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Symproic

Generic Name: Naldemedine Tosylate
Class: GI Drugs, Miscellaneous
Chemical Name: 17-(Cyclopropylmethyl)-6,7-didehydro-4,5-epoxy-3,6,14-trihydroxy-N-[1-methyl-1-(3-phenyl-1,2,4-oxadiazol-5-yl)ethyl]-,(5a)-, 4-methylbenzenesulfonate (1:1) morphinan-7-carboxamide
Molecular Formula: C32H34N4O6 • C7H8O3S
CAS Number: 1345728-04-2

Medically reviewed on Aug 27, 2018

Introduction

Peripherally acting μ-opiate receptor antagonist.1 4 5

Uses for Symproic

Opiate-induced Constipation

Management of opiate-induced constipation in patients with chronic non-cancer-related pain, including those with chronic pain related to prior cancer or its treatment who do not require frequent (e.g., weekly) increases in opiate dosage.1 3 7

Symproic Dosage and Administration

General

  • Changes in analgesic dosing regimen not required prior to initiating naldemedine.1

  • Patients receiving opiates for <4 weeks may be less responsive to naldemedine.1

  • Discontinue naldemedine if opiate therapy is discontinued.1

Administration

Oral Administration

Administer orally without regard to food.1

Dosage

Available as naldemedine tosylate; dosage expressed in terms of naldemedine.1

Adults

Opiate-induced Constipation
Oral

0.2 mg once daily.1

Special Populations

Hepatic Impairment

Mild or moderate hepatic impairment: Dosage adjustment not needed.1

Severe hepatic impairment: Avoid use.1 (See Special Populations under Pharmacokinetics.)

Renal Impairment

Manufacturer makes no specific dosage recommendations.1 (See Special Populations under Pharmacokinetics.)

Geriatric Patients

Manufacturer makes no specific dosage recommendations.1 (See Geriatric Use under Cautions and see Special Populations under Pharmacokinetics.)

Cautions for Symproic

Contraindications

  • Patients with known or suspected GI obstruction or at increased risk of recurrent GI obstruction.1 (See GI Perforation under Cautions.)

  • Known hypersensitivity to naldemedine.1

Warnings/Precautions

GI Perforation

GI perforation reported with use of methylnaltrexone, another peripherally acting opiate antagonist, in patients with underlying conditions that may be associated with localized or diffuse reduction of structural integrity in the GI tract wall (e.g., peptic ulcer disease, Ogilvie’s syndrome, diverticular disease, infiltrative GI tract malignancies or peritoneal metastases).1 2 Carefully consider risks and benefits of naldemedine in patients with these conditions or with other conditions that might result in impaired integrity of the GI tract wall (e.g., Crohn’s disease).1

Monitor patients receiving naldemedine for development of severe, persistent, or worsening abdominal pain; discontinue the drug if such symptoms occur.1

Opiate Withdrawal

Manifestations consistent with opiate withdrawal (e.g., hyperhidrosis, chills, increased lacrimation, hot flush/flushing, pyrexia, sneezing, feeling cold, abdominal pain, diarrhea, nausea, vomiting) reported.1

Patients with disruptions in the blood-brain barrier may be at increased risk for opiate withdrawal or reduced analgesia; carefully consider risks and benefits of naldemedine in such patients, and monitor these patients for symptoms of opiate withdrawal.1

Sensitivity Reactions

Hypersensitivity reactions, including bronchospasm and rash, reported.1

Specific Populations

Pregnancy

Use only if potential benefits justify potential risk to fetus.1 No adequate and well-controlled studies in pregnant women.1

Crosses the placenta; because of the immature fetal blood-brain barrier, use during pregnancy may precipitate opiate withdrawal in the fetus.1

No adverse effects on embryofetal development observed in animal studies.1

Lactation

Distributed into milk in rats; not known whether naldemedine distributes into human milk, affects milk production, or affects the breast-fed infant.1

Because of the potential for serious adverse effects, including opiate withdrawal, in nursing infants, discontinue nursing or the drug.1 Nursing may be resumed 3 days following the final dose of naldemedine.1

Pediatric Use

Safety and efficacy not established in pediatric patients.1

Geriatric Use

No overall differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1

Hepatic Impairment

Avoid use in severe hepatic impairment.1 Effect of severe hepatic impairment on naldemedine pharmacokinetics not established.1

