▶ Specification : 75ml
▶ Category : Other digestive system drugs
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Domperidone 10mg/75mL
Adults and children (12 years or older, at least 35kg) : Orally administer 10mg as domperidone (5mg if administering levodopa) three times a day before meals. Max. daily dose is 30mg. In general, do not use for more than 1 week.
Alleviation of nausea and vomiting symptoms
1. Do not administer to the following patients.
1) Patients with hypersensitivity to ingredients of this drug or a history thereof
2) Patients where promotion of gastric activity is dangerous (patients with gastroenteric bleeding, mechanical obstruction or perforations)
3) Patients with prolactin secreting tumors (antidopamine action may promote prolactin secretion)
4) Patients being administered strong CYP3A4 inhibitors concomitantly (See 5. Interactions)
5) Patients being administered drugs that delay QTc intervals concomitantly (See 5. Interactions)
6) Patients with moderately severe to severe liver impairment (See 11. Misc.)
7) Pregnant or potentially pregnant women (See 6. Administration to pregnant women and nursing mothers)
8) Patients exhibiting extended cardiac conduction intervals such as QTc, patients exhibiting electrolyte imbalance (hypokalemia, hyperkalemia, hypomagnesemia), patients with underlying heart conditions such as heart failure (See 4. General precautions)
9) This drug containslcatose. Do not administer to patients with genetic problems such as galactose intolerance, Lapp lactose deficiency, or glucose-galactose malabsorption.
2. Administer carefully to the following.
1) Children
2) Patients with renal impairment or mild liver impairment (strong adverse reactions may appear) (See 11. Misc.)
3) Elderly patients (See 3. Adverse reactions)
4) Patients with heart disease or history of heart disease (See 4. General precautions)
3. Adverse reactions
1) Clinical trial data
Safety of this drug was evaluated through 31 double-blind placebo-controlled tests with 1,275 patients having indigestion, gastroesophageal reflux, hypersensitive bowel syndrome, nausea, vomiting or other associated symptoms. All patients were 15 years or older, and administered this drug at least once. The median daily administration dose was 30mg (range: 10 to 80mg), and the median administration duration was 28 days (range : 1 to 28). Studies on patient groups with diabetic gastroparesis or symptoms associated with chemotherapy or Parkinson’s disease were excluded.
Table 1. Adverse reactions reported in 1% or more of cases from 31 clinical trials
Table 2. Adverse reactions reported in less than 1% of cases from 31 clinical trials
In 45 clinical trials including diabetic gastroparesis patients, doses exceeding 80mg/day and administration for more than 28 days, a high rate of adverse reactions (especially pharmacologically predictable prolactin-related adverse reactions) was reported. Along with the above adverse reactions, restlessness, mammary secretions, mastauxe, swelling of breasts, depression, hypersensitivity, nursing difficulties and irregular menstruation were reported.
2) Post-marketing cases
In addition to adverse reactions reported during clinical trials and the adverse reactions mentioned in the above, the following adverse reactions were reported. In the respective table, the frequency of adverse reactions is listed depending on the following frequencies.
Very frequent : 1/10 or higher, Frequent : At least 1/100 and less than 1/10, Infrequent : At least 1/1,000 and less than 1/100, Rarely : At least 1/10,000 and less than 1/1,000, Very rarely : Less than 1/10,000, including unknown frequency
(1) In Table 3, adverse reactions are shown by frequency depending on voluntary reporting rate.
Table 3. Adverse reactions by frequency depending on voluntary reporting rate in PMS
* Results of epidemiological investigation (See 5) of 4. General precautions)
(2) Extrapyramidal disorder usually occurs in newborns and infants. Spasms, anxiety and other central nervous system-related adverse reactions usually appear in infants or children.
3) Analysis of domestic voluntary adverse reaction reports (1989 to 2014) has shown that adverse reactions whose number of reports was statistically significantly higher than other drugs where adverse reactions were reported were as follows. However, this does not prove a causal relationship between the ingredients at hand and the following adverse cases.
- Systemic anomalies and anomalies around site of administration : Edema
4. General precautions
1) This drug is mainly metabolized in the liver; administer carefully to patients with liver damage.
2) In patients with severe renal failure (serum creatinine > 6mg/100mL), the elimination half-life of domperidone is increased; when administering repeatedly, reduce the number of administrations per day to once or twice a day depending on the degree of renal damage, as well as dose. Patients requiring long-term therapy need regular examination. (See 11. Misc.)
3) Breast cancer is thought to be prolactin secretion dependent; administer this drug with caution to patients with histories of breast cancer.
4) The film-coated tablets contains lactose and may not be suitable for patients with lactose intolerance, galactosemia or glucose/galactose malabsorption (Applicable film-coated tablet only)
5) Drowsiness and dizziness have been observed after taking domperidone. Until the effects of domperidone on the patient have been identified, refrain from driving or using machinery requiring mental focus.
