TORISEL® Adverse Reactions

(temsirolimus)

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)].

•
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 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:

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 ReactionTORISEL
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.
†
Includes edema, facial edema, and peripheral edema
‡
Includes aphthous stomatitis, glossitis, mouth ulceration, mucositis, and stomatitis
§
Includes infections not otherwise specified (NOS) and the following infections that occurred infrequently as distinct entities: abscess, bronchitis, cellulitis, herpes simplex, and herpes zoster
Includes cystitis, dysuria, hematuria, urinary frequency, and urinary tract infection
#
Includes eczema, exfoliative dermatitis, maculopapular rash, pruritic rash, pustular rash, rash (NOS), and vesiculobullous rash
Þ
Includes taste loss and taste perversion

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%).

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

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.

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Adverse Reactions

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)].

•
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 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:

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 ReactionTORISEL
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.
†
Includes edema, facial edema, and peripheral edema
‡
Includes aphthous stomatitis, glossitis, mouth ulceration, mucositis, and stomatitis
§
Includes infections not otherwise specified (NOS) and the following infections that occurred infrequently as distinct entities: abscess, bronchitis, cellulitis, herpes simplex, and herpes zoster
Includes cystitis, dysuria, hematuria, urinary frequency, and urinary tract infection
#
Includes eczema, exfoliative dermatitis, maculopapular rash, pruritic rash, pustular rash, rash (NOS), and vesiculobullous rash
Þ
Includes taste loss and taste perversion

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%).

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

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.
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