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LUBIPROSTONE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Lubiprostone is a chloride-channel activator in the apical membrane of the gastrointestinal epithelium that enhances intestinal fluid secretion without altering sodium and potassium levels in the serum.

Specific Substances

    1) Lubiprostona
    2) Lubiprostonum
    3) RU-0211
    4) SPI-0211
    5) (-)-7-[(2R,4aR,5R,7aR)-2-(1,1-Difluoropentyl)-2-hydroxy-6-oxooctahydrocyclopenta[b]pyran-5-yl]heptanoic acid
    6) Molecular Formula: C20-H32-F2-O5
    7) CAS 136790-76-6
    8) CAS 333963-40-9

Available Forms Sources

    A) FORMS
    1) Lubiprostone is available as capsules containing 8 mcg and 24 mcg of lubiprostone for oral administration (Prod Info AMITIZA(R) oral capsules, 2008).
    B) USES
    1) Lubiprostone is used to treat adult patients with chronic idiopathic constipation (Prod Info AMITIZA(R) oral capsules, 2008).
    2) Lubiprostone is also used to treat women (18 years and older) with irritable bowel syndrome and constipation (Prod Info AMITIZA(R) oral capsules, 2008).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Lubiprostone is used to treat adult patients with chronic idiopathic constipation and irritable bowel syndrome with constipation.
    B) PHARMACOLOGY: Lubiprostone is a chloride channel activator that acts locally to increase intestinal fluid secretion. It specifically activates the ClC2 receptor, a chloride channel that resides in the apical membrane of the intestine. Increased chloride-containing intestinal fluid secretion results, functioning to increase motility and the passage of stools through the intestine. Activation of ClC2 is independent of protein kinase A. In vitro studies have indicated that the activity of lubiprostone and its metabolites is primarily only on the apical (luminal) epithelium of the gastrointestinal tract. Sodium and potassium concentrations in the serum are not affected.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: Nausea, diarrhea, and headache. OTHER EFFECTS: Abdominal pain, flatulence, vomiting, dyspepsia, sinusitis, urinary tract infections, upper respiratory tract infection, dizziness, peripheral edema, fatigue, chest pain or discomfort, fever, arthralgia, back pain, pain in extremity, muscle cramp, dyspnea, cough, weight increase, depression, anxiety, insomnia, and hypertension.
    E) WITH POISONING/EXPOSURE
    1) Overdose data is limited. The following adverse events were reported in 51 patients who received a single oral dose of 144 mcg of lubiprostone (6 times the normal single dose): nausea (45.1%), vomiting (27.5%), diarrhea (25.5%), dizziness (17.6%), loose or watery stools (13.7%), headache (11.8%), retching (7.8%), abdominal pain (5.9%), flushing (5.9%), dyspnea (3.9%), pallor (3.9%), stomach discomfort (3.9%), syncope (3.9%), upper abdominal pain (2%), anorexia (2%), asthenia (2%), chest discomfort (2%), dry mouth (2%), hyperhidrosis (2%), skin irritation (2%), and vasovagal episode (2%).
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) Fever has been reported in patients taking lubiprostone in clinical trials.
    0.2.20) REPRODUCTIVE
    A) Lubiprostone is classified as US pregnancy category C. There are no adequate and well-controlled studies of lubiprostone in pregnant women. Although animal studies in monkeys and rabbits showed no increase in structural malformations, increased incidences of early resorptions and soft tissue malformations (situs inversus, cleft palate) were noted when lubiprostone was administered to rats during organogenesis at the maternally toxic doses (approximately 338 times the recommended human dose, based on BSA). In addition, a dose-dependent increase in fetal loss occurred when lubiprostone was administered to guinea pigs. Therefore, it is recommended that lubiprostone be used in pregnant women only if the potential benefit outweighs the potential risk to the fetus.

