Xermelo

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

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

• Take Xermelo with food
  [see Clinical Pharmacology (

  12.3 Pharmacokinetics

  Absorption

  After a single oral dose of telotristat ethyl to healthy subjects, telotristat ethyl was absorbed and metabolized to its active metabolite, telotristat. Peak plasma concentrations of telotristat ethyl were achieved within 0.5 to 2 hours, and those of telotristat within 1 to 3 hours. Plasma concentrations thereafter declined in a biphasic manner. Following administration of a single 500 mg dose of telotristat ethyl (twice the recommended dosage) under fasted conditions in healthy subjects, the mean C_maxand AUC_0-infwere 4.4 ng/mL and 6.23 ng•hr/mL, respectively for telotristat ethyl. The mean C_maxand AUC_0-infwere 610 ng/mL and 2320 ng•hr/mL, respectively for telotristat. Peak plasma concentrations and AUC of telotristat ethyl and telotristat appeared to be dose proportional following administration of a single dose of telotristat ethyl in the range of 100 mg (0.4 times the lowest recommended dose to 1000 mg [4 times the highest recommended dose]) under fasted conditions.

  Following multiple-dose administration of telotristat ethyl 500 mg three times daily, there was negligible accumulation at steady state for both telotristat ethyl and telotristat.

  In patients with metastatic neuroendocrine tumors and carcinoid syndrome diarrhea treated with SSA therapy, the median T_maxfor telotristat ethyl and telotristat was approximately 1 and 2 hours, respectively. Following administration of 500 mg telotristat ethyl three times daily, with meals in patients, the mean C_maxand AUC_0-6hrwere approximately 7 ng/mL and 22 ng•hr/mL, respectively, for telotristat ethyl. The mean C_maxand AUC_0-6hrwere approximately 900 ng/mL and 3000 ng•hr/mL, respectively for telotristat. The pharmacokinetic parameters for both telotristat ethyl and telotristat were highly variable with about 55% coefficient of variation.

  Food Effect

  Administration of a single 500 mg dose of Xermelo (twice the recommended dose) with food resulted in higher exposure to both telotristat ethyl and telotristat. The systemic exposure to telotristat ethyl, was significantly increased following administration with a high-fat meal, with C_max, and AUC_0-infbeing 112%, and 264% higher, respectively compared to the fasted state. Following administration of a single 500 mg dose of telotristat ethyl under fed conditions in healthy subjects, the mean C_maxand AUC_0-infwere 10.5 ng/mL and 21.6 ng•hr/mL, respectively for telotristat ethyl. The C_maxand AUC_0-infvalues for telotristat were also increased by 47% and 33%, respectively, with a high-fat meal compared to the fasted state. The mean C_maxand AUC_0-infwere 908 ng/mL and 2980 ng•hr/mL, respectively for telotristat under fed conditions

  [see Dosage and Administration ]

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  Distribution

  Both telotristat ethyl and telotristat are greater than 99% bound to human plasma proteins.

  In vitro data suggests that telotristat is a substrate of P-glycoprotein.

  Elimination

  Following a single 500 mg oral dose of telotristat ethyl in healthy subjects, the apparent half-life was approximately 0.6 hours for telotristat ethyl and 5 hours for telotristat. The apparent total clearance at steady state (CL/F_ss) following oral dosing with telotristat ethyl 500 mg three times daily for 14 days (twice the recommended dosage) in healthy subjects was 2.7 and 152 L/hr for telotristat ethyl and telotristat, respectively.

  Metabolism

  After oral administration, telotristat ethyl undergoes hydrolysis via carboxylesterases to telotristat, its active metabolite. Telotristat is further metabolized. Among the metabolites of telotristat, the systemic exposure to an acid metabolite of oxidative deaminated decarboxylated telotristat was about 35% of that of telotristat. In vitro data suggest that telotristat ethyl and telotristat are not substrates for CYP enzymes.

  Excretion

  Following a single 500 mg oral dose of¹⁴C-telotristat ethyl, 93.2% of the dose was recovered over 240 hours: 92.8% was recovered in the feces, with less than 0.4% being recovered in the urine.

  Specific Populations

  Age and Sex

  Population pharmacokinetic analysis indicated that age (18 to 83 years) and sex do not affect the pharmacokinetics of telotristat.

  Renal Impairment

  Exposure to telotristat ethyl and its active metabolite, telotristat, was similar in patients with severe renal impairment or end-stage renal disease without dialysis (eGFR < 30 mL/min/1.73 m²) compared with subjects with normal renal function following a single oral dose of Xermelo

  [see Use in Specific Populations ]

  . Xermelo was not studied in patients with end-stage renal disease who require dialysis (eGFR < 15 mL/min/1.73 m²).

