"Nov. 2, 2012 -- Safety steps taken in the wake of the fungal meningitis outbreak have worsened drug shortages, raising questions about whether the U.S. must choose between the safety and the availability of crucial medicines.
Cases of gastrointestinal perforation have been reported in adult patients with opioidinduced constipation and advanced illness with conditions that may be associated with localized or diffuse reduction of structural integrity in the wall of the gastrointestinal tract (e.g., peptic ulcer disease, Ogilvie's syndrome, diverticular disease, infiltrative gastrointestinal tract malignancies or peritoneal metastases). Take into account the overall risk-benefit profile when using RELISTOR in patients with these conditions or other conditions which might result in impaired integrity of the gastrointestinal tract wall (e.g., Crohn's disease). Monitor for the development of severe, persistent, or worsening abdominal pain; discontinue RELISTOR in patients who develop this symptom [see CONTRAINDICATIONS].
Severe Or Persistent Diarrhea
If severe or persistent diarrhea occurs during treatment, advise patients to discontinue therapy with RELISTOR and consult their healthcare provider.
Symptoms consistent with opioid withdrawal, including hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, and yawning have occurred in patients treated with RELISTOR [see ADVERSE REACTIONS]. Patients having disruptions to the blood-brain barrier may be at increased risk for opioid withdrawal and/or reduced analgesia. Take into account the overall risk-benefit profile when using RELISTOR in such patients. Monitor for adequacy of analgesia and symptoms of opioid withdrawal in such patients.
Patient Counseling Information
Advise patients to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).
Advise all patients to:
- Inject RELISTOR subcutaneously in the upper arm, abdomen or thigh. Do not inject at the same spot each time (rotate injection sites).
- Safely dispose of needles by following the sharps disposal recommendations described in the RELISTOR Instructions for Use.
- Be within close proximity to toilet facilities once RELISTOR is administered.
- Discontinue RELISTOR if treatment with the opioid pain medication is also discontinued.
Advise chronic non-cancer pain patients receiving RELISTOR for opioid-induced constipation to:
- Discontinue all maintenance laxative therapy prior to initiation of RELISTOR. Laxative(s) can be used as needed if there is a suboptimal response to RELISTOR after three days.
- Inject one dose every day.
- Inform their healthcare provider if their opioid regimen is changed, to avoid adverse reactions, such as diarrhea.
Advise patients with advanced illness receiving RELISTOR for opioid-induced constipation to:
- Inject one dose every other day, as needed, but no more frequently than one dose in a 24-hour period.
Advise patients to discontinue RELISTOR and to promptly seek medical attention if they develop unusually severe, persistent, or worsening abdominal pain [see WARNINGS AND PRECAUTIONS].
Severe or Persistent Diarrhea
Advise patients to discontinue RELISTOR if they experience severe or persistent diarrhea.
Advise patients that symptoms consistent with opioid withdrawal may occur while taking RELISTOR, including sweating, chills, diarrhea, abdominal pain, anxiety, and yawning [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].
Advise females of reproductive potential, who become pregnant or are planning to become pregnant that the use of RELISTOR during pregnancy may precipitate opioid withdrawal in a fetus due to the undeveloped blood brain barrier.
Advise females who are nursing against breastfeeding during treatment with RELISTOR due to the potential for opioid withdrawal in nursing infants.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Two-year oral carcinogenicity studies have been conducted with methylnaltrexone in CD-1 mice at doses up to 200 mg/kg/day (about 81 times the maximum recommended human (MRHD) dose of 0.2 mg/kg/day based on body surface area) in males and 400 mg/kg/day (about 162 times the MRHD of 0.2 mg/kg/day based on body surface area) in females and in Sprague Dawley rats at oral doses up to 300 mg/kg/day (about 243 times the MRHD of 0.2 mg/kg/day based on body surface area). Oral administration of methylnaltrexone for 104 weeks did not produce tumors in mice and rats.
Methylnaltrexone bromide was negative in the Ames test, chromosome aberration tests in Chinese hamster ovary cells and human lymphocytes, in the mouse lymphoma cell forward mutation tests and in the in vivo mouse micronucleus test.
Impairment of Fertility
Methylnaltrexone bromide at subcutaneous doses up to 150 mg/kg/day (about 122 times the MRHD of 0.2 mg/kg/day based on body surface area) was found to have no adverse effect on fertility and reproductive performance of male and female rats.
Use In Specific Populations
Pregnancy Category C
There are no adequate and well-controlled studies with RELISTOR in pregnant women. The use of RELISTOR during pregnancy may precipitate opioid withdrawal in a fetus due to the immature fetal blood brain barrier. In animal reproduction studies, no effects on embryo-fetal development were observed with the administration of intravenous methylnaltrexone during organogenesis in rats and rabbits at doses up to 20 times and 26 times, respectively, the maximum recommended human dose (MRHD) of 0.2 mg/kg/day. RELISTOR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Reproduction studies have been performed with methylnaltrexone administered during the period of organogenesis to rats at intravenous doses up to 25 mg/kg/day (about 20 times the MRHD of 0.2 mg/kg/day based on body surface area) and did not cause any adverse effects on embryofetal development. In rabbits, intravenous doses of methylnaltrexone up to 16 mg/kg/day (about 26 times the MRHD of 0.2 mg/kg/day based on body surface area) did not show any embryofetal toxicity. A pre- and postnatal development study in rats showed no evidence of any adverse effect on pre- and postnatal development at subcutaneous doses of methylnaltrexone up to 100 mg/kg/day (about 81 times the MRHD of 0.2 mg/kg/day based on body surface area).
It is not known whether RELISTOR is present in human milk.
However, methylnaltrexone bromide is present in rat milk. Because of the potential for serious adverse reactions, including opioid withdrawal, in nursing infants, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Safety and effectiveness of RELISTOR have not been established in pediatric patients.
In juvenile rats administered intravenous methylnaltrexone bromide for 13 weeks, adverse clinical signs such as convulsions, tremors and labored breathing were observed, and the juvenile rats were found to be more sensitive to the adverse effects of methylnaltrexone bromide when compared to adult animals. Juvenile dogs administered intravenous methylnaltrexone bromide for 13 weeks had a toxicity profile similar to adult dogs [see Nonclinical Toxicology].
In the double-blind studies, a total of 118 (14%) patients aged 65-74 years (79 methylnaltrexone bromide, 39 placebo) and a total of 108 (13%) patients aged 75 years or older (64 methylnaltrexone bromide, 44 placebo) were enrolled. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Based on pharmacokinetic data, and safety and efficacy data from controlled clinical trials, no dose adjustment based on age is recommended.
No dose adjustment is required in patients with mild or moderate renal impairment. Dose-reduction by one half is recommended in patients with severe renal impairment (creatinine clearance less than 30 mL/min as estimated by Cockcroft-Gault) [see DOSAGE AND ADMINISTRATION].
No dose adjustment is required for patients with mild or moderate hepatic impairment [see CLINICAL PHARMACOLOGY].
Last reviewed on RxList: 10/20/2014
This monograph has been modified to include the generic and brand name in many instances.
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