. ( 4 )

6 ADVERSE REACTIONS The following serious adverse reactions have been associated with Temsirolimus injection 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 )] Hyperlipidemia [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 )] The most common (≥ 30%) adverse reactions observed with Temsirolimus injection are rash, asthenia, mucositis, nausea, edema, and anorexia. The most common (≥30%) laboratory abnormalities observed with Temsirolimus injection are anemia, hyperglycemia, hyperlipidemia, hypertriglyceridemia, lymphopenia, elevated alkaline phosphatase, elevated serum creatinine, hypophosphatemia, thrombocytopenia, elevated AST, and leukopenia. 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, hyperlipidemia, hypertriglyceridemia, elevated alkaline phosphatase, elevated serum creatinine, lymphopenia, hypophosphatemia, thrombocytopenia, elevated AST, and leukopenia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 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, Temsirolimus injection alone, and Temsirolimus injection and IFN-α, a total of 616 patients were treated. Two hundred patients received IFN-α weekly, 208 received Temsirolimus injection 25 mg weekly, and 208 patients received a combination of Temsirolimus injection and IFN-α weekly [see Clinical Studies ( 14 )]. Treatment with the combination of Temsirolimus injection 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 Temsirolimus injection 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 Temsirolimus injection or IFN- in the Randomized Trial * Common Toxicity Criteria for Adverse Events (CTCAE), Version 3.0. a Includes edema, facial edema, and peripheral edema b Includes aphthous stomatitis, glossitis, mouth ulceration, mucositis, and stomatitis c Includes infections not otherwise specified (NOS) and the following infections that occurred infrequently as distinct entities: abscess, bronchitis, cellulitis, herpes simplex, and herpes zoster d Includes cystitis, dysuria, hematuria, urinary frequency, and urinary tract infection e Includes eczema, exfoliative dermatitis, maculopapular rash, pruritic rash, pustular rash, rash (NOS), and vesiculobullous rash f Includes taste loss and taste perversion Adverse Reaction Temsirolimus injection 25 mg n=208 IFN-α n=200 All Grades* n (%) Grades 3&4* n …

7 DRUG INTERACTIONS Strong inducers of CYP3A4/5 and inhibitors of CYP3A4 may affect concentrations of the primary metabolite of temsirolimus injection. If alternatives cannot be used, dose modifications of temsirolimus injection are recommended. ( 7.1 , 7.2 , 7.3 ) 7.1 Agents Inducing CYP3A Metabolism Co-administration of temsirolimus injection 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 temsirolimus injection treatment alone. If alternative treatment cannot be administered, a dose adjustment should be considered [see Dosage and Administration ( 2.4 )] . 7.2 Agents Inhibiting CYP3A Metabolism Co-administration of temsirolimus injection 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 temsirolimus injection alone. If alternative treatment cannot be administered, a dose adjustment should be considered [see Dosage and Administration ( 2.4 )] . 7.3 Angioedema with ACE inhibitors and Calcium Channel Blockers 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 an angiotensin converting enzyme (ACE) inhibitors (e.g., ramipril) or calcium channel blockers (CCB) (e.g., amlodipine).

8 USE IN SPECIFIC POPULATIONS Lactation: Do not breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary Based on findings in animal studies and its mechanism of action, temsirolimus can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 )] . Although there are no data on the use of Temsirolimus injection in pregnant women, there are limited data on the use of sirolimus, the active metabolite of temsirolimus, during pregnancy; however, these data are insufficient to inform a drug-associated risk of adverse developmental outcomes. In animal reproductive studies, oral daily administration of temsirolimus to pregnant rats and rabbits during organogenesis caused adverse embryo-fetal effects at approximately 0.04 and 0.12 times the AUC in patients at the recommended dose, respectively (see Data ) . Advise pregnant women of the potential hazard to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Data Animal Data Temsirolimus administered daily as an oral formulation throughout organogenesis caused adverse embryo-fetal effects 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 adverse embryo-fetal effects were observed at the oral dose of 2.7 mg/m2/day (approximately 0.04-fold the AUC in patients with cancer at the human recommended dose). In rabbits, the adverse embryo-fetal effects were observed at the oral dose of ≥7.2 mg/m2/day (approximately 0.12-fold the AUC in patients with cancer at the recommended human dose). 8.2 Lactation Risk Summary There is no information regarding the presence of Temsirolimus injection or its metabolites in human milk, or their effects on the breastfed child or milk production. Trace amounts of sirolimus, the active metabolite of temsirolimus, were present in milk from lactating rats administered sirolimus. Because of the potential for serious adverse reactions in a breastfed child from Temsirolimus injection, advise a lactating woman not to breastfeed during treatment with Temsirolimus injection and for 3 weeks after the final dose. 8.3 Females and Males of Reproductive Potential Contraception Females Temsirolimus injection can cause fetal harm when administered to a pregnant woman [see Use in Specific Population ( 8.1 )] . Advise females of reproductive potential to use effective contraception during treatment with Temsirolimus injection and for 3 months after the last dose. Males Advise males with partners of reproductive potential to use effective contraception during treatment with Temsirolimus injection and for 3 months after the last dose [see Nonclinical Toxicology ( 13.1 )]. Infertility Based on the findings in animal fertility studies, male and female fertility may be compromised by the treatment with Temsirolimus injection. It is not known if the effects on fertility in animal studies were reversible [see Nonclinical Toxicology ( 13.1 )]. 8.4 Pediatric Use 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. Temsirolimus injection 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 Temsirolimus injection at doses ranging f …

