Pariet Pharmacy 10mg Gastro-Resistant Tablets
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Pariet Pharmacy 10mg gastro-resistant tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
10mg rabeprazole sodium, equivalent to 9.42mg rabeprazole For a full list of excipients, see 6.1.
3 PHARMACEUTICAL FORM
Gastro-resistant tablet.
10mg: Pink, film coated biconvex tablet with 'E 241' printed on one side.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Short-term symptomatic treatment of gastro-oesophageal reflux - like symptoms (e.g. heartburn) in patients aged 18 and over.
4.2 Posology and method of administration
Adults/elderly:
The dosage is 10mg once daily in patients with heartburn. If symptomatic relief has not been achieved within two weeks or if continuous treatment for more than four weeks is required, then the patient should be referred to their doctor.
It might be necessary to take the tablets for 2-3 consecutive days to achieve improvement of symptoms.
PARIET PHARMACY tablets should ideally be taken in the morning, before eating; and although neither the time of day nor food intake was shown to have any effect on rabeprazole sodium activity, this regimen will facilitate treatment compliance.
Patients should be cautioned that the PARIET PHARMACY tablets should not be chewed or crushed, but should be swallowed whole.
Renal and hepatic impairment: No dosage adjustment is necessary for patients with renal or hepatic impairment.
See section 4.4 Special Warnings and Precautions for Use of PARIET PHARMACY in the treatment of patients with severe hepatic impairment.
Children and adolescents under 18 years.
PARIET PHARMACY is not recommended for use in children and adolescents under 18 years, as there is no experience of its use in this group.
4.3 Contraindications
PARIET PHARMACY is contra-indicated in patients with known hypersensitivity to rabeprazole sodium, or to any excipient used in the formulation.
PARIET PHARMACY is contra-indicated in pregnancy and during breast feeding (see section 4.6).
4.4 Special warnings and precautions for use
Special warnings and precautions for patients taking non-prescription indigestion or heartburn remedies:
Patients should be referred to their doctor if:
• They have had to take an indigestion or heartburn remedy continuously for 4 or more weeks in order to control their symptoms
• They are aged over 55 years with new or recently changed symptoms
• If they have unintentional weight loss, anaemia, gastrointestinal bleeding, dysphagia, pain on swallowing, persistent vomiting or vomiting with blood, epigastric mass, previous gastric ulcer or surgery, jaundice or any other significant medical condition (including hepatic and renal impairment).
Patients with long-term recurrent symptoms of indigestion or heartburn should see their doctor at regular intervals. Patients aged over 55 years taking any “over the counter” (OTC, non-prescription) indigestion or heartburn remedy on a daily basis should inform their pharmacist or doctor.
Patients should not take another “acid suppressor” e.g. H2 antagonist or proton pump inhibitor concomitantly.
Patients should consult their doctor before taking this product if they are due to have an endoscopy.
Patients should avoid use prior to a urea breath test.
The Patient Information Leaflet will contain advice that the tablets will not provide immediate relief of symptoms.
A risk of cross-hypersensitivity reactions with other proton pump inhibitor or substituted benzimidazoles cannot be excluded.
Decreased gastric acidity, due to any means - including proton- pump inhibitors - increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with acid reducing drugs leads to a slightly increased risk of gastrointestinal infections such as salmonella, campylobacter or Clostridium difficile.
Patients should be cautioned that PARIET tablets should not be chewed or crushed, but should be swallowed whole.
No evidence of significant drug related safety problems was seen in a study of patients with mild to moderate hepatic impairment versus normal age and sex matched controls. However because there are no clinical data on the use of PARIET PHARMACY in the treatment of patients with severe hepatic dysfunction and patients should consult their doctor prior to initiating use. It is advised to exercise caution when treatment with PARIET PHARMACY is first initiated in such patients.
Hepatic enzyme abnormalities have been seen in clinical trials and have also been reported since market authorisation. In the majority of cases where an alternative aetiology cannot be identified, the events were uncomplicated and resolved on discontinuation of rabeprazole.
There have been post marketing reports of blood dyscrasias (thrombocytopenia and neutropenia). In the majority of cases where an alternative aetiology cannot be identified, the events were uncomplicated and resolved on discontinuation of rabeprazole.
PARIET PHARMACY is not recommended for use in children, as there is no experience of its use in this group.
Co-administration of atazanavir with PARIET PHARMACY is not recommended (see section 4.5).
4.5 Interaction with other medicinal products and other forms of interaction
As with many indigestion and heartburn remedies, rabeprazole may interact with other medications. Therefore, patients who are also taking other medications should first consult with either their pharmacist or doctor before taking rabeprazole.
