- Reflux oesophagitis

- Gastric and duodenal ulcer

- Zollinger-Ellison Syndrome and other pathological hypersecretory conditions.

This medicine should be administered by a healthcare professional and under appropriate medical supervision.

Intravenous administration of Toprazole is recommended only if oral application is not appropriate. Data are available on intravenous use for up to 7 days. Therefore, as soon as oral therapy is possible, treatment with Toprazole i.v. should be discontinued and 40 mg pantoprazole p.o. should be administered instead.

Posology

Gastric and duodenal ulcer, reflux oesophagitis

The recommended intravenous dose is one vial of Toprazole (40 mg pantoprazole) per day.

Zollinger-Ellison Syndrome and other pathological hypersecretory conditions

For the long-term management of Zollinger-Ellison Syndrome and other pathological hypersecretory conditions patients should start their treatment with a daily dose of 80 mg Toprazole. Thereafter, the dose can be titrated up or down as needed using measurements of gastric acid secretion to guide. With doses above 80 mg daily, the dose should be divided and given twice daily. A temporary increase of the dose above 160 mg pantoprazole is possible but should not be applied longer than required for adequate acid control.

In case a rapid acid control is required, a starting dose of 2 x 80 mg Toprazole is sufficient to manage a decrease of acid output into the target range (<10 mEq/h) within one hour in the majority of patients.

Special populations

Pediatric population

The experience in children is limited. Therefore, Toprazole is not recommended for use in patients below 18 years of age until further data become available.

Hepatic Impairment

A daily dose of 20 mg pantoprazole (half a vial of Toprazole) should not be exceeded in patients with severe liver impairment.

Renal Impairment

No dose adjustment is necessary in patients with impaired renal function.

Elderly

No dose adjustment is necessary in elderly patients.

Method of administration

A ready-to-use solution is prepared in 10 ml of sodium chloride (0.9 %) solution for injection. For instructions for preparation of the medicinal product before administration see section 6.6. The prepared solution may be administered directly or may be administered after mixing it with 100 ml sodium chloride (0.9 %) solution for injection or glucose (5 %) solution for injection.

After preparation the solution must be used within 12 hours.

The medicinal product should be administered intravenously over 2 - 15 minutes.

Hypersensitivity to the active substance, substituted benzimidazoles, or to any of the excipients.

In presence of alarm symptoms

In the presence of any alarm symptom (e. g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis, anaemia or melaena) and when gastric ulcer is suspected or present, malignancy should be excluded, as treatment with pantoprazole may alleviate symptoms and delay diagnosis.

Further investigation is to be considered if symptoms persist despite adequate treatment.

Hepatic Impairment

In patients with severe liver impairment, the liver enzymes should be monitored during therapy. In the case of a rise of the liver enzymes, the treatment should be discontinued.

Co-administration with atazanavir

Co-administration of atazanavir with proton pump inhibitors is not recommended. If the combination of atazanavir with a proton pump inhibitor is judged unavoidable, close clinical monitoring (e.g. virus load) is recommended in combination with an increase in the dose of atazanavir to 400 mg with 100 mg of ritonavir. A pantoprazole dose of 20 mg per day should not be exceeded.

Gastrointestinal infections caused by bacteria

Pantoprazole, like all proton pump inhibitors (PPIs), might be expected to increase the  counts of bacteria normally present in the upper gastrointestinal tract. Treatment with Toprazole may lead to a slightly increased risk of gastrointestinal infections caused by bacteria such as Salmonella and Campylobacter.

Hypomagnesaemia

Severe hypomagnesaemia has been reported in patients treated with PPIs like pantoprazole 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 PPIs with digoxin or drugs that may cause hypomagnesaemia (e.g., diuretics), health care professionals should consider measuring magnesium levels before starting PPI treatment and periodically during treatment. Proton pump inhibitors, especially if used in high doses and over long durations (>1 year), may modestly increase the risk of hip, wrist and spine fracture, predominantly in the elderly or in presence of other recognised risk factors. Observational studies suggest that proton pump inhibitors may increase the overall risk of fracture by 10–40%. Some of this increase may be due to other risk factors. Patients at risk of osteoporosis should receive care according to current clinical guidelines and they should have an adequate intake of vitamin D and calcium.

Sodium

This medicinal product contains less than 1 mmol (23 mg) sodium per dose, i.e. essentially “sodium-free”.

 

Effect of pantoprazole on the absorption of other medicinal products

Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may reduce the absorption of drugs with a gastric pH dependent bioavailability, e.g. some azole antifungals as ketoconazole, itraconazole, posaconazole and other medicine as erlotinib.

HIV medications (atazanavir)

Co-administration of atazanavir and other HIV medications whose absorption is pH-dependent with proton-pump inhibitors might result in a substantial reduction in the bioavailability of these HIV medications and might impact the efficacy of these medicines. Therefore, the co-administration of proton pump inhibitors with atazanavir is not recommended.

