BELVIQ XR Extended Release Extended Release (Page 3 of 8)

5.7 Heart Rate Decreases

In clinical trials of at least 1-year in duration, the mean change in heart rate (HR) was -1.2 beats per minute (bpm) in lorcaserin and -0.4 bpm in placebo-treated patients without diabetes and -2.0 beats per minute (bpm) in lorcaserin and -0.4 bpm in placebo-treated patients with type 2 diabetes. The incidence of HR less than 50 bpm was 5.3% in lorcaserin and 3.2% in placebo-treated patients without diabetes and 3.6% in lorcaserin and 2.0% in placebo-treated patients with type 2 diabetes. In the combined population, adverse reactions of bradycardia occurred in 0.3% of lorcaserin and 0.1% of placebo-treated patients. Use with caution in patients with bradycardia or a history of heart block greater than first degree.

5.8 Hematological Changes

In clinical trials of at least one year in duration, adverse reactions of decreases in white blood cell count (including leukopenia, lymphopenia, neutropenia, and decreased white cell count) were reported in 0.4% of patients treated with lorcaserin as compared to 0.2% of patients treated with placebo. Adverse reactions of decreases in red blood cell count (including anemia and decreases in hemoglobin and hematocrit) were reported by 1.3% of patients treated with lorcaserin as compared to 1.2% treated with placebo [s ee Adverse Reactions (6.1)]. Consider periodic monitoring of complete blood count during treatment with BELVIQ XR.

5.9 Prolactin Elevation

Lorcaserin moderately elevates prolactin levels. In a subset of placebo-controlled clinical trials of at least one year in duration, elevations of prolactin greater than the upper limit of normal, two times the upper limit of normal, and five times the upper limit of normal, measured both before and 2 hours after dosing, occurred in 6.7%, 1.7%, and 0.1% of lorcaserin-treated patients and 4.8%, 0.8%, and 0.0% of placebo-treated patients, respectively [see Adverse Reactions (6.1)]. Prolactin should be measured when symptoms and signs of prolactin excess are suspected (e.g., galactorrhea, gynecomastia). There was one patient treated with lorcaserin who developed a prolactinoma during the trial. The relationship of lorcaserin to the prolactinoma in this patient is unknown.

5.10 Pulmonary Hypertension

Certain centrally-acting weight loss agents that act on the serotonin system have been associated with pulmonary hypertension, a rare but lethal disease. Because of the low incidence of this disease, the clinical trial experience with lorcaserin is inadequate to determine if BELVIQ XR increases the risk for pulmonary hypertension.

6 ADVERSE REACTIONS

The following important adverse reactions are described below and elsewhere in labeling:

6.1 Clinical Trials Experience

In the lorcaserin placebo-controlled clinical database of trials of at least one year in duration, of 6888 patients (3451 lorcaserin vs. 3437 placebo; age range 18-66 years, 79.3% women, 66.6% Caucasians, 19.2% Blacks, 11.8% Hispanics, 2.4% other, 7.4% type 2 diabetics), a total of 1969 patients were exposed to immediate-release lorcaserin hydrochloride 10 mg twice daily for 1 year and 426 patients were exposed for 2 years.

In clinical trials of at least one year in duration, 8.6% of patients treated with lorcaserin prematurely discontinued treatment due to adverse reactions, compared with 6.7% of placebo-treated patients. The most common adverse reactions leading to discontinuation more often among lorcaserin-treated patients than placebo were headache (1.3% vs. 0.8%), depression (0.9% vs. 0.5%) and dizziness (0.7% vs. 0.2%).

Most Common Adverse Reactions

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.

The most common adverse reactions for non-diabetic patients (greater than 5% and more commonly than placebo) treated with lorcaserin compared to placebo were headache, dizziness, fatigue, nausea, dry mouth, and constipation. The most common adverse reactions for diabetic patients were hypoglycemia, headache, back pain, cough, and fatigue. Adverse reactions that were reported by greater than or equal to 2% of patients and were more frequently reported by patients taking lorcaserin compared to placebo are summarized in Table 2 (non-diabetic subjects) and Table 3 (subjects with type 2 diabetes mellitus).