Rabeprazole sodium produces a profound and long lasting inhibition of gastric acid secretion. An interaction with compounds whose absorption is pH dependent may occur. Co-administration of rabeprazole sodium with ketoconazole or itraconazole may result in a significant decrease in antifungal plasma levels.
In clinical trials, antacids were used concomitantly with the administration of rabeprazole and, in a specific drug-drug interaction study, no interaction with liquid antacids was observed.
Co-administration of atazanavir 300mg/ritonavir 100mg with omeprazole (40mg once daily) or atazanavir 400mg with lansoprazole (60mg once daily) to healthy volunteers resulted in a substantial reduction in atazanavir exposure. The absorption of atazanavir is pH dependent. Although not studied, similar results are expected with other proton pump inhibitors. Therefore PPIs, including rabeprazole, should not be co-administered with atazanavir (see Section 4.4).
4.6 Pregnancy and lactation
Pregnancy:
There are no data on the safety of rabeprazole in human pregnancy. Reproduction studies performed in rats and rabbits have revealed no evidence of impaired fertility or harm to the foetus due to rabeprazole sodium, although low foeto-placental transfer occurs in rats. PARIET PHARMACY is contraindicated during pregnancy.
Lactation:
It is not known whether rabeprazole sodium is excreted in human breast milk. No studies in lactating women have been performed. Rabeprazole sodium is however excreted in rat mammary secretions. Therefore PARIET PHARMACY should not be used during breast feeding.
Effects on ability to drive and use machines
4.7
Based on the pharmacodynamic properties and the adverse events profile, it is unlikely that PARIET PHARMACY would cause an impairment of driving performance or compromise the ability to use machinery. If, however, alertness is impaired due to somnolence, it is recommended that driving and operating complex machinery be avoided.
4.8 Undesirable effects
The most commonly reported adverse drug reactions during controlled clinical trials with rabeprazole were headache, diarrhoea, abdominal pain, asthenia, flatulence, rash and dry mouth. The majority of adverse events experienced during clinical studies were mild or moderate in severity, and transient in nature.
The following adverse events have been reported from clinical trial and post-marketed experience.
Frequencies are defined as: common ( > 1/100, < 1/10), uncommon ( >
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1/1,000, < 1/100), rare ( >1/10,000, <1/1 |
000) and very rare ( <1/10,000). | ||||
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System Organ Class |
Common |
Uncommon |
Rare |
Very Rare |
Not Known |
|
Infections and infestations |
Infection | ||||
|
Blood and the lymphatic system disorders |
Neutropenia Leucopenia Thrombocytopenia Leucocytosis | ||||
|
Immune system disorders |
Hypersensitivity ’ | ||||
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Metabolism and nutrition disorders |
Anorexia |
Hyponatremia | |||
|
Psychiatric disorders |
Insomnia |
Nervousness |
Depression |
Confusion | |
|
Nervous system disorders |
Headache Dizziness |
Somnolence | |||
|
Eye disorders |
Visual disturbance | ||||
|
Vascular Disorders |
Peripheral Oedema | ||||
|
Respiratory, thoracic and mediastinal |
Cough Pharyngitis Rhinitis |
Bronchitis Sinusitis | |||
|
System Organ Class |
Common |
Uncommon |
Rare |
Very Rare |
Not Known |
|
disorders | |||||
|
Gastrointestinal disorders |
Diarrhoea Vomiting Nausea Abdominal pain Constipation Flatulence |
Dyspepsia Dry mouth Eructation |
Gastritis Stomatitis Taste disturbance | ||
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Hepato-biliary disorders |
Hepatitis Jaundice Hepatic encephalopathy3 | ||||
|
Skin and subcutaneous tissue disorders |
Rash Erythema2 |
Pruritus Sweating 2 Bullous reactions |
Erythema multiforme, toxic epidermal necrolysis (TEN), Stevens- Johnson syndrome (SJS) | ||
|
Musculoskeletal connective tissue and bone disorders |
Nonspecific pain Back pain |
Myalgia Leg cramps Arthralgia | |||
|
Renal and urinary disorders |
Urinary tract infection |
Interstitial nephritis | |||
|
Reproductive system and breast disorders |
Gynaecomastia | ||||
|
General disorders and administration site conditions |
Asthenia Influenza like illness |
Chest pain Chills Pyrexia | |||
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Investigations |
Increased hepatic enzymes3 |
Weight increased |
1 Includes facial swelling, hypotension and dyspnoea
2 Erythema, bullous reactions and hypersensitivity reactions have usually resolved after discontinuation of therapy.
3 Rare reports of hepatic encephalopathy have been received in patients with underlying cirrhosis. In treatment of patients with severe hepatic dysfunction the prescriber is advised to exercise caution when treatment with PARIET is first initiated in such patients (see section 4.4).