6) Administration of this drug may cause adverse reactions such as endocrine function regulation anomalies in the diencephalon and extrapyramidal disorder; give sufficient consideration to efficacy and safety when administering this drug.
7) In epidemiological investigation, domperidone was shown to be associated with increased risk of serious ventricular arrhythmia or sudden cardiac death (See 3. Adverse reactions). In these studies, such risks appear to be higher in patients taking 30mg or more oral preparations daily, or who are 60 years of age or older. Accordingly, this drug must be administered carefully to elderly patients, and patients 60 year or older should consult a physician before taking this drug. This drug is contraindicated for patients exhibiting extended cardiac conduction intervals such as QTc, patients exhibiting electrolyte imbalance (hypokalemia, hyperkalemia, hypomagnesemia), patients with heart disease such as ischemic heart failure, and patients with bradycardia. Electrolyte imbalances and bradycardia are reported to increase the risk of arrhythmia. If symptoms or signs associated with ventricular arrhythmia are observed, this drug should be discontinued, and the patient should consult a physician.
5. Interactions
1) Concomitant administration with the following drugs may lead to endocrine function regulation anomalies or extrapyramidal symptoms. In inevitable cases of concomitant administration, observe sufficiently and administer carefully : phenothiazine drugs (prochlorperazine, chlorpromazine, thiethylperazine), butyrophenone drugs (haloperidol, etc.), Rauwolfia alkaloid drugs (reserpine, etc.)
2) May hide nausea, vomiting and loss of appetite symptoms that indicate digitalis drug saturation; for patients receiving digitalis drugs, observe sufficiently and observe carefully.
3) Concomitant administration with anticholinergics (hyoscine butylbromide, tiquizium bromide, timepidium bromide, etc.) may suppress digestive promotion action and reduce the gastric emptying action of this drug. Accordingly, reduce or discontinue one depending on symptoms, or administer at intervals.
4) Theoretically, the gastric activity promotion of this drug may impact absorption of oral preparations such as extended-release or enteric coated drugs. In the case of patients stabilized to digoxin or acetaminophen, concomitant administration of these drugs did not impact their blood concentration.
5) This drug is reported to not increase the effect of neuroleptics.
6) This drug is reported to suppress peripheral adverse reactions of dopamine agonists (bromocriptine, levodopa) such as indigestion, nausea or vomiting without impacting central effects.
7) Antacids and proton pump inhibitors may lower the bioavailability of this drug and should not be administered at the same time as this drug. When administering concomitantly, take this drug before food, and take antacids or PPIs after food.
8) The gastroenteric action of this drug may be blocked by antimuscarinics and opioid analgesics.
9) This drug is mainly metabolized by CYP3A4; concomitant administration of strong CYP3A4 suppressors and domperidone showed clinical changes in QT intervals. Accordingly, concomitant administration of domperidone and such drugs is prohibited. Caution is required when administering concomitantly with strong CYP3A4 suppressants (e.g. indinavir) with which domperidone is shown not to cause extension of QT intervals. The patient should be carefully observed for symptoms or signs or cardiovascular adverse reactions.
Take caution when administering the following drugs that cause extension of QT intervals with domperidone. The patient should be carefully observed for symptoms or signs or cardiovascular adverse reactions.
<QTc-prolonging medicinal products>
- anti-arrhythmics class IA (e.g., disopyramide, hydroquinidine, quinidine)
- anti-arrhythmics class III (e.g., amiodarone, dofetilide, dronedarone, ibutilide, sotalol)
- certain antipsychotics (e.g., haloperidol, pimozide, sertindole)
- certain antidepressants (e.g., citalopram, escitalopram)
- certain antibiotics (e.g. , erythromycin, levofloxacin, moxifloxacin, spiramycin)
- certain antifungal agents (e.g., pentamidine)
- certain antimalarial agents (in particular halofantrine, lumefantrine)
- certain gastro-intestinal medicines (e.g., cisapride, dolasetron, prucalopride)
- certain antihistaminics (e.g., mequitazine, mizolastine)
- certain medicines used in cancer (e.g., toremifene, vandetanib, vincamine)
- certain other medicines (e.g., bepridil, diphemanil, methadone)
<Potent CYP3A4 inhibitors>
- azole antifungals : fluconazole, itraconazole, ketoconazole, voriconazole
- macrolide antibiotics : clarithromycin, erythromycin, telithromycin
- HIV protease inhibitors : saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, fosamprenavir, lopinavir, atazanavir, tipranavir
Separate in vivo pharmacokinetic/pharmacodynamic interaction studies with oral ketoconazole or oral erythromycin in healthy subjects confirmed a marked inhibition of domperidone's CYP3A4 mediated first pass metabolism by these drugs.
