Xermelo

XERMELO- telotristat ethyl tablet
TerSera Therapeutics LLC

1 INDICATIONS AND USAGE

Xermelo is indicated for the treatment of carcinoid syndrome diarrhea in combination with somatostatin analog (SSA) therapy in adults inadequately controlled by SSA therapy.

2 DOSAGE AND ADMINISTRATION

The recommended dosage of Xermelo in adult patients is 250 mg three times daily for patients whose diarrhea is inadequately controlled by SSA therapy.

Administration

  • Take Xermelo with food [see Clinical Pharmacology (12.3), Clinical Studies (14)].
  • When short-acting octreotide is used in combination with Xermelo, administer short-acting octreotide at least 30 minutes after administering Xermelo [see Drug Interactions (7.3)].
  • 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.
  • Discontinue Xermelo if severe constipation develops [see Warnings and Precautions (5.1)].

3 DOSAGE FORMS AND STRENGTHS

Tablets: 250 mg telotristat ethyl; white to off-white, coated and oval with “T-E” debossed on one side and “250” debossed on the other side.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Constipation

Xermelo reduces bowel movement frequency. In a 12-week, placebo-controlled trial, in which patients had 4 or greater bowel movements per day, 2 out of 45 patients treated with a higher than recommended dosage of Xermelo reported constipation. In one patient the constipation was serious, resulting in hospitalization. During the 36-week extension period with higher than the recommended dosage, 10 of 115 patients reported constipation: one developed intestinal perforation and one developed obstruction. In another 12-week, placebo-controlled trial in which patients had less than 4 bowel movements per day, 4 out of 25 patients treated with the recommended dosage of Xermelo reported constipation. Given that patients with metastatic carcinoid tumors may have impaired integrity of the gastrointestinal tract wall, monitor for the development of constipation and/or severe, persistent, or worsening abdominal pain in patients taking Xermelo. Discontinue Xermelo if severe constipation or severe persistent or worsening abdominal pain develops [see Dosage and Administration (2), Adverse Reactions (6.1)].

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.

Xermelo was studied in a double-blind, placebo-controlled clinical trial of 90 patients with metastatic neuroendocrine tumors and carcinoid syndrome diarrhea. Patients reported between 4 to 12 bowel movements daily despite the use of SSA therapy at a stable dose for at least 3 months [see Clinical Studies (14)]. Placebo or Xermelo 250 mg was administered three times daily for 12 weeks. Concomitant anti-diarrheal medications (e.g., loperamide) were used by 43% (36% and 51% in the placebo and Xermelo group, respectively), pancreatic enzyme replacement medications by 39% (36% and 42% in the placebo and Xermelo group, respectively), and opioid analgesics by 29% (24% and 33% in the placebo and Xermelo group, respectively) of patients during the 12-week double-blind period of the trial.

Table 1 below lists adverse reactions occurring at an incidence of at least 5% in the Xermelo group (N=45) and at an incidence greater than placebo (N=45) during the 12-week placebo-controlled period of the trial.

Table 1: Percent Common Adverse Reactionsa by Treatment Group at 12-Weeks in a Double-Blind Placebo-Controlled Clinical Trial of Patients with Carcinoid Syndrome Diarrhea

a incidence of at least 5% in the Xermelo group and at an incidence greater than placebo

b including depression, depressed mood and decreased interest

Adverse Reaction Xermelo 250 mg Three Times Daily, N=45 (%) Placebo, N=45 (%)
Nausea 13 11
Headache 11 4
Increased gamma-glutamyl-transferase (GGT) 9 0
Depressionb 9 7
Peripheral edema 7 2
Flatulence 7 2
Decreased appetite 7 4
Pyrexia 7 4

In another placebo-controlled clinical trial of patients with carcinoid syndrome diarrhea and less than 4 bowel movements per day, the following additional adverse reactions, not listed in Table 1, of abdominal pain (including upper and lower abdominal pain, abdominal distention and gastrointestinal pain) and constipation were reported in at least 5% of patients in the Xermelo treated group and at an incidence greater than placebo [see Warnings and Precautions (5.1)].

Less Common Adverse Reactions:

The following is a list of adverse reactions occurring in less than 5% of patients receiving Xermelo during the 12-week placebo-controlled period of the clinical trial:

Investigations: increased alkaline phosphatase, increased alanine aminotransferase, and increased aspartate aminotransferase.

Fecaloma was reported in one patient treated with Xermelo during the 36-week open-label extension period following the 12-week double-blind period of the trial.

7 DRUG INTERACTIONS

7.1 CYP3A4 Substrates

Concomitant use of Xermelo may decrease the efficacy of drugs that are CYP3A4 substrates (e.g., midazolam) by decreasing their systemic exposure. Monitor patients’ response to CYP3A4 substrates when co-administered with Xermelo and consider increasing the dosage of the interacting drug, if necessary [see Clinical Pharmacology (12.3)].

7.2 CYP2B6 Substrates

Concomitant use of Xermelo may decrease the efficacy of drugs that are CYP2B6 substrates (e.g., bupropion, efavirenz) by decreasing their systemic exposure. Monitor patients’ response to CYP2B6 substrates when co-administered with Xermelo and consider increasing the dosage of the interacting drug, if necessary [see Clinical Pharmacology (12.3)].

7.3 Short-Acting Octreotide

Concurrent administration of short-acting octreotide with Xermelo significantly decreased the systemic exposure of telotristat ethyl and telotristat, the active metabolite. If treatment with short-acting octreotide is needed in combination with Xermelo, administer short-acting octreotide at least 30 minutes after administration of Xermelo [see Clinical Pharmacology (12.3)].

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