INSTRUCTION for medical use DOMRID SR

Transcription

1 APPROVED Order of the Ministry of Health of Ukraine Registration certificate UA/8976/03/01 INSTRUCTION for medical use DOMRID SR Composition: active substance: domperidone maleate; 1 tablet contains domperidone maleate equivalent to domperidone 30 mg; excipients: lactose monohydrate, povidone, quinoline yellow (Е 104), croscarmellose sodium, magnesium stearate, colloidal silicon dioxide anhydrous, hydroxymethyl propyl cellulose, talk. Pharmaceutical form. Sustained release tablets. Basic physico-chemical properties: white-yellow, double layer round plain tablets with bevel edge and a K-shaped logo on the yellow layer of the tablet. Pharmacotherapeutic group. Propulsives. ATC code А03F A03. Pharmacological properties. Pharmacodynamics. Domperidone is dopamine antagonist with antiemetic properties. Domperidone slightly penetrates through the blood-brain barrier. The use of domperidone is rarely accompanied by extrapyramidal side effects, especially in adults, but domperidone stimulates prolactin from the pituitary gland. Its antiemetic activity is probably caused by a combination of peripheral (gastrokinetic) effect and antagonism to dopamine receptors in the chemoreceptor trigger zone, which is outside the bloodbrain barrier in the back area (area postrema). Animal studies and low concentrations detected in the brain indicate a predominantly peripheral effect of domperidone on dopamine receptors. Studies in humans have shown that when used orally, domperidone increases the pressure in the lower esophagus, improves antroduodenal motility and enhances gastric emptying. Domperidone has no effect on gastric secretion. Pharmacokinetics. Absorption. Domperidone is rapidly absorbed after oral administration under fasting condition; the maximum concentration in plasma is reached after about 60 minutes. The low absolute bioavailability of oral domperidone (approximately 15%) is due to extensive first pass metabolism in the gut wall and liver. However, in healthy individuals, bioavailability of domperidone is increased when administered after a meal; patients complaining on the gastrointestinal tract should take domperidone minutes before a meal. Reduced gastric acidity reduces absorption of domperidone. When oral administration after a meal, maximum absorption is slightly slowed down, and the area under the curve (AUC) is slightly increased. Clinical characteristics. Indications. To relieve symptoms of nausea and vomiting.

2 Contraindications. Domrid SR is contraindicated: - in patients with known hypersensitivity to the drug or its excipients; - in patients with prolactin-secretory pituitary tumor (prolactinoma); - in patients with severe or moderate dysfunction of liver and/or kidneys (see section «Administration details»); - in patients with known prolongation of the QTc interval, patients with significant electrolyte imbalance or with background heart diseases, such as congestive heart failure (see section «Administration details»); - in patients with hepatic failure; - if stimulation of motor function of the stomach can be dangerous, e.g., in case of gastro-intestinal bleeding mechanical obstruction or perforation; - concomitant use of ketoconazole, erythromycin or other strong CYP3A4 inhibitors is contraindicated; - concomitant use of medicinal products that prolong the QT interval, such as fluconazole, erythromycin, itraconazole, oral ketoconazole, posaconazole, ritonavir, saquinavir, telaprevir, voriconazole, clarithromycin, amiodarone, telithromycin etc. is contraindicated (see sections «Administration details» and «Interaction with other medicinal products and other types of interaction»). Interaction with other medicinal products and other types of interaction. Anticholinergic drugs may neutralize anti-dyspeptic effect of domperidone. Due to the pharmacodynamic and/or pharmacokinetic interactions, the risk of the QT interval prolongation increases. It is not recommended to take antacids and antisecretory drugs concomitantly with domperidone, since they decrease its bioavailability after oral administration (see section «Administration details»). Domperidone is metabolized mostly by CYP3A4. According to the studies, in vitro and in humans, concomitant use of medicinal products that significantly inhibit this enzyme may increase plasma level of domperidone. When using domperidone concomitantly with potent CYP3A4 inhibitors that are able to prolong the QT interval, clinically significant changes in the QT interval were observed. Therefore, the use of domperidone with some preparations is contraindicated. (see section «Contraindications»). Concomitant use of the following medicinal agents with domperidone is contraindicated. All medicinal agents that prolong the QT interval: - class IA antiarrhythmic drugs (e.g., disopyramide, quinidine, hydroquinidine); - class III antiarrhythmic drugs (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 antifungals (e.g., pentamidine); - certain anti-malarial drugs (e.g., halofantrine, lumefantrine); - certain gastro-intestinal drugs (e.g., cisapride, dolasetron, prucalopride); - certain antihistamines (e.g., mequitazine, mizolastine); - certain drugs used in oncology (e.g., toremifene, vandetanib, vincamine); - certain other drugs (e.g., bepridil, methadone, diphemanil). In concomitant oral use of ketoconazole or erythromycin in vivo, it has been proved that these drugs significantly inhibit CYP3A4-mediated presystemic metabolism of domperidone. When concomitant oral use of 10 mg of domperidone 2 times per day during the follow-up period, average the QTc interval prolongation by 9.8 msec has been marked; some values varied between 1.2 and 17.5 msec. When concomitant use of10 mg of domperidone 4 times per day and 500 mg of erythromycin per os 3 times per day, the QTc interval during the follow-up period was prolonged on average by 9.9 msec, the interval of some values was 1.6 to 14.3 msec. The equilibrium values of Cmax and AUC increased approximately three-fold in each of the interaction studies. The impact

