Source: European Medicines Agency (EU) Revision Year: 2017 Publisher: PharmaSwiss Česká republika s.r.o., Jankovcova 1569/2c, 170 00, Praha 7, Czech republic
Pharmacotherapeutic group: Laxatives, Peripheral opioid receptor antagonists
ATC code: A06AH01
Methylnaltrexone bromide is a selective antagonist of opioid binding at the mu-receptor. In vitro studies have shown methylnaltrexone bromide to be a mu-opioid receptor antagonist (inhibition constant [Ki]=28 nM), with 8-fold less potency for kappa opioid receptors (Ki=230 nM) and much reduced affinity for delta opioid receptors.
As a quaternary amine, the ability of methylnaltrexone bromide to cross the blood-brain barrier is restricted. This allows methylnaltrexone bromide to function as a peripherally acting mu-opioid antagonist in tissues such as the gastrointestinal tract, without impacting opioid-mediated analgesic effects on the central nervous system.
The efficacy and safety of methylnaltrexone bromide in the treatment of opioid-induced constipation in patients with chronic non-cancer pain were demonstrated in a randomized, double-blind, placebo-controlled study (Study 3356). In this study, the median patient age was 49 years (range 23-83); 60% were females. The majority of patients had a primary diagnosis of back pain.
Study 3356 compared 4-week treatment regimens of methylnaltrexone bromide 12 mg once daily and methylnaltrexone bromide 12 mg every other day with placebo. The 4-week, double-blind period was followed by an 8-week, open-label period during which methylnaltrexone bromide was to be used as needed, but no more frequently than once daily. A total of 460 patients (methylnaltrexone bromide 12 mg once daily, n=150, methylnaltrexone bromide 12 mg every other day, n=148, placebo, n=162) were treated in the double-blind period. Patients had a history of chronic non-cancer pain and were taking opioids with stable doses of at least 50 mg of oral morphine equivalents per day. Patients had opioid-induced constipation (<3 rescue medication-free bowel movements per week during the screening period). Patients were required to discontinue all previous laxative therapy.
The first co=primary endpoint was the proportion of patients having a rescue free bowel movements (RFBMs) within 4 hours of the first dose administration and the second the percentage of active injections resulting in any RFBM within 4 hours during the double-blind phase. A RFBM was defined as a bowel movement that occurred without laxative use during the previous 24 hours.
The proportion of patients having an RFBM within 4 hours of the first dose was 34.2% in the combined methylnaltrexone bromide group versus 9.9% in the placebo group (p<0.001). The mean percentage of methylnaltrexone bromide resulting in any RFBM within 4 hours were 28.9% and 30.2% respectively for the once daily and every other day dose groups compared with 9.4% and 9.3% respectively for the corresponding placebo regimen (p < 0.001).
The key secondary endpoint of adjusted mean change from baseline in weekly RFBMs was 3.1 in the methylnaltrexone bromide 12 mg once daily treatment group, 2.1 in the methylnaltrexone bromide 12 mg every other day treatment group, and 1.5 in the placebo treatment group during the 4-week double-blind period. The difference between methylnaltrexone bromide 12 mg once daily and placebo of 1.6 RFBMs per week is statistically significant (p < 0.001) and clinically meaningful.
Another secondary endpoint evaluated the proportion of patients with ≥3 RFBMs per week during the 4-week double-blind phase. This was achieved in 59% of the patients in the group receiving daily methylnaltrexone 12 mg (p<0.001 vs. placebo), in 61% of those receiving it every other day (p<0.001 vs. placebo), and in 38% of the placebo treated patients. A supplementary analysis evaluated the percentage of patients achieving ≥3 complete RFBMs per week and an increase of ≥1 complete RFBMs per week in at least 3 of the 4 treatment weeks. This was achieved in 28.7% of the patients in the group receiving daily methylnaltrexone 12 mg (p<0.001 vs. placebo), in 14.9% of those receiving it every other day (p=0.012 vs. placebo), and in 6.2% of the placebo treated patients.
There was no evidence of a differential effect of gender on safety or efficacy. The effect on race could not be analysed because the study population was predominantly Caucasian (90%). Median daily opioid dose did not vary meaningfully from baseline in either methylnaltrexone bromide-treated patients or in placebo-treated patients.
There were no clinically relevant changes from baseline in pain scores in either the methylnaltrexone bromide or placebo-treated patients.
The use of methylnaltrexone bromide for treating opioid-induced constipation beyond 48 weeks has not been evaluated in clinical trials.
The efficacy and safety of methylnaltrexone bromide in the treatment of opioid-induced constipation in patients receiving palliative care was demonstrated in two randomised, double-blind, placebo- controlled studies. In these studies, the median age was 68 years (range 21-100); 51% were females. In both studies, patients had advanced terminal illness and limited life expectancy, with the majority having a primary diagnosis of incurable cancer; other primary diagnoses included end-stage COPD/emphysema, cardiovascular disease/heart failure, Alzheimer’s disease/dementia, HIV/AIDS, or other advanced illnesses. Prior to screening, patients had opioid-induced constipation defined as either <3 bowel movements in the preceding week or no bowel movement for >2 days.
