Chemical formula: C₂₀H₃₂F₂O₅ Molecular mass: 390.468 g/mol PubChem compound: 157920
Following oral administration, concentrations of lubiprostone in plasma are below the level of quantitation; however, one of the metabolites, M3, has measurable systemic concentrations. Limited available data with lubiprostone use in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes. Animal reproduction studies did not show an increase in structural malformations. Although 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/m²)), these effects were probably secondary to maternal toxicity and occurred after the period of organogenesis (see Data).
The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
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 (MRHD) based on body surface area (mg/m²). 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 (situs inversus, 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/m²)); however, these effects were probably secondary to maternal toxicity. 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 MRHD based on body surface area (mg/m²)). 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.
There are no data available on the presence of lubiprostone in human milk or the effect of lubiprostone on milk production. There are limited data available on the effect of lubiprostone on the breastfed infant. Neither lubiprostone nor its active metabolite (M3) were present in the milk of lactating rats. When a drug is not present in animal milk, it is likely that the drug will not be present in human milk. If present, lubiprostone may cause diarrhea in the breastfed infant. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for lubiprostone and any potential adverse effects on the breastfed infant from lubiprostone or from the underlying maternal condition.
Infants of nursing mothers being treated with lubiprostone should be monitored for diarrhea.
Two 2-year oral (gavage) carcinogenicity studies (one in Crl:B6C3F1 mice and one in Sprague-Dawley rats) were conducted with lubiprostone. In the 2-year carcinogenicity study in mice, lubiprostone doses of 25, 75, 200, and 500 mcg/kg/day (approximately 2, 6, 17, and 42 times the maximum recommended human dose, respectively, based on body surface area (mg/m²)) were used. In the 2-year rat carcinogenicity study, lubiprostone doses of 20, 100, and 400 mcg/kg/day (approximately 3, 17, and 68 times the maximum recommended human dose, respectively, based on body surface area (mg/m²)) were used. In the mouse carcinogenicity study, there was no significant increase in any tumor incidences. There was a significant increase in the incidence of interstitial cell adenoma of the testes in male rats at the 400 mcg/kg/day dose. In female rats, treatment with lubiprostone produced hepatocellular adenoma at the 400 mcg/kg/day dose.
Lubiprostone was not genotoxic in the in vitro Ames reverse mutation assay, the in vitro mouse lymphoma (L5178Y TK +/−) forward mutation assay, the in vitro Chinese hamster lung (CHL/IU) chromosomal aberration assay, and the in vivo mouse bone marrow micronucleus assay.
Lubiprostone, at oral doses of up to 1000 mcg/kg/day, had no effect on the fertility and reproductive function of male and female rats. However, the number of implantation sites and live embryos were significantly reduced in rats at the 1000 mcg/kg/day dose as compared to control. The number of dead or resorbed embryos in the 1000 mcg/kg/day group was higher compared to the control group, but was not statistically significant. The 1000 mcg/kg/day dose in rats is approximately 169 times the maximum recommended human dose of 48 mcg/day, based on body surface area (mg/m²).
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 lubiprostone for CIC, OIC, and IBS-C, 1648 patients were treated with lubiprostone for 6 months and 710 patients were treated for 1 year (not mutually exclusive).
Adverse reactions in adult dose-finding, efficacy, and long-term clinical studies: The data described below reflect exposure to lubiprostone 24 mcg twice daily in 1113 patients with CIC over 3- or 4-week, 6-month, and 12-month treatment periods; and from 316 patients receiving placebo over short-term exposure (≤4 weeks). The placebo population (N=316) had a mean age of 48 (range 21 to 81) years; was 87% female; 81% Caucasian, 10% African American, 7% Hispanic, 1% Asian, and 12% elderly (≥65 years of age). Of those patients treated with lubiprostone 24 mcg twice daily (N=1113), the mean age was 50 (range 19-86) years; 87% were female; 86% Caucasian, 8% African American, 5% Hispanic, 1% Asian, and 17% elderly (≥65 years of age).
The most common adverse reactions (>4%) in CIC were nausea, diarrhea, headache, abdominal pain, abdominal distension, and flatulence.
Table 1 presents data for the adverse reactions that occurred in at least 1% of patients and that occurred more frequently with lubiprostone than placebo.
Table 1. Adverse Reactions* in Clinical Trials of Adults with CIC:
| System/Adverse Reaction | Placebo | Lubiprostone 24 mcg Twice Daily |
|---|---|---|
| N=31 % | N=1113 % | |
| Nausea | 3 | 29 |
| Diarrhea | 1 | 12 |
| Headache | 5 | 11 |
| Abdominal pain | 3 | 8 |
| Abdominal distension | 2 | 6 |
| Flatulence | 2 | 6 |
| Vomiting | 0 | 3 |
| Loose stools | 0 | 3 |
| Edema | <1 | 3 |
| Abdominal discomfort?footnote? | 1 | 3 |
| Dizziness | 1 | 3 |
| Chest discomfort/pain | 0 | 2 |
| Dyspnea | 0 | 2 |
| Dyspepsia | <1 | 2 |
| Fatigue | 1 | 2 |
| Dry mouth | <1 | 1 |
* Reported in at least 1% of patients treated with lubiprostone and greater than placebo
† This term combines “abdominal tenderness,” “abdominal rigidity,” “gastrointestinal discomfort,” “stomach discomfort”, and "abdominal discomfort."
