12.72 mg as domperidone maleate
Ranbaxy Pharmaceuticals Canada Inc. DATE OF PREPARATION 2630 Skymark Avenue, Suite 701 April 4, 2007 Mississauga, ON L4W 5A4 Control Number: 111445
PRODUCT MONOGRAPH
Pr
RAN-DOMPERIDONE 10 mg tablets
12.72 mg as domperidone maleate
Modifier of upper gastrointestinal motility
Domperidone is a peripheral dopamine antagonist that selectively blocks the effect of dopamine at D2 receptors in myenteric motor neurons and the chemoreceptor trigger zone (CTZ). Through this action it stimulates peristalsis and helps coordinate antral and duodenal contractions, improving gastric motility.
Its antiemetic effects are largely due to blockade of dopamine receptors in the CTZ, although there is indirect evidence to suggest that some of the antiemetic effect stems from domperidone's prokinetic properties. Domperidone does not readily cross the blood-brain barrier and has no appreciable effect on dopamine receptors in the brain. Domperidone has been shown not to have a significant effect on D1 receptors in kidneys or in the periphery.
In patients with symptoms of upper gastrointestinal tract dysmotility such as those resulting from chronic and subacute gastritis and diabetic gastroparesis, domperidone has been shown to significantly improve gastric emptying rates.
Domperidone also normalizes gastric slow-wave activity that can contribute to symptoms of nausea in patients with upper gastrointestinal motility disorders. It help synchronize peristaltic contraction, thus improving the movement of both solids and liquids through the gastrointestinal tract. Domperidone has no effect on esophageal or colonic motility. Domperidone also stimulates release of prolactin from the pituitary gland.
Absorption: Domperidone is rapidly absorbed with a tmax of 0.5 hours when the drug is administered orally under fasting conditions. Bioavailability is low at 13 to 17% due to a high degree of both hepatic first-pass and gut wall metabolism. Bioavailability increases significantly when the drug is administered following a meal, though tmax is increased. Nonetheless, patients taking the drug for dysmotility should take it 15 to 30 minutes before eating.
Domperidone is rapidly and extensively distributed into tissues with an apparent volume of distribution of 5.7 L/kg. Plasma protein binding is approximately 92%.
Domperidone is subject to extensive first-pass metabolism both in the gut wall and liver. Major metabolic pathways are via hydroxylation (CYP3A4, 1A2, 2E1) and oxidative N-dealkylation (3A4) to two inactive metabolites.
A small amount of domperidone (less than 1%) is excreted unchanged in urine and approximately 6% in the feces. Elimination half-life upon oral administration is 12.6 to 16 hours.
Patients may exhibit elevated serum prolactin levels. Elevations of serum AST, ALT and cholesterol have also been noted (<1%).
The relative bioavailability of RAN-Domperidone 10 mg tablets (which is identical to the cross-referenced product ratio-Domperidone(r) 10 mg tablets) was compared to Motilium 10 mg tablets of Janssen Pharmaceutical Inc. 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:
| AUC 0-t ng.h/mL | Tmaxh | Cmaxng/mL | AUC infng.h/mL | |
| Ranbaxy | 210.73 | 0.91 | 71.72 | 223.86 |
| Janssen | 217.10 | 0.83 | 74.76 | 231.49 |
Based on the bioavailability study, Ranbaxy's domperidone 10 mg tablets are judged to be comparable in both rate and extent of absorption to Janssen's formulation (Motilium(r)) domperidone 10 mg tablets.
Domperidone maleate is indicated for the treatment of symptoms of upper gastrointestinal dysmotility caused by chronic and subacute gastritis and diabetic gastroparesis. Symptoms that can be improved by use of domperidone include nausea, vomiting, bloating, early satiety and gastric distention. Domperidone maleate is indicated for adjunctive therapy in Parkinson's disease to manage nausea vomiting and postural hypotension caused by levodopa or dopamine agonists. It is also used in the treatment of acute nausea and vomiting, both nonspecific and cytotoxic induced and as adjunctive therapy for migraines accompanied by nausea and vomiting. Domperidone has been used in patient with anorexia nervosa to combat gastric stasis in the early stages of re-feeding.
Domperidone maleate is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the various formulations. Domperidone should not be used where gastrointestinal stimulation could prove dangerous, such as in cases of pre-existing gastrointestinal haemorrhage, perforation or obstruction. Domperidone is also contraindicated in patients with a prolactin releasing pituitary tumor (prolactinoma). The co-administration of domperidone with ketoconazole is contraindicated (see Warnings and Precautions, Cardiovascular section and Drug Interactions section).
