Domperidone is a peripheral dopamine antagonist structurally related to the butyrophenones with antiemetic and gastroprokinetic properties. Domperidone effectively increases oesophageal peristalsis and lower oesophageal sphincter pressure (LESP), increases gastric motility and peristalsis, enhances gastroduodenal coordination and consequently facilitates gastric emptying and decreases small bowel transit time. The mechanism of action of domperidone is related to its peripheral dopamine receptor blocking properties. Emesis induced by apomorphine, hydergine, morphine or levodopa through stimulation of the chemoreceptor trigger zone (situated outside the blood-brain barrier) can be blocked by domperidone. There is indirect evidence that emesis is also inhibited at the gastric level, since domperidone also inhibits emesis induced by oral levodopa, and local gastric wall concentrations following oral domperidone are much greater than those of the plasma and other organs. Domperidone does not readily cross the blood-brain barrier and therefore is not expected to have central effects. Domperidone elevates serum prolactin levels but has no effect on circulating aldosterone levels. In man, peak plasma levels of domperidone occur within 10 to 30 minutes following intramuscular injection and 30 minutes after oral (fasted) administration. Plasma concentrations two hours after oral administration are lower than following intramuscular injection, and this is likely the result of hepatic first- pass and gut wall metabolism. Peak plasma concentrations are 40 ng/mL following an i.m. injection of 10 mg, 20 ng/mL after a single 10 mg tablet, and 70-100 ng/mL after oral doses of 60 mg (tablets or oral drops). The half-life was calculated as approximately 7.0 hours in each case. The degree of human plasma protein binding was calculated from tritiated domperidone concentrations of 10 and 100 ng/mL as 91.7 and 93.0%, respectively. The major metabolic pathways for domperidone in man are hydroxylation and oxidative N-dealkylation, the products of which are hydroxy-domperidone and 2,3 dihydro-2-oxo-1-H- benzimidazole-1-propionic acid, respectively. After oral administration of 40 mg 14C-domperidone to healthy volunteers, 31% of the radioactivity is excreted in the urine and 66% in the feces over a period of 4 days. A comparative bioavailability study was performed using 14 healthy male volunteers. The rate and extent of absorption of domperidone following administration of a single oral 60 mg (6 x 10 mg tablets) dose of Apo-Domperidone or Motilium were measured and compared. Plasma concentrations of domperidone were determined and results summarized as follows: Geometric Mean Arithmetic Mean (C.V.)

57.9 (23) 68.6 (29) 85.8 Tmax * (hr) 0.90 (0.32) 1.01 (0.90) - t1/2 * (hr) 3.83 (0.45) 4.10 (0.94) - *For the Tmax and t1/2 parameters, these are the arithmetic means (standard deviation).

Ratio of Means (%)
AUC T	167	174	96.0
(ng * hr/mL)	173 (27)	181 (29)
AUC I	182	191	95.5
(ng * hr/mL)	188 (25)	198 (28)

INDICATIONS AND CLINICAL USE

APO-DOMPERIDONE (domperidone maleate) is indicated in the symptomatic management of upper gastrointestinal motility disorders associated with chronic and subacute gastritis and diabetic gastroparesis. APO-DOMPERIDONE may also be used to prevent gastrointestinal symptoms associated with the use of dopamine agonist antiparkinsonian agents.

CONTRAINDICATIONS

APO-DOMPERIDONE (domperidone maleate) is contraindicated in patients with known sensitivity or intolerance to the drug. Domperidone should not be used whenever gastrointestinal stimulation might be dangerous, i.e., gastrointestinal haemorrhage or mechanical obstruction. The co-administration of domperidone with ketoconazole is contraindicated (see Warnings and Precautions, Cardiovascular section and Drug Interaction section).

WARNINGS

Dopamine receptor blocking agents elevate prolactin levels; the elevation persists during chronic administration. Tissue culture experiments indicate that approximately one-third 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 with a previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin levels is unknown for most patients. An increase in mammary neoplasms has been found in rodents after chronic administration of dopamine receptor blocking agents. Neither clinical studies nor epidemiologic studies conducted to date, however, have shown an association between chronic administration of these drugs and mammary tumorigenesis. The available evidence is considered too limited to be conclusive at this time.