Common Adverse Effects

Abdominal pain,1 7 diarrhea,1 7 nausea,1 7 vomiting,1 gastroenteritis.1

Interactions for Symproic

Metabolized principally by CYP3A4, with minimal contribution from uridine diphosphate-glucuronosyltransferase (UGT) 1A3; substrate of P-glycoprotein (P-gp).1

Did not inhibit CYP isoenzyme 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5, or 4A11 in vitro at clinically relevant concentrations.1 Did not substantially induce CYP 1A2, 2B6, or 3A4, or UGT 1A2, 1A6, or 2B7.1

Does not inhibit organic anion transport protein (OATP) 1B1 or 1B3, organic cation transporter (OCT) 1 or 2, organic anion transporter (OAT) 1 or 3, breast cancer resistance protein (BCRP), or P-gp.1

Drugs Affecting Hepatic Microsomal Enzymes

Moderate or potent CYP3A inhibitors: Possible increased plasma concentrations of naldemedine.1 Monitor for naldemedine-related adverse effects.1

Potent CYP3A inducers: May substantially reduce plasma naldemedine concentrations and may decrease the efficacy of naldemedine.1 Avoid concomitant use.1

Drugs Affecting P-glycoprotein

P-gp inhibitors: Possible increased naldemedine exposure.1 3

Specific Drugs

Drug

Interaction

Comments

Amiodarone

Possible increased naldemedine concentrations1

Monitor for naldemedine-related adverse effects1

Anticonvulsants (carbamazepine, phenytoin)

Possible substantial decrease in naldemedine peak concentration and AUC; possible decreased naldemedine efficacy1

Avoid concomitant use1

Antifungals, azole (fluconazole, itraconazole, ketoconazole)

Increased naldemedine peak concentration and AUC1 3

Monitor for naldemedine-related adverse effects1

Aprepitant

Possible increased naldemedine concentrations1

Monitor for naldemedine-related adverse effects1

Captopril

Possible increased naldemedine concentrations1

Monitor for naldemedine-related adverse effects1

Cyclosporine

Increased naldemedine peak concentration and AUC1 3

Monitor for naldemedine-related adverse effects1

Diltiazem

Possible increased naldemedine concentrations1

Monitor for naldemedine-related adverse effects1

Efavirenz

Pharmacokinetic simulations suggest decreased naldemedine exposure1

Clinical importance unknown1

HIV protease inhibitors (e.g., atazanavir, ritonavir, saquinavir)

Possible increased naldemedine concentrations1

Monitor for naldemedine-related adverse effects1

Macrolides (clarithromycin, erythromycin)

Possible increased naldemedine concentrations1

Monitor for naldemedine-related adverse effects1

Opiate antagonists

Possible additive opiate receptor antagonism and increased risk of opiate withdrawal1

Avoid concomitant use1

Quercetin

Possible increased naldemedine concentrations1

Monitor for naldemedine-related adverse effects1

Quinidine

Possible increased naldemedine concentrations1

Monitor for naldemedine-related adverse effects1

Rifampin

Substantially reduced naldemedine peak concentration and AUC; possible decreased naldemedine efficacy1 3

Avoid concomitant use1

St. John's wort (Hypericum perforatum)

Possible substantial decrease in naldemedine peak concentration and AUC; possible decreased naldemedine efficacy1

Avoid concomitant use1

Verapamil

Possible increased naldemedine concentrations1

Monitor for naldemedine-related adverse effects1

Symproic Pharmacokinetics

Absorption

Onset

Peak plasma concentration attained approximately 45 minutes after oral administration in the fasting state.1

Peak plasma concentration and AUC increase in dose-proportional or almost dose-proportional manner.1

Food

High-fat meal decreases peak plasma concentration by approximately 35% and delays time to peak plasma concentration by approximately 1.75 hours, but does not affect extent of absorption.1

Distribution

Extent

Crosses placenta.1

Distributed into milk in rats; not known whether distributed into human milk.1

Plasma Protein Binding

93–94%.1

Elimination

Metabolism

Metabolized principally by CYP3A4, with minor contribution from UGT1A3, to form nornaldemedine and naldemedine 3-glucuronide, respectively.1 Also is cleaved in the GI tract to form benzamidine and naldemedine carboxylic acid.1

