Domperidone maleate is a peripheral dopamine antagonist structurally related to the butyrophenones with antiemetic and gastroprokinetic properties. The action of domperidone is defined by an effective increase of esophageal peristalsis and of lower esophageal sphincter pressure (LESP), an increase in gastric motility and peristalsis, an enhancement of gastroduodenal coordination and, as a consequence, to facilitated gastric emptying and decreased small bowel transit time. The mechanism of action of domperidone is attributed to its peripheral dopamine receptors blocking properties. The antiemetic effect of domperidone was demonstrated by the blockage of emesis induced stimulation of the chemoreceptor trigger zones (situated outside the blood-brain barrier) by apomorphine, hydergine, morphine or levodopa. Indirect evidence exists that emesis is also inhibited at the gastric level, as domperidone inhibits emesis induced by oral levodopa and concentrations localized on the gastric wall following oral administration of domperidone are much greater than the concentrations found in the plasma or other organs. Domperidone was not found to produce central effects, due to the fact that it does not readily cross the blood-brain barrier. Domperidone produces an elevation of serum prolactin levels without changes in circulating aldosterone levels. In man, the absorption of domperidone is defined by a peak plasma level within 10 to 30 minutes following intramuscular injection, and 30 minutes after oral (fasted) administration. Two hours after oral administration, plasma concentrations are lower than after intramuscular injection, indicating the occurrence of hepatic first-pass and gut wall metabolism. Peak plasma concentrations after an i.m. injection of 10 mg are 40 ng/mL, 20 ng/mL after a single 10 mg tablet, and 70-100 ng/mL after an oral dose of 60 mg (tablets or oral drops). The half-life was approximately 7.0 hours for each dosage form. Plasma protein binding as calculated from tritiated domperidone concentrations of 10 and 100 ng/mL, were 91.7% and 93.0%, respectively. Domperidone's metabolism was characterised by the hydroxylation and oxidative N- dealkylation pathways, resulting in two products: hydroxydomperidone and 2,3-dihydro- 2-oxo-1-H-benzimidazol-1-propionic acid. Radiolabelling experiments with oral doses of 40 mg 14C-domperidone in healthy volunteers showed an excretion of 31% of the radioactivity in urine and 66% in faeces over a period of 4 days.

BIOAVAILABILITY

The relative bioavailability of ratiopharm Inc.'s domperidone 10 mg tablets and Motilium(r) 10 mg tablets of Janssen Pharmaceutica Inc. was compared. The study was a single dose (6 x 10 mg tablets) administered to each of 24 fasted healthy male volunteers in a balanced randomized 2-way (crossover design). Blood samples were collected pre-dose and at the following times after dosing, 10, 20, 30 and 45 min. and 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours. Blood samples were determined according to the HPLC method with UV detection. The results of this biostudy are summarized in the following table:

Based on the bioavailability study, ratiopharm Inc.'s domperidone 10 mg tablets are judged to be comparable in both rate and extent of absorption to Janseen's formulation (Motilium(r)) domperidone 10 mg tablets.

CONTRAINDICATIONS

Domperidone maleate is contraindicated in patients with known sensitivity or intolerance to the drug. The use of domperidone should be contraindicated when the situation of gastrointestinal stimulation might be dangerous eg. gastrointestinal haemorrhage, mechanical obstruction. Domperidone is also contraindicated in patients with a prolactin releasing pituitary tumour (prolactinoma). The co-administration of domperidone with ketoconazole is contraindicated (see Warnings, Cardiovascular section and Precautions, Drug Interactions section).

WARNINGS

Dopamine receptor blocking agents produce an elevation of prolactin levels which persists during chronic administration. Tissue culture experiments demonstrate that approximately 1/3 of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient having previously been detected as having breast cancer. Although elevated serum prolactin levels were observed with certain disturbances such as galactorrhea, amenorrhea, gynecomastia and impotence, its clinical significance remains unknown for most patients. An increase in mammary neoplasm has been observed in rodents after chronic administration of dopamine receptor blocking agents. The association of mammary tumorigenesis with chronic administration of these drugs was not demonstrated by either clinical studies or epidemiologic studies. Insufficient data is available to develop a conclusion at this time.

