Naldemedine
Clinical data | |
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Trade names | Symproic, Rizmoic |
Other names | S-297,995 |
AHFS/Drugs.com | Monograph |
MedlinePlus | a617031 |
License data |
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Routes of administration | By mouth |
ATC code | |
Legal status | |
Legal status |
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Pharmacokinetic data | |
Protein binding | 93–94% |
Metabolism | primarily CYP3A4 |
Elimination half-life | 11 hrs |
Excretion | Urine, feces |
Identifiers | |
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Naldemedine (brand name Symproic in the US and Rizmoic in the European Union) is a medication that is used for the treatment of
Medical uses
In the US, naldemedine is approved for the treatment of opioid induced constipation in adults with chronic non-cancer pain, including those who have chronic pain related to prior cancer or its treatment and do not need frequent opioid dosage escalation.[3]
In the European Union, naldemedine is also approved for the treatment of opioid induced constipation in adults, but as a second-line therapy after treatment with a laxative.[4]
Contraindications
The drug is contraindicated in patients with gastrointestinal obstruction or perforation, or those at risk for these problems.[3][4]
Side effects
Side effects in studies were abdominal pain (8–11% of patients as compared to 2–5% under
Overdose
Single doses up to 500 times the recommended dose, as well as multiple doses up to 150 times the recommended dose for ten days, resulted in an increase of the mentioned side effects. Theses side effects were mild to moderate.[3][4]
Interactions
As naldemedine is mainly metabolized by the liver enzyme
Strong inhibitors of the pump P-glycoprotein such as ciclosporin may increase naldemedine concentrations in the blood plasma.[3][4]
Pharmacology
Mechanism of action
Naldemedine is a derivative of
Pharmacokinetics
After oral intake, naldemedine has an absolute
Naldemedine is mainly metabolized by the enzyme CYP3A4 to nor-naldemedine
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Nor-naldemedine, the main metabolite
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Minor metabolites: blue are glucuronidation sites, brown is the hydroxylation site, and green the cleavage site
Naldemedine and its metabolites are excreted via urine and faeces. The part of the molecule "left" of the cleavage line (the sum of original substance, nor-naldemedine, glucuronides, hydroxy-derivative, and carboxylic acid) is found to 20.4% in the urine and to 64.3% in the faeces, while the part "right" to the line (the sum of original substance, nor-naldemedine, glucuronides, hydroxy-derivative, and benzamidine) is found to 57.3% in the urine and to 34.8% in the faeces. This indicates that benzamidine is predominantly excreted in the urine and the carboxylic acid is predominantly excreted in the faeces. The
Chemistry
Naldemedine is used in form of the
Society and culture
Commercialization
Naldemedine is manufactured by Shionogi Inc., a United States-based subsidiary of Shionogi & Co., Ltd. Shionogi & Co., Ltd. (SGIOF) is a pharmaceutical company founded in 1878 based in
In the US market, Shionogi Inc. has partnered with Purdue Pharma in a joint venture for US commercialization of Symproic.[7] Purdue Pharma LP is a privately held pharmaceutical company based in the United States that specializes in chronic pain disorders.[8]
Purdue Pharma appealed to remove the Class II scheduling of Symproic as accordant to the Controlled Substances Act. The appeal was posted to the Federal Register on July 12, 2017.[9] The Drug Enforcement Administration officially removed the Class II scheduling in September 2017.[10]
Manufacturer finances
Since 2015, Shionogi & Co., Ltd. has produced increasing net income. At the end of fiscal year 2016, Shionogi & Co., Ltd. had a net income of $66,687,000. At the end of fiscal year 2017, they increased their net income to $83,879,000.[11] How much of this is attributed to sales of Symproic is unknown. Shionogi & Co., Ltd. ends their fiscal year on March 31 of each year. Considering the drug was only FDA approved on March 23 of 2017, the true valuation of the drug is yet to be seen. Purdue Pharma has begun advertising for the medication to be available by October 2017.[12]
Intellectual property
There are currently three patents issued for naldemedine tosylate by the United States Patent and Trademark Office. All patents are owned by Shionogi Inc. and will expire from 2026 to 2031.[13] Naldemedine tosylate has 46 other patents in 18 different countries.[14]
Clinical trials
The approval of naldemedine came from the results of the COMPOSE program, a phase three clinical studies program conducted in adults 18–80 years of age with chronic non-cancer pain opioid induced constipation. COMPOSE-I and COMPOSE-II were 12-week double blind randomized controlled trials comparing the use of naldemedine to placebo in the patient population. COMPOSE-I began in August 2013 until January 2015 in 68 outpatient clinic in seven countries. COMPOSE-II began in November 2013 until June 2015 taking place in 69 outpatient clinics in six countries. In both trials, patients were randomly assigned to receive either naldemedine 0.2 mg or placebo once daily for 12 weeks. A responder had at least three spontaneous bowel movements per week with an increase of one spontaneous bowel movement for nine of the 12 weeks, including three of the final four weeks of the study. In COMPOSE-I and COMPOSE-II, the proportion of responders were significantly higher in the naldemedine group than the placebo group. Adverse events were similar in both trials, however, patients in the naldemedine group had slightly higher rates of adverse events.[15]
COMPOSE-III was a 52-week clinical trial examining the long term safety with naldemedine in patients with non cancer chronic pain. Results from this trial showed statistical significance for increased weekly bowel movements and no opioid withdrawal symptoms. The study also concluded adverse effects were more similar between two groups.[16]
All trials were conducted following Good Clinical Practice guidelines.[16]
See also
References
- ^ "FDA Approves Symproic (naldemedine) for the Treatment of Opioid-Induced Constipation - Chemdiv". Chemdiv. 2017-03-27. Retrieved 2017-04-05.
- ^ Shionogi (2009-03-27). "Research and Development at Shionogi (as of March 2009)" (PDF). Archived from the original (PDF) on 2013-05-22. Retrieved 2012-05-12.
- ^ a b c d e f g h FDA Professional Drug Information on Symproic.
- ^ a b c d e f g h i "Rizmoic: EPAR – Product information" (PDF). European Medicines Agency (EMA). 2019-08-29.
- S2CID 53036507.
- ^ a b c "Rizmoic: EPAR – Public assessment report" (PDF). European Medicines Agency (EMA). 2018-12-14.
- ^ "Shionogi and Purdue Pharma establish alliance for joint U.S. commercialization of naldemedine". Purdue Pharma. Retrieved 31 October 2017.
- ^ "FDA Approves Symproic (naldemedine) Once-Daily Tablets C-II for the Treatment of Opioid-Induced Constipation in Adults with Chronic Non-Cancer Pain". Purdue Pharma. Retrieved 31 October 2017.
- ^ "Schedules of controlled substances: removal of naldemedine from control" (PDF). Federal Register. Retrieved 1 November 2017.
- ^ "Symproic Now Available for Opioid-Induced Constipation". MPR. 2017-10-12. Retrieved 2017-11-08.
- ^ "Shionogi & Co., Ltd". Yahoo Finance. Retrieved 31 October 2017.
- ^ "Opioid Induced Constipation". Opioid Induced Constipation. Purdue Pharma. Retrieved 31 October 2017.
- ^ "Generic Symproic Availability". Drugs.com. Retrieved 31 October 2017.
- ^ "Naldemedine tosylate - generic drug details". Drug Patent Watch. Retrieved 31 October 2017.
- PMID 28576452.
- ^ a b "Center for Drug Evaluaiton and Research Medication Review" (PDF). FDA. Retrieved 31 October 2017.
External links
- "Naldemedine". Drug Information Portal. U.S. National Library of Medicine.