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 )
Contraindications
Temsirolimus injection is contraindicated in patients with bilirubin >1.5×ULN [see Warnings and Precautions ( 5.2 )]. Temsirolimus injection 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 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 )
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.
5.2Hepatic 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 >1.5×ULN experienced greater toxicity than patients with baseline bilirubin ≤1.5×ULN 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 >1.5×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 Temsirolimus injection must be given in patients with mild hepatic impairment (bilirubin >1 – 1.5×ULN or AST >ULN but bilirubin ≤ULN), reduce the dose of Temsirolimus injection to 15 mg/week [see Dosage and Administration ( 2.4 )].
5.3Hyperglycemia/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.
5.4Infections
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.
5.5Interstitial 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.
5.6Hyperlipidemia
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 dos
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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).
Pregnancy and breastfeeding
8.1Pregnancy 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).
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
6.1Clinical 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 (%) All Grades* n (%) Grades 3&4* n (%) General disorders Asthenia Edema a Pain Pyrexia Weight Loss Headache Chest Pain Chills 106 (51) 73 (35) 59 (28) 50 (24) 39 (19) 31 (15) 34 (16) 17 (8) 23 (11) 7 (3) 10 (5) 1 (1) 3 (1) 1 (1) 2 (1) 1 (1) 127 (64) 21 (11) 31 (16) 99 (50) 50 (25) 30 (15) 18 (9) 59 (30) 52 (26) 1 (1) 4 (2) 7 (4) 4 (2) 0 (0) 2 (1) 3 (2) Gastrointestinal disorders Mucositis b Anorexia Nausea Diarrhea Abdominal Pain Constipation Vomiting 86 (41) 66 (32) 77 (37) 56 (27) 44 (21) 42 (20) 40 (19) 6 (3) 6 (3) 5 (2) 3 (1) 9 (4) 0 (0) 4 (2) 19 (10) 87 (44) 82 (41) 40 (20) 34 (17) 36 (18) 57 (29) 0 (0) 8 (4) 9 (5) 4 (2) 3 (2) 1 (1) 5 (3) Infections Infections c Urinary tract infection d Pharyngitis Rhinitis 42 (20) 31 (15) 25 (12) 20 (10) 6 (3) 3 (1) 0 (0) 0 (0) 19(10) 24(12) 3(2) 4(2) 4 (2) 3 (2) 0 (0) 0 (0) Musculoskeletal and connective tissue disorders Back Pain Arthralgia Myalgia 41 (20) 37 (18) 16 (8) 6(3) 2( 1) 1 (1) 28(14) 29 (15) 29 (15) 7 (4) 2 (1) 2 (1) Respiratory, thoracic and mediastinal disorders Dyspnea Cough Epistaxis 58 (28) 53 (26) 25 (12) 18 (9) 2 (1) 0 (0) 48 (24) 29 (15) 7 (4) 11 (6) 0 (0) 0 (0) Skin and subcutaneous tissue disorders Rash e Pruritus Nail Disorder Dry Skin Acne 97 (47) 40 (19) 28 (14) 22 (11) 21 (10) 10 (5) 1 (1) 0 (0) 1 (1) 0 (0) 14 (7) 16 (8) 1 (1) 14 (7) 2 (1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Nervous system disorders Dysgeusia f Insomnia Depression 41 (20) 24 (12) 9 (4) 0 (0) 1 (1) 0 (0) 17 (9) 30 (15) 27 (14) 0 (0) 0 (0) 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 *NCI CTC version 3.0 **Grade 1 toxicity may be under-reported for lymphocytes and neutrophils Laboratory Abnormality Temsirolimus injection 25 mg n=208 IFN-α n=200 All Grades* n (%) Grades 3&4* n (%) All Grades* n (%) Grades 3&4* n (%) Any 208 (100) 162 (78) 195 (98) 144 (72) Hematology Hemoglobin Decreased Lymphocytes Decreased** Neutrophils Decreased** Platelets Decreased Leukocytes Decreased 195 (94) 110 (53) 39 (19) 84 (40) 67 (32) 41 (20) 33 (16) 10 (5) 3 (1) 1 (1) 180 (90) 106 (53) 58 (29) 51 (26) 93 (47) 43 (22) 48 (24) 19 (10) 0 (0) 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)
6.2Post-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
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Composition
Active ingredients
TEMSIROLIMUS 25MG/ML (25MG/ML)
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