Laboratory Monitoring

    A) Monitor vital signs in symptomatic patients.
    B) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with vomiting or diarrhea.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Severe toxicity is not expected after overdose of lubiprostone.
    C) DECONTAMINATION
    1) PREHOSPITAL: Lubiprostone undergoes minimal absorption from the gastrointestinal tract. Severe toxicity is not expected after overdose of lubiprostone. Gastrointestinal decontamination is generally not necessary.
    2) HOSPITAL: Lubiprostone undergoes minimal absorption from the gastrointestinal tract. Severe toxicity is not expected after overdose of lubiprostone. Gastrointestinal decontamination is generally not necessary. Consider activated charcoal only after very large ingestions or if coingestants with significant toxicity are involved.
    D) AIRWAY MANAGEMENTS
    1) Should not be required in these cases.
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION
    1) There is no information regarding the effectiveness of hemodialysis or hemoperfusion for the removal of lubiprostone from plasma. Since systemic absorption is minimal, methods to enhance systemic elimination are unlikely to be necessary.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours to assess electrolyte and fluid balance and gastrointestinal function. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients should be admitted for severe vomiting, profuse diarrhea, severe abdominal pain, dehydration, and electrolyte abnormalities.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    H) PHARMACOKINETICS
    1) Lubiprostone has low systemic availability after oral administration. It is approximately 94% bound to human plasma proteins. Following administration of a single, oral 72-mcg dose of radiolabeled lubiprostone, 60% of the total administered radioactivity was recovered in the urine within 24 hours; 30% of the total administered radioactivity was recovered in the feces within 168 hours. The half-life of M3, the active metabolite of lubiprostone, is 0.9 to 1.4 hours.
    I) DIFFERENTIAL DIAGNOSIS
    1) Patients with a history of decreased gastrointestinal motility due to other causes. Patients with underlying cardiac dysrhythmias or electrolyte imbalance may develop more severe symptoms.

Range Of Toxicity

    A) Overdose data is limited. An adult took 96 mcg/day for 8 days without adverse effects. A 3-year-old ingested 7 or 8 capsules of lubiprostone (24 mcg each) and recovered. The following adverse events were reported in a Phase 1 cardiac repolarization study after 51 patients received a single oral dose of 144 mcg of lubiprostone (6 times the normal single dose): Nausea, vomiting, diarrhea, dizziness, loose or watery stools, headache, retching, abdominal pain, flushing, dyspnea, pallor, stomach discomfort, syncope, upper abdominal pain, anorexia, asthenia, chest discomfort, dry mouth, hyperhidrosis, skin irritation, and vasovagal episode.
    B) THERAPEUTIC DOSE: ADULTS: Chronic idiopathic constipation: 24 mcg orally twice daily. Irritable bowel syndrome with constipation: 8 mcg orally twice daily. CHILDREN: The safety and efficacy of lubiprostone have not been established in children.

Clinical Effects

Summary Of Exposure

    A) USES: Lubiprostone is used to treat adult patients with chronic idiopathic constipation and irritable bowel syndrome with constipation.
    B) PHARMACOLOGY: Lubiprostone is a chloride channel activator that acts locally to increase intestinal fluid secretion. It specifically activates the ClC2 receptor, a chloride channel that resides in the apical membrane of the intestine. Increased chloride-containing intestinal fluid secretion results, functioning to increase motility and the passage of stools through the intestine. Activation of ClC2 is independent of protein kinase A. In vitro studies have indicated that the activity of lubiprostone and its metabolites is primarily only on the apical (luminal) epithelium of the gastrointestinal tract. Sodium and potassium concentrations in the serum are not affected.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: Nausea, diarrhea, and headache. OTHER EFFECTS: Abdominal pain, flatulence, vomiting, dyspepsia, sinusitis, urinary tract infections, upper respiratory tract infection, dizziness, peripheral edema, fatigue, chest pain or discomfort, fever, arthralgia, back pain, pain in extremity, muscle cramp, dyspnea, cough, weight increase, depression, anxiety, insomnia, and hypertension.
    E) WITH POISONING/EXPOSURE
    1) Overdose data is limited. The following adverse events were reported in 51 patients who received a single oral dose of 144 mcg of lubiprostone (6 times the normal single dose): nausea (45.1%), vomiting (27.5%), diarrhea (25.5%), dizziness (17.6%), loose or watery stools (13.7%), headache (11.8%), retching (7.8%), abdominal pain (5.9%), flushing (5.9%), dyspnea (3.9%), pallor (3.9%), stomach discomfort (3.9%), syncope (3.9%), upper abdominal pain (2%), anorexia (2%), asthenia (2%), chest discomfort (2%), dry mouth (2%), hyperhidrosis (2%), skin irritation (2%), and vasovagal episode (2%).

