Summary Basis of Decision for Relistor ™
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
RelistorTM
Methylnaltrexone bromide, 20 mg/mL, Solution, Subcutaneous injection
Wyeth Canada
Submission control no: 114266
Date issued: 2008-12-11
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02308215
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On March 28, 2008, Health Canada issued a Notice of Compliance to Wyeth Canada for the drug product, Relistor.
Relistor contains the medicinal ingredient methylnaltrexone bromide which is a µ-opioid receptor antagonist.
Relistor is indicated for the treatment of opioid-induced constipation in patients with advanced illness, receiving palliative care. When response to laxatives has been insufficient, Relistor should be used as an adjunct therapy to induce a prompt bowel movement. Relistor is not indicated for use in children and adolescents.
Methylnaltrexone is a selective antagonist of opioid binding at the μ-opioid receptor. As a quaternary amine, the ability of methylnaltrexone to cross the blood brain barrier is restricted. This allows methylnaltrexone to function as a peripherally acting μ-opioid antagonist in tissues such as the gastrointestinal tract, without impacting opioid mediated analgesic effects on the central nervous system. Neither opioid withdrawal syndrome nor changes in pain scores were consistently shown in the Relistor treatment group. Furthermore the need to increase opioid dose in either the placebo or Relistor group was not evident.
The market authorization was based on quality, non-clinical, and clinical information submitted. The efficacy and safety of Relistor was evaluated in two double blind, placebo controlled trials in patients receiving palliative care: a single dose trial, and a multiple dose trial. Relistor subcutaneous administration resulted in a higher proportion of patients with rescue-free laxation within 4 hours as compared to placebo treated patients. In addition, the proportion of patients who had a laxation response within 4 hours after at least 2 of the first 4 doses (the first week of treatment) was also higher in the Relistor than in the placebo group. There was no difference in the efficacy or safety profile in elderly patients when compared to younger patients.
Relistor (20 mg/ml, methylnaltrexone bromide) is presented as a solution. Relistor should be administered as a subcutaneous injection in the upper arm, abdomen or thigh. Patients should be seated or recumbent during dosing and care should be taken when the patient stands following dosing. Injections should be administered every other day, as needed. Physicians should consider discontinuing treatment in patients who fail to show an adequate response after 4 doses (1 week). Dosing guidelines are available in the Product Monograph.
Relistor is contraindicated in patients with known or suspected mechanical gastrointestinal obstruction or acute surgical abdomen and in patients who are hypersensitive to Relistor or any of its components. Relistor should not be used for treatment of patients with constipation not related to opioid use. Patients with severe renal impairment should receive half of the recommended dose.
Relistor should be only administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Relistor are described in the Product Monograph.
The drug submission for Relistor was reviewed under the Priority Review Policy. The efficacy and safety and tolerability demonstrated on a background of laxative treatment provides evidence that Relistor could be used as needed in addition to ongoing laxative therapy in advanced illness patients receiving palliative opioid therapy. The results demonstrated that the overall constipation regimen is more effective when it includes Relistor than when it does not (placebo). The benefit to risk ratio is positive in this population.
Based on the review of safety, efficacy and quality data, Health Canada considers that the benefit/risk profile of Relistor is favourable for the treatment of opioid-induced constipation in patients with advanced illness receiving palliative care.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Methylnaltrexone bromide, the medicinal ingredient of Relistor, is a μ-opioid receptor antagonist. Relistor is indicated for the treatment of opioid-induced constipation in patients with advanced illness, receiving palliative care. When response to laxatives has been insufficient, Relistor should be used as an adjunct therapy to induce a prompt bowel movement. Relistor is not indicated for use in children and adolescents.
Methylnaltrexone is a selective antagonist of opioid binding at the μ-opioid receptor. As a quaternary amine, the ability of methylnaltrexone to cross the blood brain-barrier is restricted. This allows methylnaltrexone to function as a peripherally acting μ-opioid antagonist in tissues such as the gastrointestinal tract, without impacting opioid mediated analgesic effects on the central nervous system.
Manufacturing Process and Process Controls
Methylnaltrexone is manufactured via a multi-step synthesis. Each step of the manufacturing process is considered to be controlled within acceptable limits:
- The sponsor has provided information on the quality and controls for all materials used in the manufacture of the drug substance.
- The drug substance specifications are found to be satisfactory. Impurity limits meet ICH requirements.
- The processing steps have been evaluated and the appropriate ranges for process parameters have been established.
Characterization
The structure of methylnaltrexone is considered to be adequately elucidated and the representative spectra have been provided. Physical and chemical properties have been described and are found to be satisfactory.
Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were found to be within ICH established limits and/or were qualified from batch analysis and therefore, are considered to be acceptable.
Control of Drug Substance
The drug substance specifications and analytical methods used for quality control of methylnaltrexone are considered acceptable.
The drug substance packaging is considered acceptable.
