Kontraindikasjoner

• Pasienter med kjent eller mistenkt gastrointestinal obstruksjon, perforasjon eller pasienter med økt risiko for tilbakevendende obstruksjon, grunnet fare for gastrointestinal perforasjon (se pkt. 4.4 i SPC).

Forsiktighetsregler

Det skal utvises forsiktighet ved bruk av naldemedin hos pasienter med tilstander som eventuelt kan medføre redusert integritet i gastrointestinaltraktus.

Pasienter skal rådes til å rapportere sterke, vedvarende eller forverrede symptomer på gastrointestinale bivirkninger.

• Bruk av naldemedin anbefales ikke til pasienter med alvorlig nedsatt leverfunksjon (se pkt. 4.2 i SPC).

Les mer om Rizmoic^® (naldemedin) på Felleskatalogen.no

NO-RIZM-2024-00008 | 11-2024

• 1 tablett daglig
• Med eller uten mat
• Anbefalt til samme tid hver dag
• Med eller uten laksantia

Behandling innledes med forsiktighet hos pasienter ≥75 år.

Pasienter med alvorlig nedsatt nyrefunksjon overvåkes innledningsvis (se pkt. 4.4 i SPC).

NO-RIZM-2024-00009 | 11-2024

 

Rizmoic er indisert til behandling av opioidindusert forstoppelse hos voksne som tidligere har blitt behandlet med et laksativ.

NO-RIZM-2024-00010 | 11-2024

Opioider spiller fortsatt en sentral rolle i behandlingen av både sterke kroniske og akutte smerter. Dette til tross for at bruk av opioider fører til betydelige bivirkninger:

• En viktig bivirkning å være oppmerksom på er opioidindusert forstoppelse, OIC, som rammer over 50 % av pasienter med kreftrelaterte smerter og 40 % av de med ikke-maligne smerter.¹

 Rizmoic^® er et nytt legemiddel for behandling av OIC. Pasientene kan behandles for å unngå forstoppelse forårsaket av opioidbruk uten at det påvirker de smertelindrende effektene av opioider.

Utfordringen med opioidindusert forstoppelse

Forstoppelse er en kjent bivirkning ved opioidbehandling.³ Opioider gir smertestillende effekt ved å binde seg til µ-opioidreseptorer i sentralnervesystemet.² Reseptorene er også til stede i mage-tarmkanalen.⁴ Når opioider binder seg til disse reseptorene i tarmen, hemmer de tarmens peristaltikk, noe som fører til forstoppelse. Opioidindusert forstoppelse er vist å påvirke pasientens livskvalitet i stor grad, samt å kunne påvirke selve smertebehandlingen.³

Virkemåten til Rizmoic

Rizmoic^® er et legemiddel spesifikt utviklet for behandling av opioidindusert forstoppelse, OIC.⁵ Virkestoffet naldemedin, er en perifert virkende μ-opioidreseptorantagonist (PAMORA) og binder seg til my-, delta- og kappa-opioidreseptorene i mage-tarm.⁵ 

Rizmoic^® er utviklet slik at det i svært liten grad krysser blod-hjernebarrieren. Selektiviteten til perifere opioidreseptorer sikrer at legemidlet ikke forstyrrer opioiders smertelindrende effekt i sentralnervesystemet.^5,6

Naldemedin er et derivat av naltrekson, modifisert med en ekstra sidekjede som fører til større molekylmasse og polart overflateareal⁵, noe som øker spesifisiteten for perifere opioidreseptorer. Samtidig hemmes passasje til sentralnervesystemet, det er avgjørende for å opprettholde den smertestillende effekten av opioid-behandlingen. I tillegg er naldemedin et substrat for efflukstransportøren P-glykoprotein (P-gp), som spiller en rolle i å begrense molekylets passasje inn i sentralnerve-systemet.⁵ Naldemedin passerer i ubetydelig grad over i sentralnervesystemet ved anbefalte doser. Disse egenskapene sikrer at legemidlet kun påvirker reseptorene som styrer tarmfunksjonen, uten å påvirke reseptorene som regulerer smerte.^5,6

Kliniske konsekvenser ved bruk av Rizmoic^®

Ved effektivt å hemme forstoppelse uten å påvirke de smertestillende effektene av opioider, kan Rizmoic^® forbedre pasientens mulighet til å følge den foreskrevne smertebehandlingen.

