Diaremix

INSTRUCTIONS for medical use of the medicinal product DIAREMIX (DIAREMIX)

Composition:

Active substances: Lactic Acid Bacillus (Bacillus coagulans/Lb.sporogenes), loperamide hydrochloride, dicyclomine hydrochloride;

1 capsule contains Lactic Acid Bacillus (Bacillus coagulans/Lb.sporogenes) 60 million spores, loperamide hydrochloride 2 mg, dicyclomine hydrochloride 10 mg;

Excipients: colloidal anhydrous silicon dioxide; talc; lactose monohydrate; maize starch;

Capsule shell: carmoisine (E 122), ponceau 4R (E 124), yellow west FCF (E 110), titanium dioxide (E 171), gelatin, iron oxide red (E 172).

Pharmaceutical form. Capsules.

Main physicochemical characteristics: hard gelatin capsules with a white body and a red cap, containing a crystalline powder with particles of varying sizes ranging from light yellow to yellow and/or pink.

Pharmacotherapeutic group. Loperamide, combinations. ATC code A07DA53.

Pharmacological Properties

Pharmacodynamics.

Diarimix is a combination drug containing loperamide, dicyclomine hydrochloride, and Lactic Acid Bacillus (Bacillus coagulans (Lb. sporogenes).

Loperamide exerts an antidiarrheal effect by reducing intestinal peristalsis, thereby slowing the transit of intestinal contents and increasing the time for absorption of water and electrolytes.

Loperamide increases anal sphincter tone, which helps retain fecal mass and reduces the urge for defecation. It practically does not cross the blood-brain barrier and does not cause dependence or addiction.

Dicyclomine hydrochloride has anticholinergic activity and directly relaxes smooth muscle.

Lb. sporogenes are present in the form of viable spores. The bacterial spores are activated in the stomach and then transform into the active vegetative form in the duodenum, creating favorable conditions for the development of beneficial intestinal microflora through the production of L(+) lactic acid. The inhibitory effect is directed against pathogenic microorganisms such as enterococci, Escherichia coli, Salmonella, Shigella, Proteus, Pseudomonas aeruginosa, Vibrio, yeasts, and others.

Pharmacokinetics.

Loperamide is a highly specific agent for intestinal walls, reaching systemic circulation in limited amounts and practically not crossing the blood-brain barrier. The threshold for central effects is much higher than the dose producing the maximum antidiarrheal effect.

Loperamide hydrochloride is readily absorbed from the intestine but is almost completely extracted and metabolized by the liver, where it undergoes conjugation and is excreted via bile.

The elimination half-life of loperamide in humans averages 11 hours (9–14 hours). Plasma protein binding is 95%, primarily to albumins. Excretion occurs mainly in feces.

The plasma half-life of dicyclomine is 4–6 hours.

Dicyclomine is predominantly excreted by the kidneys (79.5%).

Lb. sporogenes are highly stable, resistant to high temperatures, gastric acidity, bile, and many antibacterial agents. After forming the vegetative form, the spores multiply by simple nuclear division in the intestine, increasing the stationary number of bacteria and gradually producing lactic acid.

Clinical characteristics.

Indications.

Diarrhea of various etiologies:

acute and chronic, allergic, psychoemotional, associated with resection or irradiation/radiotherapy of various intestinal tumors;

caused by changes in diet and food quality (traveler's diarrhea);

in irritable bowel syndrome with diarrhea.

Contraindications.

Diarimex is contraindicated in patients with hypersensitivity to any of its components to prevent severe skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme. Pediatric use under 12 years of age; intestinal obstruction (including cases where inhibition of peristalsis must be avoided), megacolon, and toxic megacolon; acute ulcerative colitis or pseudomembranous colitis associated with broad-spectrum antibiotic use; hemorrhagic colitis, bacterial enterocolitis caused by microorganisms of the Salmonella, Shigella, and Campylobacter families; acute diarrhea accompanied by fever and bloody stools; severe impairment of liver function required for drug metabolism (as this may lead to relative overdose).

Acute dysentery characterized by the presence of blood in stools and elevated body temperature.

Gastrointestinal obstruction/stenosis, peptic ulcer of the stomach and duodenum, gastroesophageal reflux, benign prostatic hyperplasia with urinary retention, glaucoma, myasthenia gravis.

