CONTROLOC CONTROL 20mg gastro-resistant tablets medication leaflet

CONTROLOC Control 20 mg gastro-resistant tablets

Each gastro-resistant tablet contains 20 mg pantoprazole (as sodium sesquihydrate).

For the full list of excipients, see section 6.1.

Gastro-resistant tablet.

Yellow, oval, biconvex film-coated tablets imprinted with “P20” in brown ink on one side.

CONTROLOC Control is indicated for short-term treatment of reflux symptoms (e.g. heartburn, acidregurgitation) in adults.

The recommended dose is 20 mg pantoprazole (one tablet) per day.

It might be necessary to take the tablets for 2-3 consecutive days to achieve improvement ofsymptoms. Once complete relief of symptoms has occurred, treatment should be discontinued.

The treatment should not exceed 4 weeks without consulting a doctor.

If no symptom relief is obtained within 2 weeks of continuous treatment, the patient should beinstructed to consult a doctor.

No dose adjustment is necessary in elderly patients or in those with impaired renal or liver function.

CONTROLOC Control is not recommended for use in children and adolescents below 18 years of agedue to insufficient data on safety and efficacy.

CONTROLOC Control 20 mg gastro-resistant tablets should not be chewed or crushed, and should beswallowed whole with liquid before a meal.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Co-administration of pantoprazole is not recommended with HIV protease inhibitors for whichabsorption is dependent on acidic intragastric pH such as atazanavir, nelfinavir; due to significantreduction in their bioavailability (see section 4.5).

Patients should be instructed to consult a doctor if:

* They have unintentional weight loss, anaemia, gastrointestinal bleeding, dysphagia, persistentvomiting or vomiting with blood, since pantoprazole may alleviate symptoms and delaydiagnosis of a severe condition. In these cases, malignancy should be excluded.

* They have had previous gastric ulcer or gastrointestinal surgery.

* They are on continuous symptomatic treatment of indigestion or heartburn for 4 or more weeks.

* They have jaundice, hepatic impairment, or liver disease.

* They have any other serious disease affecting general well-being.

* They are aged over 55 years with new or recently changed symptoms.

Patients with long-term recurrent symptoms of indigestion or heartburn should see their doctor atregular intervals. Especially, patients over 55 years taking any non-prescription indigestion orheartburn remedy on a daily basis should inform their pharmacist or doctor.

Patients should not take another proton pump inhibitor or H2 antagonist concomitantly.

Patients should consult their doctor before taking this medicinal product if they are due to have anendoscopy or urea breath test.

Patients should be advised that the tablets are not intended to provide immediate relief.

Patients may start to experience symptomatic relief after approximately one day of treatment withpantoprazole, but it might be necessary to take it for 7 days to achieve complete heartburn control.

Patients should not take pantoprazole as a preventive medicinal product.

Gastrointestinal infections caused by bacteria

Decreased gastric acidity, due to any means - including proton pump inhibitors - increases gastriccounts of bacteria normally present in the gastrointestinal tract. Treatment with acid-reducingmedicinal products leads to a slightly increased risk of gastrointestinal infections such as Salmonella,

Campylobacter, or Clostridium difficile.

Severe cutaneous adverse reactions (SCARs) including erythema multiforme, Stevens-Johnsonsyndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemicsymptoms (DRESS) which can be life-threatening or fatal, have been reported in association withpantoprazole with frequency not known (see section 4.8).

Patients should be advised of the signs and symptoms and monitored closely for skin reactions.

If signs and symptoms suggestive of these reactions appear, pantoprazole should be withdrawnimmediately and an alternative treatment considered.

Subacute cutaneous lupus erythematosus (SCLE)

Proton pump inhibitors are associated with very infrequent cases of SCLE. If lesions occur, especiallyin sun-exposed areas of the skin, and if accompanied by arthralgia, the patient should seek medicalhelp promptly and the health care professional should consider stopping CONTROLOC Control.