There have been reports of QT-prolongation and ventricular tachyarrhythmias when high doses of domperidone were given by the intravenous route. 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.
Caution is advised when administering domperidone to patients with a history of breast cancer, as certain breast cancers are theorized to be prolactin-dependant. Domperidone administration leads to increased serum prolactin levels. Raised levels are maintained with chronic administration and fall to baseline level upon discontinuation of therapy. Galactorrhea and breast tenderness are occasionally reported in women. Galactorrhea usually occurs within the first 14 days of therapy but can take as long as 3 months to appear. Upon discontinuation, galactorrhea usually resolves within a week but may resolve gradually over a period of 2 months.
Since domperidone is metabolized primarily in the liver, it should be used with caution in patients with hepatic impairment.
Domperidone does not readily cross the blood-brain barrier; CNS effects occur rarely. Extrapyramidal symptoms are more likely to be reported in infants and in patients given more than the maximum recommended dosage.
Domperidone has been shown not to interact with dopamine (D1) receptors in the kidneys or periphery, and has no appreciable effect on plasma renin or aldosterone levels. 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 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. Pharmacokinetic studies in animals indicate that a small percentage of maternal dose crosses the placenta.
Domperidone is excreted to a minor extent in breast milk, with drug concentrations approximately 75% lower than corresponding maternal serum concentrations. It exhibits high plasma protein binding (> 90%) and has a relatively high molecular weight, both of which help explain this phenomenon. Domperidone is considered by the American Academy of Pediatrics to be usually compatible with breastfeeding.
Domperidone maleate should not be used for children since its safety and efficacy have not been adequately established in children.
The beneficial effects of domperidone maleate may be compromised by the concomitant use of anticholinergic drugs. Preliminary studies suggest that anticholinergics may antagonize the prokinetic effects of domperidone. Since domperidone decreases gastric emptying times, it could potentially alter the absorption of concomitantly administered medications. Closer monitoring of serum levels, particularly for drugs with narrow therapeutic indices, is advised. CYP3A4, 1A2 and 2E1 are the major hepatic enzymes involved in domperidone metabolism. The potential exists for interactions between domperidone and drugs that either induce or inhibit these enzymes (e.g., phenobarbital, phenytoin, azole antifungals). To date, no clinically significant interactions involving the CYP450 family of enzymes have been reported. Domperidone should be carefully administered in combination with MAO inhibitors due to the possible hypertensive crisis effect. This is a theoretical caution based on increased catecholamine levels when MAOIs are given with domperidone. Domperidone maleate absorption (bioavailability) was possibly decreased when taken in combination with high doses 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 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).
Central Nervous System:
(1.2%), insomnia, nervousness, dizziness, thirst, lethargy, irritability (all <1%). Acute dystonic reactions (rare in adults)
Gastrointestinal:
Abdominal cramps, diarrhea, regurgitation, appetite changes, nausea, heartburn, constipation (all <1%). Dry mouth (1.9%).
Endocrine and Metabolism:
Breast enlargement, hot flushes, mastalgia, galactorrhea, menstrual irregularities, elevated serum prolactin. (1.3%)
Dermatologic:
Skin rash, itching, urticaria (all <1%).
Miscellaneous:
stomatitis, conjunctivitis, urinary frequency, dysuria, leg cramps, asthenia, drug intolerance, elevation of AST, ALT, cholesterol (all <1%).
Cardiovascular:
Edema, palpitations (0.5%).
Post-Market Adverse Drug Reactions: Sudden death and torsade de pointes.
For management of a suspected drug overdose, it is recommended to contact your
.
Duration of Therapy: The recommended maximum duration of therapy is 12 weeks, although longer courses of therapy are sometimes prescribed.
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 and Precautions, Renal section).
In adults, the usual dosage is 10 mg orally 3 to 4 times daily, 15 to 30 minutes before meals and at bedtime if needed; may be increased to a maximum of 20 mg 3 to 4 times daily if optimal response is not achieved. The maximun recommended total daily dose is 80 mg. Higher doses may be required to achieve symptom control while titration of the anti- parkinsonian medication is occurring.
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
Physical form: White to off white crystalline powder.
| Solubility: | In water: | 0.10% |
| In ethanol: | 0.1% | |
| In PEG | 400:0.5% | |
| In PPG: | 1.3% | |
| In CHCl3 | 0.004% |
pka value: pka = 7.890
o
Partition coefficient: log P= 3.90 at pH 10.2 Melting range: 225 to 231 C.