3 of the increased plasma concentrations on the observed effect on the QTc is unknown. In these studies, in case of monotherapy with domperidone (10 mg per os 4 times per day) the QTc interval is prolonged on average by 1.6 msec (studies of ketoconazole) and 2.5 msec (studies of erythromycin) while using ketoconazole only (200 mg 2 times per day) or erythromycin (500 mg 3 times a day) prolonged the QTc interval during the observation period by 3.8 and 4.9 msec, respectively. Due to the pharmacodynamic and/or pharmacokinetic interactions, the risk of the QTc interval prolongation. Examples of strong CYP3A4 inhibitors, coadministration of which with Domrid SR is not recommended: - azole antifungals, such as fluconazole*, itraconazole, ketoconazole* and voriconazole*; - macrolide antibiotics, such as clarithromycin* and erythromycin*; - protease inhibitors; - HIV-protease inhibitors, such as amprenavir, atazanavir, fosamprenavir, indinavir, nelfinavir, ritonavir and saquinavir; - Calcium antagonists, such as diltiazem and verapamil; - amiodarone *; - apreрitant; - nefazodone; - telithromycin *. *- prolong the QTc interval. Concomitant administration of the following substances requires caution. Caution is necessary when using with the drugs that cause bradycardia and hypokalemia, as well as with the following macrolides that may prolong the QT interval: azithromycin and roxithromycin (clarithromycin is contraindicated as it is a potent CYP3A4 inhibitor). Caution is required when using domperidone concomitantly with potent CYP3A4 inhibitors that do not prolong the QT interval, such as indinavir, and the patients should be under close supervision in case in case there may be signs or symptoms of adverse reactions. The following list is representative, but not exhaustive. Domrid SR may be combined with: - neuroleptics, the effect of which it increases; - dopaminergic agonists (bromocriptine, L-dopa), adverse peripheral effects of which, such as indigestion, nausea, vomiting, it inhibits without neutralizing the basic properties. Since domperidone has prokinetic effect on the stomach, theoretically this may affect absorption on oral drugs used concomitantly, particularly on sustained release or enteric formulations. However, in patients whose condition has already stabilized at the background of using digoxin or paracetamol, concomitant use of domperidone had no effect on the blood levels of these drugs. Administration details. Domrid SR is not recommended for use in motion sickness. Domrid SR should be used with caution in elderly patients or patients with heart diseases or with the history of the heart diseases. Cardiovascular effects. Domperidone was associated with prolongation of the QT interval on ECG. During the post-marketing study very rare cases of prolongation of the QT interval and torsade de pointes have been observed in patients using domperidone. These reports included information about the patients with other risk factors, electrolyte imbalance and concomitant therapy that may be contributing factors. Prolongation of the QT interval observed in healthy volunteers using domperidone according to the recommended dosage regimen in usual therapeutic doses (10 or 20 mg 4 times a day), had no clinical significance. Warning. Domperidone should be used with caution in patients with mild hepatic and/or renal dysfunction. Due to the increased risk of ventricular arrhythmia, Domrid SR is not recommended for use in patients with prolonged intervals of cardiac conductivity, particularly the QTc, patients with significant electrolyte imbalance (hypokalemia, hyperkalemia, hypomagnesemia) or bradycardia, or

