INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT DOMILIUM ODT (DOMILIUM ODT)

Composition:

Active ingredient: domperidone;

One tablet contains 10 mg of domperidone;

Excipients: mannitol, colloidal anhydrous silicon dioxide, microcrystalline cellulose, aspartame, crospovidone, peppermint flavor, magnesium stearate.

Pharmaceutical form. Orodispersible tablets.

Main physicochemical properties: white or almost white, round, flat tablets with bevelled edges, smooth on both sides, with a peppermint odor.

Pharmacotherapeutic group. Agents used in functional gastrointestinal disorders. Prokinetic agents. ATC code A03F A03.

Pharmacological properties.

Pharmacodynamics.

Domperidone is a dopamine antagonist with antiemetic properties. Domperidone penetrates the blood-brain barrier to a minimal extent. The use of domperidone is very rarely associated with extrapyramidal side effects, particularly in adults; however, domperidone stimulates prolactin release from the pituitary gland. Its antiemetic effect may be due to a combination of peripheral (gastrokinetic) action and antagonism at dopamine receptors in the chemoreceptor trigger zone located outside the blood-brain barrier in the posterior region (area postrema). Animal studies, as well as low brain concentrations detected, indicate that domperidone acts predominantly peripherally on dopamine receptors.

Studies have shown that in humans, following oral administration, domperidone increases lower esophageal sphincter pressure, improves antroduodenal motility, and accelerates gastric emptying. Domperidone does not affect gastric secretion.

Effect on QT interval/QTc and cardiac electrophysiology

According to ICH E14 international guidelines, a thorough QT interval study was conducted in healthy subjects. This was a double-blind, placebo-controlled study using recommended and supratherapeutic doses (10 and 20 mg four times daily). In this study, the maximum difference in QTc between the domperidone group (20 mg four times daily) and placebo was observed on day 4 of treatment and amounted to 3.4 ms. The two-sided 90% upper confidence limit (1.0 to 5.9 ms) did not exceed 10 ms. No clinically significant QTc effect was observed with domperidone administration up to 80 mg/day (i.e., more than twice the recommended dose).

However, two previous drug interaction studies clearly demonstrated QTc prolongation with domperidone used as monotherapy (10 mg four times daily). The greatest mean difference in QTcF between the domperidone and placebo groups was 5.4 ms (95% confidence interval: 1.7–12.4) and 7.5 ms (95% confidence interval: 0.6–14.4), respectively.

Pharmacokinetics.

Absorption.

Domperidone is rapidly absorbed after oral administration, with peak plasma concentrations reached approximately within 60 minutes. Cmax and AUC values of domperidone increased proportionally with doses in the range of 10 to 20 mg. A 2–3-fold accumulation of domperidone (AUC) was observed with repeated dosing four times daily (every 5 hours) over 4 days. The low absolute oral bioavailability of domperidone (approximately 15%) is due to extensive first-pass metabolism in the intestinal wall and liver. Although domperidone bioavailability increases when administered after food in healthy subjects, patients with gastrointestinal symptoms should take domperidone 15–30 minutes before meals. Reduced gastric acidity decreases domperidone absorption. Oral bioavailability is reduced when co-administered with cimetidine and sodium bicarbonate. When administered after food, peak absorption is slightly delayed, while AUC is slightly increased.

Distribution.

After oral administration, domperidone does not accumulate and does not induce its own metabolism; peak plasma levels at 90 minutes (21 ng/mL) after two weeks of oral dosing at 30 mg/day were nearly the same as after the first dose (18 ng/mL). Domperidone is 91–93% bound to plasma proteins. Distribution studies in animals using radiolabeled domperidone showed extensive tissue distribution but low brain concentrations. In animals, small amounts of the drug cross the placenta.

Metabolism.

Domperidone is rapidly and extensively metabolized in the liver via hydroxylation and N-dealkylation. In vitro metabolism studies using diagnostic inhibitors have shown that CYP3A4 is the main cytochrome P450 isoenzyme involved in N-dealkylation of domperidone, while CYP3A4, CYP1A2, and CYP2E1 are involved in aromatic hydroxylation of domperidone.

Elimination.

Excretion in urine and feces accounts for 31% and 66% of the oral dose, respectively. Excretion of unchanged drug is minimal (10% in feces and approximately 1% in urine). The elimination half-life in plasma after a single dose is 7–9 hours in healthy volunteers but is prolonged in patients with severe renal impairment.

