Lorcaserin

Risk Summary

Lorcaserin is contraindicated during pregnancy, because weight loss offers no benefit to a pregnant woman and may result in fetal harm. Limited data on lorcaserin use in pregnant women are not sufficient to determine a drug-associated risk of major congenital malformations or miscarriage. No adverse developmental effects were observed when lorcaserin was administered to pregnant rats and rabbits during organogenesis at exposures up to 44- and 19-times the clinical dose of 20 mg daily, respectively. In rats, maternal exposure to lorcaserin in late pregnancy resulted in lower body weight in offspring which persisted to adulthood [see Data]. Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage of clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryofetal risk

Appropriate weight gain based on pre-pregnancy weight is currently recommended for all pregnant women, including those who are already overweight or obese, due to the obligatory weight gain that occurs in maternal tissues during pregnancy.

Data

Animal Data

Reproduction studies were performed in pregnant rats and rabbits that were administered lorcaserin hydrochloride during the period of embryofetal organogenesis. Plasma exposures up to 44 and 19 times the clinical dose of 20 mg daily in pregnant rats and rabbits, respectively, did not reveal evidence of teratogenicity or embryolethality with lorcaserin hydrochloride.

In a pre- and postnatal development study, maternal rats were dosed from gestation through post-natal day 21 at 5, 15, and 50 mg/kg lorcaserin hydrochloride; pups were indirectly exposed in utero and throughout lactation. Stillborns and lower pup viability was observed at 50 mg/kg, or 44 times the clinical dose of 20 mg daily, based on AUC. All other doses lowered pup body weight similarly at birth which persisted to adulthood; however, no developmental abnormalities were observed and reproductive performance was not affected.

Risk Summary

There are no data on the presence of lorcaserin in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed infant, advise women that use of lorcaserin is not recommended while breastfeeding.

Mutagenesis

Lorcaserin was not mutagenic in an in vitro bacterial mutation assay (Ames test), was not clastogenic in an in vitro chromosome aberration assay in Chinese hamster ovary cells, and was not genotoxic in an in vivo micronucleus assay in rat bone marrow.

Carcinogenesis

The carcinogenic potential of lorcaserin was assessed in two-year carcinogenicity studies in mice and rats. CD-1 mice received doses of 5, 25 and 50 mg/kg. There were no treatment-related increases in the incidence of any tumor in mice at doses that produced plasma exposure in males and females of 8 and 4-times the daily human clinical dose, respectively.

In the rat carcinogenicity study, male and female Sprague-Dawley rats received 10, 30, and 100 mg/kg lorcaserin hydrochloride. In females, mammary adenocarcinoma increased at 100 mg/kg, which was associated with plasma exposures that were 87-times the daily human clinical dose. The incidence of mammary fibroadenoma was increased in female rats at all doses with no safety margin to the clinical dose. The increases in adenocarcinomas and fibroadenomas may be associated with lorcaserin-induced changes in prolactin homeostasis in rats. The relevance of the increased incidence of mammary adenocarcinomas and fibroadenomas in rats to humans is unknown.

In male rats, treatment-related neoplastic changes were observed in the subcutis (fibroma, Schwannoma), the skin (squamous cell carcinoma), mammary gland (adenocarcinoma and fibroadenoma), and the brain (astrocytoma) at greater than or equal to 30 mg/kg (plasma exposure 17-times human clinical dose). At higher exposure, liver adenoma and thyroid follicular cell adenoma were increased but were considered secondary to liver enzyme induction in rats and are not considered relevant to humans. Human brain exposure (AUC_24h,ss) to lorcaserin at the clinical dose is estimated to be 70-fold lower than brain exposure in rats at the dose at which no increased incidence of astrocytoma was observed. Excluding the liver and thyroid tumors, these neoplastic findings in male rats are of unknown relevance to humans.

Impairment of Fertility

Potential effects on fertility were assessed in Sprague-Dawley rats in which males were dosed with lorcaserin hydrochloride for 4 weeks prior to and through the mating period, and females were dosed for 2 weeks prior to mating and through gestation day 7. Lorcaserin had no effects on fertility in rats at exposures up to 29 times the human clinical dose.

• Serotonin Syndrome or NMS-like Reactions
• Valvular Heart Disease
• Cognitive Impairment
• Psychiatric Disorders
• Hypoglycemia
• Heart Rate Decreases
• Hematological Changes
• Prolactin Elevation

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 lorcaserin 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:

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:

Other Adverse Reactions

Serotonin-associated Adverse Reactions

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 lorcaserin and serotonin syndrome cannot be excluded on the basis of clinical trial results.

Hypoglycemia in Patients with Type 2 Diabetes

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.

Cognitive 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. 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 Abnormalities

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.

Prolactin: 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 lorcaserin. 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.

Table 4. Incidence of FDA-Defined Valvulopathy at Week 52 by Treatment Group¹:

¹ Patients without valvulopathy at baseline who received study medication and had a postbaseline echocardiogram; ITT-intention-to-treat; LOCF-last observation carried forward

Postmarketing Experience

The following adverse reactions have been identified during post approval use. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune System Disorders: drug hypersensitivity