Drug Interaction Studies

Neither plecanatide nor its active metabolite inhibited the cytochrome

P450 (CYP) enzymes 2C9 and 3A4, and they did not induce CYP3A4 in vitro.

Plecanatide and its active metabolite are neither substrates nor inhibitors

 of the transporters P-glycoprotein (P-gp) or breast cancer resistance

 protein (BCRP) in vitro.

 

BRIEF SUMMARY

 

PLECANATIDE -(Jan 2017)

 

Indn-         To treat Chronic Idiopathic Constipation (CIC)  in adult patients

 

Comp-      Tablets: 3 mg     The recommended adult dosage of TRULANCE is 3 mg taken orally once daily. 

 

ADR-      Because clinical studies are conducted under widely varying conditions

 adverse reaction rates observed in the clinical trials of a drug 

cannot be directly compared with rates in the clinical trials of another drug and

 may not reflect the rates observed in practice.

 

CI-       Patients less than 6 years of age due to the risk of serious dehydratio

 [see Warnings and Precautions 

Patients with known or suspected mechanical gastrointestinal obstruction.

 

 WARNINGS-

 

1. Risk of Serious Dehydration in Pediatric Patients-

TRULANCE is contraindicated in patients less than 6 years of age. 

The safety and effectiveness of TRULANCE in patients less than 

18 years of age  have not been established. 

 

Pat Infn-

 

 

 

 

===============================================================

 

U.S. FDA APPROVED  DRUGS DURING 2017

 

Sr.No-  1

  

Name of the  Drug-            TRULANCE

 

Active Ingredient-            Plecanatide                                                                                                                                                                                                             Pharmacological Classification-

 

                               To treat Chronic Idiopathic Constipation (CIC)  in adult patients

                                                                                                                           

Date of Approval-                            01-19-2017

 

 (Ref- FDA approved List 2017)                                                                                                                                                                                                                      HIGHLIGHTS OF PRESCRIBING INFORMATION 

These highlights do not include all the information needed to use 

TRULANCE safely and effectively. See full prescribing information for TRULANCE.

 

TRULANCE (plecanatide) tablets, for oral use Initial U.S. Approval: 2017

 

WARNING: RISK OF SERIOUS DEHYDRATION IN

PEDIATRIC PATIENTS

See full prescribing information for complete boxed warning.

 

TRULANCE is contraindicated in patients less than 6 years of age;

 in young juvenile mice, plecanatide caused death due to dehydration. 

 

Avoid use of TRULANCE in patients 6 years to less than 18 years of age. 

 

The safety and effectiveness of TRULANCE have not been established in patients

 less than 18 years of age.

 

                                                                                                                                                                                                  

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               

 

 

 ADVERSE REACTIONS

 

1. Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions

 adverse reaction rates observed in the clinical trials of a drug 

cannot be directly compared with rates in the clinical trials of another drug and

 may not reflect the rates observed in practice.

 

The safety data described below reflect data from 1733 adult patients 

with CIC randomized in two double-blind, placebo-controlled 

clinical trials (Study 1 and Study 2) to receive placebo or 3 mg o

 TRULANCE once daily for 12 weeks. Demographic characteristics 

were comparable between the TRULANCE and placebo groups..

 

 CONTRAINDICATIONS-

TRULANCE is contraindicated in:

 

Patients less than 6 years of age due to the risk of serious dehydratio

 [see Warnings and Precautions 

Patients with known or suspected mechanical gastrointestinal obstruction.

 

 WARNINGS AND PRECAUTIONS

 

1. Risk of Serious Dehydration in Pediatric Patients-

TRULANCE is contraindicated in patients less than 6 years of age. 

The safety and effectiveness of TRULANCE in patients less than 

18 years of age  have not been established. 

 

In young juvenile mice (human age equivalent of approximately

1 month to less than 2 years), plecanatide increased fluid-secretion

 into the intestines as a consequence of stimulation of guanylate 

cyclase-C (GC-C), resulting in mortality in some mice within the first 24 hours,

 apparently due to dehydration. 

 

Due to increased intestinal expression of GC-C, patients less than 6 years

of age may be more likely than patients 6 years of age and olde

 to develop severe diarrhea and its potentially serious consequences.

 

Avoid the use of TRULANCE in patients 6 years to less than 18 years of age.

 Although there were no deaths in older juvenile mice, given the deaths

 in younger mice and the lack of clinical safety and efficacy data

 in pediatric patients, avoid the use of TRULANCE in patients 6 years

 to less than 18 years of age..

 

2. Diarrhea

Diarrhea was the most common adverse reaction in the two placebo-controlled 

clinical trials. Severe diarrhea was reported in 0.6% of patients 

 

 If severe diarrhea occurs, suspend dosing and rehydrate the patient.

 

 

INDICATIONS AND USAGE

 

TRULANCE is a guanylate cyclase-C agonist indicated in adults for treatment

 of chronic idiopathic constipation (CIC).

 

DOSAGE AND ADMINISTRATION

The recommended adult dosage of TRULANCE is 3 mg taken orally once daily. 

 

Administration Instructions 

Take with or without food.

Swallow tablets whole.

For patients who have difficulty swallowing tablets whole or those with

 a nasogastric or gastric feeding tube, see full prescribing information 

with instructions for crushing the tablet and administering with applesauce or water.

 

DOSAGE FORMS AND STRENGTHS

Tablets: 3 mg 

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

 

Advise Patients:

Diarrhea

To stop TRULANCE and contact their healthcare provider if they experience

 severe diarrhea.