Special patient populations

Hepatic impairment

In patients with moderate hepatic impairment (7–9 points on the Child-Pugh scale, class B), AUC and Cmax of domperidone were 2.9 and 1.5 times higher, respectively, compared to healthy volunteers. The unbound fraction increased by 25%, and the terminal half-life was prolonged from 15 to 23 hours. In patients with mild hepatic impairment, slightly lower exposure was observed compared to healthy volunteers in terms of Cmax and AUC, without changes in protein binding or terminal half-life. The use of domperidone in patients with severe hepatic impairment has not been studied. Domperidone is contraindicated in patients with moderate or severe hepatic impairment (see section "Contraindications").

Renal impairment

In patients with severe renal impairment (serum creatinine clearance < 30 mL/min/1.73 m²), the elimination half-life of domperidone is prolonged from 7.4 to 20.8 hours, but plasma drug concentrations are lower than in patients with normal renal function. Since only a very small amount of the drug (approximately 1%) is excreted unchanged in urine, dose adjustment is unlikely to be required for single doses in patients with renal impairment. However, with repeated administration, the dosing frequency should be reduced to 1–2 times daily depending on the severity of impairment, and dose reduction may also be necessary.

Clinical characteristics.

Indications.

For relief of symptoms of nausea and vomiting.

Contraindications.

Domilium ODT is contraindicated:

in patients with known hypersensitivity to the active substance or to any of the excipients;
in patients with prolactin-secreting pituitary tumors (prolactinoma);
in patients with severe or moderate hepatic and/or renal impairment (see sections "Special precautions for use", "Pharmacological properties");
in patients with known prolongation of cardiac conduction intervals, particularly QTc, in patients with significant electrolyte imbalances or underlying heart diseases such as congestive heart failure (see section "Special precautions for use");
in patients with hepatic insufficiency;
when stimulation of gastric motility may be dangerous, e.g., in gastrointestinal hemorrhage, mechanical obstruction, or perforation;
during concomitant use of ketoconazole, erythromycin, or other potent inhibitors of CYP3A4;
during concomitant use of medicinal products that prolong the QT interval (except apomorphine), such as fluconazole, erythromycin, itraconazole, oral ketoconazole, posaconazole, ritonavir, saquinavir, telaprevir, voriconazole, clarithromycin, amiodarone, telithromycin (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Domperidone is primarily metabolized via CYP3A4. In vitro studies indicate that concomitant administration of drugs that strongly inhibit this enzyme may lead to increased plasma levels of domperidone. Due to pharmacodynamic and/or pharmacokinetic interactions, the risk of QT interval prolongation increases.

Anticholinergic drugs may counteract the anti-dyspeptic effect of domperidone.

Antacids and antisecretory agents should not be taken simultaneously with domperidone, as they reduce its bioavailability after oral administration (see section "Special precautions for use").

Clinically significant QT interval changes have been observed when domperidone was used concomitantly with potent CYP3A4 inhibitors capable of prolonging the QT interval (see section "Contraindications").

Concomitant use with levodopa. Although dose adjustment of levodopa is not considered necessary, increased plasma concentrations of domperidone (up to 30–40%) have been observed when administered concomitantly with levodopa.

Concomitant use is contraindicated with the following medicinal products:

Medicinal products that prolong the QT interval (risk of "torsade de pointes"):

Class IA antiarrhythmics (e.g., disopyramide, quinidine, hydroquinidine);
Class III antiarrhythmics (e.g., amiodarone, dofetilide, dronedarone, ibutilide, sotalol);
certain neuroleptics (e.g., haloperidol, pimozide, sertindole);
certain antidepressants (e.g., citalopram, escitalopram);
certain antibiotics (e.g., levofloxacin, moxifloxacin, erythromycin, spiramycin);
certain antifungal agents (e.g., fluconazole, pentamidine);
certain antimalarials (e.g., halofantrine, lumefantrine);
certain gastrointestinal drugs (e.g., cisapride, dolasetron, prucalopride);
certain antihistamines (e.g., mequitazine, mizolastine);
certain oncology drugs (e.g., toremifene, vandetanib, vincamine);
certain other drugs (e.g., bepridil, methadone, diphenylpyraline);
apomorphine, except when the benefit of concomitant use outweighs the risks and strict adherence to recommended precautionary measures is ensured (see the apomorphine product information).

With strong CYP3A4 inhibitors (regardless of their ability to prolong the QT interval):

protease inhibitors* (e.g., ritonavir, saquinavir, telaprevir);
systemic azole antifungal agents such as fluconazole*, itraconazole, ketoconazole*, posaconazole, and voriconazole*;
certain macrolides (erythromycin*, clarithromycin*, telithromycin*) (see section "Contraindications");
HIV protease inhibitors such as amprenavir, atazanavir, fosamprenavir, indinavir, nelfinavir, ritonavir, and saquinavir;
calcium channel antagonists such as diltiazem and verapamil;
amiodarone*;
aprepitant;
nefazodone.

