Lenalidomide (Page 4 of 12)

5.7 Increased Mortality in Patients with MM When Pembrolizumab Is Added to a Thalidomide Analogue and Dexamethasone

In two randomized clinical trials in patients with MM, the addition of pembrolizumab to a thalidomide analogue plus dexamethasone, a use for which no PD-1 or PD-L1 blocking antibody is indicated, resulted in increased mortality. Treatment of patients with MM with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

5.8 Hepatotoxicity

Hepatic failure, including fatal cases, has occurred in patients treated with lenalidomide in combination with dexamethasone. In clinical trials, 15% of patients experienced hepatotoxicity (with hepatocellular, cholestatic and mixed characteristics); 2% of patients with MM and 1% of patients with myelodysplasia had serious hepatotoxicity events. The mechanism of drug-induced hepatotoxicity is unknown. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically. Stop lenalidomide upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered.

5.9 Severe Cutaneous Reactions

Severe cutaneous reactions including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported. DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive lenalidomide capsules. Consider lenalidomide capsules interruption or discontinuation for Grade 2-3 skin rash. Permanently discontinue lenalidomide capsules for Grade 4 rash, exfoliative or bullous rash, or for other severe cutaneous reactions such as SJS, TEN or DRESS [see Dosage and Administration (2.5)].

5.10 Tumor Lysis Syndrome

Fatal instances of tumor lysis syndrome (TLS) have been reported during treatment with lenalidomide. The patients at risk of TLS are those with high tumor burden prior to treatment. Monitor patients at risk closely and take appropriate preventive approaches.

5.11 Tumor Flare Reaction

Tumor flare reaction (TFR), including fatal reactions, have occurred during investigational use of lenalidomide for CLL and lymphoma, and is characterized by tender lymph node swelling, low grade fever, pain and rash. Lenalidomide is not indicated and not recommended for use in CLL outside of controlled clinical trials.

Monitoring and evaluation for TFR is recommended in patients with MCL. Tumor flare reaction may mimic progression of disease (PD).

In the MCL trial, 13/134 (10%) of subjects experienced TFR; all reports were Grade 1 or 2 in severity. All of the events occurred in Cycle 1 and one patient developed TFR again in Cycle 11. In a separate MCL phase 2 trial, one case of TFR resulted in a fatal outcome.

Lenalidomide may be continued in patients with Grade 1 and 2 TFR without interruption or modification, at the physician’s discretion. Patients with Grade 1 and 2 TFR may also be treated with corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and/or narcotic analgesics for management of TFR symptoms. In patients with Grade 3 or 4 TFR, it is recommended to withhold treatment with lenalidomide until TFR resolves to ≤ Grade 1. Patients with Grade 3 or 4 TFR may be treated for management of symptoms per the guidance for treatment of Grade 1 and 2 TFR.

5.12 Impaired Stem Cell Mobilization

A decrease in the number of CD34+ cells collected after treatment (> 4 cycles) with lenalidomide has been reported. In patients who are auto-HSCT candidates, referral to a transplant center should occur early in treatment to optimize the timing of the stem cell collection. In patients who received more than 4 cycles of a lenalidomide-containing treatment or for whom inadequate numbers of CD 34+ cells have been collected with G-CSF alone, G-CSF with cyclophosphamide or the combination of G-CSF with a CXCR4 inhibitor may be considered.

5.13 Thyroid Disorders

Both hypothyroidism and hyperthyroidism have been reported [see Adverse Reactions (6.2)]. Measure thyroid function before start of lenalidomide capsules treatment and during therapy.

5.14 Early Mortality in Patients with MCL

In another MCL study, there was an increase in early deaths (within 20 weeks), 12.9% in the lenalidomide arm versus 7.1% in the control arm. On exploratory multivariate analysis, risk factors for early deaths include high tumor burden, MIPI score at diagnosis, and high WBC at baseline (≥ 10 x 109 /L).

5.15 Hypersensitivity

Hypersensitivity, including angioedema, anaphylaxis, and anaphylactic reactions to lenalidomide capsules have been reported. Permanently discontinue lenalidomide capsules for angioedema and anaphylaxis [see Dosage and Administration (2.2)].

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described in detail in other sections of the prescribing information:

  • Embryo-Fetal Toxicity [see Boxed Warning, Warnings and Precautions (5.1, 5.2)]
  • Hematologic Toxicity [see Boxed Warning, Warnings and Precautions (5.3)]
  • Venous and Arterial Thromboembolism [see Boxed Warning, Warnings and Precautions (5.4)]
  • Increased Mortality in Patients with CLL [see Warnings and Precautions (5.5)]
  • Second Primary Malignancies [see Warnings and Precautions (5.6)]
  • Increased Mortality in Patients with MM When Pembrolizumab Is Added to a Thalidomide Analogue and Dexamethasone [see Warnings and Precautions (5.7)]
  • Hepatotoxicity [see Warnings and Precautions (5.8)]
  • Severe Cutaneous Reactions [see Warnings and Precautions (5.9)]
  • Tumor Lysis Syndrome [see Warnings and Precautions (5.10)]
  • Tumor Flare Reactions [see Warnings and Precautions (5.11)]
  • Impaired Stem Cell Mobilization [see Warnings and Precautions (5.12)]
  • Thyroid Disorders [see Warnings and Precautions (5.13)]
  • Early Mortality in Patients with MCL [see Warnings and Precautions (5.14)]
  • Hypersensitivity [see Warnings and Precautions (5.15)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Newly Diagnosed MM – Lenalidomide Capsules Combination Therapy:

Data were evaluated from 1613 patients in a large phase 3 study who received at least one dose of lenalidomide with low dose dexamethasone (Rd) given for 2 different durations of time (i.e., until progressive disease [Arm Rd Continuous; N=532] or for up to eighteen 28-day cycles [72 weeks, Arm Rd18; N=540] or who received melphalan, prednisone and thalidomide (Arm MPT; N=541) for a maximum of twelve 42-day cycles (72 weeks). The median treatment duration in the Rd Continuous arm was 80.2 weeks (range 0.7 to 246.7) or 18.4 months (range 0.16 to 56.7).