Table 2. Adverse Reactions Reported by Greater Than or Equal to 2% of Lorcaserin Patients and More Commonly than with Placebo in Patients without Diabetes Mellitus
Adverse Reaction Number of patients (%)
Lorcaserin * N=3195 Placebo N=3185
Gastrointestinal Disorders
Nausea 264 (8.3) 170 (5.3)
Diarrhea 207 (6.5) 179 (5.6)
Constipation 186 (5.8) 125 (3.9)
Dry mouth 169 (5.3) 74 (2.3)
Vomiting 122 (3.8) 83 (2.6)
General Disorders And Administration Site Conditions
Fatigue 229 (7.2) 114 (3.6)
Infections And Infestations
Upper respiratory tract infection 439 (13.7) 391 (12.3)
Nasopharyngitis 414 (13.0) 381 (12.0)
Urinary tract infection 207 (6.5) 171 (5.4)
Musculoskeletal And Connective Tissue Disorders
Back pain 201 (6.3) 178 (5.6)
Musculoskeletal pain 65 (2.0) 43 (1.4)
Nervous System Disorders
Headache 537 (16.8) 321 (10.1)
Dizziness 270 (8.5) 122 (3.8)
Respiratory, Thoracic And Mediastinal Disorders
Cough 136 (4.3) 109 (3.4)
Oropharyngeal pain 111 (3.5) 80 (2.5)
Sinus congestion 93 (2.9) 78 (2.4)
Skin And Subcutaneous Tissue Disorders
Rash 67 (2.1) 58 (1.8)
* Immediate-release lorcaserin hydrochloride, 10 mg twice daily
Table 3. Adverse Reactions Reported by Greater Than or Equal to 2% of Lorcaserin Patients and More Commonly than with Placebo in Patients with Type 2 Diabetes Mellitus
Number of patients (%)
Adverse Reaction Lorcaserin * N=256 Placebo N=252
Gastrointestinal Disorders
Nausea 24 (9.4) 20 (7.9)
Toothache 7 (2.7) 0
General Disorders And Administration Site Conditions
Fatigue 19 (7.4) 10 (4.0)
Peripheral edema 12 (4.7) 6 (2.4)
Immune System Disorders
Seasonal allergy 8 (3.1) 2 (0.8)
Infections And Infestations
Nasopharyngitis 29 (11.3) 25 (9.9)
Urinary tract infection 23 (9.0) 15 (6.0)
Gastroenteritis 8 (3.1) 5 (2.0)
Metabolism And Nutrition Disorders
Hypoglycemia 75 (29.3) 53 (21.0)
Worsening of diabetes mellitus 7 (2.7) 2 (0.8)
Decreased appetite 6 (2.3) 1 (0.4)
Musculoskeletal And Connective Tissue Disorders
Back pain 30 (11.7) 20 (7.9)
Muscle spasms 12 (4.7) 9 (3.6)
Nervous System Disorders
Headache 37 (14.5) 18 (7.1)
Dizziness 18 (7.0) 16 (6.3)
Psychiatric Disorders
Anxiety 9 (3.5) 8 (3.2)
Insomnia 9 (3.5) 6 (2.4)
Stress 7 (2.7) 3 (1.2)
Depression 6 (2.3) 5 (2.0)
Respiratory, Thoracic And Mediastinal Disorders
Cough 21 (8.2) 11 (4.4)
Vascular Disorders
Hypertension 13 (5.1) 8 (3.2)
* Immediate-release lorcaserin hydrochloride, 10 mg twice daily

Other Adverse Reactions

Serotonin -a ssociated A dverse R eaction s

SSRIs, SNRIs, bupropion, tricyclic antidepressants, and MAOIs were excluded from the lorcaserin trials. Triptans and dextromethorphan were permitted: 2% and 15%, respectively, of patients without diabetes and 1% and 12%, respectively, of patients with type 2 diabetes experienced concomitant use at some point during the trials. Two patients treated with lorcaserin in the clinical program experienced a constellation of symptoms and signs consistent with serotonergic excess, including one patient on concomitant dextromethorphan who reported an event of serotonin syndrome. Some symptoms of possible serotonergic etiology that are included in the criteria for serotonin syndrome were reported by patients treated with lorcaserin and placebo during clinical trials of at least 1 year in duration. In both groups, chills were the most frequent of these events (1.0% vs. 0.2%, respectively), followed by tremor (0.3% vs. 0.2%), confusional state (0.2% vs. less than 0.1%), disorientation (0.1% vs. 0.1%) and hyperhidrosis (0.1% vs. 0.2%). Because serotonin syndrome has a very low incidence, an association between BELVIQ XR and serotonin syndrome cannot be excluded on the basis of clinical trial results [s ee Warnings and Precautions (5.1)].

Hypoglycemia in Patients with Type 2 D iabetes

In a clinical trial of patients with type 2 diabetes mellitus, severe hypoglycemia (requiring the assistance of another person, requiring intravenous glucose, or hospitalization) occurred in 4 (1.6%) of lorcaserin-treated patients and in 1 (0.4%) placebo-treated patient. Of these 4 lorcaserin-treated patients, all were concomitantly using a sulfonylurea (with or without metformin). Lorcaserin has not been studied in patients taking insulin. Hypoglycemia defined as blood sugar less than or equal to 65 mg/dL and with symptoms occurred in 19 (7.4%) lorcaserin-treated patients and 16 (6.3%) placebo-treated patients.