With the combination of oral domperidone 10mg four times daily and ketoconazole 200mg twice daily, a mean QTc prolongation of 9.8 msec was seen over the observation period, with changes at individual time points ranging from 1.2 to 17.5 msec. With the combination of domperidone 10mg four times daily and oral erythromycin 500mg three times daily, mean QTc over the observation period was prolonged by 9.9 msec, with changes at individual time points ranging from 1.6 to 14.3 msec. Both the Cmax and AUC of domperidone at steady state were increased approximately three-fold in each of these interaction studies. In these studies domperidone monotherapy at 10mg given orally four times daily resulted in increases in mean QTc of 1.6 msec (ketoconazole study) and 2.5 msec (erythromycin study), while Ketoconazole monotherapy (200mg twice daily) led to increases in QTc of 3.8 and 4.9 msec, respectively, over the observation period.
Single repeated administration of domperidone at 40mg four times a day (total dose of 160mg/day; double the max. daily dose) showed no significant increase in QTc at plasma concentrations of domperidone similar to those observe during concomitant administration in the interaction study.
10) Caution is necessary when administering concomitantly with drugs associated with prolongation of the QT interval and torsades de pointes (antiarrhythmics, quinolone antibiotics, antipsychotics, 5-HT3 blockers, beta-2 adrenergic receptor effectors, antimalarials, SSRI, tricyclic antidepressants, etc.). Take caution when using in patients with prolonged QT intervals on the electrocardiogram or patients having fundamental heart disease such as ischemic heart failure or significant electrolyte disturbances, especially in patients with risk of Torsades des pointes.
11) Theoretically, concomitant administration of this drug with monoamine oxidase inhibitors may increase the dopamine concentration of the sympathetic ganglia. Administer carefully as there may be a possibility of hypertensive crisis.
6. Administration to pregnant women and nursing mothers
1) There are limited post-marketing data on the use of domperidone in pregnant women. A study in rats has shown reproductive toxicity at a high, maternally toxic dose (reports of deformities such as musculoskeletal and organ deformities). The potential risk for humans is unknown. Therefore, domperidone should only be used during pregnancy when justified by the anticipated therapeutic benefit.
2) Excretion in milk of this drug was observed during animal testing with rats (Usually excreted as metabolite : After oral and intravenous administration of 2.5mg/kg dose, max. concentration excreted in milk was 40ng/mL and 800ng/mL, respectively. Domperidone concentration in human milk is around 10 to 50% of plasma concentration, and is expected not to exceed 10ng/mL.
3) Domperidone is excreted in human milk and breast-fed infants receive less than 0.1% of the maternal weight-adjusted dose. Occurrence of adverse effects, in particular cardiac effects cannot be excluded after exposure via breast milk. A decision should be made whether to discontinue breast-feeding or to discontinue/abstain from domperidone therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the women. Caution should be exercised in case of QTc prolongation risk factor in breast-fed infants.
7. Administration to children
<Tablet, liquid>
Domperidone tablets are unsuitable for use in children and adolescents weighing less than 35 kg. Overdosage may cause neurological side effects in children (See 9. Action for overdosage).
In post-marketing experience, there were no differences in safety between adults and children excluding extrapyramidal symptoms and other central nervous system-related adverse reactions. Extrapyramidal symptoms usually occur in newborns and infants up to 1 year of age. Spasms, anxiety and other central nervous system-related adverse reactions usually appear in infants or children.
<Granule, powder, suspension>
Avoid overdosing children, administering carefully. Be especially careful with infants under 1. Overdosing may cause neurological symptoms in children (See 8. Action for overdosage).
In post-marketing experience, there were no differences in safety between adults and children excluding extrapyramidal symptoms and other central nervous system-related adverse reactions. Extrapyramidal symptoms usually occur in newborns and infants up to 1 year of age. Spasms, anxiety and other central nervous system-related adverse reactions usually appear in infants or children.
8. Administration to elderly patients
Elderly patients generally have lowered physiological functions; administer with caution, reducing dose as necessary.
9. Action for overdosage
1) Symptoms : Overdose has been reported primarily in infants and children. Symptoms of overdosage may include agitation, altered consciousness, convulsions, disorientation, somnolence and extrapyramidal reactions. Parkinson’s syndrome (shaking, rigidity, slowness of movement) may also appear.
2) Treatment : There is no specific antidote to domperidone, but in the event of overdose, standard symptomatic treatment should be given immediately. Gastric lavage as well as the administration of activated charcoal, may be useful. ECG monitoring should be undertaken, because of the possibility of QT interval prolongation. Close medical supervision and supportive therapy is recommended.
Anticholinergic, anti-parkinson drugs may be helpful in controlling the extrapyramidal reactions.
10. Storage and handling precautions
1) Keep out of reach of children.
2) Removing drugs from their original container and storing them in other container may lead to accidents due to misuse or lower quality; be sure to keep in tightly closed original container.