In general, the most frequently reported adverse reactions were comparable in Arm Rd Continuous and Arm Rd18, and included diarrhea, anemia, constipation, peripheral edema, neutropenia, fatigue, back pain, nausea, asthenia, and insomnia. The most frequently reported Grade 3 or 4 reactions included neutropenia, anemia, thrombocytopenia, pneumonia, asthenia, fatigue, back pain, hypokalemia, rash, cataract, lymphopenia, dyspnea, DVT, hyperglycemia, and leukopenia. The highest frequency of infections occurred in Arm Rd Continuous (75%) compared to Arm MPT (56%). There were more grade 3 and 4 and serious adverse reactions of infection in Arm Rd Continuous than either Arm MPT or Rd18.

In the Rd Continuous arm, the most common adverse reactions leading to dose interruption of lenalidomide were infection events (28.8%); overall, the median time to the first dose interruption of lenalidomide was 7 weeks. The most common adverse reactions leading to dose reduction of lenalidomide in the Rd Continuous arm were hematologic events (10.7%); overall, the median time to the first dose reduction of lenalidomide was 16 weeks. In the Rd Continuous arm, the most common adverse reactions leading to discontinuation of lenalidomide were infection events (3.4%).

In both Rd arms, the frequencies of onset of adverse reactions were generally highest in the first 6 months of treatment and then the frequencies decreased over time or remained stable throughout treatment, except for cataracts. The frequency of onset of cataracts increased over time with 0.7% during the first 6 months and up to 9.6% by the 2nd year of treatment with Rd Continuous.

Table 4 summarizes the adverse reactions reported for the Rd Continuous, Rd18, and MPT treatment arms.

Table 4: All Adverse Reactions in ≥5% and Grade 3/4 Adverse Reactions in ≥1% of Patients with MM in the Rd Continuous or Rd18 Arms*

Body System

Adverse Reaction

All Adverse Reactionsa

Grade 3/4 Adverse Reactionsb

Rd Continuous

(N=532)

Rd18

(N=540)

MPT

(N=541)

Rd Continuous

(N=532)

Rd18

(N=540)

MPT

(N=541)

General disorders and administration site conditions

Fatigue%

173 (33)

177 (33)

154 (28)

39 (7)

46 (9)

31 (6)

Asthenia

150 (28)

123 (23)

124 (23)

41 (8)

33 (6)

32 (6)

Pyrexiac

114 (21)

102 (19)

76 (14)

13 (2)

7 (1)

7 (1)

Non-cardiac chest painf

29 (5)

31 (6)

18 (3)

<1%

< 1%

< 1%

Gastrointestinal disorders

Diarrhea

242 (45)

208 (39)

89 (16)

21 (4)

18 (3)

8 (1)

Abdominal pain%f

109 (20)

78 (14)

60 (11)

7 (1)

9 (2)

< 1%

Dyspepsiaf

57 (11)

28 (5)

36 (7)

<1%

< 1%

0 (0)

Musculoskeletal and connective tissue disorders

Back painc

170 (32)

145 (27)

116 (21)

37 (7)

34 (6)

28 (5)

Muscle spasmsf

109 (20)

102 (19)

61 (11)

< 1%

< 1%

< 1%

Arthralgiaf

101 (19)

71 (13)

66 (12)

9 (2)

8 (1)

8 (1)

Bone painf

87 (16)

77 (14)

62 (11)

16 (3)

15 (3)

14 (3)

Pain in extremityf

79 (15)

66 (12)

61 (11)

8 (2)

8 (1)

7 (1)

Musculoskeletal painf

67 (13)

59 (11)

36 (7)

< 1%

< 1%

< 1%

Musculoskeletal chest painf

60 (11)

51 (9)

39 (7)

6 (1)

< 1%

< 1%

Muscular weaknessf

43 (8)

35 (6)

29 (5)

< 1%

8 (1)

< 1%

Neck painf

40 (8)

19 (4)

10 (2)

< 1%

< 1%

< 1%

Infections and infestations

Bronchitisc

90 (17)

59 (11)

43 (8)

9 (2)

6 (1)

< 1%

Nasopharyngitisf

80 (15)

54 (10)

33 (6)

0 (0)

0 (0)

0 (0)

Urinary tract infectionf

76 (14)

63 (12)

41 (8)

8 (2)

8 (1)

< 1%

Upper respiratory tract infectionc% f

69 (13)

53 (10)

31 (6)

< 1%

8 (1)

< 1%

Pneumoniac@

93 (17)

87 (16)

56 (10)

60 (11)

57 (11)

41 (8)

Respiratory tract infection%

35 (7)

25 (5)

21 (4)

7 (1)

< 1%

< 1%

Influenzaf

33 (6)

23 (4)

15 (3)

< 1%

< 1%

0 (0)

Gastroenteritisf

32 (6)

17 (3)

13 (2)

0 (0)

< 1%

< 1%

Lower respiratory tract infection

29 (5)

14 (3)

16 (3)

10 (2)

< 1%

< 1%

Rhinitisf

29 ( 5)

24 (4)

14 (3)

0 (0)

0 (0)

0 (0)

Cellulitisc

< 5%

< 5%

< 5%

8 (2)