*Prolong QTc interval.

Domperidone should not be taken concomitantly with moderate CYP3A4 inhibitors, such as diltiazem, verapamil, and certain macrolides (see section "Contraindications").

Concomitant use of the following substances requires caution.

Use with caution together with drugs that may cause bradycardia and hypokalemia, as well as with macrolides that may prolong the QT interval, such as azithromycin and roxithromycin (clarithromycin is contraindicated due to its potent CYP3A4 inhibition).

Domperidone should be used cautiously with potent CYP3A4 inhibitors that do not prolong the QT interval, such as indinavir, and patients should be closely monitored for signs or symptoms of adverse reactions.

Domperidone may be combined with:

neuroleptics, whose effects it potentiates;
dopaminergic agonists (bromocriptine, L-dopa), whose peripheral adverse effects such as digestive disturbances, nausea, and vomiting it suppresses without neutralizing their main therapeutic properties.

The above list is representative but not exhaustive.

In specific in vivo pharmacokinetic/pharmacodynamic interaction studies, co-administration of ketoconazole or erythromycin in healthy volunteers confirmed that these drugs significantly inhibit the presystemic metabolism of domperidone mediated by CYP3A4.

When 10 mg domperidone was administered orally four times daily concomitantly with 200 mg ketoconazole orally twice daily, QTc interval prolongation averaged 9.8 msec during the observation period; individual values ranged from 1.2 to 17.5 msec. When 10 mg domperidone was administered four times daily concomitantly with 500 mg erythromycin orally three times daily, QTc interval prolongation averaged 9.9 msec during the observation period, with individual values ranging from 1.6 to 14.3 msec. Steady-state Cmax and AUC values of domperidone increased approximately threefold in each of these interaction studies.

The impact of elevated plasma concentrations of domperidone on QTc prolongation is unknown. In these studies, monotherapy with domperidone (10 mg orally four times daily) prolonged the QTc interval by an average of 1.6 msec (ketoconazole study) and 2.5 msec (erythromycin study), whereas administration of ketoconazole alone (200 mg twice daily) or erythromycin alone (500 mg three times daily) increased the QTc interval during the observation period by 3.8 and 4.9 msec, respectively.

Theoretically, since domperidone exerts a prokinetic effect on the stomach, it may affect the absorption of concomitantly administered oral drugs, particularly prolonged-release formulations or enteric-coated preparations. However, in patients already stabilized on digoxin or paracetamol, concomitant administration of domperidone did not affect blood levels of these drugs.

Special precautions for use.

Renal impairment. The elimination half-life of domperidone is prolonged in severe renal impairment. In chronic administration, the dosing frequency of domperidone should be reduced to once or twice daily depending on the severity of impairment. Dose reduction may also be necessary.

Cardiovascular effects. Domperidone has been associated with QT interval prolongation on ECG. In post-marketing surveillance, very rare cases of QT prolongation and ventricular fibrillation/torsades de pointes have been reported in patients receiving domperidone. These reports included information on patients with other risk factors, electrolyte disturbances, and concomitant therapies that could be contributing factors (see section "Side effects"). Epidemiological studies have shown that domperidone use is associated with an increased risk of ventricular arrhythmias and sudden cardiac death (see section "Side effects"). The higher risk was observed in patients aged 60 years and older who daily received more than 00 mg of domperidone, and who were also taking other medicinal products with a known risk factor for QT interval prolongation or strong CYP3A4 inhibitors. Therefore, the medicinal product should be used with caution in elderly patients. Patients aged 60 years and older should consult a physician before taking domperidone.

Domperidone should be used at the lowest effective dose in adults and children.

Domperidone is contraindicated in patients with diagnosed prolongation of cardiac conduction intervals, particularly QT, with significant electrolyte imbalances (hypokalemia, hyperkalemia, hypomagnesemia) or bradycardia, and in patients with cardiac disorders such as congestive heart failure due to an increased risk of developing ventricular arrhythmia (see section "Contraindications"). Electrolyte imbalances (hypokalemia, hyperkalemia, hypomagnesemia) and bradycardia are factors that increase the proarrhythmic risk.

Domperidone is not recommended for use in motion sickness.

Domperidone should be used with caution in elderly patients and in patients with existing heart disease or history of heart disease.

