Pantoprazole (EC) and Domperidone (SR) Capsules IP 40mg/30mg (PANTOTAJ-DSR) Taj Pharma

1. Name of the medicinal product

a) Pantoprazole (EC) and Dompiridone (SR) Capsules IP 40mg/30mg Taj Pharma
b) Pantoprazole (EC) and Dompiridone (SR) Capsules IP 40mg/40mg Taj Pharma

2. Composition

a) Each hard gelatin Capsule contains:
Pantoprazole Sodium IP Equibvalent to
Pantoprazole 40mg
(As enteric coated granules)
Domperidone IP 30mg
(As sustained release granules)
Excipients q.s.

b) Each hard gelatin Capsule contains:
Pantoprazole Sodium IP Equibvalent to
Pantoprazole 40mg
(As enteric coated granules)
Domperidone IP 40mg
(As sustained release granules)
Excipients q.s.

3.PHARMACEUTICAL FORM:

Capsule for oral administration

4.CLINICAL PARTICULARS:

4.1 Therapeutic indications:

• Gastro-esophageal reflux disease(GERD)
• Erosive esophagitis
• Gastric and duodenal ulcers
• The relief of the symptoms of nausea and vomiting, epigastric sense of fullness, upper abdominal discomfort and regurgitation of gastric contents.

4.2. Dosage and administration:

The recommended dose of PANTOTAJ-DSRcapsules is one capsule daily before breakfast.

4.3. Contraindications:

PANTOTAJ-DSR capsules are contraindicated in the following:

• In patients with a known hypersensitivity to pantoprazole or domperidone or any other inactive ingredients of the tablets.
• Prolactin-releasing pituitary tumour (prolactinoma).
• When stimulation of the gastric motility could be harmful: gastrointestinal haemorrhage, mechanical obstruction or perforation.
• Hepatic and/or renal impairment.
  • Warnings and Precautions:
• Pantoprazole
  Concurrent Gastric Malignancy
  Symptomatic response to therapy with pantoprazole does not preclude the presence of gastric malignancy.
• Atrophic Gastritis
  Atrophic gastritis has been noted occasionally in gastric corpus biopsies from patients treated long-term with pantoprazole, particularly in patients who were Helicobacter pylori
• Cyanocobalamin (Vitamin B12) Deficiency
  Generally, daily treatment with any acid-suppressing medications over a long period of time (e.g., longer than 3 years) may lead to malabsorption of cyanocobalamin (Vitamin B12) caused by hypo- or achlorhydria. Rare reports of cyanocobalamin deficiency occurring with acidsuppressing therapy have been reported in the literature. This diagnosis should be considered if clinical symptoms consistent with cyanocobalamin deficiency are observed.

4. Bone Fracture
   Several published observational studies suggest that PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines.

• Hypomagnesaemia                        
  Hypomagnesaemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least 3 months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias and seizures. In most patients, treatment of hypomagnesaemia required magnesium replacement and discontinuation of the PPI.

For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesaemia (e.g., diuretics), healthcare professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically.

• Tumourigenicity
  Due to the chronic nature of GERD, there may be a potential for prolonged administration of pantoprazole. In long-term rodent studies, pantoprazole was carcinogenic and caused rare types of gastrointestinal tumours. The relevance of these findings to tumour development in humans is unknown.
• Long-term Treatment
  In long-term treatment, especially when exceeding a treatment period of 1 year, patients should be kept under regular surveillance.
• Gastrointestinal Infections Caused by Bacteria
  Pantoprazole, like all PPIs, might be expected to increase the counts of bacteria normally present in the upper gastrointestinal tract. Treatment with pantoprazole may lead to a slightly increased risk of gastrointestinal infections caused by bacteria such as Salmonella and Campylobacter.
• Domperidone
  Patients who find they have post-prandial symptoms that persist, and are having to take domperidone continuously for more than 2 weeks should consult their doctor. Patients who find that their nausea and vomiting persists for more than 48 hours should consult their doctor. Domperidone is not recommended for the treatment of motion sickness. Domperidone is also not recommended for use in patients with underlying cardiac disease without medical supervision.

These tablets contain lactose and may be unsuitable for patients with lactose intolerance, galactosaemia or glucose/galactose malabsorption.