While animal studies have not shown drug related teratogenic or primary embryotoxic effects on animal fetuses (see TOXICOLOGY), comparable studies have not been performed in pregnant women. For this reason, APO-DOMPERIDONE (domperidone maleate) should not be used in pregnant women unless the expected benefit outweighs the potential hazard.

Domperidone is excreted in breast milk in very low concentrations. Caution should be exercised when domperidone is administered to nursing mothers.

The safety and efficacy of domperidone in children have not been established. Therefore, domperidone should not be used in children.

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 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 mmol/l) the elimination half-life of domperidone was increased from 7.4 to 20.8 hours, but plasma drug level 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.

PRECAUTIONS

In the event that the patient develops galactorrhea and/or gynecomastia, withdrawal of the drug will result in alleviation of these symptoms.

In vivo interactions 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 than 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 risk for torsade de pointes (see Contraindication, Warnings and Precautions, Cardiovascular sections). The concomitant administration of anticholinergic drugs may compromise the beneficial effects of APO- DOMPERIDONE (domperidone maleate). Since domperidone enhances gastric and small intestinal motility, it may accelerate absorption of drugs from the small bowel while slowing absorption of drugs taken up from the stomach. Care should be exercised when domperidone is administered in combination with MAO inhibitors. The concomitant administration of domperidone with antacids or H2-receptor blockers does not decrease the absorption of domperidone.

ADVERSE REACTIONS

In clinical studies with oral domperidone the overall incidence of side effects was <7%. Some of these side effects are an extension of the dopamine antagonist properties of domperidone. Most side effects resolve spontaneously during continued therapy or are easily tolerated. The more serious or troublesome side effects (galactorrhea, gynecomastia, menstrual irregularities) are dose-related and gradually resolve after lowering the dose or discontinuing therapy. Central Nervous System (4.6%): dry mouth (1.9%), headache/migraine (1.2%), insomnia, nervousness, dizziness, thirst, lethargy, irritability (all <1%). Gastrointestinal (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 (0.8%): urinary frequency, dysuria. Cardiovascular (0.5%): edema, palpitations. Musculoskeletal (0.1%): leg cramps, asthenia. Miscellaneous (0.1%): drug intolerance. Laboratory parameters: elevated serum prolactin, elevation of SGOT, SGPT and cholesterol (all <1.0%). Post-Market Drug Reactions: sudden death and torsade de pointes.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

There has been no experience with overdosage of domperidone. However, based on the pharmacological properties of domperidone, CNS effects (dyskinesias) and cardiovascular effects (arrhythmia, hypotension) might possibly occur. Treatment is gastric lavage with close observation and supportive therapy.

DOSAGE AND ADMINISTRATION

Upper gastrointestinal motility disorders: The usual dosage in adults is 10 mg orally 3 to 4 times a day, 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 a day.

Nausea and vomiting associated with dopamine agonist antiparkinsonian agents: The usual dosage in adults is 20 mg orally 3 to 4 times a day. Higher doses may be required to achieve symptom control while titration of the antiparkinsonian medication is occurring.

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 dose may need to be reduced. Generally, patients on prolonged therapy should be reviewed regularly (see Warnings and Precautions, Renal section).

PHARMACEUTICAL INFORMATION

Proper/Common Name: domperidone maleate Chemical Name: 2H-benzimidazol-2-one,5-chloro-1-[1-[3-(2,3-dihydro-2-oxo-1H- benzimidazol-1-yl)-propyl]-4-piperidinyl]-1,3-dihydro-,(Z)-2- butenedioate Structural Formula:

: Domperidone maleate is a white to slightly beige coloured powder, soluble in N,N- dimethylformamide; slightly soluble in methanol, ethanol, tetrahydrofuran and propylene glycol; and insoluble in water.

In addition to domperidone maleate, each tablet contains the non-medicinal ingredients fumaric acid, magnesium stearate, colloidal silicon dioxide, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl methylcellulose, polyethylene glycol and titanium dioxide.

AVAILABILITY OF DOSAGE FORM

Each white, round, biconvex, film-coated tablet engraved "APO" on one side and "10" on the other, contains domperidone maleate equivalent to 10 mg of domperidone. APO-DOMPERIDONE tablets are available in bottles of 100 and 500. Domperidone is a Schedule F drug.

