Lubiprostone - Indications, Dosage, and Side Effects

Introduction:

Lubiprostone is derived from prostaglandin and is used to treat constipation from irritable bowel syndrome. In addition, it is a drug used to manage chronic constipation. It is a bicyclic fatty acid that acts on chloride channels on the apical side of the gastrointestinal epithelial cells. These channels, on activation, increase the secretion of the chloride-containing fluid that softens the stool and increases gastrointestinal motility and bowel movements.

Indications of Lubiprostone:

Lubiprostone is indicated for:

• Treatment of chronic idiopathic constipation in adults.

• Treatment of opioid-induced constipation in adults dealing with chronic or non-cancer pain, which includes patients having chronic pain prior to cancer or in its treatment that does not require opioids.

• Treatment of irritable bowel syndrome along with constipation in women above 18.

Dosage:

• Dosage Form: Capsules.

• Dosage Strength: 24 mcg (micrograms).

Administration:

• Take the whole capsule without breaking it and with water and food.

• Chronic Idiopathic and Opioid-Induced Constipation: The recommended dosage for these patients is 24 mcg taken twice daily.

• Irritable Bowel Syndrome with Constipation: The recommended dosage for these patients is 8 mcg taken twice daily.

Contraindication:

• It is contraindicated in patients who have suspected mechanical gastrointestinal obstruction.

Warnings and Precautions:

• Nausea: The patient, after usage of Lubiprostone, can have nausea.

• Diarrhea: Lubiprostone is avoided in patients who are suffering from diarrhea. If the symptom starts appearing after usage, it is instructed to stop using Lubiprostone.

• Syncope and Hypotension: Syncope and hypotension can occur after taking the first dose of Lubiprostone but can resolve soon. If the symptoms continue, then the patient should consult the doctor.

• Dyspnea: Dyspnea can occur after the first dose of Lubiprostone and resolves within three hours. But if continued after the repeat dosing, consult a doctor before having Lubiprostone.

• Bowel Obstruction: The patient should evaluate the symptoms of gastrointestinal obstruction before starting the medicine Lubiprostone.

Special Considerations:

• Pregnancy: The use of Lubiprostone is not safe for pregnant women. As the data suggests, the drug can cause miscarriages; hence it is not used in pregnant women.

• Nursing Mothers: Cautious use of Lubiprostone is required in nursing mothers because it is unknown whether Lubiprostone is excreted in the milk or not.

• Pediatric Use: Lubiprostone's safe usage and effectiveness in children are yet to be established.

• Geriatric Use: The studies of the safety and efficiency of Lubiprostone in the elderly population are not concluded completely on whether they respond differently when younger patients.

• Renal Impairment: No dosage adjustments are required in patients with renal impairments.

• Hepatic Impairment: No dosage adjustment is required in patients with mild hepatic impairment. For the patient suffering from chronic idiopathetic constipation, the starting dose of Lubiprostone should be reduced with moderate and severe hepatic impairment.

For Patients:

Why Is Lubiprostone Used?

Lubiprostone is a laxative medicine. It provides an easy passage of the stool by increasing the fluid flow going to the bowel and allowing the stool to pass more easily. Lubiprostone is used to treat stomach pain, bloating, and strains and helps to produce softer and better bowel movements in a patient with chronic idiopathetic constipation. Lubiprostone treats irritable bowel syndrome accompanied by constipation in women above 18. Lubiprostone is also used to treat constipation initiated by opioids and chronic non-cancer pain.

How Is Lubiprostone Used?

Lubiprostone comes in the form of capsules and is taken by mouth. It is taken with food and water twice daily in the morning and evening. The capsule is swallowed as a whole without chewing or crushing it. The patient should take medicine as recommended by the doctor. The patient should not stop taking medicine without consulting the doctor; continue taking medicine even if the symptoms are resolved.

What Are the Precautions Before Starting Lubiprostone?

• If the patient is allergic to Lubiprostone, inform the doctor.

• Inform the doctor if the patient is suffering from any medical conditions like high blood pressure so that the doctor can change the dosage accordingly.

• Inform the doctor about any previous bowel or stomach problems so that the doctor can examine the patient for any other issues before starting with Lubiprostone.

• The patient should inform the doctor about severe diarrhea or liver diseases if the patient suffers.

• The doctor should be informed about the pregnancy and breastfeeding.

• Inform the doctor about any other medication the patient takes, like birth control, vitamins, or minerals.

What Is the Diet of the Patient Having Lubiprostone?

The patient can continue with the regular diet unless the doctor recommends any supplementary diet to follow along with Lubiprostone.

What to Do if the Patient Forgets to Take Lubiprostone Medicine?