Kliniske studier har vist at Rizmoic^® effektivt lindrer symptomer på OIC.^7,8,9 Pasientene rapporterer om forbedret tarmfunksjon, redusert ubehag og en generelt bedre livskvalitet. Disse fordelene kan være betydelige for pasienter som skal stå på opioider for langvarig smertebehandling.

• Det er en risiko for at pasienter slutter med opioider fordi de gastrointestinale bivirkningene oppleves mer ubehagelige enn den opprinnelige smerten.  

Det er vist i studiene at Rizmoic^®har en gunstig sikkerhetsprofil.^7,8,9 Den minimale absorpsjon av legemidlet til sentralnervesystemet begrenser risikoen for potensielle bivirkninger forbundet med tradisjonelle opioidantagonister, som symptomer på opioidabstinens eller redusert smertelindring.¹⁰

Integrering av Rizmoic^® i klinisk praksis

God pasientbehandling inkluderer å informere pasientene om potensielt negative aspekter ved opioidbehandling, inkludert forstoppelse.¹¹ Ved å følge opp behandlingen og be pasienten beskrive opplevd effekt og/eller bivirkninger, kan du gi pasientene en mulighet til å ta en aktiv rolle i behandlingen og sette inn tidlige tiltak for å lindre gastrointestinale bivirkninger.

Oppsummert

Rizmoic^® er en perifer reseptorantagonist med målrettet virkningsmekanisme mot opioidindusert forstoppelse, og er et svært godt alternativ til tradisjonelle avføringsmidler til opioidpasienter.

NO-RIZM-2024-00007 | 11-2024

 

Opioid-induced constipation (OIC) remains a significant challenge in the management of chronic non-cancer pain, affecting patient compliance and quality of life. Naldemedine, a peripherally acting μ-opioid receptor antagonist, offers a promising solution by selectively blocking opioid effects in the gastrointestinal tract without impacting central analgesia. This article delves into the results of two pivotal phase 3 trials, COMPOSE-1 and COMPOSE-2, evaluating the efficacy and safety of naldemedine in managing OIC.

Study design

Both COMPOSE-1 and COMPOSE-2 were multicenter, phase 3, randomized, double-blind, placebo-controlled trials conducted across several countries including the USA and parts of Europe. The primary objective was to evaluate the efficacy of naldemedine compared to placebo in alleviating constipation symptoms in adults receiving stable opioid dosages for chronic non-cancer pain, who had discontinued all other laxative treatments. The primary endpoint was the proportion of responders, defined by an increase in weekly spontaneous bowel movements (SBMs).

Participants were adults aged 18 to 80 years who had been on a stable opioid regimen and exhibited fewer than four spontaneous bowel movements per week, among other criteria. They were randomized in a 1:1 ratio to receive either 0.2 mg of naldemedine or a matching placebo once daily for 12 weeks, following a 2–4 week screening phase. Randomization was stratified based on the average total daily opioid dose into two categories: 30–100 mg and over 100 mg of oral morphine sulphate equivalents.

The trials collectively enrolled over 1,100 participants, with COMPOSE-1 and COMPOSE-2 including 547 and 553 patients respectively. These participants had demonstrated clinical signs of OIC and had not used any laxatives or were willing to discontinue such treatments during the study period.

Efficacy outcomes

The primary efficacy endpoint was the percentage of patients achieving at least three spontaneous bowel movements per week, with an increase of at least one bowel movement per week over baseline for at least 9 of the 12 weeks of the trial, including 3 of the last 4 weeks.

• COMPOSE-1: The naldemedine group showed a significantly higher percentage of responders (47.6%) compared to the placebo group (34.6%), with a statistical significance of p=0.0020.
• COMPOSE-2: Similarly, a higher responder rate was observed in the naldemedine group (52.5%) compared to placebo (33.6%), with p < 0.0001.

These results highlighted the effectiveness of naldemedine in improving bowel function among patients suffering from OIC due to opioid therapy.

Adapted by Viatris from Hale et al (2017)

Safety and tolerability

The safety profile of naldemedine was closely monitored throughout the trials, with particular attention given to treatment-emergent adverse events (TEAEs). The most common TEAEs included gastrointestinal symptoms such as abdominal pain and diarrhea, which were generally mild to moderate in severity.

• In COMPOSE-1, 49% of the naldemedine group experienced any TEAEs, compared to 45% in the placebo group.
• In COMPOSE-2, these figures were 50% for naldemedine and 48% for placebo.