PHARMACOLOGY

Domperidone is a dopamine antagonist which does not readily cross the blood-brain barrier and exerts its primary effect on peripheral dopamine receptors. While 3H-domperidone binds specifically and selectively to mouse and rat striatal dopamine receptors in vitro, domperidone, administered in vivo, showed no displacement of 3H-spiperone in rat brain dopaminergic areas and did not increase rat brain homovanillic acid (HVA) concentrations. Accordingly, domperidone had no effect on behaviour, conditioned reflexes, intracranial self-stimulation or EEG tracings at concentrations up to 100 times in excess of the antiemetic dose. These studies indicate that domperidone does not cross the blood brain barrier. In baboons and in the dog, domperidone given intravenously produced a dose-dependent increase in lower oesophageal sphincter pressure. Gastric relaxation studies in the dog showed that at i.v. doses of 1 and 3 mg/kg domperidone increased gastric tone. In the dog, dopamine-induced gastric relaxation was prevented by domperidone i.v. at a dose of 0.3 mg/kg. In the isolated guinea-pig stomach-duodenum preparation, dopamine and noradrenaline produced gastric relaxations which could be antagonized in a dose-dependent manner by domperidone. Domperidone also increased the amplitude and decreased the frequency of peristaltic waves in the same in

preparation. In female dogs, domperidone (1 mg/kg) increased the antral contraction pressure while decreasing the frequency. A dose of 0.3 mg/kg i.v. domperidone also prevented both the gastric relaxation and the reduced amplitude of phasic activity induced by dopamine. Domperidone also improved antroduodenal coordination (defined as the propagation of peristaltic waves from the stomach to the duodenum) in the isolated guinea-pig stomach-duodenum preparation. In the dog, intravenous administration of 0.31 mg/kg domperidone resulted in an increase in antroduodenal coordination from 35% to 80%. In dogs, 0.35 and 0.7 mg/kg i.v. domperidone significantly increased the distention of the pyloric sphincter. Gastric emptying studies performed in the dog showed that domperidone 0.4 mg/kg i.v. significantly decreased the stationary phase of a solid meal by 50% and also increased the emptying rate. Domperidone also reversed the dopamine-induced prolongation of the stationary phase of both solid and semi-solid meals.

Domperidone was found to be a potent inhibitor of apomorphine-induced emesis in the dog. After a s.c. injection of 0.31 mg/kg apomorphine, the ED50 was 0.007 mg/kg s.c. and 0.031 mg/kg p.o. for domperidone. Domperidone was also highly effective in preventing emesis induced by hydergine, levodopa and morphine but ineffective in preventing copper sulfate induced emesis. In rats, domperidone induced a significant rise in plasma prolactin levels. This effect could be reversed by apomorphine. In rats treated with 0.25 mg/kg/day domperidone for 14 days, prolactin levels were found to be significantly higher than those of untreated animals.

TOXICOLOGY

Acute Toxicity

Domperidone was administered orally, intraperitoneally (mice and rats only), intravenously and subcutaneously to mice, rats and dogs. Domperidone was suspended in 0.03% aqueous Tween 80 for p.o., i.p., and s.c. administration; it was dissolved in 0.1 M lactic acid solution for i.v. administration. For mice and rats, LD50 at 14 days was calculated by the Litchfield Wilcoxon method; for dogs LD50 at 7 days was calculated by the Van Der Warden method. Sex LD50 (mg/kg)

Following oral administration: in mice: at maximum dose (8000 mg/kg): decreased movement in 2 or 3 hours, eyestrain, diarrhea. After 5-6 days these symptoms disappeared and eyes became normal. in rats: eyestrain, decreased eye movement, gait abnormalities. After 1 hour, sleep, salivation and lacrimation were observed. Death due to difficulty in breathing occurred from 4 hours to 2-3 days post-dosing. Survivors exhibited weight loss and diarrhea. Following i.v. administration: in mice: coarse hair, rapid breathing, convulsions, jumping, difficulty breathing ($41.7 mg/kg) and death (in 50% at 50 mg/kg). in rats: similar to mice. in dogs: less energy, increased urine output, salivation, lacrimation, sleep, increased pulse rate, lower body temperature, difficulty breathing and death. Following s.c. or i.p. administration: in mice: at maximum dose (8000 mg/kg): dizziness after 2 or 3 hours, decreased movement. in rats: i.p. administration resulted in decreased movement, lacrimation, sleep, difficulty in breathing and death (>83.3 mg/kg for males and 57.9 mg/kg for females).