< 1%

< 1%

Sepsisc@

33 (6)

26 (5)

18 (3)

26 (5)

20 (4)

13 (2)

Nervous system disorders

Headachef

75 (14)

52 (10)

56 (10)

< 1%

< 1%

< 1%

Dysgeusiaf

39 (7)

45 (8)

22 (4)

< 1%

0 (0.0)

< 1%

Blood and lymphatic system disordersd

Anemia

233 (44)

193 (36)

229 (42)

97 (18)

85 (16)

102 (19)

Neutropenia

186 (35)

178 (33)

328 (61)

148 (28)

143 (26)

243 (45)

Thrombocytopenia

104 (20)

100 (19)

135 (25)

44 (8)

43 (8)

60 (11)

Febrile neutropenia

7 (1)

17 (3)

15 (3)

6 (1)

16 (3)

14 (3)

Pancytopenia

< 1%

6 (1)

7 (1)

< 1%

< 1%

< 1%

Respiratory, thoracic and mediastinal disorders

Coughf

121 (23)

94 (17)

68 (13)

< 1%

< 1%

< 1%

Dyspneac,e

117 (22)

89 (16)

113 (21)

30 (6)

22 (4)

18 (3)

Epistaxisf

32 (6)

31 (6)

17 (3)

< 1%

< 1%

0 (0)

Oropharyngeal painf

30 (6)

22 (4)

14 (3)

0 (0)

0 (0)

0 (0)

Dyspnea exertionale

27 (5)

29 (5)

< 5%

6 (1)

< 1%

0 (0)

Metabolism and nutrition disorders

Decreased appetite

123 (23)

115 (21)

72 (13)

14 (3)

7 (1)

< 1%

Hypokalemia%

91 (17)

62 (11)

38 (7)

35 (7)

20 (4)

11 (2)

Hyperglycemia

62 (12)

52 (10)

19 (4)

28 (5)

23 (4)

9 (2)

Hypocalcemia

57 (11)

56 (10)

31 (6)

23 (4)

19 (4)

8 (1)

Dehydration%

25 (5)

29 (5)

17 (3)

8 (2)

13 (2)

9 (2)

Gout e

< 5%

< 5%

< 5%

8 (2)

0 (0)

0 (0)

Diabetes mellitus% e

< 5%

< 5%

< 5%

8 (2)

< 1%

< 1%

Hypophosphatemiae

< 5%

< 5%

< 5%

7 (1)

< 1%

< 1%

Hyponatremia% e

< 5%

< 5%

< 5%

7 (1)

13 (2)

6 (1)

Skin and subcutaneous tissue disorders

Rash

139 (26)

151 (28)

105 (19)

39 (7)

38 (7)

33 (6)

Pruritus f

47 (9)

49 (9)

24 (4)

< 1%

< 1%

< 1%

Psychiatric disorders

Insomnia

147 (28)

127 (24)

53 (10)

< 1%

6 (1)

0 (0)

Depression

58 (11)

46 (9)

30 (6)

10 (2)

< 1%

< 1%

Vascular disorders

Deep vein thrombosisc %

55 (10)

39 (7)

22 (4)

30 (6)

20 (4)

15 (3)

Hypotensionc %

51 (10)

35 (6)

36 (7)

11 (2)

8 (1)

6 (1)

Injury, Poisoning, and Procedural Complications

Fallf

43 (8)

25 (5)

25 (5)

< 1%

6 (1)

6 (1)

Contusionf

33 (6)

24 (4)

15 (3)

< 1%

< 1%

0 (0)

Eye disorders

Cataract

73 (14)

31 (6)

< 1%

31 (6)

14 (3)

< 1%

Cataract subcapsulare

< 5%

< 5%

< 5%

7 (1)

0 (0)

0 (0)

Investigations

Weight decreased

72 (14)

78 (14)

48 (9)

11 (2)

< 1%

< 1%

Cardiac disorders

Atrial fibrillationc

37 (7)

25 (5)

25 (5)

13 (2)

9 (2)

6 (1)

Myocardial infarction (including acute)c,e

< 5%

< 5%

< 5%

10 (2)

< 1%

< 1%

Renal and Urinary disorders

Renal failure (including acute)c@,f

49 (9)

54 (10)

37 (7)

28 (5)

33 (6)

29 (5)

Neoplasms benign, malignant and unspecified (Including cysts and polyps)

Squamous cell carcinomac e

< 5%

< 5%

< 5%

8 (2)

< 1%

0 (0)

Basal cell carcinomac e,f

< 5%

< 5%

< 5%

< 1%

< 1%

0 (0)

Note: A subject with multiple occurrences of an adverse reaction is counted only once under the applicable Body System/Adverse Reaction.

a All treatment-emergent adverse events in at least 5% of subjects in the Rd Continuous or Rd18 Arms and at least a 2% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm.

b All grade 3 or 4 treatment-emergent adverse events in at least 1% of subjects in the Rd Continuous or Rd18 Arms and at least a 1% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm.

c Serious treatment-emergent adverse events in at least 1% of subjects in the Rd Continuous or Rd18 Arms and at least a 1% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm.

d Preferred terms for the blood and lymphatic system disorders body system were included by medical judgment as known adverse reactions for Rd Continuous/Rd18, and have also been reported as serious.

e Footnote “a” not applicable.

f Footnote “b” not applicable.

@ — adverse reactions in which at least one resulted in a fatal outcome.

% — adverse reactions in which at least one was considered to be life threatening (if the outcome of the reaction was death, it is included with death cases).