4 patients with background cardiac diseases, such as congestive heart failure. It is known that electrolyte imbalance (hypokalemia, hyperkalemia, hypomagnesemia) and bradycardia are the conditions that increase proarrhythmogenic risk. In case of signs or symptoms that may be associated with cardiac arrhythmia, the use of Domrid SR should be stopped, and the patient should immediately consult the doctor. Renal dysfunction. The half-life of domperidone in severe renal dysfunction is prolonged. When long-term use, the dosage frequency of domperidone should be changed to one or two times per day depending on the severity of the dysfunction. Also, dose reduction may be necessary. Antacids or antisecretory drugs should not be taken concomitantly with the drug Domrid SR, since they reduce oral bioavailability of domperidone (see section «Interaction with other medicinal products and other types of interaction»). When concomitant administration, the drug Domrid SR should be taken before meal, and antacids or antisecretory drugs should be taken after meal. Use with ketoconazole. In studies of interaction with oral form of ketoconazole, prolongation of the QT interval was marked. Though the significance of this study has not been determined, alternative treatment should be chosen if antifungal therapy with ketoconazole is indicated (see section «Interaction with other medicinal products and other types of interaction»). The following information on the development of complications of cardio-vascular diseases caused by medicinal agents that contain domperidone should be taken into account: Some epidemiological studies have shown that domperidone may be associated with the increased risk of severe ventricular arrhythmias or a sudden cardiac death. The risk of serious ventricular arrhythmias or a sudden cardiac death may be higher in patients aged 60 and more or with oral use of the drug doses more than 30 mg per day. Therefore, caution is required when using Domrid SR in elderly patients. Patients aged 60 and more should consult their doctor. Domperidone should be administered in adults and children in the lowest effective dose. The risk/benefit ration of the use of domperidone remains favorable. If a patient has intolerance of some sugars, he should consult his doctor before taking this medicinal product, since the drug contains lactose. Use during pregnancy or breast-feeding. The data on postmarketing use of domperidone in pregnant women are limited. Therefore, during pregnancy, Domrid should be administered only when the expected positive effect for the mother overweighs the potential risk for the fetus, according to the doctor. The amount of domperidone that may penetrate into the body of the child with the breast milk is extremely low. The maximum relative dose for the babies (%) is evaluated at the level of approximately 0.1% of the dose taken by the mother, adjusted for the body weight. It is unknown whether it harms the baby, therefore, mothers taking Domrid should refrain from breast feeding. After exposure due to excretion of the drug into the breast milk, adverse effects, including cardiac effects, may not be excluded. Caution should be exercised in case of presence of the risk factors of QTc interval prolongation in breast-fed children. Effect on reaction rate when driving motor transport or using other mechanisms. Taking into account the adverse effects on the nervous system, the patients should be attentive when driving motor transport or working with other mechanisms. Dosage and administration. To relieve symptoms of nausea and vomiting. Adults. 1 tablet 1 time a day for minutes before meals. Treatment duration should not exceed 1 week. The maximum daily dose is 30 mg. Children. Children drug use in another dosage form

5 Overdose. Symptoms. The symptoms of overdose may be agitation, impairment of consciousness, seizures, somnolence, disorientation and extrapyramidal reactions, especially in children. Treatment. There is no specific antidote for domperidone, but in case of significant overdose, gastric lavage within 1 hour after the intake of the drug and activated charcoal is recommended, as well as close supervision over the patient and supportive therapy. Anticholinergic drugs, drugs for treating Parkinson s disease may be effective for control of extrapyramidal reactions. Adverse reactions. On condition on compliance with the recommendations regarding the dosage and duration of treatment, domperidone is normally well tolerated, and the adverse events occur rarely. Immune system: allergic reactions, including anaphylaxis, anaphylactic shock, hypersensitivity. Endocrine system: increase in prolactin level. Mental disorders: nervousness, irritation, excitation, depression, anxiety, decreased or absent libido. Nervous system: extrapyramidal disorders, insomnia, dizziness, thirst, seizures, apathy, headache, somnolence, akathisia. Cardiovascular system: edema, palpitation, disorders of heart rhythm and heart rate, prolonged QT interval, serious ventricular arrhythmia, ventricular arrhythmia of the type torsade de pointes, sudden cardiac death. Gastrointestinal tract: dry mouth, transient intestinal spasms, diarrhea, gastrointestinal disorders, including abdominal pain, regurgitation, change of the appetite, nausea, heartburn, constipation. Organs of vision: oculogyric crisis. Skin and subcutaneous tissues: itching, rash, urticaria, angioedema. Reproductive system and mammary glands: galactorrhea, breast enlargement / gynecomastia, breast sensitivity, discharge from the breasts, amenorrhea, breast swelling, pain in the breast, violation of lactation, irregular menstrual cycle. Musculoskeletal system and connective tissue: pain in the legs. Urinary system: urinary retention, dysuria, frequent urination. General disorders: asthenia. Other: conjunctivitis, stomatitis. Changes in the laboratory values: abnormal liver function tests, increased levels of ALT, AST and cholesterol, increased blood level of prolactin. Since the pituitary gland is outside the blood-brain barrier, domperidone may increase the prolactin level. In isolated cases such hyperprolactinemia may lead to neuroendocrine adverse effects, such as galactorrhea, gynecomastia and amenorrhea. During the post-marketing use of the drug, no differences have been noticed in the safety profile of the drug in adults and children, except for extrapyramidal disorders and other phenomena, convulsions and agitation associated with the central nervous system, observed mainly in children. Shelf life. 2 years. Storage conditions. Keep at the temperature below 25 С, in the original package. Keep out of reach of children. Package. 10 tablets are in a blister. 1 or 3 blisters are in a carton package. Condition of supply. By prescription. Manufacturer.

6 KUSUM PHARM LLC. Address , Ukraine, Sumy Oblast, Sumy, Skryabina Str., 54. Date of last revision