Amitiza 0.024 MG Oral Capsule
DRUG INTERACTIONS
7 No drug-drug interaction studies have been performed with Amitiza.
in vivo Based upon the results of human microsome studies, there is low likelihood of pharmacokinetic drug-drug interactions.
studies using human liver microsomes indicate that cytochrome P450 isoenzymes are not involved in the metabolism of lubiprostone.
Further studies indicate microsomal carbonyl reductase may be involved in the extensive biotransformation of lubiprostone to the metabolite M3 [see ].
Additionally, studies in human liver microsomes demonstrate that lubiprostone does not inhibit cytochrome P450 isoforms 3A4, 2D6, 1A2, 2A6, 2B6, 2C9, 2C19, or 2E1, and studies of primary cultures of human hepatocytes show no induction of cytochrome P450 isoforms 1A2, 2B6, 2C9, and 3A4 by lubiprostone.
Based on the available information, no protein binding–mediated drug interactions of clinical significance are anticipated.
in vitro In vitro in vitro Clinical Pharmacology (12.3) in vitro in vitro Interaction potential with diphenylheptane opioids (e.g.
methadone): Non-clinical studies have shown opioids of the diphenylheptane chemical class (e.g., methadone) 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.
Concomitant use of diphenylheptane opioids (e.g., methadone) may interfere with the efficacy of Amitiza ( ) • 7
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 healthy volunteers 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 volunteers 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 a chloride channel activator for oral use.
The chemical name for lubiprostone is (–)-7-[(2 ,4a ,5 ,7a )-2-(1,1-difluoropentyl)-2-hydroxy-6-oxooctahydrocyclopenta[ ]pyran-5-yl]heptanoic acid.
The molecular formula of lubiprostone is C H F O with a molecular weight of 390.46 and a chemical structure as follows: R R R R b 20 32 2 5 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.
Chemical Structure
CLINICAL STUDIES
14 14.1 Chronic Idiopathic Constipation 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 spontaneous bowel movements (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 47.2 [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 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 5).
Table 5: Spontaneous Bowel Movement Frequency Rates Frequency rates are calculated as 7 times (number of SBMs) / (number of days observed for that week).
(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 1.4 ± 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 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).
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 The efficacy of Amitiza in the treatment of opioid-induced constipation 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 20–82) and 63.1% were female.
In Study 2, the median age was 50 years (range 21–77) and 64.4% were female.
In Study 3, the median age was 50 years (range 21–89) and 60.1% 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 ≥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.
and 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 24.3% in the group receiving Amitiza compared to 15.4% 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 15.3% in the patients receiving Amitiza compared to 13.0% 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% (1/47) in the group receiving Amitiza compared to 12.2% (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 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) 25% hard stools, and 3) > 25% SBMs 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% ≥ 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.
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.
Results in men: During a 4-week randomized withdrawal period following Study 1, patients who received Amitiza during the 12-week treatment period were re-randomized to receive either placebo or to continue treatment with Amitiza.
In Amitiza-treated patients who were “overall responders” during Study 1 and who were re-randomized to placebo, SBM frequency rates did not result in worsening compared to baseline.
HOW SUPPLIED
16 /STORAGE AND HANDLING NDC:68151-5003-6 in a PACKAGE of 1 CAPSULE, GELATIN COATEDS
RECENT MAJOR CHANGES
Indications and Usage ( ) 1.2 04/2013 Dosage and Administration ( ) 2.1 04/2013 Warnings and Precautions, Pregnancy ( ) 5.1 removed 11/2012
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 24 mcg twice daily experienced a lower rate of associated nausea compared to the overall study population taking Amitiza (19% vs.
29%, respectively).
Opioid -induced Constipation The safety profile of Amitiza in the elderly (≥ 65 years of age) subpopulation (8.8% were ≥ 65 years of age and 1.6% 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.
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 • 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.
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 studies of ischemic porcine intestine.
ex vivo
INDICATIONS AND USAGE
1 Amitiza is a chloride channel activator indicated for: Treatment of chronic idiopathic constipation in adults • (1.1) Treatment of opioid-induced constipation in adults with chronic, non-cancer pain ( ) • 1.2 Treatment of irritable bowel syndrome with constipation in women ≥ 18 years old • (1.3) Limitations of Use: Effectiveness of Amitiza in the treatment of opioid-induced constipation in patients taking diphenylheptane opioids (e.g., methadone) has not been established ( ) ( ) 1 14.2 1.1 Chronic Idiopathic Constipation Amitiza is indicated for the treatment of chronic idiopathic constipation in adults.
® 1.2 Opioid-induced Constipation Amitiza is indicated for the treatment of opioid -induced constipation (OIC) in adults with chronic non-cancer pain.
Limitations of Use: • Effectiveness of Amitiza in the treatment of opioid -induced constipation in patients taking diphenylheptane opioids (e.g., methadone) has not been established.
[see Clinical Studies ( )] 14.2 1.3 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 established.
PREGNANCY
8.1 Pregnancy Pregnancy Category C.
Risk Summary There are no adequate and well-controlled studies with Amitiza in pregnant women.
A dose dependent increase in fetal loss was observed in pregnant guinea pigs that received lubiprostone doses equivalent to 0.2 to 6 times the maximum recommended human dose (MRHD) based on body surface area (mg/m ).
