Coventry & Warwickshire Area Prescribing Committee
Drug Positioning Statement DPS102 Naldemedine (Rizmoic®▼) December 2020
VERDICT
The Coventry and Warwickshire Area Prescribing Committee recommends that Naldemedine (Rizmoic®q) is used within its marketing authorisation as stated in NICE TA651, as an option for treating opioid-induced constipation in adults who have had laxative treatment.
Specialist Drugs Status: Specialist Initiated (SI)
SUMMARY NOTES
Indication: For the treatment of opioid-induced constipation (OIC) in adult patients who have previously been treated with a laxative.1 Pharmacological action: Naldemedine acts as a peripherally-acting mu-opioid receptor antagonist (PAMORA) in tissues such as the gastrointestinal tract, thereby decreasing the constipating effects of opioids without reversing the central nervous system mediated opioid effects .1 Presentation: 200 micrograms film coated tablets1 Dose: 200 micrograms daily. Naldemedine may be used with or without laxative(s). Alteration of the analgesic dosing regimen prior to initiating naldemedine is not required. Naldemedine must be discontinued if treatment with the opioid pain medicinal product is discontinued.1
Cost comparison: (28 days)2 Naldemedine 200mcg tablets £41.72 Naloxegol 25 mg (or 12.5 mg) daily £51.52 Senna 15 mg daily £2.05 Lactulose 15 mL twice daily £6.08 Macrogol compound 1 sachet daily £3.68 Ispaghula husk 1 sachet daily £2.64 Prucalopride 2 mg daily £59.52 Docusate 100 mg capsules 2 daily £3.90 Methylnaltrexone s/c 12 mg £84.20 maximum per week - 4 weeks is £336.80 (4 doses weekly)
DRUG PROFILE
Clinical Effectiveness - NICE considered data from the phase 3 COMPOSE series of clinical trials, demonstrating that treatment with naldemedine in cancer and non-cancer pain can increase the frequency of bowel movements compared with placebo and is well tolerated. NICE assessed naldemedine to be cost- effective for both pure opioid-induced constipation (OIC) and mixed aetiology constipation.
The primary outcome for COMPOSE-1, -2 and -4 was the proportion of people who had spontaneous bowel movements (SBMs) defined as those having ≥3 SBMs per week and an increase from baseline of ≥1 SBM per week for that week (a positive response week) for ≥9 weeks out of the 12-week treatment period and ≥3 of the last 4 weeks of the 12-week treatment period.
For COMPOSE-3, the primary outcome was measures of treatment-emergent adverse events. The proportion of people who had SBMs was significantly greater in the naldemedine arm compared with placebo for COMPOSE-1, -2 and -4: • COMPOSE-1: naldemedine 48%, placebo 35%, percentage change 13.0% (95% confidence interval [CI] 4.8 to 21.2). • COMPOSE-2: naldemedine 53%, placebo 34%, percentage change 18.9% (95% CI 10.8 to 27.0). • COMPOSE-4: naldemedine 71%, placebo 34%, percentage change 36.8% (95% CI 23.7 to 49.9).2
The committee discussed the response rates in the COMPOSE trials and noted that there was response in both the naldemedine and placebo groups. The clinical expert explained that pure opioid-induced constipation should respond to a PAMORA (including naloxegol and methylnaltrexone). Because the response rates in the COMPOSE trials were not 100%, this suggests that patients having naldemedine had mixed aetiology constipation. The expert explained that many other factors other than opioid use can contribute to constipation. These include gastrointestinal pathol ogy, other medications including antiemetics and painkillers, level of mobility and diet. These causes of constipation would not respond to a PAMORA and in some cases would not respond to a conventional laxative. The clinical expert also explained that the frequency of bowel motions is not as important to patients as other symptoms of opioid-induced constipation such as bloating, straining and incomplete evacuations, which affect the patient's quality of life.
