1.1 Chronic Idiopathic Constipation in Adults

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

1.2 Opioid-Induced Constipation in Adult Patients with Chronic Non-Cancer Pain

Amitiza is indicated for the treatment of opioid-induced constipation (OIC) in adult patients with chronic non-cancer pain, including patients with chronic pain related to prior cancer or its treatment who do not require frequent (e.g., weekly) opioid dosage escalation.

1.3 Irritable Bowel Syndrome with Constipation

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

2.1 Recommended Dosage

The recommended oral dosage of Amitiza by indication and adjustments for patients with moderate (Child Pugh Class B) and severe (Child Pugh Class C) hepatic impairment are shown in Table 1.

2.2 Administration Instructions

• Take Amitiza orally with food and water.
• Swallow capsules whole and do not break apart or chew.
• Physicians and patients should periodically assess the need for continued therapy.

5.1 Nausea

Patients taking Amitiza may experience nausea. Concomitant administration of food with Amitiza may reduce symptoms of nausea [see Adverse Reactions (6.1)].

5.2 Diarrhea

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 healthcare provider if severe diarrhea occurs [see Adverse Reactions (6.1)].

5.3 Syncope and Hypotension

Syncope and hypotension have been reported with Amitiza in the postmarketing setting and a few of these adverse reactions resulted in hospitalization. Most cases occurred in patients taking 24 mcg twice daily and some occurred within an hour after taking the first dose or subsequent doses of Amitiza. Some patients had concomitant diarrhea or vomiting prior to developing the adverse reaction. Syncope and hypotension generally resolved following Amitiza discontinuation or prior to next dose, but recurrence has been reported with subsequent doses. Several cases reported concomitant use of medications known to lower blood pressure, which may increase the risk for the development of syncope or hypotension.

Patients should be aware of the risk of syncope and hypotension during treatment and that other adverse reactions may increase this risk, such as diarrhea or vomiting.

5.4 Dyspnea

In clinical trials, dyspnea was reported by 3%, 1%, and < 1% of the treated CIC, OIC, and IBS-C populations receiving Amitiza, respectively, compared to 0%, 1%, and < 1% of placebo-treated patients. There have been postmarketing reports of dyspnea when using Amitiza 24 mcg twice daily. Some patients have discontinued treatment 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 to 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. Instruct patients to contact their healthcare provider if dyspnea occurs.

5.5 Bowel Obstruction

In patients with symptoms suggestive of mechanical gastrointestinal obstruction, perform a thorough evaluation to confirm the absence of an obstruction prior to initiating therapy with Amitiza [see Contraindication (4)].

6.1 Clinical Trials 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.

During clinical development of Amitiza for CIC, OIC, and IBS-C, 1648 patients were treated with Amitiza for 6 months and 710 patients were treated for 1 year (not mutually exclusive).

6.2 Postmarketing Experience

The following additional adverse reactions have been identified during post-approval use of Amitiza. 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.

Cardiovascular: syncope and/or hypotension [see Warnings and Precautions (5.3)], tachycardia

Gastrointestinal: ischemic colitis

General: asthenia

Immune System: hypersensitivity reactions including rash, swelling, and throat tightness malaise

Muscoskeletal: muscle cramps or muscle spasms.

7.1 Methadone

Diphenylheptane opioids (e.g., methadone) have been shown in nonclinical studies to dose-dependently reduce the activation of ClC-2 by lubiprostone in the gastrointestinal tract. There is a possibility of a dose-dependent decrease in the efficacy of Amitiza in patients using diphenylheptane opioids. No in vivo interaction studies have been conducted.

The effectiveness of Amitiza in the treatment of OIC in patients taking diphenylhepatane opioids (e.g., methadone) has not been established [see Indications and Usage (1.2)].

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Safety and effectiveness have not been established in pediatric patients with IBS-C, pediatric functional constipation (PFC), and OIC.

Efficacy was not demonstrated for the treatment of PFC in patients 6 years of age and older in a 12 week, randomized, double-blind, placebo-controlled trial conducted in 606 patients 6 to 17 years with PFC comparing Amitiza to placebo. The primary efficacy endpoint was an overall response based on spontaneous bowel movement frequency over the duration of the trial; the treatment difference from placebo was not statistically significant. In this age group, adverse reactions to Amitiza were similar to those reported in adults. In a 36-week, long-term safety extension trial after approximately 9 months of treatment with Amitiza, a single case of reversible elevation of ALT (17-times upper limit of normal [ULN]), AST (13-times ULN), and GGT (9-times [ULN]) was observed in a child with baseline elevated values (less than or equal to 2.5-times ULN).

8.5 Geriatric Use

8.6 Hepatic Impairment

Patients with moderate hepatic impairment (Child-Pugh Class B) and severe hepatic impairment (Child-Pugh Class C) experienced markedly higher systemic exposure of lubiprostone active metabolite M3, when compared to subjects with normal hepatic function [see Clinical Pharmacology (12.3)]. Clinical safety results demonstrated an increased incidence and severity of adverse events in subjects with greater severity of hepatic impairment.