Stability
Stability study results based on accelerated and long-term testing show that methylnaltrexone is a stable compound when packaged as proposed over the proposed storage period. The bulk drug is also stable under the proposed storage conditions.
3.1.2 Drug Product
Description and Composition
Relistor (methylnaltrexone bromide) is a clear, colourless to pale yellow, aqueous solution. The drug product is packaged in 3 mL Type I flint glass vials with Flurotec coated grey rubber stoppers.
Relistor contains 20 mg/mL methylnaltrexone bromide and the following inactive ingredients: sodium chloride, edetate calcium disodium, glycine hydrochloride, and sterile water for injection.
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of Relistor with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Pharmaceutical development data, including development of the container closure system, are considered acceptable. Data provided in this section include composition of Relistor, rationale for choice of formulation, manufacturing process including packaging, information on batches used in in vitro studies for characterization and discussion on the effect of formulation change on the safety and/or efficacy of Relistor. Studies which justified the type and proposed concentration of excipients to be used in the drug product were also reviewed and are considered to be acceptable.
Manufacturing Process and Process Controls
Methylnaltrexone bromide is obtained from Mallinckrodt Inc. of St. Louis, MO. Relistor is manufactured and packaged by DSM Pharmaceuticals of Greenville, North Carolina. It is manufactured as a single presentation: vials containing 0.6 mL of solution to provide 12 mg of active substance. The product is sterilized filtered, filled, and stoppered. The formulation is not preserved, and each vial is intended for the administration of a single dose.
The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.
Control of Drug Product
Relistor is tested to verify that the identity, appearance, content uniformity, levels of degradation products, and microbiological impurities are within acceptance criteria. The test specifications and analytical methods are considered acceptable; the shelf-life and the release limits, for individual and total degradation products, are within acceptable limits.
The validation process is considered to be complete. Validation reports were submitted for in-process and release testing of the drug product, and no anomalies were present. The results for all of the batches were within the proposed specification limits.
Stability
The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.
3.1.3 Facilities and Equipment
The design, operations, and controls of the facility and equipment that are involved in the production are considered suitable for the activities and products manufactured.
All of the proposed manufacturing sites comply with the requirements of Division 2 of the Food and Drug Regulations.
All sites are compliant with Good Manufacturing Practices (GMP).
3.1.4 Adventitious Agents Safety Evaluation
Not applicable. None of the components in the Relistor solution are of human or animal origin.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Relistor has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
To assess the effects of methylnaltrexone bromide, 29 in vitro and in vivo studies were conducted to evaluate the primary and secondary pharmacodynamics (PD). These studies were conducted in mice, guinea pigs, rabbits, rats, monkeys, and dogs, with emphasis of methylnaltrexone bromide activity in the gastrointestinal (GI) tract.
Methylnaltrexone bromide is a selective μ-opioid receptor antagonist which is a quaternary derivative of the narcotic antagonist naltrexone. Known opioid antagonists like naltrexone, naloxone, and nalmefene are uncharged tertiary compounds, are lipid soluble, and are able to cross the blood-brain barrier. The addition of the methyl group to naltrexone at the nitrogen position forms methylnaltrexone (or N-methylnaltrexone), an inherently charged compound with greater polarity and lower lipid solubility. Methylnaltrexone bromide is restricted from crossing the blood-brain barrier in animals at clinically relevant doses. Methylnaltrexone bromide binds to isolated human μ-opioid receptors and binds with 8-fold less potency to the kappa receptor. It does not interact with delta receptors or a variety of other receptors in vitro.
GI
Direct antagonism of μ-opioid actions in the gut tissue from animals and humans was observed in several studies. In one in vitro study, methylnaltrexone bromide prevented the inhibition of electrically induced gut contractions in guinea pig ileum by morphine. A concentration of 15 nM (5.3 ng/mL) methylnaltrexone bromide was effective in producing opioid antagonism. In another study, methylnaltrexone bromide prevented morphine-induced inhibition of electrically-stimulated gut contractions of isolated guinea pig ileum and human small intestine. A concentration of 100 nM (35.6 ng/mL) methylnaltrexone bromide was 70% effective in blocking morphine's effect in either preparation.
Pretreatment of rats with methylnaltrexone bromide was found to inhibit morphine-induced slowing of GI transit time while sparing opioid-mediated analgesic effects. Subcutaneous (SC) methylnaltrexone bromide dosages of 1, 4, 8, 16, and 30 mg/kg were significantly active in antagonizing morphine effects. In another study, SC dosages of 1, 3, or 10 mg/kg were also effective, producing a median effective dose (ED50) of 2.5 mg/kg. Attenuation of prostaglandin-induced diarrhea in mice and morphine-induced inhibition of gut electrical activity in dogs were also demonstrated. Methylnaltrexone bromide was shown to reverse opioid-induced emesis in dogs at a dosage of 0.25 mg/kg intramuscularly (IM) or 0.2 mg/kg intravenously (IV). Methylnaltrexone bromide also decreased morphine-induced kaolin intake in rats (a surrogate model for emesis) and reversed morphine-induced cough suppression in guinea pigs. The opioid antagonistic activity of methylnaltrexone bromide at its site of action was transitory and reversible, showing attenuation over a period of 1 to 2 hours after dosing. These studies support the use of methylnaltrexone bromide in the treatment of the peripheral side effects of opioid action and indicate that methylnaltrexone bromide is sufficiently potent to act when administered SC to opioid-treated animals.