Each white 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%, croscarmelose sodium, polyethylene glycol
hydroxypropyl methylcellulose, polydextrose, triacetin, hydroxypropyl cellulose, sorbitol, titanium dioxide.
Store at room temperature between 15 and 30degC. Protect from light and moisture.
RAN-DOMPERIDONE is a round, plain-coated, biconvex white tablet, engraved "R113" on one side and plain on the other side. Available in HDPE bottles containing 500 tablets.
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 ug/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.
| 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 | 56.3 (43.1- 73.6) | |
| 30 F | 68.8 (52.5 - 89.9) | ||
| Guinea-pigs | 30 M | 42.9 (32.8 - 56.1) | |
| 30 F | 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 | > 1280 | |
| 20 F | > 1280 | ||
| Guinea-pigs | 30 M | 796 (424-1493) | |
| 30 F | > 1280 | ||
| Dogs | 6 M & F | > 160 | |
| S.C. | Dogs | 6 M & F | > 160 |
Signs of toxicity:
Following i.v. administration:
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 Following oral administration: 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 Following subcutaneous administration: in dogs: edation and cataleptic immobility
R
oute: i.v.
Species: Wistar rats # of animals: 10 M & 10 F/group Dose administered: 0, 2.5, 10 or 40 mg/kg once daily, six days a week. Duration: 3 weeks Results: No effect on mortality, behavior and appearance. 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). Route: i.v. Species: Beagle dogs # of animals: 3 M & 3 F/group Dose administered: 0, 1.25, 5 or 20 mg/kg once a day, six days a week. Duration: 3 weeks Results: No effect on mortality. 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. Route: p.o. Species: Wistar rats # of animals: 10 M & 10 F/group Dose administered: 0, 10, 40 or 160 mg/kg. Duration: 15 weeks Results: 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). Route: p.o. Species: Beagle dogs # of animals: 3 M & 3 F/group Dose administered: 0, 2.5, 10 or 40 mg/kg. Duration: 15 weeks Results: 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).
Route: p.o. Species: Wistar rats # of animals: 40 M & 40 F/group Dose administered: 0, 10, or 160 mg/kg daily, seven days a week. Duration: 6-12-18 months. Results: 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:
enhanced prostatins at all doses except with 10 mg/kg after 6 months.
progestational aspect of female genital tract at all doses after 6 and 12 months.
female aspect or atrophy of mammary gland in males at all doses.
stimulation of mammary glands in females at all doses after 6 and 12 months and at 160 kg/mg after 6 and 18 months.
inverted or irregular gradient of adrenal fat in males at 160 mg/kg after 6, 12 and 18 months and in females at 40 mg/kg after 6 and 12 months. Absence of fat gradient in females at 160 kg/mg after 6 months.
chronic stimulations of the chromophobe or erythrosinophilic tissues of the hypophylis at all doses.
R
oute: p.o.
Species: Beagle dogs # of animals: 12 M & 12 F Dose administered: 0, 2.5, 10, or 40 mg/kg daily, seven days a week. Duration: 12 months. Results: 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).
Route: p.o. Species: Albino Swiss mice # of animals: 200 M & 200 F Dose administered: 0, 2.5, 10, or 40 mg/kg body/weight/day. Duration: 8 months. Results: 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. Mutagenicity studies: 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.
Intravenous embryotoxicity and teratogenicity study in Wistar rats
| 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. Pregnancy Dosage (mg/kg) rate % 95 0 85 160 20 320 25 640 |
| 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. | ||
| No. of animals | Dose administered | Results |
| 40 M 120 F | 0, 10, 40 or 160 mg/100 g food, from day 0 of mating and further through breeding and weaning | Significant lower body weight was observed in the first generation at 160 mg/100 g (correlated with decreased of food consumption). No mortality and pregnancy rates differences were observed between groups. Decrease in litter size and number of live foetuses were observed at 160 mg/100 g in second generation which was attributed to maternal toxicity. No differences in abnormalities were observed between treated and untreated groups. |
| No. of animals | Dose administered | Results |
| 60 F group of 20 | 0, 0.63, 1.25 mg/kg/day from day 6 to day 18 of gestation | Dosage 0 0.63 1.25 Survival rate % 100 85 100 Pregnancy rate 100 85 90 % live 90.2 99.2 97.1 % dead 0 0 0 % resorbed foetuses 0.9 0.8 2.9 average birthweight of live pups(g) 34.6 35.3 36.9 24 hr. survival rate of incubated pups 77.7 76.7 76.5 Three animals died at 0.63 mk/kg. No changes were observed in body weight gains. No embryotoxic or teratogenic effects were observed with domperidone. |
R
oute: I.V.