Not to be used for commercial purposes The information in this review is believed to be true and accurate. It is issued on the understanding that it is the best available from the resources at our disposal at the time of issue DPS102 Published: December 2020 Version: 1.0 Page 1 DRUG PROFILE cont’d
Opioids may also affect other functions in the gut, causing symptoms such as nausea and gastroparesis. The expert explained that PAMORAs not only increase the frequency of bowel movements but also help to manage these other side effects of opioids. The committee concluded that the increase in quality of life for people whose constipation had a response to naldemedine compared with placebo includes relief of other opioid- induced symptoms, which may be directly or indirectly related to constipation.2
Safety - Adverse effects: The most commonly reported adverse reactions in patients with chronic non-cancer pain and OIC were abdominal pain (7.8%), diarrhoea (5.9%), nausea (3.6%), and vomiting (1.1%). The majority of these gastrointestinal adverse reactions were of mild to moderate severity and resolved without discontinuation of naldemedine treatment. One serious case of abdominal pain and one serious case of nausea were reported in patients with chronic non-cancer pain and OIC. The most commonly reported adverse reactions in patients with cancer and OIC were diarrhoea (24.5%) and abdominal pain (3.9%). The majority of these gastrointestinal adverse reactions were of mild to moderate severity and resolved with treatment. Two serious cases of diarrhoea were reported in patients with cancer and OIC.1
Cautions - Gastrointestinal perforation: Cases of gastrointestinal perforation have been reported in the post-marketing setting, including fatal cases, when naldemedine was used in patients who were at an increased risk of gastrointestinal (GI) perforation, (e.g. diverticular disease and underlying malignancies of the gastrointestinal tract or peritoneal metastases). Naldemedine must not be used in patients with known or suspected GI obstruction or in patients at increased risk of recurrent obstruction, due to the potential for GI perforation. 1 Opioid withdrawal syndrome: Opioid withdrawal syndrome is a cluster of three or more of the following signs or symptoms: dysphoric mood, nausea or vomiting, muscle aches, lacrimation or rhinorrhoea, pupillary dilation or piloerection or sweating, diarrhoea, yawning, fever or insomnia. Opioid withdrawal syndrome typically develops within minutes to several days following administration of an opioid antagonist. Caution should be exercised with regards to opioid withdrawal. Patients should be advised to discontinue naldemedine and to contact their physician if opioid withdrawal occurs. Cases of possible opioid withdrawal syndrome have been reported in the naldemedine clinical programme. 1 Patients having disruptions to the blood-brain barrier (e.g., primary brain malignancies, central nervous system (CNS) metastases or other inflammatory conditions, active multiple sclerosis and advanced Alzheimer's disease) may be at increased risk of opioid withdrawal or reduced analgesia. The overall benefit-risk of naldemedine should be considered in these patients with close monitoring for symptoms of opioid withdrawal.1 Patients with cardiovascular conditions: Naldemedine was not studied in the clinical trial programme in patients who had a recent history of myocardial infarction, stroke or transient ischaemic attack within 3 months of screening. These patients should be clinically monitored when taking Rizmoic®.1 Elderly patients (≥ 65 years old): No dose adjustment is required in patients older than 65 years of age Due to the limited therapeutic experience in patients 75 years old and older, naldemedine therapy should be initiated with caution in this age group.1 Renal impairment: No dose adjustment is required in patients with renal impairment Due to the limited therapeutic experience, patients with severe renal impairment should be clinically monitored when initiating therapy with naldemedine.1 Hepatic impairment: No dose adjustment is required in patients with mild or moderate hepatic impairment. Use in patients with severe hepatic impairment is not recommended.1
Pregnancy: There are no data from the use of naldemedine in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. The use of naldemedine during pregnancy may precipitate opioid withdrawal in a foetus due to the immature foetal blood brain barrier. Naldemedine should not be used during pregnancy unless the clinical condition of the woman requires treatment with naldemedine. Breast-feeding: It is unknown whether naldemedine/metabolites are excreted in human milk. Available data in rats have shown excretion of naldemedine in milk. At therapeutic doses, most opioids (e.g. morphine, meperidine, methadone) are excreted into breast milk in minimal amounts. There is a theoretical possibility that naldemedine provokes opioid withdrawal in a breast-fed neonate whose mother is taking an opioid receptor agonist. A risk to the suckling child cannot be excluded. Naldemedine should not be used during breast-feeding. Contraindications - Hypersensitivity to the active substance or to any of the excipients contained in naldemedine tablets. Patients with known or suspected gastrointestinal obstruction or perforation or patients at increased risk of recurrent obstruction, due to the potential for gastrointestinal perforation.