Blood-Brain Barrier
Several studies were published, using a variety of animal species to show that peripheral or systemic administration of methylnaltrexone bromide does not interfere with opioid analgesia at dosages that relieve opioid-induced GI side effects. Methylnaltrexone bromide failed to block morphine analgesia in the mouse hot plate test (10 mg/kg SC), the rat hot plate test [10, 30, 100, or 300 mg/kg intraperitoneally (IP) in one study and 1, 4, 8, 16, 30, or 60 mg/kg SC in another study], the rat tail flick assay (10 mg/kg SC), and the guinea pig toe pinch test (0.8, 1.6, or 2 mg/kg IP). This lack of interference with opioid analgesia was not due to a failure of brain opioid receptors to recognize methylnaltrexone bromide, as direct administration of methylnaltrexone bromide into the brains of animals was shown to produce opioid antagonism. Similarly, methylnaltrexone bromide did not produce signs of withdrawal in chronically opioid exposed mice, rats, dogs, or monkeys. There are reports of high dosages of methylnaltrexone bromide reversing opioid analgesia in rodents. The sparing of centrally-mediated opioid analgesia by systemically-administered methylnaltrexone bromide is likely due to the restricted ability of methylnaltrexone bromide to cross the blood-brain barrier. These findings might also be related to the ability of rodents to demethylate methylnaltrexone bromide to naltrexone at a low rate. Demethylation at the nitrogen position would produce naltrexone, an opioid antagonist that crosses the blood-brain barrier. Demethylation is very low in dogs and essentially non-existent in humans.
QTc
Studies using anesthetized open-chest dogs were used to characterize the acute effects of IV bolus dosages of methylnaltrexone bromide on cardiovascular and circulatory functions. Methylnaltrexone bromide at IV dosages ranging from 1 to 25 mg/kg produced a mild(<20%) to moderate (20% to 27%) transient decrease in several cardiovascular parameters. The magnitude and duration of the effects on heart rate, cardiac output and +dP/dt appeared to be dose-related.
Studies using conscious telemetrized dogs who received IV methylnaltrexone bromide at dosages of 1, 5, or 20 mg/kg had no systemic effect on cardiovascular or circulatory function except for blood pressure. Dosages up to 20 mg/kg resulted in dose-dependent decreases in systolic pressure in two of the four animals. The maximum decreases were approximately 20 to 30 mmHg and were within the normal range of variability. Therefore, this finding was not considered to be indicative of cardiovascular risk.
Methylnaltrexone bromide was tested in a dose-response comparison with cisapride, a compound known be a potent inhibitor of human ether-a-go-go related gene (hERG) channels. These studies included a dose-response comparative study for hERG inhibition in human embryonic kidney (HEK) cells, studies on action potential duration and other parameters in isolated Purkinje fibers from dogs and rabbits, and a study in conscious guinea pigs from which QTc data was obtained. In the Purkinje fibers, methylnaltrexone bromide produced effects on action potential duration in fibers from dogs and no effect in fibers from rabbits. The changes recorded for methylnaltrexone bromide in dog fibers were neither concentration-dependent nor rate-dependent. The positive control cisapride significantly prolonged action potential duration in these studies, being up to 10-fold more potent and greater than 1000-fold more potent than methylnaltrexone bromide in dog and rabbit fibers, respectively. Results from the study involving the conscious guinea pigs, with doses up to 20 mg/kg, produced no changes in QTc. Cisapride, in contrast, produced this effect at 3 mg/kg IV, representing 6.6-fold higher potency.
Methylnaltrexone bromide was used at dosages or concentrations that exceeded by wide margins the highest proposed human dose (0.3 mg/kg, with a Cmax of 554 nM) indicating that methylnaltrexone bromide is not an inhibitor of hERG channels at clinically relevant concentrations. However, cisapride was at least 19,600-fold more potent than methylnaltrexone bromide as an inhibitor of hERG channels. Based on results from the in vitro cardiac and IV in vivo cardiovascular studies, methylnaltrexone bromide does not appear to present a risk of QTc prolongation at concentrations up to those expected at the highest proposed clinical SC dose.
3.2.2 Pharmacokinetics
No gender differences in pharmacokinetic parameters were observed in rats and dogs.