3) Do not mix : When dispensing with concomitantly prescribed aminophylline drugs in the same medicine sachet, discoloration of this drug may occur. Dispense in separate medicine sachets.
11. Misc.
<Pharmacological properties>
In accordance with ICH-E14 guidelines, a thorough QT study was performed. This study included a placebo, an active comparator and a positive control and was conducted in healthy subjects with up to 80 mg per day 10 or 20 mg administered 4 times a day of domperidone. This study found a maximal difference of QTc between domperidone and placebo in LS-means in the change from baseline of 3.4 msec for 20 mg domperidone administered 4 times a day on Day 4. The 2-sided 90% CI (1.0 to 5.9 msec) did not exceed 10 msec. No clinically relevant QTc effects were observed in this study when domperidone was administered at up to 80 mg/day (i.e., more than twice the maximum recommended dosing).
However, two previous drug-drug interaction studies showed some evidence of QTc prolongation when domperidone was administered as monotherapy (10 mg 4 times a day). The largest time-matched mean difference of QTcF between domperidone and placebo was 5.4 msec (95 % CI: -1.7 to 12.4) and 7.5msec (95 % CI: 0.6 to 14.4), respectively.
<Pharmacokinetic properties>
Absorption
Domperidone is rapidly absorbed after oral administration with peak plasma concentrations occurring at approximately 1 hr after dosing.. The Cmax and AUC values of domperidone increased proportionally with dose in the 10 mg to 20 mg dose range. A 2- to 3-fold accumulation of domperidone AUC was observed with repeated four times daily (every 5 hr) dosing of domperidone for 4 days.
Although domperidone's bioavailability is enhanced in normal subjects when taken after a meal, patients with gastrointestinal complaints should take domperidone 15-30 minutes before a meal. Reduced gastric acidity impairs the absorption of domperidone. Oral bioavailability is decreased by prior concomitant administration of cimetidine and sodium bicarbonate. The time of peak absorption is slightly delayed and the AUC somewhat increased when the oral drug is taken after a meal.
Hepatic impairment
In subjects with moderate hepatic impairment (Pugh score 7 to 9, Child-Pugh rating B), the AUC and Cmax of domperidone is 2.9- and 1.5- fold higher, respectively, than in healthy subjects.
The unbound fraction is increased by 25%, and the terminal elimination half-life is prolonged from 15 to 23 hours. Subjects with mild hepatic impairment have a somewhat lower systemic exposure than healthy subjects based on Cmax and AUC, with no change in protein binding or terminal half-life. Subjects with severe hepatic impairment were not studied. Domperidone is contraindicated in patients with moderate or severe hepatic impairment.
Renal impairment
In subjects with renal insufficiency (CCR<30ml/min/1.73m2) the elimination half-life of domperidone was increased from 7.4 to 20.8 hours, but plasma drug levels were lower than in healthy volunteers.
Since very little unchanged drug (approximately 1%) is excreted via the kidneys, it is unlikely that the dose of a single administration needs to be adjusted in patients with renal insufficiency.
However, on repeated administration, the dosing frequency should be reduced to once or twice daily depending on severity of the impairment, and the dose may need to be reduced.
<Preclinical data>
Electrophysiological in vitro and in vivo studies indicate an overall moderate risk of domperidone to prolong the QT interval in humans. In in vitro experiments on isolated cells transfected with hERG and on isolated guinea pig myocytes exposure ratios ranged between 26 – 47-fold, based on IC50 values inhibiting currents through IKr ion channels in comparison to the free plasma concentrations in humans after administration of the maximum daily dose of 10 mg administered 3 times a day. safety margins for prolongation of action potential duration in in vitro experiments on isolated cardiac tissues exceeded the free plasma concentrations in humans at maximum daily dose (10 mg administered 3 times a day) by 45-fold. Safety margins in in vitro proarrhythmic models (isolated Langendorff perfused heart) exceeded the free plasma concentrations in humans at maximum daily dose (10 mg administered 3 times a day) by 9- up to 45-fold. In in vivo models the no effect levels for QTc prolongation in dogs and induction of arrhythmias in a rabbit model sensitized for torsade de pointes exceeded the free plasma concentrations in humans at maximum daily dose (10 mg administered 3 times a day) by more than 22-fold and 435-fold, respectively. In the anesthetized guinea pig model following slow intravenous infusions, there were no effects on QTc at total plasma concentrations of 45.4ng/ml, which are 3-fold higher than the total plasma levels in humans at maximum daily dose (10 mg administered 3 times a day). The relevance of the latter study for humans following exposure to rally administered domperidone is uncertain.
In the presence of inhibition of the metabolism via CYP3A4 free plasma concentrations of domperidone can rise up to 3-fold.
At a high, maternally toxic dose (more than 40 times the recommended human dose), teratogenic effects were seen in the rat. No teratogenicity was observed in mice and rabbits.