SCLE after previous treatment with a proton pump inhibitor may increase the risk of SCLE with otherproton pump inhibitors.

Increased Chromogranin A (CgA) level may interfere with investigations for neuroendocrine tumours.

To avoid this interference, CONTROLOC Control treatment should be stopped for at least 5 daysbefore CgA measurements (see section 5.1). If CgA and gastrin levels have not returned to referencerange after initial measurement, measurements should be repeated 14 days after cessation of protonpump inhibitor treatment.

The following additional risks are considered relevant for long-term use:

This medicinal product is intended for short-term use (up to 4 weeks) only (Refer to section 4.2).

Patients should be warned about additional risks with long-term use of the medicinal products and theneed for prescription and regular surveillance should be emphasised.

Influence on vitamin B12 absorption

Pantoprazole, as all acid-blocking medicines, may reduce the absorption of vitamin B12(cyanocobalamin) due to hypo- or achlorhydria. This should be considered in patients with reducedbody stores or risk factors for reduced vitamin B12 absorption on long-term therapy or if respectiveclinical symptoms are observed.

Bone fracture

Proton pump inhibitors, especially if used in high doses and over long durations (> 1 year), maymodestly increase the risk of hip, wrist and spine fracture, predominantly in the elderly or in thepresence of other recognised risk factors. Observational studies suggest that proton pump inhibitorsmay increase the overall risk of fracture by 10-40%. Some of this increase may be due to other riskfactors. Patients at risk of osteoporosis should receive care according to current clinical guidelines andthey should have an adequate intake of vitamin D and calcium.

Hypomagnesaemia

Severe hypomagnesaemia has been rarely reported in patients treated with proton pump inhibitors(PPIs) like pantoprazole for at least three months, and in most cases for a year. Serious manifestationsof hypomagnesaemia such as fatigue, tetany, delirium, convulsions, dizziness, and ventriculararrhythmia can occur, but they may begin insidiously and be overlooked. Hypomagnesaemia may leadto hypocalcaemia and/or hypokalaemia (see section 4.8). In most affected patients, hypomagnesaemia(and hypomagnesaemia associated hypocalcaemia and/or hypokalaemia) improved after magnesiumreplacement and discontinuation of the PPI.

For patients expected to be on prolonged treatment or who take PPIs with digoxin or medicinalproducts that may cause hypomagnesaemia (e.g., diuretics), health care professionals should considermeasuring magnesium levels before starting PPI treatment and periodically during treatment.

CONTROLOC Control contains sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially‘sodium-free’.

Medicinal products with pH-dependent absorption pharmacokinetics

CONTROLOC Control may reduce the absorption of active substances whose bioavailability isdependent on the gastric pH (e.g., ketoconazole).

HIV protease inhibitors

Co-administration of pantoprazole is contraindicated with HIV protease inhibitors for whichabsorption is dependent on acidic intragastric pH such as atazanavir, nelfinavir; due to significantreduction in their bioavailability (see section 4.3).

Coumarin anticoagulants (phenprocoumon or warfarin)

Although no interaction during concomitant administration of phenprocoumon or warfarin has beenobserved in clinical pharmacokinetic studies, a few isolated cases of changes in International

Normalised Ratio (INR) have been reported during concomitant treatment in the post-marketingperiod. Therefore, in patients treated with coumarin anticoagulants (e.g., phenprocoumon or warfarin),monitoring of prothrombin time/INR is recommended after initiation, termination or during irregularuse of pantoprazole.

Concomitant use of high-dose methotrexate (e.g., 300 mg) and proton pump inhibitors has beenreported to increase methotrexate levels in some patients. Therefore, in settings where high-dosemethotrexate is used, for example cancer and psoriasis, a temporary withdrawal of pantoprazole mayneed to be considered.

