Torisel Side Effects

Generic Name: temsirolimus

Please note - some side effects for Torisel may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Torisel - for the Consumer

Torisel

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Torisel:

Acne; back pain; constipation; diarrhea; dry skin; fingernail or toenail changes; headache; joint or muscle pain; loss of appetite; mouth pain or sores; nausea; nosebleed; runny nose; stomach pain or upset; taste changes; trouble sleeping; vomiting; weakness; weight loss.

Seek medical attention right away if any of these SEVERE side effects occur when using Torisel:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); black or bloody stools; calf or leg pain, swelling, redness, or tenderness; chest pain; cough; coughing blood; decreased, difficult, or painful urination; depression; eye pain, redness, or swelling; fast or irregular heartbeat; fever, chills, or sore throat; new or worsening shortness of breath or other breathing problems; pain, redness, swelling, or warmth at the injection site; red, swollen, blistered, or peeling skin; severe or persistent dizziness or headache; severe or persistent stomach pain or diarrhea; severe tiredness or weakness; swelling of the hands, feet, or ankles; symptoms of high blood sugar (eg, increased hunger, thirst, or urination; confusion; unusual drowsiness); unusual bruising or bleeding; yellowing of the eyes or skin.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Torisel Side Effects - for the Professional

Torisel

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/Infusion Reactions [see Warnings and Precautions (5.1)]

Hyperglycemia/Glucose Intolerance [see Warnings and Precautions (5.3)]

Interstitial Lung Disease [see Warnings and Precautions (5.5)]

Hyperlipemia [see Warnings and Precautions (5.6)]

Bowel Perforation [see Warnings and Precautions (5.7)]

Renal Failure [see Warnings and Precautions (5.8)]

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.

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)].

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

Adverse Reaction	Torisel 25 mg n=208		IFN-α n=200
	All Grades* n (%)	Grades 3&4* n (%)	All Grades* n (%)	Grades 3&4* n (%)
* 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
Any	208 (100)	139 (67)	199 (100)	155 (78)
General disorders      Asthenia      Edemaa      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      Mucositisb      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      Infectionsc      Urinary tract infectiond      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      Rashe      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      Dysgeusiaf      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 - Fatal bowel perforation occurred in 1 patient (1%).

Eye Disorders - Conjunctivitis (including lacrimation disorder) occurred in 15 patients (7%).

Immune System - Allergic/Hypersensitivity reactions occurred in 18 patients (9%).

Angioneurotic edema-type reactions (including delayed reactions occurring two months following initiation of therapy) have been observed in some patients who received Torisel and ACE inhibitors concomitantly.

Infections - Pneumonia occurred in 17 patients (8%); upper respiratory tract infection occurred in 14 patients (7%).

General Disorders and Administration Site Conditions - Impaired wound healing occurred in 3 patients (1%).

Respiratory, Thoracic and Mediastinal Disorders – Interstitial lung disease occurred in 5 patients (2%), including rare fatalities.

Vascular - Hypertension occurred in 14 patients (7%); venous thromboembolism (including deep vein thrombosis and pulmonary embolus [including fatal outcomes]) occurred in 5 patients (2%); thrombophlebitis occurred in 2 patients (1%).

Table 2 – Incidence of Selected Laboratory Abnormalities in Patients Who Received 25 mg IV Torisel or IFN-α in the Randomized Trial

Laboratory Abnormality	Torisel 25 mg n=208		IFN-α n=200
	All Grades* n (%)	Grades 3&4* n (%)	All Grades* n (%)	Grades 3&4* n (%)
*NCI CTC version 3.0 **Grade 1 toxicity may be under-reported for lymphocytes and neutrophils
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    AST Increased    Creatinine Increased    Glucose Increased    Phosphorus Decreased    Total Bilirubin Increased    Total Cholesterol Increased    Triglycerides Increased    Potassium Decreased	141 (68) 79 (38) 119 (57) 186 (89) 102 (49) 16 (8) 181 (87) 173 (83) 43 (21)	7 (3) 5 (2) 7 (3) 33 (16) 38 (18) 2 (1) 5 (2) 92 (44) 11 (5)	111 (56) 103 (52) 97 (49) 128 (64) 61 (31) 25 (13) 95 (48) 144 (72) 15 (8)	13 (7) 14 (7) 2 (1) 6 (3) 17 (9) 4 (2) 2 (1) 69 (35) 0 (0)

Post-marketing and Other Clinical Experience

The following adverse reactions have been identified during post approval use of Torisel. 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: pleural effusion, hemodynamically significant pericardial effusions requiring intervention, convulsions, rhabdomyolysis, Stevens-Johnson Syndrome, and complex regional pain syndrome (reflex sympathetic dystrophy).