Absorption
Bioavailability (based on the exposure value AUC) of methylnaltrexone bromide administered by the SC route in rats and dogs was essentially 100% relative to IV dosing. Exposure (AUC and Cmax) is slightly greater than dose-proportional after SC, IV, and oral dosing in rats and dogs. However, plasma concentrations were consistently dose-proportional.
Distribution
Methylnaltrexone bromide was distributed mostly to the small intestine, liver, and kidney in the rat, with the brain and skeletal muscle having the lowest concentrations at 1 hour after dosing. Penetration to the brain was extremely limited with lower concentrations in the brain than in all other tissues. Minimal amounts of methylnaltrexone bromide were found in brain of rat and rabbit after administration of high IV or epidural dosages.
Tissue distribution in the rat was examined after IV administration of a single 10 mg/kg dosage of radioactive methylnaltrexone bromide. Concentrations in the small intestine, liver, and kidney and most other tissues decreased over time but the tissue-to-plasma ratios increased from 2 to 12 hours, suggesting that the drug was cleared faster from the plasma than from tissues.
Tissue-to-plasma ratios in male rats remained high at 24 hours in thyroid, brown fat, heart, testes, eyes, and peritoneal fat, and these same tissues had the highest concentrations at 120 hours. The tissues with the highest concentrations in female rats at 120 hours after dosing were brown fat, salivary gland, kidney, heart, eyes, and Harderian gland. Plasma concentrations of radioactivity in female rats were not detectable after 12 hours.
In pregnant rats, methylnaltrexone bromide-derived radioactivity rapidly crossed the placenta; however, the fetal exposure was approximately 10% of the maternal exposure.
Metabolism
Protein binding in plasma was minimal. In vivo, methylnaltrexone bromide was not extensively metabolized in mice, rats, or dogs. The metabolic pathways included hydroxylation, reduction, methylation, sulfation, and glucuronidation. Plasma metabolite profiles suggest minimal metabolism of methylnaltrexone bromide in human subjects after IV administration. The most abundant metabolites in human plasma were methylnaltrexone bromide sulfate, and methyl-6a-naltrexol and methyl-6b-naltrexol isomers. Methylnaltrexone bromide sulfate and methyl-6b-naltrexol were also observed in rat plasma. The major circulating metabolite in dogs was methylnaltrexone bromide glucuronide.
Protein binding was determined in concentration ranges of 0.2 to 75 μg/mL in rat and dog plasma, and 0.2 to 2.0 μg/mL in human plasma. The fraction unbound ranged from 86.7% to 90.6% in rats, from 87.1% to 99.6% in dogs, and from 84.7% to 89.0% in humans. The overall average percentages of bound methylnaltrexone bromide in rat, dog, and human plasma were 12.9%, 6.3%, and 13.2%, respectively. Binding was independent of the concentration tested.
The extent of demethylation of methylnaltrexone bromide to form naltrexone in vivo was been determined in a study where methylnaltrexone bromide labeled with [14C] at the N-methyl group was administered to mice, rats, dogs, and cancer patients and [14C]-labeled carbon dioxide was measured in expired air. The fraction of the administered dose of [14C] recovered in expired air represented the extent of demethylation to naltrexone. The cumulative percentages of radioactivity recovered were 0.48, 1.17, 0.14, and < 0.0001% for mice, rats, dogs, and humans, respectively, indicating that conversion to naltrexone is essentially nonexistent in humans and is highest in rats. The data from a study of the [14C]-N-methylnaltrexone mass balance (IV dosing) suggest that even in rats, demethylation occurs only at trace levels, since the fraction of administered radioisotope recovered in the carbon dioxide trap was less than 0.05%. In another study, naltrexone was observed at very low levels in brains of rats after IV administration of tritium labeled methylnaltrexone bromide. These data indicate that the extent of demethylation is low in all species examined.
Excretion
Significant methylnaltrexone bromide levels in the large intestine after IV administration were indicative of excretion into bile. This is consistent with the presence of methylnaltrexone bromide in feces after IV injection. Approximately 30% of an IV administered dose of methylnaltrexone bromide in rats and dogs was recovered in feces and 50% to 58% was recovered in urine. Oral dosing in dogs resulted in 71% recovery in feces and 15% in urine. In bile duct cannulated rats, 15.9% of the dose after IV administration was recovered in bile and 9.1% was recovered in feces.
In lactating rats, methylnaltrexone bromide-derived radioactivity was excreted into milk. Methylnaltrexone bromide was not a p-glycoprotein substrate in Caco-2 cell monolayers. Methylnaltrexone bromide was a substrate of the human OCT1 transporter, consistent with pharmacokinetic findings in humans indicating that methylnaltrexone bromide is actively secreted into urine.
Drug-Drug Interactions
Methylnaltrexone bromide inhibited the activity of the CYP isozyme CYP2D6, with a Ki value of 7.9 μM in human liver microsomes. Based on Cmax and Ki values, clinical metabolic drug-drug interactions involving methylnaltrexone bromide and CYP2D6 substrates could be possible after IV administration but are not likely to occur after oral or SC administration of methylnaltrexone bromide at therapeutic doses.