 

Accidental Ingestion

Accidental ingestion of TRULANCE in children, especially in children less 

than 6 years of age, may result in severe diarrhea and dehydration. Instruct

patients to take steps to store TRULANCE securely and out of reach 

of children and to dispose of unused TRULANCE 

 

Administration and Handling Instructions

 

1.To take TRULANCE once daily with or without food 

 

2.If a dose is missed, skip the missed dose and take the next dose 

at the regular time. Do not take two doses at the same time.

 

3.To swallow TRULANCE tablets whole.

 

4.If adult patients have swallowing difficulties, 

 TRULANCE tablets can be crushed and administered orally in either

  applesauce or with water, or administered with water via a nasogastric

  or gastric feeding tube, as described in the Medication Guide.

 

5.To keep TRULANCE in a dry place. Protect from moisture.

 

6.  For bottles, keep TRULANCE in the original bottle.

   Do not remove desiccant from the bottle. Do not subdivide or repackage. 

  Remove and discard polyester coil after opening. Keep bottles closed tightly

 

TRULANCE is a trademark of Synergy Pharmaceuticals Inc.

 

 

Manufactured for:

Synergy Pharmaceuticals Inc.

420 Lexington Avenue, Suite 2012

New York, New York 10170

 

 CLINICAL PHARMACOLOGY

 

1. Mechanism of Action

Plecanatide is structurally related to human uroguanylin, and similar to uroguanylin

plecanatide functions as a guanylate cyclase-C (GC-C) agonist. 

 

Both plecanatide and its active metabolite bind to GC-C and act locally on

 the luminal surface of the intestinal epithelium. Activation of GC-C results 

in an increase in both intracellular and extracellular concentrations of 

cyclic guanosine monophosphate (cGMP). 

 

Elevation of intracellular cGMP stimulates secretion of chloride and

bicarbonate into the intestinal lumen, mainly through activation of the

 cystic fibrosis transmembrane conductance regulator (CFTR) ion channel,

 resulting in increased intestinal fluid and accelerated transit.

 

 

2. Pharmacodynamics

Food Effect

Subjects who received either a low-fat, low calorie (LF-LC) meal or a high fat,

 high calorie (HF-HC) meal reported looser stools than fasted subjects up to 

24 hours after a single dose of TRULANCE 9 mg (3 times the recommended dose). 

In clinical studies, TRULANCE was administered with or without food ..

 

3. Pharmacokinetics

Absorption

Plecanatide is minimally absorbed with negligible systemic availability following

 oral administration. Concentrations of plecanatide and its active metabolite

 in plasma are below the limit of quantitation after an oral TRULANCE dose of 3 mg. 

 

Therefore, standard pharmacokinetic parameters such as AUC, maximum 

concentration (Cmax), and half-life (t½) cannot be calculated.

 

Distribution

Given that plecanatide concentrations following clinically relevant oral doses

 are not measurable, plecanatide is expected to be minimally distributed in tissues. 

 

Oral plecanatide is localized to the GI tract where it exerts its effects as a GC-C

 agonist with negligible systemic exposure. 

 

Plecanatide exhibits little to no binding to human serum albumin or human á-1-acid glycoprotein.

 

Elimination

Metabolism

Plecanatide is metabolized in the GI tract to an active metabolite by loss of

 the terminal leucine moiety. Both plecanatide and the metabolite are 

proteolytically degraded within the intestinal lumen to smaller peptides 

and naturally occurring amino acids.

 

Excretion

No excretion studies have been conducted in humans.

 Plecanatide and its active metabolite are not measurable in plasma 

following administration of the recommended clinical doses.

 

Drug Interaction Studies

Neither plecanatide nor its active metabolite inhibited the cytochrome

P450 (CYP) enzymes 2C9 and 3A4, and they did not induce CYP3A4 in vitro.

Plecanatide and its active metabolite are neither substrates nor inhibitors

 of the transporters P-glycoprotein (P-gp) or breast cancer resistance

 protein (BCRP) in vitro.

 

USE IN SPECIFIC POPULATIONS

 

1 Pregnancy

Risk Summary

Plecanatide and its active metabolite are negligibly absorbed systemically

 following oral administration and maternal use is not expected to result

 in fetal exposure to the drug. 

 

The available data on TRULANCE use in pregnant women are not sufficient 

to inform any drug-associated risks for major birth defects and miscarriage. 

 

 

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 United States 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.

 

2. Lactation

Risk Summary

There is no information regarding the presence of plecanatide in human milk,

or its effects on milk production or the breastfed infant. 

 

No lactation studies in animals have been conducted.  

 

It is unknown whether the negligible systemic absorption of plecanatide 

by adults will result in a clinically relevant exposure to breastfed infants

 

 Exposure to plecanatide in breastfed infants has the potential for serious

adverse effects. 

 

The developmental and health benefits of breastfeeding should be 

considered along with the mother’s clinical need for TRULANCE

 and any potential adverse effects on the breastfed infant from

TRULANCE or from the underlying maternal condition.

 

3.Pediatric Use

TRULANCE is contraindicated in pediatric patients less than 6 years of age. 

Avoid use of TRULANCE in patients 6 years to less than 18 years of age.

 

The safety and effectiveness of TRULANCE in patients less than 18 years

 of age have not been established.

 

4. Geriatric Use

Clinical studies of TRULANCE did not include sufficient numbers of patients

 aged 65 and over to determine whether they respond differently from 

patients 18 years to less than 65 years of age.

 

 Of 2601 subjects in clinical trials of TRULANCE, 273 (10%) were 65 years

 of age and over, and 47 (2%) were 75 years and over.

 

In general, dose selection for an elderly patient should be cautious, 

reflecting the greater frequency of decreased hepatic, renal, or cardiac function

 and of concomitant disease or other drug therapy.