Drug Facts
Composition & Profile
Identifiers & Packaging
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 72611-780-01). 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 72611-782-01). A KIT of temsirolimus injection, 25 mg/mL; Single carton containing both the vials (NDC 72611-785-02). 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 8ºC (36º to 46ºF). Protect from light. Temsirolimus injection is a cytotoxic drug. Follow applicable special handling and disposal procedures.; PRINCIPAL DISPLAY PANEL - 25 mg/mL vial NDC 72611- 780 -01 Temsirolimus Injection 25 mg/mL per vial* *Each vial contains 0.2 mL overfill For Intravenous Infusion Only MUST BE DILUTED 10 mg/mL after initial dilution Sterile - Refrigerate Single-Dose Vial temsirolimus-concentrate-vial; PRINCIPAL DISPLAY PANEL - diluent vial NDC 72611- 782 -01 DILUENT for Temsirolimus Injection 2.2 mL Not for direct administration Only for dilution of temsirolimus injection vial Sterile - Refrigerate Single-Dose Vial diluent-vial; PRINCIPAL DISPLAY PANEL - carton Retain in carton until time of use NDC 72611- 785 -02 Temsirolimus Injection 25 mg/mL per vial* *each single-dose vial contains 0.2 mL overfill For Intravenous Infusion Only CONCENTRATED - Requires two dilutions before administration 10 mg/mL after Initial dilution *Each carton contains: 1 single-dose vial Temsirolimus Injection 25 mg/mL 1 single-dose vial DILUENT for Temsirolimus Injection Sterile - Refrigerate kit-carton
- 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 72611-780-01). 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 72611-782-01). A KIT of temsirolimus injection, 25 mg/mL; Single carton containing both the vials (NDC 72611-785-02). 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 8ºC (36º to 46ºF). Protect from light. Temsirolimus injection is a cytotoxic drug. Follow applicable special handling and disposal procedures.
- PRINCIPAL DISPLAY PANEL - 25 mg/mL vial NDC 72611- 780 -01 Temsirolimus Injection 25 mg/mL per vial* *Each vial contains 0.2 mL overfill For Intravenous Infusion Only MUST BE DILUTED 10 mg/mL after initial dilution Sterile - Refrigerate Single-Dose Vial temsirolimus-concentrate-vial
- PRINCIPAL DISPLAY PANEL - diluent vial NDC 72611- 782 -01 DILUENT for Temsirolimus Injection 2.2 mL Not for direct administration Only for dilution of temsirolimus injection vial Sterile - Refrigerate Single-Dose Vial diluent-vial
- PRINCIPAL DISPLAY PANEL - carton Retain in carton until time of use NDC 72611- 785 -02 Temsirolimus Injection 25 mg/mL per vial* *each single-dose vial contains 0.2 mL overfill For Intravenous Infusion Only CONCENTRATED - Requires two dilutions before administration 10 mg/mL after Initial dilution *Each carton contains: 1 single-dose vial Temsirolimus Injection 25 mg/mL 1 single-dose vial DILUENT for Temsirolimus Injection Sterile - Refrigerate kit-carton
Overview
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. structure
Indications & 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 )
Dosage & 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) <1,000/mm 3 , platelet count <75,000/mm 3 , or NCI CTCAE grade 3 or greater adverse reactions. Once toxicities have resolved to grade 2 or less, temsirolimus injection 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 temsirolimus injection must be given in patients with mild hepatic impairment (bilirubin >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 >1.5xULN [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, rifampicin, 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° to 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), which may be leached from PVC infusion bags or sets, the final temsirolimus injection dilution for infusion should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets. Temsirolimus injection 25 mg/mL must be diluted with the supplied diluent before further dilution in 0.9% Sodium Chloride Injection, USP. Please note that both the temsirolimus 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 TEMSIROLIMUS INJECTION 25 MG/ML WITH SUPPLIED DILUENT Each vial of temsirolimus injection 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 temsirolimus injection 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 temsirolimus injection is first added to 0.9% Sodium Chloride Injection, USP. Temsirolimus injection 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. Temsirolimus injection, 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 temsirolimus injection, including storage time elapsed when in direct contact with PVC following constitution. Compatibilities and Incompatibilities Undiluted temsirolimus injection should not be added directly to aqueous infusion solutions. Direct addition of temsirolimus injection to aqueous solutions will result in precipitation of drug. Always combine temsirolimus injection with DILUENT for temsirolimus injection before adding to infusion solutions. It is recommended that temsirolimus injection be administered in 0.9% Sodium Chloride Injection after combining with diluent. The stability of temsirolimus injection in other infusion solutions has not been evaluated. Addition of other drugs or nutritional agents to admixtures of temsirolimus injection 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.