3.2.3 Toxicology
A comprehensive toxicological evaluation was performed to support the clinical use of Relistor (methylnaltrexone bromide) for the treatment of opioid-induced constipation in patients with advanced illness, receiving palliative care. The studies were performed using methylnaltrexone bromide which is proposed for human use. Non-clinical toxicology studies have indicated that the CNS and cardiovascular systems are potential target organs for methylnaltrexone bromide induced toxicity.
Single-Dose Toxicity
There were no test-article-related effects in animals receiving a single SC dose of MOA-728 up to 200 mg/kg in a volume of 2 mL/kg. Single dosages of 500 mg/kg (in 2 mL/kg dose volume), and 400 or 500 mg/kg MOA-728 (in 5 mL/kg volume) resulted in adverse clinical signs that were not life threatening. Therefore, the highest single subcutaneous dosage that did not cause life-threatening toxicity was 500 mg/kg. Multiple doses (4 doses) at 200 mg/kg/day resulted in mortality and adverse clinical signs and were not considered tolerated.
Repeat-Dose Toxicity
In a 3-month repeat-dose IV toxicity study in dogs, there were no changes in heart rate, pulse rate, or QRS intervals of the ECG. Adverse increases in the QTc interval of males (≥ 15%) were seen at 20 mg/kg/day. No adverse increases the in QTc interval (< 10%) were seen at an IV dosage of 5 mg/kg/day (the NOAEL in this study).
There appeared to be no gender-related differences in toxicokinetic parameters. No signs of accumulation were evident in repeat-dose studies in spite of the fact that t1/2 in some species ranged up to 15 hours.
Genotoxicity/ Mutagenicity
The genotoxicity of methylnaltrexone bromide was evaluated in a battery of six studies using both in vitro and in vivo models. Each of the six studies was negative, indicating that methylnaltrexone bromide is not genotoxic or mutagenic.
Carcinogenicity
Studies to evaluate the carcinogenic potential of methylnaltrexone bromide were not performed.
Reproductive and Developmental Toxicity
In pregnant and lactating rats, methylnaltrexone bromide rapidly crossed the placenta and was excreted into milk. No adverse effects on fertility or perinatal/postnatal toxicity were observed in rats given methylnaltrexone bromide by SC injection for up to 51 days in males and 38 days in females. Doses were up to 38 times higher than exposure (AUC) in humans given SC doses of 0.15 mg/kg.
Local Tolerance
No formal local tolerance studies were conducted, however in studies with rats, when administering methylnaltrexone bromide SC, there was discolouration at the injection site. Administration via IV showed no discolouration. Both methods also showed necrosis at the injection site.
3.2.4 Conclusion
Methylnaltrexone bromide was shown to be active and well tolerated for the treatment of peripheral side effects of opiate therapy. The pharmacological effects are specific, and the toxicological effects of the drug are limited and reversible, indicating an adequate safety profile for the proposed human use of this drug. The nonclinical studies conducted with methylnaltrexone bromide are considered adequate to support the safe SC administration of methylnaltrexone bromide in humans.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
One pilot study on the potential benefit of methylnaltrexone bromide in limiting or reversing opioid-induced bladder (detrusor) dysfunction, and concomitant urinary retention was conducted. The study was carried out in 13 healthy male volunteers with normal urinary function. This was a cross over, single-center, double-blind, randomized, placebo- and active-comparator (naloxone)-controlled study. All drugs were administered via IV following administration of a short-acting opioid, remifentanil (REMI). Methylnaltrexone bromide was dosed at 0.3 mg/kg and naloxone at 0.01 mg/kg. The IV naloxone inhibited both opioid-induced miosis and depression of normal bladder function. In contrast, IV methylnaltrexone bromide had a negligible effect on miosis, but inhibited opioid-induced depression of bladder function in 3 out of 11 subjects (27%). The data suggest that methylnaltrexone bromide effects on detrussor function may be partially mediated through local, non-CNS pathways.
3.3.2 Pharmacokinetics
There were six Phase I pharmacokinetic studies that were carried out in healthy volunteers.
Absorption
Methylnaltrexone bromide was absorbed rapidly following subcutaneous administration, with peak plasma concentrations (Cmax) achieved at approximately 0.5 hours. Peak plasma concentration and exposure (AUC) increased in a dose-proportional manner with mean AUC values of about 180 ng•h/mL at 0.15 mg/kg, 376 ng•h/mL at 0.30 mg/kg and 593 ng•h/ml at 0.50 mg/kg. Absolute bioavailability of a 0.3 mg/kg SC dose versus a 0.3 mg/kg IV dose was 82%.