  Hepatic Impairment

  Following a single dose of Xermelo 500 mg, systemic exposure (AUC_0-last) to telotristat ethyl was 2.3- and 3.2-fold higher in subjects with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment, respectively, than in subjects with normal hepatic function. In subjects with severe (Child-Pugh C) hepatic impairment, following a single Xermelo 250 mg dose, systemic exposure (AUC_0-last), was 4-fold higher than in subjects with normal hepatic function. In these same studies, AUC_0-lastfor telotristat (active metabolite) was 2.4-, 3.5-, and 5-fold higher in subjects with mild, moderate, and severe hepatic impairment, respectively

  [see Use in Specific Populations ]

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  In patients with metastatic neuroendocrine tumors and carcinoid syndrome diarrhea, population pharmacokinetic analysis indicated that mild hepatic impairment (defined as total bilirubin greater than 1 to 1.5 times the upper limit of normal [ULN] or AST greater than the ULN) did not affect the pharmacokinetics of telotristat.

  Drug Interaction Studies

  Effect of Telotristat Ethyl on Other Drugs

  In vitro studies

  Based on in vitro studies, the potential for telotristat ethyl, telotristat, and the acid metabolite of telotristat to inhibit major CYP enzymes (1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4/5) and to induce CYP1A2 is low at the recommended dosage of Xermelo.

  Based on in vitro studies, potential induction of CYP2B6 in vivo by Xermelo cannot be ruled out

  [see Drug Interactions ]

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  In vitro telotristat ethyl, but not telotristat, inhibited breast cancer resistance protein (BCRP) at the clinically relevant concentrations. However, in vivo drug interaction potential via inhibition of BCRP is low based on in vitro studies and in vivo findings.

  Based on in vitro studies, in vivo drug interaction potential via inhibition of organic cation transporter 1 (OCT1), OCT2, organic anion transporter 1 (OAT1), OAT3, organic anion transporting polypeptide 1B1 (OATP1B1), OATP1B3, or bile salt export pump (BSEP) transporters by telotristat ethyl and telotristat is low at the recommended dosage.

  Based on in vitro study results, the potential for the acid metabolite of telotristat to inhibit P-gp, BCRP, OCT1, OCT2, OAT1, OAT3, OATP1B1, OATP1B3, BSEP, and MRP2 transporters is low at the recommended dosage.

  Midazolam (sensitive CYP3A4 substrate)

  Following administration of multiple doses of telotristat ethyl, the systemic exposure to concomitant midazolam was significantly decreased. When 3 mg midazolam was co-administered orally after 5 day treatment with telotristat ethyl 500 mg three times daily (twice the recommended dosage), the mean C_max, and AUC_0-inffor midazolam were decreased by 25%, and 48%, respectively, compared to administration of midazolam alone. The mean C_max, and AUC_0-inffor the active metabolite, 1'-hydroxymidazolam, were also decreased by 34%, and 48%, respectively. The reduction in the systemic exposure to both midazolam and its active metabolite suggests that the glucuronidation of 1'-hydroxymidazolam may have been increased by telotristat ethyl

  [see Drug Interactions ]

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  Fexofenadine (sensitive P-gp substrate)

  In vitro telotristat ethyl, but not telotristat, inhibited P-glycoprotein (P-gp). In healthy volunteers, the C_maxand AUC of fexofenadine increased by 16% when a single 180 mg dose of fexofenadine was co-administered orally with the final dose of telotristat ethyl 500 mg administered three times daily (twice the recommended dosage) for 5 days. Clinically meaningful interactions with P-gp substrates are unlikely.

  Effect of Other Drugs on Telotristat Ethyl

  Short-Acting Octreotide

  The mean C_maxand AUC_0-lastof telotristat ethyl were decreased by 86% and 81%, respectively, following administration of a single 500 mg dose of Xermelo (twice the recommended dose), co-administered with short-acting octreotide 200 mcg injected subcutaneously in healthy subjects. The mean C_maxand AUC_0-lastof telotristat were decreased by 79% and 68%, respectively.

  Gastric Acid Reducers (Proton Pump Inhibitor and H₂-Receptor Antagonist)

  Omeprazole:

  The C_maxand AUC_infof telotristat ethyl were increased by 68% and 185%, respectively, when a single 250 mg dose of Xermelo was coadministered with a 40 mg dose of omeprazole once daily compared to administration of Xermelo alone. No significant change (<9%) in AUC and C_maxof the active metabolite, telotristat, was observed following coadministration of Xermelo with omeprazole compared to administration of Xermelo alone. These changes in exposure of telotristat ethyl and telotristat are not considered to be clinically meaningful.

  Famotidine:

  The C_maxand AUC_infof telotristat ethyl were increased by 22% and 111%, respectively, when a single 250 mg dose of Xermelo was coadministered with a 40 mg dose of famotidine twice daily. No significant change (<5%) in AUC and C_maxto the active metabolite, telotristat, was observed following coadministration of Xermelo with famotidine compared to administration of Xermelo alone. These changes in exposure are not considered to be clinically meaningful.

  ), Clinical Studies (

  14 CLINICAL STUDIES

  A 12-week double-blind, placebo-controlled, randomized, multicenter trial of Xermelo was conducted in adult patients with a well-differentiated metastatic neuroendocrine tumor and carcinoid syndrome diarrhea who were having between 4 to 12 daily bowel movements despite the use of SSA therapy at a stable dose for at least 3 months. Patients were randomized to placebo or treatment with Xermelo 250 mg three times daily.