* Adverse reactions included in combined adverse reaction terms:

Abdominal Pain: Abdominal pain, abdominal pain upper, abdominal pain lower, gastrointestinal pain

Pneumonias: Pneumonia, lobar pneumonia, pneumonia pneumococcal, bronchopneumonia, pneumocystis jiroveci pneumonia, pneumonia legionella, pneumonia staphylococcal, pneumonia klebsiella, atypical pneumonia, pneumonia bacterial, pneumonia escherichia, pneumonia streptococcal, pneumonia viral

Sepsis: Sepsis, septic shock, urosepsis, escherichia sepsis, neutropenic sepsis, pneumococcal sepsis, staphylococcal sepsis, bacterial sepsis, meningococcal sepsis, enterococcal sepsis, klebsiella sepsis, pseudomonal sepsis

Rash: Rash, rash pruritic, rash erythematous, rash maculo-papular, rash generalized, rash papular, exfoliative rash, rash follicular, rash macular, drug rash with eosinophilia and systemic symptoms, erythema multiforme, rash pustular

Deep Vein Thrombosis: Deep vein thrombosis, venous thrombosis limb, venous thrombosis

After At Least One Prior Therapy for MM:

Data were evaluated from 703 patients in two studies who received at least one dose of lenalidomide/dexamethasone (353 patients) or placebo/dexamethasone (350 patients).

In the lenalidomide/dexamethasone treatment group, 269 patients (76%) had at least one dose interruption with or without a dose reduction of lenalidomide compared to 199 patients (57%) in the placebo/dexamethasone treatment group. Of these patients who had one dose interruption with or without a dose reduction, 50% in the lenalidomide/dexamethasone treatment group had at least one additional dose interruption with or without a dose reduction compared to 21% in the placebo/dexamethasone treatment group. Most adverse reactions and Grade 3/4 adverse reactions were more frequent in patients who received the combination of lenalidomide/dexamethasone compared to placebo/dexamethasone.

Tables 6, 7, and 8 summarize the adverse reactions reported for lenalidomide/dexamethasone and placebo/dexamethasone groups.

Table 6: Adverse Reactions Reported in ≥5% of Patients and with a ≥2% Difference in Proportion of Patients with MM between the Lenalidomide/dexamethasone and Placebo/dexamethasone Groups

Body System Adverse Reaction

Lenalidomide/Dex

(N=353)

n (%)

Placebo/Dex

(N=350)

n (%)

Blood and lymphatic system disorders

Neutropenia%

149 (42)

22 (6)

Anemia@

111 (31)

83 (24)

Thrombocytopenia@

76 (22)

37 (11)

Leukopenia

28 (8)

4 (1)

Lymphopenia

19 (5)

5 (1)

General disorders and administration site conditions

Fatigue

155 (44)

146 (42)

Pyrexia

97 (27)

82 (23)

Peripheral edema

93 (26)

74 (21)

Chest pain

29 (8)

20 (6)

Lethargy

24 (7)

8 (2)

Gastrointestinal disorders

Constipation

143 (41)

74 (21)

Diarrhea@

136 (39)

96 (27)

Nausea@

92 (26)

75 (21)

Vomiting@

43 (12)

33 (9)

Abdominal pain@

35 (10)

22 (6)

Dry mouth

25 (7)

13 (4)

Musculoskeletal and connective tissue disorders

Muscle cramp

118 (33)

74 (21)

Back pain

91 (26)

65 (19)

Bone pain

48 (14)

39 (11)

Pain in limb

42 (12)

32 (9)

Nervous system disorders

Dizziness

82 (23)

59 (17)

Tremor

75 (21)

26 (7)

Dysgeusia

54 (15)

34 (10)

Hypoesthesia

36 (10)

25 (7)

Neuropathyª

23 (7)

13 (4)

Respiratory, thoracic and mediastinal disorders

Dyspnea

83 (24)

60 (17)

Nasopharyngitis

62 (18)

31 (9)

Pharyngitis

48 (14)

33 (9)

Bronchitis

40 (11)

30 (9)

Infectionsb and infestations

Upper respiratory tract infection

87 (25)

55 (16)

Pneumonia@

48 (14)

29 (8)

Urinary tract infection

30 (8)

19 (5)

Sinusitis

26 (7)

16 (5)

Skin and subcutaneous system disorders

Rashc

75 (21)

33 (9)

Sweating increased

35 (10)

25 (7)

Dry skin

33 (9)

14 (4)

Pruritus

27 (8)

18 (5)

Metabolism and nutrition disorders

Anorexia

55 (16)

34 (10)

Hypokalemia

48 (14)

21 (6)

Hypocalcemia

31 (9)

10 (3)

Appetite decreased

24 (7)

14 (4)

Dehydration

23 (7)

15 (4)

Hypomagnesemia

24 (7)

10 (3)

Investigations

Weight decreased

69 (20)

52 (15)

Eye disorders

Blurred vision

61 (17)

40 (11)

Vascular disorders

Deep vein thrombosis%

33 (9)

15 (4)

Hypertension

28 (8)

20 (6)

Hypotension

25 (7)

15 (4)

Table 7: Grade 3/4 Adverse Reactions Reported in ≥2% Patients and with a ≥1% Difference in Proportion of Patients with MM between the Lenalidomide/dexamethasone and Placebo/dexamethasone groups

Body System

Adverse Reaction

Lenalidomide/Dex

(N=353)

n (%)

Placebo/Dex

(N=350)

n (%)

Blood and lymphatic system disorders

Neutropenia%

118 (33)

12 (3)

Thrombocytopenia@

43 (12)

22 (6)

Anemia@

35 (10)

20 (6)

Leukopenia

14 (4)

< 1%

Lymphopenia

10 (3)

4 (1)

Febrile neutropenia%

8 (2)

0 (0)

General disorders and administration site conditions

Fatigue

23 (7)