4.9 Overdose
Experience to date with deliberate or accidental overdose is limited. The maximum established exposure has not exceeded 60mg twice daily, or 160mg once daily. Effects are generally minimal, representative of the known adverse event profile and reversible without further medical intervention. No specific antidote is known. Rabeprazole sodium is extensively protein bound and is, therefore, not dialysable. As in any case of overdose, treatment should be symptomatic and general supportive measures should be utilised.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Alimentary tract and metabolism, Drugs for peptic ulcer and gastro-oesophageal reflux disease (GORD), proton pump inhibitors,
ATC code: A02B C04
Mechanism of Action: Rabeprazole sodium belongs to the class of anti-secretory compounds, the substituted benzimidazoles, that do not exhibit anticholinergic or H2 histamine antagonist properties, but suppress gastric acid secretion by the specific inhibition of the H+/K+-ATPase enzyme (the acid or proton pump). The effect is dose-related and leads to inhibition of both basal and stimulated acid secretion irrespective of the stimulus. Animal studies indicate that after administration, rabeprazole sodium rapidly disappears from both the plasma and gastric mucosa. As a weak base, rabeprazole is rapidly absorbed following all doses and is concentrated in the acid environment of the parietal cells. Rabeprazole is converted to the active sulphenamide form through protonation and it subsequently reacts with the available cysteines on the proton pump.
Anti-secretory Activity: In a study involving 24 healthy volunteers following administration of 10 and 20 mg rabeprazole for 7 days, the percent of time the gastric pH remained above 3 was 72% with 10 mg and 73% with 20 mg rabeprazole administration. In the same study oral administration of 10 mg or 20 mg rabeprazole resulted in an approximately 4 and 5-fold decrease in intragastric acidity (measured as 24-h median integrated acidity) respectively, relative to placebo.
Serum Gastrin Effects: In clinical studies patients were treated once daily with 10 or 20mg rabeprazole sodium, for up to 43 months duration. Serum gastrin levels increased during the first 2 to 8 weeks reflecting the inhibitory effects on acid secretion and remained stable while treatment was continued. Gastrin values returned to pre-treatment levels, usually within 1 to 2 weeks after discontinuation of therapy.
Human gastric biopsy specimens from the antrum and the fundus from over 500 patients receiving rabeprazole or comparator treatment for up to 8 weeks have not detected changes in ECL cell histology, degree of gastritis, incidence of atrophic gastritis, intestinal metaplasia or distribution of H. pylori infection. In over 250 patients followed for 36 months of continuous therapy, no significant change in findings present at baseline was observed.
Other Effects: Systemic effects of rabeprazole sodium in the CNS, cardiovascular and respiratory systems have not been found to date. Rabeprazole sodium, given in oral doses of 20mg for 2 weeks, had no effect on thyroid function, carbohydrate metabolism, or circulating levels of parathyroid hormone, cortisol, oestrogen, testosterone, prolactin, cholecystokinin, secretin, glucagon, follicle stimulating hormone (FSH), luteinising hormone (LH), renin, aldosterone or somatotrophic hormone.
Studies in healthy subjects have shown that rabeprazole sodium does not have clinically significant interactions with amoxicillin. Rabeprazole does not adversely influence plasma concentrations of amoxicillin or clarithromycin when coadministered for the purpose of eradicating upper gastrointestinal H. pylori infection.
5.2 Pharmacokinetic properties
Absorption: PARIET PHARMACY is an enteric-coated (gastro-resistant) tablet formulation of rabeprazole sodium. This presentation is necessary because rabeprazole is acid-labile. Absorption of rabeprazole therefore begins only after the tablet leaves the stomach. Absorption is rapid, with peak plasma levels of rabeprazole occurring approximately 3.5 hours after a 10 mg or 20mg dose. Peak plasma concentrations (C max) of rabeprazole and AUC are linear over the dose range of 10mg to 40mg. Absolute bioavailability of an oral 20mg dose (compared to intravenous administration) is about 52% due in large part to pre-systemic metabolism. Additionally the bioavailability does not appear to increase with repeat administration. In healthy subjects the plasma half-life is approximately one hour (range 0.7 to 1.5 hours), and the total body clearance is estimated to be 283 ± 98 ml/min. There was no clinically relevant interaction with food. Neither food nor the time of day of administration of the treatment, affect the absorption of rabeprazole sodium.
Distribution: Rabeprazole is approximately 97% bound to human plasma proteins.