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Fever has been reported in patients taking lubiprostone in clinical trials.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) FEVER - Pyrexia occurred in 1.1% of patients (n=1113) in clinical trials who received lubiprostone 24 micrograms twice daily for the treatment of chronic idiopathic constipation, compared to 0.3% of patients (n=316) who received placebo (Prod Info Amitiza(R) oral capsules, 2011).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) PERIPHERAL EDEMA
    1) WITH THERAPEUTIC USE
    a) Peripheral edema occurred in 3.8% of patients (n=1113) in clinical trials who received lubiprostone 24 micrograms twice daily for the treatment of chronic idiopathic constipation, compared to 0.3% of patients (n=316) who received placebo (Prod Info Amitiza(R) oral capsules, 2011).
    B) CHEST PAIN
    1) WITH THERAPEUTIC USE
    a) Chest pain occurred in 1.1% of patients (n=1113) in clinical trials who received lubiprostone 24 micrograms twice daily for the treatment of chronic idiopathic constipation, compared to 0% of patients (n=316) who received placebo (Prod Info Amitiza(R) oral capsules, 2011).
    b) Chest discomfort occurred in 1.6% of patients (n=1113) in clinical trials who received lubiprostone 24 micrograms twice daily for the treatment of chronic idiopathic constipation, compared to 0% of patients (n=316) who received placebo (Prod Info Amitiza(R) oral capsules, 2011).
    C) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypertension occurred in 1% of patients (n=1113) in clinical trials who received lubiprostone 24 micrograms twice daily for the treatment of chronic idiopathic constipation, compared to 0% of patients (n=316) who received placebo (Prod Info Amitiza(R) oral capsules, 2011).
    D) SYNCOPE
    1) WITH POISONING/EXPOSURE
    a) In a study of 51 patients taking a single oral dose of 144 mcg of lubiprostone (6 times the normal single dose), syncope was reported in 3.9% (Prod Info Amitiza(R) oral capsules, 2011).
    E) CHEST DISCOMFORT
    1) WITH POISONING/EXPOSURE
    a) In a study of 51 patients taking a single oral dose of 144 mcg of lubiprostone (6 times the normal single dose), chest discomfort was reported in 2% (Prod Info Amitiza(R) oral capsules, 2011).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) SINUSITIS
    1) WITH THERAPEUTIC USE
    a) Sinusitis occurred in 4.9% of patients (n=1113) in clinical trials who received lubiprostone 24 micrograms twice daily for the treatment of chronic idiopathic constipation, compared to 1.6% of patients (n=316) who received placebo (Prod Info Amitiza(R) oral capsules, 2011).
    B) UPPER RESPIRATORY INFECTION
    1) WITH THERAPEUTIC USE
    a) Upper respiratory tract infections occurred in 3.7% of patients (n=1113) in clinical trials who received lubiprostone 24 micrograms twice daily for the treatment of chronic idiopathic constipation, compared to 0.9% of patients (n=316) who received placebo (Prod Info Amitiza(R) oral capsules, 2011).
    C) INFLUENZA
    1) WITH THERAPEUTIC USE
    a) Influenza occurred in 2% of patients (n=1113) in clinical trials who received lubiprostone 24 micrograms twice daily for the treatment of chronic idiopathic constipation, compared to 0.6% of patients (n=316) who received placebo (Prod Info Amitiza(R) oral capsules, 2011).
    D) BRONCHITIS
    1) WITH THERAPEUTIC USE
    a) Bronchitis occurred in 1.6% of patients (n=1113) in clinical trials who received lubiprostone 24 micrograms twice daily for the treatment of chronic idiopathic constipation, compared to 0.3% of patients (n=316) who received placebo (Prod Info Amitiza(R) oral capsules, 2011).
    E) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) Dyspnea occurred in 2.4% of patients (n=1113) in clinical trials who received lubiprostone 24 micrograms twice daily for the treatment of chronic idiopathic constipation, compared to 0% of patients (n=316) who received placebo (Prod Info Amitiza(R) oral capsules, 2011).