Study 301 compared methylnaltrexone bromide given as a single, double-blind, subcutaneous dose of 0.15 mg/kg, or 0.3 mg/kg versus placebo. The double-blind dose was followed by an open-label, 4-week dosing period, where methylnaltrexone bromide could be used as needed, no more frequently than 1 dose in a 24-hour period. Throughout both study periods, patients maintained their usual laxative regimen. A total of 154 patients (methylnaltrexone bromide 0.15 mg/kg, n=47; methylnaltrexone bromide 0.3 mg/kg, n=55, placebo, n=52) were treated in the double-blind period.
The primary endpoint was the proportion of patients with a rescue-free laxation within 4 hours of the double-blind dose of study medicinal product. Methylnaltrexone bromide-treated patients had a significantly higher rate of laxation within 4 hours of the double-blind dose (62% for 0.15 mg/kg and 58% for 0.3 mg/kg) than placebo-treated patients (14%); p<0.0001 for each dose versus placebo.
Study 302 compared double-blind, subcutaneous doses of methylnaltrexone bromide given every other day for 2 weeks versus placebo. During the first week (days 1, 3, 5, 7), patients received either methylnaltrexone bromide 0.15 mg/kg or placebo. In the second week, a patient’s assigned dose could be increased to 0.30 mg/kg if the patient had 2 or fewer rescue-free laxations up to day 8. At any time, the patient’s assigned dose could be reduced based on tolerability. Data from 133 (62 methylnaltrexone bromide, 71 placebo) patients were analysed. There were 2 primary endpoints: proportion of patients with a rescue-free laxation within 4 hours of the first dose of study medicinal product and proportion of patients with a rescue-free laxation within 4 hours after at least 2 of the first 4 doses of medicinal product. Methylnaltrexone bromide-treated patients had a higher rate of laxation within 4 hours of the first dose (48%) than placebo-treated patients (16%); p<0.0001. Methylnaltrexone bromide-treated patients also had significantly higher rates of laxation within 4 hours after at least 2 of the first 4 doses (52%) than did placebo-treated patients (9%); p<0.0001. Stool consistency was not meaningfully improved in patients who had soft stool at baseline.
In both studies, there was no evidence to suggest differential effects of age or gender on safety or efficacy. The effect on race could not be analysed because the study population was predominantly Caucasian (88%).
Durability of response was demonstrated in Study 302, in which the laxation response rate was consistent from dose 1 through dose 7 over the course of the 2-week, double-blind period.
The efficacy and safety of methylnaltrexone bromide were also demonstrated in open-label treatment administered from Day 2 through Week 4 in Study 301, and in two open-label extension studies (301EXT and 302EXT) in which methylnaltrexone bromide was given as needed for up to 4 months (only 8 patients up to this point). A total of 136, 21, and 82 patients received at least one open-label dose in studies 301, 301EXT, and 302EXT, respectively. Relistor was administered every 3.2 days (median dosing interval, with a range of 1-39 days).
The rate of laxation response was maintained throughout the extension studies for those patients who continued treatment.
There was no significant relationship between baseline opioid dose and laxation response in methylnaltrexone bromide-treated patients in these studies. In addition, median daily opioid dose did not vary meaningfully from baseline in either methylnaltrexone bromide-treated patients or in placebo- treated patients. There were no clinically relevant changes in pain scores from baseline in either the methylnaltrexone bromide or placebo-treated patients.
In a double-blind, randomised, parallel-group ECG study of single, subcutaneous doses of methylnaltrexone bromide (0.15, 0.30 and 0.50 mg/kg), in 207 healthy volunteers, no signal of QT/QTc prolongation or any evidence of an effect on secondary ECG parameters or waveform morphology was detected as compared to placebo and a positive control (orally administered 400 mg moxifloxacin).
Methylnaltrexone bromide is absorbed rapidly, with peak concentrations (Cmax) achieved at approximately 0.5 hours following subcutaneous administration. The Cmax and area under the plasma concentration-time curve (AUC) increase with dose increase from 0.15 mg/kg to 0.5 mg/kg in a dose-proportional manner. Absolute bioavailability of a 0.30 mg/kg subcutaneous dose versus a 0.30 mg/kg intravenous dose is 82%.
Methylnaltrexone bromide undergoes moderate tissue distribution. The steady-state volume of distribution (Vss) is approximately 1.1 L/kg. Methylnaltrexone bromide is minimally bound to human plasma proteins (11.0% to 15.3%) as determined by equilibrium dialysis. Biotransformation Methylnaltrexone bromide is metabolised to a modest extent in humans based on the amount of methylnaltrexone bromide metabolites recovered from excreta. Conversion to methyl-6-naltrexol isomers and methylnaltrexone sulphate appears to be the primary pathway to metabolism. Each of the methyl-6-naltrexol isomers has somewhat less antagonist activity than parent compound, and a low exposure in plasma of approximately 8% of the drug-related materials. Methylnaltrexone sulphate is an inactive metabolite and present in plasma at a level of approximately 25% of drug related materials. N-demethylation of methylnaltrexone bromide to produce naltrexone is not significant, accounting for 0.06% of the administered dose.