Species: New Zealand white rabbit # of animals: 60 in groups of 15 Dose administered: 0, 0.63, 1.25 and 2.5 mg/kg from day 6 to day 8 of gestation. Results: Mortality was observed in 3/15 with no drug, 1/15 at 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.
| 0 | 0.63 | 1.25 | 2.5 | |
| Average size litter | 4.9 | 3.9 | 3.9 | 1.7 |
| % live | 4.3 | 3.8 | 3.8 | 1.7 |
| % dead | 0.6 | 0.1 | 0.1 | 0 |
| % resorbed foetuses | 1.7 | 0.3 | 1.7 | 2.5 |
| At resection average birth weight of live pups (g) | 42 | 43.6 | 46.7 | 41.6 |
| 24 hr. survival rate of incubated pups | 81.4 | 80.4 | 97.4 | 60 |
No differences between groups were observed on number of live, dead and resorbed foetuses, birth weight and 24 hour survival rate. No teratogenic or embryotoxic effects were observed in rabbit foetuses.
R
oute: Oral
Species: New Zealand white rabbit # of animals: 60 F in groups of 20 Dose administered: 0, 10 or 40 mg/kg from day 6 to day 18 of gestation. Results: 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.
| 0 | 10 | 40 | |
| Rate of pregnancies (%) | 85 | 85 | 85 |
| Average litter size | 6.2 | 5.7 | 5.5 |
| % live | 83 | 72.6 | 76.6 |
| % dead | 2.6 | 1.6 | 2.6 |
| % resorbed foetuses | 15.3 | 25.8 | 20.8 |
| At resection average birth weight of live pups (g) | 41.5 | 40.7 | 36.3 |
| 24 hr. survival rate of incubated pups | 75 | 61.1 | 40.7 |
No abnormalities were observed in any group. 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.
| No. of animals | Dose administered | Results |
| 60 F | 0, 5, 20 mg/kg/day by gavage from day 6 to day 18 of gestation | Mortality was observed at 5 mg/kg (3/20) and at 20 mg/kg (12/20). Dosage 0 5 20 Pregnancy rate (%) 60 70 40 % live 70 64.6 82.4 % dead 0 0 5.9 % resorbed foetuses 30 35.4 11.7 at resection average birth weight of live pups (g) 42.5 39.0 34.7 24 hr. survival rate of incubated pups 54.3 52.4 14.3 Conclusion: No teratogenic effect was noted. Maternal toxicity was observed at 5 and 20 mg/kg as pregnancy rate decreased (at 20 mg/kg), mortality rate and weight gain decreased (at 5 and 20 m/kg). |
| No. of animals | Dose administered | Results |
| 160 M/160 F in groups of 20 | 0, 10, 40 and 160 mg/kg/day male: minimum of 60 days prior to mating with untreated female. female: minimum of 14 days prior to mating with untreated male | Body weight gain was normal in all groups except for a lower gain (due to lower food consumption) at 160 mg/kg/day in females. Mortality was noted in low dosed females (1/20) and in control group where one female was coupled with 160 mg/kg male. No difference was observed on gestation. No embryotoxic or teratogenic effect was noted and fertility was not affected in both sexes dosed with domperidone. |
| No. of animals | Dose administered | Results |
| 80 F in groups of 20 | 0, 10, 40 and 160 mg/kg/day from day 16 of gestation through a 3 week lactation period | Significant lower body weight gain with decreased of food consumption was observed with 160 mg/kg. Mortality was observed in one female at 10 mg/kg/day. Dosage 0 10 40 160 Pregnancy rate (%) 95 90 70 90 % live 97.1 98.4 92.7 86.1 % dead foetuses 2.9 1.6 7.3 13.9 3 weeks survival rate of born pups 85.5 77.2 72.1 32.3 Effects observed at 160 mg/kg/day are probably due to maternal toxicity . |
Bekhti A, Rutgeerts L.Domperidone in the treatment of functional dyspepsia in patients with delayed gastric emptying. Postgrad Med J 1979; 55(Suppl.1): 30-32
Bioavailability, randomized, 2-way crossover, single dose bioavailability study of ratiopharm Inc. and Janssen 10 mg domperidone tablets in healthy adults males.
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Date of Preparation: April 4, 2007