    2) WITH POISONING/EXPOSURE
    a) In a study of 51 patients taking a single oral dose of 144 mcg of lubiprostone (6 times the normal single dose), dyspnea was reported in 3.9% (Prod Info Amitiza(R) oral capsules, 2011).
    F) COUGH
    1) WITH THERAPEUTIC USE
    a) Cough occurred in 1.6% of patients (n=1113) in clinical trials who received lubiprostone 24 micrograms twice daily for the treatment of chronic idiopathic constipation, compared to 0.6% of patients (n=316) who received placebo (Prod Info Amitiza(R) oral capsules, 2011).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache occurred in 13.2% of patients (n=1113) in clinical trials who received lubiprostone 24 micrograms twice daily for the treatment of chronic idiopathic constipation, compared to 6.6% of patients (n=316) who received placebo (Prod Info Amitiza(R) oral capsules, 2011).
    2) WITH POISONING/EXPOSURE
    a) In a study of 51 patients taking a single oral dose of 144 mcg of lubiprostone (6 times the normal single dose), headache was reported in 11.8% (Prod Info Amitiza(R) oral capsules, 2011).
    B) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness occurred in 4.1% of patients (n=1113) in clinical trials who received lubiprostone 24 micrograms twice daily for the treatment of chronic idiopathic constipation, compared to 1.3% of patients (n=316) who received placebo (Prod Info Amitiza(R) oral capsules, 2011).
    C) INSOMNIA
    1) WITH THERAPEUTIC USE
    a) Insomnia occurred in 1.4% of patients (n=1113) in clinical trials who received lubiprostone 24 micrograms twice daily for the treatment of chronic idiopathic constipation, compared to 0.6% of patients (n=316) who received placebo (Prod Info Amitiza(R) oral capsules, 2011).
    D) ANXIETY
    1) WITH THERAPEUTIC USE
    a) Anxiety occurred in 1.4% of patients (n=1113) in clinical trials who received lubiprostone 24 micrograms twice daily for the treatment of chronic idiopathic constipation, compared to 0.3% of patients (n=316) who received placebo (Prod Info Amitiza(R) oral capsules, 2011).
    E) ASTHENIA
    1) WITH POISONING/EXPOSURE
    a) In a study of 51 patients taking a single oral dose of 144 mcg of lubiprostone (6 times the normal single dose), asthenia was reported in 2% (Prod Info Amitiza(R) oral capsules, 2011).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA
    1) WITH THERAPEUTIC USE
    a) Nausea occurred in 31.1% of patients (n=1113) in clinical trials who received lubiprostone 24 micrograms (mcg) twice daily for the treatment of chronic idiopathic constipation, compared to 5.1% of patients (n=316) who received placebo. Of the 31.1% of patients with nausea, 3.4% had severe nausea while 8.7% discontinued therapy due to nausea. Nausea is a dose-dependent adverse effect with an incidence of 17.2% with a dose of 24 mcg once daily, although cumulative exposure does not increase the incidence. Administration of lubiprostone with food also decreases nausea. The incidence of nausea is lower in males (13.2%) and in elderly patients (18.6%) (Prod Info Amitiza(R) oral capsules, 2011).
    2) WITH POISONING/EXPOSURE
    a) In a study of 51 patients taking a single oral dose of 144 mcg of lubiprostone (6 times the normal single dose), nausea was reported in 45.1% (Prod Info Amitiza(R) oral capsules, 2011).
    B) VOMITING
    1) WITH THERAPEUTIC USE
    a) Vomiting occurred in 4.6% of patients (n=1113) in clinical trials who received lubiprostone 24 micrograms twice daily for the treatment of chronic idiopathic constipation, compared to 0.9% of patients (n=316) who received placebo (Prod Info Amitiza(R) oral capsules, 2011).
    2) WITH POISONING/EXPOSURE
    a) In a study of 51 patients taking a single oral dose of 144 mcg of lubiprostone (6 times the normal single dose), vomiting was reported in 27.5% of these patients (Prod Info Amitiza(R) oral capsules, 2011).
