Side Effects Overview
6 ADVERSE REACTIONS Most common adverse reactions (≥5%) are nausea, headache, increased GGT, depression, flatulence, decreased appetite, peripheral edema, and pyrexia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact TerSera Therapeutics LLC at 1-844-334-4035 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 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 Reactions a 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 Depression b 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 (at a higher than recommended dosage) during the 36-week open-label extension period following the 12-week double-blind period of the trial. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of Xermelo. 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. Gastrointestinal: intestinal obstruction [see Warnings and Precautions ( 5.1 )] Immune system disorders: angioedema Skin and subcutaneous tissue disorders: pruritis, rash
Farmakokinetik
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 max and AUC 0-inf were 4.4 ng/mL and 6.23 ng•hr/mL, respectively for telotristat ethyl. The mean C max and AUC 0-inf were 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 max for 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 max and AUC 0-6hr were approximately 7 ng/mL and 22 ng•hr/mL, respectively, for telotristat ethyl. The mean C max and AUC 0-6hr were 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-inf being 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 max and AUC 0-inf were 10.5 ng/mL and 21.6 ng•hr/mL, respectively for telotristat ethyl. The C max and AUC 0-inf values for telotristat were also increased by 47% and 33%, respectively, with a high-fat meal compared to the fasted state. The mean C max and AUC 0-inf were 908 ng/mL and 2980 ng•hr/mL, respectively for telotristat under fed conditions [see Dosage and Administration ( 2 )] . 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 of 14 C-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 m 2 ) compared with subjects with normal renal function following a single oral dose of Xermelo [see Use in Specific Populations ( 8.6 )] . Xermelo was not studied in patients with end-stage renal disease who require dialysis (eGFR < 15 mL/min/1.73 m 2 ). 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-last for 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 ( 8.7 )] . 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 ( 7.2 )] . 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-inf for midazolam were decreased by 25%, and 48%, respectively, compared to administration of midazolam alone. The mean C max , and AUC 0-inf for 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 ( 7.1 )] . Fexofenadine (sensitive P-gp substrate) In vitro telotristat ethyl, but not telotristat, inhibited P-glycoprotein (P-gp). In healthy volunteers, the C max and 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 max and AUC 0-last of 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 max and AUC 0-last of telotristat were decreased by 79% and 68%, respectively. Gastric Acid Reducers (Proton Pump Inhibitor and H 2 -Receptor Antagonist) Omeprazole: The C max and AUC inf of 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 max of 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 max and AUC inf of 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 max to 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.