1.1 Chronic Idiopathic Constipation

Amitiza® is indicated for the treatment of chronic idiopathic constipation in adults.

1.2 Irritable Bowel Syndrome with Constipation

Amitiza is indicated for the treatment of irritable bowel syndrome with constipation (IBS-C) in women ≥ 18 years old.

2.1 Chronic Idiopathic Constipation

24 mcg twice daily orally with food and water.

2.2 Irritable Bowel Syndrome with Constipation

8 mcg twice daily orally with food and water.

5.1 Pregnacy

The safety of Amitiza in pregnancy has not been evaluated in humans. In guinea pigs, lubiprostone has been shown to have the potential to cause fetal loss. Amitiza should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women who could become pregnant should have a negative pregnancy test prior to beginning therapy with Amitiza and should be capable of complying with effective contraceptive measures. See Use in Specific Populations (8.1).

5.2 Nausea

Patients taking Amitiza may experience nausea. If this occurs, concomitant administration of food with Amitiza may reduce symptoms of nausea. See Adverse Reactions (6.1).

5.3 Diarrhea

Amitiza should not be prescribed to patients that have severe diarrhea. Patients should be aware of the possible occurrence of diarrhea during treatment. Patients should be instructed to inform their physician if severe diarrhea occurs. See Adverse Reactions (6.1).

5.4 Dyspnea

In clinical trials conducted to study Amitiza in treatment of chronic idiopathic constipation and IBS-C there were reports of dyspnea. This was reported at 2.5% of the treated chronic idiopathic constipation population and at 0.4% in the treated IBS-C population. Although not classified as serious adverse events, some patients discontinued treatment on study because of this event. There have been postmarketing reports of dyspnea when using Amitiza 24 mcg. Most have not been characterized as serious adverse events, but some patients have discontinued therapy because of dyspnea. These events have usually been described as a sensation of chest tightness and difficulty taking in a breath, and generally have an acute onset within 30–60 minutes after taking the first dose. They generally resolve within a few hours after taking the dose, but recurrence has been frequently reported with subsequent doses.

5.5 Bowel Obstruction

In patients with symptoms suggestive of mechanical gastrointestinal obstruction, the treating physician should perform a thorough evaluation to confirm the absence of such an obstruction prior to initiating therapy with Amitiza.

6.1 Clinical Studies Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Chronic Idiopathic Constipation

Adverse reactions in dose-finding, efficacy, and long-term clinical studies: The data described below reflect exposure to Amitiza in 1175 patients with chronic idiopathic constipation (29 at 24 mcg once daily, 1113 at 24 mcg twice daily, and 33 at 24 mcg three times daily) over 3- or 4-week, 6-month, and 12-month treatment periods; and from 316 patients receiving placebo over short-term exposure (less than or equal to 4 weeks). The total population (N = 1491) had a mean age of 49.7 (range 19–86) years; was 87.1% female; 84.8% Caucasian, 8.5% African American, 5.0% Hispanic, 0.9% Asian; and 15.5% elderly (greater than or equal to 65 years of age). Table 1 presents data for the adverse reactions that occurred in at least 1% of patients who received Amitiza 24 mcg twice daily and that occurred more frequently with study drug than placebo. In addition, corresponding adverse reaction incidences in patients receiving Amitiza 24 mcg once daily is shown.

Table 1: Percent of Patients with Adverse Reactions (Chronic Idiopathic Constipation)

System/Adverse Reaction1	Placebo N = 316 %	Amitiza 24 mcg Once Daily N = 29 %	Amitiza 24 mcg Twice Daily N = 1113 %
Gastrointestinal disorders
Nausea	3	17	29
Diarrhea	less than 1	7	12
Abdominal pain	3	3	8
Abdominal distension	2	-	6
Flatulence	2	3	6
Vomiting	-	-	3
Loose stools	-	-	3
Abdominal discomfort2	less than 1	3	2
Dyspepsia	less than 1	-	2
Dry mouth	less than 1	-	1
Stomach discomfort	less than 1	-	1
Nervous system disorders
Headache	5	3	11
Dizziness	less than 1	3	3
General disorders and site administration conditions
Edema	less than 1	-	3
Fatigue	less than 1	-	2
Chest discomfort/pain	-	3	2
Respiratory, thoracic, and mediastinal disorders
Dyspnea	-	3	2

1   Includes only those events associated with treatment (possibly, probably, or definitely related, as assessed by the investigator).
2   This term combines "abdominal tenderness," "abdominal rigidity," "gastrointestinal discomfort," and "abdominal discomfort."

