Caryn Domenici, RPh, Alka Patel, PharmD

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.

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.

 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.

 IBS is characterized by cramping, abdominal pain or discomfort, bloating, and either constipation, diarrhea, or both.

 Women are more likely to experience IBS than men (2:1 ratio).

Amitiza selectively stimulates chloride channels (specifically ClC-2) in the apical membrane of the small intestine.

 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.

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.

Amitiza 8 mcg for IBS-C was approved on the successful outcome of 2 doubleblind, placebo-controlled, phase 3 trials. 

 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).

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.

 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.

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.

Amitiza [prescribing information]. Bethesda, MD and Deerfield, IL: Sucampo Pharmaceuticals Inc and Takeda Pharmaceuticals North America Inc. 

Sucampo Pharmaceuticals Inc: "Dear Healthcare Professional Letter." 

Articles

The FDA recently approved Amitiza for the treatment of irritable bowel syndrome with constipation in women aged 18 years and older.

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

Both Ms. Domenici and Dr. Patel arepharmacists at Brigham and Women'sHospital, Boston, Mass. Mr. Sullivanis a sixth-year PharmD candidatefrom Northeastern University School ofPharmacy currently on clinical clerkshipin the Investigational Drug Service atBrigham and Women?s Hospital.

Procter & Gamble's andsanofi-aventis' Actonel

On April 22, 2008, the FDA approvedthe use of Actonel (risedronate sodium)150-mg tablets as a once-monthly doseto treat and prevent postmenopausalosteoporosis.

 Actonel's original 1998approval was for the treatment andprevention of postmenopausal osteoporosis,men with osteoporosis, glucocorticoid-induced osteoporosis, andPaget's disease.

The new approval was based ona trial comparing risedronate 150mg once a month with risedronate 5mg daily. Actonel treatment at oncedaily,once-weekly, and 2 consecutivedays per month has shown to beeffective in postmenopausal womenwith osteoporosis. Treatment withActonel slows the increased rate ofbone turnover that is usually seen inpostmenopausal women.

Actonel acts as an antiresorptive agentdue to its affinity for hydroxyapatitecrystals. Actonel inhibits osteoclasts atthe cellular level where the osteoclastsadhere normally to the bone surface,but there is reduced active resorption.

Actonel is excreted primarily unchangedvia the kidneys, and clearanceof the drug decreases with decreasingkidney function. Actonel is not recommendedfor those with severe renalimpairment (creatinine clearance [CrCl]<30 mL/min); however, no dosageadjustment is necessary for those witha CrCl of ≥30 mL/min.

A randomized, double-blind, active-controlled,parallel-group study was conductedcomparing risedronate 150 mgonce a month (n = 650) with risedronate5 mg daily (n = 642) for the treatmentof postmenopausal osteoporosis.

The study was conducted over 2 years;however, data for the second year arestill being evaluated,

 according to themanufacturer (telephone interview July2008). The study enrolled women aged50 or older with postmenopausal osteoporosis.

 was definedas last menses at least 5 years prior.

The primary efficacy end pointwas the mean percent change frombaseline in lumbar spine bone mineraldensity after 1 year, which was 3.4%(3.03%-3.82%) in the daily group and3.5% (3.15%-3.93%) in the once-a-monthgroup. Increase in bone mineral densityfrom baseline at sites in the hip (totalproximal femur, femoral neck, femoraltrochanter) was seen in both groups,with no significant difference observedbetween the 2 groups. The 150-mg dosewas found to be noninferior to the 5-mgdose.

The adverse-events profile was similarbetween the 2 treatment arms.

Among the most common adverseevents, diarrhea (8.2% vs. 4.7%) andinfluenza (8.9% vs. 4.2%) occurred morefrequently in the once-monthly group,compared with the daily group, respectively.Symptoms potentially associatedwith an acute phase reaction (influenza-like illness and/or pyrexia startingwithin 3 days following the first doseand having duration of 7 days or less),were slightly higher in the once-monthlygroup (1.4%) than in the once-dailygroup (0.2%).

 Of note, there were noreported cases of osteonecrosis of thejaw.

It is important to note that theprimary population in this studyis postmenopausal women, andthese results do not necessarilyapply to the other populationsfor which Actonel once daily hasbeen approved. This is why oncea-month Actonel is approved onlyfor postmenopausal women.

Actonel is effective when administered30 minutes prior to breakfast.

Actonel 150 mg once a month producesclinical effects that are similar to thoseseen with a 5-mg daily dose regimen.It is different than currently availableonce-monthly osteoporosis medicationsin that it not only helps prevent fracturesin the spine, but also at sites beyond thespine. Patients should be advised totake Actonel while the patient is in anupright position and with a full glassof plain water (6-8 oz). Patients shouldnot lie down for 30 minutes after takingActonel.

FDA approves new once-a-month dose of Actonel for postmenopausal osteoporosis [press release]. 

FDA. Actonel [consumer drug information sheet]. 

www.fda.gov/CDER/consumerinfo/druginfo/actonel.htm

Actonel [package insert]. Cincinnati, OH and Bridgewater, NJ: Procter & Gamble Pharmaceuticals Inc and sanof-aventis US LLC; 2008.

Delmas PD, McClung MR, Zanchetta JR, et al. Efficacy and safety of risedronate 150 mg once a month in the treatment of postmenopausal osteoporosis. 