Adjust the dosage of Amitiza in patients with severe hepatic impairment for all indications. Dosage adjustment is also needed for patients with moderate hepatic impairment treated for CIC, and OIC [see Dosage and Administration (2.1)]. No dosing adjustment is required in patients with mild hepatic impairment (Child-Pugh Class A).

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.

Lubiprostone, via activation of apical ClC-2 channels in intestinal epithelial cells, bypasses the antisecretory action of opiates that results from suppression of secretomotor neuron excitability.

Activation of ClC-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.

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

Following oral administration, 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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14.1 Chronic Idiopathic Constipation in Adults

Two double-blinded, placebo-controlled studies of identical design were conducted in patients with CIC. CIC was defined as, on average, less than 3 SBMs per week (a SBM is a bowel movement occurring in the absence of laxative use) along with one or more of the following symptoms of constipation for at least 6 months prior to randomization: 1) very hard stools for at least a quarter of all bowel movements; 2) sensation of incomplete evacuation following at least a quarter of all bowel movements; and 3) straining with defecation at least a quarter of the time.

Following a 2-week baseline/washout period, a total of 479 patients (mean age 47 [range 20 to 81] years; 89% female; 81% Caucasian, 10% African American, 7% Hispanic, 2% Asian, 11% at least 65 years of age) were randomized and received Amitiza 24 mcg twice daily or placebo twice daily for 4 weeks. The primary endpoint of the studies was SBM frequency. The studies demonstrated that patients treated with Amitiza had a higher frequency of SBMs during Week 1 than the placebo patients. In both studies, results similar to those in Week 1 were also observed in Weeks 2, 3, and 4 of therapy (Table 6).

In both studies, Amitiza demonstrated increases in the percentage of patients who experienced SBMs within the first 24 hours after administration when compared to placebo (57% vs. 37% in Study 1 and 63% vs. 32% in Study 2, respectively). Similarly, the time to first SBM was shorter for patients receiving Amitiza than for those receiving placebo.

Signs and symptoms related to constipation, including abdominal bloating, abdominal discomfort, stool consistency, and straining, as well as constipation severity ratings, were also improved with Amitiza versus placebo. The results were consistent in subpopulation analyses for gender, race, and elderly patients at least 65 years of age.

During a 7-week randomized withdrawal study, patients who received Amitiza during a 4-week treatment period were then randomized to receive either placebo or to continue treatment with Amitiza. In Amitiza-treated patients randomized to placebo, SBM frequency rates returned toward baseline within 1 week and did not result in worsening compared to baseline. Patients who continued on Amitiza maintained their response to therapy over the additional 3 weeks of treatment.

14.2 Opioid-Induced Constipation in Adults with Chronic Non-Cancer Pain

The efficacy of Amitiza in the treatment of OIC in patients receiving opioid therapy for chronic, non-cancer-related pain was assessed in three randomized, double-blinded, placebo-controlled studies. In Study 1, the median age was 52 years (range 20 to 82) and 63% were female. In Study 2, the median age was 50 years (range 21 to 77) and 64% were female. In Study 3, the median age was 50 years (range 21 to 89) and 60% were female. Patients had been receiving stable opioid therapy for at least 30 days prior to screening, which was to continue throughout the 12-week treatment period. At baseline, mean oral morphine equivalent daily doses (MEDDs) were 99 mg and 130 mg for placebo-treated and Amitiza-treated patients, respectively, in Study 1. Baseline mean MEDDs were 237 mg and 265 mg for placebo-treated and Amitiza-treated patients, respectively, in Study 2. In Study 3, baseline mean MEDDs were 330 mg and 373 mg for placebo-treated and Amitiza-treated patients, respectively. The Brief Pain Inventory-Short Form (BPI-SF) questionnaire was administered to patients at baseline and monthly during the treatment period to assess pain control. Patients had documented opioid-induced constipation at baseline, defined as having less than 3 spontaneous bowel movements (SBMs) per week, with at least 25% of SBMs associated with one or more of the following conditions: (1) hard to very hard stool consistency; (2) moderate to very severe straining; and/or (3) having a sensation of incomplete evacuation. Laxative use was discontinued at the beginning of the screening period and throughout the study. With the exception of the 48-hour period prior to first dose and for at least 72 hours (Study 1) or 1 week (Study 2 and Study 3) following first dose, use of rescue medication was allowed in cases where no bowel movement had occurred in a 3-day period. Median weekly SBM frequencies at baseline were 1.5 for placebo patients and 1.0 for Amitiza patients in Study 1 and, for both Study 2 and Study 3, median weekly SBM frequencies at baseline were 1.5 for both treatment groups.

