CONTROLOC Control 20 mg gastro-resistant tablets

CONTROLOC Control contains the active substance pantoprazole, which blocks the ?pump? that produces stomach acid. Hence it reduces the amount of acid in your stomach.

CONTROLOC Control is used for the short-term treatment of reflux symptoms (for example heartburn, acid regurgitation) in adults.
Reflux is the backflow of acid from the stomach into the gullet (?foodpipe?), which may become inflamed and painful. This may cause you symptoms such as a painful burning sensation in the chest rising up to the throat (heartburn) and a sour taste in the mouth (acid regurgitation).

You may experience relief from your acid reflux and heartburn symptoms after just one day of treatment with CONTROLOC Control, but this medicine is not meant to bring immediate relief. It may be necessary to take the tablets for 2-3 consecutive days to relieve the symptoms.

Do not take CONTROLOC Control:

• if you are allergic (hypersensitive) to pantoprazole, to soya or to any of the other ingredients of CONTROLOC Control (listed insection 6 ?What CONTROLOC Control contains?).
• if you are taking a medicine containing atazanavir (for the treatment of HIV-infection)
• if you are under 18 years of age
• if you are pregnant or breast-feeding.

Take special care with CONTROLOC Control

Talk to your doctor first if:

• you have been treated for heartburn or indigestion continuously for 4 or more weeks
• you are over 55 years old and taking non-prescription indigestion treatment on a daily basis
• you are over 55 years old with new or recently changed symptoms
• you have previously had a gastric ulcer or stomach surgery
• you have liver problems or jaundice (yellowing of skin or eyes)
• you regularly see your doctor for serious complaints or conditions
• you are due to have an endoscopy or a breath test called a C-urea test.

Tell your doctor immediately, before or after taking this medicine, if you notice any of the following symptoms, which could be a sign of another, more serious, disease:

• an unintentional loss of weight (not related to a diet or an exercise programme)
• vomiting, particularly if repeated
• vomiting blood; this may appear as dark coffee grounds in your vomit
• you notice blood in your stools; which may be black or tarry in appearance
• difficulty in swallowing or pain when swallowing
• you look pale and feel weak (anaemia)
• chest pain
• stomach pain
• severe and/or persistent diarrhoea, because CONTROLOC Control has been associated with a small increase in infectious diarrhoea. Your doctor may decide that you need some tests.

If you are due to have a blood test, tell your doctor that you are taking this medicine.

You may experience relief from your acid reflux and heartburn symptoms after just one day of treatment with CONTROLOC Control, but this medicine is not meant to bring immediate relief. You should not take it as a preventive measure.

If you have been suffering from repetitive heartburn or indigestion symptoms for some time, remember to see your doctor regularly.

Using other medicines
CONTROLOC Control may stop certain other medicines from working properly. Tell yourdoctor or pharmacist if you are using anymedicines containing one of the following active substances:

• ketoconazole (used for fungal infections).
• warfarin and phenprocoumon(used to thin blood and prevent clots). You may need further blood tests
• atazanavir (used to treat HIV-infection). You must not use CONTROLOC Control if you are taking atazanavir.

Do not take CONTROLOC Control with other medicines which limit the amount of acid produced in your stomach, such as another proton pump inhibitor (omeprazole, lansoprazole or rabeprazole) or an H2 antagonist (e.g. ranitidine, famotidine).
However, you may take CONTROLOC Control with antacids (e.g. magaldrate, alginic acid, sodium bicarbonate, aluminium hydroxide, magnesium carbonate, or combinations thereof), if needed.

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. This alsoincludes herbal or homeopathic remedies.

UsingCONTROLOC Control with food and drink
The tablets should be swallowed whole with liquid before a meal.

Pregnancy and breast-feeding

Do not take CONTROLOC Control if you are pregnant, think you may be pregnant, or are breast-feeding.
Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines
If you experience side effects like dizziness or disturbed vision, you should not drive or operate machines.

Important information about some of the ingredients of CONTROLOC Control CONTROLOC Control contains soya lecithin. If you are allergic to peanut or soya, do not use this medicine.

Always take CONTROLOC Control exactly as described in this leaflet. You should check with your doctor orpharmacist if you are not sure.

Take one tablet a day. Do not exceed this recommended dose of 20 mg pantoprazole daily.