In an interaction study, when domperidone was administered with ketoconazole, an increase in the QT interval was observed. The increase was greater than that observed when ketoconazole was administered alone (see Drug Interactions section below). Co- administration of ketoconazole with domperidone is contraindicated. QT prolongation was not observed at oral doses of domperidone of up to 160 mg/day, i.e., twice the maximum recommended daily therapeutic dose. It is noteworthy that cardiac arrhythmia and death were reported following very high parenteral doses of domperidone. These results should be considered when domperidone is prescribed with other CYP3A4 inhibitors (e.g. azole antifungals, macrolide antibiotics, HIV protease inhibitors, grapefruit juice), which may increase plasma levels of domperidone. Consideration need to be given also when domperidone is co-administered with drugs associated with QT prolongation or torsade de pointes (e.g. drugs in classes such as antiarrhythmics, quinolone antibiotics, antipsychotics, 5-HT3 antagonists, beta-2 adrenoreceptor agonists, azole antifungals, macrolides and analogues, antimalarials, SSRIs, tri/tetracyclic antidepressants), especially in patients at risk for torsade de pointes.

In patients with severe renal insufficiency (serum creatinine > 6 mg/100 mL or > 0.6 m mol/l) 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 is excreted via the kidneys, it is unlikely that 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 the severity of the impairment, and the dose may need to be reduced. Generally, patients on prolonged therapy should be reviewed regularly.

Although animal studies have not shown drug related teratogenic or primary embryotoxic effects on animal foetuses (see Toxicology section), no comparable studies have been performed in pregnant women. Therefore, domperidone maleate should not be used in pregnant women unless the benefits outweigh the potential hazards to the mother and embryo or foetus.

Very low concentrations of domperidone are excreted in breast milk. Caution should be exercised when domperidone is administered to nursing mothers.

Domperidone maleate should not be used for children since its safety and efficacy have not been adequately established in children.

PRECAUTIONS

In patients who develop galactorrhea and/or gynecomastia, withdrawal of the drug will result in the relief of these symptoms.

The beneficial effects of domperidone maleate may be compromised by the concomitant use of anticholinergic drugs. Since domperidone produces an increase of gastric and small intestinal motility, absorption of the drug may be accelerated in the small intestine, while absorption of the drug through the stomach is slower. Domperidone should be carefully administered in combination with MAO inhibitors. Domperidone maleate absorption was not decreased when taken in combination with antacids or H2-receptor blockers. In vivo interaction studies have shown that ketoconazole strongly inhibits the CYP3A4- dependent metabolism of domperidone. Pharmacokinetic studies showed 3-10 fold increase in the area under curve (AUC) and the peak concentration (Cmax) of domperidone when ketoconazole was co-administered. This co-administration resulted also in a prolongation of the QT interval (maximum of 10-20 msec) which was greater that the prolongation observed with ketoconazole alone. QT prolongation was not observed at oral doses of domperidone of up to 160 mg/day, i.e., twice the maximum recommended daily therapeutic dose. It is important to note that cardiac arrhythmia and death were reported following high parenteral doses of domperidone. Results of the interaction study should be considered when domperidone is prescribed with CYP3A4 inhibitors (which may increase plasma levels of domperidone) or with drugs that can cause QT prolongation or torsade de pointes, especially in patients at high risk for torsade de pointes (see Contraindications, Warnings, Cardiovascular sections).

Since domperidone is highly metabolized in the liver, it should be used with caution in patients with hepatic impairment.

