Pariet Pharmacy 10mg Gastro-Resistant Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
PARIET PHARMACY 10 mg gastro-resistant tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each gastro-resistant tablet contains 10 mg rabeprazole sodium, equivalent to 9.42 mg rabeprazole
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Gastro-resistant tablet
PARIET PHARMACY 10 mg gastro - resistant tablets are pink, film coated biconvex tablets embossed with 'E 241' printed on one side.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
PARIET PHARMACY tablets are indicated for the symptomatic treatment of gastro-oesophageal reflux - like symptoms (e.g. heartburn) in patients aged 18 and over.
4.2 Posology and method of administration
Posology
Adults/Elderly:
The initial dosage is 10 mg once daily in patients with heartburn. If symptom control has not been achieved within four weeks, the patient should be further investigated. Once symptoms have resolved, subsequent symptom control can be achieved using an on-demand regimen taking
10 mg once daily when needed. 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 the use of PARIET PHARMACY tablets in the treatment of patients with severe hepatic impairment.
Paediatric population
PARIET PHARMACY tablets are not recommended for use in children and adolescents under 18 years, as there is no experience of its use in this group.
Method of administration
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.
4.3 Contraindications
Hypersensitivity to rabeprazole sodium, or to any of the excipients listed in section 6.1. PARIET PHARMACY is contra-indicated in pregnancy and during breast feeding.
4.4 Special warnings and precautions for use
Gastrointestinal Conditions: Special warnings and precautions for patients taking nonprescription 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).
Symptomatic response to therapy with rabeprazole sodium does not preclude the presence of gastric or oesophageal malignancy, therefore the possibility of malignancy should be excluded prior to commencing treatment with PARIET PHARMACY.
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 concomitantly.
Patients should consult their doctor before taking this product if they are due to have an endoscopy.
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.
Patients should be cautioned that PARIET PHARMACY tablets should not be chewed or crushed, but should be swallowed whole.
Hepatic Impairment: 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.
Co-administration of atazanavir with PARIET PHARMACY is not recommended (see section 4.5).
Hypomagnesaemia
Severe hypomagnesaemia has been reported in patients treated with proton pump inhibitors like rabeprazole sodium for at least three months, and in most cases for a year. Serious manifestations of hypomagnesaemia such as fatigue, tetany, delirium, convulsions, dizziness and ventricular arrhythmia can occur but they may begin insidiously and be overlooked. In most affected patients, hypomagnesaemia improved after magnesium replacement and discontinuation of the PPI.
For patients expected to be on prolonged treatment or who take proton pump inhibitors with digoxin or drugs that may cause hypomagnesaemia (e.g., diuretics), health care professionals should consider measuring magnesium levels before starting proton pump inhibitor treatment and periodically during treatment.
Influence on vitamin B12 absorption
Rabeprazole sodium, as all acid-blocking medicines, may reduce the absorption of vitamin B12 (cyanocobalamin) due to hypo- or a- chlorhydria. This should be considered in patients with reduced body stores or risk factors for reduced vitamin B12 absorption on long-term therapy or if respective clinical symptoms are observed.
Subacute cutaneous lupus erythematosus (SCLE)
Proton pump inhibitors are associated with very infrequent cases of SCLE. If lesions occur, especially in sun-exposed areas of the skin, and if accompanied by arthralgia, the patient should seek medical help promptly and the health care professional should consider stopping PARIET. SCLE after previous treatment with a proton pump inhibitor may increase the risk of SCLE with other proton pump inhibitors.
Paediatric population
PARIET PHARMACY is not recommended for use in children, as there is no experience of its use in this group.
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 300 mg/ritonavir 100 mg with omeprazole (40 mg once daily) or atazanavir 400 mg with lansoprazole (60 mg 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).
Methotrexate
Concomitant use of PPIs with methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration, a temporary withdrawal of the PPI may be considered.
4.6 Fertility, 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.
Breast-feeding
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.
