RELEXXII
Clinical safety rating: caution
Comprehensive clinical and safety monograph for RELEXXII (RELEXXII).
RELEXXII is a fixed-dose combination of buprenorphine, a partial mu-opioid receptor agonist, and naloxone, a mu-opioid receptor antagonist. Buprenorphine binds to mu-opioid receptors with high affinity, producing dose-dependent opioid agonist effects such as analgesia and euphoria, but with a ceiling effect on respiratory depression. Naloxone is included to deter intravenous abuse; when administered sublingually, naloxone has poor bioavailability and negligible effect, but if injected, it precipitates withdrawal in opioid-dependent individuals.
| Metabolism | Buprenorphine undergoes primarily hepatic metabolism via N-dealkylation by CYP3A4 to norbuprenorphine, which is further glucuronidated. Naloxone is metabolized in the liver primarily by glucuronidation. |
| Excretion | Primarily renal as unchanged drug (70-80%), with approximately 20% metabolized to inactive metabolites; less than 5% fecal. |
| Half-life | Terminal elimination half-life is 2-4 hours, prolonged in renal impairment (up to 8-10 hours in severe impairment). |
| Protein binding | Approximately 20-30% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | 0.5-1.0 L/kg, indicating distribution into total body water. |
| Bioavailability | Intramuscular: 100%; subcutaneous: 80-100%. |
| Onset of Action | Intravenous: immediate; intramuscular: 5-10 minutes; subcutaneous: 15-30 minutes. |
| Duration of Action | Intravenous: 30-60 minutes; intramuscular/subcutaneous: 1-2 hours, depending on dose and patient response. |
1 tablet (5 mg/325 mg) orally every 6 hours as needed for pain; maximum 4 tablets (20 mg/2,600 mg) in 24 hours.
| Dosage form | TABLET, EXTENDED RELEASE |
| Renal impairment | For CrCl 30-60 mL/min: use with caution, reduce dose by 50% or extend dosing interval to every 8 hours. For CrCl < 30 mL/min: avoid use or use with extreme caution, consider alternative therapy. |
| Liver impairment | Child-Pugh Class A: no adjustment. Class B: reduce dose by 50% and extend interval to every 8 hours. Class C: avoid use. |
| Pediatric use | Not recommended for use in pediatric patients under 18 years of age due to risk of opioid-induced respiratory depression and addiction. |
| Geriatric use | Start at lowest effective dose (e.g., half tablet) and titrate slowly; monitor for respiratory depression, sedation, and constipation due to age-related changes in pharmacokinetics and increased sensitivity. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for RELEXXII (RELEXXII).
| Breastfeeding | Methadone is excreted into breast milk. M/P ratio approximately 0.83. Concentrations in milk are low to moderate, with estimated relative infant dose less than 3% of maternal weight-adjusted dose. Beneficial for neonatal withdrawal. Caution if maternal dose > 100 mg/day; monitor infant for sedation and respiratory depression. |
| Teratogenic Risk | Methadone, active ingredient of RELEXXII, is not a major human teratogen. First trimester exposure is not associated with increased risk of major congenital malformations above baseline. Second and third trimester use may be associated with neonatal abstinence syndrome (NAS), growth restriction, and preterm birth. Chronic use can lead to fetal dependence. |
■ FDA Black Box Warning
WARNING: RISK OF RESPIRATORY DEPRESSION, NEONATAL OPIOID WITHDRAWAL SYNDROME, AND RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS. Respiratory depression may occur, particularly in non-tolerant patients, and can be life-threatening. Prolonged use during pregnancy can result in neonatal opioid withdrawal syndrome, which is life-threatening. Concomitant use of buprenorphine with benzodiazepines or other CNS depressants increases the risk of respiratory depression, profound sedation, coma, and death. Reserve concomitant prescribing for patients for whom alternative treatment options are inadequate.
| Serious Effects |
["Hypersensitivity to buprenorphine or naloxone","Significant respiratory depression","Acute or severe bronchial asthma","Known or suspected gastrointestinal obstruction, including paralytic ileus"]
| Precautions | ["Risk of respiratory depression and death, particularly in non-tolerant patients or when used with CNS depressants","Neonatal opioid withdrawal syndrome with prolonged use during pregnancy","Adrenal insufficiency reported with opioid agonists","Hepatitis, hepatic injury, and hepatic events; monitor liver function","Hypersensitivity reactions including bronchospasm and angioedema","Orthostatic hypotension and syncope","Physical dependence and withdrawal upon abrupt discontinuation","Impairment of ability to drive or operate machinery"] |
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| Fetal Monitoring | Monitor maternal vital signs, respiratory rate, and sedation level. During pregnancy, monitor for signs of withdrawal, compliance, and concurrent substance use. Fetal monitoring: assess growth (ultrasound), fetal heart rate, and biophysical profiles as clinically indicated. Monitor neonate for NAS using standardized scoring (e.g., Finnegan). |
| Fertility Effects | Methadone may cause erectile dysfunction, decreased libido, and menstrual irregularities. In males, can reduce serum testosterone. In females, may disrupt ovulatory cycles. Effects on fertility are generally reversible upon dose reduction or discontinuation. |