Methylnaltrexone bromide is eliminated primarily as the unchanged active substance. Approximately half of the dose is excreted in the urine and somewhat less in faeces. The terminal disposition half-life (t1/2) is approximately 8 hours.
The effect of mild and moderate hepatic impairment on the systemic exposure to methylnaltrexone bromide has been studied in 8 subjects each, with Child-Pugh Class A and B, compared to healthy subjects. Results showed no meaningful effect of hepatic impairment on the AUC or Cmax of methylnaltrexone bromide. The effect of severe hepatic impairment on the pharmacokinetics of methylnaltrexone bromide has not been studied.
In a study of volunteers with varying degrees of renal impairment receiving a single dose of 0.30 mg/kg methylnaltrexone bromide, renal impairment had a marked effect on the renal excretion of methylnaltrexone bromide. The renal clearance of methylnaltrexone bromide decreased with increasing severity of renal impairment. Severe renal impairment decreased the renal clearance of methylnaltrexone bromide by 8- to 9-fold; however, this resulted in only a 2-fold increase in total methylnaltrexone bromide exposure (AUC). Cmax was not significantly changed. No studies were performed in patients with end-stage renal impairment requiring dialysis.
No studies have been performed in the paediatric population (see section 4.2).
In a study comparing single and multiple-dose pharmacokinetic profiles of intravenous methylnaltrexone bromide at a dose of 24 mg between healthy, young (18 to 45 years of age n=10) and elderly (65 years of age and over n=10) subjects, the effect of age on exposure to methylnaltrexone bromide was found to be minor. The mean steady-state Cmax and AUC for the elderly were 545 ng/mL and 412 ng•h/mL, approximately 8.1% and 20%, respectively, greater than those for young subjects. Therefore, no dose adjustment is recommended based on age.
No meaningful gender differences have been observed.
An integrated analysis of pharmacokinetic data from healthy subjects indicated that methylnaltrexone bromide mg/kg dose-adjusted exposure increased as body weight increased. The mean methylnaltrexone bromide exposure at 0.15 mg/kg over a weight range of 38 to 114 kg was 179 (range=139-240) ng•h/mL. This exposure for the 0.15 mg/kg dose can be achieved with a weight-band-based dose adjustment using an 8 mg dose for body weight 38 to less than 62 kg and a 12 mg dose for body weight 62 to 114 kg, yielding a mean exposure of 187 (range=148-220) ng•h/mL. In addition, the analysis showed that 8 mg dose for body weight 38 to less than 62 kg and a 12 mg dose for body weight 62 to 114 kg correspond to mean doses of 0.16 (range=0.21-0.13) mg/kg and 0.16 (range=0.19-0.11) mg/kg, respectively, based on the body weight distribution of patients participating in studies 301 and 302.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential. Cardiac effects were observed in some non-clinical studies in canines (prolongation of action potentials in Purkinje fibers or prolongation of the QTc interval). The mechanism of this effect is unknown; however, the human cardiac potassium ion channel (hERG) appears not to be involved.
Subcutaneous injections of Relistor at 150 mg/kg/day decreased fertility in rats. Doses up to 25 mg/kg/day (18 times the exposure [AUC] in humans at a subcutaneous dose of 0.3 mg/kg) did not affect fertility or general reproductive performance.
There was no evidence of teratogenicity in rats or rabbits. Subcutaneous injections of Relistor at 150/100 mg/kg/day to rats resulted in decreased offspring weights; doses up to 25 mg/kg/day (18 times the exposure [AUC] in humans at a subcutaneous dose of 0.3 mg/kg) had no effect on labour, delivery, or offspring survival and growth.
Methylnaltrexone bromide is excreted via the milk of lactating rats.
Studies have been conducted in juvenile rats and dogs. Following intravenous injection of methylnaltrexone bromide, juvenile rats were found to be more sensitive than adult rats to methylnaltrexone-related toxicity. In juvenile rats administered intravenous methylnaltrexone bromide for 13 weeks, adverse clinical signs (incidences of convulsions and labored breathing) occurred at dosages (≥3 mg/kg/day) and exposures (5.4 times the exposure {AUC} in adult humans at a subcutaneous dose of 0.15 mg/kg) that were lower than those that caused similar toxicity in adult rats (20 mg/kg/day). No adverse effects occurred in juvenile rats at 1 mg/kg/day or in adult rats at 5 mg/kg/day (1.6 times and 7.8 times, respectively, the exposure {AUC} in adult humans at a subcutaneous dose of 0.15 mg/kg).
Following intravenous injection of methylnaltrexone bromide for 13 weeks, similar methylnaltrexone related toxicity was observed in both juvenile and adult dogs. In adult and juvenile dogs given methylnaltrexone bromide at 20 mg/kg/day, clinical signs indicative of CNS toxicity and prolongation of QTc interval were observed. No adverse effects occurred in either juvenile or adult dogs at a dose of 5 mg/kg/day (44 times the exposure {AUC} in adult humans at a subcutaneous dose of 0.15 mg/kg).
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