Domperidone 10mg/75mL
Adults and children (12 years or older, at least 35kg) : Orally administer 10mg as domperidone (5mg if administering levodopa) three times a day before meals. Max. daily dose is 30mg. In general, do not use for more than 1 week.
Alleviation of nausea and vomiting symptoms
1. Do not administer to the following patients.
1) Patients with hypersensitivity to ingredients of this drug or a history thereof
2) Patients where promotion of gastric activity is dangerous (patients with gastroenteric bleeding, mechanical obstruction or perforations)
3) Patients with prolactin secreting tumors (antidopamine action may promote prolactin secretion)
4) Patients being administered strong CYP3A4 inhibitors concomitantly (See 5. Interactions)
5) Patients being administered drugs that delay QTc intervals concomitantly (See 5. Interactions)
6) Patients with moderately severe to severe liver impairment (See 11. Misc.)
7) Pregnant or potentially pregnant women (See 6. Administration to pregnant women and nursing mothers)
8) Patients exhibiting extended cardiac conduction intervals such as QTc, patients exhibiting electrolyte imbalance (hypokalemia, hyperkalemia, hypomagnesemia), patients with underlying heart conditions such as heart failure (See 4. General precautions)
9) This drug containslcatose. Do not administer to patients with genetic problems such as galactose intolerance, Lapp lactose deficiency, or glucose-galactose malabsorption.
2. Administer carefully to the following.
1) Children
2) Patients with renal impairment or mild liver impairment (strong adverse reactions may appear) (See 11. Misc.)
3) Elderly patients (See 3. Adverse reactions)
4) Patients with heart disease or history of heart disease (See 4. General precautions)
3. Adverse reactions
1) Clinical trial data
Safety of this drug was evaluated through 31 double-blind placebo-controlled tests with 1,275 patients having indigestion, gastroesophageal reflux, hypersensitive bowel syndrome, nausea, vomiting or other associated symptoms. All patients were 15 years or older, and administered this drug at least once. The median daily administration dose was 30mg (range: 10 to 80mg), and the median administration duration was 28 days (range : 1 to 28). Studies on patient groups with diabetic gastroparesis or symptoms associated with chemotherapy or Parkinson’s disease were excluded.
Table 1. Adverse reactions reported in 1% or more of cases from 31 clinical trials
Table 2. Adverse reactions reported in less than 1% of cases from 31 clinical trials
In 45 clinical trials including diabetic gastroparesis patients, doses exceeding 80mg/day and administration for more than 28 days, a high rate of adverse reactions (especially pharmacologically predictable prolactin-related adverse reactions) was reported. Along with the above adverse reactions, restlessness, mammary secretions, mastauxe, swelling of breasts, depression, hypersensitivity, nursing difficulties and irregular menstruation were reported.
2) Post-marketing cases
In addition to adverse reactions reported during clinical trials and the adverse reactions mentioned in the above, the following adverse reactions were reported. In the respective table, the frequency of adverse reactions is listed depending on the following frequencies.
Very frequent : 1/10 or higher, Frequent : At least 1/100 and less than 1/10, Infrequent : At least 1/1,000 and less than 1/100, Rarely : At least 1/10,000 and less than 1/1,000, Very rarely : Less than 1/10,000, including unknown frequency
(1) In Table 3, adverse reactions are shown by frequency depending on voluntary reporting rate.
Table 3. Adverse reactions by frequency depending on voluntary reporting rate in PMS
* Results of epidemiological investigation (See 5) of 4. General precautions)
(2) Extrapyramidal disorder usually occurs in newborns and infants. Spasms, anxiety and other central nervous system-related adverse reactions usually appear in infants or children.
3) Analysis of domestic voluntary adverse reaction reports (1989 to 2014) has shown that adverse reactions whose number of reports was statistically significantly higher than other drugs where adverse reactions were reported were as follows. However, this does not prove a causal relationship between the ingredients at hand and the following adverse cases.
- Systemic anomalies and anomalies around site of administration : Edema
4. General precautions
1) This drug is mainly metabolized in the liver; administer carefully to patients with liver damage.
2) In patients with severe renal failure (serum creatinine > 6mg/100mL), the elimination half-life of domperidone is increased; when administering repeatedly, reduce the number of administrations per day to once or twice a day depending on the degree of renal damage, as well as dose. Patients requiring long-term therapy need regular examination. (See 11. Misc.)
3) Breast cancer is thought to be prolactin secretion dependent; administer this drug with caution to patients with histories of breast cancer.
4) The film-coated tablets contains lactose and may not be suitable for patients with lactose intolerance, galactosemia or glucose/galactose malabsorption (Applicable film-coated tablet only)
5) Drowsiness and dizziness have been observed after taking domperidone. Until the effects of domperidone on the patient have been identified, refrain from driving or using machinery requiring mental focus.
