XERMELO

1 Dosing Considerations Available data suggest that clinical response is usually achieved within 12 weeks of treatment. After 12 weeks of treatment with XERMELO, patients should be reassessed to determine the appropriateness of ongoing treatment with XERMELO.

Concomitant use with Short-acting Octreotide When short-acting octreotide is used in combination with XERMELO, administer short-acting octreotide at least 30 minutes after administering XERMELO (see DRUG INTERACTIONS). 2 Recommended Dose and Dosage Adjustment The recommended dose of XERMELO is 250 mg three times a day (tid), taken orally.

Renal impairment No change in dosage is required in patients with mild, moderate or severe renal impairment; who are not requiring dialysis (see ACTION AND CLINICAL PHARMACOLOGY). As a precautionary measure, it is recommended that patients with severe renal impairment will be monitored for signs of reduced tolerability.

The use of XERMELO is not recommended in patients with end-stage renal disease requiring XERMELO Product Monograph Page 5 of 28 dialysis (eGFR < 15 mL/min). Hepatic impairment In patients with mild hepatic impairment (Child Pugh score A), the recommended dose of XERMELO is 250 mg twice daily, based on tolerability.

In patients with moderate hepatic impairment (Child Pugh score B), the recommended dose of XERMELO is 250 mg once daily, based on tolerability. The use of XERMELO is not recommended in patients with severe hepatic impairment (Child Pugh score C) (see ACTION AND CLINICAL PHARMACOLOGY).

Elderly patients (65 years of age and above) No dosage adjustments are required in elderly patients, but greater sensitivity of some older individuals cannot be ruled out (see ACTION AND CLINICAL PHARMACOLOGY). Pediatrics Health Canada has not authorized an indication for pediatric use.

4 Administration Take XERMELO with food (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics, Food Effect). 5 Missed Dose If a dose is missed, take the next dose at the regular time. Do not take 2 doses at the same time to make up for a missed dose.

1 Adverse Reaction Overview The overall safety of XERMELO was evaluated in 239 patients, of whom 131 patients were exposed to XERMELO for at least 48 weeks (mean duration of treatment 67 weeks), and 83% of these patients were exposed to XERMELO for at least 72 weeks (mean duration of treatment 107 weeks).

, telotristat ethyl 500 mg tid. The placebo-controlled safety dataset was derived from two 12-week placebo-controlled, double- blind studies, that included Study LX-301, the pivotal registration study, and Study LX-303, a supportive clinical study.

Safety was assessed using the incidence of treatment-emergent XERMELO Product Monograph Page 8 of 28 adverse events in both studies. This dataset includes 211 patients with carcinoid syndrome, with 70 patients treated with XERMELO 250 mg tid, 70 patients with telotristat ethyl 500 mg tid, and 71 with placebo.

The most frequently reported adverse events (AEs) in the placebo-controlled dataset were gastrointestinal disorders, including nausea and abdominal pain. 9%) patients in the placebo group, discontinued study treatment due to AEs. The AEs leading to discontinuation were most frequently related to gastrointestinal or liver disorders for patients treated with XERMELO.

8%, were due to abdominal pain, respectively. 4%, and 0% of patient discontinuations, respectively. 9%) patients with placebo. 2 Clinical Trial Adverse Reactions Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug.

Adverse reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. Adverse Events in Two 12-week Controlled Studies In two 12-week, double-blind, placebo-controlled studies, 70 patients with carcinoid syndrome received XERMELO 250 mg tid in combination with SSA therapy.

Driving and Operating Machinery Due caution should be exercised when driving or operating a vehicle or potentially dangerous machinery. Fatigue may occur following administration of XERMELO. Gastrointestinal Constipation and Intestinal Obstruction XERMELO reduces bowel movement (BM) frequency.

, telotristat ethyl 500 mg tid (see ADVERSE REACTIONS, Gastrointestinal Disorders). Patients should be monitored for signs and symptoms of constipation. If constipation develops, the use of XERMELO and other concomitant therapies affecting bowel motility should be re-evaluated.

Cases of intestinal obstruction have been reported during post-approval use of XERMELO (see ADVERSE REACTIONS, Post-Market Adverse Reactions). In the majority of cases where time to onset was reported, intestinal obstruction occurred within 3 months.

, ileus of any type) may also be at higher risk of intestinal obstruction. If intestinal obstruction develops, dose reduction, interruption, or discontinuation of XERMELO should be considered. Hepatic/Biliary/Pancreatic Hepatic Enzyme Elevations Elevations in hepatic enzymes were observed in clinical studies (see ADVERSE REACTIONS, Hepatic Enzyme Elevations).

Laboratory monitoring of hepatic enzymes prior to and during XERMELO therapy is recommended as clinically indicated. In patients with hepatic impairment, continuous monitoring for adverse events related to worsening of liver function is recommended.

Patients who develop symptoms suggestive of hepatic dysfunction should have liver enzymes checked and XERMELO should be discontinued if liver injury is suspected. Therapy with XERMELO should not be resumed unless liver injury can be explained by another cause.

, telotristat ethyl 500 mg tid (see ADVERSE REACTIONS, Depression). Patients should be advised to report any symptoms of depression, depressed mood and decreased interest to their physicians. Reproductive Health Fertility No studies on the effect of Xermelo on human fertility have been conducted.

XERMELO is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.