ADVERSE REACTIONS

In clinical studies, the overall incidence of side effects after oral administration was <7% of which some were an extension of the dopamine antagonist properties of domperidone. Most side effects resolve spontaneously during continued therapy or are easily tolerated. The most serious or troublesome side effects are galactorrhea, gynecomstia and menstrual irregularities. These side effects are dose-related and are gradually resolved after reduction of dosage or discontinuation of therapy.

Central nervous system

(4.6%):

Dry mouth (1.9%), headache/migraine (1.2%), insomnia, nervousness, dizziness, thirst, lethargy, irritability (all <1%).

Gastrointestinal tract

(2.4%):

Abdominal cramps, diarrhea, regurgitation, changes in appetite, nausea, heartburn, constipation (all <1%).

Endocrinological

(1.3%):

Hot flushes, mastalgia, galactorrhea, gynecomastia, menstrual irregularities.

Mucocutaneous

(1.1%):

Rash, pruritus, urticaria, stomatitis, conjunctivitis.

Urinary tract

(0.8%): Urinary frequency, dysuria.

Cardiovascular system

(0.5%): Edema, palpitations.

Musculoskeletal

(0.1%): Leg cramps, asthenia.

Drug intolerance.

Laboratory parameters:

Elevated serum prolactin, elevation of SGOT, SGPT and cholesterol (all <1.0%). Extrapyramidal phenomena are rare in adults; they reverse spontaneously as soon as treatment is stopped. When the blood-brain barrier is immature (as in infants) or impaired, the possible occurrence of neurological side effects cannot be excluded. Post-Market Adverse Drug Reactions: Sudden death and torsade de pointes.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

No incidence of domperidone maleate overdosage has been reported. However, based on the pharmacological properties of domperidone, central nervous system (drowsiness, disorientation and extrapyramidal reactions, especially in children) and cardiovascular (arrhytmias, hypotension) effects might possibly occur. Symptoms are self-limiting and usually disappear within 24 hours.

Treatment:

Anticholinergic, anti-parkinsonian drugs or antihistamines with anticholinergic properties may be helpful in controlling the extrapyramidal reactions. There is no specific antidote to domperidone but in the event of overdosage, gastric lavage as well as the administration of activated charcoal may be useful. Close observation and supportive therapy are recommended. Symptoms are self-limiting and usually disappear within 24 hours.

DOSAGE AND ADMINISTRATION

Upper gastrointestinal motility disorders:

In adults, the usual dosage is 10 mg orally 3 to 4 times daily, 15 to 30 minutes before meals and at bedtime if required. In severe or resistant cases, the dose may be increased to a maximum of 20 mg 3 to 4 times daily.

Nausea and vomiting associated with dopamine agonist antiparkinsonian agents:

In adults, the usual dosage is 20 mg orally 3 to 4 times daily. Higher doses may be required to achieve symptom control while titration of the anti-parkinsonian medication is occurring.

Dosing Considerations:

Patients with renal impairment:

Since very little unchanged drug is excreted via the kidneys, it is unlikely that 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 the severity of the impairment, and the dose may need to be reduced. Generally, patients on prolonged therapy should be reviewed regularly (see Warnings, Renal section).

PHARMACEUTICAL INFORMATION

Drug Substance:

Proper or common name: Domperidone Maleate Chemical name: 5-chloro-1-[1-3-(2,3-dihydro-2-oxo-1H-benzimidazol-1- yl)propyl]-4-piperidinyl]-1,3-dihydro-2 H- benzimidazol-2-one (z)-2-butenedioate (1:1) Structural formula: Molecular formula: C22H24N5O2Cl * C4H404 Molecular weight: 541.99

Description

in water:	0.10%
In ethanol:	0.1%
In PEG 400:	0.5%
In PPG:	1.3%
In CHCl3	0.004%

Physical form: White to off white crystalline powder. Solubility: pka value: pka = 7.890 Partition coefficient: log P= 3.90 at pH 10.2

Melting range: 225 to 231 C.

