Naloxegol Descheduled by DEA
Naloxegol was approved in September 2014, for the treatment of opioid-induced constipation and is part of a class of medications known as PAMORAs (Peripherally Acting Mu Opioid Receptor Antagonists). Other Food and Drug Administration (FDA)-approved agents in this category include alvimopan (Entereg) and methylnaltrexone (Relistor).
Naloxegol was initially designated a scheduled II controlled substance by the DEA because of its structural resemblance to noroxymorphone.
The DEA’s decision to schedule naloxegol in any category was disillusioned at best, and was more likely a knee-jerk reaction to the recent high scrutiny attributable to the purported 'opioid epidemic.'The abuse and dependence potential of the agent have been evaluated in clinical studies, and according to the labeling, naloxegol has no risk of abuse or dependence.1
Naloxegol is a PEGylated offshoot of naloxone, which limits its permeability across the blood brain barrier and into the central nervous system (CNS). This negligible penetration into the CNS prevents naloxegol from affecting opioid analgesia occurring centrally. High fat meals have been shown to increase the extent and rate of absorption explaining the administration recommendation of taking naloxegol on an empty stomach. The volume of distribution ranged from 968 to 2140 L with low plasma protein binding. Naloxegol undergoes metabolism through the CYP3A4 system and is a substrate for p-glycoprotein (pGP); it is excreted primarily as metabolites via the feces (8%).1
It is worth noting that the PEGylation is most probably the reason for pGP absorption dependence across the GI tissue and the blood brain barrier, as naloxone does not share this pharmacokinetic characteristic. Because of property, we can expect theoretically that pGP inducers such as rifampin could significantly increase naloxegol levels within the GI tract and also reduce serum blood levels. On the other hand, pGP inhibitors such as telaprevir could theoretically decrease naloxegol concentrations in the gut and increase blood levels. In the authors’ experience, such interactions are not generally recognized by community or institutional pharmacy computer software and should be considered if a patient has an unusual response to naloxegol.
Based on drug interaction studies, naloxegol is not expected to alter the clearance of drugs metabolized by CYP enzymes. However, naloxegol clearance may be affected by CYP3A4 inhibitors and inducers. It is recommended to avoid the concomitant use of naloxegol with strong CYP3A4 inhibitors and inducers, as well as to avoid the consumption of grapefruit juice or other natural products/vitamin supplements that could inhibit this enzyme. If unable to avoid moderate CYP3A4 inhibitors with naloxegol, it is advised to reduce the dose of naloxegol to 12.5 mg daily.1