The medication must be discontinued immediately if constipation, abdominal distension, or partial intestinal obstruction develops.

Interaction with other medicinal products and other forms of interactions.

Since Diarimex contains loperamide, it should not be co-administered with atropine and other anticholinergic agents (to prevent mutual enhancement of effects), erythromycin, or metoclopramide. Cholestyramine should be administered no later than 2 hours before taking Diarimex.

Concomitant use of centrally acting central nervous system depressants should be avoided in children.

Preclinical data indicate that loperamide is a substrate of P-glycoprotein. Concomitant administration of loperamide (single dose of 16 mg) with P-glycoprotein inhibitors (quinidine, ritonavir) resulted in a 2- to 3-fold increase in plasma loperamide levels. The clinical significance of this pharmacokinetic interaction when loperamide is used at recommended doses (2 to 16 mg) is unknown.

Concomitant administration of loperamide (4 mg single dose) and itraconazole, an inhibitor of CYP3A4 and P-glycoprotein, led to a 3- to 4-fold increase in loperamide plasma concentrations. In the same study, gemfibrozil, a CYP2C8 inhibitor, increased loperamide levels by approximately 2-fold. Combined use of itraconazole and gemfibrozil resulted in a 4-fold increase in maximum plasma loperamide concentration and a 13-fold increase in total plasma concentration. This increase was not associated with effects on the central nervous system.

Concomitant administration of loperamide (16 mg single dose) and ketoconazole, an inhibitor of CYP3A4 and P-glycoprotein, led to a 5-fold increase in loperamide plasma concentration. This increase was not associated with enhanced pharmacodynamic effects as measured by pupillometry.

Concomitant treatment with oral desmopressin resulted in a 3-fold increase in desmopressin plasma concentration, likely due to slower gastrointestinal motility.

Medicinal products with similar pharmacological properties are expected to potentiate the effects of loperamide, while medicinal products that accelerate gastrointestinal transit may reduce its efficacy.

The effects of dicyclomine, a component of the drug, including adverse effects, may be enhanced by medicinal products with anticholinergic activity: amantadine, antiarrhythmics (e.g., quinidine), antihistamines, antipsychotics (e.g., phenothiazines), benzodiazepines, monoamine oxidase inhibitors (MAO inhibitors), hypnotics, analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetics, tricyclic antidepressants, and other agents with anticholinergic effects.

Anticholinergic agents, including dicyclomine, enhance the effects of glaucoma medications. Anticholinergics may be harmful when used concomitantly with corticosteroids in cases of increased intraocular pressure. They may affect gastrointestinal absorption of various drugs, such as digoxin, potentially leading to increased serum digoxin concentrations; they may enhance the effects of drugs affecting gastrointestinal motility, such as metoclopramide. Since antacid agents may interfere with the absorption of anticholinergic drugs, concomitant use should be avoided. Slowing of gastric acid secretion by anticholinergic agents counteracts the action of substances used to treat achlorhydria or to test gastric secretion.

Special precautions for use.

Treatment of diarrhea is symptomatic. The use of the drug does not replace etiological therapy of diarrhea, if the etiology of the disease can be determined (or if it is indicated that this should be done); specific treatment should be carried out whenever possible, along with measures to correct disturbances in water-electrolyte balance.

In patients with diarrhea, especially in children, dehydration and electrolyte imbalance may occur. In such cases, the most important measure is replacement therapy to replenish fluids and electrolytes. The use of Diarex medication does not replace the administration of adequate amounts of fluid and restoration of electrolytes.

Since persistent diarrhea may indicate potentially more serious conditions, the drug should not be used for prolonged periods until the cause of diarrhea has been investigated.

Patients with acquired immunodeficiency syndrome (AIDS) who are taking Diarex must discontinue treatment immediately upon the first signs of abdominal distension. There have been isolated reports of toxic megacolon occurring in AIDS patients with infectious colitis of both viral and bacterial origin during treatment with loperamide hydrochloride.

Misuse or inappropriate use of loperamide as an opioid substitute has been described in individuals with opioid dependence.

Caution is required when administering Diarex to patients with impaired liver function due to slowed first-pass metabolism. Patients with impaired liver function should be under close medical supervision to ensure timely detection of signs of toxic central nervous system effects.