Composition:

Each white to faintly cream film-coated tablet contains:

domperidone maleate 12.72 mg (equivalent to domperidone 10 mg), lactose and cornstarch, microcrystalline cellulose, povidone, magnesium stearate, sodium docusate 85%-sodium benzoate 15% and croscarmelose sodium, polyethylene glycol, hydroxypropyl methylcellulose, titanium dioxide, polydextrose, triacetin.

Stability and Storage

Recommendations

Store at room temperature between 15 and 30/C.

Protect from light and moisture.

AVAILABILITY OF DOSAGE FORMS

ratio-DOMPERIDONE

is a round, plain-coated, biconvex white tablet, engraved "rph D51" on one side and plain on the other side. Available in HDPE bottles containing 100 or 500 tablets.

PHARMACOLOGY

Domperidone is a dopamine antagonist which does not readily cross the blood-brain barrier and exerts its primary effect on peripheral dopamine receptors. In vitro, 3H-domperidone binds specifically and selectively the striatal dopamine receptors in mice and rats. In vivo, no displacement of 3H-piperone in rat brain dopaminergic areas and no increase in rat brain homovanillic acid (HVA) concentrations were observed. In addition, domperidone at doses up to 100 times in excess of the anti-emetic dose produced no changes in behaviour, conditioned reflexes, intracranial self-stimulation or EEG tracings. These studies indicate that domperidone does not cross the blood-brain barrier. Intravenous doses of domperidone given in dogs and baboons, produced a dose- dependent increase of the resting tone of the lower esophageal sphincter. Gastric relaxation induced by apomorphine was completely blocked by injecting 1 mg/kg i.v. domperidone in anaesthetized dogs. In the isolated gastroduodenal preparation of the guinea pig, domperidone antagonized dopamine's antroduodenal coordination but not the antroduodenal coordination effect of noradrenaline. In dogs, 0.35 mg/kg and 0.7 mg/kg i.v. domperidone significantly increased the distension of the pyloric sphincter without affecting the frequency of the pyloric relaxation. In beagle dogs, intravenous doses of 200 or 1 000 :g/kg domperidone produced a significant increase in the contractile activity in the antrum, without changing the mean blood pressure. In dogs, domperidone produced no changes on the emptying pattern of semi-solid, but significantly reduced the stationary phase of a solid meal by 50%. Emptying rate of solids was unchanged. In dogs, the apomorphine-induced emesis (s.c. injection of 0.31 mg/kg) was completely inhibited by domperidone. ED50 s.c. was 0.007 mg/kg, 0.031 mg/kg orally, and 0.10 mg/kg rectally. In addition, domperidone was very effective against emesis induced by hydergine, levodopa and morphine, but it was ineffective against copper sulphate-induced emesis. In rats, domperidone significantly increased plasma prolactin release, which was more pronounced (4-fold) in female rats than in male rats. In Rhesus monkeys, domperidone also induced a marked increase in plasma prolactin concentration without changes in plasma 18-hydroxycortisone and aldosterone.

in mice: ptosis ( $20 mg/kg), sedation ($40 mg/kg), tremors and convulsions (> 80 mg/kg) in rats: ptosis, sedation and catalepsy ($5 mg/kg), convulsions ($80 mg/kg) in guinea-pigs: ptosis, and sedation ($20 mg/kg) and dyspnea before death at 40 mg/kg in dogs: ataxia, sedation and vomiting starting at 10 mg/kg

in mice: ptosis, sedation and occasionally ataxia ($320 mg/kg) in rats: ptosis, sedation and catalepsy ($40 mg/kg) in guinea-pigs: ptosis, sedation and occasionally diarrhea ($320 mg/kg) in dogs: vomiting at 160 mg/kg

At 40 mg/kg: Significant reduction of food consumption and body weight in males. Increase of segmented heterophils and decrease of lymphocytes. Increase in alkaline phosphatase in females (at all dosages), and increase of heptoglobin in both sexes. Moderate to strong irritation of the tail with progressive necrosis. Stimulation of the mammary glands in several females. Decrease in spleen weight, decrease in the weight of most organs (especially in males). Histopathology examination reveals reduction of number of corpora lutea in the ovary, reduction of oesinophilic infiltration of the uterine wall and more folded uterine mucosa, mucification of the vagina, female aspect of mammary glands in males, and glandular development with secretion in females, more extended chromophobe tissue of the hypophysis (in all dosages).