• Use with Potent CYP3A4 Inhibitors
  Co-administration with oral ketoconazole, erythromycin or other potent CYP3A4 inhibitors that prolong the QTc interval should be avoided.
• Cardiac Effects
  Some epidemiological studies showed that domperidone may be associated with an increased risk of serious ventricular arrhythmias or sudden cardiac death. The risk may be higher in patients older than 60 years and at daily doses of more than 30 mg. Domperidone should be used at the lowest effective dose in adults and children.

Use of domperidone and other drugs which prolong QTc intervals requires that caution be exercised in patients who have existing prolongation of cardiac conduction intervals, particularly the QTc, and in patients with significant electrolyte disturbances or underlying cardiac diseases such as congestive heart failure.

• Drug Interactions:

Pantoprazole
Pantoprazole is extensively metabolized in the liver via the CYP450 enzyme system. The main metabolic pathway is demethylation by CYP2C19 and other metabolic pathways include oxidation by CYP3A4.

Interaction studies with drugs also metabolized with these pathways,such ascarbamazepine, diazepam, glibenclamide, nifedipine and an oral contraceptive containing levonorgestrel and ethinyloestradiol, did not reveal clinically significant interactions.

Results from a range of interaction studies demonstrate that pantoprazole does not affect the metabolism of active substances metabolized by CYP1A2 (such as caffeine, theophylline), CYP2C9 (such as piroxicam, diclofenac, naproxen), CYP2D6 (such as metoprolol) and CYP2E1 (such as ethanol), or does not interfere with P-glycoprotein-related absorption of digoxin.

Antacids
There were no interactions with concomitantly administered antacids.

Interference with Antiretroviral Therapy
Concomitant use of atazanavir or nelfinavir with PPIs is not recommended. Co-administration of atazanavir or nelfinavir with PPIs is expected to substantially decrease atazanavir or nelfinavir plasma concentrations and may result in a loss of therapeutic effect and development of drug resistance.

Coumarin Anticoagulants      
There have been postmarketing reports of increased international normalized ratio (INR) and prothrombin time in patients receiving PPIs, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with PPIs and warfarin concomitantly should be monitored for increases in INR and prothrombin time.

Clopidogrel
Concomitant administration of pantoprazole and clopidogrel in healthy subjects had no clinically important effect on exposure to the active metabolite of clopidogrel or clopidogrel-induced platelet inhibition. No dose adjustment of clopidogrel is necessary when administered with an approved dose of pantoprazole.

Drugs for Which Gastric pH Can Affect Bioavailability
Pantoprazole causes long-lasting inhibition of gastric acid secretion. Therefore, 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).

False-Positive Urine Tests for THC
There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs. An alternative confirmatory method should be considered to verify positive results.

Methotrexate
Case reports, published population pharmacokinetic studies, and retrospective analyses suggest that concomitant administration of PPIs and methotrexate (primarily at high doses; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate. However, no formal drug interaction studies of methotrexate with PPIs have been conducted.

Domperidone
The main metabolic pathway of domperidone is through CYP3A4. in vitro data suggest that the concomitant use of drugs that significantly inhibit this enzyme may result in increased plasma levels of domperidone.

Domperidone suppresses the peripheral effects (digestive disorders, nausea and vomiting) of dopaminergic agonists. Since domperidone has gastroprokinetic 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.

Oral Ketoconazole and Oral Erythromycin
Separate in vivo pharmacokinetic/pharmacodynamic interaction studies with oral ketoconazole or oral erythromycin in healthy subjects confirmed a marked inhibition of domperidone’s CYP3A4-mediated first pass metabolism by these drugs. With the combination of oral domperidone 10 mg four times daily and ketoconazole 200 mg twice daily, a mean QTc prolongation of 9.8 msec was seen over the observation period, with changes at individual time points ranging from 1.2 to 17.5 msec. With the combination of domperidone 10 mg four times daily and oral erythromycin 500 mg three times daily, mean QTc over the observation period was prolonged by 9.9 msec, with changes at individual time points ranging from 1.6 to 14.3 msec. Both the C_max and AUC of domperidone at the steady state were increased approximately three-fold in each of these interaction studies. In these studies, domperidone monotherapy at 10 mg given orally four times daily resulted in increases in the mean QTc of 1.6 msec (ketoconazole study) and 2.5 msec (erythromycin study), while ketoconazole monotherapy (200 mg twice daily) and erythromycin monotherapy (500 mg three times daily) led to increases in the QTc of 3.8 and 4.9 msec, respectively, over the observation period.