Nausea: Approximately 29% of patients who received Amitiza 24 mcg twice daily experienced an adverse reaction of nausea; 4% of patients had severe nausea while 9% of patients discontinued treatment due to nausea. The rate of nausea associated with Amitiza (any dosage) was substantially lower among male (7%) and elderly patients (18%). Further analysis of the safety data revealed that long-term exposure to Amitiza does not appear to place patients at an elevated risk for experiencing nausea. The incidence of nausea increased in a dose-dependent manner with the lowest overall incidence for nausea reported at the 24 mcg once daily dosage (17%). In open-labeled, long-term studies, patients were allowed to adjust the dosage of Amitiza down to 24 mcg once daily from 24 mcg twice daily if experiencing nausea. Nausea decreased when Amitiza was administered with food. No patients in the clinical studies were hospitalized due to nausea.

Diarrhea: Approximately 12% of patients who received Amitiza 24 mcg twice daily experienced an adverse reaction of diarrhea; 2% of patients had severe diarrhea while 2% of patients discontinued treatment due to diarrhea.

Electrolytes: No serious adverse reactions of electrolyte imbalance were reported in clinical studies, and no clinically significant changes were seen in serum electrolyte levels in patients receiving Amitiza.

Less common adverse reactions: The following adverse reactions (assessed by investigator as probably or definitely related to treatment) occurred in less than 1% of patients receiving Amitiza 24 mcg twice daily in clinical studies, occurred in at least two patients, and occurred more frequently in patients receiving study drug than those receiving placebo: fecal incontinence, muscle cramp, defecation urgency, frequent bowel movements, hyperhidrosis, pharyngolaryngeal pain, intestinal functional disorder, anxiety, cold sweat, constipation, cough, dysgeusia, eructation, influenza, joint swelling, myalgia, pain, syncope, tremor, decreased appetite.

Irritable Bowel Syndrome with Constipation

Adverse reactions in dose-finding, efficacy, and long-term clinical studies: The data described below reflect exposure to Amitiza 8 mcg twice daily in 1011 patients with IBS-C for up to 12 months and from 435 patients receiving placebo twice daily for up to 16 weeks. The total population (N = 1267) had a mean age of 46.5 (range 18–85) years; was 91.6% female; 77.5% Caucasian, 12.9% African American, 8.6% Hispanic, 0.4% Asian; and 8.0% elderly (greater than or equal to 65 years of age). Table 2 presents data for the adverse reactions that occurred in at least 1% of patients who received Amitiza 8 mcg twice daily and that occurred more frequently with study drug than placebo.

Table 2: Percent of Patients with Adverse Reactions (IBS-C Studies)

System/Adverse Reaction1	Placebo N = 435 %	Amitiza 8 mcg Twice Daily N = 1011 %
Gastrointestinal disorders
Nausea	4	8
Diarrhea	4	7
Abdominal pain	5	5
Abdominal distension	2	3

1    Includes only those events associated with treatment (possibly or probably related, as assessed by the investigator).

Less common adverse reactions: The following adverse reactions (assessed by investigator as probably related to treatment) occurred in less than 1% of patients receiving Amitiza 8 mcg twice daily in clinical studies, occurred in at least two patients, and occurred more frequently in patients receiving study drug than those receiving placebo: dyspepsia, loose stools, vomiting, fatigue, dry mouth, edema, increased alanine aminotransferase, increased aspartate aminotransferase, constipation, eructation, gastroesophageal reflux disease, dyspnea, erythema, gastritis, increased weight, palpitations, urinary tract infection, anorexia, anxiety, depression, fecal incontinence, fibromyalgia, hard feces, lethargy, rectal hemorrhage, pollakiuria.