Other interactions studies

Pantoprazole is metabolised in the liver via the cytochrome P450 enzyme system. Interaction studieswith carbamazepine, caffeine, diazepam, diclofenac, digoxin, ethanol, glibenclamide, metoprolol,naproxen, nifedipine, phenytoin, piroxicam, theophylline and an oral contraceptive containinglevonorgestrel and ethinyl oestradiol did not reveal clinically significant interactions. However, aninteraction of pantoprazole with other substances which are metabolised by the same enzyme systemcannot be excluded.

There were no interactions with concomitantly administered antacids.

Drug-laboratory test interactions

There have been reports of false-positive results in some urine screening tests for tetrahydrocannabinol(THC) in patients receiving pantoprazole. An alternative confirmatory method should be considered toverify positive results.

There are no adequate data from the use of pantoprazole in pregnant women. Studies in animals haveshown reproductive toxicity. Preclinical studies revealed no evidence of impaired fertility orteratogenic effects (see section 5.3). The potential risk for humans is unknown. Pantoprazole shouldnot be used during pregnancy.

Pantoprazole/metabolites have been identified in human milk. The effect of pantoprazole onnewborns/infants is unknown. CONTROLOC Control should not be used during breast-feeding.

There was no evidence of impaired fertility following the administration of pantoprazole in animalstudies (see section 5.3).

CONTROLOC Control has no or negligible influence on the ability to drive and use machines.

However adverse reactions such as dizziness and visual disturbances may occur (see section 4.8). Ifaffected, patients should not drive or use machines.

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

The following adverse reactions have been reported with pantoprazole.

Within the following table, adverse reactions are ranked under the MedDRA 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 theavailable data). Within each frequency grouping, adverse reactions are presented in order ofdecreasing seriousness.

Table 1. Adverse reactions with pantoprazole in clinical trials and post-marketing experience

Frequency Common Uncommon Rare Very rare Not known

Systemorgan class

Blood and Agranulocytosis Thrombocytopenia,lymphatic Leukopenia,system disorders Pancytopenia

Immune system Hypersensitivitydisorders (incl. anaphylacticreactions andanaphylacticshock)

Metabolism and Hyperlipidaemias Hyponatraemia,nutrition and lipid Hypomagnesaemia,disorders increases Hypocalcaemia(1)(triglycerides, Hypokalaemia(1)cholesterol),

Psychiatric Sleep disorders Depression (and Disorientation (and Hallucination,disorders all aggravations) all aggravations) Confusion (especiallyin pre-disposedpatients, as well asthe aggravation ofthese symptoms incase of pre-existence)

Nervous system Headache, Taste disorders Paraesthesiadisorders Dizziness

Frequency Common Uncommon Rare Very rare Not known

Systemorgan class

Eye disorders Disturbances invision/blurredvision

Gastrointestinal Fundic gland Diarrhoea, Microscopic colitisdisorders polyps Nausea /(benign) vomiting,

Abdominaldistension andbloating,

Constipation,

Dry mouth,

Abdominal painand discomfort

Hepatobiliary Liver enzymes Bilirubin Hepatocellular injury,disorders increased increased Jaundice,(transaminases, Hepatocellular failureγ-GT)

Skin and Rash/exanthema Urticaria, Stevens-Johnsonsubcutaneous/eruption, Angioedema syndrome,tissue disorders Pruritus Lyell syndrome(TEN),

Drug reaction witheosinophilia andsystemic symptoms(DRESS),

Erythemamultiforme,

Photosensitivity,

Subacute cutaneouslupus erythematosus(see section 4.4).

Musculoskeletal Fracture of wrist, Arthralgia;and connective hip and spine. Myalgiatissue disorders

Renal and Tubulointerstitialurinary disorders nephritis (TIN) (withpossible progressionto renal failure)

Reproductive Gynaecomastiasystem andbreast disorders

General Asthenia, fatigue Body temperaturedisorders and and malaise increased;administration Oedemasite conditions peripheral(1) Hypocalcaemia and/or hypokalaemia may be related to the occurrence of hypomagnesaemia (see section 4.4)

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Doses up to 240 mg administered intravenously over 2 minutes were well tolerated.

As pantoprazole is extensively protein bound, it is not readily dialysable.