6) Administration of this drug may cause adverse reactions such as endocrine function regulation anomalies in the diencephalon and extrapyramidal disorder; give sufficient consideration to efficacy and safety when administering this drug.
7) In epidemiological investigation, domperidone was shown to be associated with increased risk of serious ventricular arrhythmia or sudden cardiac death (See 3. Adverse reactions). In these studies, such risks appear to be higher in patients taking 30mg or more oral preparations daily, or who are 60 years of age or older. Accordingly, this drug must be administered carefully to elderly patients, and patients 60 year or older should consult a physician before taking this drug. This drug is contraindicated for patients exhibiting extended cardiac conduction intervals such as QTc, patients exhibiting electrolyte imbalance (hypokalemia, hyperkalemia, hypomagnesemia), patients with heart disease such as ischemic heart failure, and patients with bradycardia. Electrolyte imbalances and bradycardia are reported to increase the risk of arrhythmia. If symptoms or signs associated with ventricular arrhythmia are observed, this drug should be discontinued, and the patient should consult a physician.
5. Interactions
1) Concomitant administration with the following drugs may lead to endocrine function regulation anomalies or extrapyramidal symptoms. In inevitable cases of concomitant administration, observe sufficiently and administer carefully : phenothiazine drugs (prochlorperazine, chlorpromazine, thiethylperazine), butyrophenone drugs (haloperidol, etc.), Rauwolfia alkaloid drugs (reserpine, etc.)
2) May hide nausea, vomiting and loss of appetite symptoms that indicate digitalis drug saturation; for patients receiving digitalis drugs, observe sufficiently and observe carefully.
3) Concomitant administration with anticholinergics (hyoscine butylbromide, tiquizium bromide, timepidium bromide, etc.) may suppress digestive promotion action and reduce the gastric emptying action of this drug. Accordingly, reduce or discontinue one depending on symptoms, or administer at intervals.
4) Theoretically, the gastric activity promotion of this drug may impact absorption of oral preparations such as extended-release or enteric coated drugs. In the case of patients stabilized to digoxin or acetaminophen, concomitant administration of these drugs did not impact their blood concentration.
5) This drug is reported to not increase the effect of neuroleptics.
6) This drug is reported to suppress peripheral adverse reactions of dopamine agonists (bromocriptine, levodopa) such as indigestion, nausea or vomiting without impacting central effects.
7) Antacids and proton pump inhibitors may lower the bioavailability of this drug and should not be administered at the same time as this drug. When administering concomitantly, take this drug before food, and take antacids or PPIs after food.
8) The gastroenteric action of this drug may be blocked by antimuscarinics and opioid analgesics.
9) This drug is mainly metabolized by CYP3A4; concomitant administration of strong CYP3A4 suppressors and domperidone showed clinical changes in QT intervals. Accordingly, concomitant administration of domperidone and such drugs is prohibited. Caution is required when administering concomitantly with strong CYP3A4 suppressants (e.g. indinavir) with which domperidone is shown not to cause extension of QT intervals. The patient should be carefully observed for symptoms or signs or cardiovascular adverse reactions.
Take caution when administering the following drugs that cause extension of QT intervals with domperidone. The patient should be carefully observed for symptoms or signs or cardiovascular adverse reactions.
<QTc-prolonging medicinal products>
- anti-arrhythmics class IA (e.g., disopyramide, hydroquinidine, quinidine)
- anti-arrhythmics class III (e.g., amiodarone, dofetilide, dronedarone, ibutilide, sotalol)
- certain antipsychotics (e.g., haloperidol, pimozide, sertindole)
- certain antidepressants (e.g., citalopram, escitalopram)
- certain antibiotics (e.g. , erythromycin, levofloxacin, moxifloxacin, spiramycin)
- certain antifungal agents (e.g., pentamidine)
- certain antimalarial agents (in particular halofantrine, lumefantrine)
- certain gastro-intestinal medicines (e.g., cisapride, dolasetron, prucalopride)
- certain antihistaminics (e.g., mequitazine, mizolastine)
- certain medicines used in cancer (e.g., toremifene, vandetanib, vincamine)
- certain other medicines (e.g., bepridil, diphemanil, methadone)
<Potent CYP3A4 inhibitors>
- azole antifungals : fluconazole, itraconazole, ketoconazole, voriconazole
- macrolide antibiotics : clarithromycin, erythromycin, telithromycin
- HIV protease inhibitors : saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, fosamprenavir, lopinavir, atazanavir, tipranavir
Separate in vivo pharmacokinetic/pharmacodynamic interaction studies with oral ketoconazole or oral erythromycin in healthy subjects confirmed a marked inhibition of domperidone's CYP3A4 mediated first pass metabolism by these drugs.
