Telotristat ethyl

Mechanism of Action

Telotristat, the active metabolite of telotristat ethyl, inhibits tryptophan hydroxylase, which mediates the rate-limiting step in serotonin biosynthesis

Serotonin plays a role in mediating secretion, motility, inflammation, and sensation of the GI tract, and is overproduced in patients with carcinoid syndrome

In vitro inhibitory potency of telotristat towards tryptophan hydroxylase is 29 times higher than that of telotristat ethyl

Absorption

Peak plasma time: 1 hr (telotristat ethyl); 2 hr (telotristat)

Peak plasma concentration: 7 ng/mL (telotristat ethyl); 900 ng/mL (telotristat)

AUC: 22 ng·hr/mL (telotristat ethyl); 3000 ng·hr/mL (telotristat)

Administration with food significantly increases systemic exposure of telotristat ethyl and telotristat

Distribution

Protein bound: >99% (both telotristat ethyl and telotristat)

P-gp substrate

Metabolism

Telotristat ethyl undergoes hydrolysis via carboxylesterases to telotristat, its active metabolite

Telotristat is further metabolized

Telotristat ethyl and telotristat are not substrates for CYP enzymes

Elimination

Half-life: 0.6 hr (telotristat ethyl); 5 hr (telotristat)

Total clearance: 2.7 L/hr (telotristat ethyl); 152 L/hr (telotristat)

Excretion: <0.4% urine; 92.8% feces

Usual Adult Dose for Carcinoid Tumor:

250 mg orally 3 times a day

Comments:
-Patients should take this drug with food.
-If needed, short-acting octreotide should be given at least 30 minutes after administration of this drug.
-Patients should discontinue use if severe constipation occurs.

Use: Treatment of carcinoid syndrome diarrhea in combination with somatostatin analog (SSA) therapy in patients whose diarrhea is inadequately controlled by SSA therapy

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For telotristat ethyl, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to telotristat ethyl or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of Xermelo™ in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of Xermelo™ in the elderly.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking telotristat ethyl, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using telotristat ethyl with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Octreotide

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

• It is used to treat carcinoid syndrome diarrhea.

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using telotristat ethyl while you are pregnant.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Very hard stools (constipation).
• Very bad belly pain.
• Low mood (depression).
• Swelling in the arms or legs.
• Fever.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Upset stomach.
• Headache.
• Gas.
• Not hungry.
• Belly pain.
• Hard stools (constipation).

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

Refer to adult dosing.

CloZAPine: CYP3A4 Inducers (Weak) may decrease the serum concentration of CloZAPine. Monitor therapy

HYDROcodone: CYP3A4 Inducers (Weak) may decrease the serum concentration of HYDROcodone. Monitor therapy

NiMODipine: CYP3A4 Inducers (Weak) may decrease the serum concentration of NiMODipine. Monitor therapy

Octreotide: May decrease the serum concentration of Telotristat Ethyl. Management: Administer short-acting octreotide at least 30 minutes after administration of telotristat ethyl and monitor for decreased telotristat ethyl efficacy. Consider therapy modification

Commonly reported side effects of telotristat include: constipation. See below for a comprehensive list of adverse effects.

250 mg orally 3 times a day

Comments:
-Patients should take this drug with food.
-If needed, short-acting octreotide should be given at least 30 minutes after administration of this drug.
-Patients should discontinue use if severe constipation occurs.

Use: Treatment of carcinoid syndrome diarrhea in combination with somatostatin analog (SSA) therapy in patients whose diarrhea is inadequately controlled by SSA therapy