Pantoprazole 40 Mg Powder For Solution For Injection
SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT
Pantoprazole 40 mg, powder for solution for injection.
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each vial contains 40 mg of pantoprazole (as sodium sesquihydrate).
Excipients with known effect:
Each vial contains 5.0 mg of sodium citrate dihydrate and sodium hydroxide q.s.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Powder for solution for injection.
White or almost white, uniform porous cake.
For the solution reconstituted with 10 ml of 0.9% NaCl solution the pH is approximately 10 and the osmolality is approximately 382 mOsm/Kg
For the solution reconstituted with a further 100 ml of 0.9% NaCl solution or 5% glucose solution the pH is approximately 9 and 8.5, respectively
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
- Reflux oesophagitis
- Gastric and duodenal ulcer
- Zollinger - Ellison Syndrome and other pathological hypersecretory conditions.
4.2 Posology and method of administration
Posology
This medicine should be administered by a healthcare professional and under appropriate medical supervision.
The intravenous administration of pantoprazole 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 pantoprazole i.v. should be discontinued and 40 mg pantoprazole p.o. should be administered instead.
Recommended dose:
Gastric and duodenal ulcer, reflux oesophagitis
The recommended intravenous dose is one vial of pantoprazole (40 mg) 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 of pantoprazole i.v. Thereafter, the dosage 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 dosage 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 of pantoprazole i.v. 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
Elderly patients
No dose adjustment is necessary in elderly patients.
Patients with hepatic impairment
A daily dose of 20 mg pantoprazole (half a vial of 40 mg pantoprazole) should not be exceeded in patients with severe liver impairment (see section 4.4).
Patients with renal impairment
No dose adjustment is necessary in patients with impaired renal function.
Paediatric population
The experience in children is limited. Therefore, pantoprazole i.v. is not recommended for use in patients below 18 years of age until further data become available.
Method of administration
A ready-to-use solution is prepared in 10 ml of sodium chloride 9 mg/ml (0.9%) solution for injection. For instructions for preparation see section 6.6. The prepared solution may be administered directly or may be administered after mixing it with 100 ml of 9 mg/ml (0.9%) sodium chloride injection, or 55 mg/ml glucose (5%) solution for injection.
After preparation the solution must be used within 12 hours. (See section 6.3).
The medicinal product should be administered intravenously over 2 - 15 minutes.
4.3 Contraindications
Hypersensitivity to the active substance, substituted benzimidazoles or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
Hepatic impairment
In patients with severe liver impairment liver enzymes should be monitored during therapy. In case of a rise in the liver enzymes, pantoprazole i.v. should be discontinued. (See also section 4.2).
Combination therapy
In the case of combination therapy, the summaries of product characteristics of the respective medical products should be observed.
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.
Co-administration with atazanavir
Co-administration of atazanavir with proton pump inhibitors is not recommended (see section 4.5). 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 pantoprazole may lead to a slightly increased risk of gastrointestinal infections caused by bacteria such as Salmonella and Campylobacter and C. difficile.
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.
Bone fractures
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".
4.5 Interaction with other medicinal products and other forms of interaction
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 dependant bioavailability, e.g. some azole
antifungals such as ketoconazole, intraconazole, posaconazole and other medicines such 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 have an impact on the efficacy of these medicines. Therefore, the co-administration of proton pump inhibitors with atazanavir and is not recommended (see section 4.4).
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.
Methotrexate
Concomitant use of high dose methotrexate (e.g. 300 mg) and proton-pump inhibitors has been reported to increase methotrexate levels in some patients. Therefore in settings where high-dose methotrexate is used, for example cancer and psoriasis, a temporary withdrawal of pantoprazole may need to be considered.
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 metabolised 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 digoxin.
There were also no interactions with concomitantly administered antacids.
Interaction studies have been performed administering pantoprazole concomitantly with the respective antibiotics (clarithromycin, metronidazole, amoxicillin). No clinically relevant interactions were found.
4.6 Fertility, pregnancy and lactation
Pregnancy
There are no adequate data from the use of pantoprazole in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Pantoprazole should not be used during pregnancy unless clearly necessary.
Breastfeeding
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 treatment with pantoprazole should be made taking into account the benefit of breast-feeding to the child and the benefit of pantoprazole therapy to women.
4.7 Effects on ability to drive and use machines
Adverse drug reactions such as dizziness and visual disturbances may occur (see section 4.8). If affected, patients should not drive or operate machines. .
4.8 Undesirable effects
Approximately 5% of patients can be expected to experience adverse drug reactions (ADRs). The most commonly reported ADR is injection site thrombophlebitis. Diarrhoea and headache occurred in approximately 1% of patients.