If the patient forgets to take the Lubiprostone dose on time, he should take medicine as soon as possible upon remembering, but if the timing for the next dose is near, then take medicine according to the next dose and skip the missed dose.

What Are the Side Effects of Lubiprostone?

Side effects of Lubiprostone are

• Nausea.

• Vomiting.

• Stomach pain.

• Gas.

• Heartburn.

• Dizziness.

• Swelling of hands, feet, ankles, or lower legs.

• Chest discomfort.

• Tiredness.

Adverse effects are serious effects that require a doctor's attention immediately.

They are,

• Severe diarrhea.

• Shortness of breath.

• Chest tightness.

• Fainting.

• Rash.

• Swelling of face, lips, mouth, and tongue.

• Throat tightness.

How Is the Lubiprostone Stored and Disposed Of?

Lubiprostone is stored in closed, tight containers, away from children. Therefore, the storage should be at room temperature and away from light and heat.

The unrequired medicine is disposed of in a particular way to ensure that no one can consume the medicine, including pets, children, and people. And the medicine should not flush into the toilet; instead, learn the take-back program to dispose of the medicine safely.

What Happens if Overdosage Occurs?

Overdosage occurs when Lubiprostone is taken in excess. If the patient shows the symptoms of seizures or troublesome breathing, then the patient requires immediate doctor attention.

Symptoms of overdosage include,

• Nausea.

• Vomiting.

• Diarrhea.

• Dizziness.

• Headaches.

• Stomach pains or discomfort.

• Flushing.

• Shortness of breath.

• Pale skin.

• Weakness.

• Chest discomfort.

• Dry mouth.

• Excessive sweating.

• Fainting.

• Loss of appetite.

For Doctors:

Lubiprostone:

Lubiprostone is a prostaglandin E1 metabolite derivative. It is a bicyclic fatty acid that acts by activating the chloride channels on the apical of gastrointestinal epithelial cells. The chemical name of Lubiprostone is difluropentyl-2-hydroxy-6-oxooctahydrocyclopentaheptanoic acid. It has a molecular weight of 390.46. It has a white, odorless crystal and powder that is insoluble in water but soluble in ethanol. It has a tautomerize between two forms; its second is the active form. The color of the Lubiprostone capsule is different, containing 8 mcg and 10 mcg. The capsule contains other inactive ingredients like triglycerides, gelatin, sorbitol, titanium oxide, ferric oxide, and purified water.

Pharmacokinetics:

Lubiprostone's metabolism occurs in the gastrointestinal tract by the microsomal carbonyl reductase, as the cytochrome P450 system is not involved. Approximately 94 % is bound to human plasma proteins. The half-life of M3 is approximately 0.9 to 1.4 hours.

Pharmacodynamics:

Chronic idiopathic constipation is associated with abdominal pain, discomfort, bloating, straining, and hard stools; all this is because of abnormal colonic motility, which delays the intestinal contents and evacuation of rectal stools. Lubiprostone is an activator of the chloride channel that increases intestinal chloride and fluid secretion without changing sodium or potassium concentrations in the serum.

Mechanism of Action:

Lubiprostone acts by activating chloride channels, as it is the normal constituent of the apical membrane of the human intestine, in a protein kinase A action. Activating the chloride channels causes an efflux of chloride into lumens, further forming an efflux of sodium ions by paracellular pathways for neutrality. As a result, water follows into the lumen to maintain isotonic equilibrium, thereby increasing intestinal fluid secretion. On increasing the fluid secretion, Lubiprostone increases motility in the intestine and increases the passage of the stool. In addition, the chloride channel activation stimulates the mucosal barrier's recovery by tight junction protein complexes in the intestine.

Absorption:

Lubiprostone has low availability in the body following oral administration and concentration of Lubiprostone in plasma.

Metabolism:

Lubiprostone is rapidly metabolized by 15-position reduction, alpha-chain, and beta-oxidation. They are expressed by carbonyl reductase. M3 is a metabolite of Lubiprostone which is formed by the reduction of the carbonyl group at the 15-hydroxyl moiety that consists of alpha-hydroxy and beta-hydroxy epimers.

Elimination:

Lubiprostone is not found in the plasma. The majority of the drug is excreted in the urine within 48 hours. Lubiprostone and M3 are found in human feces. The half-life of Lubiprostone is 0.9 to 1.4 hours.

What Are the Indications and Usage of Lubiprostone?

• Chronic Idiopathic Constipation: Lubiprostone is used to treat chronic constipation in adults.

• Opioid-Induced Constipation in Adult Patients with Chronic Non-Cancer Pain: Lubiprostone treats opioid-induced constipation in adults with chronic non-cancer pain, including chronic pains related to previous cancer or treatment that does not require regular opioid dosage.

• Irritable Bowel Syndrome with Constipation: It is indicated for treating irritable bowel syndrome with constipation in women 18 years or above.