Anticholinergic Drugs
Anticholinergic drugs may inhibit the anti-dyspeptic effects of domperidone.

Antimuscarinic Agents
Antimuscarinic agents and opoid analgesics may antagonize the effect of domperidone.

Antacids and Antisecretory Agents
Antacids and antisecretory agents lower the oral bioavailability of domperidone. Reduced gastric acidity impairs the absorption of domperidone. Oral bioavailability is reduced by prior administration of cimetidine or sodium carbonate.

4.6.  Pregnancy, lactation and others:

Pregnancy

Pantoprazole
Pregnancy Category B
Reproduction studies have been performed in rats at oral doses up to 88 times the recommended human dose and in rabbits at oral doses up to 16 times the recommended human dose and have revealed no evidence of impaired fertility or harm to the foetus due to pantoprazole. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Domperidone
There are limited post-marketing data on the use of domperidone in pregnant women. Studies in animals have shown reproductive toxicity at maternally toxic doses. Domperidone should only be used during pregnancy when justified by the anticipated therapeutic benefit.

Lactation

Pantoprazole
Pantoprazole and its metabolites are excreted in the milk of rats. Pantoprazole excretion in human milk has been detected in a study of a single nursing mother after a single 40 mg oral dose. The clinical relevance of this finding is not known. Many drugs that are excreted in human milk have a potential for serious adverse reactions in nursing infants. Based on the potential for tumourigenicity shown for pantoprazole in rodent carcinogenicity studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the benefit of the drug to the mother.

Domperidone
Domperidone concentrations in breast milk of lactating women are 10 to 50% of the corresponding plasma concentrations and expected not to exceed 10ng/ml. The total amount of domperidone excreted in human breast milk is expected to be less than 7μg per day at the highest recommended dosing regimen. It is not known whether this is harmful to the newborn. Therefore breast-feeding is not recommended for mothers who are taking domperidone.

Pediatric Use

Pantoprazole
The safety and effectiveness of pantoprazole for shortterm treatment (up to 8 weeks) of erosive esophagitis (EE) associated with GERD have been established in paediatric patients 1 year through 16 years of age. Effectiveness for EE has not been demonstrated in patients less than 1 year of age. In addition, for patients less than 5 years of age, there is no appropriate dosage strength in an age-appropriate formulation available. Therefore, pantoprazole is indicated for the short-term treatment of EE associated with GERD for patients 5 years and older. The safety and effectiveness of pantoprazole for paediatric uses other than EE have not been established.

1 Year through 16 Years of Age
Use of pantoprazole in paediatric patients 1 year through 16 years of age for short-term treatment (up to 8 weeks) of EE associated with GERD is supported by a) extrapolation of results from adequate and well-controlled studies that supported the approval of pantoprazole for treatment of EE associated with GERD in adults; and, b) safety, effectiveness, and pharmacokinetic studies performed in paediatric patients.

Safety of pantoprazole in the treatment of EE associated with GERD in paediatric patients, 1 through 16 years of age, was evaluated in three multicentre, randomized, double-blind, parallel-treatment studies, involving 249 paediatric patients, including 8 with EE (4 patients aged 1 year to 5 years; and 4 patients aged 5 years to 11 years). The children aged 1 year to 5 years with endoscopically diagnosed EE (defined as an endoscopic Hetzel-Dent score ≥2) were treated once daily for 8 weeks with one of two dose levels of pantoprazole (approximating 0.6 mg/kg or 1.2 mg/kg). All 4 of these patients with EE were healed (HetzelDent score of 0 or 1) at 8 weeks. Because EE is uncommon in the paediatric population, predominantly paediatric patients with endoscopically-proven or symptomatic GERD were also included in these studies. Patients were treated with a range of doses of pantoprazole once daily for 8 weeks. Because these paediatric trials had no placebo, active comparator or evidence of a dose response, the trials were inconclusive regarding the clinical benefit of pantoprazole for symptomatic GERD in the paediatric population. The effectiveness of pantoprazole for treating symptomatic GERD in paediatric patients has not been established.

Although the data from the clinical trials support use of pantoprazole for the short-term treatment of EE associated with GERD in paediatric patients, 1 year through 5 years, there is no commercially available dosage formulation appropriate for patients less than 5 years of age.