You should take this medicine for at least 2-3 consecutive days. Stop taking CONTROLOC Control when you are completely symptom-free. You may experience relief from your acid reflux and heartburn symptoms after just one day of treatment with CONTROLOC Control, but this medicine is not meant to bring immediate relief.

If you have no symptom-relief after taking this medicine for 2 weeks continuously, consult your doctor.
Do not take CONTROLOC Control tablets for more than 4 weeks without consulting your doctor.

Take the tablet before a meal, at the same time every day. You should swallow the tablet whole with some water. Do not chew or break the tablet.

Childrenand adolescents
CONTROLOC Control should not be used by children and young people under 18 years of age.

If you take more CONTROLOC Control than you should
Tell your doctor or pharmacist straight away. If possible take your medicine and this leaflet with you. There are no known symptoms of overdose.

If you forget to take CONTROLOC Control
Do not take a double dose to make up for the forgotten dose. Take your next, normal dose, the next day, at your usual time.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

Like all medicines, CONTROLOC Control can cause side effects, although not everybody gets them.

Tellyour doctor immediately or contact the casualty department at your nearest hospital, if you get any of the following serious side effects. Stop taking this medicine straight away, but take this leaflet and/or the tablets with you.

• Seriousallergic reactions (rare): Hypersensitivity reactions, so-called anaphylactic reactions, anaphylactic shock and angioedema. Typical symptoms are: swelling of the face, lips, mouth, tongue and/or throat, which may cause difficulty in swallowing or breathing, hives (nettle rash), severe dizziness with very fast heartbeat and heavy sweating.
• Serious skin reactions (frequency not known): rash with swelling, blistering or peeling of the skin, losing skin and bleeding around eyes, nose, mouth or genitals and rapid deterioration of your general health, or rash when exposed to the sun.
• Other serious reactions (frequency not known):yellowing of the skin and eyes (due to severe liver damage), or kidney problems such as painful urination and lower back pain with fever.

Side effects may occur with certain frequencies, which are defined as follows:

very common: affects more than 1 user in 10
common: affects 1 to 10 users in 100
uncommon: affects 1 to 10 users in 1,000
rare: affects 1 to 10 users in 10,000
very rare: affects less than 1 user in 10,000
not known: frequency cannot be estimated from the available data.

• Uncommon side effects: headache; dizziness; diarrhoea; feeling sick, vomiting; bloating and flatulence (wind); constipation; dry mouth; bellyache and discomfort; skin rash or hives; itching; feeling weak, exhausted or generally unwell; sleep disorders; increase in liver enzymes in a blood test.
• Rareside effects: disturbances in vision such as blurred vision; pain in the joints; muscle pains; weight changes; raised body temperature; swelling of the extremities; allergic reactions; depression; increased bilirubin and fat levels in blood (seen in blood tests).
• Very rare side effects: disorientation; reduction in the number of blood platelets, which may cause you to bleed or bruise more than normal; reduction in the number of white blood cells, which may lead to more frequent infections.
• Frequency not known:hallucination, confusion (especially in patients with a history of these symptoms); decreased level of sodium in blood.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

Keep out of the reach and sight of children.

Do not use CONTROLOC Control after the expiry date, which isstated on the carton and the blister. The expiry date refers to the last day of that month.

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

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

What CONTROLOC Control contains

• The active substance is pantoprazole. Each tablet contains 20 mg pantoprazole (as sodium sesquihydrate).
• The other ingredients are:
• Core: sodium carbonate (anhydrous), mannitol, crospovidone, povidone K90, calcium stearate.
• Coating: hyprome llose, povidone, titanium dioxide (E171), yellow iron oxide (E172), propylene glycol, methacrylic acid-ethyl acrylate copolymer, sodium lauril sulfate, polysorbate 80, triethyl citrate.
• Printing ink: shellac, red, black and yellow iron oxide (E172), soya lecithin, titanium dioxide (E 171) and antifoam DC 1510.

What CONTROLOC Control looks like and contents of the pack

The gastro-resistant tablets are yellow, oval, biconvex film-coated tablets imprinted with ?P20? on one side.
CONTROLOC Control is available in Alu/Alu blisters with or without cardboard reinforcement. Packs containing 7 or 14 gastro-resistant tablets. Not all pack sizes may be marketed.

Marketing Authorisation Holder

Nycomed GmbH
Byk-Gulden-Straße 2, 78467 Konstanz
Germany

Manufacturer

Nycomed GmbH
Production site Oranienburg
Lehnitzstraße 70-98, 16515 Oranienburg
Germany

For any information about this medicine, please contact the Marketing Authorisation Holder.

