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Logo PANTOLOC® (Enteric-coated tablets)

SCHEDULING STATUS
S4

PROPRIETARY NAME
(and dosage form)

PANTOLOC® (Enteric-coated tablets)

COMPOSITION
Each tablet contains 45,1 mg
pantoprazole sodium sesquihydrate equivalent to 40 mg pantoprazole.

PHARMACOLOGICAL CLASSIFICATION
A. 11.4.3 Medicines acting on the gastro-intestinal tract.

PHARMACOLOGICAL ACTION
Site and mechanism of action
Pantolocis a proton pump inhibitor, i.e., it inhibits specifically and dose-proportionally H+,K+-ATPase, the enzyme which is responsible for gastric acid secretion in the parietal cells of the stomach.
Pantoprazole is a substituted benzimidazole which accumulates in the acidic compartment of the parietal cells after absorption. In the parietal cell it is protonated and chemically re-arranged to the active inhibitor, a cyclic sulphenamide, which binds to the H+,K+-ATPase, thus inhibiting the proton pump and causing suppression of stimulated and basal gastric acid secretion after single and multiple intravenous and oral pantoprazole dosing. Because pantoprazole acts distal to the receptor level, it can influence gastric acid secretion irrespective of the nature of the stimulus.
Pantoprazole exerts its full effect in a strongly acidic environment (pH< 3) and remains mostly inactive at higher pH values, which explains its selectivity for the acid secreting parietal cells of the stomach. Therefore, the complete pharmacological and therapeutic effect of pantoprazole can only be achieved in the acid-secreting parietal cells. By means of a feedback mechanism this effect is diminished at the same rate as acid secretion is inhibited.

Effect on gastric acid secretion
The mean inhibition of pentagastrin stimulated acid output is 85% after seven days, 2½ to 3½ hours after dosing. After stopping the intake of pantoprazole, there is no evidence of rebound hypersecretion and 7 days after taking the last dose the acid output is normal.
Pantoprazole maintains the physiological pH-rhythm, the values, however, are shifted to higher levels. During the night, periods with pH close to placebo values were found.
Although pantoprazole has a half-life of approximately 1 hour, the antisecretory effect increases during repeated once daily administration, demonstrating that the duration of action markedly exceeds the serum elimination half-life.

Pharmacokinetics
Absorption and distribution
Pantoprazole is unstable in acid and is administered orally in the form of an enteric coated tablet. Absorption takes place in the small intestine. On average, the maximum serum/plasma concentrations are approximately 2 to 3 µg/mL about 2½ hours after administration of 40 mg Pantoloc as single or multiple daily doses in healthy volunteers. The absolute systemic bioavailability of pantoprazole from single and multiple oral doses of Pantoloc is approximately 77%.
Following intravenous administration pantoprazole serum/plasma concentrations decline biexponentially. The terminal half-life (t½) is about 1 hour. The total serum clearance is approximately 0,1 L/h/kg and the volume of distribution is about 0,15 L/kg respectively.
The plasma kinetics for pantoprazole after both oral and intravenous administration are linear over the dose range 10-80 mg.
Metabolism
Pantoprazole is almost exclusively metabolised in the liver. The main metabolite is desmethylpantoprazole which is conjugated with sulphate.
Elimination
Renal elimination represents the most important route of excretion (approximately 80%) for the metabolites of pantoprazole, the rest are excreted via the faeces. The half-life of the main metabolite is approximately 1½ hours which is slightly longer than that of pantoprazole.
Pharmacokinetic profile in patients
In subpopulations of subjects suffering from liver cirrhosis the half-life increases from 1 hour to between 7 and 9 hours and the AUC values are increased by a factor of 6 to 8, but the maximum serum concentration increases only by a factor of 1½ in comparison with healthy subjects.
In patients with renal impairment the half-life of the main metabolite is moderately increased but there is no accumulation at therapeutic doses. The half-life of pantoprazole in patients with renal impairment is comparable to the half-life of pantoprazole in healthy subjects. Pantoprazole is poorly dialysable.
A slight increase in AUC and Cmax occurs in elderly volunteers compared with younger people.
Interactions
Concomitant intake of food has no influence on the bioavailability.
Studies with Pantoloc in humans reveal no interaction with the cytochrome P450-system of the liver. There was no induction of the P450-system after chronic administration as shown with marker antipyrine and no interactions were observed after concomitant administration of Pantoloc with either antipyrine, diazepam, theophylline, digoxin, oral contraceptives, phenytoin, nifedipine, carbamazepine, diclofenac, metoprolol, glibenclamide, ethanol and caffeine. Concomitant administration of warfarin or phenprocoumon has no influence on its effect on coagulation factors. Antacids do not interact with Pantoloc.

INDICATIONS
Pantoloc is indicated for the short-term treatment of duodenal ulcer, gastric ulcer and reflux oesophagitis.
If the duodenal ulcer has been demonstrated to be associated with Helicobacter pylori infection, Pantoloc used in combination with appropriate antibiotics may be useful.

CONTRA-INDICATIONS
Hypersensitivity to pantoprazole. Safety in pregnancy and during lactation has not been established. Safety and efficacy in children have not been established.

DOSAGE AND DIRECTIONS FOR USE
The recommended 40 mg once daily dosage should be taken in the morning. Pantoloc should be swallowed whole with a little water either before or during breakfast.
Duodenal ulcer
The recommended oral dosage is 40 mg Pantoloc once daily in the morning for 2 to 4 weeks.
If the duodenal ulcer has been demonstrated to be associated with Helicobacter pylori infection, Pantoloc used in combination with appropriate antibiotics may be useful.
Gastric ulcer
The recommended oral dosage is 40 mg Pantoloc once daily in the morning for 4 to 8 weeks.
In the case of a suspected gastric ulcer, malignancy of gastric carcinoma should be excluded, as treatment could conceal the symptoms and may delay diagnosis.
Reflux oesophagitis
The recommended oral dosage is 40 mg Pantoloc once daily in the morning for 4 to 8 weeks.
Long-term treatment
Long-term treatment with Pantoloc is currently not indicated since sufficient clinical data is not available.
Elderly patients
No dosage adjustment is necessary in the elderly.
Impaired renal and liver function
No dose adjustment is required in the presence of impaired renal and liver function.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Headaches and diarrhoea have been reported. In most cases the complaints improve despite continued treatment. There have been reports of skin rashes, pruritus and dizziness.
In cases of gastric ulcer the possibility of malignancy should be excluded as treatment with pantoprazole may delay diagnosis by alleviating symptoms.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
There are no known symptoms of overdosage in man. No specific therapeutic recommendation can be made in cases of overdosage.

IDENTIFICATION
Yellow, oval, biconvex enteric-coated tablets, imprinted "P40" on the one side.

STORAGE INSTRUCTIONS
Store below 25°C.
Keep out of reach of children

PRESENTATION
Pantoloc 40 mg tablets in polyethylene containers of 14 and 28 tablets.

REGISTRATION NUMBER
28/11.4.3/0407

NAME AND BUSINESS ADDRESS OF APPLICANT
Byk Madaus (Pty.) Ltd.
2nd Road (cnr 16th Road)
Randjespark
Midrand 1685

DATE OF PUBLICATION OF THIS INSERT
24 February 1994

                        PPI 03/98/02

SAFR F.1/1096/3.9604.13

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