At 20 mg/kg: Emesis and reduced appetite were observed. Marginal decrease in haematocrit and haemoglobin were observed. Heart rate, ECG, blood pressure, serum analysis and urinalysis remained normal. Slight increase in relative liver weight and slight decrease in absolute and relative adrenal weight. Histopathology examinations showed a reduction and absence of germatogenisis, atrophy of the prostate, degranulation of the erythrosinophilic cells of the hypophysis.

At 160 mg/kg: Decrease in appetite and weight gain. Two deaths were noted unrelated to drug administration. Hematology, serum analysis and urinalysis were normal except for a decrease in creatinine. Stimulation of the mammary glands was noted (in all cases) Histopathology examination showed a mucification of the vaginal epithalium, reduction in number of corpora luted (in all doses), female aspect with secretions in males, marked development of glandular tissue with secretions in females (at all doses).

At 40 mg/kg: Decrease in appetite, ocular discharge and ptosis. Decreased food consumption and persistent body weight loss were observed. Heart rate, ECG, and blood pressure were normal. Haematological parameters were normal except for a decrease in haematocrit, haemoglobin and red blood cells. Relative liver weight increase in dose-related. Histopathological examination revealed desquamation and some degeneration of germinal epithelium with absence of spleenatogenesis in 75% of males, prostatic atrophy (also at 10 mg/kg), thymus involution in 75% of females. More extended erythrosinophilic tissue in the hypophysis in males and females (at mid-dose also).

No dose-related mortality was observed in 6, 12 and 18 months. Increased appetite with 10 and 40 mg/kg in females especially after 12 and 18 months. Stimulation of mammary glands in females at all doses and in males at 160 mg/kg after 18 months. Decreased food consumption at 160 mg/kg in both sexes after 6 months and in males only after 12 and 18 months. Hematology and biochemistry evaluations revealed: slight increase of non-pigmented heterophiles in females with 40 and 160 mg/kg after 12 months, marginal increase of monocytes in females with 40 and 160 mg/kg after 18 months and marginal increase of monocytes in females with 40 and 160 mg/kg after 12 months. Necropsy examinations in dosed as well as non-dosed animals revealed pneumonia, lung abcesses, alopecia, thymus involution. Stimulation of mammary glands in females at all doses at 6, 12 and 18 months, and in males with 160 mg/kg after 18 months. Histopathological examinations revealed:

One death was observed at 8 weeks of 40 mg/kg domperidone due to gastroenteritis and peritonitis (not drug-related). No behaviour and appearance abnormalities were drug-related.

At 40 mg/kg: Decreased food consumption causing a lower terminal body weight. ECG, heart rate and blood pressure were normal. Slight decrease of haemotocrit, haemoglobin and red blood cells (also at 10 mg/kg), and slight increase in monocytes and thrombocytes. Marginal to moderate increase of haptoglobin (also 10 mg/kg). Increase of relative liver weight. Hispathological examinations revealed changes in testis (degeneration with impairment of spermatogenesis), prostate (atrophy and/or fibrosis) and eyes (keratitis).

