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| Clinical data | |
|---|---|
| Trade names | Symproic, Rizmoic |
| Other names | S-297,995 |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a617031 |
| License data | |
| Routes of administration | By mouth |
| ATC code | |
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| Pharmacokinetic data | |
| Protein binding | 93–94% |
| Metabolism | primarilyCYP3A4 |
| Eliminationhalf-life | 11 hrs |
| Excretion | Urine, feces |
| Identifiers | |
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| CAS Number | |
| PubChemCID | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| KEGG | |
| Chemical and physical data | |
| Formula | C32H34N4O6 |
| Molar mass | 570.646 g·mol−1 |
| 3D model (JSmol) | |
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Naldemedine, sold under the brand nameSymproic in the US andRizmoic in the European Union, is a medication that is used for the treatment ofopioid-inducedconstipation in adults who have previously been treated with a laxative in the European Union, or to treat opioid induced constipation in adults with chronic non-cancer pain in the US. It is aperipherally acting μ-opioid receptor antagonist and was developed byShionogi.[3] Clinical studies have found it to possess statistically significant effectiveness for these indications and to be generally well tolerated, with predominantly mild to moderategastrointestinal side effects.[4] Effects indicative ofcentralopioid withdrawal or impact on theanalgesic ormiotic effects of co-administered opioids have only been observed in a small number of patients.[1]
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.[1]
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 alaxative.[5]
The drug is contraindicated in patients withgastrointestinal obstruction orperforation, or those at risk for these problems.[1][5]
Side effects in studies were abdominal pain (8–11% of patients as compared to 2–5% underplacebo, depending on the study), diarrhea (7% versus 2–3%),nausea (4–6% versus 2–5%), vomiting (3% versus 2%),gastroenteritis (2–3% versus 1%), andopioid withdrawal syndrome (1.5–3.2% versus 0.5–1.5%). The latter was severe but manageable in one patient, and otherwise mild to moderate.Hypersensitivity reactions were rare; they occurred in two patients.[1][5]
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.[1][5]
As naldemedine is mainly metabolized by the liver enzymeCYP3A4, inhibitors of this enzyme can increase its concentrations in the body and thus its potential for side effects. Examples includeitraconazole (which increased naldemedine exposure 2.9-fold in a study),ketoconazole,clarithromycin andgrapefruit juice. Conversely, CYP3A4inducers such asrifampicin andSt John's wort decrease naldemedine concentrations; with rifampicin, the reduction was 83% in a study.[1][5]
Strong inhibitors of the pumpP-glycoprotein such asciclosporin may increase naldemedine concentrations in theblood plasma.[1][5]
Naldemedine is a derivative ofnaltrexone and, like this substance, blocksopioid receptors of the typesμ (mu),δ (delta) andκ (kappa). While naltrexone is able to cross theblood–brain barrier and can therefore be used to treatopioid dependence, the largehydrophilic side chain of naldemedine and its affinity to P-glycoprotein result in negligible concentrations in thecentral nervous system when recommended doses are applied. Instead, it acts mainly on μ-receptors in the gastrointestinal tract, where it counteracts the constipation inducing effects of opioid drugs.[5]
After oral intake, naldemedine has an absolutebioavailability in the range of 20% to 56% and reaches highest blood plasma levels after 0.75 hours when taken without food and 2.5 hours when taken with a high-fat meal. As thearea under the curve is not significantly different with or without a meal, the drug can be taken independently of food. Once in the bloodstream, 93 to 94% of the substance is bound toplasma proteins, mainly toalbumin.[1][5]
Naldemedine is mainly metabolized by the enzyme CYP3A4 to nor-naldemedine[6] (which makes up about 9–13% of the circulating substance), and to a much lesser extent byUGT1A3 to naldemedine 3-glucuronide. Minor metabolites are the 6-glucuronide, the 7-(R/S)-hydroxy-derivates, and two products formed byenterobacteria through cleaving theoxadiazole ring: naldemedine carboxylic acid andbenzamidine. Nor-naldemedine, the glucuronides, and the carboxylic acid are opioid receptor antagonists, but less potent than the original substance.[7]
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, andcarboxylic 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, andbenzamidine) 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. Theterminal half-life is about 11 hours.[5][7]
Naldemedine is used in form of thetosylate, a white to light tan powder. It is nothygroscopic and has a high water solubility at a physiologicpH.[7]
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 inOsaka, Japan. Shionogi Inc. is fully funded by its parent company, Shionogi & Co., Ltd. The parent company specializes in pharmaceuticals, diagnostic reagents and medical devices in Japan and internationally. Naldemedine is their only gastroenterology product in the United States.
In the US market, Shionogi Inc. has partnered withPurdue Pharma in a joint venture for US commercialization of Symproic.[8] Purdue Pharma LP is a privately held pharmaceutical company based in the United States that specializes in chronic pain disorders.[9]
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 12 July 2017.[10] TheDrug Enforcement Administration officially removed the Class II scheduling in September 2017.[11]
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.[12] How much of this is attributed to sales of Symproic is unknown. Shionogi & Co., Ltd. ends their fiscal year on 31 March of each year. Considering the drug was only FDA approved on 23 March 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.[13]
There are 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.[14] Naldemedine tosylate has 46 other patents in 18 different countries.[15]
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.[16]
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.[17]