    C) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea occurred in 13.2% of patients (n=1113) in clinical trials who received lubiprostone 24 micrograms twice daily for the treatment of chronic idiopathic constipation, compared to 0.9% of patients (n=316) who received placebo. Of the 13.2% of patients with diarrhea, 3.4% had severe diarrhea while 2.2% discontinued therapy due to diarrhea. Diarrhea does not appear to be dose-dependent. Clinically significant changes in electrolyte balances were not observed in clinical trials (Prod Info Amitiza(R) oral capsules, 2011).
    2) WITH POISONING/EXPOSURE
    a) In a study of 51 patients taking a single oral dose of 144 mcg of lubiprostone (6 times the normal single dose), diarrhea and loose or watery stools were reported in 25.5% and 13.7% of these patients, respectively (Prod Info Amitiza(R) oral capsules, 2011).
    D) ABDOMINAL DISTENSION
    1) WITH THERAPEUTIC USE
    a) Abdominal distension occurred in 7.1% of patients (n=1113) in clinical trials who received lubiprostone 24 micrograms twice daily for the treatment of chronic idiopathic constipation, compared to 2.2% of patients (n=316) who received placebo (Prod Info Amitiza(R) oral capsules, 2011).
    E) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Abdominal pain occurred in 6.7% of patients (n=1113) in clinical trials who received lubiprostone 24 micrograms twice daily for the treatment of chronic idiopathic constipation, compared to 2.8% of patients (n=316) who received placebo (Prod Info Amitiza(R) oral capsules, 2011).
    b) Lower abdominal pain occurred in 1.9% of patients (n=1113) in clinical trials who received lubiprostone 24 micrograms twice daily for the treatment of chronic idiopathic constipation, compared to 0.6% of patients (n=316) who received placebo (Prod Info Amitiza(R) oral capsules, 2011).
    c) Abdominal discomfort occurred in 1.5% of patients (n=1113) in clinical trials who received lubiprostone 24 micrograms twice daily for the treatment of chronic idiopathic constipation, compared to 0% of patients (n=316) who received placebo (Prod Info Amitiza(R) oral capsules, 2011).
    2) WITH POISONING/EXPOSURE
    a) In a study of 51 patients taking a single oral dose of 144 mcg of lubiprostone (6 times the normal single dose), abdominal pain and stomach discomfort were reported in 5.9% (2% upper abdominal pain) and 3.9% of these patients, respectively (Prod Info Amitiza(R) oral capsules, 2011).
    F) FLATULENCE/WIND
    1) WITH THERAPEUTIC USE
    a) Flatulence occurred in 6.1% of patients (n=1113) in clinical trials who received lubiprostone 24 micrograms twice daily for the treatment of chronic idiopathic constipation, compared to 1.9% of patients (n=316) who received placebo (Prod Info Amitiza(R) oral capsules, 2011).
    G) LOOSE STOOL
    1) WITH THERAPEUTIC USE
    a) Loose stools occurred in 3.4% of patients (n=1113) in clinical trials who received lubiprostone 24 micrograms twice daily for the treatment of chronic idiopathic constipation, compared to 0% of patients (n=316) who received placebo (Prod Info Amitiza(R) oral capsules, 2011).
    H) INDIGESTION
    1) WITH THERAPEUTIC USE
    a) Dyspepsia occurred in 2.9% of patients (n=1113) in clinical trials who received lubiprostone 24 micrograms twice daily for the treatment of chronic idiopathic constipation, compared to 1.3% of patients (n=316) who received placebo (Prod Info Amitiza(R) oral capsules, 2011).
    I) GASTROESOPHAGEAL REFLUX DISEASE
    1) WITH THERAPEUTIC USE
    a) Gastroesophageal reflux disease occurred in 1.8% of patients (n=1113) in clinical trials who received lubiprostone 24 micrograms twice daily for the treatment of chronic idiopathic constipation, compared to 0.6% of patients (n=316) who received placebo (Prod Info Amitiza(R) oral capsules, 2011).
    J) APTYALISM
    1) WITH THERAPEUTIC USE
    a) Dry mouth occurred in 1.5% of patients (n=1113) in clinical trials who received lubiprostone 24 micrograms twice daily for the treatment of chronic idiopathic constipation, compared to 0.3% of patients (n=316) who received placebo (Prod Info Amitiza(R) oral capsules, 2011).
