torisel

Important safety information

Hypersensitivity/Infusion Reactions (including some life-threatening and rare fatal reactions) can occur early in the first infusion of TORISEL. Patients should be monitored throughout the infusion. ( 5.1 ) • To treat hypersensitivity reactions, stop TORISEL and treat with an antihistamine. TORISEL may be restarted at physician discretion at a slower rate. ( 5.1 ) • Hepatic Impairment: Use caution when treating patients with mild hepatic impairment and reduce dose. ( 2.4 , 5.2 ) • Hyperglycemia and 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 TORISEL, and consider use of corticosteroids and/or antibiotics. ( 5.5 ) • Bowel perforation may occur. Evaluate fever, abdominal pain, bloody stools, and/or acute abdomen promptly. ( 5.7 ) • Renal failure, sometimes fatal, has occurred. Monitor renal function at baseline and while on TORISEL. ( 5.8 ) • Due to abnormal wound healing, use TORISEL with caution in the perioperative period. ( 5.9 ) • Proteinuria and nephrotic syndrome may occur. Monitor urine protein prior to the start of TORISEL therapy and periodically thereafter. Discontinue TORISEL 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. 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 H 1 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 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 TORISEL infusion. The infusion may then be resumed at a slower rate (up to 60 minutes). A benefit-risk assessment should be done prior to the continuation of temsirolimus therapy in patients with severe or life-threatening reactions. 5.2 Hepatic Impairment The safety and pharmacokinetics of TORISEL were evaluated in a dose escalation phase 1 study in 110 patients with normal or varying degrees of hepatic impairment. Patients with baseline bilirubin >1.5×ULN experienced greater toxicity than patients with baseline bilirubin ≤1.5×ULN when treated with TORISEL. The overall frequency of ≥ grade 3 adverse reactions and deaths, including deaths due to progressive disease, were greater in patients with baseline bilirubin >1.5×ULN due to increased risk of death [see Contraindications (4) ] . Use caution when treating patients with mild hepatic impairment. Concentrations of temsirolimus and its metabolite sirolimus were increased in patients with elevated AST or bilirubin levels. If TORISEL must be given in patients with mild hepatic impairment (bilirubin >1 – 1.5×ULN or AST >ULN but bilirubin ≤ULN), reduce the dose of TORISEL to 15 mg/week [see Dosage and Administration (2.4) ] . 5.3 Hyperglycemia/Glucose Intolerance The use of TORISEL is likely to result in increases in serum glucose. In the phase 3 trial, 89% of patients receiving TORISEL had at least one elevated serum glucose while on treatment, and 26% of patients reported hyperglycemia as an adverse event. This may result in the need for an increase in the dose of, or initiation of, insulin and/or oral hypoglycemic agent therapy. Serum glucose should be tested before and during treatment with TORISEL. Patients should be advised to report excessive thirst or any increase in the volume or frequency of urination. 5.4 Infections The use of TORISEL may result in immunosuppression. Patients should be carefully observed for the occurrence of infections, including opportunistic infections [see Adverse Reactions (6.1) ] . Pneumocystis jiroveci pneumonia (PJP), including fatalities, has been reported in patients who received temsirolimus. This may be associated with concomitant use of corticosteroids or other immunosuppressive agents. Prophylaxis of PJP should be considered when concomitant use of corticosteroids or other immunosuppressive agents are required. 5.5 Interstitial Lung Disease Cases of interstitial lung disease, some resulting in death, occurred in patients who received TORISEL. Some patients were asymptomatic, or had minimal symptoms, with infiltrates detected on computed tomography scan or chest radiograph. Others presented with symptoms such as dyspnea, cough, hypoxia, and fever. Some patients required discontinuation of TORISEL and/or treatment with corticosteroids and/or antibiotics, while some patients continued treatment without additional intervention. Patients should be advised to report promptly any new or worsening respiratory symptoms. It is recommended that patients undergo baseline radiographic assessment by lung computed tomography scan or chest radiograph prior to the initiation of TORISEL therapy. Follow such assessments periodically, even in the absence of clinical respiratory symptoms. It is recommended that patients be followed closely for occurrence of clinical respiratory symptoms. If clinically significant respiratory symptoms develop, consider withholding TORISEL administration until after recovery of symptoms and improvement of radiographic findings related to pneumonitis. Empiric treatment with corticosteroids and/or antibiotics may be considered. Opportunistic infections such as PJP should be considered in the differential diagnosis. For patients who require use of corticosteroids, prophylaxis of PJP may be considered. 5.6 Hyperlipidemia The use of TORISEL is likely to result in increases in serum triglycerides and cholesterol. In the phase 3 trial, 87% of patients receiving TORISEL had at least one elevated serum cholesterol value and 83% had at least one elevated serum triglyceride value. This may require initiation, or increase in the dose, of lipid-lowering agents. Serum cholesterol and triglycerides should be tested before and during treatment with TORISEL. 5.7 Bowel Perforation Cases of fatal bowel perforation occurred in patients who received TORISEL. These patients presented with fever, abdominal pain, metabolic acidosis, bloody stools, diarrhea, and/or acute abdomen. Patients should be advised to report promptly any new or worsening…