Animal studies did not show an increase in structural malformations.
Amitiza should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
2 Clinical Considerations Current available data suggest that miscarriage occurs in 15-18% of clinically recognized pregnancies, regardless of any drug exposure.
Consider the risks and benefits of available therapies when treating a pregnant woman for chronic idiopathic constipation, opioid-induced constipation or irritable bowel syndrome with constipation.
Animal Data In developmental toxicity studies, pregnant rats and rabbits received oral lubiprostone during organogenesis at doses up to approximately 338 times (rats) and approximately 34 times (rabbits) the maximum recommended human dose (MHRD) based on body surface area (mg/m ).
Maximal animal doses were 2000 mcg/kg/day (rats) and 100 mcg/kg/day (rabbits).
In rats, there were increased incidences of early resorptions and soft tissue malformations ( cleft palate) at the 2000 mcg/kg/day dose; however, these effects were probably secondary to maternal toxicity.
A dose-dependent increase in fetal loss occurred when guinea pigs received lubiprostone after the period of organogenesis, on days 40 to 53 of gestation, at daily oral doses of 1, 10, and 25 mcg/kg/day (approximately 0.2, 2 and 6 times the MRHD based on body surface area (mg/m )).
The potential of lubiprostone to cause fetal loss was also examined in pregnant Rhesus monkeys.
Monkeys received lubiprostone post-organogenesis on gestation days 110 through 130 at daily oral doses of 10 and 30 mcg/kg/day (approximately 3 and 10 times the MHRD based on body surface area (mg/m )).
Fetal loss was noted in one monkey from the 10-mcg/kg dose group, which is within normal historical rates for this species.
There was no drug-related adverse effect seen in monkeys.
2 situs inversus , 2 2
NUSRING MOTHERS
8.3 Nursing Mothers It is not known whether lubiprostone is excreted in human milk.
In rats, neither lubiprostone nor its active metabolites were detectable in breast milk following oral administration of lubiprostone.
Because lubiprostone increases fluid secretion in the intestine and intestinal motility, human milk-fed infants should be monitored for diarrhea.
Caution should be exercised when Amitiza is administered to a nursing woman.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Patients may experience nausea; concomitant administration of food may reduce this symptom • (5.1) Do not prescribe for patients that have severe diarrhea • (5.2) 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 • (5.3) Evaluate patients with symptoms suggestive of mechanical gastrointestinal obstruction prior to initiating treatment with Amitiza • (5.4) 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 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 discontinue Amitiza and inform their physician if severe diarrhea occurs [see ].
Adverse Reactions ( ) 6.1 5.3 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 30–60 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.
5.4 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.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Physicians and patients should periodically assess the need for continued therapy.
17.1 Nausea, Dyspnea or Diarrhea Instruct patients to take Amitiza twice daily with food and water to reduce the occurrence of nausea.
Patients taking Amitiza may experience dyspnea within an hour of the first dose.
Dyspnea generally resolves within 3 hours, but may recur with repeat dosing.
Patients on treatment who experience severe nausea, dyspnea, or diarrhea should notify their physician.
17.2 Nursing Mothers Advise lactating women to monitor their human milk-fed infants for diarrhea while taking Amitiza [see ].
Use in Specific Populations ( ) 8.3 Marketed by: Sucampo Pharma Americas, LLC Bethesda, MD 20814 and Takeda Pharmaceuticals America, Inc.
Deerfield, IL 60015 Amitiza is a registered trademark of Sucampo AG.
®
DOSAGE AND ADMINISTRATION
2 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.
Capsules should be swallowed whole and should not be broken apart or chewed ( ) 2 Chronic Idiopathic Constipation and Opioid -induced Constipation 24 mcg taken twice daily orally with food and water • (2.1) Reduce the dosage in patients with moderate and severe hepatic impairment ( ) 2.1 Irritable Bowel Syndrome with Constipation 8 mcg taken twice daily orally with food and water • (2.2) Reduce the dosage in patients with severe hepatic impairment ( ) 2.2 2.1 Chronic Idiopathic Constipation and Opioid-induced Constipation The recommended dose is 24 mcg twice daily orally with food and water.
Dosage in patients with hepatic impairment For patients with moderately impaired hepatic function (Child-Pugh Class B), the recommended starting dose is 16 mcg twice daily.
For patients with severely impaired hepatic function (Child-Pugh Class C), the recommended starting dose is 8 mcg twice daily.
If this dose is tolerated and an adequate response has not been obtained after an appropriate interval, doses can then be escalated to full dosing with appropriate monitoring of patient response and .
[see Use in Specific Populations ( ) 8.7 Clinical Pharmacology ( )] 12.3 2.2 Irritable Bowel Syndrome with Constipation The recommended dose is 8 mcg twice daily orally with food and water.
Dosage in patients with hepatic impairment For patients with severely impaired hepatic function (Child-Pugh Class C), the recommended starting dose is 8 mcg once daily.
If this dose is tolerated and an adequate response has not been obtained after an appropriate interval, doses can then be escalated to full dosing with appropriate monitoring of patient response.
Dosage adjustment is not required for patients with moderately impaired hepatic function (Child-Pugh Class B) .
[see Use in Specific Populations ( ) and Clinical Pharmacology ( )] 8.7 12.3