4.7 Effects on ability to drive and use machines
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 to < 1/10), uncommon (> 1/1,000 to < 1/100), rare (> 1/10,000 to < 1/1000); very rare (< 1/10,000) and not known (cannot be estimated from the available data).
|
System Organ Class |
Common |
Uncommon |
Rare |
Very Rare |
Not Known |
|
Infections and infestations |
Infection | ||||
|
Blood and the lymphatic system disorders |
Neutropenia Leucopenia Thrombocyto penia Leucocytosis | ||||
|
Immune system disorders |
Hypersensitiv ity, | ||||
|
Metabolism and nutrition disorders |
Anorexia |
Hyponatremia Hypomagnesa emia | |||
|
Psychiatric disorders |
Insomnia |
Nervousness |
Depression |
Confusion | |
|
Nervous system disorders |
Headache Dizziness |
Somnolence | |||
|
Eye disorders |
Visual disturbance | ||||
|
Vascular Disorders |
Peripheral Oedema | ||||
|
Respiratory, thoracic and |
Cough |
Bronchitis |
|
mediastinal disorders |
Pharyngitis Rhinitis |
Sinusitis | |||
|
Gastrointestinal disorders |
Diarrhoea Vomiting Nausea Abdomin al pain Constipation Flatulence |
Dyspepsia Dry mouth Eructation |
Gastritis Stomatitis Taste disturbance | ||
|
Hepato-biliary disorders |
Hepatitis Jaundice Hepatic encephalopath 3 y | ||||
|
Skin and subcutaneous tissue disorders |
Rash 2 Erythema |
Pruritus Sweating Bullous reactions2 |
Erythema multiforme, toxic epidermal necrolysis (TEN), Stevens- Johnson syndrome (SJS) |
Subacute cutaneous lupus erythematosu s4 | |
|
Musculoskeletal connective tissue and bone disorders |
Non-specific pain Back pain |
Myalgia Leg cramps Arthralgia | |||
|
Renal and urinary disorders |
Urinary tract infection |
Interstitial nephritis | |||
|
Reproductive system and breast disorders |
Gynaecomasti a | ||||
|
General disorders and administration site conditions |
Asthenia Influenza like illness |
Chest pain Chills Pyrexia | |||
|
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 PHARMACY is first initiated in such patients (see section 4.4).
4
See Special warnings and precautions for use (4.4)
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal
product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
4.9 Overdose
Experience to date with deliberate or accidental overdose is limited. The maximum established exposure has not exceeded 60 mg twice daily, or 160 mg 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: After oral administration of a 20 mg dose of rabeprazole sodium the onset of the anti-secretory effect occurs within one hour, with the maximum effect occurring within two to four hours. Inhibition of basal and food stimulated acid secretion 23 hours after the first dose of rabeprazole sodium are 69% and 82% respectively and the duration of inhibition lasts up to 48 hours. The inhibitory effect of rabeprazole sodium on acid secretion increases slightly with repeated once-daily dosing, achieving steady state inhibition after three days. When the drug is discontinued, secretory activity normalises over 2 to 3 days.
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 20 mg 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 20 mg dose. Peak plasma concentrations (C max) of rabeprazole and AUC are linear over the dose range of 10 mg to 40 mg. Absolute bioavailability of an oral 20 mg 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.
Biotransformation/Elimination
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:
Adjusted for body mass and height, there are no significant gender differences in pharmacokinetic parameters following a single 20 mg dose of rabeprazole.
Renal dysfunction:
In patients with stable, end-stage, renal failure requiring maintenance haemodialysis (creatinine clearance 5 ml/min/1.73 m ), 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 20 mg 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 20 mg 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 20 mg 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%.
5.3 Preclinical safety data
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
Tablet core
Mannitol
Magnesium oxide
Low-substituted hyprolose
Hyprolose
Magnesium stearate
Film Coating Ethylcellulose,
Magnesium oxide Hypromellose phthalate Diacetylated monoglycerides Talc
Titanium dioxide (E171)
Red iron oxide (E172)
Carnauba wax White Shellac Black iron oxide (E172)
Dehydrated Ethyl Alcohol,
1-Butanol
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 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
8 MARKETING AUTHORISATION NUMBER(S)
PL 10555/0028
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 25/01/2012
10 DATE OF REVISION OF THE TEXT
12/01/2016