Amitiza 8 MCG Oral Capsule
DRUG INTERACTIONS
7 Based upon the results of in vitro human microsome studies, there is low likelihood of drug–drug interactions.
In vitro studies using human liver microsomes indicate that cytochrome P450 isoenzymes are not involved in the metabolism of lubiprostone.
Further in vitro studies indicate microsomal carbonyl reductase may be involved in the extensive biotransformation of lubiprostone to the metabolite M3 (See Pharmacokinetics [12.3] .).
Additionally, in vitro studies in human liver microsomes demonstrate that lubiprostone does not inhibit cytochrome P450 isoforms 3A4, 2D6, 1A2, 2A6, 2B6, 2C9, 2C19, or 2E1, and in vitro studies of primary cultures of human hepatocytes show no induction of cytochrome P450 isoforms 1A2, 2B6, 2C9, and 3A4 by lubiprostone.
No drug–drug interaction studies have been performed.
Based on the available information, no protein binding–mediated drug interactions of clinical significance are anticipated.
OVERDOSAGE
10 There have been two confirmed reports of overdosage with Amitiza.
The first report involved a 3-year-old child who accidentally ingested 7 or 8 capsules of 24 mcg of Amitiza and fully recovered.
The second report was a study patient who self-administered a total of 96 mcg of Amitiza per day for 8 days.
The patient experienced no adverse reactions during this time.
Additionally, in a Phase 1 cardiac repolarization study, 38 of 51 patients given a single oral dose of 144 mcg of Amitiza (6 times the highest recommended dose) experienced an adverse event that was at least possibly related to the study drug.
Adverse reactions that occurred in at least 1% of these patients included the following: nausea (45%), diarrhea (35%), vomiting (27%), dizziness (14%), headache (12%), abdominal pain (8%), flushing/hot flash (8%), retching (8%), dyspnea (4%), pallor (4%), stomach discomfort (4%), anorexia (2%), asthenia (2%), chest discomfort (2%), dry mouth (2%), hyperhidrosis (2%), and syncope (2%).
DESCRIPTION
11 Amitiza (lubiprostone) is chemically designated as (–)-7-[(2 R ,4a R ,5 R ,7a R )-2-(1,1-difluoropentyl)-2-hydroxy-6-oxooctahydrocyclopenta[ b ]pyran-5-yl]heptanoic acid.
The molecular formula of lubiprostone is C 20 H 32 F 2 O 5 with a molecular weight of 390.46 and a chemical structure as follows: Lubiprostone drug substance occurs as white, odorless crystals or crystalline powder, is very soluble in ether and ethanol, and is practically insoluble in hexane and water.
Amitiza is available as an imprinted, oval, soft gelatin capsule in two strengths.
Pink capsules contain 8 mcg of lubiprostone and the following inactive ingredients: medium-chain triglycerides, gelatin, sorbitol, ferric oxide, titanium dioxide, and purified water.
Orange capsules contain 24 mcg of lubiprostone and the following inactive ingredients: medium-chain triglycerides, gelatin, sorbitol, FD&C Red #40, D&C Yellow #10, and purified water.
image of chemical structure
CLINICAL STUDIES
14 14.1 Chronic Idiopathic Constipation Dose-finding Study A dose-finding, double-blinded, parallel-group, placebo-controlled, Phase 2 study was conducted in patients with chronic idiopathic constipation.
Following a 2-week baseline/washout period, patients (N = 127) were randomized to receive placebo (n = 33), Amitiza 24 mcg/day (24 mcg once daily; n = 29), Amitiza 48 mcg/day (24 mcg twice daily; n = 32), or Amitiza 72 mcg/day (24 mcg three times daily; n = 33) for 3 weeks.
Patients were chosen for participation based on their need for relief of constipation, which was defined as less than 3 spontaneous bowel movements (SBMs) per week.
The primary efficacy variable was the daily average number of SBMs.
The study demonstrated that all patients who took Amitiza experienced a noticeable improvement in clinical response.
Based on the efficacy analysis, there was no statistically significant improvement in the clinical response beyond a total daily dose of 24 mcg during treatment weeks 2 and 3 (Figure 1).
Figure 1: Weekly Mean (± Standard Error) Spontaneous Bowel Movements (Dose-finding Study) Efficacy Studies Two double-blinded, placebo-controlled studies of identical design were conducted in patients with chronic idiopathic constipation.
Chronic idiopathic constipation was defined as, on average, less than 3 SBMs per week 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 47.2 [range 20–81] years; 88.9% female; 80.8% Caucasian, 9.6% African American, 7.3% Hispanic, 1.5% Asian; 10.9% ≥ 65 years of age) were randomized and received Amitiza 24 mcg twice daily (48 mcg/day) 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 3).
