Amitiza (Page 2 of 6)

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.

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

7 DRUG INTERACTIONS

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.

8 USE IN SPECIFIC POPULATIONS

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

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.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

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.

8.6 Renal Impairment

No dosage adjustment is required in patients with renal impairment [see ]. Clinical Pharmacology ( ) 12.3

8.7 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 normal subjects [see ]. Clinical safety results demonstrated an increased incidence and severity of adverse events in subjects with greater severity of hepatic impairment. Clinical Pharmacology ( ) 12.3

In case of chronic idiopathic constipation or opioid-induced constipation indications, the starting dosage of Amitiza should be reduced in patients with moderate hepatic impairment. The starting dose of Amitiza should be reduced in all patients with severe hepatic impairment, regardless of the indication [see ]. No dosing adjustment is required in patients with mild hepatic impairment (Child-Pugh Class A). Dosage and Administration ( , ) 2.12.2

10 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%).

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