Subacute Toxicity

Four week old rats (10M, 10F/group) weighing 90-115 g received 0, 10, 30, 70, 200, 500 and 1400 mg/kg domperidone by gavage for a period of 30 days. At the higher doses a decrease in food consumption and body weight was observed. Water comsumption was decreased in medium and high dosed animals. At high dose, 3 males and 4 females died between days 13 and 25. Hematology and serum analyses were normal except for a decrease in white blood cells (at 140 mg/kg), anemia ($500 mg/kg) and an increase in cholesterol and neutral lipids. At the highest dose, the level of A1-P and GPT were slightly increased in females. Urinalyses revealed a decrease in urine volume and an increase in urine density ($200 mg/kg) and an increase in proteinuria ($500 mg/kg). Anatomically, extensive changes to reproductive organs (shrinkage of testes, seminal vesicles, prostate, ovary and uterus) were observed at doses of 500 mg/kg and greater. Organ weights were comparable in all groups with the following exception: decrease in absolute and relative organ weight of testes, seminal vesicles, prostate, ovary, uterus and thymus at the 2 highest doses. Histopathology revealed the following changes: swelling of centrilobular hepatic cells, focal granuloma and deposition of yellow pigments (1400 mg/kg), vacuolation of renal tubular epithelial cells (1400 mg/kg), dilatation of renal tubules (500 mg/kg), decrease in thymus cells (1400 mg/kg), hypoplastic bone marrow ($500 mg/kg), hypospermatogenesis ($500 mg/kg), atrophy and hyposecretion of the prostate and seminal vesicles ($500 mg/kg), decrease of ovarian lutein, atrophy of uterus and hypermucification of vaginal mucosa ($500 mg/kg), hyperplasia and hypersecretion of mammary glands and dilatation of ducts and glands ($10 mg/kg).

Six groups of five week old Wistar rats (15M, 15F/group) received 0, 10, 30, 60 and 100 mg/kg domperidone administered intrarectally for 30 days. There was no effect on behaviour or mortality. From day 10, animal coat became coarse. While all dosed males exhibited a decrease in body weight gain, the higher dosed females (60 and 100 mg/kg) gained significantly more body weight and consumed more food than controls. No significant changes in hematological, blood chemistry, or urine tests were consistently reported for treated groups. At high dose, some organ weights decreased with obvious atrophy of the uterus and hypermucification of vaginal mucosa in females receiving 60 mg/kg and more. Histopathological studies revealed a shrinkage and hyposecretion of seminal vesicles, testes and prostate in males receiving 100 mg/kg domperidone. Females exhibited a dose-related hyperplasia, dilatation and hypersecretion of the mammary glands as well as dilatation of the ducts.

Eight-month old Beagle dogs (3M, 3F/group) were given 0, 2.5, 10, 40 or 160 mg/kg of domperidone orally for 30 days. One female in the 160 mg/kg group died on day 26. This dog exhibited a significantly decreased food consumption from day 10 and its hair became coarse. Autopsy revealed bleeding in the lungs. Dogs at the 2 highest doses showed less movement. At the highest dose, salivation, vomiting, ocular discharge and tremor were sometimes seen but regressed within 5 hours. Doses of 160 mg/kg caused body weight loss of one male and one female from day 10 which correlated with a decrease in food consumption beginning on day 6. Hematological parameters and urinalysis were normal except at the highest dose where animals had a slightly decreased urine output and decreased white blood cell counts (females). Blood chemistry tests also revealed an increase in cholesterol levels in the 40 mg/kg group. Anatomical observations included weight loss of testes, atrophy of seminiferous tubules and hypospermatogenesis in males receiving 160 mg/kg. In females, administration of 10 mg/kg resulted in hyperplasia of the corpus lutea, hyperplasia of the inner uterine wall, and hyperplasia and hypersecretion of mammary glands. The following histopathological observations were also noted: spleen congestion and cysts on the thymus (160 mg/kg group).