17 (5)

Vascular disorders

Deep vein thrombosis%

29 (8)

12 (3)

Infections and infestations

Pneumonia@

30 (8)

19 (5)

Urinary tract infection

5 (1)

< 1%

Metabolism and nutrition disorders

Hypokalemia

17 (5)

5 (1)

Hypocalcemia

13 (4)

6 (2)

Hypophosphatemia

9 (3)

0 (0)

Respiratory, thoracic and mediastinal disorders

Pulmonary embolism@

14 (4)

< 1%

Respiratory distress@

4 (1)

0 (0)

Musculoskeletal and connective tissue disorders

Muscle weakness

20 (6)

10 (3)

Gastrointestinal disorders

Diarrhea@

11 (3)

4 (1)

Constipation

7 (2)

< 1%

Nausea@

6 (2)

< 1%

Cardiac disorders

Atrial fibrillation@

13 (4)

4 (1)

Tachycardia

6 (2)

< 1%

Cardiac failure congestive@

5 (1)

< 1%

Nervous system disorders

Syncope

10 (3)

< 1%

Dizziness

7 (2)

< 1%

Eye disorders

Cataract

6 (2)

< 1%

Cataract unilateral

5 (1)

0 (0)

Psychiatric disorder

Depression

10 (3)

6 (2)

Table 8: Serious Adverse Reactions Reported in ≥1% Patients and with a ≥1% Difference in Proportion of Patients with MM between the Lenalidomide/dexamethasone and Placebo/dexamethasone Groups

Body System

Adverse Reaction

Lenalidomide/Dex

(N=353)

n (%)

Placebo/Dex

(N=350)

n (%)

Blood and lymphatic system disorders

Febrile neutropenia%

6 (2)

0 (0)

Vascular disorders

Deep vein thrombosis%

26 (7)

11 (3)

Infections and infestations

Pneumonia@

33 (9)

21 (6)

Respiratory, thoracic, and mediastinal disorders

Pulmonary embolism@

13 (4)

< 1%

Cardiac disorders

Atrial fibrillation@

11 (3)

< 1%

Cardiac failure congestive@

5 (1)

0 (0)

Nervous system disorders

Cerebrovascular accident@

7 (2)

< 1%

Gastrointestinal disorders

Diarrhea@

6 (2)

< 1%

Musculoskeletal and connective tissue disorders

Bone pain

4 (1)

0 (0)

For Tables 6, 7 and 8 above:

@ — adverse reactions in which at least one resulted in a fatal outcome.

% — adverse reactions in which at least one was considered to be life threatening (if the outcome of the reaction was death, it is included with death cases).

Median duration of exposure among patients treated with lenalidomide/dexamethasone was 44 weeks while median duration of exposure among patients treated with placebo/dexamethasone was 23 weeks. This should be taken into consideration when comparing frequency of adverse reactions between two treatment groups lenalidomide/dexamethasone vs. placebo/dexamethasone.

Venous and Arterial Thromboembolism [see Boxed Warning, Warnings and Precautions (5.4)]

VTE and ATE are increased in patients treated with lenalidomide capsules.

Deep vein thrombosis (DVT) was reported as a serious (7.4%) or severe (8.2%) adverse drug reaction at a higher rate in the lenalidomide/dexamethasone group compared to 3.1 % and 3.4% in the placebo/dexamethasone group, respectively in the 2 studies in patients with at least 1 prior therapy with discontinuations due to DVT adverse reactions reported at comparable rates between groups. In the NDMM study, DVT was reported as an adverse reaction (all grades: 10.3%, 7.2%, 4.1%), as a serious adverse reaction (3.6%, 2.0%, 1.7%), and as a Grade 3/4 adverse reaction (5.6%, 3.7%, 2.8%) in the Rd Continuous, Rd18, and MPT Arms, respectively. Discontinuations and dose reductions due to DVT adverse reactions were reported at comparable rates between the Rd Continuous and Rd18 Arms (both <1%). Interruption of lenalidomide treatment due to DVT adverse reactions was reported at comparable rates between the Rd Continuous (2.3%) and Rd18 (1.5%) arms. Pulmonary embolism (PE) was reported as a serious adverse drug reaction (3.7%) or Grade 3/4 (4.0%) at a higher rate in the lenalidomide/dexamethasone group compared to 0.9% (serious or grade 3/4) in the placebo/dexamethasone group in the 2 studies in patients with, at least 1 prior therapy, with discontinuations due to PE adverse reactions reported at comparable rates between groups. In the NDMM study, the frequency of adverse reactions of PE was similar between the Rd Continuous, Rd18, and MPT Arms for adverse reactions (all grades: 3.9%, 3.3%, and 4.3%, respectively), serious adverse reactions (3.8%, 2.8%, and 3.7%, respectively), and grade 3/4 adverse reactions (3.8%, 3.0%, and 3.7%, respectively).

Myocardial infarction was reported as a serious (1.7%) or severe (1.7%) adverse drug reaction at a higher rate in the lenalidomide/dexamethasone group compared to 0.6% and 0.6% respectively in the placebo/dexamethasone group. Discontinuation due to MI (including acute) adverse reactions was 0.8% in lenalidomide/dexamethasone group and none in the placebo/dexamethasone group. In the NDMM study, myocardial infarction (including acute) was reported as an adverse reaction (all grades: 2.4%, 0.6%, and 1.1%), as a serious adverse reaction, (2.3%, 0.6%, and 1.1%), or as a severe adverse reaction (1.9%, 0.6%, and 0.9%) in the Rd Continuous, Rd18, and MPT Arms, respectively.