The table below lists adverse reactions reported with pantoprazole, ranked under the following frequency classification:
- 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, adverse reactions are presented in order of decreasing seriousness. Tabulated list of adverse reactions
Table 1. Adverse reactions with pantoprazole in clinical trials and post-marketing experience
|
Frequency System''-^ organ class'^ |
Common |
Uncommon |
Rare |
Very rare |
Not known |
|
Blood and lymphatic system disorders |
Agranulocytosis |
Thrombo cytopenia: Leukopenia; Pancytopenni a |
|
Frequency System\^ organ class"'''\ |
Common |
Uncommon |
Rare |
Very rare |
Not known |
|
Immune system disorders |
Hypersensitivity (including anaphylactic reactions and anaphylactic shock) | ||||
|
Metabolism and nutrition disorders |
Hyperlipidaemia and lipid increases (triglycerides, cholesterol); Weight changes |
Hyponatraemia; Hypomagnesaemia (see section 4.4); Hypocalcaemia in association with hypomagnesaemia ; Hypokalaemia | |||
|
Psychiatric disorders |
Sleep disorders |
Depression (and all aggravations) |
Disorientation (and all aggravations) |
Hallucination: Confusion (especially in predisposed patients, as well as the aggravation of these symptoms in case of preexistence) | |
|
Nervous system disorders |
Headache; Dizziness |
Taste disorders |
Parasthesia | ||
|
Eye disorders |
Disturbances in vision/blurred vision | ||||
|
Gastrointestinal disorders |
Diarrhoea; Nausea/ vomiting; Abdominal distension and bloating; Constipation; Dry mouth; Abdominal pain and discomfort. | ||||
|
Hepatobiliary disorders |
Liver enzymes increased (transaminase s, Y-GT) |
Bilirubin increased |
Hepato-cellular injury; Jaundice; Hepato-cellular failure | ||
|
Skin and subcutaneous tissue disorders |
Rash/ exanthema/ eruption; Pruritus |
Urticaria; Angioedema |
Stevens-Johnson syndrome; Lyell syndrome; Erythema multiforme;Photo- sensitivity | ||
|
Musculoskeletal and |
Fracture of the hip, wrist |
Arthralgia; Myalgia |
Muscle spasm as a consequence of |
|
Frequency System^ organ class"'''\ |
Common |
Uncommon |
Rare |
Very rare |
Not known |
|
connective tissue disorders |
or spine (see section 4.4) |
electrolyte disturbances | |||
|
Renal and urinary disorders |
Interstitial nephritis (with possible progression to renal failure) | ||||
|
Reproductive system and breast disorders |
Gynaeco-mastia | ||||
|
General disorders and administration site conditions |
Injection site thrombo phlebitis |
Asthenia, fatigue and malaise |
Body temperature increased; Oedema peripheral |
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
Symptoms
There are no known symptoms of overdose in man.
Systemic exposure with up up to 240 mg administered intravenously over 2 minutes were well tolerated.
Management
As pantoprazole is extensively protein bound, it is not readily dialysable.
In case of overdose with clinical signs of intoxication, apart from symptomatic and supportive treatment, no specific therapeutic recommendations can be made.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
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 blockade 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 an increase in 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, the substance can affect 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 precursosrs (atypical hyperplasia) or gastric carcinoids as were found in animal experiments (see section 5.3) 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.
5.2 Pharmacokinetic properties
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 plasma protein binding is about 98%. Volume of distribution is about 0.15 l/kg.
Elimination
The substance is almost exclusively metabolised 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 few cases of subjects with delayed elimination. Because of 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 in the faeces. The main metabolite in both the plasma and urine is desmethylpantoprazole 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:
Renal impairment
No dose reduction is required when pantoprazole is administered to patients with impaired kidney function (including dialysis patients). As with healthy subjects, pantoprazole's half-life is short. Only very small amounts of pantoprazole are dialysed. Although the main metabolite has a moderately delayed half-life (2-3 hours), excretion is still rapid and thus accumulation does not occur.
Hepatic impairment
Although for patients with hepatic cirrhosis (classes A and B according to Child) the half-life values increased to between 7 and 9 hours and the AUC values increased by a factor of 5 to 7, the maximum plasma concentration only increased slightly by a factor of 1.5 compared with healthy subjects.
Elderly
A slight increase in AUC and Cmax in elderly volunteers compared with younger counterparts is also not clinically relevant.
Other special populations
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.
Paediatric population
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.
5.3 Preclinical safety data
Preclinical data reveal no special hazard to humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.
In the 2-year carcinogenicity study 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 treatment. In the two-year rodent studies an increased number of liver tumours 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 does 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, the concentration of pantoprazole in the foetus is increased shortly before birth.
6.1 List of excipients
Mannitol
Sodium citrate dihydrate
Sodium hydroxide (for pH adjustment)
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
6.3 Shelf life
As packaged for sale: 3 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.
6.4 Special precautions for storage
Do not store above 25°C. Keep the vial in the outer carton to protect from light.
For storage conditions of the reconstituted and diluted medicinal product see section 6.3.
6.5 Nature and contents of container
15 ml, type I, colourless glass vial, sealed with a grey chlorobutyl stopper and an aluminium flip-off cap, containing 40 mg powder for solution for injection.
Pack sizes: 1, 5, 10 and 20 vials
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
A ready-to-use intravenous solution is prepared by injecting 10 ml of sodium chloride 9 mg/ml (0.9%) solution for injection into the vial containing the lyophilised powder. The reconstituted solution should be clear and colourless. This solution may be administered directly or may be administered after mixing it with 100 ml of sodium chloride 9 mg/ml (0.9%) solution for injection or glucose 50 mg/ml (5%) solution for injection. Glass or plastic containers should be used for dilution
Pantoprazole 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.
7 MARKETING AUTHORISATION HOLDER
KRKA, d.d.,
Novo mesto,
Smarjeska cesta 6,
8501 Novo mesto,
Slovenia
8 MARKETING AUTHORISATION NUMBER(S)
PL 01656/0052
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
21/04/2010
10 DATE OF REVISION OF THE TEXT
28/05/2014