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FDA Responds to Mallinckrodt’s Supplemental New Drug Application for New Indication for AMITIZA® (Lubiprostone)

April 30, 2018

Mallinckrodt, a leading global specialty pharmaceutical company, confirmed it has received a supplement approval letter from the U.S. Food and Drug Administration (FDA) on the supplemental New Drug Application (sNDA) for indicated use of AMITIZA® (lubiprostone) in children 6 to 17 years of age with pediatric functional constipation (PFC). The FDA’s completed review of this sNDA has allowed the company to meet a component of its pediatric post-approval obligations. Although a specific pediatric indication was not established, the safety and tolerability profile of AMITIZA was confirmed.

“We are pleased that we have received a supplement approval letter from the FDA, indicating that we have met a component of our pediatric post-approval obligation,” said Steven Romano, M.D., Executive Vice President and Chief Scientific Officer, Mallinckrodt. “Given the need for therapeutic options for the treatment of constipation disorders in the pediatric population, we had hoped for inclusion of additional AMITIZA data in certain subpopulations from the PFC study to help inform prescribers. AMITIZA remains an important treatment option for adult patients suffering from multiple forms of chronic constipation for which the drug is approved and indicated. The pediatric adverse reactions reported in children 6 to 17 years of age were similar to those reported in adults. We will continue discussions with the agency regarding any future pediatric clinical studies.”

The AMITIZA sNDA, accepted for filing on September 28, 2017, included data from a Phase 3 pivotal efficacy and safety clinical trial of 606 participants aged 6 to 17 years titled “A Multicentre, Randomised, Placebo-Controlled, Double-blind Study of the Efficacy, Safety, and Pharmacokinetics of Lubiprostone in Paediatric Subjects Aged ≥ 6 Years to < 18 Years With Functional Constipation.” This trial was run as part of the Pediatric Research Equity Act (PREA) to assess the safety and effectiveness of lubiprostone in relevant pediatric subpopulations. In a 36-week, long-term safety extension trial, a single case of reversible elevation of hepatic enzymes was observed in a child with baseline elevated values. Find more about the study here, on the ClinicalTrials.gov website.

ABOUT AMITIZA
AMITIZA (lubiprostone) is a chloride channel activator that acts locally in the small intestine. By increasing intestinal fluid secretion, lubiprostone increases motility in the intestine, thereby facilitating the passage of stool and alleviating symptoms associated with chronic idiopathic constipation. Lubiprostone, via activation of apical CIC-2 channels in intestinal epithelial cells, bypasses the antisecretory action of opiates that results from suppression of secretomotor neuron excitability. Activation of CIC-2 by lubiprostone has also been shown to stimulate recovery of mucosal barrier function and reduce intestinal permeability via the restoration of tight junction protein complexes in ex vivo studies of ischemic porcine intestine.

AMITIZA (24 mcg capsules twice daily) is indicated in the U.S. for the treatment of adults with chronic idiopathic constipation (CIC) and opioid induced constipation (OIC) with chronic, non-cancer pain, including chronic pain related to prior cancer or its treatment who do not require frequent (e.g. weekly) opioid dose escalation. The effectiveness in patients with OIC taking diphenylheptane opioids (e.g. methadone) has not been established. AMITIZA (8 mcg capsules twice daily) is also approved in the U.S. for irritable bowel syndrome with constipation (IBS-C) in women 18 years of age and older. In Japan, AMITIZA (24 mcg twice daily) is indicated for the treatment of chronic constipation (excluding constipation caused by organic diseases). AMITIZA is also approved in other countries for various constipation-related indications in 8 mcg twice daily and 24 mcg twice daily dosage strengths.

Important Safety Information
AMITIZA (lubiprostone) is contraindicated in patients with known or suspected mechanical gastrointestinal obstruction. Patients with symptoms suggestive of mechanical gastrointestinal obstruction should be thoroughly evaluated by the treating healthcare provider (HCP) to confirm the absence of such an obstruction prior to initiating AMITIZA treatment.

Patients taking AMITIZA may experience nausea. Concomitant administration of food with AMITIZA may reduce symptoms of nausea.

Avoid use of AMITIZA in patients with severe diarrhea. Patients should be aware of the possible occurrence of diarrhea during treatment. Instruct patients to discontinue AMITIZA and contact their HCP if severe diarrhea occurs.

