Amitiza

Chloride Channel Activators
Chloride Channel Activators for Constipation

Patients should swallow capsules whole. Do not break apart or chew.
Administer with food. Administration with food minimizes the symptoms of drug-induced nausea.

dyspnea / Early / 0-3.0
peripheral edema / Delayed / 3.0-3.0
chest pain (unspecified) / Early / 2.0-2.0
fecal incontinence / Early / 0-1.0
palpitations / Early / 0-1.0
wheezing / Rapid / 0-1.0
hypotension / Rapid / Incidence not known

nausea / Early / 8.0-29.0
diarrhea / Early / 7.0-12.0
headache / Early / 2.0-11.0
abdominal pain / Early / 4.0-8.0
flatulence / Early / 4.0-6.0
dizziness / Early / 1.0-3.0
dyspepsia / Early / 2.0-2.0
fatigue / Early / 2.0-2.0
fecal urgency / Early / 0-1.0
tremor / Early / 0-1.0
urticaria / Rapid / 0-1.0
malaise / Early / 0-1.0
dysgeusia / Early / 0-1.0
hyperhidrosis / Delayed / 0-1.0
flushing / Rapid / 0-1.0
vertigo / Early / 0-1.0
asthenia / Delayed / 0-1.0
chills / Rapid / 0-1.0
rash / Early / 0-1.0
paresthesias / Delayed / 0-1.0
anxiety / Delayed / 0-1.0
syncope / Early / Incidence not known
vomiting / Early / Incidence not known

Amitiza

Rx

Chloride channel (CIC-2) activator
Used to treat adults with chronic idiopathic constipation or opiate agonist-induced constipation (OIC), and in adult women with constipation-predominant irritable bowel syndrome (IBS-C)
Most common side effect is nausea

24 mcg PO twice daily with food and water. Periodically assess the need for continued therapy. In clinical trials, some patients received a reduction in dosage to 24 mcg PO once daily if significant side effects (e.g., nausea) occurred.

8 mcg PO twice daily.

24 mcg PO twice daily with food and water. Lubiprostone improves spontaneous bowel movements in patients taking non-diphenylheptane opioids like morphine. Effectiveness in the treatment of opioid-induced constipation in patients taking diphenylheptane opioids (e.g., methadone) has not been established; patients in clinical trials who were taking methadone had responder rates to lubiprostone that were worse than placebo, and other studies have indicated methadone may actually negate lubiprostone's effects.

For chronic idiopathic constipation and opiate agonist-induced constipation: The recommended dose is 16 mcg PO twice daily in patients with moderate hepatic impairment (Child-Pugh Class B) and 8 mcg PO twice daily in patients with severe hepatic impairment (Child-Pugh Class C). If tolerated, the dose may be increased to reach desired clinical effect; however, close monitoring is warranted. No dosage adjustment is needed in patients with mild hepatic impairment (Child-Pugh Class A).
For irritable bowel syndrome with constipation: The recommended dose is 8 mcg PO once daily in patients with severe hepatic impairment (Child-Pugh Class C). If tolerated, the dose may be increased to reach desired clinical effect; however, close monitoring is warranted. No dosage adjustment is needed in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment.

No dosage adjustment is needed in patients with renal impairment.