No dose-related effects on health, behaviour, appearance, overall survival rate or gross pathology were observed. Histopathological examinations revealed no difference on number of tumor-bearing mice were observed between groups. Increase in mammary carcinomas was significantly observed with 40 mg/kg in females. No dose-related effects on health, behaviour, appearance, survival rate or gross pathology were seen. Histopathological examination revealed no difference on total incidence of tumor- bearing rats between groups. At 40 mg/kg, marginal increase of incidence of pituitary adenomas in males, and slight tendency towards an increase in mammary carcinomas in females were noted. High number of thyroid adenomas was observed in the mid- dosed females which was not so with those dosed at 40 mg/kg.

No evidence of any mutagenic potential of domperidone was noted in vitro, chromosomal aberrations in human lymphocytes, in micronucleus test in mice and in rats, chromosomal aberrations in liver enzyme rats, in dominant lethal test in male and female germ cells, and in sex-linked recessive lethal test on drosophila.

Pregnancy rate % Dosage (mg/kg) Resorptions increased with dose and was 100% with 640 mg/kg. Decrease of litter size and pup weight at delivery were observed at 160 and 320 mg/kg. No teratogenicity drug related was noted, but maternal toxicity was observed at 640 mg/kg.

Intravenous embryotoxicity and teratogenicity study in the New Zealand white rabbit.

Intravenous embryotoxicity and teratogenicity study in New Zealand white rabbit (Segment II)

0.63 mg/kg, 2/15 at 1.25 mg/kg and 8/15 at 2.5 mg/kg. No pregnancy rates differences were observed between groups.

No differences between groups were observed on number of live, dead and resorbed foetuses, birthweight and 24 hour survival rate. No teratogenic or embryotoxic effects were observed in rabbit foetuses.

Mortality was noted at 10 mg/kg (1/20) and 40 mg/kg (9/20). The causality of death was lobular pneumonia in 2 cases, enteritis in one case, and pneumonia with mucoid enteritis in another case.

Conclusion: Domperidone did not produce teratogenic effects at doses of 10 and 40 mg/kg. However, a slight increase in resorptions in dosed animals with evidence of maternal toxicity was observed.

Oral embryotoxicity and teratogenicity study in Wistar rats during pre- and post- natal periods (Segment III)

