Sprout’s Addyi Loses Blanket Alcohol Contraindication And REMS Distribution Restrictions
Executive Summary
US FDA’s approval of labeling supplements for the hypoactive sexual desire disorder drug followed Sprout’s appeal of a safety-related change order; boxed warning now states patients should wait at least two hours after drinking alcohol before taking flibanserin.
Sprout Pharmaceuticals Inc.’s Addyi (flibanserin) has shed its labeled alcohol contraindication and restricted distribution requirements, but not without more tension between the company and the US Food and Drug Administration.
On 9 October, the agency approved two labeling supplements for the hypoactive sexual desire disorder drug.
One supplement removed a blanket contraindication against use of alcohol in patients taking flibanserin. It also revised, but did not remove, a boxed warning about use of alcohol with the drug.
The new boxed warning states that patients should wait at least two hours after consuming one or two alcoholic drinks before taking the drug, or should skip their Addyi dose if they have consumed three or more standard alcoholic drinks. (See table, below.) The boxed warning also retains contraindications against use in patients taking moderate or strong CYP3A4 inhibitors and those with hepatic impairment due to risk of severe hypotension and syncope.
The revised Warnings and Precautions section of labeling defines one standard alcoholic drink as containing “14 grams of pure alcohol and is equivalent to one 12-ounce regular beer (5% alcohol), 5-ounces wine (12% alcohol), or 1.5 ounces of distilled spirits/shot (40% alcohol).”
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Original Boxed Alcohol Warning |
Revised Boxed Alcohol Warning |
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Contraindicated with Alcohol |
Interaction with Alcohol |
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The use of ADDYI and alcohol increases the risk of severe hypotension and syncope [see Warnings and Precautions (5.1)]. Therefore, alcohol use is contraindicated in patients taking ADDYI [see Contraindications (4)]. Before prescribing ADDYI, assess the likelihood of the patient abstaining from alcohol, taking into account the patient’s current and past drinking behavior, and other pertinent social and medical history. Counsel patients who are prescribed ADDYI about the importance of abstaining from alcohol use.
Because of the increased risk of hypotension and syncope due to an interaction with alcohol, ADDYI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ADDYI REMS Program [see Warnings and Precautions (5.2)]. |
The use of ADDYI and alcohol together close in time increases the risk of severe hypotension and syncope [see Warnings and Precautions (5.1)]. Counsel patients to wait at least two hours after consuming one or two standard alcoholic drinks before taking ADDYI at bedtime or to skip their ADDYI dose if they have consumed three or more standard alcoholic drinks that evening. |
Losing The Certification Requirement
The second supplement removed the Risk Evaluation and Mitigation Strategy's elements to assure safe use (ETASU) that required special certification of prescribers and pharmacies, as well as the related implementation system. The supplement also brings the Medication Guide into the REMS program.
In its approval letter, the agency said it determined the ETASU “are no longer necessary because new information from the Phase I studies (SPR-18-001 and SPR-18-002) of Addyi and alcohol showed that the risk with alcohol is narrower than understood at the time of approval.”
Specifically, the postmarketing studies showed that waiting at least two hours after drinking up to two standard alcoholic drinks prior to taking Addyi mitigates the risk for syncope and hypotension, the agency said. “Given this new information, the current ETASU REMS is no longer necessary and is being removed to minimize burden on the health care system.”
Disputes Over The Substance Of Labeling Changes…
The labeling and REMS changes were not without controversy and generated unusual disclosures by both the agency and sponsor about their interactions with each other.
In April, the FDA announced it had ordered Sprout to make certain labeling revisions reflecting the results of the new alcohol interaction studies. (Also see "US FDA Squashes Sprout's Attempt To Remove Boxed Warning From Addyi Label" - Pink Sheet, 14 Apr, 2019.)
The agency said it disagreed with Sprout’s proposal to entirely eliminate the boxed warning on the risks of hypotension and syncope from the interaction of Addyi with alcohol, with moderate/strong CYP3A4 inhibitors, and in patients with hepatic impairment. The agency also objected to Sprout’s proposal to remove the alcohol contraindication.
Postmarketing studies affirmed the need for warnings about alcohol use with Addyi, the agency said. The boxed warning, contraindications and other sections of labeling were being updated to specify that women should discontinue drinking alcohol at least two hours before taking Addyi at bedtime or to skip the Addyi dose that evening, the agency said.
At the time, Sprout characterized the labeling change as a positive development. However, the company initiated dispute resolution to get agreement for removal of the alcohol contraindication and the restrictive elements of the REMS.
Sprout’s 11 September Press Release
“The Director of FDA’s Office of New Drugs stated, ‘My assessment is that the new information narrows the risk of the flibanserin-alcohol interaction and that a [boxed warning] and a verifiably comprehensible medication guide should provide appropriate management of the risk. Based upon this, a REMS that includes a medication guide, but not ETASU, is appropriate to ensure that the benefits outweigh the risks. The company should submit a request to modify the REMS, as described above.’
“Regarding the Contraindication, the Director stated, ‘The labeling should, therefore, be revised so that the [contraindication] is limited to women on moderate or strong CYP3A4 inhibitors or who have hepatic impairment, populations for whom the benefit of treatment do not outweigh its risks. The Company can submit a proposed revised labeling that removes the contraindication for use of alcohol with flibanserin.’”
In an 11 September press release, the company said the appeal process concluded on 18 August “with a final decision from the Office of New Drugs at FDA stating their agreement on these two points.”
The press release includes quotes from what Sprout described as the decision of OND Director Peter Stein. (See box.)
The agency told the Pink Sheet it would not release the 18 August decision without a Freedom of Information Act request, and Sprout declined to release the full text of the decision. The FDA's labeling supplement approval letter refers to the 18 August decision as "our formal dispute resolution denial letter."
… And A Press Release
Sprout submitted the labeling supplements in late August. On 4 September it issued a press release announcing these finalized submissions and the new labeling language.
On 6 September, the FDA “informed Sprout that it objected to our press release and asked that we take the release down," the company said. "In an effort to be cooperative, Sprout took its release down early on September 7th. Starting September 10th, FDA began alerting media outlets that ‘at this time’ FDA has not made these changes.”
Sprout said it issued the 11 September press release with the timeline of events “for absolute clarity.”
How much of a commerical boost Addyi might get from the easing of the labeling language about alcohol use and removal of the REMS distribution restrictions remains to be seen. The oral drug now has competition in the HSDD market from AMAG Pharmaceuticals Inc.’s injectable Vyleesi (bremelanotide), which was approved in June.
Sprout told the Pink Sheet the removal of the alcohol contraindication and elimination of “unnecessary certification for doctors or pharmacists, or for women to sign paperwork regarding their prescription … represents a significant change in access for Addyi and for women seeking treatment for HSDD. Addyi is the first and only non-hormonal FDA-approved pill for HSDD.”