  Study medication was administered within 15 minutes before or within 1 hour after a meal or snack

  [see Dosage and Administration ]

  . All patients were required to stay on their baseline SSA regimen and were allowed to use rescue medication (short-acting octreotide) and antidiarrheals (e.g., loperamide) for symptomatic relief. A total of 90 patients were evaluated for efficacy. The mean age of the population was 63 years of age (range 37 to 83 years), 50% were male, and 90% were White.

  The primary efficacy endpoint was the change from baseline in the number of daily bowel movements averaged over the 12-week treatment period. The analysis results can be found in Table 2below. The average was based on the number of days with valid, non-missing data. When a patient had more than 6 weeks of missing data, the change from baseline was considered equal to zero. A week of missing data was defined as a patient missing at least 4 days of diary data in that week.

  Table 2: Change from Baseline in Bowel Movements/Day Averaged Over 12 Weeks in Adult Patients with Carcinoid Syndrome Diarrhea

  	Parameter	Xermelo 250 mg three times daily	Placebo
  CL=confidence limit; SD=standard deviation.
  aBaseline Bowel Movements/Day was assessed over the 3-4 week screening/run-in period.
  bStatistical tests used a blocked 2-sample Wilcoxon Rank Sum statistic (van Elteren test) stratified by the u5-HIAA stratification at randomization. CLs were based on the Hodges-Lehmann estimator of the median paired difference.
  cp<0.001
  Bowel Movements/Day At Baseline a	Number of Patients	45	45
  	Baseline Mean (SD) Median (Min, Max)	6.1 (2.1) 5.5 (3.5, 13.0)	5.2 (1.4) 5.1 (3.5, 9.0)
  Change From Baseline In Bowel Movements/Day Averaged Over 12 Weeks	Change Averaged over 12 Weeks: Mean (SD) Median (Min, Max)	˗1.4 (1.4) -1.3 (-6.1, 1.6)	˗0.6 (0.8) -0.6 (-2.7, 0.8)
  	Estimate of Treatment Difference (97.5% CL)b	˗0.8c (˗1.3, ˗0.3)	---

  In the 12-week study, a difference in average weekly reductions in bowel movement frequency between Xermelo and placebo was observed as early as 1 to 3 weeks, and persisted for the remaining 9 weeks of the study.

  To aid in the interpretation of the bowel movement reduction results, the proportion of patients reporting any particular level of reduction in overall average bowel movement frequency is depicted in Figure 1 below. For example, 33% of patients randomized to Xermelo and 4% of patients randomized to placebo experienced a reduction in overall average bowel movements from baseline of at least 2 bowel movements per day.

  Figure 1: Cumulative Proportion of Patients with Carcinoid Syndrome Diarrhea Reporting Change in Overall Average Bowel Movement Frequency

  

  Other symptoms of carcinoid syndrome (abdominal pain or flushing) did not show improvement in the comparison of Xermelo to placebo.

  The average number of daily short-acting octreotide injections used for rescue therapy over the 12-week double-blind treatment period was 0.3 and 0.7 in the Xermelo and placebo groups, respectively. In the subgroup of patients who received short-acting octreotide injections, observed reductions in the number of bowel movements per day and treatment differences were generally consistent with the reductions and differences observed in patients who did not receive rescue therapy, and were similar to the overall data presented in Table 2above

  [see Dosage and Administration , Drug Interactions ]

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  A third randomized treatment arm of Xermelo 500 mg three times daily did not demonstrate additional treatment benefit on the primary endpoint and had a greater incidence of adverse reactions than Xermelo 250 mg three times daily.  Therefore, Xermelo 500 mg three times daily is not recommended

  [see Dosage and Administration ].

  

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• 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 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 ]

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• 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 Constipation

  Xermelo reduces bowel movement frequency and may lead to constipation. Serious complications of constipation have been reported during clinical trials and postmarketing.

  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 of Xermelo, 10 of 115 patients reported constipation, with individual reports of intestinal perforation, obstruction, and fecaloma. 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.

  Serious complications of constipation in patients treated with Xermelo at the recommended dosage (e.g., intestinal obstruction) have also been reported in the postmarket setting. Most patients had additional risk factors, including underlying disease and concomitant constipating medications.

  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 , Adverse Reactions ]

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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.

There are no human data with Xermelo use in pregnant women to inform a drug-associated risk. In animal reproduction studies, no effects on embryo-fetal development were observed with the administration of oral telotristat ethyl to rats during organogenesis at doses up to 750 mg/kg/day (approximately 9 times the exposure at the RHD [recommended human dose]). Treatment of pregnant rabbits with oral telotristat ethyl during organogenesis produced maternal toxicity and post-implantation loss at doses of 250 mg/kg/day or higher (approximately 15 times the exposure at the RHD), and reduced fetal weight at 500 mg/kg/day (approximately 33 times the exposure at the RHD). In a pre-/postnatal development study, an increased incidence of mortality in rat offspring was observed during postnatal days 0 to 4 at the maternal oral dose of 500 mg/kg/day (approximately 5 times the exposure at the RHD), given during organogenesis through lactation

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.