Shionogi & Co., Ltd. (hereafter "Shionogi"), a research-driven pharmaceutical company, announced today thatthe European Commission(EC) has granted Marketing Authorisation(MA) for Rizmoic® (naldemedine), for the treatment of opioid-induced constipation (OIC) in adult patients who have previously been treated with a laxative.

This decision by the EC has followed adoption of the positive opinion of the Committee for Medicinal Products for Human Use (CHMP) in December 2018.

Welcoming the announcement,Dr. John Keller, Chief Executive Officer of Shionogi Limited, said

"Today's EU marketing authorisation for RIZMOIC allows patients with opioid-induced constipation already taking laxatives access to an important new treatment that can relieve their suffering from this much under-recognised condition that can significantly affect their quality of life."

Dr. Viola Andresen, specialist in Internal Medicine at the Israelitic Hospital in Hamburg, Germany, commented

"We as physicians are highly welcoming this announcement, because the peripherally acting µ-opioid antagonist (PAMORA) naldemedine is an effective and well-tolerated therapy for opioid-induced constipation and will therefore add an important value for the therapeutic management of patients suffering from OIC. "

OIC is a prevalent and distressing side effect of opioid therapy that does not reliably respond to treatment with conventional laxatives.1

The efficacy and safety of naldemedine has been established in 2 replicate 12-week, phase 3, randomised, double-blind, placebo-controlled studies in patients with chronic non-cancer pain and OIC (V9231 and V9232)2. A phase 3 long-term (52-week) randomised double-blind, placebo-controlled study in subjects with chronic non-cancer pain and OIC was conducted to evaluate long term safety.3,4 Efficacy and safety were also established in randomised, double-blind, placebo group, comparator studies in patients with cancer and OIC (V9236).5,6 The results of these studies support the efficacy of naldemedine, showing treatment with naldemedine was associated with a statistically significant increase in the spontaneous bowel movement (SBM) response rate over 12 weeks compared to placebo (47.6% vs. 34.6%, p=0.002; 52.5% vs. 33.6%, p<0.0001, respectively)2 in the two studies in patients with non-cancer pain, and a statistically significant increase in the SBM response rate over 2 weeks compared to placebo (71.1% vs 34.4%, p<0.0001) in a study in patients with cancer.5The most common side effects are abdominal pain, diarrhoea, nausea, and vomiting.2

Naldemedine, which has already been approved for routine use in the US and Japan, is an antagonist of opioid binding at the mu-, delta-, and kappa-opioid receptors. Naldemedine is a derivative of naltrexone to which a side chain has been added that increases the molecular weight and the polar surface area, thereby reducing its ability to cross the blood-brain barrier (BBB); the CNS penetration of naldemedine is expected to be negligible at the recommended dose.  Additionally, naldemedine is a substrate of the P-glycoprotein (P-gp) efflux transporter, which may also be involved in reducing naldemedine penetration into the CNS.  Based on this, naldemedine is expected to exert its anti-constipating effects on opioids without reversing their CNS-mediated analgesic effects.

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