REFERENCES

Drugs 1982; 24: 353-400 Brouwers JRBJ, Assies J, Wiersinga WM, Huizing G, Tytgat GN. Plasma prolactin levels after acute and subchronic oral administration of domperidone and of metoclopramide: A cross-over study in healthy volunteers. Clin Endocrinol 1980; 12: 435-440 Carter DA, Pennington JM, Whitehead SA. In-vivo and in-vitro effects of domperidone on the release of prolactin and LH in male and female rats. J. Reprod. Fert. 1982; 64: 191-197. Corinaldesi R. Stanghellini V, Zarabini GE et al. The effect of domperidone on the gastric emptying of solid and liquid phases of a mixed meal in patients with dyspepsia. Curr Ther Res 1983; 34: 982-986 Cunningham D, Evans C, Gazet J-C, Ford H, Pople A, Dearling J, Chappell D, Coombes C. Comparison of antiemetic efficacy of domperidone, metoclopramide, and dexamethasone in patients receiving outpatient chemotherapy regimens. Br. Med. J. 1987; 295: 250 Davis RH, Clench MH, Mathias JR. Effects of domperidone in patients with chronic unexplained upper gastrointestinal symptoms: A double-blind, placebo- controlled study. Dig Dis Sci, 1988: 33(12):1505-1511. Goethals C. Domperidone in the treatment of postprandial symptoms suggestive of gastroesophageal reflux. Curr Ther Res 1979; 26: 874-880 Gonce M, Bury J, Burton L, Delwaide PJ. Syndrome neurodysleptique induit par le domperidone. Nouv. Presse Med. 1982; 11(30): 2298 Heykants J, Hendriks R, Meuldermans W, Michiels M, Scheygrond H, Reyntjens H. On the pharmacokinetics of domperidone in animals and man. IV. The pharmacokinetics of intravenous domperidone and its bioavailability in man following intramuscular, oral and rectal administration. Eur J Drug Metab Pharmacokinet 1981; 6(1): 61-70 Hoffbrand BI ed. Domperidone in the treatment of upper gastrointestinal symptoms. Postgrad Med J 1979; 55 (Suppl. 1) Hofmeyr GJ, Van Iddekinge B, Blott JA. Domperidone: secretion in breast milk and effect on puerperal prolactin levels. Br. J Obstet Gynaecol 1985; 92: 141-144 Jacobs F, Akkermans LMA, Hong Yoe O, Wittebol P. Effects of domperidone on gastric emptying of semi-solid and solid food. Progress with domperidone, a gastrokinetic and anti-emetic agent: Royal Society of medicine International Congress and Symposium Series No. 36. 1981 P. 11-20 Jay GT, Chow MSS. Feldman TA. Focus on domperidone: A selective dopamine antagonist for diabetic gastroparesis and idiopathic gastric stasis. Hosp. Formul. 1991; 26: 171-183 Kessler E, Bremner CH, Bremner CG. The effect of intravenous domperidone on the resting lower oesophageal sphincter pressure in dogs and baboons. S. Afr. Medical J. 1979; 56: 679-680 Kozarek R. Domperidone for symptomatic management of diabetic gastroparesis in metoclopramide treatment failures. Advances in therapy 1990; 7(2): 61-68 Laduron PM, Leysen JE. Domperidone, a specific in vitro dopamine antagonist, devoid of in vivo central dopaminergic activity. Biochem Pharmacol 1979; 28: 2161-2165 Lefebvre RA, Willems JL. Gastric relaxation by apomorpohine and ATP in the conscious dog. J Pharm Pharmacol 1979; 31: 561-563 Lienard J, Janssen J, Verhaegen H, Bourgeois E, Willocx R. Oral domperidone (r) 33 812) in the treatment of chronic dyspepsia: A multicenter evaluation. Curr. Ther. Res. 1978; 23(5): 529-537 Mangel AW, Stavorski JR, Pendleton RG. Effects of bethanechol, metoclopramide and domperidone on antral contraction in cats and dogs. Digestion 1983; 28: 205-209 Meuldermans W, Hurkmans R, Swysen E, Hendrickx J, Michiels M, Lauwers W, Heykants J. On the pharmacokinetics of domperidone in animals and man. III. Comparative study on the excretion and metabolism of domperidone in rats, dogs and man. Eur J Drug Metab Pharmacokinet 1981; 6(1): 49-60 Milo, R. Use of the peripheral dopamine antagonist, domperidone, in the management of gastrointestinal symptoms in patients with irritable bowel syndrome. Curr Med Res Opin 1980; 6: 577-584 Niemegeers CJE, Schellekens KHL, Janssen PAJ. The antiemetic effects of domperidone, a novel potent gastrokinetic. Arch Int Pharmacodyn 1980; 244: 130-140 Platteborse R, Hermans C, Van Loon J, Smet F, Loots W, Van Gorp A, Jageneau A. The effects of domperidone on pyloric activity in dog and in man. Postgrad Med J. 1979; 55(Suppl.1): 15-18 Quinn N, Illas A, Lhermitte F. Agid Y. Bromocriptine and domperidone in the treatment of Parkinson disease. Neurology 1981; 31: 662-667 Schuurkes JAJ, Van Nueten JM. Domperidone improves myogenically transmitted antroduodenal coordination by blocking dopaminergic receptor sites. Scand. J. Gastroenterol Suppl. 1984; 96: 101-110 Van Der Steen M, Du Caju MVL, Van Acker KJ. Gynaecomastia in a male infant given domperidone. Lancet 1982: 884-885 Sol P, Pelet B., Quignard J-P. Extrapyramidal reactions due to domperidone. Lancet 1980: 802 Sowers JR, Eggena P, Phillips D. Effect of metoclopramide and domperidone on aldosterone, 18-hydroxycorticosterone and prolactin secretion in the Rhesus monkey. Metabolism 1982; 31(12): 1219-1223 Van Ganse W, Van Damme L, Van de Mierop L, Deruyttere M, Lauwers W, Coenegrachts J. Chronic dyspepsia: Double-blind treatment with domperidone (r) 33 812) or a placebo. A multicentre therapeutic evaluation. Curr. Ther. Res. 1978; 23(6): 695-701 Vanparys Ph, Fabry L, Leonard A, Marsboom R. Mutagenicity tests with domperidone in vitro and in vivo. Toxicol Lett 1982; 12: 215-222 Vanparys Ph, Gilot-Delhalle J, Moutschen J, Moutschen-Dahmen M, Marsboom R. In vivo mutagenicity evaluation of domperidone in drosophila germ cells and rat bone marrow cells. Toxicology 1985; 36: 147-150 Wauquier A, Niemegeers CJE, Janssen PAJ. Neuropharmacological comparison between domperidone and metoclopramide. Japan J. Pharmacol. 1981; 31: 305- 314 Weihrauch TR, Forster Ch. F, Krieglstein J. Evaluation of the effect of domperidoneon human oesophageal and gastroduodenal motility by intraluminal manometry. Postgrad. Med. J. 1979; 55(Suppl.1): 7-10 Date of Revision: April 4, 2007