Table 3: Spontaneous Bowel Movement Frequency Rates1 (Efficacy Studies) Trial Study Arm Baseline Mean ± SD Median Week 1 Mean ± SD Median Week 2 Mean ± SD Median Week 3 Mean ± SD Median Week 4 Mean ± SD Median Week 1 Change from Baseline Mean ± SD Median Week 4 Change from Baseline Mean ± SD Median Placebo 1.6 ± 1.3 1.5 3.5 ± 2.3 3.0 3.2 ± 2.5 3.0 2.8 ± 2.2 2.0 2.9 ± 2.4 2.3 1.9 ± 2.2 1.5 1.3 ± 2.5 1.0 Study 1 Amitiza 24 mcg Twice Daily 1.5 ± 0.8 1.5 5.7 ± 4.4 5.0 5.1 ± 4.1 4.0 5.3 ± 4.9 5.0 5.3 ± 4.7 4.0 4.3 ± 4.3 3.5 3.9 ± 4.6 3.0 Placebo 1.5 ± 0.8 1.5 4.0 ± 2.7 3.5 3.6 ± 2.7 3.0 3.4 ± 2.8 3.0 3.5 ± 2.9 3.0 2.5 ± 2.6 1.5 1.9 ± 2.7 1.5 Study 2 Amitiza 24 mcg Twice Daily 1.3 ± 0.9 1.5 5.9 ± 4.0 5.0 5.0 ± 4.2 4.0 5.6 ± 4.6 5.0 5.4 ± 4.8 4.3 4.6 ± 4.1 3.8 4.1 ± 4.8 3.0 1 Frequency rates are calculated as 7 times (number of SBMs) / (number of days observed for that week).
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 (56.7% vs.
36.9% in Study 1 and 62.9% vs.
31.9% 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 (≥ 65 years of age).
Following 4 weeks of treatment with Amitiza 24 mcg twice daily, withdrawal of Amitiza did not result in a rebound effect.
Long-term Studies Three open-labeled, long-term clinical safety and efficacy studies were conducted in patients with chronic idiopathic constipation receiving Amitiza 24 mcg twice daily.
These studies comprised 871 patients (mean age 51.0 [range 19–86] years; 86.1% female; 86.9% Caucasian, 7.3% African American, 4.5% Hispanic, 0.7% Asian; 18.4% ≥ 65 years of age) who were treated for 6–12 months (24–48 weeks).
Patients provided regular assessments of abdominal bloating, abdominal discomfort, and constipation severity.
These studies demonstrated that Amitiza decreased abdominal bloating, abdominal discomfort, and constipation severity over the 6–12-month treatment periods.
image of figure 1 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.
HOW SUPPLIED
16 /STORAGE AND HANDLING Amitiza is available as an oval, soft gelatin capsule containing 8 mcg or 24 mcg of lubiprostone with “SPI” printed on one side.
Amitiza is available as follows: 8-mcg pink capsule Bottles of 60 ( NDC 54868-6153-0 ) 24-mcg orange capsule Bottles of 60 ( NDC 54868-5971-0 ) Store at 25°C (77°F); excursions permitted to 15°–30°C (59°–86°F).
PROTECT FROM EXTREME TEMPERATURES.
GERIATRIC USE
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.
DOSAGE FORMS AND STRENGTHS
3 Amitiza is available as an oval, gelatin capsule containing 8 mcg or 24 mcg of lubiprostone.
8-mcg capsules are pink and are printed with “SPI” on one side 24-mcg capsules are orange and are printed with “SPI” on one side Gelatin capsules: 8 mcg and 24 mcg (3)
MECHANISM OF ACTION
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.
INDICATIONS AND USAGE
1 Enter section text here Amitiza is a chloride channel activator indicated for: Treatment of chronic idiopathic constipation in adults (1.1) Treatment of irritable bowel syndrome with constipation in women ≥ 18 years old (1.2) 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.
PEDIATRIC USE
8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been studied.
PREGNANCY
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.
NUSRING MOTHERS
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.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Enter section text here Women who could become pregnant should have a negative pregnancy test prior to beginning therapy and should be capable of complying with effective contraceptive measures (8.1) Use during pregnancy only if the potential benefit justifies the potential risk to the fetus (5.1) Patients may experience nausea; concomitant administration of food may reduce this symptom (5.2) Do not prescribe for patients that have severe diarrhea (5.3) Patients taking Amitiza may experience dyspnea within an hour of first dose.
This symptom generally resolves within 3 hours, but may recur with repeat dosing (5.4) Evaluate patients with symptoms suggestive of mechanical gastrointestinal obstruction prior to initiating treatment with Amitiza (5.5) 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.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Enter section text here 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
DOSAGE AND ADMINISTRATION
2 Amitiza should be taken twice daily orally with food and water.
Physicians and patients should periodically assess the need for continued therapy.
Chronic idiopathic constipation 24 mcg taken twice daily orally with food and water (2.1) Irritable bowel syndrome with constipation 8 mcg taken twice daily orally with food and water (2.2) 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.