Stroke (CVA) was reported as a serious (2.3%) or severe (2.0%) adverse drug reaction in the lenalidomide/dexamethasone group compared to 0.9% and 0.9% respectively in the placebo/dexamethasone group. Discontinuation due to stroke (CVA) was 1.4% in lenalidomide/dexamethasone group and 0.3% in the placebo/dexamethasone group. In the NDMM study, CVA was reported as an adverse reaction (all grades: 0.8%, 0.6%, and 0.6%), as a serious adverse reaction (0.8%, 0.6 %, and 0.6%), or as a severe adverse reaction (0.6%, 0.6%, 0.2%) in the Rd Continuous, Rd18, and MPT arms respectively.

Other Adverse Reactions: After At Least One Prior Therapy for MM

In these 2 studies, the following adverse drug reactions (ADRs) not described above that occurred at ≥1% rate and of at least twice of the placebo percentage rate were reported:

Blood and lymphatic system disorders: pancytopenia, autoimmune hemolytic anemia

Cardiac disorders: bradycardia, myocardial infarction, angina pectoris

Endocrine disorders: hirsutism

Eye disorders: blindness, ocular hypertension

Gastrointestinal disorders: gastrointestinal hemorrhage, glossodynia

General disorders and administration site conditions: malaise

Investigations: liver function tests abnormal, alanine aminotransferase increased

Nervous system disorders: cerebral ischemia

Psychiatric disorders: mood swings, hallucination, loss of libido

Reproductive system and breast disorders: erectile dysfunction

Respiratory, thoracic and mediastinal disorders: cough, hoarseness

Skin and subcutaneous tissue disorders: exanthem, skin hyperpigmentation

Myelodysplastic Syndromes:

A total of 148 patients received at least 1 dose of 10 mg lenalidomide in the del 5q MDS clinical study. At least one adverse reaction was reported in all of the 148 patients who were treated with the 10 mg starting dose of lenalidomide capsules. The most frequently reported adverse reactions were related to blood and lymphatic system disorders, skin and subcutaneous tissue disorders, gastrointestinal disorders, and general disorders and administrative site conditions.

Thrombocytopenia (61.5%; 91/148) and neutropenia (58.8%; 87/148) were the most frequently reported adverse reactions. The next most common adverse reactions observed were diarrhea (48.6%; 72/148), pruritus (41.9%; 62/148), rash (35.8%; 53/148) and fatigue (31.1%; 46/148). Table 9 summarizes the adverse reactions that were reported in ≥ 5% of the lenalidomide treated patients in the del 5q MDS clinical study. Table 10 summarizes the most frequently observed Grade 3 and Grade 4 adverse reactions regardless of relationship to treatment with lenalidomide. In the single-arm studies conducted, it is often not possible to distinguish adverse reactions that are drug-related and those that reflect the patient’s underlying disease.

Table 9: Summary of Adverse Reactions Reported in ≥5% of the Lenalidomide Treated Patients in del 5q MDS Clinical Study

Body System

Adverse Reaction a

10 mg Overall

(N=148)

Patients with at least one adverse reaction

148

(100)

Blood and Lymphatic System Disorders

Thrombocytopenia

91

(61)

Neutropenia

87

(59)

Anemia

17

(11)

Leukopenia

12

(8)

Febrile Neutropenia

8

(5)

Skin and Subcutaneous Tissue Disorders

Pruritus

62

(42)

Rash

53

(36)

Dry Skin

21

(14)

Contusion

12

(8)

Night Sweats

12

(8)

Sweating Increased

10

(7)

Ecchymosis

8

(5)

Erythema

8

(5)

Gastrointestinal Disorders

Diarrhea

72

(49)

Constipation

35

(24)

Nausea

35

(24)

Abdominal Pain

18

(12)

Vomiting

15

(10)

Abdominal Pain Upper

12

(8)

Dry Mouth

10

(7)

Loose Stools

9

(6)

Respiratory, Thoracic and Mediastinal Disorders

Nasopharyngitis

34

(23)

Cough

29

(20)

Dyspnea

25

(17)

Pharyngitis

23

(16)

Epistaxis

22

(15)

Dyspnea Exertional

10

(7)

Rhinitis

10

(7)

Bronchitis

9

(6)

General Disorders and Administration Site Conditions

Fatigue

46

(31)

Pyrexia

31

(21)

Edema Peripheral

30

(20)

Asthenia

22

(15)

Edema

15

(10)

Pain

10

(7)

Rigors

9

(6)

Chest Pain

8

(5)

Musculoskeletal and Connective Tissue Disorders

Arthralgia

32

(22)

Back Pain

31

(21)

Muscle Cramp

27

(18)

Pain in Limb

16

(11)

Myalgia

13

(9)

Peripheral Swelling

12

(8)

Nervous System Disorders

Dizziness

29

(20)

Headache

29

(20)

Hypoesthesia

10

(7)

Dysgeusia

9

(6)

Peripheral Neuropathy

8

(5)

Infections and Infestations

Upper Respiratory Tract Infection

22

(15)

Pneumonia

17

(11)

Urinary Tract Infection

16

(11)

Sinusitis

12

(8)

Cellulitis

8

(5)

Metabolism and Nutrition Disorders

Hypokalemia

16

(11)

Anorexia

15

(10)

Hypomagnesemia

9

(6)

Investigations

Alanine Aminotransferase Increased

12

(8)

Psychiatric Disorders

Insomnia

15

(10)

Depression

8

(5)

Renal and Urinary Disorders

Dysuria

10

(7)

Vascular Disorders

Hypertension

9

(6)

Endocrine Disorders

Acquired Hypothyroidism

10

(7)

Cardiac Disorders

Palpitations

8

(5)

a Body System and adverse reactions are coded using the MedDRA dictionary. Body System and adverse reactions are listed in descending order of frequency for the Overall column. A patient with multiple occurrences of an adverse reaction is counted only once under the applicable Body System/Adverse Reaction.