Syncope and hypotension have been reported with AMITIZA in the postmarketing setting and a few of these adverse reactions resulted in hospitalization. Most reports occurred in patients taking 24 mcg twice daily. Patients should be aware that the risk of syncope and hypotension may be increased with concomitant diarrhea, vomiting, or use of medications known to lower blood pressure. Inform patients that syncope and hypotension may occur within an hour of the first dose or subsequent doses of AMITIZA and generally resolve prior to the next dose, but may recur with repeat dosing. Instruct patients to discontinue AMITIZA and contact their HCP if these reactions occur.

Dyspnea may occur within an hour of first dose. This symptom generally resolves within three hours, but may recur with repeat dosing. Instruct patients to contact their HCP if dyspnea occurs. Some patients have discontinued therapy because of dyspnea.

In clinical trials of AMITIZA (24 mcg twice daily vs placebo; N=1113 vs N=316, respectively) in patients with CIC, the most common adverse reactions (incidence > 4%) were nausea (29% vs 3%), diarrhea (12% vs 1%), headache (11% vs 5%), abdominal pain (8% vs 3%), abdominal distension (6% vs 2%), and flatulence (6% vs 2%).

In clinical trials of AMITIZA (24 mcg twice daily vs placebo; N=860 vs N=632, respectively) in patients with OIC, the most common adverse reactions (incidence > 4%) were nausea (11% vs 5%) and diarrhea (8% vs 2%).

In clinical trials of AMITIZA (8 mcg twice daily vs placebo; N=1011 vs N=435, respectively) in patients with IBS-C, the most common adverse reactions (incidence > 4%) were nausea (8% vs 4%), diarrhea (7% vs 4%), and abdominal pain (5% vs 5%).

Concomitant use of diphenylheptane opioids (e.g., methadone) may interfere with the efficacy of AMITIZA.

The safety of AMITIZA in pregnancy has not been evaluated in humans. Based on animal data, AMITIZA may cause fetal harm. AMITIZA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Caution should be exercised when AMITIZA is administered to a nursing woman. Advise nursing women to monitor infants for diarrhea.

Reduce the dosage in CIC and OIC patients with moderate and severe hepatic impairment. Reduce the dosage in IBS-C patients with severe hepatic impairment.

Please see the complete Prescribing Information for AMITIZA.

ABOUT MALLINCKRODT
Mallinckrodt is a global business that develops, manufactures, markets and distributes specialty pharmaceutical products and therapies. Areas of focus include autoimmune and rare diseases in specialty areas like neurology, rheumatology, nephrology, pulmonology and ophthalmology; immunotherapy and neonatal respiratory critical care therapies; analgesics and gastrointestinal products. The company's Specialty Brands segment includes branded medicines and its Specialty Generics segment includes specialty generic drugs, active pharmaceutical ingredients and external manufacturing. To learn more about Mallinckrodt, visit www.mallinckrodt.com.

Mallinckrodt uses its website as a channel of distribution of important company information, such as press releases, investor presentations and other financial information. It also uses its website to expedite public access to time-critical information regarding the company in advance of or in lieu of distributing a press release or a filing with the U.S. Securities and Exchange Commission (SEC) disclosing the same information. Therefore, investors should look to the Investor Relations page of the website for important and time-critical information. Visitors to the website can also register to receive automatic e-mail and other notifications alerting them when new information is made available on the Investor Relations page of the website.

CAUTIONARY STATEMENTS RELATED TO FORWARD-LOOKING STATEMENTS
This release includes forward-looking statements concerning AMITIZA including expectations with regard to future regulatory actions and potential impact on patients. The statements are based on assumptions about many important factors, including the following, which could cause actual results to differ materially from those in the forward-looking statements: satisfaction of regulatory and other requirements; actions of regulatory bodies and other governmental authorities; changes in laws and regulations; issues with product quality, manufacturing or supply, or patient safety issues; future commercialization efforts; and other risks identified and described in more detail in the "Risk Factors" section of Mallinckrodt's most recent Annual Report on Form 10-K and other filings with the SEC, all of which are available on its website. The forward-looking statements made herein speak only as of the date hereof and Mallinckrodt does not assume any obligation to update or revise any forward-looking statement, whether as a result of new information, future events and developments or otherwise, except as required by law.

CONTACTS
Investor Relations
Daniel J. Speciale, CPA
Investor Relations and Strategy Officer
314-654-3638
daniel.speciale@mnk.com

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Rhonda Sciarra
Senior Communications Manager
908-238-6765
rhonda.sciarra@mnk.com
 
Meredith Fischer
Chief Public Affairs Officer
314-654-3318
meredith.fischer@mnk.com