Since 2007, I’ve been following and informing others regarding the ongoing saga of the abortive medication Midrin and equivalents for Migraine treatment. In 2007, Midrin became unavailable for a time due to a shortage of one of the ingredients. When the shortage was resolved, Caraco (the manufacturer) began making and shipping it again. Later on, Caraco ran into some issues with the FDA over manufacturing issues. In the end, Caraco permanently discontinued manufacturing brand name Midrin.
Brand name Midrin, which was prescribed for tension-type Headache and Migraine, contained:
- acetaminophen, 325 mg: an analgesic
- isometheptene mucate, 65 mg: a vasoconstrictor that works to constrict dilated cranial and cerebral blood vessels
- dichloralphenazone, 100 mg: a mild sedative
Prodrin was a similar medication that contained two of the three ingredients that were in Midrin, plus caffeine:
- acetaminophen, 325 mg
- isometheptene mucate, 65 mg
- caffeine, 20 mg
For some time, a medication equivalent to Midrin was available from Macoven Pharmaceuticals in Magnolia, Texas. The label on the prescription bottle for this product was generally marked, “Isometh/Dich/Apap.”
Now, the FDA has issued a notice that puts an end to the distribution of Midrin and equivalents for Migraine. The notice states:
We are aware that your firm distributes the following prescription drug product containing
isometheptene mucate without an FDA-approved application:
- Isometheptene Mucate, Dichloralphenazone, and Acetaminophen Capsule/Tablets
(isometheptene mucate, USP 65mg, dichloralphenazone, USP 100mg, and acetaminophen, USP
325mg) NDC xxxxx-xxx.
- Isometheptene Mucate, Caffeine, and Acetaminophen Capsules/Tablets (isometheptene mucate, USP 65mg, caffeine, USP 20mg, and acetaminophen, USP 325mg) NDC xxxxx-xxx.
Federal Register Notice issued January 2014
Isometheptene mucate was originally approved in 1948 for safety only; its efficacy as an adjunct to
peptic ulcer treatment and for other indications, including the treatment of migraine headaches was reviewed under the Drug Efficacy Study Implementation (DESI) process [(Docket no. FDA-1975 N0355 (formerly 75N-0185) (DESI 3265)]. In a January 10, 2014, Federal Register Notice (FRN), FDA announced that all outstanding hearing requests for DESI 3265 have been withdrawn. It is unlawful to introduce into interstate commerce any products identified in this docket, or any identical, related, or similar (IRS) product to the products in this docket, that are not the subject of an approved new drug application (NDA) or abbreviated new drug application (ANDA). (See 79 FR 1875 at http://www.gpo.gov/fdsys/pkg/FR-2014-01-10/pdf/2014-00256.pdf.) FDA considers your product to be subject to the closed DESI 3265. Companies interested in marketing isometheptene containing drug products are required to obtain approval of a NDA or ANDA prior to marketing. However, according to the information you provided to FDA, your firm continues to distribute this unapproved drug product.
You should immediately cease the distribution of the product identified above and any additional products you distribute that were identified in Docket no. FDA-1975-N-0355 (DESI 3265) or IRS to the products in this docket. (See the docket at https://www.regulations.gov/docket?D=FDA-1975-N-0355.)
Failure to promptly stop distributing these products may result in immediate enforcement action without further notice, including, without limitation, seizure and injunction. It is your responsibility to assure your firm complies with all requirements of federal law and FDA regulations.
Within 45 working days of receipt of this letter, please confirm with this office in writing that you have ceased distribution of the above drug product and updated your listing in FDA’s electronic Drug Registration and Listing System (eDRLS) as required under section 510(j) of the Federal Food, Drug and Cosmetic Act (FD&C Act) to reflect the discontinuation of all drugs, including unapproved products [21 CFR 207.57(b)(1)(ii)]. If you no longer market the above products, your response should indicate so, including the reasons, and the date on which you ceased production. Your listings are also required to be updated for products no longer marketed. You should contact FDA’s unapproved drugs coordinator, Dr. Sally Loewke, at 301-796-0710 for assistance in communicating with the FDA on the application process for your unapproved drugs.
Your reply should be directed to the U.S. Food and Drug Administration, Attention: Tamika White, Project Manager, Food and Drug Administration, CDER Office of Compliance, 10903 New Hampshire Avenue, Building 51, Room 5284, Silver Spring, MD 20993. If you have questions regarding any issue in the content of this letter, please contact Ms. White at 301-796-0310.
Unapproved Isometheptene Mucate Drug Products and NDCs
71186-005: Isometheptene Mucate, Dichloralphenazone, and Acetaminophen
35573-310: Isometheptene Mucate, Caffeine, and Acetaminophen
35573-311: Isometheptene Mucate, Dichloralphenazone, and Acetaminophen
44183-440: Isometheptene Mucate, Dichloralphenazone, and Acetaminophen
51293-617: Isometheptene Mucate/Dichloralphenazone/Acetaminophen
42195-145: Isometheptene Mucate, Caffeine, and Acetaminophen
58716-937L Isometheptene Mucate, Caffeine, and Acetaminophen
Dr. David Watson, who is a UCNS certified Migraine specialist, director of the Headache Center and chairman of the Department of Neurology at West Virginia University, and the chair of our medical advisory board, commented:
“People with migraine have long struggled with limited treatment options, and so it is always concerning when one of those options disappears. Midrin and the equivalents were not the option of choice for most patients, but remained a useful tool for some with Migraine disease. However, I respect the FDA’s concerns of lack of evidence of benefit as well. In reality, what this challenge proves is that people with Migraine deserve better than decades-old unproven medication options and that the NIH needs to aggressively support the discovery and development of new therapeutics in Migraine and other Headache disorders.”
Comments and implications for patients
Midrin and equivalents for Migraine have been standards for years now. The FDA issue stems from Midrin having been developed before the current FDA drug approval process and the failure of pharmaceutical companies producing both brand name Midrin and the equivalents to perform clinical trials to prove their efficacy.
Some people have thought that Midrin and equivalents were safe for people for whom triptans and ergotamines were contraindicated due to history of cardiovascular issues. There has not, however, been a consensus about this in the “Headache medicine” field because isometheptene mucate has vasoconstrictor properties.
The bottom line here is that patients who have been using Midrin and equivalents for Migraine should talk with their doctors about alternatives since Midrin and equivalents will no longer be available.
FDA. “FDA Notification Regarding Isometheptene-Containing Drug Products.” June 18, 2018.
Interview with David B. Watson, MD. August 22, 2018.