Alosetron: (Moderate) Alosetron can decrease GI motility and may antagonize the effects of drugs used to treat constipation, such as lubiprostone. In general, it would be illogical to concurrently administer antidiarrheals in combination with lubiprostone. However, lubiprostone may cause diarrhea as a side effect, but drug discontinuation alone may resolve the diarrhea.
Anticholinergics: (Moderate) Antimuscarinic drugs can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation, such as lubiprostone. The clinical significance of these potential interactions is uncertain.
Belladonna; Opium: (Moderate) Opium can decrease GI motility and may antagonize the effects of drugs used to treat constipation, such as lubiprostone. In general, it would be illogical to concurrently administer antidiarrheals in combination with lubiprostone.
Bumetanide: (Moderate) Loop diuretics may increase the risk of hypokalemia especially in patients receiving prolonged therapy with laxatives. Monitor serum potassium levels to determine the need for potassium supplementation and/or alteration in drug therapy.
Calcium Phosphate, Supersaturated: (Moderate) Sodium phosphate monobasic monohydrate; sodium phosphate dibasic anhydrous should not be combined with additional laxatives or purgatives when being used to evacuate the bowel prior to colonic radiologic examinations or surgery.
Crofelemer: (Moderate) Crofelemer, through its local effects as an antidiarrheal on chloride channels in the intestine, may theoretically antagonize the pharmacologic effects of lubiprostone. In general, it would be illogical to concurrently administer crofelemer in combination with lubiprostone. While lubiprostone may cause diarrhea as a side effect, drug discontinuation alone may resolve the diarrhea.
Dichlorphenamide: (Moderate) Use dichlorphenamide and lubiprostone together with caution. Dichlorphenamide increases potassium excretion and can cause hypokalemia and should be used cautiously with other drugs that may cause hypokalemia including laxatives. Measure potassium concentrations at baseline and periodically during dichlorphenamide treatment. If hypokalemia occurs or persists, consider reducing the dichlorphenamide dose or discontinuing dichlorphenamide therapy.
Ethacrynic Acid: (Moderate) Loop diuretics may increase the risk of hypokalemia especially in patients receiving prolonged therapy with laxatives. Monitor serum potassium levels to determine the need for potassium supplementation and/or alteration in drug therapy.
Furosemide: (Moderate) Loop diuretics may increase the risk of hypokalemia especially in patients receiving prolonged therapy with laxatives. Monitor serum potassium levels to determine the need for potassium supplementation and/or alteration in drug therapy.
Lactulose: (Major) In general, other laxatives, such as lubiprostone, should not be used concurrently with lactulose, especially during the initial phase of therapy for portal-systemic encephalopathy, because the loose stools resulting from their use may falsely suggest that adequate lactulose dosage has been achieved.
Loop diuretics: (Moderate) Loop diuretics may increase the risk of hypokalemia especially in patients receiving prolonged therapy with laxatives. Monitor serum potassium levels to determine the need for potassium supplementation and/or alteration in drug therapy.
Methadone: (Major) Non-clinical studies have shown that opioids of the diphenylheptane chemical class (e.g., methadone) 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 lubiprostone in patients using diphenylheptane opioids. Effectiveness in the treatment of opioid-induced constipation in patients taking diphenylheptane opioids (e.g., methadone) has not been established; patients taking methadone during clinical trials for opioid induced constipation had lower response rates than placebo-treated patients.
Sodium Phosphate Monobasic Monohydrate; Sodium Phosphate Dibasic Anhydrous: (Moderate) Sodium phosphate monobasic monohydrate; sodium phosphate dibasic anhydrous should not be combined with additional laxatives or purgatives when being used to evacuate the bowel prior to colonic radiologic examinations or surgery.
Solifenacin: (Moderate) Antimuscarinic drugs can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation, such as lubiprostone. The clinical significance of these potential interactions is uncertain.
Torsemide: (Moderate) Loop diuretics may increase the risk of hypokalemia especially in patients receiving prolonged therapy with laxatives. Monitor serum potassium levels to determine the need for potassium supplementation and/or alteration in drug therapy.

Amitiza/Lubiprostone Oral Cap: 8mcg, 24mcg

Females: 48 mcg/day PO for chronic idiopathic constipation and opiate agonist-induced constipation; 16 mcg/day PO for irritable bowel syndrome.
Males: 48 mcg/day PO for chronic idiopathic constipation and opiate agonist-induced constipation; safety and efficacy have not been established for irritable bowel syndrome.

Females: 48 mcg/day PO for chronic idiopathic constipation and opiate agonist-induced constipation; 16 mcg/day PO for irritable bowel syndrome.
Males: 48 mcg/day PO for chronic idiopathic constipation and opiate agonist-induced constipation; safety and efficacy have not been established for irritable bowel syndrome.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Not indicated.

Not indicated.

Lubiprostone increases intestinal fluid secretion. Lubiprostone acts by specifically activating ClC-2 chloride channels; the action of lubiprostone and its metabolites is observed only on the apical (luminal) portion of the gastrointestinal epithelium. Activation of the CIC-2 channels produces a chloride-rich intestinal fluid secretion without altering serum electrolyte concentrations. This action softens the stool, increases motility in the intestine, promotes spontaneous bowel movements, and thereby alleviates signs and symptoms (e.g., bloating, discomfort, straining, hard stools) associated with constipation.
 
Clinically, the administration of lubiprostone typically produces clinical results within 1 week, and an increase in spontaneous bowel movements may be noted in some patients within 24 hours of administration. Unlike many laxatives, tolerance to use has not been observed. Following 4 weeks of treatment during clinical trials, withdrawal of the drug did not result in rebound effect. After cessation of treatment there is a gradual decrease in the frequency of bowel movements to pre-treatment levels.

Lubiprostone is administered orally. Human and animal studies indicate that lubiprostone is rapidly and extensively metabolized by reduction and oxidation, and this extensive metabolism appears to be mediated by carbonyl reductase. Biotransformation is not mediated by the hepatic CYP450 system. M3 is the only measurable metabolite and makes up < 10% of a total administered dose; the half-life of M3 is roughly 0.9—1.4 hours. Animal data indicate that metabolism occurs locally within the stomach and jejunum; similar metabolism is assumed in humans. After a single oral dose of 72 mcg of radiolabeled lubiprostone, 60% of the total dose was recovered in the urine within 24 hours; 30% of the radioactivity is recovered in the feces by 168 hours. Lubiprostone and the M3 active metabolite are only detected in trace amounts in feces in humans.

Following oral administration, lubiprostone has a low systemic availability and plasma concentrations are below the level of quantitation (< 10 pg/ml), and standard pharmacokinetic parameters for the parent drug cannot be calculated. Plasma levels of M3, the only measurable active metabolite, are also very low. Minimal distribution occurs beyond the gastrointestinal tissues.

Limited available data with lubiprostone use in pregnancy 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. 

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; therefore, infants of nursing mothers being treated with lubiprostone should be monitored for diarrhea. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.