In a population pharmacokinetic analysis, clearance values in children aged 1 to 5 years old with endoscopically proven GERD had a median value of 2.4 L/h. Following a 1.2 mg/kg equivalent dose (15 mg for ≤12.5 kg and 20 mg for >12.5 to

Neonates to <1 Year of Age    
Pantoprazole was not found to be effective in a multicentre, randomized, double-blind, placebocontrolled, treatment-withdrawal study of 129 paediatric patients,1 through 11 months of age. Patients were enrolled if they had symptomatic GERD based on medical history and had not responded to non-pharmacologic interventions for GERD for 2 weeks. Patients received pantoprazole daily for 4 weeks in an open-label phase; then, patients were randomized in equal proportion to receive pantoprazole treatment or placebo for the subsequent 4 weeks in a double-blind manner. Efficacy was assessed by observing the time from randomization to study discontinuation due to symptom worsening during the 4-week treatment-withdrawal phase. There was no statistically significant difference between pantoprazole and placebo in the rate of discontinuation.

In this trial, the adverse reactions that were reported more commonly (difference of ≥4%) in the treated population compared to the placebo population were elevated creatine kinase, otitis media, rhinitis and laryngitis.

In a population pharmacokinetic analysis, the systemic exposure was higher in patients less than 1 year of age with GERD compared to adults who received a single 40 mg dose (geometric mean AUC was 103% higher in pre-term infants and neonates receiving a single dose of 2.5 mg of pantoprazole, and 23% higher in infants, 1 through 11 months of age, receiving a single dose of approximately 1.2 mg/kg). In these patients, the apparent clearance (CL/F) increased with age (median clearance: 0.6 L/hr, range: 0.03 to 3.2 L/hr).

These doses resulted in pharmacodynamic effects on gastric but not oesophageal pH. Following once-daily dosing of 2.5 mg of pantoprazole in pre-term infants and neonates, there was an increase in the mean gastric pH (from 4.3 at baseline to 5.2 at the steadystate) and in the mean percent time that gastric pH was >4 (from 60% at baseline to 80% at the steadystate). Following once-daily dosing of approximately 1.2 mg/kg of pantoprazole in infants 1 through 11 months of age, there was an increase in the mean gastric pH (from 3.1 at baseline to 4.2 at the steadystate) and in the mean % time that gastric pH was >4 (from 32% at baseline to 60% at the steadystate). However, no significant changes were observed in mean intra-oesophageal pH or % time that oesophageal pH was

Because pantoprazole was not shown to be effective in the randomized, placebo-controlled study in this age group, the use of pantoprazole for treatment of symptomatic GERD in infants less than 1 year of age is not indicated.

Domperidone
Domperidone is not recommended in cases other than that of nausea and vomiting during cancer therapy. There may be an increased risk for extra-pyramidal reactions in young children because of an incompletely developed blood-brain barrier.

Hence, PANTOTAJ-DSR capsules are not recommended in paediatric patients.

Geriatric Use

No special precautions are necessary while recommending PANTOTAJ-DSRcapsules to older patients.

4.7. Undesirable Effects

Pantoprazole

Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Adults
Safety in nine randomized comparative US clinical trials in patients with GERD included 1,473 patients on oral pantoprazole (20 mg or 40 mg), 299 patients on an H₂-receptor antagonist, 46 patients on another PPI, and 82 patients on placebo. The most frequently occurring adverse reactions are listed in Table 1.

Table 1: Adverse Reactions Reported in Clinical Trials of Adult Patients with GERD at a Frequency of >2%:

Pantoprazole(n=1,473)%           Comparators(n=345)%  Placebo(n=82)%

Headache         12.2     12.8     8.5

Diarrhoea         8.8       9.6       4.9

Nausea 7.0       5.2       9.8

Abdominal pain 6.2       4.1

Vomiting          4.3       3.5       2.4

Flatulence        3.9       2.9       3.7

Dizziness         3.0       2.9       1.2

Arthralgia         2.8       1.4       1.2

Additional adverse reactions that were reported for pantoprazole in clinical trials with a frequency of ≤2% are listed below by body system:

Body as a Whole

Allergic reaction, pyrexia, photosensitivity reaction, facial oedema.