With the combination of oral domperidone 10mg four times daily and ketoconazole 200mg twice daily, a mean QTc prolongation of 9.8 msec was seen over the observation period, with changes at individual time points ranging from 1.2 to 17.5 msec. With the combination of domperidone 10mg four times daily and oral erythromycin 500mg three times daily, mean QTc over the observation period was prolonged by 9.9 msec, with changes at individual time points ranging from 1.6 to 14.3 msec. Both the Cmax and AUC of domperidone at steady state were increased approximately three-fold in each of these interaction studies. In these studies domperidone monotherapy at 10mg given orally four times daily resulted in increases in mean QTc of 1.6 msec (ketoconazole study) and 2.5 msec (erythromycin study), while Ketoconazole monotherapy (200mg twice daily) led to increases in QTc of 3.8 and 4.9 msec, respectively, over the observation period.
Single repeated administration of domperidone at 40mg four times a day (total dose of 160mg/day; double the max. daily dose) showed no significant increase in QTc at plasma concentrations of domperidone similar to those observe during concomitant administration in the interaction study.
10) Caution is necessary when administering concomitantly with drugs associated with prolongation of the QT interval and torsades de pointes (antiarrhythmics, quinolone antibiotics, antipsychotics, 5-HT3 blockers, beta-2 adrenergic receptor effectors, antimalarials, SSRI, tricyclic antidepressants, etc.). Take caution when using in patients with prolonged QT intervals on the electrocardiogram or patients having fundamental heart disease such as ischemic heart failure or significant electrolyte disturbances, especially in patients with risk of Torsades des pointes.
11) Theoretically, concomitant administration of this drug with monoamine oxidase inhibitors may increase the dopamine concentration of the sympathetic ganglia. Administer carefully as there may be a possibility of hypertensive crisis.
6. Administration to pregnant women and nursing mothers
1) There are limited post-marketing data on the use of domperidone in pregnant women. A study in rats has shown reproductive toxicity at a high, maternally toxic dose (reports of deformities such as musculoskeletal and organ deformities). The potential risk for humans is unknown. Therefore, domperidone should only be used during pregnancy when justified by the anticipated therapeutic benefit.
2) Excretion in milk of this drug was observed during animal testing with rats (Usually excreted as metabolite : After oral and intravenous administration of 2.5mg/kg dose, max. concentration excreted in milk was 40ng/mL and 800ng/mL, respectively. Domperidone concentration in human milk is around 10 to 50% of plasma concentration, and is expected not to exceed 10ng/mL.
3) Domperidone is excreted in human milk and breast-fed infants receive less than 0.1% of the maternal weight-adjusted dose. Occurrence of adverse effects, in particular cardiac effects cannot be excluded after exposure via breast milk. A decision should be made whether to discontinue breast-feeding or to discontinue/abstain from domperidone therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the women. Caution should be exercised in case of QTc prolongation risk factor in breast-fed infants.
7. Administration to children
<Tablet, liquid>
Domperidone tablets are unsuitable for use in children and adolescents weighing less than 35 kg. Overdosage may cause neurological side effects in children (See 9. Action for overdosage).
In post-marketing experience, there were no differences in safety between adults and children excluding extrapyramidal symptoms and other central nervous system-related adverse reactions. Extrapyramidal symptoms usually occur in newborns and infants up to 1 year of age. Spasms, anxiety and other central nervous system-related adverse reactions usually appear in infants or children.
<Granule, powder, suspension>
Avoid overdosing children, administering carefully. Be especially careful with infants under 1. Overdosing may cause neurological symptoms in children (See 8. Action for overdosage).
In post-marketing experience, there were no differences in safety between adults and children excluding extrapyramidal symptoms and other central nervous system-related adverse reactions. Extrapyramidal symptoms usually occur in newborns and infants up to 1 year of age. Spasms, anxiety and other central nervous system-related adverse reactions usually appear in infants or children.
8. Administration to elderly patients
Elderly patients generally have lowered physiological functions; administer with caution, reducing dose as necessary.
9. Action for overdosage
1) Symptoms : Overdose has been reported primarily in infants and children. Symptoms of overdosage may include agitation, altered consciousness, convulsions, disorientation, somnolence and extrapyramidal reactions. Parkinson’s syndrome (shaking, rigidity, slowness of movement) may also appear.
2) Treatment : There is no specific antidote to domperidone, but in the event of overdose, standard symptomatic treatment should be given immediately. Gastric lavage as well as the administration of activated charcoal, may be useful. ECG monitoring should be undertaken, because of the possibility of QT interval prolongation. Close medical supervision and supportive therapy is recommended.
Anticholinergic, anti-parkinson drugs may be helpful in controlling the extrapyramidal reactions.
10. Storage and handling precautions
1) Keep out of reach of children.
2) Removing drugs from their original container and storing them in other container may lead to accidents due to misuse or lower quality; be sure to keep in tightly closed original container.