In Study 1, patients receiving non-diphenylheptane (e.g., non-methadone) opioids (n = 431) were randomized to receive placebo (n = 217) or Amitiza 24 mcg twice daily (n = 214) for 12 weeks. The primary efficacy analysis was a comparison of the proportion of "overall responders" in each treatment arm. A patient was considered an "overall responder" if ≥1 SBM improvement over baseline were reported for all treatment weeks for which data were available and ≥3 SBMs/week were reported for at least 9 of 12 treatment weeks. The proportion of patients in Study 1 qualifying as an "overall responder" was 27.1% in the group receiving Amitiza 24 mcg twice daily compared to 18.9% of patients receiving placebo twice daily (treatment difference = 8.2%; p-value = 0.03). Examination of gender and race subgroups did not identify differences in response to Amitiza among these subgroups. There were too few elderly patients (≥ 65 years of age) to adequately assess differences in effects in that population.

In Study 2, patients receiving opioids (N = 418) were randomized to receive placebo (n = 208) or Amitiza 24 mcg twice daily (n = 210) for 12 weeks. Study 2 did not exclude patients receiving diphenylheptane opioids (e.g., methadone). The primary efficacy endpoint was the mean change from baseline in SBM frequency at Week 8; 3.3 vs. 2.4 for Amitiza and placebo-treated patients, respectively; treatment difference = 0.9; p-value = 0.004. The proportion of patients in Study 2 qualifying as an "overall responder," as prespecified in Study 1, was 24% in the group receiving Amitiza compared to 15% of patients receiving placebo. In the subgroup of patients in Study 2 taking diphenylheptane opioids (baseline mean [median] MEDDs of 691 [403] mg and 672 [450] mg for placebo and Amitiza patients, respectively), the proportion of patients qualifying as an "overall responder" was 20.5% (8/39) in the group receiving Amitiza compared to 6.3% (2/32) of patients receiving placebo. Examination of gender and race subgroups did not identify differences in response to Amitiza among these subgroups. There were too few elderly patients (≥ 65 years of age) to adequately assess differences in effects in that population.

In Study 3, patients receiving opioids (N = 451) were randomized to placebo (n = 216) or Amitiza 24 mcg twice daily (n = 235) for 12 weeks. Study 3 did not exclude patients receiving diphenylheptane opioids (e.g., methadone). The primary efficacy endpoint was the change from baseline in SBM frequency at Week 8. The study did not demonstrate a statistically significant improvement in SBM frequency rates at Week 8 (mean change from baseline of 2.7 vs. 2.5 for Amitiza and placebo-treated patients, respectively; treatment difference = 0.2; p-value = 0.76). The proportion of patients in Study 3 qualifying as an "overall responder," as prespecified in Study 1, was 15% in the patients receiving Amitiza compared to 13% of patients receiving placebo. In the subgroup of patients in Study 3 taking diphenylheptane opioids (baseline mean [median] MEDDs of 730 [518] mg and 992 [480] mg for placebo and Amitiza patients, respectively), the proportion of patients qualifying as an "overall responder" was 2% (1/47) in the group receiving Amitiza compared to 12% (5/41) of patients receiving placebo.

14.3 Irritable Bowel Syndrome with Constipation

Two double-blinded, placebo-controlled studies of similar design were conducted in adult 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) <3 spontaneous bowel movements (SBMs) per week, 2) >25% hard stools, and 3) >25% SBMs associated with straining.

Following a 4-week baseline/washout period, a total of 1154 patients (mean age 47 [range 18 to 85] years; 92% female; 77% Caucasian, 13% African American, 9% Hispanic, 0.4% Asian; 8% at least 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 14% in the group receiving Amitiza 8 mcg twice daily compared to 8% of patients receiving placebo twice daily. In Study 2, 12% of patients in the Amitiza 8 mcg group were "overall responders" versus 6% of patients in the placebo group. In both studies, the treatment differences between the placebo and Amitiza groups were statistically significant.

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

Protect from light and extreme temperatures.

Diarrhea

Inform patients that they may experience diarrhea during treatment with Amitiza. Instruct patients to discontinue Amitiza and contact their healthcare provider if severe diarrhea occurs [see Warnings and Precautions (5.2)].

Syncope and Hypotension

Inform patients that they may experience syncope and hypotension after taking the first dose or subsequent doses of Amitiza. Syncope and hypotension generally resolve prior to the next dose, but may recur with repeat dosing. Instruct patients to discontinue Amitiza and to contact their healthcare provider if these reactions occur [see Warnings and Precautions (5.3)]. Inform patients that other adverse reactions may increase the risk of syncope and hypotension, such as diarrhea or vomiting.

Dyspnea

Inform patients that they may experience dyspnea within an hour of the first dose. Dyspnea generally resolves within 3 hours, but may recur with repeat dosing. Instruct patients to inform their healthcare provider if dyspnea occurs [see Warnings and Precautions (5.4)].

Lactation

Advise lactating women to monitor their human milk-fed infants for diarrhea while taking Amitiza [see Use in Specific Populations (8.2)].