Rabzole

Gastro-resistant tablets.

Therapeutic indications:
Rabzole tablets are indicated for the treatment of:
• active duodenal ulcer;
• active benign gastric ulcer
• symptomatic erosive or ulcerative• Gastro-oesophageal (ulcerative Gastro-oesophageal) reflux disease (GORD); Gastro-Oesophageal Reflux Disease Long-term Management (GORD Maintenance); symptomatic gastro-oesophageal reflux disease (symptomatic GORO).

In combination with appropriate antibacterial therapeutic regimens for:
• the eradication of Helicobacter pylori in patients with peptic ulcer disease or chronic gastritis;
• the healing and the prevention of relapse of peptic ulcers in patients with H. pylori associated ulcers.

Posology and method of administration

Adults/Elderly:
Active Duodenal Ulcer and Active Benign Gastric Ulcer: The recommended oral dose for both active duodenal ulcer and active benign gastric ulcer is 20 mg to be taken once daily in the morning.
Some patients with active duodenal ulcer may respond to one 10 mg tablet to be taken once daily in the morning.
Most patients with active duodenal ulcer heal within two to four weeks.
A few refractory patients may require an additional four weeks of therapy to achieve healing.

Most patients with active benign gastric ulcer heal within six weeks. A few refractory patients may require an additional six weeks of therapy to achieve healing.
Erosive or Ulcerative Gastro-Oesophageal Reflux Disease (GORD):
The recommended oral dose for this condition is 20 mg to be taken once daily for four to eight weeks.
Gastro-Oesophageal Reflux Disease Long-term Management (GORD Maintenance):
For long-term management, a maintenance dose of Rabzole 20 mg once daily can be used depending upon patient response.
Symptomatic gastro-oesophageai reflux disease (symptomatic GORD):
10 mg or 20 mg once daily in patients without oesophagitis. If symptom control has not been achieved during 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.

Eradication of H. pylori:
Patients with gastro-duodenal ulcers or chronic gastritis due to H. pylori infection should be treated with eradication therapy with appropriate combinations of antibiotics. One of the following combinations given for 7 days is recommended. Rabzole 20 mg twice daily + clarithromycin 500 mg twice daily and amoxycillin 1g twice daily or Rabzole 20 mg twice daily + clarithromycin 500 mg twice daily and metronidazole 400 mg twice daily.
The best eradication results, which exceed 90%, are obtained when rabeprazole is used in combination with clarithromycin and amoxycillin.

For further information on the other components of the H. pylori eradication therapy see the individual product data sheet. Eradication of H. pylori with anyone of the above regimens has been shown to result in the healing of duodenal or gastric ulcers without the need for continued ulcer therapy.

For indications requiring once daily treatment, Rabzole tablets should 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.

For H. pylori eradication, Rabzole – in combination regimens with two appropriate antibiotics – should be taken twice daily.

Patients should be cautioned that the Rabzole 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 “Special Warnings and Precautions for Use” in the treatment of patients with severe hepatic impairment.

Children:
Rabzole is not recommended for use in children, as there is no experience of its use in this group.

Contra indications:
Rabzole is contraindicated in patients with known hypersensitivity to rabeprazole sodium, substituted benzimidazoles or to any excipient used in the formulation.

Rabzole is contra-indicated in pregnancy and during breast-feeding.

Special warnings and special precautions for use 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 Rabzole.

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 Rabzole in the treatment of patients with severe hepatic dysfunction the prescriber is advised to exercise caution when treatment with Rabzole is first initiated in such patients.

Interaction with other medicaments and other forms of interaction 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 metebolising system. Studies in healthy subjects have shown that rabeprazole sodium does not have clinically significant interactions with the drugs studied including warfarin, phenytoin, theophylline or diazepam rnetabolised by the CYP450 system.

Rabeprazole sodium produces a profound and long lasting inhibition of gastric acid secretion. An interaction with compounds whose absorption is pH dependent may occur, therefore the potential for such interaction was investigated. Co-administration of rabeprazole sodium results in a 33% decrease in ketoconazole levels and a 22% increase in trough digoxin levels in normal subjects. Therefore individual patients may need to be monitored to determine if a dosage adjustment is necessary when such drugs are taken concomitantly with Rabzole. In clinical trials, antacids were used concomitantly with the administration of Rabzole, in a specific study designed to define this interaction, no interaction with liquid antacids was observed. There was no clinically relevant inter­action with food.

In vitro studies with human liver microsomes, indicated that rapebrazole sodium is metabolised by isoenzymes of CYP450 (CYP2C19 and CYP3A4). In these studies, at expected human plasma con­centrations rabeprazo!e neither induces nor inhibits CYP3A4; and although in vitro studies may not always be predictive in vivo status these findings indicate that no interaction is expected between rabeprazole and cyclosporin.

Pregnancy and lactation

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. Rabzole is contraindicated during pregnancy.

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 Rabzole should not be used during breastfeeding.

Undesirable effects

Rabzole was generally well tolerated during clinical trials. The observed undesirable effects have generally been mild/moderate and transient in nature.

In clinical trials, the most common adverse events (incidence 0:5%) were headache, diarrhoea and nausea. Other adverse events (incidence <5% and <12%) were rhinitis, abdominal pain, asthenia, flatulence, pharyngitis, vomiting, non-specific pain, back pain, dizziness, flu like syndrome, infection, cough, constipation and insomnia.

Further less frequent adverse events (incidence =1%) were rash, myalgia, chest pain, dry mouth, dyspepsia, nervousness, somnolence, bronchitis, sinusitis, chills, eructation, leg cramps, urinary tract infection, arthralgia, and fever.

In isolated cases, anorexia, gastritis, weight gain, depression, pruritus, vision or taste disturbances, stomatitis, sweating, leucocytosis have been observed.

However, only headaches, diarrhoea, abdominal pain, asthenia, flatulence, rash, and dry mouth have been associated with the use of Rabzole tablets.

PHARMACOLOGICAL PROPERTIES

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.

Rabeprazole has been shown to have a bactericidal effect on H. pylori in vitro. Eradication of H. pylori with Rabzole and antimicrobials is associated with high rates of healing of mucosal lesions. Clinical experience from controlled randomised clinical trials indicate that rabeprazole 20 mg twice daily in combination with two antibiotics e.g. clarithromycin and amoxycillin or clarithromycin and metronidazole (given at approved dose levels) for 1 week achieve >80% H. pylori eradication rate in patients with gastro-duodenal ulcers. As expected, there was a trend towards significantly lower eradication rates in patients with baseline metronidazole resistant H. pylori iso­lates and a trend towards the development of secondary resistance.

Hence, local information on the prevalence of resistance and local therapeutic guidelines should be taken in account in the choice of an appropriate combination regimen for H. pylori eradication therapy.

Pharmacokinetic properties

Absorption

Rabzole 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. 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

Following a single 20 mg 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 =5ml/min/1.73m2), 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 patents 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.

Elderly:

Elimination of rabeprazole was somewhat decreased in the elderly. Following 7 days of daily dosing with 20 mg of rabeprazole sodium, the AUC approximately doubled, the Cmax increased by 60% and t1/2 increased by approximately 30% as compared to young healthy volunteers. However there was no evidence of rabeprazole accumulation.

Tell your Doctor or Pharmacist if you notice any undesirable symptoms, even those not mentioned in this write up.