3) Do not mix : When dispensing with concomitantly prescribed aminophylline drugs in the same medicine sachet, discoloration of this drug may occur. Dispense in separate medicine sachets.
11. Misc.
<Pharmacological properties>
In accordance with ICH-E14 guidelines, a thorough QT study was performed. This study included a placebo, an active comparator and a positive control and was conducted in healthy subjects with up to 80 mg per day 10 or 20 mg administered 4 times a day of domperidone. This study found a maximal difference of QTc between domperidone and placebo in LS-means in the change from baseline of 3.4 msec for 20 mg domperidone administered 4 times a day on Day 4. The 2-sided 90% CI (1.0 to 5.9 msec) did not exceed 10 msec. No clinically relevant QTc effects were observed in this study when domperidone was administered at up to 80 mg/day (i.e., more than twice the maximum recommended dosing).
However, two previous drug-drug interaction studies showed some evidence of QTc prolongation when domperidone was administered as monotherapy (10 mg 4 times a day). The largest time-matched mean difference of QTcF between domperidone and placebo was 5.4 msec (95 % CI: -1.7 to 12.4) and 7.5msec (95 % CI: 0.6 to 14.4), respectively.
<Pharmacokinetic properties>
Absorption
Domperidone is rapidly absorbed after oral administration with peak plasma concentrations occurring at approximately 1 hr after dosing.. The Cmax and AUC values of domperidone increased proportionally with dose in the 10 mg to 20 mg dose range. A 2- to 3-fold accumulation of domperidone AUC was observed with repeated four times daily (every 5 hr) dosing of domperidone for 4 days.
Although domperidone's bioavailability is enhanced in normal subjects when taken after a meal, patients with gastrointestinal complaints should take domperidone 15-30 minutes before a meal. Reduced gastric acidity impairs the absorption of domperidone. Oral bioavailability is decreased by prior concomitant administration of cimetidine and sodium bicarbonate. The time of peak absorption is slightly delayed and the AUC somewhat increased when the oral drug is taken after a meal.
Hepatic impairment
In subjects with moderate hepatic impairment (Pugh score 7 to 9, Child-Pugh rating B), the AUC and Cmax of domperidone is 2.9- and 1.5- fold higher, respectively, than in healthy subjects.
The unbound fraction is increased by 25%, and the terminal elimination half-life is prolonged from 15 to 23 hours. Subjects with mild hepatic impairment have a somewhat lower systemic exposure than healthy subjects based on Cmax and AUC, with no change in protein binding or terminal half-life. Subjects with severe hepatic impairment were not studied. Domperidone is contraindicated in patients with moderate or severe hepatic impairment.
Renal impairment
In subjects with renal insufficiency (CCR<30ml/min/1.73m2) the elimination half-life of domperidone was increased from 7.4 to 20.8 hours, but plasma drug levels were lower than in healthy volunteers.
Since very little unchanged drug (approximately 1%) is excreted via the kidneys, it is unlikely that the dose of a single administration needs to be adjusted in patients with renal insufficiency.
However, on repeated administration, the dosing frequency should be reduced to once or twice daily depending on severity of the impairment, and the dose may need to be reduced.
<Preclinical data>
Electrophysiological in vitro and in vivo studies indicate an overall moderate risk of domperidone to prolong the QT interval in humans. In in vitro experiments on isolated cells transfected with hERG and on isolated guinea pig myocytes exposure ratios ranged between 26 – 47-fold, based on IC50 values inhibiting currents through IKr ion channels in comparison to the free plasma concentrations in humans after administration of the maximum daily dose of 10 mg administered 3 times a day. safety margins for prolongation of action potential duration in in vitro experiments on isolated cardiac tissues exceeded the free plasma concentrations in humans at maximum daily dose (10 mg administered 3 times a day) by 45-fold. Safety margins in in vitro proarrhythmic models (isolated Langendorff perfused heart) exceeded the free plasma concentrations in humans at maximum daily dose (10 mg administered 3 times a day) by 9- up to 45-fold. In in vivo models the no effect levels for QTc prolongation in dogs and induction of arrhythmias in a rabbit model sensitized for torsade de pointes exceeded the free plasma concentrations in humans at maximum daily dose (10 mg administered 3 times a day) by more than 22-fold and 435-fold, respectively. In the anesthetized guinea pig model following slow intravenous infusions, there were no effects on QTc at total plasma concentrations of 45.4ng/ml, which are 3-fold higher than the total plasma levels in humans at maximum daily dose (10 mg administered 3 times a day). The relevance of the latter study for humans following exposure to rally administered domperidone is uncertain.
In the presence of inhibition of the metabolism via CYP3A4 free plasma concentrations of domperidone can rise up to 3-fold.
At a high, maternally toxic dose (more than 40 times the recommended human dose), teratogenic effects were seen in the rat. No teratogenicity was observed in mice and rabbits.