Distribution
Methylnaltrexone bromide underwent moderate distribution into the extra vascular space, with a mean Vss of 1.1 L/kg. Methylnaltrexone bromide was minimally bound to human plasma proteins as determined by equilibrium analysis. The binding of methylnaltrexone bromide to human plasma proteins ranged from 11.0% to 16.4%. Levels of total radioactivity in plasma were roughly twice of those that were in the whole blood, suggesting minimal penetration into blood cells.
Metabolism
Methylnaltrexone bromide was minimally metabolized in humans following 0.3 mg/kg of 14C- dose administered by IV to healthy volunteers. Conversion to methyl-6-naltrexol isomers and methylnaltrexone sulphate appeared to be the primary pathways of metabolism. N-demethylation of methylnaltrexone bromide to produce naltrexone was not significant (0.06% of the administered dose). Overall metabolism appears to account for less than 10% of methylnaltrexone bromide clearance.
Excretion
Methylnaltrexone bromide was eliminated primarily as unchanged drug. Approximately half of the dose was excreted in the urine and less in feces; renal clearance of methylnaltrexone bromide exceeded creatinine clearance, indicating a significant active renal secretion. Renal clearance of methylnaltrexone bromide accounts for roughly half of the total clearance, suggesting appreciable non-renal elimination. The terminal half-life (t1/2) was approximately 8 hours. However, depending on the final time of blood collection, the half life (t1/2) of methylnaltrexone bromide following SC administration ranged from 6-13 hours.
Special Populations
Results from an animal study using 3H-labeled methylnaltrexone indicated that methylnaltrexone is excreted via the milk of lactating rats. It is not known whether this drug is excreted in human milk, thus caution should be exercised when Relistor is administered to a nursing woman.
Patients with severe renal impairment (creatinine clearance less than 30 mL/min), dose reductions are recommended.
3.3.3 Clinical Efficacy
The efficacy of Relistor was evaluated in two double blind randomized, placebo controlled Phase III studies and in one pilot Phase II randomized, double blind study, which provided an initial demonstration of activity. All the clinical studies assessed efficacy objectively based on bowel movement response (laxation) during the 4 hours, and the first 24 hours following dosing; and subjectively by patients evaluation of bowel movement (consistency and difficulty), and assessment of constipation severity/ distress. In addition, investigator global ratings of change in constipation, and use of laxatives were assessed.
The Phase III studies consisted of double blind and open phases. The treatment period of the double blind phases were 1 day in Study-301 (followed by a one month open label period); and 2 weeks in Study-302. Doses were a single Relistor (methylnaltrexone bromide) dose of 0.15 mg/kg and 0.3 mg/kg in Study-301 and 0.15 mg/kg every other day in Study-302. Each study had a three month open label extension to assess long term safety data. During the extension phases, patients were allowed to be dosed as needed at 0.15 mg/kg once per day. Doses could be adjusted according to efficacy and adverse effects to 0.3 mg/kg or 0.075 mg/kg, respectively.
Patients enrolled in the studies had advance illnesses (cancer, cardiovascular disease, COPD/ emphysema, etc) with a life expectancy of >1 month and <6 months who were receiving both palliative opioid therapy for pain associated with their illness and background laxative regime for opioid-induced constipation. Prior to treatment with Relistor, patients had either <3 bowel movements during the previous week or no clinical significant laxation within 48 hours prior to the first dose of the study drug. Patients were on a stable laxative regime for at least three days prior to the first dose of the study drug.
The primary endpoint in all studies was the proportion of patients with rescue-free laxation during 4 hours after study drug administration. In addition, subjective secondary endpoints were used to assess patient's distress, global assessment of treatment, bowel movement consistency and difficulty. Although the primary intent of the open-label extensions was to obtain safety data, efficacy also was evaluated. The open-label design of the extension periods was considered appropriate as studies involving chronic administration of placebo are not acceptable in the target population.
Patients treated with Relistor had a significantly higher rate of laxation than those receiving the placebo. No improvement was found between the 0.3 mg/kg dose when compared to the 0.15 mg/kg dose. The time to rescue-free laxation after receiving the first dose of the study drug was significantly shorter in the Relistor group than in the placebo group in both studies (301 and 302). In study 301, the median time to rescue-free laxation was 1.1 hours for the 0.15 mg/kg group, 0.8 hours for the 0.30 mg/kg group, and >24 hours for the placebo group. In study 302, based on patients who had laxation, the median time to laxation was 1 hour in the Relistor group and 11.2 hours in the placebo group after the first dose. The median times to laxation after subsequent doses ranged from 1.1 to 2.6 hours in the Relistor group and from 7.2 to 22 hours in the placebo group. Based on the pooled results, the response rates with Relistor were similar for older patients (> 65 years of age) and younger patients (< 65 years of age), as well there was no difference based on gender. Logistic regression with sex, age, and baseline opioid use indicated that none of these covariants has an influence on the outcome.
From the extension phases during which patients were dosed as needed, tolerance did not develop over time.
The issue of laxative(s) which remained part of the study design was not addressed in the studies. No information can be derived on whether patients were able to stop their laxatives and treat their constipation with Relistor without adjunctive laxatives.