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

Pharmacotherapeutic group: Proton pump inhibitors, ATC code: A02BC02

Pantoprazole is a substituted benzimidazole which inhibits the secretion of hydrochloric acid in thestomach by specific blockade of the proton pumps of the parietal cells.

Pantoprazole is converted to its active form, a cyclic sulphenamide, in the acidic environment in theparietal cells where it inhibits the H+, K+-ATPase enzyme, i.e., the final stage in the production ofhydrochloric acid in the stomach.

The inhibition is dose-dependent and affects both basal and stimulated acid secretion. In most patients,freedom from heartburn and acid reflux symptoms is achieved in 1 week. Pantoprazole reduces acidityin the stomach and thereby increases gastrin in proportion to the reduction in acidity. The increase ingastrin is reversible. Since pantoprazole binds to the enzyme distal to the receptor level, it can inhibithydrochloric acid secretion independently of stimulation by other substances (acetylcholine,histamine, gastrin). The effect is the same whether the active substance is given orally orintravenously.

The fasting gastrin values increase under pantoprazole. On short-term use, in most cases they do notexceed the upper limit of normal. During long-term treatment, gastrin levels double in most cases. Anexcessive increase, however, occurs only in isolated cases. As a result, a mild to moderate increase inthe number of specific endocrine (ECL) cells in the stomach is observed in a minority of cases duringlong-term treatment (simple to adenomatoid hyperplasia). However, according to the studiesconducted so far, the formation of carcinoid precursors (atypical hyperplasia) or gastric carcinoids aswere found in animal experiments (see section 5.3) have not been observed in humans.

During treatment with antisecretory medicinal products, serum gastrin increases in response to thedecreased acid secretion. Also CgA increases due to decreased gastric acidity. The increased CgAlevel may interfere with investigations for neuroendocrine tumours.

Available published evidence suggests that proton pump inhibitors should be discontinued between5 days and 2 weeks prior to CgA measurements. This is to allow CgA levels that might be spuriouslyelevated following PPI treatment to return to reference range.

In a retrospective analysis of 17 studies in 5960 patients with gastro-oesophageal reflux disease(GORD) who were treated with 20 mg pantoprazole monotherapy, the symptoms associated with acidreflux e.g., heartburn and acid regurgitation were evaluated according to a standardised methodology.

Studies selected had to have at least one acid reflux symptom recording point at 2 weeks. GORDdiagnosis in these studies was based on endoscopic assessment, with the exception of one study inwhich the inclusion of the patients was based on symptomatology alone.

In these studies, the percentage of patients experiencing complete relief from heartburn after 7 dayswas between 54.0% and 80.6% in the pantoprazole group. After 14 and 28 days, complete heartburnrelief was experienced in 62.9% to 88.6% and 68.1% to 92.3% of the patients, respectively.

For the complete relief from acid regurgitation, similar results were obtained as for heartburn. After7 days the percentage of patients experiencing complete relief from acid regurgitation wasbetween 61.5% and 84.4%, after 14 days between 67.7% and 90.4%, and after 28 days between 75.2%and 94.5%, respectively.

Pantoprazole was consistently shown to be superior to placebo and H2RA and non-inferior to other

PPIs. Acid-reflux symptom relief rates were largely independent of the initial GORD stage.

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.

Pantoprazole is completely and rapidly absorbed after oral administration. The absolute bioavailabilityfrom the tablet was found to be about 77%. On average, at about 2.0 h - 2.5 h post administration (tmax)of a single 20 mg oral dose, the maximum serum concentrations (Cmax) of about 1-1.5 µg/mL areachieved, and these values remain constant after multiple administration. Concomitant intake of foodhad no influence on bioavailability (AUC or Cmax), but increased the variability of the lag-time (tlag).

Volume of distribution is about 0.15 L/kg and serum protein binding is about 98%.

Pantoprazole is almost exclusively metabolised in the liver.