Chronic Toxicity

Groups of 15 male and 15 female rats received domperidone orally at doses of 0, 1, 3, 10, 30, 70 and 200 mg/kg during 180 days, so that a total of 210 animals were used throughout the course of the study. Only 5 deaths occurred (1 male and 4 female high dosed rats). High dose animals exhibited dirty mouth and nose, coarse hair and weight loss. Hematological tests and urinalysis were normal. Blood chemistry analyses revealed increases in cholesterol in males ($10 mg/kg), decreases in cholesterol in females ($1 mg/kg), decreases in neutral lipids in males (20 mg/kg), decreases in free fatty acids in females (200 mg/kg), and slight decreases in A1-P levels. No adverse effect on organ weight was noted except for a decrease in uterus weight. The lower part of the abdomen and mammary gland of female rats were yellowish in colour and emitted an odour. Histopathological changes were described as follows:

Groups of ten male and ten female rats received 0, 0.3, 1, 3 and 10 mg/kg domperidone intrarectally for 180 days. No drug-related effects on mortality were observed. Drug symptoms similar to those in the subacute toxicity studies appeared such as thicker and coarser hair. Increased body weight gain in females correlated with changes in food consumption. There were no significant changes in hematological, blood chemistry, urine or organ weight parameters. Histopathological tests revealed hyperplasia and hypersecretion of mammary glands and dilatation of ducts and glands (10 mg/kg group). High dose female rats exhibited hypermucification of vaginal mucosa and atrophy of the uterus as well as hyperplasia and hypersecretion of the mammary glands and dilatation of the mammary ducts and glands.

Five groups of 3 male and 3 female dogs received domperidone orally each day, at doses of 0, 1.25, 2.5, 10 and 40 mg/kg for a period of 180 days. No deaths were reported. Doses of 10 mg/kg and greater resulted in slight sedation, tremor and lacrimation (primarily in females) which usually regressed 5-6 hours after administration. Beginning 2 months after the onset of the study, slight tremor and decreased movement were observed with doses as low as 2.5 mg/kg. Decreases in food and water consumption could be correlated with lower body weight but were not dose-related. Hematological parameters and urinalysis remained normal except for a slight decrease in hematocrit, hemoglobin and red blood cells; and an elevation in cholesterol level (40 mg/kg). Gross pathological changes were limited to atrophy of the uterus (10 and 40 mg/kg dosed females) and atrophy of the prostate (40 mg/kg dosed males). Organ weights were normal except at high dose, at which point liver weight increased. Histopathological changes were described as follows: Testes: hypospermatogenesis in 1 dog at 10 mg/kg and 3 dogs at 40 mg/kg. Prostate: atrophy of the prostate characterized the 40 mg/kg dosed males and to a lesser extent the 10 mg/kg dosed males.

Uterus: atrophic uterine wall was observed in 2 females receiving 40 mg/kg and 1 receiving 10 mg/kg.

Reproduction and Teratogenicity Studies

In reproduction studies, ten-week old female Wistar rats (20/group) received 0, 0.3, 1 or 10 mg/kg intraperitoneally either 14 days prior to mating and on days 1 or 7 of pregnancy. Five week old males (20/group) received domperidone in the same doses 60 days prior to mating. Domperidone was administered as an aqueous solution of 0.03% Tween 80. The decrease in mating rate (50% at 1 mg/kg, 20% at 10 mg/kg) was dose-related but fertility was not significantly affected. When the animals were sacrificed (day 20), there were no significant abnormalities observed with respect to the number of corpus lutea, implants and live fetuses, dead fetuses, sex ratio, body weight or appearance, or skeletal or organ parameters.

10 week-old female Wistar rats (30/group) received 0, 10, 70 and 200 mg/kg; 10-week old ICR-JCL female mice (30/group) and 8 month old Japanese white rabbits (10/group) received 4, 10, 70 and 120 mg/kg domperidone. Domperidone was administered by gavage from days 7-17 of pregnancy in rats, from days 6-15 of pregnancy in mice and from days 6 to 18 of pregnancy in rabbits. No parent mortality of rats or mice was reported. Body weight of parents decreased in rats ($70 mg/kg), mice (120 mg/kg) and rabbits (120 mg/kg). Six of 10 rabbits died in the 120 mg/kg dosed group. Body weight of mothers decreased in mice (120 mg/kg), rats ($70 mg/kg), and rabbits ($10 mg/kg). An increase in the percentage of dead fetuses was also reported in both mice ($70 mg/kg) and rats (200 mg/kg). Fetal abnormalities (anophthalmia and microphthalmia, displacement of subclavian artery) were only observed in rats (200 mg/kg); ossification was observed in rats ($70 mg/kg) and mice (70 mg/kg). The survival rate of pups 0-4 days old decreased in rats (200 mg/kg). No fetuses of mice receiving 120 mg/kg survived. Body weight of surviving rat offspring was also decreased in the two highest dose groups.

