Amitiza Information
Amitiza () Dosage And Administration
Amitiza () should be taken orally with food and water. Physicians and patients should periodically assess the need for continued therapy.
Amitiza () Dosage Forms And Strengths
Amitiza () is available as an oval, gelatin capsule containing 8 mcg or 24 mcg of lubiprostone.
Amitiza () Contraindications
Amitiza () is contraindicated in patients with known or suspected mechanical gastrointestinal obstruction.
Amitiza () Adverse Reactions
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:
Nausea:
Diarrhea:
Electrolytes:
Less common adverse reactions:
Irritable Bowel Syndrome with Constipation
Adverse reactions in dose-finding, efficacy, and long-term clinical studies:
Less common adverse reactions:
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% ≥ 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.
The following additional 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, and asthenia.
Amitiza () Drug Interactions
Based upon the results of human microsome studies, there is low likelihood of 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. No drug–drug interaction studies have been performed. Based on the available information, no protein binding–mediated drug interactions of clinical significance are anticipated.
Amitiza () Use In Specific Populations
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.
Amitiza () Overdosage
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%).
Amitiza () Description
Amitiza () (lubiprostone) is chemically designated as (–)-7-[(2,4a,5,7a)-2-(1,1-difluoropentyl)-2-hydroxy-6-oxooctahydrocyclopenta[]pyran-5-yl]heptanoic acid. The molecular formula of lubiprostone is CHFO 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.
Amitiza () Clinical Pharmacology
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 (C), and half-life (t) 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 C was 41.5 pg/mL and the mean AUC was 57.1 pg∙hr/mL. The AUC of M3 increases dose proportionally after single 24-mcg and 144-mcg doses of lubiprostone.
Distribution
In vitro
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 t ranging from 0.9 to 1.4 hours. After a single oral dose of 72 mcg of H-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 H-labeled lubiprostone to evaluate the potential of a food effect on lubiprostone absorption, metabolism, and excretion. Pharmacokinetic parameters of total radioactivity demonstrated that C decreased by 55% while AUC 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.
Special Populations
Amitiza () Clinical Studies
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 4).
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.
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) 25% hard stools, and 3) > 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% ≥ 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:
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.
Amitiza () How Supplied/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
24-mcg orange capsule
Amitiza ()
Amitiza ()