This leaflet was last approved in

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The following recommendations for lifestyle and dietary changes may also help to relieve heartburn or acid related symptoms.

• Avoid large meals
• Eat slowly
• Stop smoking
• Reduce alcohol and caffeine consumption
• Reduce weight (if overweight)
• Avoid tight-fitting clothing or belts
• Avoid eating less than three hours before bedtime
• Elevate bedhead (if you suffer from nocturnal symptoms)
• Reduce intake of food that can cause heartburn. These might include: Chocolate, peppermint, spearmint, fatty and fried food, acidic food, spicy food, citrus fruits and fruit juices, tomatoes.

ANNEX IV

SCIENTIFIC CONCLUSIONS AND GROUNDS FOR REFUSAL ON THE CLAIM FOR ONE-YEAR DATA EXCLUSIVITY PRESENTED BY THE EMEA

25

SCIENTIFIC CONCLUSIONS AND GROUNDS FOR REFUSAL ON THE CLAIM FOR ONE-YEAR DATA EXCLUSIVITY PRESENTED BY THE EMEA

With reference to Article 74a of Directive 2001/83/EC, as amended, the applicant requested one year data exclusivity for the data submitted for the change of the classification of the medicinal product from prescription to non-prescription. Such exclusivity requires that the change of classification ?has been authorised on the basis of significant preclinical tests or clinical trials?.

The justification of the applicant was based on 6 ?non-published? studies, 5 full and one published by abstract only, which have been provided in support of the application (BY1023/BGI022, BY1023/BF010, BY1023/ESP009, BY1023/MEX020, BY1023/FK3037 and BY1023/VMG309). It was stated that these 6 studies support the proposed new indication and treatment duration by providing at least one symptom recording point of reflux-related symptoms during the first 14 days of treatment with pantoprazole and therefore are considered significant for the application. Study BY1023/BGI022 was particularly emphasised. During the procedure, the applicant further substantiated the justification. The applicant emphasised that these studies demonstrated efficacy in the non-prescription setting regarding the proposed indication and related posology which differs from that of the prescription product. The applicant, in addition to study BGI022 (CSR 257/2004), referred to study MEX020 (CSR 200/2004). The applicant also referred to studies BF010 (CSR 298E/99) and VMG309 (CSR 323/2004) which were considered to provide data for early onset of relief of reflux symptoms. Overall the applicant considered that the new data from the aforementioned studies added significant support to the classification as non-prescription product as they provided both effect and relevance to the assessment.

The CHMP reviewed the clinical data submitted, taking into account the provisions of Article 74a of Directive 2001/83/EC, as amended, in support of the classification of CONTROLOC Control 20 mg gastro-resistant tablets as ?medicinal product not subject to medical prescription?.

Out of the 17 studies submitted in support of the application, the following 11 studies did not form the basis of the applicant?s request for data exclusivity:

Primary Objective Secondary Objective Treatment Duration Results Study No. CSR No. N ITT 2 weeks 219 BY1023BGSA017 24598 Relief of heartburn in GORD Stage 0 Time to freedom from key GORD symptoms Pan 20, Placebo Pantoprazole was superior to placebo 4 weeks 338 BY1023FK3059 932001 Relief of key symptoms in GORD after 28 days Relief of key symptoms in GORD after 14 days Pan 20, Ran 300 once daily Pantoprazole was superior to ranitidine 4 weeks 356 BY1023VMG306 30298 Relief of symptoms in GORD Stage 0I after 4 weeks of treatment Leading symptom relief after 2 weeks of treatment Pan 20, Ran 150 bid Pantoprazole was superior to ranitidine 4 weeks 375 BY1023VMG305 30198 Pan 20, Lan 15 Relief of symptoms in GORD Stage 0I after 4 weeks of treatment Relief of GORD symptoms after 2 weeks of treatment Pantoprazole was non-inferior to lansoprazole after 4 weeks of treatment Pan 20, 40 4 weeks 421 BY1023M3-316 1522003 Relief of symptoms in GORD Stage A-D Assessment of GI symptoms at day 14 and 28 Pantoprazole was effective and well tolerated 4 weeks 529 BY1023M3-320 1702003 Pan 20, Eso 20 Relief of GORD-related symptoms after 14 and 28 days Time to first symptom relief of GORD-related symptoms in GORD Stage 0 Both PPIs were comparably effective pantoprazole was non-inferior to esomeprazole