3.3.4 Clinical Safety
Safety and efficacy of Relistor have not been established in pediatric patients. There was no difference in the efficacy or safety profile of these elderly patients when compared to younger patients. Therefore, no dose adjustment is recommended based on age. In patients with severe renal impairment (creatinine clearance less than 30 mL/min), dose reductions are recommended.
There were 14 clinical studies conducted to evaluate the safety of Relistor for use in humans. Data specific to SC Relistor administration was provided in four Phase I studies in healthy volunteers, one Phase II study, and two Phase III studies with open-label extensions. Three Phase I studies using intravenous (IV) Relistor administration in healthy volunteers were also conducted. Although the studies with IV Relistor were not relevant to the efficacy of SC Relistor, they contributed to the pharmacology evaluation of Relistor. Methylnaltrexone bromide is an opioid antagonist, a careful evaluation was made of the potential for methylnaltrexone bromide to cause opioid withdrawal or attenuate the desired analgesia in patients who are taking opioid medication for relief of pain.
Drug-Drug Interactions
Relistor is minimally metabolized by cytochrome P450 (CYP) isozymes. Relistor does not affect the pharmacokinetics of drugs metabolized by CYP isozymes. In vitro drug metabolism studies suggest that Relistor does not inhibit the activity of CYP1A2, CYP2A6, CYP2C9, CYP2C19 or CYP3A4, but is a weak inhibitor of the metabolism of CYP2D6. In a clinical drug interaction study in healthy adult male subjects, a subcutaneous dose of 0.30 mg/kg Relistor did not significantly affect the metabolism of dextromethorphan, a prototype CYP2D6 substrate. Therefore, the likelihood of any clinically relevant metabolically-based drug interactions occurring is very low for Relistor.
Renal clearance of methylnaltrexone bromide accounts for slightly more than half the total clearance. Renal clearance of methylnaltrexone bromide exceeds creatinine clearance, indicating a significant extent of tubular excretion. The potential for drug interactions between methylnaltrexone bromide and drugs that are actively secreted by the kidney exists. Given an 8- to 9-fold reduction of renal clearance of methylnaltrexone bromide in patients with severe renal impairment (CLR = 52 ± 28 mL/min) resulted in only a 2-fold increase in total exposure, clinically-significant drug-drug interactions resulting from inhibition of active urinary secretion of methylnaltrexone bromide are expected to be limited. Nevertheless, this drug-drug interaction potential is currently being investigated in a clinical study. It is possible that competition with other actively secreted drugs and methylnaltrexone bromide may occur.
Cardiovascular
Two randomized, double-blind, placebo- and positive-controlled studies evaluated of the effects of Relistor on ECG parameters and cardiac repolarization in normal subjects: one after subcutaneous dosing (0.15 and 0.5 mg/kg doses) in 207 healthy volunteers, the other after intravenous dosing (0.3 and 0.64 mg/kg over 20 minute infusions). Plasma levels achieved in the subcutaneous study met and exceeded the expected therapeutic exposure, while those in the intravenous study represented a substantial multiple of expected therapeutic exposure. Methylnaltrexone did not prolong ventricular repolarization (QT/QTc interval), atrioventricular conduction (PR interval), or intraventricular conduction (QRS duration) at the exposure levels achieved in these clinical studies.
Methylnaltrexone caused a transient increase in heart rate when administered as an IV infusion in Study 3200L2-104-US and as a SC injection of 0.30 mg/kg or 0.50 mg/kg.
The heart rate effects appeared to be minimal at the therapeutic dose, and the Phase II and III safety database did not reveal tachycardia as a cause of concern.
One shortcoming of the studies was the fact that the positive control arm was open label. For ECG assessment studies in which the test drug and the positive control had different administration routes, a double-dummy design is recommended. Another criticism of the studies was that the positive control, moxifloxacin 400 mg, produced rather low increases in QTc interval. Thus, sensitivity of this study for detection of drug effects near the threshold of regulatory concern was not unequivocally established by the selected positive control.
CNS
Relistor given IV at 0.30 mg/kg did not affect central nervous system (CNS) reflex functions but did antagonize peripherally-mediated depression of bladder function. Unlike naloxone, which was used as a positive control, a single IV dose of Relistor had no effect on opioid-induced miosis, indicating that Relistor has no demonstrable effects on the central nervous system.
The Modified Himmelsbach scale, pain score, opioid use and adverse event data indicate that systemic opioid withdrawal, a typical effect of centrally-acting μ antagonists, was not observed with Relistor, supporting that the drug has restricted access to the CNS. However, sporadic reports of adverse events linked to items on the Himmelsbach scale were more frequent with Relistor than placebo and may represent peripheral rather than central effects.