Nornaldemedine and naldemedine 3-glucuronide are less-potent opiate receptor antagonists,1 but are not expected to contribute to the drug's pharmacologic effects at usual clinical concentrations.3

Elimination Route

Excreted in urine (57%) and feces (35%); 16–18% of dose excreted in urine as unchanged drug, 32% excreted in urine as benzamidine, and 20% excreted in feces as benzamidine.1

Half-life

11 hours.1

Special Populations

Mild or moderate (Child-Pugh class A or B) hepatic impairment does not alter pharmacokinetics.1 Effect of severe (Child-Pugh class C) hepatic impairment not established.1

Renal impairment, including end-stage renal disease requiring hemodialysis, does not alter pharmacokinetics.1 Naldemedine is not removed by hemodialysis.1

Age, sex, and race do not appear to alter pharmacokinetics.1

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).1

Actions

  • Peripherally acting μ-opiate receptor antagonist that also binds to and exhibits antagonistic activity at δ- and κ-opiate receptors.1 4 5 6

  • Blocks μ-opiate receptors in the GI tract, thereby reversing opiate-induced constipating effects (e.g., slowing of GI transit).1

  • Differs structurally from naltrexone by addition of large polar side chain that decreases ability of the drug to cross the blood-brain barrier.1 4

  • CNS penetration expected to be negligible at recommended dosage, limiting the potential for interference with centrally mediated opiate analgesia.1 4 5 6

Advice to Patients

  • Importance of reading the manufacturer's medication guide.1

  • Importance of discontinuing naldemedine following discontinuance of opiate analgesics.1

  • Possible risk of GI perforation.1 Importance of discontinuing naldemedine and promptly seeking medical attention if unusually severe, persistent, or worsening abdominal pain occurs.1

  • Potential for manifestations consistent with opiate withdrawal; importance of informing clinician if such manifestations occur.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Inform women that naldemedine use during pregnancy may precipitate opiate withdrawal in the fetus because the fetal blood-brain barrier is immature.1 Advise women not to breast-feed while receiving naldemedine and for 3 days following the final dose because of the potential for opiate withdrawal in nursing infants.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs (especially those that alter CYP3A4 activity), as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Naldemedine Tosylate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

0.2 mg (of naldemedine)

Symproic

Purdue

AHFS DI Essentials™. © Copyright 2018, Selected Revisions August 27, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Purdue Pharma. Symproic (naldemedine tosylate) tablets prescribing information. Stamford, CT; 2017 Aug.

2. Salix Pharmaceuticals. Relistor (methylnaltrexone bromide) tablets and subcutaneous injection prescribing information. Bridgewater, NJ; 2017 Sep.

3. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 208854Orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208854Orig1s000ClinPharmR.pdf

4. Katakami N, Oda K, Tauchi K et al. Phase IIb, Randomized, Double-Blind, Placebo-Controlled Study of Naldemedine for the Treatment of Opioid-Induced Constipation in Patients With Cancer. J Clin Oncol. 2017; :JCO2016708453. http://www.ncbi.nlm.nih.gov/pubmed/28445097?dopt=AbstractPlus

5. Webster LR, Yamada T, Arjona Ferreira JC. A Phase 2b, Randomized, Double-Blind Placebo-Controlled Study to Evaluate the Efficacy and Safety of Naldemedine for the Treatment of Opioid-Induced Constipation in Patients with Chronic Noncancer Pain. Pain Med. 2017; http://www.ncbi.nlm.nih.gov/pubmed/28371937?dopt=AbstractPlus

6. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 208854Orig1s000: Pharmacology review. From FDA website. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208854Orig1s000PharmR.pdf

7. Hale M, Wild J, Reddy J et al. Naldemedine versus placebo for opioid-induced constipation (COMPOSE-1 and COMPOSE-2): two multicentre, phase 3, double-blind, randomised, parallel-group trials. Lancet Gastroenterol Hepatol. 2017; 2:555-564. http://www.ncbi.nlm.nih.gov/pubmed/28576452?dopt=AbstractPlus

8. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 208854Orig1s000: Medical review(s). From FDA website. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208854Orig1s000MedR.pdf

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