12.1 Mechanism of Action 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.

11 DESCRIPTION Temsirolimus, an inhibitor of mTOR, is an antineoplastic agent. Temsirolimus is a white to off-white powder with a molecular formula of C 56 H 87 NO 16 and a molecular weight of 1030.30. It is non-hygroscopic. Temsirolimus is practically insoluble in water and soluble in alcohol. It has no ionizable functional groups, and its solubility is independent of pH. The chemical name of temsirolimus is (3 S ,6 R ,7 E ,9 R ,10 R ,12 R ,14 S ,15 E ,17 E ,19 E ,21 S ,23 S ,26 R ,27 R ,34a S )-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy-3-[(1 R )-2-[(1 S ,3 R ,4 R )-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26­-hexamethyl-23,27-epoxy-3 H -pyrido[2,1- c ][1,4]oxaazacyclohentriacontine­-1,5,11,28,29(4 H ,6 H ,31 H )-pentone 4′-[2,2-bis(hydroxymethyl)propionate]; or Rapamycin, 42-[3-­hydroxy-2-(hydroxymethyl)-2-methylpropanoate]. Temsirolimus injection, 25 mg/mL, is a clear, colorless to light yellow, non-aqueous, ethanolic, sterile solution. Temsirolimus injection requires two dilutions prior to intravenous infusion. Temsirolimus injection should be diluted only with the supplied DILUENT for Temsirolimus injection. DILUENT for Temsirolimus injection is a sterile, non-aqueous solution that is supplied with Temsirolimus injection, as a kit. Temsirolimus injection, 25 mg/mL: Active ingredient: temsirolimus (25 mg/mL) Inactive ingredients: dehydrated alcohol (49.90 % v/v), butylated hydroxy anisole (0.0003 % w/v), butylated hydroxy toluene (0.002 % w/v), propylene glycol (50.3% w/v), and anhydrous citric acid (0.0025% w/v). DILUENT for Temsirolimus injection: Inactive ingredients: polysorbate 80 (40.0% w/v), polyethylene glycol 400 (42.8% w/v) and dehydrated alcohol (25.14% v/v). After the Temsirolimus injection vial has been diluted with DILUENT for Temsirolimus injection, in accordance with the instructions in section 2.5, the solution contains 35.04 % alcohol. Temsirolimus injection and DILUENT for Temsirolimus injection are filled in clear glass vials with butyl rubber stoppers. Temsirolimus-SPL-structure

10 OVERDOSAGE There is no specific treatment for temsirolimus injection intravenous overdose. Temsirolimus injection has been administered to patients with cancer in phase 1 and 2 trials with repeated intravenous doses as high as 220 mg/m 2 . The risk of several serious adverse events, including thrombosis, bowel perforation, interstitial lung disease (ILD), seizure, and psychosis, is increased with doses of temsirolimus injection greater than 25 mg.

16 HOW SUPPLIED/STORAGE AND HANDLING Temsirolimus injection 25 mg/mL is available as “a clear, colorless to light yellow viscous solution and is supplied in single-dose vial of 25 mg/mL (NDC 68083-200-01)”. Diluent for Temsirolimus injection is available as “a clear, colorless to light yellow non aqueous solution and is supplied in single-dose vial of 2.2 mL (NDC 68083-201-01)”. A KIT of Temsirolimus injection, 25 mg/mL; Single carton containing both the vials (NDC 68083-202-01). Each kit is supplied in a single carton containing one single-dose 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 to 8o C (36o–46o F) and Protect from light. Temsirolimus injection is a cytotoxic drug. Follow applicable special handling and disposal procedures.