Rx Product News: Profile: A Closer Look at New FDA Actions: Amitiza

Both Ms. Domenici and Dr. Patel are pharmacists at Brigham and Women's Hospital, Boston, Massachusetts. Mr. Schick is a third-year PharmD candidate from Northeastern University School of Pharmacy currently on co-op clerkship in the Investigational Drug Service at Brigham and Women's Hospital.

Sucampo and Takeda?s Amitiza

On April 29, 2008, the FDA approved Takeda Pharmaceuticals America Inc and Sucampo Pharmaceuticals Inc's 8-mcg Amitiza (lubiprostone) to treat irritable bowel syndrome with constipation (IBS-C) in women aged 18 years and older.¹ Amitiza was originally approved on January 31, 2006, to treat chronic idiopathic constipation in adults with a larger dose of one 24-mcg capsule twice a day. Amitiza is marketed by Sucampo Pharmaceuticals Inc and Takeda Pharmaceuticals America Inc.² IBS is characterized by cramping, abdominal pain or discomfort, bloating, and either constipation, diarrhea, or both.³ Women are more likely to experience IBS than men (2:1 ratio).³

Pharmacology/Pharmacokinetics

Amitiza selectively stimulates chloride channels (specifically ClC-2) in the apical membrane of the small intestine.⁴ When stimulated, ClC-2 secretes a chloride- rich fluid without affecting levels of sodium or potassium. By increasing the fluid levels in the bowels, Amitiza increases gastric motility, thus improving fecal transit. Amitiza is thought to provide relief from IBS-C through these secretions as well, by stimulating the repair of tight junction protein complexes and thus aiding in the restoration of the mucosal membrane of the small intestine.⁴

Following oral administration, Amitiza is very low, reaching peak plasma levels below the level of quantitation (10 pg/ mL). After a single 24-mcg dose, the only measurable active metabolite, M3, shows peak plasma levels of 41.5 pg/ mL at around 1.10 hours, with a half-life between 0.9 and 1.4 hours. Lubiprostone is rapidly and extensively metabolized by ubiquitously expressed carbonyl reductase, mostly in the stomach and jejunum. Cytochrome P450 is believed to be uninvolved. Whereas no drug. drug interaction studies have been performed, because Amitiza is not broken down in the liver, it is not anticipated there will be any interactions of clinical significance.⁴

Clinical Trials

Amitiza 8 mcg for IBS-C was approved on the successful outcome of 2 doubleblind, placebo-controlled, phase 3 trials. ⁴ Protocol defined IBS as abdominal pain for at least 6 months with one or more of the following characteristics: relieved with defecation; onset associated with change in stool frequency; and/ or onset associated with change in stool form. Patients were diagnosed with IBS-C if they had 2 of the 3 symptoms: fewer than 3 spontaneous bowel movements per week, hard stool, and/or significant straining (>25%) during bowel movements. Both studies enrolled 1154 patients aged 18 to 85 (97 men).⁴

The patients first entered 4 weeks of a "washout" period to achieve a baseline for comparison where no OTC/prescription laxatives were taken. The patients continued to take their fiber laxatives if they were stabilized.⁵ The participants were then given 8 mcg Amitiza or placebo twice a day for 12 weeks. The patients were asked to rate their level of relief of abdominal discomfort/pain, bowel habits, and other IBS symptoms on a 7-point scale, from "significantly worse" to "significantly better." In both studies, the Amitiza group had a higher overall response to relief of the IBS-C symptoms: study 1 = 13.8% versus 7.8%, and study 2 = 12.1% versus 5.7%.

The most common side effects with Amitiza are nausea, diarrhea, abdominal pain, and abdominal distension. Dyspnea occurred upon first use in >1% of patients and generally resolved itself in several hours.

Conclusion

Whereas Amitiza showed similar effects in men and the elderly (.65), the sample size was insufficient to determine if they responded differently to the drug.

Amitiza is contraindicated in patients who have or may have constipation due to a physical bowel obstruction or patients experiencing severe diarrhea. It also has not been studied in pregnant women and children. If nausea, diarrhea, or upset stomach occurs, Amitiza can be taken with food and water. If these effects continue or worsen, a primary care provider should be contacted.

References

• FDA Web site. www.accessdata.fda.gov.
• Sucampo Pharmaceuticals Inc's Web site. investor.sucampo.com.
• Mayer E. Irritable bowel syndrome. N Engl J Med 2008;358(16):1692-1699.
• Amitiza [prescribing information]. Bethesda, MD and Deerfield, IL: Sucampo Pharmaceuticals Inc and Takeda Pharmaceuticals North America Inc.
• Sucampo Pharmaceuticals Inc: "Dear Healthcare Professional Letter."