Coumarin anticoagulants (phenprocoumon or warfarin)

Although no interaction during concomitant administration of phenprocoumon or warfarin has been observed in clinical pharmacokinetic studies, a few isolated cases of changes in International Normalised Ratio (INR) have been reported during concomitant treatment in the post-marketing period. Therefore, in patients treated with coumarin anticoagulants (e.g. phenprocoumon or warfarin), monitoring of prothrombin time/INR is recommended after initiation, termination or during irregular use of pantoprazole.

Other interactions studies

Pantoprazole is extensively metabolised in the liver via the cytochrome P450 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, like carbamazepine, diazepam, glibenclamide, nifedipine, and an oral contraceptive containing levonorgestrel and ethinyl oestradiol did not reveal clinically significant interactions.

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

There were no interactions with concomitantly administered antacids.

Interaction studies have also been performed administering pantoprazole concomitantly with the respective antibiotics (clarithromycin, metronidazole, amoxicillin) No clinically relevant interactions were found.

Pregnancy

Teratogenic Effects

Pregnancy Category B

Reproduction studies have been performed in rats at intravenous doses up to 20 mg/kg/day

(4 times the recommended human dose based on body surface area) and rabbits at

intravenous doses up to 15 mg/kg/day (6 times the recommended human dose based on body

surface area) and have revealed no evidence of impaired fertility or harm to the fetus 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.

Breast-feeding

Animal studies have shown excretion of pantoprazole in breast milk. Excretion into human

milk has been reported. Therefore a decision on whether to continue/discontinue breastfeeding

or to continue/discontinue therapy with Toprazole should be made taking into

account the benefit of breast-feeding to the child and the benefit of Toprazole therapy to woman.

Adverse drug reactions such as dizziness and visual disturbances may occur. If affected,

patients should not drive or operate machines.

Approximately 5% of patients can be expected to experience adverse drug reactions

(ADRs). The most commonly reported ADRs are diarrhea and headache, both occurring in

approximately 1% of patients.

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); very rare (<1/10,000), not known (cannot be estimated from

the available data). For all adverse reactions reported from post-marketing experience, it is

not possible to apply any Adverse Reaction frequency and therefore they are mentioned with

a “not known” frequency. Within each frequency grouping, adverse reactions are presented

in order of decreasing seriousness.

Adverse reactions with pantoprazole in clinical trials and post-marketing experience:

Blood and lymphatic system disorders

Very rare: thrombo-cytopenia; leukopenia.

Immune system disorders

Rare: hyper-sensitivity (including anaphylactic reactions and anaphylactic shock).

Metabolism and nutrition disorders

Rare: hyperlipidaemias and lipid increases (triglycerides, cholesterol); weight changes.

Not known: hyponatraemia, hypomagnesaemia.

Psychiatric disorders

Uncommon: sleep disorders.

Rare: depression (and all aggravations).

Very rare: disorientation (and all aggravations).

Not known: hallucination; confusion (especially in pre-disposed patients, as well as the

aggravation of these symptoms in case of pre-existence).

Nervous system disorders

Uncommon: headache, dizziness.

Eye disorders

Rare: disturbances in vision/ blurred vision.

Gastrointestinal disorders

Uncommon: diarrhea; nausea / vomiting; abdominal distension and bloating; constipation; dry mouth; abdominal pain and discomfort.

hepatobiliary disorders

Uncommon: liver enzymes increased (transaminases, γ-GT).

Rare: bilirubin increased.

Not known: hepatocellular injury; jaundice; hepatocellular failure.

Skin and sub-cutaneous tissue disorders

Uncommon: rash / exanthema / eruption; pruritus.

Rare: urticaria; angioedema.

Not known: stevens-John-son syndrome; Lyell syndrome; erythema multiforme; photosensitivity.

Musculoskeletal and connective tissue disorders

Uncommon: Fracture of the hip, wrist or spine.

Rare: arthralgia; myalgia.

Renal and urinary disorders

Not known: interstitial nephritis.

Reproductive system and breast disorders

Rare: gynaecomastia

General disorders and administration site conditions

Common: injection site thrombophlebitis

Uncommon: asthenia, fatigue and malaise

Rare: body temperature increased; oedema peripheral 

- To report any side effect

National Pharmacovigilance and Drug Safety Center (NPC)

Fax: +966-11-205-7662

Call NPC at +966-11-2038222 Exts: 2317-2356-2353-2354-2334-2340

Toll free phone: 8002490000

E-mail: npc.drug@sfda.gov.sa

Website: www.sfda.gov.sa/npc

There are no known symptoms of overdose in man.

Systemic exposure with up to 240 mg administered intravenously over 2 minutes were well tolerated.

Pantoprazole is extensively protein bound, it is not readily dialyzable.

In the case of overdose with clinical signs of intoxication, apart from symptomatic and supportive treatment, no specific therapeutic recommendations can be made.

Pharmacotherapeutic group: Proton pump inhibitors, ATC code: A02BC02

Mechanism of action

Pantoprazole is a substituted benzimidazole which inhibits the secretion of hydrochloric acid

in the stomach by specific action 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 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 stimulation by other substances (acetylcholine, histamine, gastrin). The

effect is the same whether the product is given orally or intravenously.