Warnings & Precautions
Hypersensitivity/Infusion Reactions (including some life-threatening and rare fatal reactions) can occur early in the first infusion of temsirolimus injection. Patients should be monitored throughout the infusion. ( 5.1 ) To treat hypersensitivity reactions, stop temsirolimus injection and treat with an antihistamine. Temsirolimus injection 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 hyperlipidemia are likely and may require treatment. Monitor glucose and lipid profiles. ( 5.3 , 5.6 ) Infections may result from immunosuppression. ( 5.4 ) Monitor for symptoms or radiographic changes of interstitial lung disease (ILD). If ILD is suspected, discontinue temsirolimus injection, 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 temsirolimus injection. ( 5.8 ) Due to abnormal wound healing, use temsirolimus injection with caution in the perioperative period. ( 5.9 ) Proteinuria and nephrotic syndrome may occur. Monitor urine protein prior to the start of temsirolimus injection therapy and periodically thereafter. Discontinue temsirolimus injection in patients with who develop nephrotic syndrome. ( 5.11 ) Live vaccinations and close contact with those who received live vaccines should be avoided. ( 5.14 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of the potential hazard to the fetus and to use effective contraception. ( 5.15 , 8.1 , 8.3 ) Elderly patients may be more likely to experience certain adverse reactions, including diarrhea, edema and pneumonia. ( 5.16 ) 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. Temsirolimus injection 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 temsirolimus injection. An H 1 antihistamine should be administered to patients before the start of the intravenous temsirolimus infusion. Temsirolimus injection 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 temsirolimus injection 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 H 1 -receptor antagonist (such as diphenhydramine), if not previously administered [see Dosage and Administration ( 2.2 )] , and/or an H 2 -receptor antagonist (such as intravenous famotidine 20 mg or intravenous ranitidine 50 mg) approximately 30 minutes before restarting the temsirolimus injection 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 temsirolimus injection were evaluated in a dose escalation phase 1 study in 110 patients with normal or varying degrees of hepatic impairment. Patients with baseline bilirubin >1.5xULN experienced greater toxicity than patients with baseline bilirubin ≤1.5xULN when treated with temsirolimus injection. The overall frequency of ≥ grade 3 adverse reactions and deaths, including deaths due to progressive disease, were greater in patients with baseline bilirubin >1.5xULN 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 temsirolimus injection must be given in patients with mild hepatic impairment (bilirubin >1 – 1.5xULN or AST >ULN but bilirubin ≤ULN), reduce the dose of temsirolimus injection to 15 mg/week [see Dosage and Administration ( 2.4 )] . 5.3 Hyperglycemia/Glucose Intolerance The use of temsirolimus injection is likely to result in increases in serum glucose. In the phase 3 trial, 89% of patients receiving temsirolimus injection 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 temsirolimus injection. Patients should be advised to report excessive thirst or any increase in the volume or frequency of urination. 5.4 Infections The use of temsirolimus injection 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. 5.5 Interstitial Lung Disease Cases of interstitial lung disease, some resulting in death, occurred in patients who received temsirolimus injection. 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 temsirolimus injection 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 temsirolimus injection 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 temsirolimus injection 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 Hyperlipidemia The use of temsirolimus injection is likely to result in increases in serum triglycerides and cholesterol. In the phase 3 trial, 87% of patients receiving temsirolimus injection 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 temsirolimus injection. 5.7 Bowel Perforation Cases of fatal bowel perforation occurred in patients who received temsirolimus injection. 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 temsirolimus injection. Some of these cases were not responsive to dialysis. 5.9 Wound Healing Complications Use of temsirolimus injection has been associated with abnormal wound healing. Therefore, caution should be exercised with the use of temsirolimus injection 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 temsirolimus injection. 5.11 Proteinuria and Nephrotic syndrome Proteinuria (including cases of nephrotic syndrome) has occurred in patients treated with temsirolimus injection. Monitor urine protein prior to the start of temsirolimus injection therapy and periodically thereafter. Discontinue temsirolimus injection in patients who develop nephrotic syndrome. 5.12 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 temsirolimus injection plasma concentrations unpredictably. Patients receiving temsirolimus injection 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 )] . 5.13 Concomitant use of Temsirolimus with Sunitinib The combination of temsirolimus injection 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 temsirolimus injection 15 mg IV per week and sunitinib 25 mg oral per day (Days 1-28 followed by a 2-week rest). 5.14 Vaccinations The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with temsirolimus injection. Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines. 5.15 Embryo-Fetal Toxicity Based on findings in animal studies and its mechanism of action, temsirolimus injection 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 temsirolimus injection and for 3 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with temsirolimus injection and for 3 months after the last dose [see Clinical Pharmacology ( 12.1 ) and Use in Specific Populations ( 8.1 , 8.3 )] . 5.16 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 )] .
Contraindications
Temsirolimus injection is contraindicated in patients with bilirubin >1.5xULN [see Warnings and Precautions ( 5.2 )] . Temsirolimus injection is contraindicated in patients with bilirubin >1.5 x ULN. ( 4 )
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 Almaject, Inc. at 1-866-770-3024 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-α in the Randomized Trial Adverse Reaction Temsirolimus Injection 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) Edema Includes 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 Mucositis Includes 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 Infections Includes 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 infection Includes 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 Rash Includes 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 Dysgeusia Includes 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 temsirolimus injection 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 Temsirolimus Injection or IFN-α in the Randomized Trial Laboratory Abnormality Temsirolimus Injection 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 Decreased Grade 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) 6.2 Post-marketing and Other Clinical Experience The following adverse reactions have been identified during post approval use of temsirolimus injection. 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.
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).
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