The incidence of serious TEAEs was low and comparable between the naldemedine and placebo groups across both trials. Importantly, there was no significant impact on opioid-mediated analgesia, nor was there a notable increase in opioid withdrawal symptoms, underscoring the peripheral specificity of naldemedine.

Created by Viatris based on Hale et al (2017)

Clinical implications

The results from COMPOSE-1 and COMPOSE-2 suggest that naldemedine is an effective and safe option for the management of OIC in patients with chronic non-cancer pain. Its ability to improve bowel function without affecting central opioid effects represents a significant advantage over traditional laxatives, which do not target the underlying pathophysiology of OIC.

For healthcare professionals managing patients with chronic pain, naldemedine offers a clinically validated option to alleviate the burdensome symptoms of OIC. Its once-daily oral dosing can be easily integrated into most patient routines, potentially improving compliance and overall quality of life. Yet, it is important to consider individual patient profiles and potential interactions with other medications due to naldemedine's mechanism of action involving P-glycoprotein substrates.

Conclusion

Naldemedine has been shown to relieve constipation in patients following opioid treatment for chronic non-cancer pain. The COMPOSE-1 and COMPOSE-2 trials underscore its efficacy and safety profile, supporting its use as a targeted treatment option that can improve patient outcomes and quality of life as discussed in Camilleri's paper. Healthcare providers should consider naldemedine as a key component of the therapeutic arsenal for managing OIC in patients undergoing long-term opioid therapy for non-cancer pain.

NO-RIZM-2024-00001 | 11-2024

Opioid-induced constipation (OIC) is a prevalent and debilitating side effect experienced by patients undergoing long-term opioid therapy. The COMPOSE-3 trial 1 was designed to assess the long-term safety and efficacy of naldemedine, a peripherally acting μ-opioid receptor antagonist, over a 52-week period, providing critical insights into its use in clinical practice.

Study design

The primary goal of COMPOSE-3 was to evaluate the long-term safety and efficacy of naldemedine in adults with chronic non-cancer pain who have been receiving a stable opioid dose for over a month and who have opioid-induced constipation. This trial aimed to establish whether naldemedine could be safely administered over an extended period without diminishing its efficacy or altering the primary analgesic treatment.

COMPOSE-3 was a multicenter, phase 3, double-blind, randomized, parallel-group trial involving 1246 participants. These participants were randomly assigned in a 1:1 ratio to receive either 0.2 mg of naldemedine or a matching placebo orally once per day for 52 weeks following a screening period of 14-28 days. Randomization was stratified based on the total mean daily opioid dose during the 14-day qualifying period, categorized into 30–100 mg and greater than 100 mg oral morphine sulfate equivalents.

Participants ranged in age from 18 to 80 years, all suffering from chronic non-cancer pain and stable opioid use, with a stratification based on total mean daily dose of opioid during the 14-consecutive-day qualifying period. This diverse population provided a broad basis for evaluating the effects of naldemedine across various demographics. The inclusion criteria ensured that all participants had experienced fewer than four spontaneous bowel movements per week during the qualification period, indicating moderate to severe OIC.

Results

The primary efficacy endpoint was the frequency of occurrence of adverse reactions, including the incidence of treatment-emergent adverse events (TEAEs), serious adverse events, and adverse events leading to treatment discontinuation. The trial's results were pivotal in understanding the long-term tolerability of naldemedine.

• Safety and tolerability: Naldemedine demonstrated a safety profile consistent with previous shorter-term studies. TEAEs were reported in 68.4% of the naldemedine group compared to 72.1% in the placebo group (difference of proportion: 23.6%; 95% confidence interval: 28.7 to 1.5;), showing no significant increase in adverse effects due to long-term treatment.
• Treatment discontinuations: TEAEs leading to discontinuation were slightly higher in the naldemedine group (6.3%) compared to the placebo group (5.8%), indicating that naldemedine was generally well tolerated.
• Gastrointestinal disorders: As expected with a drug targeting opioid receptors in the gut, gastrointestinal disorders were the most commonly reported adverse events. However, these did not lead to a significant increase in discontinuation rates, suggesting that they were manageable within the clinical context.

Adapted by Viatris from Webster et al, 2018

Clinical implications

The findings from COMPOSE-3 provide compelling evidence supporting the long-term use of naldemedine for managing OIC in patients with chronic non-cancer pain. Importantly, the trial confirmed that naldemedine does not interfere with opioid-mediated analgesia nor does it precipitate opioid withdrawal, addressing two critical concerns in OIC management.

