Regulatory Decision Summary for Penthrox
The Regulatory Decision Summary explains Health Canada’s decision for the product seeking market authorization. The Regulatory Decision Summary includes the purpose of the submission and the reason for the decision.
Type of submission:
What was the purpose of this submission?
This New Drug Submission (NDS) was filed to obtain market authorisation for Penthrox (methoxyflurane) inhalation for the treatment of moderate to severe acute pain. The Penthrox Inhaler is intended for patient self-use, under the supervision of a health care professional.
Why was the decision issued?
Penthrox is a product that delivers methoxyflurane inhalation for the management of moderate to severe acute pain. Penthrox consists of an inhaler which is loaded with 3 mL of methoxyflurane liquid, supplied in a separate bottle, prior to use. The inhaler is intended for personal use over a single treatment course, and allows for individualized delivery of analgesia in appropriate patients. Once charged with methoxyflurane, the Penthrox inhaler may be used as required to control pain, with the frequency of inhalations at the discretion of the patient, based on therapeutic effect and patient tolerability. With regular repeated inhalations, administration of 3 mL of methoxyflurane is expected to last 20-25 minutes, while intermittent use of the inhaler allows for administration over about one hour per 3 mL vial. Although Penthrox is intended for patient self-administration, it is prescribed by and to be used under the supervision of a health care professional.
The efficacy of Penthrox in the management of moderate to severe acute pain was demonstrated in 2 pivotal, double-blind, placebo-controlled trials in patients with trauma-related pain and pain during short-lasting medical interventions, such as bone marrow aspiration. The evidence of safety and efficacy from the trials was supplemented by data from a number of studies in the literature, which examined methoxyflurane inhalation in the treatment of acute pain in the Emergency Department and in the pre-hospital setting, as well as during burn dressing applications or changes, and during dental procedures. All showed methoxyflurane to be an effective analgesic for treatment of moderate to severe acute pain, with rapid onset of effect.
Methoxyflurane inhalation was previously widely used as an anesthetic in the 1960s and 1970s at substantially higher doses than proposed for Penthrox analgesic use. Post-marketing, methoxyflurane inhalation at the higher doses used for anesthesia demonstrated an unacceptable incidence of serious, irreversible nephrotoxicity, resulting in the drugs market withdrawal as an anesthetic. Serious, irreversible nephrotoxicity has also been reported historically when methoxyflurane was used for analgesia at substantially higher doses than the Penthrox recommended dosing. However, when Penthrox has been used at currently proposed doses, no cases of definite or probable drug-induced nephrotoxicity have been reported since 1993, after more than 5.5 million vials were dispensed worldwide. Based on expected levels of methoxyflurane exposure with the proposed dosing of Penthrox, an adequate safety margin appears to exist before subclinical nephrotoxicity might be expected to occur. To help ensure that excessive dosing of Penthrox does not occur, the Product Monograph (PM) includes a Serious Warning Box cautioning against exceeding recommended dosing. In addition, Penthrox is contraindicated in patients with underlying clinically significant renal impairment.
Very rare idiopathic hepatotoxicity has been reported with methoxyflurane administration; most, but not all, cases were reversible without sequelae. Although apparently more common with substantially higher methoxyflurane exposures than expected with Penthrox, a handful of cases have been reported at exposures comparable to that which might be seen during recommended Penthrox dosing. Accordingly, this information is also included in the PM Serious Warning Box, and Penthrox use is contraindicated in patients with a history of liver dysfunction following previous exposure to methoxyflurane or other halogenated anesthetics. Penthrox is contraindicated for use as an anesthetic agent.
Under normal conditions of use in generally healthy patients, Penthrox inhalation is not expected to lead to significant hemodynamic instability, as may occur at anesthetic doses of other halogenated anesthetics. However, caution should be exercised with use in the elderly or other vulnerable patients with respect to potential acute blood pressure lowering.
As a volatile hydrocarbon, methoxyflurane may have the potential for abuse, misuse, or diversion. However, only a handful of misuse cases were identified from the literature over decades of use in association with anesthesia or historical use of high dose methoxyflurane for analgesia, and most of the cases were also associated with a history of significant psychoactive drug abuse. Since 1993, no cases of Penthrox abuse or misuse have been identified.
Data were not adequate to recommend use of Penthrox during pregnancy or in the peripartum period, or in pediatric patients under the age of 18 years.
The benefit-risk profile of Penthrox is considered favourable for treatment of moderate to severe acute pain in appropriately selected patients. Given the unique mechanism of action and mode of administration of methoxyflurane, a Risk Management Plan, including a Canadian Drug Utilization Study (DUS), will be instituted to ensure optimal management of identified and potential risks. The sponsor is conducting additional pharmacovigilance activities in Europe for the specific risks of hepatotoxicity and nephrotoxicity through a post authorisation safety study (PASS), and the results of this PASS will be submitted to Health Canada by the sponsor upon completion, which is expected shortly.
Approved; issued a Notice of Compliance in accordance with the Food and Drug Regulations.