Table 10: Most Frequently Observed Grade 3 and 4 Adverse Reactions 1 Regardless of Relationship to Study Drug Treatment in the del 5q MDS Clinical Study

Adverse Reactions 2

10 mg

(N=148)

Patients with at least one Grade 3/4 AE

131 (89)

Neutropenia

79 (53)

Thrombocytopenia

74 (50)

Pneumonia

11 (7)

Rash

10 (7)

Anemia

9 (6)

Leukopenia

8 (5)

Fatigue

7 (5)

Dyspnea

7 (5)

Back Pain

7 (5)

Febrile Neutropenia

6 (4)

Nausea

6 (4)

Diarrhea

5 (3)

Pyrexia

5 (3)

Sepsis

4 (3)

Dizziness

4 (3)

Granulocytopenia

3 (2)

Chest Pain

3 (2)

Pulmonary Embolism

3 (2)

Respiratory Distress

3 (2)

Pruritus

3 (2)

Pancytopenia

3 (2)

Muscle Cramp

3 (2)

Respiratory Tract Infection

2 (1)

Upper Respiratory Tract Infection

2 (1)

Asthenia

2 (1)

Multi-organ Failure

2 (1)

Epistaxis

2 (1)

Hypoxia

2 (1)

Pleural Effusion

2 (1)

Pneumonitis

2 (1)

Pulmonary Hypertension

2 (1)

Vomiting

2 (1)

Sweating Increased

2 (1)

Arthralgia

2 (1)

Pain in Limb

2 (1)

Headache

2 (1)

Syncope

2 (1)

1 Adverse reactions with frequency ≥1% in the 10 mg Overall group. Grade 3 and 4 are based on National Cancer Institute Common Toxicity Criteria version 2.

2 Adverse reactions are coded using the MedDRA dictionary. A patient with multiple occurrences of an adverse reaction is counted only once in the adverse reaction category.

In other clinical studies of lenalidomide in MDS patients, the following serious adverse reactions (regardless of relationship to study drug treatment) not described in Table 9 or 10 were reported:

Blood and lymphatic system disorders: warm type hemolytic anemia, splenic infarction, bone marrow depression, coagulopathy, hemolysis, hemolytic anemia, refractory anemia

Cardiac disorders: cardiac failure congestive, atrial fibrillation, angina pectoris, cardiac arrest, cardiac failure, cardio-respiratory arrest, cardiomyopathy, myocardial infarction, myocardial ischemia, atrial fibrillation aggravated, bradycardia, cardiogenic shock, pulmonary edema, supraventricular arrhythmia, tachyarrhythmia, ventricular dysfunction

Ear and labyrinth disorders: vertigo

Endocrine disorders: Basedow’s disease

Gastrointestinal disorders: gastrointestinal hemorrhage, colitis ischemic, intestinal perforation, rectal hemorrhage, colonic polyp, diverticulitis, dysphagia, gastritis, gastroenteritis, gastroesophageal reflux disease, obstructive inguinal hernia, irritable bowel syndrome, melena, pancreatitis due to biliary obstruction, pancreatitis, perirectal abscess, small intestinal obstruction, upper gastrointestinal hemorrhage

General disorders and administration site conditions: disease progression, fall, gait abnormal, intermittent pyrexia, nodule, rigors, sudden death

Hepatobiliary disorders: hyperbilirubinemia, cholecystitis, acute cholecystitis, hepatic failure

Immune system disorders: hypersensitivity

Infections and infestations: infection bacteremia, central line infection, clostridial infection, ear infection, Enterobacter sepsis, fungal infection, herpes viral infection NOS, influenza, kidney infection, Klebsiella sepsis, lobar pneumonia, localized infection, oral infection, Pseudomonas infection, septic shock, sinusitis acute, sinusitis, Staphylococcal infection, urosepsis

Injury, poisoning and procedural complications: femur fracture, transfusion reaction, cervical vertebral fracture, femoral neck fracture, fractured pelvis, hip fracture, overdose, post procedural hemorrhage, rib fracture, road traffic accident, spinal compression fracture

Investigations: blood creatinine increased, hemoglobin decreased, liver function tests abnormal, troponin I increased

Metabolism and nutrition disorders: dehydration, gout, hypernatremia, hypoglycemia

Musculoskeletal and connective tissue disorders: arthritis, arthritis aggravated, gouty arthritis, neck pain, chondrocalcinosis pyrophosphate

Neoplasms benign, malignant and unspecified: acute leukemia, acute myeloid leukemia, bronchoalveolar carcinoma, lung cancer metastatic, lymphoma, prostate cancer metastatic

Nervous system disorders: cerebrovascular accident, aphasia, cerebellar infarction, cerebral infarction, depressed level of consciousness, dysarthria, migraine, spinal cord compression, subarachnoid hemorrhage, transient ischemic attack

Psychiatric disorders: confusional state

Renal and urinary disorders: renal failure, hematuria, renal failure acute, azotemia, calculus ureteric, renal mass

Reproductive system and breast disorders: pelvic pain

Respiratory, thoracic and mediastinal disorders: bronchitis, chronic obstructive airways disease exacerbated, respiratory failure, dyspnea exacerbated, interstitial lung disease, lung infiltration, wheezing

Skin and subcutaneous tissue disorders: acute febrile neutrophilic dermatosis

Vascular system disorders: deep vein thrombosis, hypotension, aortic disorder, ischemia, thrombophlebitis superficial, thrombosis

Mantle Cell Lymphoma:

In the MCL trial, a total of 134 patients received at least 1 dose of lenalidomide. Their median age was 67 (range 43 to 83) years, 128/134 (96%) were Caucasian, 108/134 (81%) were males and 82/134 (61%) had duration of MCL for at least 3 years.