Metabolism and excretion: Rabeprazole sodium, as is the case with other members of the proton pump inhibitor (PPI) class of compounds, is metabolised through the cytochrome P450 (CYP450) hepatic drug metabolising system. In vitro studies with human liver microsomes indicated that rabeprazole sodium is metabolised by isoenzymes of CYP450 (CYP2C19 and CYP3A4). In these studies, at expected human plasma concentrations rabeprazole neither induces nor inhibits CYP3A4; and although in vitro studies may not always be predictive of in vivo status these findings indicate that no interaction is expected between rabeprazole and cyclosporin. In humans the thioether (M1) and carboxylic acid (M6) are the main plasma metabolites with the sulphone (M2), desmethyl-thioether (M4) and mercapturic acid conjugate (M5) minor metabolites observed at lower levels.
Only the desmethyl metabolite (M3) has a small amount of anti-secretory activity, but it is not present in plasma.
Following a single 20mg 14C labelled oral dose of rabeprazole sodium, no unchanged drug was excreted in the urine. Approximately 90% of the dose was eliminated in urine mainly as the two metabolites: a mercapturic acid conjugate (M5) and a carboxylic acid (M6), plus two unknown metabolites. The remainder of the dose was recovered in faeces.
Gender: Data from two pharmacokinetic studies involving 42 male and 28 female healthy subjects who were administered a single dose of 10 mg rabeprazole tablets, show that female subjects had a 61.5 % higher systemic exposure (AUC0-t) than males and a 48.8 % higher peak plasma concentration of rabeprazole than males. However, clinical studies suggest no difference in safety and efficacy based on gender.
Renal dysfunction: In patients with stable, end-stage, renal failure requiring maintenance haemodialysis (creatinine clearance ^ 5ml/min/1.73m ), the disposition of rabeprazole was very similar to that in healthy volunteers. The AUC and the Cmax in these patients was about 35% lower than the corresponding parameters in healthy volunteers. The mean half-life of rabeprazole was 0.82 hours in healthy volunteers, 0.95 hours in patients during haemodialysis and 3.6 hours post dialysis. The clearance of the drug in patients with renal disease requiring maintenance haemodialysis was approximately twice that in healthy volunteers.
Hepatic dysfunction: Following a single 20mg dose of rabeprazole to patients with chronic mild to moderate hepatic impairment the AUC doubled and there was a 2-3 fold increase in half-life of rabeprazole compared to the healthy volunteers. However, following a 20mg dose daily for 7 days the AUC had increased to only 1.5-fold and the Cmax to only 1.2-fold. The half-life of rabeprazole in patients with hepatic impairment was 12.3 hours compared to 2.1 hours in healthy volunteers. The pharmacodynamic response (gastric pH control) in the two groups was clinically comparable.
Elderly: Elimination of rabeprazole was somewhat decreased in the elderly. Following 7 days of daily dosing with 20mg of rabeprazole sodium, the AUC approximately doubled, the Cmax increased by 60% and t/ increased by approximately 30% as compared to young healthy volunteers. However there was no evidence of rabeprazole accumulation.
CYP2C19 Polymorphism: Following a 20mg daily dose of rabeprazole for 7 days, CYP2C19 slow metabolisers, had AUC and t/ which were approximately 1.9 and 1.6 times the corresponding parameters in extensive metabolisers whilst Cmax had increased by only 40%.
Preclinical safety data
5.3
Non-clinical effects were observed only at exposures sufficiently in excess of the maximum human exposure that make concerns for human safety negligible in respect of animal data.
Studies on mutagenicity gave equivocal results. Tests in mouse lymphoma cell line were positive, but in vivo micronucleus and in vivo and in vitro DNA repair tests were negative. Carcinogenicity studies revealed no special hazard for humans.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Core tablet:
Mannitol Magnesium oxide Low-substituted hyprolose,
Hyprolose Magnesium stearate
Undercoating:
Ethylcellulose,
Magnesium oxide
Enteric coating:
Hypromellose phthalate Diacetylated monoglycerides Talc
Titanium dioxide (E171)
Red iron oxide (E172)
Carnauba wax
Printing ink - PARIET Pharmacy 10mg:
White Shellac
Black iron oxide (E172)
Dehydrated Ethyl Alcohol 1-Butanol.
6.2
Incompatibilities
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Do not store above 25°C. Do not refrigerate
6.5 Nature and contents of container
Blister strips (aluminium/aluminium)
Pack size: 14 tablets
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Eisai Ltd., European Knowledge Centre,
Hatfield, Hertfordshire AL10 9SN, United Kingdom.
MARKETING AUTHORISATION NUMBER(S)
8
PL 10555/0028
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
25/01/2012
10 DATE OF REVISION OF THE TEXT
25/01/2012