One open-labeled, long-term clinical study was conducted in patients with IBS-C receiving Amitiza 8 mcg twice daily. This study comprised 476 intent-to-treat patients (mean age 47.5 [range 21–82] years; 93.5% female; 79.2% Caucasian, 11.6% African American, 8.6% Hispanic, 0.2% Asian; 7.8% greater than or equal to 65 years of age) who were treated for an additional 36 weeks following an initial 12–16-week, double-blinded treatment period. The adverse reactions that were reported during this study were similar to those observed in the two double-blinded, controlled studies.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Amitiza 24 mcg for the treatment of chronic idiopathic constipation. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Voluntary reports of adverse reactions occurring with the use of Amitiza include the following: syncope, allergic-type reactions (including rash, swelling, and throat tightness), malaise, increased heart rate, muscle cramps or muscle spasms, rash, and asthenia.

8.1 Pregnancy

Teratogenic effects: Pregnancy Category C. [See Warnings and Precautions(5.1).]

Teratology studies with lubiprostone have been conducted in rats at oral doses up to 2000 mcg/kg/day (approximately 332 times the recommended human dose, based on body surface area), and in rabbits at oral doses of up to 100 mcg/kg/day (approximately 33 times the recommended human dose, based on body surface area). Lubiprostone was not teratogenic in rats or rabbits. In guinea pigs, lubiprostone caused fetal loss at repeated doses of 10 and 25 mcg/kg/day (approximately 2 and 6 times the highest recommended human dose, respectively, based on body surface area) administered on days 40 to 53 of gestation.

There are no adequate and well-controlled studies in pregnant women. However, during clinical testing of Amitiza, six women became pregnant. Per protocol, Amitiza was discontinued upon pregnancy detection. Four of the six women delivered healthy babies. The fifth woman was monitored for 1 month following discontinuation of study drug, at which time the pregnancy was progressing as expected; the patient was subsequently lost to follow-up. The sixth pregnancy was electively terminated.

Amitiza should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. If a woman is or becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus.

8.3 Nursing Mothers

It is not known whether lubiprostone is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from lubiprostone, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been studied.

8.5 Geriatric Use

Chronic Idiopathic Constipation

The efficacy of Amitiza in the elderly (≥ 65 years of age) subpopulation was consistent with the efficacy in the overall study population. Of the total number of constipated patients treated in the dose-finding, efficacy, and long-term studies of Amitiza, 15.5% were ≥ 65 years of age, and 4.2% were ≥ 75 years of age. Elderly patients taking Amitiza (any dosage) experienced a lower incidence rate of associated nausea compared to the overall study population taking Amitiza (18% vs. 29%, respectively).

Irritable Bowel Syndrome with Constipation

The safety profile of Amitiza in the elderly (≥ 65 years of age) subpopulation (8.0% were ≥ 65 years of age and 1.8% were ≥ 75 years of age) was consistent with the safety profile in the overall study population. Clinical studies of Amitiza did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients.

8.6 Renal Impairment

Amitiza has not been studied in patients who have renal impairment.

8.7 Hepatic Impairment

Amitiza has not been studied in patients who have hepatic impairment.

12.1 Mechanism of Action

Lubiprostone is a locally acting chloride channel activator that enhances a chloride-rich intestinal fluid secretion without altering sodium and potassium concentrations in the serum. Lubiprostone acts by specifically activating ClC-2, which is a normal constituent of the apical membrane of the human intestine, in a protein kinase A–independent fashion. 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. Patch clamp cell studies in human cell lines have indicated that the majority of the beneficial biological activity of lubiprostone and its metabolites is observed only on the apical (luminal) portion of the gastrointestinal epithelium. Additionally, activation of ClC-2 by lubiprostone has been shown to stimulate recovery of mucosal barrier function via the restoration of tight junction protein complexes in ex vivo studies of ischemic porcine intestine.

12.2 Pharmacodynamics

Although the pharmacologic effects of lubiprostone in humans have not been fully evaluated, animal studies have shown that oral administration of lubiprostone increases chloride ion transport into the intestinal lumen, enhances fluid secretion into the bowels, and improves fecal transit.

12.3 Pharmacokinetics

Lubiprostone has low systemic availability following oral administration and concentrations of lubiprostone in plasma are below the level of quantitation (10 pg/mL). Therefore, standard pharmacokinetic parameters such as area under the curve (AUC), maximum concentration (Cmax), and half-life (t½) cannot be reliably calculated. However, the pharmacokinetic parameters of M3 (only measurable active metabolite of lubiprostone) have been characterized. Gender has no effect on the pharmacokinetics of M3 following the oral administration of lubiprostone.