QT interval prolongation observed in a study using domperidone according to the recommended dosing regimen at usual therapeutic doses (10 or 20 mg four times daily) has no clinical significance.

Warnings. Domperidone should be used with caution in patients with mild hepatic and/or renal impairment.

Antacid or antisecretory agents should not be taken simultaneously with oral formulations of the medicinal product, as they reduce the oral bioavailability of domperidone (see section "Interaction with other medicinal products and other forms of interaction"). When used concomitantly, domperidone should be taken before meals, and antacid or antisecretory agents should be taken after meals.

Use with ketoconazole. In interaction studies with oral ketoconazole, QT interval prolongation was observed. Although the clinical significance of this finding is not clearly established, an alternative treatment should be considered if antifungal therapy with ketoconazole is indicated (see section "Interaction with other medicinal products and other forms of interaction").

Use with apomorphine. Domperidone is contraindicated for concomitant use with medicinal products that prolong the QT interval, including apomorphine, except when the benefit of concomitant use with apomorphine outweighs the risk, and only if strict adherence to the precautions stated in the apomorphine product information is ensured.

If signs or symptoms suggestive of cardiac arrhythmia occur, Domilium ODT should be discontinued immediately and the patient should consult a physician without delay.

Patients should immediately report any symptoms related to the heart.

Domilium ODT contains aspartame, a derivative of phenylalanine, which may be harmful to patients with phenylketonuria; therefore, the product should not be used in patients with phenylketonuria.

Use during pregnancy or breastfeeding.

Pregnancy

Data on post-marketing use of domperidone in pregnant women are limited. Therefore, Domilium ODT should be prescribed during pregnancy only if, in the opinion of the physician, the expected benefit to the woman outweighs the potential risk to the fetus.

Breastfeeding

The amount of domperidone that may pass into the infant via breast milk is extremely low. The maximum relative infant dose (%) is estimated at approximately 0.1% of the maternal dose adjusted for body weight. It is unknown whether it harms the infant; therefore, mothers taking Domilium ODT should avoid breastfeeding. The decision to discontinue breastfeeding or to discontinue domperidone therapy should be made after considering the benefits of breastfeeding for the child and the benefits of therapy for the mother. Caution should be exercised if risk factors for QTc interval prolongation are present in breastfed infants. After exposure due to passage of the drug into breast milk, adverse reactions, including cardiovascular effects, cannot be excluded.

Ability to affect reaction speed when driving or operating machinery.

Dizziness and somnolence have been reported after administration of domperidone. Therefore, patients should be advised to refrain from driving, operating machinery, or engaging in any other activity requiring concentration and coordination until they know how domperidone affects them.

Method of Administration and Dosage

Domilium ODT should be used at the lowest effective dose for the shortest duration necessary to relieve symptoms of nausea and vomiting.

It is recommended to take Domilium ODT before meals. Absorption of the drug is slightly delayed when taken after food. The patient should take the medication according to the recommended dosing regimen. If a dose is missed, the next dose should be taken according to the recommended schedule. The dose should not be doubled to make up for a missed dose. The duration of treatment should not exceed 1 week.

Since orally disintegrating tablets are quite fragile, to avoid damage, they should not be pushed through the foil.

To remove the tablet from the blister pack, proceed as follows:

grasp the foil at the edge and completely remove it from the blister cell;
gently press from the bottom;
remove the tablet from the packaging.

Orally disintegrating tablets dissolve rapidly in the mouth by means of saliva—they can be taken with or without water. When taken without water, the tablet should be placed on the tongue and allowed to dissolve in the mouth before swallowing. If necessary, a glass of water may be consumed afterward.

Adults and children aged 12 years and older with body weight of at least 35 kg: 1 tablet (10 mg) three times daily.

Maximum daily dose – 3 tablets (30 mg per day).

Hepatic Impairment

Domilium ODT is contraindicated in patients with moderate or severe hepatic impairment (see section "Contraindications"). Dose adjustment is not required in patients with mild hepatic impairment (see section "Pharmacological Properties").

Renal Impairment

Since the elimination half-life of domperidone is prolonged in patients with severe renal impairment, the frequency of administration of Domilium ODT should be reduced to once or twice daily, depending on the severity of the impairment; a dose reduction may also be necessary. Patients with severe renal impairment should be monitored regularly (see sections "Special Warnings and Precautions for Use" and "Pharmacological Properties").

Adults aged ˃ 60 years

Patients aged 60 years and older should consult a physician before taking the medication.

Children

The drug is indicated for treatment in children aged 12 years and older with body weight of at least 35 kg.