General Disorders at Site of Administration

Asthenia, fatigue and malaise, body temperature increased; oedema peripheral

Gastrointestinal

Diarrhoea; nausea/vomiting; abdominal distension and bloating; constipation; dry mouth; abdominal pain and discomfort, hepatitis.

Haematologic

Leucopenia, thrombocytopenia

Metabolic/Nutritional

Elevated creatine kinase, generalized oedema, elevated triglycerides, liver enzymes (transaminases, gamma-GT) and bilirubin elevated, weight changes.

Musculoskeletal

Fracture of the hip, wrist or spine,myalgia, athralgia.

Nervous

Depression (and all aggravations), vertigo.

Skin and Appendages

Rash/exanthema/eruption, urticaria, pruritus, angio-oedema.

Special Senses

Disturbances in vision/blurred vision.

Reproductive System and Breast Disorders

Gynaecomastia.

Paediatric Patients

Safety of pantoprazole in the treatment of erosive esophagitis (EE) associated with GERD was evaluated in paediatric patients aged 1 year through 16 years in three clinical trials. Safety trials involved paediatric patients with EE; however, as EE is uncommon in the paediatric population, 249 paediatric patients with endoscopically-proven or symptomatic GERD were also evaluated. All adult adverse reactions to pantoprazole are considered relevant to paediatric patients. In patients aged 1 year through 16 years, the most commonly reported (>4%) adverse reactions include URI, headache, fever, diarrhoea, vomiting, rash, and abdominal pain.

Additional adverse reactions that were reported for pantoprazole in paediatric patients in clinical trials with a frequency of ≤4% are listed below by body system:

Body as a Whole

Allergic reaction, facial oedema.

Gastrointestinal

Constipation, flatulence, nausea.

Metabolic/Nutritional

Elevated triglycerides, elevated liver enzymes, elevated creatine kinase.

Musculoskeletal

Arthralgia, myalgia.

Nervous

Dizziness, vertigo.

Skin and Appendages

Urticaria.

The following adverse reactions seen in adults in clinical trials were not reported in paediatric patients in clinical trials, but are considered relevant to paediatric patients: photosensitivity reaction, dry mouth, hepatitis, thrombocytopenia, generalized oedema, depression, pruritus, leucopenia, and blurred vision.

Zollinger-Ellison Syndrome

In clinical studies of Zollinger-Ellison syndrome, adverse reactions reported in 35 patients taking pantoprazole 80 mg/day to 240 mg/day for up to 2 years were similar to those reported in adult patients with GERD.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of pantoprazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

These adverse reactions are listed below by body system:

General Disorders and  Administration  Conditions:  Asthenia,  fatigue,  malaise. Hepatobiliary Disorders: Hepatocellular damage, leading to jaundice and hepatic failure. Immune System Disorders:Anaphylaxis (including anaphylactic shock).

Investigations: Weight changes.

Metabolism and Nutritional Disorders:Hyponatraemia, hypomagnesaemia.

Musculoskeletal Disorders:Rhabdomyolysis, bone  fracture. Psychiatric Disorders:Hallucination, confusion, insomnia, somnolence. Renal and Urinary Disorders: Interstitial nephritis.

Skin and Subcutaneous Tissue Disorders: Severe dermatologic reactions (some fatal), including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis ( some fatal), and angio-oedema (Quincke’s oedema).

Domperidone

The safety of domperidone was evaluated in 1,275 patients with dyspepsia, GERD, irritable bowel syndrome (IBS), nausea and vomiting or other related conditions in 31 double-blind, placebo-controlled studies.

Studies in diabetic gastroparesis or symptoms secondary to chemotherapy or Parkinsonism were excluded. The following terms and frequencies are applied: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to

<1/100), rare (≥1/10,000 to <1/1,000), and very rare (<1/10,000).

Where frequency cannot be estimated from clinical trials data, it is recorded as “Not known”.

4.8 Overdosage

Pantoprazole
Experience in patients taking very high doses of pantoprazole (>240 mg) is limited. Spontaneous postmarketing reports of overdose are generally within the known safety profile of pantoprazole.

Pantoprazole is not removed by haemodialysis. In case of overdosage, treatment should be symptomatic and supportive.

Single oral doses of pantoprazole at 709 mg/kg, 798 mg/kg and 887 mg/kg were lethal to mice, rats and dogs, respectively. The symptoms of acute toxicity were hypoactivity, ataxia, hunched sitting, limb-splay, lateral position, segregation, absence of ear reflex, and tremor.