    2) WITH POISONING/EXPOSURE
    a) In a study of 51 patients taking a single oral dose of 144 mcg of lubiprostone (6 times the normal single dose), dry mouth 2% (Prod Info Amitiza(R) oral capsules, 2011).
    K) VIRAL GASTRITIS
    1) WITH THERAPEUTIC USE
    a) Viral gastroenteritis occurred in 1% of patients (n=1113) in clinical trials who received lubiprostone 24 micrograms twice daily for the treatment of chronic idiopathic constipation, compared to 0% of patients (n=316) who received placebo (Prod Info Amitiza(R) oral capsules, 2011).
    L) LOSS OF APPETITE
    1) WITH POISONING/EXPOSURE
    a) In a study of 51 patients taking a single oral dose of 144 mcg of lubiprostone (6 times the normal single dose), anorexia was reported in 2% (Prod Info Amitiza(R) oral capsules, 2011).
    M) RETCHING
    1) WITH POISONING/EXPOSURE
    a) In a study of 51 patients taking a single oral dose of 144 mcg of lubiprostone (6 times the normal single dose), retching was reported in 7.8% (Prod Info Amitiza(R) oral capsules, 2011).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) URINARY TRACT INFECTIOUS DISEASE
    1) WITH THERAPEUTIC USE
    a) Urinary tract infections occurred in 4.4% of patients (n=1113) in clinical trials who received lubiprostone 24 micrograms twice daily for the treatment of chronic idiopathic constipation, compared to 1.9% of patients (n=316) who received placebo (Prod Info Amitiza(R) oral capsules, 2011).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) FLUSHING
    1) WITH POISONING/EXPOSURE
    a) In a study of 51 patients taking a single oral dose of 144 mcg of lubiprostone (6 times the normal single dose), flushing or hot flush were reported in 5.9% (Prod Info Amitiza(R) oral capsules, 2011).
    B) EXCESSIVE SWEATING
    1) WITH POISONING/EXPOSURE
    a) In a study of 51 patients taking a single oral dose of 144 mcg of lubiprostone (6 times the normal single dose), hyperhidrosis was reported in 2% (Prod Info Amitiza(R) oral capsules, 2011).
    C) SKIN IRRITATION
    1) WITH POISONING/EXPOSURE
    a) In a study of 51 patients taking a single oral dose of 144 mcg of lubiprostone (6 times the normal single dose), skin irritation was reported in 2% (Prod Info Amitiza(R) oral capsules, 2011).
    D) PALE - SYMPTOM
    1) WITH POISONING/EXPOSURE
    a) In a phase 1 cardiac repolarization study, 39 of 51 patients developed adverse effects after taking a single oral dose of 144 mcg of lubiprostone (6 times the normal single dose). Pallor was reported in 3.9% of these patients (Prod Info Amitiza(R) oral capsules, 2011).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) Arthralgia occurred in 3.1% of patients (n=1113) in clinical trials who received lubiprostone 24 micrograms twice daily for the treatment of chronic idiopathic constipation, compared to 0.3% of patients (n=316) who received placebo (Prod Info Amitiza(R) oral capsules, 2011).
    B) BACKACHE
    1) WITH THERAPEUTIC USE
    a) Back pain occurred in 2.3% of patients (n=1113) in clinical trials who received lubiprostone 24 micrograms twice daily for the treatment of chronic idiopathic constipation, compared to 0.9% of patients (n=316) who received placebo (Prod Info Amitiza(R) oral capsules, 2011).
    C) PAIN
    1) WITH THERAPEUTIC USE
    a) Pain in extremity occurred in 1.9% of patients (n=1113) in clinical trials who received lubiprostone 24 micrograms twice daily for the treatment of chronic idiopathic constipation, compared to 0% of patients (n=316) who received placebo (Prod Info Amitiza(R) oral capsules, 2011).
    D) CRAMP
    1) WITH THERAPEUTIC USE
    a) Muscle cramp occurred in 1% of patients (n=1113) in clinical trials who received lubiprostone 24 micrograms twice daily for the treatment of chronic idiopathic constipation, compared to 0% of patients (n=316) who received placebo (Prod Info Amitiza(R) oral capsules, 2011).