The ability to use naldemedine over an extended period without significant safety concerns or loss of efficacy offers a viable long-term solution for patients suffering from OIC.

This study supports the addition of naldemedine to a patient’s laxative regimen should patients still experience OIC.

Conclusion

The COMPOSE 3 trial was a double-blind, randomized, parallel-group trial offering robust data on the long-term use of naldemedine for the management of OIC. By demonstrating sustained safety and efficacy over a one-year period, naldemedine provides a promising option for enhancing the quality of life in patients with chronic non-cancer pain undergoing long-term opioid therapy. For clinicians, incorporating naldemedine into treatment protocols can significantly mitigate one of the most challenging side effects of opioid therapy, thereby improving overall treatment outcomes.

NO-RIZM-2024-00002 | 11-2024

The COMPOSE-4 trial was specifically designed to evaluate the efficacy and safety of naldemedine, a peripherally acting μ-opioid receptor antagonist, in alleviating OIC in this vulnerable population.

Study design

The main goal of COMPOSE-4 was to demonstrate the efficacy of naldemedine compared to placebo in treating OIC in adults with cancer pain, after a 14-day course of treatment. COMPOSE-4 was a multicenter, phase 3, double-blind, randomized, parallel-group trial conducted over two weeks. It involved 193 cancer patients who were on a stable daily dose of opioids and experiencing significant constipation as a result. Participants were randomized in a 1:1 ratio to receive either 0.2 mg of naldemedine or a placebo tablet once per day.

The inclusion criteria targeted adult cancer patients aged 20 years and older who had been receiving a stable dose of opioids for at least 2 weeks prior to randomization. These patients had a history of five or fewer spontaneous bowel movements over the 14 days before randomization, with significant constipation symptoms such as straining, incomplete evacuation, or hard stools.

Patients were required to continue their regular laxative regimen without any changes throughout the screening and treatment phases. However, if an adverse event, such as diarrhea, significantly affected the patient's quality of life, the investigator could permit a temporary halt or reduction in the laxative dosage. Additionally, patients were allowed to use rescue laxatives as necessary, except for the 24 hours before and after administering the initial dose of the study medication.

Efficacy outcomes

The primary endpoint of the trial was the proportion of patients achieving ≥3 spontaneous bowel movements (SBMs) per week with an increase of at least 1 SBM per week compared to baseline. This measure directly assessed the effectiveness of naldemedine in enhancing bowel function over the treatment period.

A significant difference was observed in the proportion of SBM responders between the naldemedine and placebo groups. Approximately 71.1% of patients in the naldemedine group met the primary endpoint compared to only 34.4% in the placebo group, with a p-value of <0.0001.

Image adapted by Viatris from Katakami et al (2017)

Safety and tolerability

Safety was a critical component of the trial, given the vulnerable condition of the patient population. The safety assessments focused on the frequency of adverse events, particularly gastrointestinal disorders, which were the most pertinent to the treatment.

• Overall incidence: Adverse events were reported in 44.3% of patients in the naldemedine group compared to 26% in the placebo group. The higher incidence in the naldemedine group was anticipated due to its pharmacological action on the gastrointestinal system.
• Discontinuations due to adverse events: A small percentage of patients discontinued treatment due to adverse events, with 9.3% in the naldemedine group and 1% in the placebo group. This reflected the generally well-tolerated nature of the treatment despite the higher incidence of adverse events.

Image adapted by Viatris from Katakami et al (2017)

Clinical implications

The COMPOSE-4 trial demonstrated that naldemedine effectively and rapidly improves bowel function in cancer patients suffering from OIC. The substantial difference in response rates between the naldemedine and placebo groups demonstrate the potential of naldemedine to provide significant relief from constipation.

For oncologists and palliative care professionals, the results from COMPOSE-4 offer a promising therapeutic option for managing OIC in cancer patients. Naldemedine may provide relief of the OIC that can help patients continue their prescribed opioid regimen effectively.

Conclusion

COMPOSE-4 adds valuable knowledge to the field of pain management in oncology, demonstrating that naldemedine is an effective and rapid treatment for OIC in cancer patients. This trial shows the potential for naldemedine to address acute constipation issues, facilitating better overall patient management in cancer pain therapy.

For more information on uncommon or rare side effects, see the Summary of Product Characteristics.

NO-RIZM-2024-00003 | 11-2024