Medicinal products that prolong gastrointestinal transit time may lead to the development of toxic megacolon in patients in this group.

Diarex should be used with caution in patients with neuropathies, impaired kidney function (reduced renal excretion may increase the risk of adverse effects), hyperthyroidism, arterial hypertension, heart diseases (ischemic heart disease, congestive heart failure, tachyarrhythmia), hiatal hernia in elderly patients, and in cases of infectious diarrhea.

In diarrhea caused by irritable bowel syndrome (IBS), Diarex should be taken only if the condition has previously been diagnosed by a physician.

The drug should not be used without prior consultation with a physician in the following cases, even if you know you have irritable bowel syndrome (IBS):

• patient age 40 years or older and some time has passed since the last IBS episode;
• patient age 40 years or older and this time the IBS symptoms are different;
• recent gastrointestinal bleeding;
• severe constipation;
• nausea or vomiting;
• loss of appetite or weight loss;
• difficult or painful urination;
• fever;
• recent international travel.

If new symptoms develop, if symptoms worsen, or if symptoms do not improve within two weeks, medical advice should be sought.

Tachycardia must be ruled out in the patient, as dicyclomine may increase heart rate. Loperamide is not typically associated with pronounced cardiovascular complications within the therapeutic concentration range. However, when these levels are significantly exceeded (up to 47 times), loperamide has demonstrated cardiovascular complications, including inhibition of potassium (hERG) and sodium currents, and arrhythmias in both in vivo and in vitro animal models.

Cases of cardiac disturbances, including QT interval prolongation, QRS complex widening, and torsades de pointes, have been reported with loperamide use at doses exceeding the recommended dose (see section "Overdose"). In some cases, fatal outcomes have been reported. Patients should not exceed the recommended dose or duration of treatment.

If the drug is used to control episodes of diarrhea caused by irritable bowel syndrome previously diagnosed by a physician, and no clinical improvement is observed within 48 hours, loperamide hydrochloride should be discontinued and medical advice sought.

Loperamide is contraindicated in situations where inhibition of peristalsis should be avoided due to the risk of serious consequences such as megacolon and toxic megacolon.

Dicyclomine should be prescribed with caution in urinary retention and benign prostatic hyperplasia, and in nonspecific ulcerative colitis (risk of paralytic ileus). It may exacerbate gastroesophageal reflux.

It should be noted that patients receiving anticholinergic drugs, including dicyclomine hydrochloride, may develop psychosis, confusion, disorientation, ataxia, increased fatigue, or, conversely, euphoria, excitement, insomnia, and affective states. These symptoms usually resolve within 12–24 hours after discontinuation of the drug.

Under high ambient temperatures, dicyclomine hydrochloride, by reducing sweating, may cause an increase in body temperature with a risk of heat stroke. If such symptoms occur, the drug should be discontinued and medical advice sought.

Excipients.

The product contains lactose monohydrate; therefore, if you have been diagnosed with intolerance to certain sugars, consult your doctor before taking this medication.

Carmoisine (E 122), Ponceau 4R (E 124), and Sunset Yellow FCF (E 110) may cause allergic reactions.

Use during pregnancy or breastfeeding.

Contraindicated during pregnancy or breastfeeding.

If use of the medicinal product is necessary, breastfeeding should be discontinued.

Ability to affect reaction speed when driving or operating machinery.

During treatment with Diarex, patients should refrain from driving vehicles or operating machinery requiring high concentration and attention.

Method of administration and dosage.

For use in adults and children aged 12 years and older, 2–3 times daily, regardless of food intake. Swallow the capsules whole without chewing, with plenty of liquid.

Symptomatic treatment of acute diarrhea in adults and children aged 12 years and older

Initial dose: 2 capsules, followed by 1 capsule after each loose stool.

Maximum daily dose in acute diarrhea must not exceed 6 capsules.

If therapeutic effect is not achieved within 2 days, the treatment strategy should be reassessed.

In chronic diarrhea: initial dose is 2 capsules, followed by 1 capsule after each bowel movement, gradually reducing the dose according to individual patient characteristics and disease pattern down to 1 capsule per day.

