6 ADVERSE REACTIONS
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)].
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- Hypersensitivity/Infusion Reactions [see Warnings and Precautions (5.1)]
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- Hepatic Impairment [see Warnings and Precautions (5.2)]
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- Hyperglycemia/Glucose Intolerance [see Warnings and Precautions (5.3)]
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- Infections [see Warnings and Precautions (5.4)]
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- Interstitial Lung Disease [see Warnings and Precautions (5.5)]
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- Hyperlipidemia [see Warnings and Precautions (5.6)]
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- Bowel Perforation [see Warnings and Precautions (5.7)]
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- Renal Failure [see Warnings and Precautions (5.8)]
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- Wound Healing Complications [see Warnings and Precautions (5.9)]
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- Intracerebral Hemorrhage [see Warnings and Precautions (5.10)]
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, hyperlipidemia, hypertriglyceridemia, lymphopenia, elevated alkaline phosphatase, elevated serum creatinine, hypophosphatemia, thrombocytopenia, elevated AST, and leukopenia.
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, 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:
| 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 (%) | |
| ||||
General disorders | ||||
Asthenia | 106 (51) | 23 (11) | 127 (64) | 52 (26) |
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‡ | 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§ | 42 (20) | 6 (3) | 19 (10) | 4 (2) |
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# | 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 | ||||
DysgeusiaÞ | 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 TORISEL 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%).
| 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 (%) | |
Any | 208 (100) | 162 (78) | 195 (98) | 144 (72) |
Hematology | ||||
Hemoglobin Decreased | 195 (94) | 41 (20) | 180 (90) | 43 (22) |
Lymphocytes Decreased† | 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 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: 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.