Domperidone
Symptoms: Overdose has been reported primarily in infants and children. Symptoms of overdosage may include agitation, altered consciousness, convulsion, disorientation, somnolence and extra-pyramidal reactions.

Treatment: There is no specific antidote to domperidone; but, in the event of overdose, gastric lavage as well as the administration of activated charcoal may be useful. Close medical supervision and supportive therapy are recommended. Anticholinergic, anti-Parkinson drugs may be helpful in controlling the extra-pyramidal reactions.

 5. PHARMACOLOGICAL PROPERTIES:

5.1. Pharmacodynamics

Pantoprazole
Mechanism of Action

Pantoprazole is a substituted benzimidazole, which inhibits the secretion of hydrochloric acid in the stomach by specific blockade of the proton pumps of the parietal cells.

Pantoprazole is converted to its active form in the acidic environment in the parietal cells where it inhibits the H⁺,K⁺-ATPase enzyme, i.e., the final stage in the production of hydrochloric acid in the stomach. The inhibition is dose-dependent and affects both basal and stimulated acid secretion. In most patients, freedom from symptoms is achieved within 2 weeks. As with other proton-pump inhibitors (PPIs) and H₂-receptor inhibitors, treatment with pantoprazole reduces acidity in the stomach and thereby increases gastrin in proportion to the reduction in acidity. The increase in gastrin is reversible. Since pantoprazole binds to the enzyme distal to the cell receptor level, it can inhibit hydrochloric acid secretion independently of the stimulation by other substances (acetylcholine, histamine, and gastrin).

Pantoprazole has the same effect whether administered orally or intravenously.

The fasting gastrin values increase under pantoprazole. In short-term use, in most cases, they do not exceed the upper limit of normal. During long-term treatment, gastrin levels double in most cases. An excessive increase, however, occurs only in isolated cases. As a result, a mild-to-moderate increase in the number of specific endocrine (ECL) cells in the stomach is observed in a minority of cases during long-term treatment (simple to adenomatoid hyperplasia). However, according to the studies conducted so far, the formation of carcinoid precursors (atypical hyperplasia) or gastric carcinoids as were found in animal experiments have not been observed in humans.

An influence of a long-term treatment with pantoprazole exceeding 1 year cannot be completely ruled out on endocrine parameters of the thyroid, according to results in animal studies.

Domperidone
Mechanism of Action           
Domperidone is a dopamine antagonist with anti-emetic properties. Domperidone does not readily cross the blood-brain barrier. In domperidone users, especially adults, extra-pyramidal side effects are very rare, but domperidone promotes the release of prolactin from the pituitary. Its anti-emetic effect may be due to a combination of peripheral (gastrokinetic) effects and antagonism of dopamine receptors in the chemoreceptor trigger zone, which lies outside the blood-brain barrier in the area postrema. Animal studies, together with the low concentrations found in the brain, indicate a predominantly peripheral effect of domperidone on dopamine receptors.

Studies in humans have shown oral domperidone to increase lower oesophageal pressure, improve antroduodenal motility and accelerate gastric emptying. There is no effect on gastric secretion.

5.2. Pharmacokinetics

Pantoprazole
Absorption
Pantoprazole is rapidly absorbed and the maximal plasma concentration is achieved even after one single 40 mg oral dose. On average at about 2.5 h p.a., the maximum serum concentrations of about 2-3 μg/ml are achieved and these values remain constant after multiple administration.

Pharmacokinetics does not vary after single or repeated administration. In the dose range of 10-80 mg, the plasma kinetics of pantoprazole is linear after both oral and intravenous administration.

The absolute bioavailability from the tablet was found to be about 77%. Concomitant intake of food had no influence on the AUC, maximum serum concentrations and, thus, bioavailability. Only the variability of the lag time will be increased by concomitant food intake.

Distribution
Pantoprazole’s serum protein binding is about 98%. Volume of distribution is about 0.15 l/kg.

Elimination
Pantoprazole is almost exclusively metabolized in the liver. The main metabolic pathway is demethylation by cytochrome (CY) P2C19, with subsequent sulphate conjugation; other metabolic pathways include oxidation by CYP3A4. Terminal half-life is about 1 hour and clearance is about 0.1 l/h/kg. There were a few cases of subjects with delayed elimination. Because of the specific binding of pantoprazole to the proton pumps of the parietal cell, the elimination half-life does not correlate with the much longer duration of action (inhibition of acid secretion).