	AUC 0-t ng.h/mL	Tmax h	Cmax ng/mL	AUC inf ng.h/mL
ratiopharm Inc.	210.73	0.91	71.72	223.86
Janssen	217.10	0.83	74.76	231.49

Route	Animals	Number of Animals	LD 5 0 mg/kg 7 days
I.V.	Mice	40 M 30 F	56.5 (43.1 - 73.8) 56.8 (43.5 - 74.2)
	Rats	50M 30 F	56.3 (43.1 - 73.6) 68.8 (52.5 - 89.9)
	Guinea-pigs	30 M 30 F	42.9 (32.8 - 56.1) 44.4 (34.0 - 58.0)
	Dogs	33 M & F	42.7 (32.7 - 55.9)
P.0.	Mice	30 M 30 F	> 1280 > 1280
	Rats	60 M 20 F	> 1280 > 1280
	Guinea-pigs	30 M 30 F	796 (424-1493) > 1280
	Dogs	6 M & F	> 160
S.C.	Dogs	6 M & F	> 160

No. of animals	Dose administered	Results
80 F	0, 2.5, 10 and 40 mg/kg day from day 6 to day 15 of gestation	No mortality was noted. Dosage 0 2.5 10 40 Pregnancy rates % 95 100 95 85 % live 97.2 94.8 92.1 90.5 % dead 0 0 0 0 % resorbed foetuses 2.8 5.2 7.9 9.5 Slight increase in resorptions with increasing dosages was observed. No difference of abnormalities were noted between dosage groups.

No. of animals	Dose administered	Results
80 F 80 F	0, 10, 40 or 160 mg/ kg daily from day 6 to day 15 of gestation 0, 5, 20 or 80 mg/kg daily from day 6 to day 15 of gestation	Pregnancy Dosage rate % (mg/kg) 65 160 100 10 90 0 No effect was observed on number of implantations, pregnancies and pups, litter size and weight at birth, number of resorptions, live and dead foetuses, number and distribution of live, dead and resorbed embryos. No embryo-toxicity or teratogenicity were observed. Pregnancy Dosage rate % (mg/kg) 95 0 80 5 100 20 95 80 No embryotoxicity or teratogenicity were observed.

No. of animals	Dose administered	Results
80 F groups of 20	0, 160, 320 or 640 mg/kg daily from day 6 to 15 of gestation	Three females died: one at 320 and 2 at 640 mg/kg. Causality of death was not established.

PRODUCT MONOGRAPH

THERAPEUTIC CLASSIFICATION

ACTIONS AND CLINICAL PHARMACOLOGY