Nausea: Approximately 29% of patients who received lubiprostone experienced nausea; 4% of patients had severe nausea and 9% of patients discontinued treatment due to nausea. The rate of nausea was lower among male (8%) and elderly (19%) patients. No patients in the clinical studies were hospitalized due to nausea.
Diarrhea: Approximately 12% of patients who received lubiprostone experienced diarrhea; 2% of patients had severe diarrhea and 2% of patients discontinued treatment due to diarrhea.
Electrolytes: No serious adverse reactions of electrolyte imbalance were reported in clinical studies, and no clinically significant changes were seen in serum electrolyte levels in patients receiving lubiprostone.
Less common adverse reactions (<1%): fecal incontinence, muscle cramp, defecation urgency, frequent bowel movements, hyperhidrosis, pharyngolaryngeal pain, intestinal functional disorder, anxiety, cold sweat, constipation, cough, dysgeusia, eructation, influenza, joint swelling, myalgia, pain, syncope, tremor, decreased appetite.
Adverse reactions in adult efficacy and long-term clinical studies: The data described below reflect exposure to lubiprostone 24 mcg twice daily in 860 patients with OIC for up to 12 months and from 632 patients receiving placebo twice daily for up to 12 weeks. The total population (N=1492) had a mean age of 50 (range 20–89) years; was 63% female; 83% Caucasian, 14% African American, 1% American Indian/Alaska Native, 1% Asian; 5% were of Hispanic ethnicity, and 9% were elderly (≥65 years of age).
The most common adverse reactions (>4%) in OIC were nausea and diarrhea.
Table 2 presents data for the adverse reactions that occurred in at least 1% of patients and that occurred more frequently with study drug than placebo.
Table 2. Adverse Reactions* in Clinical Trials of Adults with OIC:
| System/Adverse Reaction* | Placebo | Lubiprostone 24 mcg Twice Daily |
|---|---|---|
| N=632 % | N=860 % | |
| Nausea | 5 | 11 |
| Diarrhea | 2 | 8 |
| Abdominal pain | 1 | 4 |
| Flatulence | 3 | 4 |
| Abdominal distension | 2 | 3 |
| Vomiting | 2 | 3 |
| Headache | 1 | 2 |
| Peripheral edema | <1 | 1 |
| Abdominal discomfort† | 1 | 1 |
* Reported in at least 1% of patients treated with lubiprostone and greater than placebo
† This term combines “abdominal tenderness,” “abdominal rigidity,” “gastrointestinal discomfort,” “stomach discomfort”, and "abdominal discomfort."
Nausea: Approximately 11% of patients who received lubiprostone experienced nausea; 1% of patients had severe nausea and 2% of patients discontinued treatment due to nausea.
Diarrhea: Approximately 8% of patients who received lubiprostone experienced diarrhea; 2% of patients had severe diarrhea and 1% of patients discontinued treatment due to diarrhea.
Less common adverse reactions (<1%): fecal incontinence, blood potassium decreased.
Adverse reactions in adult dose-finding, efficacy, and long-term clinical studies: The data described below reflect exposure to lubiprostone 8 mcg twice daily in 1011 patients with IBS-C for up to 12 months and from 435 patients receiving placebo twice daily for up to 16 weeks. The total population (N=1267) had a mean age of 47 (range 18–85) years; was 92% female; 78% Caucasian, 13% African American, 9% Hispanic, 0.4% Asian, and 8% elderly (≥65 years of age).
The most common adverse reactions (>4%) in IBS-C were nausea, diarrhea, and abdominal pain.
Table 3 presents data for the adverse reactions that occurred in at least 1% of patients and that occurred more frequently with study drug than placebo.
Table 3. Adverse Reactions* in Clinical Trials of Adults with IBS-C:
| System/Adverse Reaction | Placebo | Lubiprostone 8 mcg Twice Daily |
|---|---|---|
| N=435 % | N=1011 % | |
| Nausea | 4 | 8 |
| Diarrhea | 4 | 7 |
| Abdominal pain | 5 | 5 |
| Abdominal distension | 2 | 3 |
* Reported in at least 1% of patients treated with lubiprostone and greater than placebo
Nausea: Approximately 8% of patients who received lubiprostone 8 mcg twice daily experienced nausea; 1% of patients had severe nausea and 1% of patients discontinued treatment due to nausea.
Diarrhea: Approximately 7% of patients who received lubiprostone 8 mcg twice daily experienced diarrhea; <1% of patients had severe diarrhea and <1% of patients discontinued treatment due to diarrhea.
Less common adverse reactions (<1%): dyspepsia, loose stools, vomiting, fatigue, dry mouth, edema, increased alanine aminotransferase, increased aspartate aminotransferase, constipation, eructation, gastroesophageal reflux disease, dyspnea, erythema, gastritis, increased weight, palpitations, urinary tract infection, anorexia, anxiety, depression, fecal incontinence, fibromyalgia, hard feces, lethargy, rectal hemorrhage, pollakiuria.
The following additional adverse reactions have been identified during post-approval use of lubiprostone. 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, tachycardia
Gastrointestinal: ischemic colitis
General: asthenia
Immune System: hypersensitivity reactions including rash, swelling, and throat tightness malaise
Muscoskeletal: muscle cramps or muscle spasms.
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