MOTEGRITY

MOTEGRITY- prucalopride succinate tablet, film coated
Takeda Pharmaceuticals America, Inc.

1 INDICATIONS AND USAGE

MOTEGRITY® is indicated for the treatment of chronic idiopathic constipation (CIC) in adults.

2 DOSAGE AND ADMINISTRATION

MOTEGRITY can be taken with or without food. The recommended dosage by patient population is shown in Table 1.

Table 1: Recommended Dosage Regimen and Dosage Adjustments by Population
Population with CIC Recommended Oral Dose Regimen
Adults 2 mg once daily
Patients with severe renal impairment (creatinine clearance (CrCL) less than 30 mL/min) [see Use in Specific Populations (8.5 and 8.6)]. 1 mg once daily

3 DOSAGE FORMS AND STRENGTHS

MOTEGRITY Tablets:

  • 1 mg prucalopride: White to off-white, round, biconvex film-coated tablet debossed with “PRU 1” on one side and no debossing on the other side.
  • 2 mg prucalopride: Pink, round, biconvex film-coated tablet debossed with “PRU 2” on one side and no debossing on the other side.

4 CONTRAINDICATIONS

MOTEGRITY is contraindicated in patients with:

  • A history of hypersensitivity to MOTEGRITY. Reactions including dyspnea, rash, pruritus, urticaria, and facial edema have been observed [(see Adverse Reactions (6.2)].
  • Intestinal perforation or obstruction due to structural or functional disorder of the gut wall, obstructive ileus, severe inflammatory conditions of the intestinal tract such as Crohn’s disease, ulcerative colitis, and toxic megacolon/megarectum.

5 WARNINGS AND PRECAUTIONS

5.1 Suicidal Ideation and Behavior

In clinical trials, suicides, suicide attempts, and suicidal ideation have been reported. Postmarketing cases of suicidal ideation and behavior as well as self-injurious ideation and new onset or worsening of depression have been reported within the first few weeks of starting MOTEGRITY [see Adverse Reactions (6.1, 6.2)].

A causal association between treatment with MOTEGRITY and an increased risk of suicidal ideation and behavior has not been established.

Monitor all patients treated with MOTEGRITY for new onset or worsening of depression or the emergence of suicidal thoughts and behaviors. Counsel patients, their caregivers, and family members of patients to be aware of any unusual changes in mood or behavior and alert the healthcare provider. Instruct patients to discontinue MOTEGRITY immediately and contact their healthcare provider if they experience any of these symptoms.

6 ADVERSE REACTIONS

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.

The data described below represent 2530 patients (1251 received MOTEGRITY 2 mg once daily and 1279 received placebo) with CIC from 6 double-blind, placebo-controlled clinical trials of 12 weeks to 24 weeks in duration. In these trials overall, patients were primarily female (76%) and white (76%). The mean age was 47 years (range 17 to 95 years) [see Clinical Studies (14)].

Common Adverse Reactions

Table 2 below summarizes the incidence (%) of common adverse reactions occurring in at least 2% of patients with CIC receiving either 2 mg of MOTEGRITY once daily or placebo and at an incidence greater than in the placebo group from the six double-blind placebo-controlled trials described above.

Table 2: Common Adverse Reactions * in Double-Blind Placebo-Controlled Trials of CIC of at least 12 Weeks Duration
Adverse Reaction MOTEGRITY2 mg Once DailyN=1251% PlaceboN=1279%
*
Reported in ≥2% of patients receiving MOTEGRITY and a rate higher than patients receiving placebo.
Includes 93 patients who started on MOTEGRITY 1 mg and increased to MOTEGRITY 2 mg.
Includes abdominal pain, upper abdominal pain, lower abdominal pain, abdominal tenderness, abdominal discomfort, and epigastric discomfort.
Headache 19 9
Abdominal pain 16 11
Nausea 14 7
Diarrhea 13 5
Abdominal distension 5 4
Dizziness 4 2
Vomiting 3 2
Flatulence 3 2
Fatigue 2 1

Less Common Adverse Reactions

Less common adverse reactions occurring in <2% of patients receiving MOTEGRITY 2 mg once daily include:

Gastrointestinal disorders: abnormal gastrointestinal sounds

Metabolism and nutrition disorders: decreased appetite

Nervous system disorders: migraine

Renal and urinary disorders: pollakiuria

Diarrhea

Of the patients who reported diarrhea, 70% (110 out of 157) reported it in the first week of treatment. Diarrhea typically resolved within a few days in 73% (80 out of 110) of those patients. Severe diarrhea was reported in 1.8% of patients treated with MOTEGRITY 2 mg compared to 1% of patients in the placebo group, and had a similar onset and duration as diarrhea overall.

Headache

Of the patients who reported headache, 66% (157 out of 237) treated with MOTEGRITY 2 mg once daily reported onset in the first 2 days of treatment. Symptoms typically resolved within a few days in 65% (102 out of 157) of those patients.

Adverse Reactions Leading to Discontinuation

In the 6 clinical trials described above, 5% of patients treated with 2 mg of MOTEGRITY once daily discontinued due to adverse reactions, compared to 3% of patients in the placebo group. The most common adverse reactions leading to discontinuation were nausea (2% MOTEGRITY, 1% placebo), headache (1% MOTEGRITY, 1% placebo), diarrhea (1% MOTEGRITY, <1% placebo), or abdominal pain (1% MOTEGRITY, 1% placebo).

Adverse Reactions of Special Interest

Adverse reactions of special interest were evaluated in a pool of 28 completed clinical trials (19 double-blind and 9 open-label) for MOTEGRITY at doses including 0.5 mg, 1 mg, 2 mg, or 4 mg per day in adult patients with CIC (the recommended dosage of MOTEGRITY for CIC is 2 mg once daily). The total exposure in the double-blind trials was 565 patient-years in the MOTEGRITY group, 384 patient-years in the placebo group, and 2769 patient-years in the double-blind and open-label clinical trials.

Cardiovascular Safety Analysis

In an evaluation by an independent adjudication committee of all potential major adverse cardiovascular events (MACE), defined as cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke, the standardized incidence rate (IR) per 1000 patient-years for MACE for MOTEGRITY was compared with the IR for placebo.

In the double-blind trials, the IR for MACE was 3.5 (2 patients out of 3366; 1 patient on 2 mg and 1 patient on 4 mg) in the MOTEGRITY group and 5.2 (2 patients out of 2019) in the placebo group. When combining the double-blind and open-label trials, the IR for MACE was 3.3 (9 patients out of 4472, doses ranging between 0.5 to 4 mg) for MOTEGRITY.

Suicidal Ideation and Behavior

In the double-blind trials, one patient reported a suicide attempt 7 days after the end of treatment with MOTEGRITY 2 mg once daily; none were reported in patients on placebo. In the open-label trials, two patients reported a suicide attempt and another patient reported suicidal ideation. Completed suicide was reported in two patients, previously treated with MOTEGRITY 2 mg or 4 mg; both discontinued MOTEGRITY for at least one month prior to the event.

Observational Cardiovascular Cohort Study

The overall cardiovascular safety of MOTEGRITY was assessed using European healthcare databases in a population-based, retrospective, observational, cohort study of adults with constipation. New users of MOTEGRITY (N=5715) were matched to new users of polyethylene glycol 3350 (PEG) (N=29,372) to estimate the standardized incidence rate ratio (SIRR) for MACE, pooled across four data sources. The 95% confidence interval for the pooled estimate of the SIRR did not demonstrate an increased MACE risk and excluded a pre-specified safety margin of a three-fold risk of MACE during prucalopride use relative to PEG use.

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