Table 11 summarizes the most frequently observed adverse reactions regardless of relationship to treatment with lenalidomide. Across the 134 patients treated in this study, median duration of treatment was 95 days (1 to 1002 days). Seventy-eight patients (58%) received 3 or more cycles of therapy, 53 patients (40%) received 6 or more cycles, and 26 patients (19%) received 12 or more cycles. Seventy-six patients (57%) underwent at least one dose interruption due to adverse reactions, and 51 patients (38%) underwent at least one dose reduction due to adverse reactions. Twenty-six patients (19%) discontinued treatment due to adverse reactions.

Table 11: Incidence of Adverse Reactions (≥10%) or Grade 3/4 AE (in at least 2 patients) in Mantle Cell Lymphoma

Body System

Adverse Reaction

All Adverse Reactions1

(N=134)

n (%)

Grade 3/4 Adverse

Reactions2 (N=134)

n (%)

General disorders and administration site conditions

Fatigue

45 (34)

9 (7)

Pyrexia$

31 (23)

3 (2)

Edema peripheral

21 (16)

0

Asthenia$

19 (14)

4 (3)

General physical health deterioration

3 (2)

2 (1)

Gastrointestinal disorders

Diarrhea$

42 (31)

8 (6)

Nausea$

40 (30)

1 (<1)

Constipation

21 (16)

1 (<1)

Vomiting$

16 (12)

1 (<1)

Abdominal pain$

13 (10)

5 (4)

Musculoskeletal and connective tissue disorders

Back pain

18 (13)

2 (1)

Muscle spasms

17 (13)

1 (<1)

Arthralgia

11 (8)

2 (1)

Muscular weakness$

8 (6)

2 (1)

Respiratory, thoracic and mediastinal disorders

Cough

38 (28)

1 (<1)

Dyspnea$

24 (18)

8 (6)

Pleural Effusion

10 (7)

2 (1)

Hypoxia

3 (2)

2 (1)

Pulmonary embolism

3 (2)

2 (1)

Respiratory distress$

2 (1)

2 (1)

Oropharyngeal pain

13 (10)

0

Infections and infestations

Pneumonia@ $

19 (14)

12 (9)

Upper respiratory tract infection

17 (13)

0

Cellulitis$

3 (2)

2 (1)

Bacteremia$

2 (1)

2 (1)

Staphylococcal sepsis$

2 (1)

2 (1)

Urinary tract infection$

5 (4)

2 (1)

Skin and subcutaneous tissue disorders

Rash +

30 (22)

2 (1)

Pruritus

23 (17)

1 (<1)

Blood and lymphatic system disorders

Neutropenia

65 (49)

58 (43)

Thrombocytopenia% $

48 (36)

37 (28)

Anemia$

41 (31)

15 (11)

Leukopenia$

20 (15)

9 (7)

Lymphopenia

10 (7)

5 (4)

Febrile neutropenia$

8 (6)

8 (6)

Metabolism and nutrition disorders

Decreased appetite

19 (14)

1 (<1)

Hypokalemia

17 (13)

3 (2)

Dehydration$

10 (7)

4 (3)

Hypocalcemia

4 (3)

2 (1)

Hyponatremia

3 (2)

3 (2)

Renal and urinary disorders

Renal failure$

5 (4)

2 (1)

Vascular disorders

Hypotension@ $

9 (7)

4 (3)

Deep vein thrombosis$

5 (4)

5 (4)

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Tumor flare

13 (10)

0

Squamous cell carcinoma of skin$

4 (3)

4 (3)

Investigations

Weight decreased

17 (13)

0

1 -MCL trial AEs – All treatment emergent AEs with ≥10% of subjects.

2 -MCL trial Grade 3/4 AEs – All treatment-emergent Grade 3/4 AEs in 2 or more subjects.

$ -MCL trial Serious AEs – All treatment-emergent SAEs in 2 or more subjects.

@ — Adverse reactions where at least one resulted in a fatal outcome.

% — Adverse reactions where at least one was considered to be Life Threatening (if the outcome of the event was death, it is included with death cases).

# — All adverse reactions under Body System of Infections except for rare infections of Public Health interest will be considered listed.

+ — All adverse reactions under HLT of Rash will be considered listed.

The following adverse reactions which have occurred in other indications including another MCL study and not described above have been reported (1% to 10%) in patients treated with lenalidomide monotherapy for mantle cell lymphoma.

Cardiac disorder: Cardiac failure

Ear and labyrinth disorders: Vertigo

General disorders and administration site conditions: Chills

Infections and infestations: Respiratory tract infection, sinusitis, nasopharyngitis, oral herpes

Musculoskeletal and connective tissue disorders: Pain in extremity

Nervous system disorders: Dysgeusia, headache, neuropathy peripheral, lethargy

Psychiatric disorders: Insomnia

Skin and subcutaneous tissue disorders: Dry skin, night sweats

The following serious adverse reactions not described above and reported in 2 or more patients treated with lenalidomide monotherapy for mantle cell lymphoma.

Blood and lymphatic system disorders: Neutropenia

Cardiac disorder: Myocardial infarction (including acute MI), supraventricular tachycardia

Infections and infestations: Clostridium difficile colitis, sepsis

Neoplasms benign, malignant and unspecified (including cysts and polyps): Basal cell carcinoma

Respiratory, thoracic, and mediastinal disorders: Chronic obstructive pulmonary disease, pulmonary embolism

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