After achieving normal stool consistency or in the absence of defecation for 12 hours, discontinue the medication.

Maximum daily dose must not exceed 6 capsules.

Daily and single doses for adults and children aged 12 years and older:

Children.

The medicinal product can be used in children aged 12 years and older.

Overdose.

Symptoms.

In overdose (including relative overdose due to impaired liver function), central nervous system depression may occur (confusion, disorientation, transient memory loss, hallucinations, dysarthria, ataxia, coma, euphoria, reduced anxiety, weakness, insomnia, agitation and restlessness, inappropriate emotional responses, stupor, impaired coordination, drowsiness, miosis, skeletal muscle hypertonia, respiratory depression), a syndrome resembling intestinal obstruction, urinary retention, dysuria, headache, vomiting, nausea, tachycardia, arterial hypertension, or exacerbation of other adverse reactions.

Children and patients with impaired liver function may be more sensitive to the effects on the central nervous system.

In individuals who have exceeded recommended doses of loperamide, QT interval prolongation and/or serious ventricular arrhythmias, including torsades de pointes, have been observed, associated with loperamide abuse or misuse.

In individuals who intentionally ingested higher doses of loperamide (doses reported from 40 to 792 mg per day), cardiac arrest and syncope have been observed. Fatal cases have also been reported (see section "Special precautions").

Abuse, misuse and/or intentional overdose with excessively high doses may lead to Brugada syndrome.

Treatment.

In case of overdose, ECG monitoring should be initiated immediately. In the event of overdose, the patient should seek immediate medical attention. If symptoms of overdose occur, naloxone may be administered intravenously at a dose of 0.4 mg/mL as an antidote. Because the duration of action of loperamide is longer than that of naloxone (1–3 hours), repeated administration of naloxone may be required. The patient should remain under close observation for at least 48 hours to detect possible central nervous system depression, and symptomatic treatment should be provided (gastric lavage, administration of activated charcoal).

Side effects.

Adults and children aged 12 years and older

Skin and subcutaneous tissue disorders: rash, urticaria, pruritus, angioedema, bullous eruptions, erythema multiforme, Stevens–Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), dry skin, and other dermatological manifestations.

Immune system disorders: hypersensitivity reactions, anaphylactic reactions including anaphylactic shock and anaphylactoid reactions.

Gastrointestinal disorders: constipation; flatulence; bloating sensation; upper abdominal pain, spasms; colic; abdominal pain and discomfort; dry mouth; thirst; loss of taste; anorexia; dyspepsia; nausea; vomiting; megacolon, including toxic megacolon; intestinal obstruction (including paralytic ileus); frequency unknown – acute pancreatitis.

Renal and urinary disorders: urinary retention, urinary hesitation.

Nervous system disorders: dizziness, headache, tremor, loss of consciousness, confusion, speech disorders, anxiety (emotional agitation), stupor, restlessness, somnolence, lethargy, insomnia, paresthesia, sensory disturbances, numbness, coordination disturbances, dyskinesia, depression of consciousness, hypertonia.

Eye disorders: blurred/unclear vision, diplopia, mydriasis, cycloplegia (paralysis of accommodation), increased intraocular pressure, miosis.

Cardiac disorders: tachycardia, palpitations, increased blood pressure, arterial hypertension.

Respiratory disorders: dyspnea, apnea, asphyxia, nasal congestion, sneezing, pharyngeal hyperemia.

Other: increased fatigue, general weakness, muscle weakness, impotence, suppression of lactation, sexual dysfunction; decreased sweating, elevated body temperature.

Shelf life. 2 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging, in a place inaccessible to children.

Packaging.

10 capsules in a blister pack, 3 blisters per cardboard box, or 8 capsules in a blister pack, 1 blister per cardboard box.

Supply classification. Over-the-counter.

Manufacturer.

Mepro Pharmaceuticals Private Limited.

Manufacturer's address.

Unit II, Q-Road, Phase IV, GIDC, Wadhwan, Surendranagar, Gujarat, 363 035, India.

Marketing Authorization Holder.

Mili Healthcare Limited.

Address of the Marketing Authorization Holder.

Second Floor Office Suite, 4 Chartfield House, Castle Street, Taunton, Somerset, England, TA1 4AS, Great Britain.