Absorption

Concentrations of lubiprostone in plasma are below the level of quantitation (10 pg/mL) because lubiprostone has a low systemic availability following oral administration. Peak plasma levels of M3, after a single oral dose with 24 mcg of lubiprostone, occurred at approximately 1.10 hours. The Cmax was 41.5 pg/mL and the mean AUC0–t was 57.1 pg∙hr/mL. The AUC0–t of M3 increases dose proportionally after single 24-mcg and 144-mcg doses of lubiprostone.

Distribution

In vitro protein binding studies indicate lubiprostone is approximately 94% bound to human plasma proteins. Studies in rats given radiolabeled lubiprostone indicate minimal distribution beyond the gastrointestinal tissues. Concentrations of radiolabeled lubiprostone at 48 hours post-administration were minimal in all tissues of the rats.

Metabolism

The results of both human and animal studies indicate that lubiprostone is rapidly and extensively metabolized by 15-position reduction, α-chain β-oxidation, and ω-chain ω-oxidation. These biotransformations are not mediated by the hepatic cytochrome P450 system but rather appear to be mediated by the ubiquitously expressed carbonyl reductase. M3, a metabolite of lubiprostone found in both humans and animals, is formed by the reduction of the carbonyl group at the 15-hydroxy moiety that consists of both α-hydroxy and β-hydroxy epimers. M3 makes up less than 10% of the dose of radiolabeled lubiprostone. Animal studies have shown that metabolism of lubiprostone rapidly occurs within the stomach and jejunum, most likely in the absence of any systemic absorption. This is presumed to be the case in humans as well.

Elimination

Lubiprostone could not be detected in plasma; however, M3 has a t½ ranging from 0.9 to 1.4 hours. After a single oral dose of 72 mcg of 3H-labeled lubiprostone, 60% of total administered radioactivity was recovered in the urine within 24 hours and 30% of total administered radioactivity was recovered in the feces by 168 hours. Lubiprostone and M3 are only detected in trace amounts in human feces.

Food Effect

A study was conducted with a single 72-mcg dose of 3H-labeled lubiprostone to evaluate the potential of a food effect on lubiprostone absorption, metabolism, and excretion. Pharmacokinetic parameters of total radioactivity demonstrated that Cmax decreased by 55% while AUC0–∞ was unchanged when lubiprostone was administered with a high-fat meal. The clinical relevance of the effect of food on the pharmacokinetics of lubiprostone is not clear. However, lubiprostone was administered with food and water in a majority of clinical trials.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Two 2-year oral (gavage) carcinogenicity studies (one in Crl:B6C3F1 mice and one in Sprague-Dawley rats) were conducted with lubiprostone. In the 2-year carcinogenicity study in mice, lubiprostone doses of 25, 75, 200, and 500 mcg/kg/day (approximately 2, 6, 17, and 42 times the highest recommended human dose, respectively, based on body surface area) were used. In the 2-year rat carcinogenicity study, lubiprostone doses of 20, 100, and 400 mcg/kg/day (approximately 3, 17, and 68 times the highest recommended human dose, respectively, based on body surface area) were used. In the mouse carcinogenicity study, there was no significant increase in any tumor incidences. There was a significant increase in the incidence of interstitial cell adenoma of the testes in male rats at the 400 mcg/kg/day dose. In female rats, treatment with lubiprostone produced hepatocellular adenoma at the 400 mcg/kg/day dose.

Mutagenesis

Lubiprostone was not genotoxic in the in vitro Ames reverse mutation assay, the in vitro mouse lymphoma (L5178Y TK +/–) forward mutation assay, the in vitro Chinese hamster lung (CHL/IU) chromosomal aberration assay, and the in vivo mouse bone marrow micronucleus assay.