Cogniti ve Impairment

In clinical trials of at least 1-year duration, adverse reactions related to cognitive impairment (e.g., difficulty with concentration/attention, difficulty with memory, and confusion) occurred in 2.3% of patients taking lorcaserin and 0.7% of patients taking placebo.

Psychiatric Disorders

Psychiatric disorders leading to hospitalization or drug withdrawal occurred more frequently in patients treated with lorcaserin (2.2%) as compared to placebo (1.1%) in non-diabetic patients.

Euphoria. In short-term studies with healthy individuals, the incidence of euphoric mood following supratherapeutic doses of lorcaserin (40 and 60 mg) was increased as compared to placebo [see Drug Abuse and Dependence (9.2)]. In clinical trials of at least 1-year duration in obese patients, euphoria was observed in 0.17% of patients taking lorcaserin and 0.03% taking placebo.

Depression and Suicidality. In trials of at least one year in duration, reports of depression/mood problems occurred in 2.6% lorcaserin-treated vs. 2.4% placebo-treated and suicidal ideation occurred in 0.6% lorcaserin-treated vs. 0.4% placebo-treated patients. 1.3% of lorcaserin patients vs. 0.6% of placebo patients discontinued drug due to depression-, mood-, or suicidal ideation-related events.

Laboratory A bnormalities

Lymphocyte and Neutrophil Counts. In clinical trials of at least 1-year duration, lymphocyte counts were below the lower limit of normal in 12.2% of patients taking lorcaserin and 9.0% taking placebo, and neutrophil counts were low in 5.6% and 4.3%, respectively.

Hemoglobin. In clinical trials of at least 1-year duration, 10.4% of patients taking lorcaserin and 9.3% taking placebo had hemoglobin below the lower limit of normal at some point during the trials.

P rolactin . In clinical trials, elevations of prolactin greater than the upper limit of normal, two times the upper limit of normal, and five times the upper limit of normal, occurred in 6.7%, 1.7%, and 0.1% of lorcaserin-treated patients and 4.8%, 0.8%, and 0.0% of placebo-treated patients, respectively.

Eye disorders

More patients on lorcaserin reported an eye disorder than patients on placebo in clinical trials of patients without diabetes (4.5% vs. 3.0%) and with type 2 diabetes (5.9% vs. 1.6%). In the population without diabetes, events of blurred vision, dry eye, and visual impairment occurred in lorcaserin-treated patients at an incidence greater than that of placebo. In the population with type 2 diabetes, visual disorders, conjunctival infections, irritations, and inflammations, ocular sensation disorders, and cataract conditions occurred in lorcaserin-treated patients at an incidence greater than placebo.

Echocardiographic Safety Assessments

The possible occurrence of regurgitant cardiac valve disease was prospectively evaluated in 7794 patients in three clinical trials of at least one year in duration, 3451 of whom took immediate-release lorcaserin hydrochloride 10 mg twice daily. The primary echocardiographic safety parameter was the proportion of patients who developed echocardiographic criteria of mild or greater aortic insufficiency and/or moderate or greater mitral insufficiency from baseline to 1 year. At 1 year, 2.4% of patients who received lorcaserin and 2.0% of patients who received placebo developed valvular regurgitation. The relative risk for valvulopathy with lorcaserin is summarized in Table 4. Lorcaserin was not studied in patients with congestive heart failure or hemodynamically-significant valvular heart disease [s ee Warnings and Precautions (5.2)].

Table 4. Incidence of FDA-Defined Valvulopathy at Week 52 by Treatment Group1
Study 1 Study 2 Study 3
Lorcaserin* N=1278 Placebo N=1191 Lorcaserin* N=1208 Placebo N=1153 Lorcaserin* N=210 Placebo N=209
FDA- defined Valvulopathy , n (%) 34 (2.7) 28 (2.4) 24 (2.0) 23 (2.0) 6 (2.9) 1 (0.5)
Relative Risk (95% CI) 1.13 (0.69, 1.85) 1.00 (0.57, 1.75) 5.97 (0.73, 49.17)
Pooled RR (95% CI) 1.16 (0.81, 1.67)
  1. Patients without valvulopathy at baseline who received study medication and had a post-baseline echocardiogram; ITT-intention-to-treat; LOCF-last observation carried forward* Immediate-release lorcaserin hydrochloride, 10 mg twice daily

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