209 BY1023FK3034 16695 Endoscopic healing of GORD Stage I 48 weeks Relief of leading GORD symptoms and other GI symptoms Pan 20, Ran 300 once daily Pantoprazole was significantly more effective than ranitidine 201 BY1023BGSA006 20895 Endoscopic healing of GORD Stage I 48 weeks Relief of leading GORD symptoms and other GI symptoms Pan 20, Ran 300 once daily Pantoprazole was significantly more effective than ranitidine 603 3001A1-300-US 319E98 Endoscopic healing erosive esophagitis Relief of typical GORD symptoms Pan 10, 20, 40, Pla 48 weeks Pantoprazole was significantly more effective than placebo 243 3001A1-301-US 320E98 Endoscopic healing erosive esophagitis Relief of typical GORD symptoms Pan 20, 40, Niz 150 bid 48 weeks Pantoprazole was significantly more effective than nizatidine 327 BY1023UK005 30398 Pan 20, Ome 20 48 weeks Endoscopic healing of GORD Stage I after 4 weeks Endoscopic healing of GORD Stage I after 8 weeks, Improvement of GORD symptoms after 2 and 4 weeks Pantoprazole and omeprazole were similarly effective CSR Clinical Study Report, N Number of Patients, Eso Esomeprazole, Lan Lansoprazole, Niz Nizatidine, Ome Omeprazole, Pan Pantoprazole, Pla Placebo, Ran Ranitidine, bid twice daily

Based on the above results the CHMP considered the following:

• pantoprazole 20mg is effective in the short-term treatment of GORD symptoms
• the applicant?s justification to extrapolate the results of these studies to the proposed non-prescription setting is acceptable
• the safety profile of pantoprazole is well established and acceptable.

Out of the 17 studies provided by the applicant, the following 6 studies formed the basis of the applicant?s request for data exclusivity:

Treatment Duration Results Comments Study No. CSR No. Primary Objective Secondary Objective N ITT 4 weeks 344 BY1023BGI022 2572004 Pan 20, Ran 150 bid Relief of heartburn in GORD Stage 0I at day 14 Relief of heartburn in GORD Stage 0I at day 28 Results are similar to published studies FK3059, VMG306, FK3034 and BGSA006 Pantoprazole was superior to ranitidine in the relief of GORD symptoms 331 BY1023BF010 298E99 Pan 20, Ome 10 48 weeks Relief of heartburn in GORD Stage 0 Quality of life, Time to heartburn relief Both medications were similarly effective Published studies showed non-inferiority of pantoprazole compared to other PPIs Study VMG305 and M3-320 2 weeks 521 BY1023VMG309 3232004 Pan 20, Ome 10 Relief of GORD symptoms, Time to heartburn relief Relief of heartburn in GORD Stage I after 1 and 2 weeks of treatment Published studies suggest non-inferiority of pantoprazole compared to other PPIs Study VMG305 and M3-320 Both PPIs were comparably effective pantoprazole was non-inferior to omeprazole, non-significant primary endpoint

270 BY1023ESP009 3962004 48 weeks Pan 20, Ran 150 bid Pantoprazole was superior to ranitidine Endoscopic healing of GORD Stage I after 8 weeks of treatment Endoscopic healing of GORD Stage I after 4 weeks of treatment Results are similar to published studies FK3059, VMG306, FK3034 and BGSA006 346 BY1023MEX020 2002004 Pan 20, Ome 10 48 weeks Endoscopic healing of GORD Stage I Relief of GORD symptoms after 7 and 28 days of treatment Pantoprazole and omeprazole were similarly effective Published studies showed non-inferiority of pantoprazole compared to other PPIs Study VMG305 and M3-320 322 BY1023FK3037 10596 Pan 20, 40, 80 48 weeks Symptom relief at 2 and 4 weeks of treatment Similar results were shown in the published study M3-316. Endoscopic healing of GORD Stage IIIII after 4 and 8 weeks of treatment There was no statistically significant difference between the treatment groups CSR Clinical Study Report, N Number of Patients, Eso Esomeprazole, Lan Lansoprazole, Niz Nizatidine, Ome Omeprazole, Pan Pantoprazole, Pla Placebo, Ran Ranitidine, bid twice daily

With reference to the above 6 studies, the CHMP made the following observations (see also comments included in the above table):

