PRAZOLE PLUS  
 
DESCRIPTIONPantoprazole + Domperidone (a Fixed dose combination of Pantoprazole and Domperidone) contains Pantoprazole which is chemically sodium

5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1 H-benzimidazole sesquihydrate and Domperidone which is chemically

5-chloro-1-]1-]3-(2-oxo-2,3-dihydro-1 H-benzimidazol-1-yl)propyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one.

Panloprazole + Domperidone capsule is TransparentiTransparent size “1″ hard gelatin capsule filled with blue & brownto yellowish brown spherical pellets.

 

FORMULATION

Each capsule contains:

Pantoprazole sodium sesquihydrate equivalent to

Pantoprazole ………………………. 40 mg

(as enteric coated pellets)

Domperidone BP ………………….. 30 mg

(as sustained release pellets)

Excipients ……………………………… q.s.

Colours : Lake of Indigo carmine, Ferric oxide (Red),

Ferric oxide (Yellow), Titanium dioxide

Approved colours used in capsule shell.

 

CLINICAL PHARMACOLOGY

Mechanism of Action

Pantoprazole, a benzimidazole sulphoxide derived prod rug, is an irreversible proton pump inhibitor. Pantoprazole, being a weak base, is highly ionized at low pH and readily accumulated in the highly acidic canalicular lumen of the stimulated parietal cell in the stomach. In this acidic environment, it is protonated and rapidly converted to a cationic cyclic sulphonamide. The sulphonamide binds covalently to cysteine residues on the luminal (acidic) surface of H+/ K+-ATPase to form a mixed disulphide; thus causing irreversible inhibition of the gastric proton pump. This inhibition of the gastric proton pump or H+ / K+ -ATPase (which represents the final step in the secretory process), suppresses gastric acid secretion 1,2. Domperidone, a benzimidazole derivative (structurally related to the butyrophenones), acts by selectively antagonizing the peripheral dopaminergic 0, receptors in the gastrointestinal (G.I.) wall, thereby enhancing gastrointestinal peristalsis and motility and increasing Lower Esophageal Sphincter (LES) tone.3

RATIONALE OF COMBINATION

The mode of action of both Pantoprazole and Domperidone are different and complimentary to each other. Upper G.I. disorders are frequently associated with a combination of hyperacidity and dysmotility. As a result, acidic chyme may either stagnate in stomach and duodenum or may be evacuated by reverse peristalsis (vomiting or nausea). Reflux of acid contents of stomach cause nerosions of lower part of esophagus which may further aggravate nausea and vomiting. Since both hyperacidity and dysmotility are present at the same time in disorders like Gastro Esophageal Reflux Disease (GERD) and Non Ulcer Dyspepsia (NUD), a combination of drugs which will take care of both would be ideal. Pantoprazole is a potent gastric acid inhibitor that blocks the final stage of acid secretion. Hence, whatever may be the stimulus, hyperacidity will be controlled by Pantoprazole. In contrast, Domperidone increases G.I. motility, thereby facilitating the movement of acid contents further down in the intestine preventing reflux esophagitis and thereby controlling nausea and vomiting. Hence, the pharmacology of Pantoprazole and Domperidone corroborates their use in combined form for the treatment of GERD, NUD and related disorders. Domperidone is usually administered at a dose of 10-20 mg, 2-3 times daily before meals. In order to enhance patient compliance, without compromising on its efficacy, sustained release (SR) domperidone is developed. Domperidone SR (30 mg) is for once daily administration since its plasma half-life is otherwise 12 to 16 hours.

PHARMACOKINETICS

Pantoprazole

Pantoprazole is rapidly absorbed after oral administration, with peak plasma concentrations (C max ) of 1.1 to 3.1. (mean 2.1) mg/L occurring within 2 to 4 (mean 2.7) hours (tmax) after ingestion of an enteric coated 40 mg tablet. The volume of distribution is low (mean 0.16 L/kg at steady state) due to high degree of plasma protein binding (-98%). Plasma Pantoprazole concentrations decline monophasically after oral administration, with a mean plasma terminal half-life (ty,P) of 0.9 to 1.9 hours. However, since inhibition of acid secretion is non-competitive or irreversible, there is no correlation between plasma levels and the duration of action of Pantoprazole. Concomitant intake of food has no influence on the bioavailability of Pantoprazole, and any possible retardant effect of food on the rate of drug absorption is not of clinical relevance, considering the prolonged antisecretory action of Pantoprazole. The enteric coating does not influence the bioavailability of Pantoprazole. Pantoprazole undergoes extensive hepatic metabolism via cytochrome P450 oxidase followed by sulphate conjugation. Elimination of Pantoprazole is predominantly renal, with -80% of an oral dose being excreted as urinary metabolite; the remainder is excreted in the feces and originates primary from biliary secretion.

 

 

Domperidone

Domperidone is rapidly and almost completely (93%) absorbed after oral administration. Peak plasma concentrations occur within 30 min. after oral administration. The peak plasma concentration value after a 20mg oral dose is in the range of 15 to 19 ng/ml. The mean elimination half-life ranges from 12 – 16 hours for an oral dose. Oral bioavailability of Domperidone is 13 – 17% because of extensive presystemic metabolism in gut wall and liver. Administration of Domperidone 90 minutes after a meal increases bioavailability whereas Cimetidine or alkali pretreatment reduces bioavailability. Domperidone is strongly bound to plasma proteins (90-93%). Domperidone undergoes extensive biotransformation with <1% excreted unchanged in urine. 3,4

 

Special populations

Pantoprazole

Hepatic impairment: There is a slight increase (1 .5 fold) in maximum drug concentrations in patients with mild to severe hepatic impairment. No dosage adjustment is needed in patients with mild to severe hepatic impairment. Renal impairment: Pharmacokinetic parameters for Pantoprazole in patients with severe renal impairment are similar to those of healthy subjects. No dosage adjustment is needed in patients with renal impairment. Gender: No dosage adjustment is needed based on gender. Pediatrics: The pharmacokinetics of Pantoprazole have not been investigated in patients <18 years of age. Geriatrics: No dosage adjustment is recommended based on age.