Reproductive

    3.20.1) SUMMARY
    A) Lubiprostone is classified as US pregnancy category C. There are no adequate and well-controlled studies of lubiprostone in pregnant women. Although animal studies in monkeys and rabbits showed no increase in structural malformations, increased incidences of early resorptions and soft tissue malformations (situs inversus, cleft palate) were noted when lubiprostone was administered to rats during organogenesis at the maternally toxic doses (approximately 338 times the recommended human dose, based on BSA). In addition, a dose-dependent increase in fetal loss occurred when lubiprostone was administered to guinea pigs. Therefore, it is recommended that lubiprostone be used in pregnant women only if the potential benefit outweighs the potential risk to the fetus.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) In reproductive studies, no drug-related adverse effects were seen in monkeys that received oral doses of lubiprostone of 10 and 30 mcg/kg/day post-organogenesis on gestation days 110 through 130. Also, no teratogenic effects were observed in rabbits at oral doses up to 100 mcg/kg/day (approximately 34 times the maximum recommended human dose, based on BSA) during organogenesis. Increased incidences of early resorptions and soft tissue malformations (situs inversus, cleft palate) were noted when lubiprostone was administered to rats during organogenesis at the maternally toxic dose of 2000 mcg/kg/day (approximately 338 times the recommended human dose, based on BSA) (Prod Info Amitiza(R) oral capsules, 2012).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Lubiprostone is classified as US pregnancy category C (Prod Info Amitiza(R) oral capsules, 2012)
    B) LACK OF EFFECT
    1) No human studies of pregnancy outcomes after exposure to lubiprostone have been published. However, miscarriage occurs in 15% to 18% of clinically recognized pregnancies, regardless of any drug exposure, according to currently available data (Prod Info Amitiza(R) oral capsules, 2012).
    C) ANIMAL STUDIES
    1) In reproductive studies, a dose-dependent increase in fetal loss occurred when lubiprostone was administered to guinea pigs at oral doses of 1, 10, and 25 mcg/kg/day (approximately 0.2, 2, and 6 times the maximum recommended human dose based on body surface area (BSA), respectively) on days 40 to 53 of gestation. Fetal loss was also noted in 1 Rhesus monkey that received 10 mcg/kg/day (approximately 3 times the maximum recommended human dose based on BSA), but this is within normal historical rates for this species (Prod Info Amitiza(R) oral capsules, 2012).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) Exercise caution when administering lubiprostone to a nursing woman, as it is unknown whether lubiprostone or its active metabolites are excreted into human breast milk. Although neither lubiprostone nor its active metabolites were detected in rat milk following oral administration, breastfed infants should be monitored for diarrhea because lubiprostone increases fluid secretion in the intestine and intestinal motility (Prod Info Amitiza(R) oral capsules, 2012).
    3.20.5) FERTILITY
    A) LACK OF EFFECT
    1) Lubiprostone, at oral doses of up to 1000 mcg/kg/day (approximately 166 times the recommended human dose of 48 mcg/day, based on the body surface area), had no effect on the fertility and reproductive function of male and female rats (Prod Info Amitiza(R) oral capsules, 2012).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) CARCINOMA
    1) Two-year oral carcinogenicity (gavage) study - When lubiprostone doses 25, 75, 200, and 500 mcg/kg/day (approximately 2, 6, 17, and 42 times the recommended human dose, respectively, based on body surface area) were given to mice, there was no significant increase in any tumor incidences. When lubiprostone doses 20, 100, and 400 mcg/kg/day (approximately 3, 17, and 68 times the recommended human dose, respectively, based on body surface area) were given to rats, 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 addition, at the 400 mcg/kg/day dose, treatment with lubiprostone caused hepatocellular adenoma in female rats (Prod Info AMITIZA(TM) oral gelatin capsules, 2006).

Genotoxicity

    A) In genetic studies of lubiprostone, no evidence of genotoxicity was found 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 (Prod Info AMITIZA(TM) oral gelatin capsules, 2006).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs in symptomatic patients.
    B) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients should be admitted for severe vomiting, profuse diarrhea, severe abdominal pain, dehydration, and electrolyte abnormalities.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours to assess electrolyte and fluid balance and gastrointestinal function. Patients that remain asymptomatic can be discharged.

Monitoring

    A) Monitor vital signs in symptomatic patients.
    B) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Lubiprostone undergoes minimal absorption from the gastrointestinal tract. Severe toxicity is not expected after overdose of lubiprostone. Gastrointestinal decontamination is generally not necessary.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Lubiprostone undergoes minimal absorption from the gastrointestinal tract. Severe toxicity is not expected after overdose of lubiprostone. Gastrointestinal decontamination is generally not necessary. Consider activated charcoal only after very large ingestions or if coingestants with significant toxicity are involved.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor vital signs in symptomatic patients.
    2) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.

Enhanced Elimination

    A) LACK OF INFORMATION
    1) There is no information regarding the effectiveness of hemodialysis or hemoperfusion for the removal of lubiprostone from plasma. Since systemic absorption is minimal, methods to enhance systemic elimination are unlikely to be necessary.

Range Of Toxicity

Summary

    A) Overdose data is limited. An adult took 96 mcg/day for 8 days without adverse effects. A 3-year-old ingested 7 or 8 capsules of lubiprostone (24 mcg each) and recovered. The following adverse events were reported in a Phase 1 cardiac repolarization study after 51 patients received a single oral dose of 144 mcg of lubiprostone (6 times the normal single dose): Nausea, vomiting, diarrhea, dizziness, loose or watery stools, headache, retching, abdominal pain, flushing, dyspnea, pallor, stomach discomfort, syncope, upper abdominal pain, anorexia, asthenia, chest discomfort, dry mouth, hyperhidrosis, skin irritation, and vasovagal episode.
    B) THERAPEUTIC DOSE: ADULTS: Chronic idiopathic constipation: 24 mcg orally twice daily. Irritable bowel syndrome with constipation: 8 mcg orally twice daily. CHILDREN: The safety and efficacy of lubiprostone have not been established in children.