Domperidone should be prescribed to children at the lowest effective dose for the shortest possible duration.

Overdose.

Symptoms: Overdose has been reported primarily in children. Symptoms of overdose may include agitation, impaired consciousness, seizures, disorientation, drowsiness, and extrapyramidal reactions.

Treatment. There is no specific antidote for domperidone. However, in cases of significant overdose, symptomatic treatment should be initiated immediately. Gastric lavage and administration of activated charcoal are recommended. ECG monitoring should be performed due to the potential for QT interval prolongation. Anticholinergic drugs and anti-Parkinsonian agents may be effective in managing extrapyramidal reactions.

Adverse Reactions.

The safety of domperidone was evaluated during clinical trials and in post-marketing use. A total of 1275 patients with dyspepsia, gastroesophageal reflux disease, irritable bowel syndrome, nausea and vomiting, or other related conditions participated in double-blind, placebo-controlled clinical trials. All patients were at least 15 years of age and received at least one dose of the drug. The mean total daily dose was 30 mg (range from 10 to 80 mg), and the median duration of exposure was 28 days (range from 1 to 28 days). Patients with diabetic gastroparesis or symptoms caused by chemotherapy or Parkinsonism were not included in the studies.

Assessment of adverse reaction frequency: very common (≥ 1/10); common (≥ 1/100 to <1/10); uncommon (≥ 1/1000 to <1/100); rare (≥ 1/10000 to <1/1000); very rare (<1/10000). If the frequency cannot be estimated from clinical trial data, it is listed as unknown.

Immune system disorders: Frequency unknown – allergic reactions, including anaphylaxis, anaphylactic shock, hypersensitivity.

Psychiatric disorders: Uncommon – decreased or absent libido, irritability, agitation, nervousness; very rare – depression, anxiety.

Nervous system disorders: Uncommon – headache, drowsiness, dizziness, extrapyramidal disorders; very rare – insomnia, thirst, lethargy, akathisia; frequency unknown – convulsions, restless legs syndrome (exacerbation of restless legs syndrome in patients with Parkinson’s disease).

Eye disorders: Frequency unknown – oculogyric crises.

Cardiac disorders: Very rare – oedema, palpitations, disturbances in heart rate and rhythm, serious ventricular arrhythmias; frequency unknown – ventricular arrhythmias, sudden cardiac death, QT interval prolongation, ventricular arrhythmias of the type "torsade de pointes".

Gastrointestinal disorders: Common – dry mouth; uncommon – diarrhoea; rare – gastrointestinal disorders including abdominal pain, regurgitation, change in appetite, nausea, heartburn, constipation; very rare – transient intestinal spasms.

Skin and subcutaneous tissue disorders: Uncommon – rash, pruritus, urticaria; frequency unknown – angioneurotic oedema.

Reproductive system and breast disorders: Rare – breast enlargement, galactorrhoea, breast oedema, lactation disorder, irregular menstrual cycle; uncommon – galactorrhoea, breast pain, breast tenderness; frequency unknown – gynaecomastia, amenorrhoea.

Musculoskeletal and connective tissue disorders: Rare – leg pain.

Renal and urinary disorders: Very rare – dysuria, frequent micturition; frequency unknown – urinary retention.

General disorders: Uncommon – asthenia.

Other: conjunctivitis, stomatitis.

Laboratory test abnormalities: Very rare – increased levels of ALT, AST, and cholesterol; frequency unknown – abnormal liver function tests, increased blood prolactin levels.

In 45 studies where domperidone was used at higher doses, for longer durations, and for additional indications including diabetic gastroparesis, the incidence of adverse reactions (except dry mouth) was significantly higher. This was particularly evident in pharmacologically predictable cases related to elevated prolactin levels.

Since the pituitary gland lies outside the blood-brain barrier, domperidone may cause an increase in prolactin levels. In isolated cases, such hyperprolactinaemia may lead to neuroendocrine adverse effects such as galactorrhoea, gynaecomastia, and amenorrhoea.

During the post-marketing period, no differences in the safety profile of the drug were observed between adults and children, except for extrapyramidal disorders and other central nervous system-related events such as convulsions and agitation, which were predominantly reported in children.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions via the national reporting system.

Shelf life.

3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of the reach of children.

Packaging.

10 tablets per blister, 3 blisters per cardboard box.

Prescription status. Over-the-counter.

Manufacturer.

Athena Drug Delivery Solutions Pvt. Ltd.

Manufacturer's address and location of operations.

Plot A1-A5, MIDC, Chemical Zone, Ambernath (West), Maharashtra, 421 501, India.

Domilium odt