Dosage and Administration:

Dosage:

• Dosage Form: It is available in an oval or gelatin form or capsule of pink or orange color.

• Dosage Strength: It is available in 8 mcg or 24 mcg of Lubiprostone.

Contraindications:

• It is contraindicated in patients who have gastrointestinal obstruction.

Drug Interactions:

There is no in vitro drug-drug interaction. However, the interaction of diphenylheptane opioids has shown a reduction in the activation of the chloride channels by Lubiprostone in the gastrointestinal tract, which can further cause a decrease in the efficacy of Lubiprostone.

Overdosage:

Overdosage can occur in patients along with symptoms like,

• Nausea.

• Diarrhea.

• Headache.

• Dyspnea.

• Vomiting.

• Dizziness.

• Abdominal pain.

• Pallor.

• Chest discomfort.

• Dry mouth.

• Syncope.

Nonclinical Toxicology:

• Carcinogenesis: No specific study on humans has proved that the effect of Lubiprostone causes is not carcinogenic. However, the study in rats has proved the carcinogenic effects.

• Mutagenesis: There are no specific reports related to a mutation in humans.

• Impairment of Fertility: Lubiprotsone has no effects on the fertility of rats, but the number of implantation of embryos has decreased.

Clinical Studies:

1. Chronic Idiopathic Constipation: Two double-blinded, placebo-control studies were performed in chronic idiopathic constipation patients. Randomized 479 patients with a washout period were made to receive Lubiprostone 24 mcg twice daily placebo for four weeks. The primary endpoint was frequent bowel movements as the patient treated with Lubiprostone had bowel movements in a higher frequency than the placebo-treated one week. And even the times taken by the first bowel movements were shorter with Lubiprostone than with placebo. For the withdrawal of the medicine, a seven-week withdrawal study was performed. The patient who had already received Lubiprostone maintained the study with three additional weeks of Lubiprostone, and it did not result in worsening.

2. Opioid-Induced Constipation in Adult Patients with Chronic Non-Cancer Pain: There were three studies performed as random, double-blind, and placebo-controlling. The first study has a population with a median age of 52 years, with 63.1% females. These patients have previously received stable opioid therapy for 30 days and have to continue the therapy for 12 weeks. At the baseline, the mean oral morphine equivalent doses were 99 mg for placebo-treated and 130 mg for Lubiprostone-treated patients. For the second study, the baseline mean of morphine equivalent doses was 237 mg for the placebo-treated, and 265 mg for the Lubiprostone treated. In the third study, the morphine equivalent daily doses were 330 mg and 373 mg for Lubiprostone. In Study 1, the patients with opioids (n=431) were randomized to take a placebo (n=217) or Lubiprostone 24 mcg twice daily for 12 weeks. The patients reported more than one bowel movement for the first week of treatment, and more than three movements were reported for 9 to 12 weeks. The patient receiving 24 mcg of Lubiprostone twice a day was 27.1 %, and the placebo twice daily receiving patients was 18.9 %. There were no differences in responses to Lubiprostone for genders or any subgroups. In Study 2, patients with opioids (n=418) were randomized to a placebo (n=208) or Lubiprostone 24 mcg twice daily (n=210) for 12 weeks. The primary efficacy endpoint is spontaneous bowel movement frequency in week 8. The patient in this study was an overall responder to diphenylheptane opioids of 691 mg for placebo and 672 mg for Lubiprostone. The portion of the patient as overall responders was 20.5% group Lubiprostone to 6.3% group placebo. There is no difference in response to Lubiprostone. In Study 3, patients with opioids (N=451) were randomized to a placebo (n=216) and Lubiprostone 24 mcg twice daily (n=235) for 12 weeks. The primary efficacy endpoint was to change the bowel movement frequency in eight weeks. The overall responder in this study received morphine daily doses of 730 mg and 992 mg for placebo and Lubiprostone. An overall responder was 2.1 % Lubiprostone compared to 12.2 % in patients with placebo.

3. Irritable Bowel Syndrome with Constipation: The study was double-blinded, placebo-control on the patient with irritable bowel syndrome. It was a four-week washout with 1154 patients who were given Lubiprostone 8 mcg twice a day or placebo twice daily for 12 weeks. The primary efficacy endpoint for comparing overall responders in each arm. The overall patient responder was 5.7 % with placebo and 12.1 % with Lubiprostone 8 mcg.

• Results in men were taken by two randomized, placebo-controlled, double-blinded with 97 male patients who responded differently to Lubiprostone from women. The patient further goes for four weeks withdrawal period after receiving Lubiprostone or a placebo for 12 weeks treatment period. The patient treated with Lubiprostone was re-randomized to a placebo as bowel movements do not result in worsening.