10 week old Wistar rats (20/group) were given 10, 70 or 120 mg/kg of domperidone for 4 days before delivery and 1-21 days of lactation. Domperidone ($70 mg/kg) caused early delivery and affected the development of sexual organs. The number of deaths of newborns in days 0-4 increased. If the pups survived for 4 days, the survival rate increased. However, no abnormality in the F1 generation was found.

Rats (20M, 20F/group) received domperidone at doses of 0, 0.04, 0.2 and 1.0 mg/kg administered intravenously. Males were injected 60 days before mating. Females were injected 14 days prior to mating and on days 1-7 of pregnancy. Mating rate decreased as dose increased ($0.2 mg/kg). Fertility rate of dosed females was still normal. There was no effect on the number of implantations, number of live and dead fetuses, sex ratio, body weight, organic or skeletal abnormalities, or ossification.

Ten week old Wistar Rats (30/group) received 0, 2, 8, 15 or 30 mg/kg domperidone intraperitoneally from days 7-17 of pregnancy. Dams were sacrificed on the 20th day and fetuses and dams were examined. Two groups (control and 15 mg/kg, 20M, 20F/group) were mated at 10 weeks of age. No mortality was observed in the F0 generation. At 30 mg/kg body weight of dams decreased as did the number and body weight of surviving fetuses; an increase in the number of dead fetuses was also reported. No external abnormalities were observed, however, doses of 15 mg/kg and greater resulted in skeletal abnormalities and variants. In some cases, fetuses of dams receiving 8 or 30 mg/kg also developed abnormalities of the left subclavian artery which led to kidney, ureter, trachea, oesophagus, heart and ocular dysfunction. Doses of 8 mg and greater decreased the number of sternums and coccygeal vertebrae and delayed ossification. Only doses of 30 mg/kg affected the F1 generation, resulting in decreased newborn body weight and survival rate, and skeletal abnormalities.

Eight month old Japanese white rabbits (10/group) were given domperidone intravenously from day 6-18 of pregnancy. Rabbits were sacrificed on the 29th day. No deaths were reported in the F0 generation. No significant changes in the number of dead fetuses, survival fetuses, sex ratio, body weight of F0 or F1 generation at birth, external, skeletal and organic abnormalities were observed.

Ten week old Wistar Rats (20/group) were given 0, 2, 8 or 15 mg/kg domperidone intraperitoneally from day 17 of pregnancy to day 21 post-partum. At the highest dose, body weight gain of dams and body weight of offspring decreased during the later stage of pregnancy. No evidence of teratogenicity was reported nor were there any significant changes in date of delivery, number of newborns or rate of newborn survival (F1 generation). The development of sexual organs of the F1 generation was not significantly affected; mating rate and fertility at 10 weeks (F1 generation) and rate of survival of the F2 generation was no different between control and treated animals.

Route i.v.	Animals Mice	M	14 days * 47.4 (43.4 - 51.8)
	(ICR)	F	46.5 (43.2 - 50.1)
	Rats	M	42.4 (40.1 - 44.8)
	(Wistar)	F	41.7 (38.8 - 44.8)
	Dogs	M	64.2 (42.3 - 83.7)
	(Beagle)	F	56.1 (43.0 - 73.1)
s.c.	Mice	M F	>8000 >8000
	Rats	M F	>8000 >8000
	Dogs	M F	>160 >160
i.p.	Mice	M	>8000
		F	>8000
	Rats	M	>8000
		F	>8000
p.o.	Mice	M	>8000
		F	>8000
	Rats	M	>8000
		F	>8000
	Dogs	M	>160
		F	>160

PRODUCT MONOGRAPH

THERAPEUTIC CLASSIFICATION

ACTIONS AND CLINICAL PHARMACOLOGY