Renal elimination represents the major route of excretion (about 80%) for the metabolites of pantoprazole; the rest is excreted with the faeces. The main metabolite in both the serum and urine is desmethylpantoprazole, which is conjugated with sulphate. The half-life of the main metabolite (about 1.5 hours) is not much longer than that of pantoprazole.

Special Populations
Renal Impairment
No dose reduction is recommended when pantoprazole is administered to patients with impaired renal function (including dialysis patients). As with healthy subjects, pantoprazole’s half-life is short. Only very small amounts of pantoprazole are dialysed. Although the main metabolite has a moderately delayed half-life (2-3 hours), excretion is still rapid and, thus, accumulation does not occur.

Hepatic Impairment
Although for patients with liver cirrhosis (Child-Pugh classes A and B), the half-life values increased to between 7 and 9 hours and the AUC values increased by a factor of 5 to 7, the maximum serum concentration only increased slightly by a factor of 1.5, compared with healthy subjects.

A slight increase in the AUC and C_max in elderly volunteers, compared with younger counterparts, is also not clinically relevant.

Paediatric
Following administration of single oral doses of 20 mg or 40 mg pantoprazole to children aged 5 to 16 years, the AUC and C_max were in the range of corresponding values in adults.

Following administration of single intravenous doses of 0.8 mg or 1.6 mg/kg pantoprazole to children aged 2 to 16 years, there was no significant association between pantoprazole clearance and age or weight. The AUC and volume of distribution were in accordance with data from adults.

Domperidone
Absorption
In fasting subjects, domperidone is rapidly absorbed after oral administration, with peak plasma concentrations at 30 to 60 minutes. The low absolute bioavailability of oral domperidone (approximately 15%) is due to an extensive first-pass metabolism in the gut wall and liver. Although domperidone’s bioavailability is enhanced in normal subjects when taken after a meal, patients with gastrointestinal complaints should take domperidone 15-30 minutes before a meal. Reduced gastric acidity impairs the absorption of domperidone. Oral bioavailability is decreased by prior concomitant administration of cimetidine and sodium bicarbonate. The time of peak absorption is slightly delayed and the AUC somewhat increased when domperidone is taken after a meal.

Distribution
Oral domperidone does not appear to accumulate or to induce its own metabolism; a peak plasma level after 90 minutes of 21 ng/ml after 2 weeks of oral administration of 30 mg per day was almost the same as that of 18 ng/ml after the first dose. Domperidone is 91-93% bound to plasma proteins. Distribution studies with radiolabelled drug in animals have shown wide tissue distribution, but low brain concentration. Small amounts of drug cross the placenta in rats

Metabolism
Domperidone undergoes rapid and extensive hepatic metabolism by hydroxylation and N-dealkylation. in vitro metabolism experiments with diagnostic inhibitors revealed that CYP3A4 is a major form of CYP450 involved in the N-dealkylation of domperidone, whereas CYP3A4, CYP1A2 and CYP2E1 are involved in domperidone aromatic hydroxylation.

Excretion
Urinary and faecal excretions amount to 31% and 66% of the oral dose, respectively. The proportion of the drug excreted unchanged is small (10% of faecal excretion and approximately 1% of urinary excretion). The plasma half-life after a single oral dose is 7-9 hours in healthy subjects, but is prolonged in patients with severe renal impairment.

Domperidone usually is administered as a 10 mg dose, two to three times a day before meals. In this combination, 10 mg domperidone is provided in an immediate-release formulation whereas 20 mg is in a sustained-release formulation. Bioavailability studies conducted on human volunteers shows a biphasic release profile of domperidone, which allows once-daily administration. This improves patient compliance without compromising on the efficacy.

6. PHARMACEUTICAL PARTICULARS:
   • Incomaptibilities:

None stated.

• Shelf life:

3 years

• Storage and handling instructions:

Store in cool and dry place.

• Packaging information:

Blister pack

7. Manufactured in India By:
TAJ PHARMACEUTICALS LTD.
29, Xcelon Industrial Park-1,
Behind Intas Pharmaceuticals,
At & Po Vasna – Chacharwadi,
Tal- Sanand, Dist- Ahmedabad-382213,
Gujarat, India