Interactions - Naldemedine is primarily metabolised by CYP3A with some contribution from UGT1A3 and is a substrate of P-glycoprotein (P-gp).
Concomitant use of naldemedine with strong CYP3A inhibitors (e.g. grapefruit juice, itraconazole, ketoconazole, ritonavir, indinavir, saquinavir, telithromycin and clarithromycin) leads to an increase in naldemedine exposure and may increase the risk of adverse reactions. Concomitant use with strong CYP3A inhibitors should be avoided. Concomitant use of naldemedine with strong CYP3A inducers (e.g. St. John's wort (Hypericum perforatum), rifampicin, carbamazepine, phenobarbital and phenytoin) leads to a decrease in naldemedine exposure and may reduce the efficacy of naldemedine. Concomitant use with strong CYP3A inducers is not recommended. Concomitant use of naldemedine with moderate CYP3A inducers (e.g. efavirenz) has not been established and should be used with caution.1 Concomitant use of P-gp inhibitors such as cyclosporin may increase plasma concentrations of naldemedine. If naldemedine is used with strong P-gp inhibitors, monitor for adverse reactions.
Not to be used for commercial purposes The information in this review is believed to be true and accurate. It is issued on the understanding that it is the best available from the resources at our disposal at the time of issue DPS102 Published: December 2020 Version: 1.0 Page 2 CURRENT PLACE IN THERAPY
National Institute for Clinical Excellence (NICE): Naldemedine is recommended, within its marketing authorisation, as an option for treating opioid- induced constipation in adults who have had laxative treatment.3 NICE CKS recommends for OIC: - Do not prescribe bulk-forming laxatives. - Offer an osmotic laxative and a stimulant laxative (or docusate is an alternative which also has stool-softening properties).4
Scottish medicines Consortium (SMC): For the treatment of opioid-induced constipation in adult patients who have previously been treated with a laxative.5 Summary • The treatment of OIC depends on whether the opioid is the only cause of the constipation or if there are other contributing factors (mixed aetiology constipation). Treatment may include a PAMORA alone, however commonly a PAMORA and a conventional laxative are used together. Naldemedine is an oral PAMORA for adults who have had laxative treatment. • Inadequate response to laxative needs to be defined. • Relevant comparators include other licensed PAMORAs, subcutaneous methylnaltrexone (Relistor®) and oral naloxegol (Moventig®). Methylnaltrexone and naloxegol are licensed for the treatment of OIC when response to laxative therapy has been inadequate, including cancer and non-cancer patients. Limitations to the use of methylnaltrexone include the route of administration and complex dosing regimen. Naloxegol would be the closest comparator since it is the only other oral PAMORA available. However, in contrast to naldemedine, naloxegol has not been specifically studied in OIC patients with cancer-related pain, and caution is advised when prescribed and used in this population6. • Other drugs used in constipation, for which efficacy in OIC has been evaluated, include prucalopride and linaclotide. It should be noted that clinical development of prucalopride for OIC was stopped for commercial reasons, while data on the use of linaclotide have not yet been published. At present, these agents are not specifically licensed for OIC.6 • To date, no head-to-head trials have been conducted • There is no specific guidance on OIC. When standard laxatives do not adequately relieve OIC, treatment with PAMORAs have been shown to be more effective than placebo. Naldemedine may offer an alternative option to other PAMORAs for patients previously treated with laxatives.
References: 1. Summary of product characteristics. Rizmoic 200micrograms film-coated tablets. Last revised 30/1/20. Available from www.medicines.org.uk
Not to be used for commercial purposes The information in this review is believed to be true and accurate. It is issued on the understanding that it is the best available from the resources at our disposal at the time of issue DPS102 Published: December 2020 Version: 1.0 Page 3