 

Domperidone

Hepatic impairment: There is no published pharmacokinetic data in patients with hepatic impairment. Because Domperidone is extensively metabolized, response to the drug should be carefully monitored in this patient population. Neonates: Domperidone is not recommended for use in neonates. Breast milk: Domperidone may precipitate galactorrhea and improve postnatal lactation. It is secreted in breast milk in very small quantities and thus insufficient to be considered harmful. Pediatrics: Domperidone is not recommended other than for treatment of nausea and vomiting in patients undergoing cancer therapy. There may be an increased risk for extrapyramidal reactions in young children because of an incompletely developed blood brain barrier. Pregnant women: The safety of Domperidone has not been proven, therefore its use is not recommended in pregnant women. Geriatrics: No special precautions are necessary in older patients. Pantoprazole + Domperidone should be used with caution in conditions where the individual drugs have been used with precautionary approach.

 

INDICATIONS

Pantoprazole + Domperidone is indicated in the management of gastroesophageal reflux disease; gastritis, non-ulcer dyspepsia, gastric or duodenal ulcer, dyspepsia, bloating, fullness, belching, NSAID-induced dyspepsia.

 

CONTRAINDICATIONS

Pantoprazole + Domperidone is contraindicated in patients with known hypersensitivity to Pantoprazole or Domperidone.Pregnancy and Lactation. Due to lack of controlled studies in pregnant and lactating women, use of Pantoprazole + Domperidone is contraindicated in this group of patients.

 

WARNINGS AND PRECAUTIONS

Pantoprazole + Domperidone shall be given with care to patients with renal dysfunction or hepatic dysfunction.

 

DRUG INTERACTIONS

Pantoprazole

Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isoenzymes, and subsequently undergoes phase II conjugation. Based on studies evaluating possible interactions of Pantoprazole with other drugs metabolized by the cytochrome P450 system, no dosage adjustment is needed with ccnccmitant use of the following drugs: theophylline, cisapride, antipyrine, caffeine, carbamezapine, diazepam, diclofenac, digoxin, ethanol, glyburide, oral ccntraceptives (Ievonorgestrel l ethynylestradiol), metoprolol, nifedipine, phenytoin or warfarin. Clinically relevant interactions of Pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when co- administered with Pantoprazole, adjustment of the dosage of Pantoprazole with such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. Because of profound and long lasting inhibition of gastric acid secretion, it is theoretically possible that Pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (e.g. Ketoconazole, Ampicillin esters, and iron salts).

 

Domperidone

Anti-cholinergic drugs may inhibit the anti-dyspeptic effects of Domperidone. Antimuscarinic agents and opioid analgesics may antagonize the effect of

Domperidone. Domperidone suppresses the peripheral effects (digestive disorders, nausea and vomiting) of dopaminergic agonists. Since Domperidone has gastro-kinetic effects, it could influence the absorption of concomitant orally administered drugs, particularly those with sustained release or enteric coated formulations. As Domperidone interferes with serum prolactin levels, it may interfere with other hypoprolactinaemic agents and with some diagnostic tests. Antacids and anti-secretory agents lower the oral bioavailability of Domperidone. They should be taken after meals and not before meals, i.e. they should not be taken simultaneously with Domperidone. Reduced gastric acidity impairs the absorption of Domperidone. Oral bioavailability is decreased by prior administration of Cimetidine or Sodium Carbonate.

ADVERSE REACTIONS

Pantoprazole

The adverse reactions associated with Pantoprazole include headache, diarrhea, Skin rash, Pruritus and Dizziness. Domperidone Serum prolactin level may rise resulting in galactorrhea in females and less frequently gynaecomastia in males due to Domperidone. Dry mouth, thirst, headache, nervousness, drowsiness, diarrhea, skin rashes and itching may follow treatment with Domperidone.

OVERDOSAGE AND TREATMENT

In the event of overdosage, gastric lavage should be performed. Symptomatic and supportive measures are recommended.

DOSAGE AND ADMINISTRATION

The usual recommended dose of Pantoprazole + Domperidone is one capsule daily before breakfast. Swallow capsule as a whole, do not chew the capsule.

STORAGE INSTRUCTIONS

Store at a temperature below 25°C, protect from light and moisture. Keep the medicine out of reach of children.

REFERENCES

1. Pantoprazole. In: Therapeutic drugs, vol. 2, Edn. Seccnd, edited by Colin Dollery, pp. 11-14

2. Fitton A; Wiseman L. Pantoprazole: A review of its pharmacological properties and therapeutic use in acid-related disorders. Drugs 1995; 51 (3):460 – 482

3. Domperidone. In: Therapeutic drugs, vol. 1, Edn. Second, edited by Colin Dollery, pp. D196-199

4. Barone JA, Domperidone: A peripherally acting dopamine 2-receptor antagonist. The Annals of Pharmacotherapy 1999, 33(4): 429 – 40.