Clearance is about 0.1 L/h/kg, and terminal half-life (t1/2) about 1 h. There were a few cases of subjectswith delayed elimination. Due to the specific binding of pantoprazole to the proton pumps within theparietal 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 ofpantoprazole; the rest is excreted with the faeces. The main metabolite in both serum and urine isdesmethylpantoprazole, which is conjugated with sulphate. The half-life of the main metabolite(about 1.5 h) is not much longer than that of pantoprazole.

No dose reduction is recommended when pantoprazole is administered to patients with impaired renalfunction (including patients on dialysis, which removes only negligible amounts of pantoprazole). Aswith healthy subjects, the half-life of pantoprazole is short. Although the main metabolite has a longerhalf-life (2-3 h), excretion is still rapid and thus accumulation does not occur.

After administration of pantoprazole to patients with liver impairment (Child-Pugh classes A, B and

C) the half-life values increased to between 3 and 7 h and the AUC values increased by a factor of 3-6,whereas the Cmax only increased slightly by a factor of 1.3 compared with healthy subjects.

The slight increase in AUC and Cmax in elderly volunteers compared with younger subjects was notclinically relevant.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity and genotoxicity.

In the 2-year carcinogenicity studies in rats, neuroendocrine neoplasms were found. In addition,squamous cell papillomas were found in the forestomach of rats in one study. The mechanism leadingto the formation of gastric carcinoids by substituted benzimidazoles has been carefully investigatedand allows the conclusion that it is a secondary reaction to the massively elevated serum gastrin levelsoccurring in the rat during chronic high-dose treatment.

In the 2-year rodent studies an increased number of liver tumours was observed in rats (in one ratstudy only) and in female mice and was interpreted as being due to pantoprazole's high metabolic ratein the liver.

A slight increase of neoplastic changes of the thyroid was observed in the group of rats receiving thehighest dose (200 mg/kg) in one 2-year study. The occurrence of these neoplasms is associated withthe pantoprazole-induced changes in the breakdown of thyroxine in the rat liver. As the therapeuticdose in man is low, no side effects on the thyroid glands are expected.

In a peri-postnatal rat reproduction study designed to assess bone development, signs of offspringtoxicity (mortality, lower mean body weight, lower mean body weight gain and reduced bone growth)were observed at exposures (Cmax) approximately 2x the human clinical exposure. By the end of therecovery phase, bone parameters were similar across groups and body weights were also trendingtoward reversibility after a drug-free recovery period. The increased mortality has only been reportedin pre-weaning rat pups (up to 21 days age) which is estimated to correspond to infants up to the ageof 2 years old. The relevance of this finding to the paediatric population is unclear. A previousperi-postnatal study in rats at slightly lower doses found no adverse effects at 3 mg/kg compared witha low dose of 5 mg/kg in this study. Investigations revealed no evidence of impaired fertility orteratogenic effects.

Penetration of the placenta was investigated in the rat and was found to increase with advancedgestation. As a result, concentration of pantoprazole in the foetus is increased shortly before birth.

Core

Sodium carbonate, anhydrous

Mannitol (E421)

Crospovidone

Povidone K90

Calcium stearate

Hypromellose

Povidone K25

Titanium dioxide (E171)

Yellow iron oxide (E172)

Propylene glycol (E1520)

Methacrylic acid-ethyl acrylate copolymer (1:1)

Sodium laurilsulfate

Polysorbate 80

Triethyl citrate

Shellac

Red iron oxide (E172)

Black iron oxide (E172)

Yellow iron oxide (E172)

Ammonia solution, concentrated

Not applicable.

3 years

Store in the original package in order to protect from moisture.

Alu/Alu blisters with or without cardboard reinforcement containing 7 or 14 gastro-resistant tablets

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Takeda GmbH

Byk-Gulden-Str. 2

D-78467 Konstanz

GermanymedinfoEMEA@takeda.com

EU/1/09/515/001-004

Date of first authorisation: 12 June 2009

Date of latest renewal: 21 February 2014

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu/.