Difficult-to-dose Opioids and the Risk Evaluation Mitigation Strategy

US Pharmacist

Abstract and Introduction

Introduction

On behalf of patient safety considerations, providers must receive the support for safely switching patients to and from oral fentanyl products. This could be accomplished with the upcoming implementation of the Risk Evaluation Mitigation Strategy (REMS) for opioids.

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Abstract and Introduction
Risk Evaluation Mitigation Strategy
Difficulties Switching from Oral Fentanyl Products
Opioid Switching
Conclusion
References

Table 1. Submitting a Comment to the Risk Evaluation Mitigation Strategy (REMS)
Please submit an electronic comment to REMS at www.regulations.gov. In the field titled "Enter Keyword or ID," type "FDA-2009-N-0143-1061" and hit Search. In the lower portion of the next screen, choose the link that says "Submit a Comment," which is located to the right of the title "Risk Evaluation and Mitigation Strategies for Certain Opioid Drugs; Notice of Public Meeting; Reopening of Comment Period." The comment period is open until October 19, 2010, at 11:59 PM. In the comment section, address your comments to the Pharmacy Education Working Group or to the Prescriber Education Working Group. The comment must be specific. Please identify the challenges with the difficult-to-dose opioid and include clear solutions on how to overcome those difficulties.

Source: Reference ^[3].

Table 2. Converting to a Nonfentanyl Opioid
Switching From Oral Actiq to a Nonfentanyl Opioid Given Orally
Determine the TDD of Actiq or its generic (oral transmucosal fentanyl citrate). Convert the TDD of Actiq to an oral morphine equivalent dose. "Relative Potency of ACTIQ to IV morphine" "20 mcg IV fentanyl: 200 mcg ACTIQ: 2–4 mg IV morphine: 6–12 mg oral morphine" Take the total oral morphine equivalent dose and convert to a nonfentanyl opioid using an equianalgesic opioid dosing chart. For example: 1,200 mcg Actiq TDD (where every 200 mcg of Actiq = 6–12 mg of oral morphine) = 36–72 mg oral morphine, which = ~5–10 mg of oral hydromorphone Be aware of incomplete cross-tolerance between opioids. To allow for incomplete cross-tolerance, one guideline recommends starting the new opioid dose at 50%–67% of the equianalgesic dose. There are nuances when converting, so please refer to the full set of guidelines (Reference ^[12]).
Switching From Oral Fentora to a Nonfentanyl Opioid Given Orally
Determine the TDD of Fentora (fentanyl buccal tablet). Convert the TDD of Fentora to the TDD of oral transmucosal fentanyl citrate (Actiq) using data from Darwish et al (Reference 13). (A 30% smaller dose of Fentora would achieve systemic exposure comparable to that seen with Actiq.) Convert the TDD of Actiq to an oral morphine equivalent dose. "Relative Potency of ACTIQ to IV morphine" "20 mcg IV fentanyl: 200 mcg ACTIQ: 2–4 mg IV morphine: 6–12 mg oral morphine" Take the total oral morphine equivalent dose and convert to a nonfentanyl opioid using an equianalgesic opioid dosing chart. For example: 1,200 mcg Fentora TDD approximates 1,560 mcg of Actiq (30% difference between Fentora and Actiq) Then 1,560 mcg of Actiq (where every 200 mcg of Actiq = 6–12 mg of oral morphine) = 46–93 mg of oral morphine, which = ~6–12 mg of oral hydromorphone Be aware of incomplete cross-tolerance between opioids. To allow for incomplete cross-tolerance, one guideline recommends starting the new opioid dose at 50%–67% of the equianalgesic dose. There are nuances when converting, so please refer to the full set of guidelines (Reference ^[12]).

TDD: total daily dose. Source: References ^[10–14].

Table 3. Select FDA-Approved REMS
Drug	Application	Approval Date	Components
Embeda (morphine sulfate and naltrexone hydrochloride) extended-release capsules	NDA 22-321	8/13/09	Medication guide, communication plan
Exalgo (hydromorphone hydrochloride) extended-release tablets	NDA 21-217	3/1/10; modified 3/24/10	Medication guide, elements to assure safe use
Morphine sulfate oral solution	NDA 22-195/S-002	1/25/10	Medication guide
Onsolis (fentanyl buccal soluble film)	NDA 22-266	7/16/09	Medication guide, communication plan, elements to assure safe use, implementation system
Tapentadol tablets	NDA 22-304	11/20/08	Medication guide
Vivitrol (naltrexone) extended-release injectable suspension	NDA 21-897/S-005, S-010	3/22/10	Medication guide

NDA: new drug application; REMS: Risk Evaluation Mitigation Strategy.
Source: Reference ^[16].

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