The fasting gastrin values increase under pantoprazole. On 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 (similar 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 one year cannot be

completely ruled out on endocrine parameters of the thyroid according to results in animal

studies.

General Pharmacokinetics

Pharmacokinetics do not vary after single or repeated administration. In the dose range of 10

to 80 mg, the plasma kinetics of pantoprazole are linear after both oral and intravenous

administration.

Distribution

Pantoprazole's serum protein binding is about 98%. Volume of distribution is about

0.15 l/kg.

Elimination

The substance is almost exclusively metabolized in the liver. The main metabolic pathway is

demethylation by CYP2C19 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 are excreted with the faeces. The main metabolite in both the serum

and urine is desmethyl pantoprazole which is conjugated with sulphate. The half-life of the

main metabolite (about 1.5 hours) is not much longer than that of pantoprazole.

Characteristics in patients/special groups of subjects

Approximately 3 % of the European population lack a functional CYP2C19 enzyme and are

called poor metabolisers. In these individuals the metabolism of pantoprazole is probably

mainly catalysed by CYP3A4. After a single-dose administration of 40 mg pantoprazole, the 

mean area under the plasma concentration-time curve was approximately 6 times higher in

poor metabolisers than in subjects having a functional CYP2C19 enzyme (extensive

metabolisers). Mean peak plasma concentrations were increased by about 60 %. These

findings have no implications for the posology of pantoprazole.

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 dialyzed.

Although the main metabolite has a moderately delayed half-life (2 - 3 h), excretion is still

rapid and thus accumulation does not occur.

Although for patients with liver cirrhosis (classes A and B according to Child) the half-life

time values increased to between 7 and 9 h and the AUC values increased by a factor of 5 -

7, the maximum serum concentration only increased slightly by a factor of 1.5 compared

with healthy subjects.

A slight increase in AUC and Cmax in elderly volunteers compared with younger

counterparts is also not clinically relevant.

Children

Following administration of single intravenous doses of 0.8 or 1.6 mg/kg pantoprazole to

children aged 2 – 16 years there was no significant association between pantoprazole

clearance and age or weight. AUC and volume of distribution were in accordance with data

from adults.

Non-clinical data reveal no special hazard to humans based on conventional studies of safety

pharmacology, repeated dose toxicity and genotoxicity.

In the two-year carcinogenicity studies in rats neuroendocrine neoplasms were found. In

addition, squamous cell papillomas were found in the forestomach of rats. The mechanism

leading to the formation of gastric carcinoids by substituted benzimidazoles has been

carefully investigated and allows the conclusion that it is a secondary reaction to the

massively elevated serum gastrin levels occurring in the rat during chronic high-dose

treatment. In the two-year rodent studies an increased number of liver tumors was observed

in rats and female mice and was interpreted as being due to pantoprazole's high metabolic

rate in the liver.

A slight increase of neoplastic changes of the thyroid was observed in the group of rats

receiving the highest dose (200 mg/kg). The occurrence of these neoplasms is associated

with the pantoprazole-induced changes in the breakdown of thyroxine in the rat liver. As the

therapeutic dose in man is low, no side effects to the thyroid glands are expected.

In animal reproduction studies, signs of slight fetotoxicity were observed at doses above

5 mg/kg.

Investigations revealed no evidence of impaired fertility or teratogenic effects.

Penetration of the placenta was investigated in the rat and was found to increase with

advanced gestation. As a result, concentration of pantoprazole in the fetus is increased

shortly before birth.

- Disodium edetate

- Sodium hydroxide for pH adjustment.

This medicinal product must not be mixed with other medicinal products except those

mentioned in section 6.6.

2 years After reconstitution, or reconstitution and dilution, chemical and physical in-use stability has been demonstrated for 12 hours at 25°C. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

Store below 25°C.

Keep the vial in the outer carton to protect from light.

Do not use beyond the expiry date or if the product shows any sign of deterioration.

10R EP type I tubular glass vials, stoppered with Grey Bromobutyl Lyo-Rubber Stopper

and sealed with Aluminum seal with center tear off plastic top flip-off seal, packaged in

carton with folded leaflet.

A ready-to-use intravenous solution is prepared by injecting 10 ml of sodium chloride

(0.9%) solution for injection into the vial containing the lyophilised powder. The

reconstituted solution should be clear colorless to pale yellow. This solution may be

administered directly or may be administered after mixing it with 100 ml of sodium chloride

(0.9%) solution for injection or glucose (5%) solution for injection. Glass or plastic

containers should be used for dilution.

Toprazole 40 mg, powder for solution for injection should not be prepared or mixed with

solvents other than those stated.

This medicine should be administered intravenously over 2- 15 minutes.

The content of the vial is for single use only. Any product that has remained in the container

or the visual appearance of which has changed (e.g. if cloudiness or precipitation is

observed) should be disposed of in accordance with local requirements.