Impairment of Fertility

Lubiprostone, at oral doses of up to 1000 mcg/kg/day, had no effect on the fertility and reproductive function of male and female rats. However, the number of implantation sites and live embryos were significantly reduced in rats at the 1000 mcg/kg/day dose as compared to control. The number of dead or resorbed embryos in the 1000 mcg/kg/day group was higher compared to the control group, but was not statistically significant. The 1000 mcg/kg/day dose in rats is approximately 166 times the highest recommended human dose of 48 mcg/day, based on body surface area.

14.2 Irritable Bowel Syndrome with Constipation

Efficacy Studies

Two double-blinded, placebo-controlled studies of similar design were conducted in patients with IBS-C. IBS was defined as abdominal pain or discomfort occurring over at least 6 months with two or more of the following: 1) relieved with defecation; 2) onset associated with a change in stool frequency; and 3) onset associated with a change in stool form. Patients were sub-typed as having IBS-C if they also experienced two of three of the following: 1) less than 3 spontaneous bowel movements per week, 2) greater than 25% hard stools, and 3) greater than 25% spontaneous bowel movements associated with straining.

Following a 4-week baseline/washout period, a total of 1154 patients (mean age 46.6 [range 18–85] years; 91.6% female; 77.4% Caucasian, 13.2% African American, 8.5% Hispanic, 0.4% Asian; 8.3% greater than or equal to 65 years of age) were randomized and received Amitiza 8 mcg twice daily (16 mcg/day) or placebo twice daily for 12 weeks. The primary efficacy endpoint was assessed weekly utilizing the patient's response to a global symptom relief question based on a 7-point, balanced scale ("significantly worse" to "significantly relieved"): "How would you rate your relief of IBS symptoms (abdominal discomfort/pain, bowel habits, and other IBS symptoms) over the past week compared to how you felt before you entered the study?"

The primary efficacy analysis was a comparison of the proportion of "overall responders" in each arm. A patient was considered an "overall responder" if the criteria for being designated a "monthly responder" were met in at least 2 of the 3 months on study. A "monthly responder" was defined as a patient who had reported "significantly relieved" for at least 2 weeks of the month or at least "moderately relieved" in all 4 weeks of that month. During each monthly evaluation period, patients reporting "moderately worse" or "significantly worse" relief, an increase in rescue medication use, or those who discontinued due to lack of efficacy, were deemed non-responders.

The percentage of patients in Study 1 qualifying as an "overall responder" was 13.8% in the group receiving Amitiza 8 mcg twice daily compared to 7.8% of patients receiving placebo twice daily. In Study 2, 12.1% of patients in the Amitiza 8 mcg group were "overall responders" versus 5.7% of patients in the placebo group. In both studies, the treatment differences between the placebo and Amitiza groups were statistically significant.

Results in men: The two randomized, placebo-controlled, double-blinded studies comprised 97 (8.4%) male patients, which is insufficient to determine whether men with IBS-C respond differently to Amitiza from women.

Study 1 also assessed the rebound effect from the withdrawal of Amitiza. Following 12 weeks of treatment with Amitiza 8 mcg twice daily, withdrawal of Amitiza did not result in a rebound effect.

17.1 Dosing Instructions

Amitiza should be taken twice daily with food and water to reduce potential symptoms of nausea. The capsule should be taken once in the morning and once in the evening daily as prescribed. The capsule should be swallowed whole and should not be broken apart or chewed. Physicians and patients should periodically assess the need for continued therapy.

Patients on treatment who experience severe nausea, diarrhea, or dyspnea should inform their physician. Patients taking Amitiza may experience dyspnea within an hour of the first dose. This symptom generally resolves within 3 hours, but may recur with repeat dosing.

Chronic Idiopathic Constipation

Patients should take a single 24 mcg capsule of Amitiza twice daily with food and water.

Irritable Bowel Syndrome with Constipation

Patients should take a single 8 mcg capsule of Amitiza twice daily with food and water.

Marketed by:

Sucampo Pharma Americas, Inc.
Bethesda, MD 20814

and

Takeda Pharmaceuticals America, Inc.
Deerfield, IL 60015

Amitiza® is a registered trademark of Sucampo Pharmaceuticals, Inc.

Relabeling of "Additional Barcode" by:
Physicians Total Care, Inc.
Tulsa, OK     74146

amitiza®
(lubiprostone) capsules
8 mcg

Rx Only

Store at 25°C (77°F); excursions 15°-30°C (59°-86°F).