• BGI022 (CSR 257/2004) In this pivotal study the differences between pantoprazole 20 mg and ranitidine 150 mg results were significant; however the unpublished study conclusion for BGI022 were very similar to those of the published ranitidine 150 mg comparative study VMG306 and overall does not add significant value to the application.
• BF010 (CSR 298E/99) This study compared the efficacy of omeprazole 10 mg versus pantoprazole 20 mg at day 28 in patients without oesophagitis established by endoscopy. No day 14 data was available in the study report. In the non-prescription product setting, the patient would be self-referring to their physician if no symptomatic relief was obtained by day 14, making this study of limited value in the non-prescription context. Additionally, the usual starting dose for omeprazole in reflux disease is 20 mg; 10 mg omeprazole is not therapeutically equivalent to 20 mg pantoprazole. The study contained a treatment phase C; days 29-56, but again, this is not relevant to a non-prescription indication of no more than 28 days. Overall this study provides no relevant data analogous to the initial non-prescription medication period of up to 14 days. Additionally, in other studies efficacy of pantoprazole was compared to other PPIs (lansoprazole, esomeprazole) and it was found to be non-inferior to these PPIs in relieving symptoms of heartburn and acid regurgitation (Study VMG305 and M3-320).
• VMG309 (CSR 323/2004) This study compared the efficacy of omeprazole 10 mg versus pantoprazole 20 mg after one and two weeks or treatment. Symptomatic relief was comparable between the products though no statistically significant differences could be found between the groups at the end of week 1. No week 2 relief rate analysis was provided. The findings of this study are in line with other published studies (Study VMG305 and M3-320), which showed that the efficacy of pantoprazole is non-inferior to other PPIs (such as lansoprazole and esomeprazole).
• ESP009 (CSR 396/2004) This study compared the efficacy of 20 mg pantoprazole once daily with 150 mg twice daily ranitidine in healing of oesophagitis and freedom from GORD symptoms after treatment. Pantoprazole was superior to ranitidine in the treatment of key GORD symptoms. Similar results were shown by study FK3059, VMG306, FK3034, BGSA006, which also showed superiority of 20 mg pantoprazole compared to 300 mg ranitidine in the treatment of reflux symptoms.
• MEX020 (CSR 200/2004) In this study the efficacy of 20 mg pantoprazole was compared to 10 mg omeprazole at day 28 in

patients with reflux oesophagitis. The study concluded that pantoprazole 20 mg has a trend to have a faster relief of symptoms during the first 7 days of treatment compared with omeprazole 10 mg, but no statistically significant differences were found after 7 days, 4 weeks or 8 weeks treatment between the groups. 14 day data was not provided by this study. The shortcomings of this study are the same as described above for study BF010: lack of day 14 makes this study of limited value in the non-prescription context where the patient would be self-referring to their physician if no symptomatic relief was obtained by day 14. The usual starting dose for omeprazole in reflux disease is 20 mg; 10 mg omeprazole is not therapeutically equivalent to 20 mg pantoprazole. Additionally, in other studies efficacy of pantoprazole was compared to other PPIs (lansoprazole, esomeprazole) and it was found to be non-inferior to these PPIs in relieving symptoms of heartburn and acid regurgitation (Study VMG305 and M3-320).

• FK3037 (CSR 105/96) This study compared the efficacy and tolerability of pantoprazole 20 mg, 40 mg, or 80 mg in healing of oesophagitis and freedom from GORD symptoms. The results showed that all of the above doses are effective and comparable in the treatment of GORD. Similar results were shown in the published study M3-316 which compared the efficacy of 20 and 40 mg pantoprazole in the treatment of GORD symptoms.

Whereas:

• to support clinical efficacy and safety, the application is based on the results of 17 clinical studies. None of the 6 above-mentioned studies provide data to support the proposed indication and treatment duration that could not be derived from the other 11 studies provided in the application. Therefore, the 6 above-mentioned studies do not provide clinical data which has genuine impact on the assessment of the application.

the CHMP concluded that the studies BY1023/BGI022, BY1023/BF010, BY1023/ESP009, BY1023/MEX020, BY1023/FK3037 and BY1023/VMG309 submitted by the applicant for which the claim of one year data exclusivity is sought, were not relevant and necessary to the classification of CONTROLOC Control 20 mg gastro-resistant tablets as ?medicinal product not subject to medical prescription?.