Therapeutic Dose

    7.2.1) ADULT
    A) CHRONIC IDIOPATHIC CONSTIPATION - 24 mcg orally twice daily with food (Prod Info AMITIZA(R) oral capsules, 2013).
    B) IRRITABLE BOWEL SYNDROME WITH CONSTIPATION - 8 mcg orally twice daily with food (Prod Info AMITIZA(R) oral capsules, 2013).
    C) OPIOID-INDUCED CONSTIPATION - 24 mcg orally twice daily with food (Prod Info AMITIZA(R) oral capsules, 2013).
    7.2.2) PEDIATRIC
    A) The safety and efficacy of lubiprostone have not been established in children (Prod Info AMITIZA(R) oral capsules, 2013).

Maximum Tolerated Exposure

    A) Overdose data is limited. The following adverse events were reported in a Phase 1 cardiac repolarization study after 51 patients received a single oral dose of 144 mcg of lubiprostone (6 times the normal single dose): Nausea, vomiting, diarrhea, dizziness, loose or watery stools, headache, retching, abdominal pain, flushing, dyspnea, pallor, stomach discomfort, syncope, upper abdominal pain, anorexia, asthenia, chest discomfort, dry mouth, hyperhidrosis, skin irritation, and vasovagal episode (Prod Info Amitiza(R) oral capsules, 2011).
    B) An adult took 96 mcg/day for 8 days without adverse effects (Prod Info Amitiza(R) oral capsules, 2011).
    C) A 3-year-old ingested 7 or 8 capsules of lubiprostone (24 mcg each) and recovered (Prod Info Amitiza(R) oral capsules, 2011).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) AUC
    a) The concentration of lubiprostone in plasma is below the level of quantitation (10 pg/mL) after therapeutic doses. AUC cannot be calculated (Prod Info AMITIZA(TM) oral gelatin capsules, 2006).
    b) The AUC of M3, the only measurable active metabolite of lubiprostone, was 59.1 pg x h/mL following a single 24-mcg oral dose of lubiprostone. The AUC of M3 increases proportionally with dose after single 24-mcg and 144-mcg doses of lubiprostone (Prod Info AMITIZA(TM) oral gelatin capsules, 2006).
    c) Administration of a single 72-mcg dose of radiolabeled lubiprostone with a high-fat meal resulted in a reduced Cmax by 55% and an unchanged AUC (Prod Info AMITIZA(TM) oral gelatin capsules, 2006).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Lubiprostone is a chloride channel activator that acts locally to increase intestinal fluid secretion. Lubiprostone specifically activates the ClC2 receptor, a chloride channel that resides in the apical membrane of the intestine. Increased chloride-containing intestinal fluid secretion results, functioning to increase motility and the passage of stools through the intestine. Activation of ClC2 is independent of protein kinase A. In vitro studies have indicated that the activity of lubiprostone and its metabolites is primarily only on the apical (luminal) epithelium of the gastrointestinal tract. Sodium and potassium concentrations in the serum are not affected (Prod Info AMITIZA(TM) oral gelatin capsules, 2006).

Physicochemical

Physical Characteristics

    A) White, odorless crystals or crystalline powder; very soluble in ether and ethanol and practically insoluble in hexane and water (Prod Info AMITIZA(TM) oral gelatin capsules, 2006).

Molecular Weight

    A) 390.46 (Prod Info AMITIZA(TM) oral gelatin capsules, 2006)

References

General Bibliography

    1) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    2) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    3) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    4) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    5) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    6) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    7) Johanson JF, Gargano MA, Holland PC, et al: Phase III, randomized withdrawal study of RU-0211, a novel chloride channel activator for the treatment of constipation (abstract 749).. Gastroenterology 2004; 126(4 Suppl 2):A-100.
    8) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    9) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    10) Product Information: AMITIZA(R) oral capsules, lubiprostone oral capsules. Sucampo Pharmaceuticals,Inc, Bethesda, MD, 2008.
    11) Product Information: AMITIZA(R) oral capsules, lubiprostone oral capsules. Sucampo Pharma Americas, LLC and Takeda Pharmaceuticals America, Inc. (per manufacturer), Bethesda, MD, 2013.
    12) Product Information: AMITIZA(TM) oral gelatin capsules, lubiprostone oral gelatin capsules. Sucampo Pharmaceuticals, Bethesda, MD, 2006.
    13) Product Information: Amitiza(R) oral capsules, lubiprostone oral capsules. Sucampo Pharma Americas, Inc and Takeda Pharmaceuticals America, Inc, Bethesda, MD, 2011.
    14) Product Information: Amitiza(R) oral capsules, lubiprostone oral capsules. Sucampo Pharma Americas, Inc. and Takeda Pharmaceuticals America, Inc. (per FDA), Bethesda, MD, 2012.
    15) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.