There are also postmarketing reports of temsirolimus extravasations resulting in swelling, pain, warmth, and erythema.

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Side Effects by Body System - for Healthcare Professionals

Respiratory

Some patients with interstitial lung disease 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 temsirolimus and/or treatment with corticosteroids and/or antibiotics, while other patients continued treatment without additional intervention. Patients should be advised to report promptly any new or worsening respiratory symptoms.

Respiratory side effects including dyspnea (28%), cough (26%), epistaxis (12%), pharyngitis (12%), rhinitis (10%), pneumonia (8%), and upper respiratory tract infection (7%) have been reported.

Interstitial lung disease has been reported in five patients (2%), including rare fatalities.

Hypersensitivity

Hypersensitivity and allergic side effects (9%) have been reported.

Hypersensitivity reactions have included anaphylaxis, dyspnea, flushing, and chest pain. Temsirolimus 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.

An H1 antihistamine should be administered to patients before the start of the intravenous temsirolimus infusion. Temsirolimus 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 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 and/or an H2-receptor antagonist (such as intravenous famotidine 20 mg or intravenous ranitidine 50 mg) approximately 30 minutes before restarting the temsirolimus infusion. The infusion may then be resumed at a slower rate (up to 60 minutes).

Hematologic

Hematologic side effects including decreased hemoglobin (94%), decreased lymphocytes (53%), decreased platelets (40%), decreased leukocytes (32%), and decreased neutrophils (19%) have been reported.

Other

Other side effects including laboratory abnormalities have been reported in 100% of patients. Blood chemistry abnormalities have included increased glucose (89%), increased total cholesterol (87%), increased triglycerides (83%), increased alkaline phosphatase (68%), increased creatinine (57%), decreased phosphorus (49%), increased AST (38%), decreased potassium (21%), and increased total bilirubin (8%).

General

General side effects including asthenia (51%), edema (35%), pain (28%), pyrexia (24%), weight loss (19%), chest pain (16%), headache (15%), chills (8%), and impaired wound healing (1%) have been reported.

Because temsirolimus has been associated with abnormal wound healing, caution should be exercised with the use of temsirolimus in the perioperative period.

Gastrointestinal

Cases of fatal bowel perforation have been reported in patients who received temsirolimus. 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.

Gastrointestinal side effects including mucositis (41%), nausea (37%), anorexia (32%), diarrhea (27%), abdominal pain (21%), constipation (20%), and vomiting (19%) have been reported. Fatal bowel perforation has also been.

Genitourinary

Genitourinary side effects including urinary tract infection (15%) have been reported.

Renal

Some of these cases of rapidly progressive acute renal failure were not responsive to dialysis.

Renal side effects including cases of rapidly progressive and sometimes fatal acute renal failure not clearly related to disease progression have been reported.

Musculoskeletal

Musculoskeletal side effects including back pain (20%), arthralgia (18%), and myalgia (8%) have been reported.

Dermatologic

Dermatologic side effects including rash (47%) pruritus (19%), nail disorder (14%), dry skin (11%), and acne (10%) have been reported.

Nervous system

Nervous system side effects including dysgeusia (including taste loss and taste perversion) (20%), insomnia (12%), and depression (4%) have been reported.

Ocular

Ocular side effects such as conjunctivitis (including lacrimation disorder) (7%) have been reported.

Cardiovascular

Cardiovascular side effects including hypertension (7%), venous thromboembolism (including deep vein thrombosis and pulmonary embolus) (2%) and thrombophlebitis (1%) have been reported.

Oncologic

Oncologic side effects have not been reported with temsirolimus. However, animal studies have reported sirolimus (the major metabolite of temsirolimus in humans) to be carcinogenic. The following effects have been reported in animals in the carcinogenicity studies conducted with sirolimus: lymphoma, hepatocellular adenoma and carcinoma, and testicular adenoma.

Metabolic

Increases in serum glucose may result in the need for an increase in the dose of, or the initiation of, insulin and/or oral hypoglycemic agent therapy. Serum glucose should be tested before and during treatment with temsirolimus. Patients should be advised to report excessive thirst or any increase in the volume or frequency of urination.

Increases in serum triglycerides and cholesterol may require the initiation of, or increase in the dose of lipid-lowering agents. Serum cholesterol and triglycerides should be tested before and during treatment with temsirolimus.

Metabolic side effects including increases in serum glucose are likely. In a phase 3 trial, 89% of patients receiving temsirolimus had at least one elevated serum glucose while on treatment, and 26% of patients reported hyperglycemia as an adverse event.

The use of temsirolimus is also likely to result in increases in serum triglycerides and cholesterol. In a phase 3 trial, 87% of patients receiving temsirolimus had at least one elevated serum cholesterol value and 83% had at least one elevated serum triglyceride value.

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