Adverse Reactions
The safety of Relistor was established in four Phase I, one Phase II study, and two Phase III studies with open-label extensions. Based on integrated safety data from 286 patients and 144 volunteers who received SC Relistor, doses of 0.15 or 0.30 mg/kg of SC Relistor were safe and well tolerated. In patients with opioid-induced constipation in the clinical studies (placebo controlled pool), the adverse drug reactions identified on the basis of frequency and mechanistic plausibility, were abdominal pain (28.5%), flatulence (13.3%), nausea (11.5%), dizziness (7.3%), and diarrhea (5.5%). These events were predominantly mild or moderate in severity. The adverse events were also detected during the extension studies (Relistor pool); no decrease in frequency was observed.
Among the 286 patients treated with Relistor in the phase II and III clinical studies, adverse events led to discontinuation in 23 (8.0%) patients.This pattern of adverse reactions was not observed in healthy volunteers, suggesting that it is specific to the stimulation and evacuation of an obstipated gut in constipated, opioid-dependent individuals.
Overall, Relistor was safe when administered every other day for up to 2 weeks in a placebo-controlled trial, and was safe when administered as needed to patients with advanced illness and OIC. Adverse drug reactions, judged in relationship to placebo, appear associated with the action of Relistor on the obstipated gut. These reactions were primarily gastrointestinal in nature and generally were not serious. Relistor did not adversely affect the survival of these fragile patients.
One death as a result of diarrhea, dehydration and exacerbation of cardiovascular condition resulted in cardiovascular collapse in one 75 year old patient.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Opioids have several common side effects, among which is constipation. In the setting of advanced illness, opioid-induced constipation is especially troublesome. Immobility, poor oral intake, and multiple concomitant medications common to this population can worsen the severity dramatically and render the constipation more refractory to standard treatment. Although stool softeners and laxatives are often utilized in an effort to decrease the severity of opioid induce constipation, these agents often offer only limited improvement, and have side effects that are themselves unpleasant. Moreover, none of the traditional laxatives counteract the specific constipating mechanism of opioids, which is decreased motility of the gastrointestinal tract.
For opioid induced constipation that is refractory to laxatives or when laxatives become intolerable due to side effects at higher doses, patients resort to more invasive maneuvers such as enemas or manual disimpaction of the rectum, which are generally uncomfortable, and cause loss of dignity for patients, or patients may resort to downward titration of opioid dose to get relief, trading off effective pain management for restoration of control of bowel function.
Management of constipation is therefore currently a need that is unmet for patients with advanced illness, and access to a reliable, safe, well tolerated agent to provide rapid relief of opioid induce constipation would significantly improve end of life care.
The results of the Phase III studies demonstrate that Relistor is effective in treating opioid-induced constipation. In each of the studies, the percentage of patients who had a laxation within 4 hours after receiving a single dose of study drug was significantly higher with Relistor than with placebo.
Assessments of pain scores, daily opioid dose, and an opioid withdrawal instrument also support treatment with Relistor as the desired analgesic effects of opioids in advanced illness patients were not affected. An advantage of methylnaltrexone bromide is the low potential to cause withdrawal symptoms as a result of crossing the blood-brain barrier and interfering with pain control by the opiods.
Safety studies showed that Relistor was well tolerated however; Relistor should not be prescribed for patients who have a known or suspected mechanical gastrointestinal obstruction, other GI conditions or continued in patients who experience severe diarrhea during treatment. In addition, patients with severe renal impairment should receive half of the recommended dose.
The drug submission for Relistor was reviewed under the Priority Review Policy. The efficacy and safety and tolerability demonstrated on a background of laxative treatment provided evidence that Relistor could be used as needed in addition to ongoing laxative therapy in patients with advanced illness receiving palliative opioid therapy. The results demonstrated that the overall constipation regimen is more effective when it includes Relistor than when it does not (placebo). The benefit to risk ratio is positive in this population.
This NDS for Relistor was granted Priority Review Status on August 3, 2007. The requested indication/disease condition qualifies for consideration for Priority Review as the condition is considered a severely debilitating disease or condition in patients with advanced illness undergoing opioid treatment for pain relief.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and effectiveness, Health Canada considers that the benefit/risk profile of Relistor is favourable in the treatment of of opioid-induced constipation in patients with advanced illness, receiving palliative care. The New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: RelistorTM
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting | 2007-06-27 |
| Request for priority status | |
| Filed | 2007-07-06 |
| Approval issued by Dr. Jacques Bouchard, Director of Bureau of Gastroenterology Infection and Viral Diseases | 2007-08-03 |
| Screening 1 | |
| Screening Acceptance Letter issued | 2007-10-01 |
| Review 1 | |
| Quality Evaluation complete | 2008-03-25 |
| Clinical Evaluation complete | 2008-03-26 |
| Labelling Review complete | 2008-03-26 |
| NOC issued by Director General | 2008-03-28 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| RELISTOR | 02308215 | SALIX PHARMACEUTICALS INC | METHYLNALTREXONE BROMIDE 20 MG / ML |