Amitiza^® (Capsules) Instructions for Use

ATC Code

A06AX03 (Lubiprostone)

Active Substance

Lubiprostone (Rec.INN registered by WHO)

Clinical-Pharmacological Group

NSAID

Pharmacotherapeutic Group

NSAID

Pharmacological Action

A locally acting chloride channel activator. By enhancing the secretion of fluid into the intestinal lumen, it does not affect the concentration of sodium and potassium ions in the blood serum, does not affect the electrolyte balance even with long-term use, and does not cause dehydration.

Lubiprostone selectively activates ClC-2 chloride channels, present on the apical membrane of human intestinal epithelial cells, via a mechanism independent of protein kinase A, thereby exerting no negative effect on the intestinal mucosa. By increasing intestinal fluid secretion, Lubiprostone facilitates the passage of intestinal contents or fecal matter, leading to an increased frequency of bowel movements, as well as the disappearance of bloating and abdominal discomfort; it also normalizes stool consistency and reduces straining time in chronic idiopathic constipation, irritable bowel syndrome, and opioid-induced constipation. The effect is independent of patient age, including in older age groups.

By activating ClC-2 chloride channels on the apical membrane of intestinal epithelial cells, Lubiprostone counteracts the antisecretory effect of opioids caused by reduced excitability of secretomotor neurons.

Furthermore, ex vivo studies on ischemic pig intestine and on a model of inflammatory bowel disease have shown that by activating ClC-2 chloride channels, Lubiprostone promotes the restoration of the mucosal barrier function and reduces intestinal mucosal permeability by restoring tight junction complex proteins.

Pharmacokinetics

When taken orally, Lubiprostone has low systemic bioavailability: the concentration of the active substance in the blood plasma does not reach the limit of quantitation (10 pg/ml). Therefore, it is not possible to reliably calculate standard pharmacokinetic parameters for lubiprostone. However, the pharmacokinetic parameters of the M3 metabolite, the only measurable active metabolite, have been described. Gender does not affect the pharmacokinetics of the M3 metabolite formed after oral administration of lubiprostone.

After a single oral dose of 24 mcg of lubiprostone, the C_max of the M3 metabolite in plasma was observed at approximately 1.1 hours. The C_max was 41.5 pg/ml, and the mean AUC_0-t was 57.1 pg/hour/ml. After a single dose of 24 mcg and 144 mcg of lubiprostone, the AUC_0-t value of the M3 metabolite increases proportionally to the drug dose.

The binding of lubiprostone to human plasma proteins is about 94%. Preclinical studies using radiolabeled lubiprostone showed its minimal distribution outside of gastrointestinal tissues. At 48 hours after administration of the labeled drug, only minimal concentrations of lubiprostone were observed in all tissues.

Based on the results of preclinical animal studies and clinical studies, Lubiprostone is rapidly and extensively metabolized by reduction of the carbonyl group at the 15-position, β-oxidation of the α-chain, and ω-oxidation of the ω-chain. The reaction of reducing the carbonyl group at the 15-position is catalyzed by carbonyl reductase expressed in various organs and tissues. The lubiprostone metabolite M3, found in animals and humans, is formed by the reduction of the carbonyl group to a hydroxyl residue at the 15-position. The latter includes both α-hydroxy and β-hydroxy epimers. The blood concentration of the M3 metabolite is less than 10% of the dose of radiolabeled lubiprostone. Preclinical studies have shown that Lubiprostone is rapidly metabolized in the stomach and jejunum, most likely without systemic absorption. A similar mechanism is presumed to occur in humans.

Lubiprostone was not detected in blood plasma; however, the T_1/2 of the M3 metabolite ranges from 0.9 hours to 1.4 hours. Within 24 hours after a single dose of 72 mcg of ³H-labeled lubiprostone, 60% of the total radioactivity was detected in the urine, and by 168 hours, 30% of the radioactivity was detected in the feces. In humans, Lubiprostone and the M3 metabolite are detected in feces only in trace amounts.

Indications

Chronic idiopathic constipation in adults (CIC); irritable bowel syndrome with constipation (IBS-C) in women aged 18 years and older; opioid-induced constipation (OIC) in patients with chronic non-cancer pain.

ICD codes

Dosage Regimen

Take capsules orally with food and water to reduce nausea.

For chronic idiopathic constipation in adults, the dose is 24 mcg twice daily.

For irritable bowel syndrome with constipation in women 18 years and older, the dose is 8 mcg twice daily.

For opioid-induced constipation in adults with chronic non-cancer pain, the dose is 24 mcg twice daily.

Swallow capsules whole; do not break or chew them.

If a dose is missed, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose.

Do not take two doses at the same time to make up for a missed dose.

For patients with moderate or severe hepatic impairment, adjust the dose for chronic idiopathic constipation and opioid-induced constipation to 16 mcg twice daily.

For patients with moderate or severe hepatic impairment and irritable bowel syndrome with constipation, adjust the dose to 8 mcg once daily.

Discontinue treatment if severe diarrhea occurs and contact your physician.

The safety of use beyond 6-12 months has not been established.

Adverse Reactions

Nervous system disorders headache, dizziness, syncope, loss of consciousness.

Cardiovascular system disorders palpitations, tachycardia/increased heart rate, flushing, arterial hypotension.

Respiratory system disorders dyspnea, feeling of throat tightness.

Gastrointestinal system disorders nausea, diarrhea, abdominal pain, flatulence, vomiting, abdominal discomfort, dyspepsia, abdominal distension.

Musculoskeletal system disorders muscle cramps/spasms.

General disorders edema; chest discomfort/pain; influenza-like illness.

Skin and subcutaneous tissue disorders rash, hyperhidrosis, rash/urticaria.

Immune system disorders hypersensitivity (allergy-like reactions).

Contraindications

Mechanical intestinal obstruction or suspicion thereof; hypersensitivity to lubiprostone; age under 18 years.

Use in Pregnancy and Lactation

Experience with use during pregnancy is limited. Use during pregnancy is possible only if the expected therapeutic benefit for the mother outweighs the potential risk to the fetus.

Results from preclinical studies indicate that no traces of lubiprostone or its active metabolites were detected in breast milk after oral administration. However, there are no data on whether Lubiprostone is excreted in human breast milk or on its potential effects on the child during breastfeeding. Caution should be exercised when considering the use of lubiprostone during breastfeeding.

Use in Renal Impairment

The drug is approved for use in patients with impaired renal function.

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

The drug is approved for use in elderly patients.

Special Precautions

Lubiprostone should not be used in patients with severe diarrhea. Patients should be informed about the possible occurrence of diarrhea during treatment. If severe diarrhea develops, a doctor should be consulted.

Dyspnea may occur during treatment with lubiprostone, which usually resolves within a few hours after taking the drug but may recur upon resumption of administration.

If mechanical gastrointestinal obstruction is suspected, a thorough examination should be performed and its absence confirmed before starting therapy with lubiprostone.

Drug Interactions

There is a possibility of a dose-dependent reduction in the effectiveness of lubiprostone in patients taking diphenylheptane-derived opioids.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Over-the-Counter

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.