RABISOP

Package leaflet: Information for the patient

Rabisop 2.5 mg/1.25 mg hard capsules, 2.5 mg/2.5 mg hard capsules, 5 mg/2.5 mg hard capsules, 5 mg/5 mg hard capsules, 10 mg/5 mg hard capsules, 10 mg/10 mg hard capsules

Ramipril / bisoprolol fumarate
Please read all of this leaflet carefully before taking this medicine, because it contains
important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor, pharmacist, or nurse.
• This medicine has been prescribed for you only. Do not give it to other people, even if they have the same symptoms as you, because it may be harmful.
• If you experience any side effect, including any not listed in this leaflet, talk to your doctor, pharmacist, or nurse. See section 4.

Contents of this leaflet:

1. What Rabisop is and what it is used for
2. What you need to know before taking Rabisop
3. How to take Rabisop
4. Possible side effects
5. How to store Rabisop
6. Contents of the pack and other information

1. What Rabisop is and what it is used for

Rabisop contains two active substances, bisoprolol fumarate and ramipril, in one capsule:

• Ramipril is an angiotensin-converting enzyme (ACE) inhibitor. It works by dilating blood vessels, allowing the heart to pump blood more easily through them.
• Bisoprolol fumarate belongs to a group of medicines called beta-blockers. Beta-blockers slow down the heart rate and make the heart more efficient at pumping blood throughout the body.

Rabisop is used to treat high blood pressure (hypertension) and/or chronic heart failure with left ventricular dysfunction (a condition in which the heart is unable to pump enough blood to meet the body's needs, resulting in breathlessness and swelling) and/or to reduce the risk of cardiac events, such as heart attack, in patients with chronic coronary artery disease (a condition in which blood flow to the heart is reduced or blocked) who have already had a heart attack and/or undergone a procedure to improve blood flow to the heart by widening the vessels supplying it, or in patients with diabetes and at least one cardiovascular risk factor.

Instead of taking bisoprolol fumarate and ramipril as separate capsules, you will take just one capsule of Rabisop containing both active substances at the same concentrations.

2. What you should know before taking Rabisop

Do not take Rabisop if:

• you are allergic to bisoprolol or any other beta-blockers, ramipril or any other ACE inhibitors, or to any of the other ingredients of this medicine (listed in section 6);
• you have heart failure that suddenly worsens and/or that may require hospitalization;
• you have cardiogenic shock (a serious heart condition caused by very low blood pressure);
• you have a heart disease characterized by a slow or irregular heartbeat (second- or third-degree atrioventricular block, sinoatrial block, sick sinus syndrome);
• you have a slow heart rate;
• you have very low blood pressure;
• you suffer from severe asthma or severe chronic lung disease;
• you have serious circulation problems in the limbs (such as Raynaud's syndrome), which may cause tingling in the fingers of the hands and feet or make them pale or blue;
• you have untreated phaeochromocytoma, a rare tumor of the adrenal gland (medulla);
• you have metabolic acidosis, a condition in which there is an excessive amount of acid in the blood;
• you have previously experienced symptoms such as difficulty breathing, swelling of the face, tongue or throat, intense itching or severe skin rashes during prior treatment with ACE inhibitors, or if you or a family member has ever had these symptoms under any circumstances (a disorder called angioedema);
• you are more than 3 months pregnant (Rabisop should also be avoided in the early stages of pregnancy – see section “Pregnancy”);
• you have diabetes or impaired kidney function and are being treated with a blood pressure-lowering medicine containing aliskiren;
• you are undergoing dialysis or any type of blood filtration. Depending on the equipment used, Rabisop may not be suitable for you;
• you have kidney problems due to reduced blood supply to the kidneys (renal artery stenosis);
• you are being treated with sacubitril/valsartan, a medicine for heart failure (see “Warnings and precautions” and “Other medicines and Rabisop”).

Warnings and precautions
Talk to your doctor or pharmacist before taking Rabisop if:

• you have diabetes,
• you have kidney problems (including kidney transplant) or are on dialysis,
• you have liver problems,
• you have aortic or mitral stenosis (narrowing of the main blood vessel leaving the heart) or hypertrophic cardiomyopathy (a heart muscle disease) or renal artery stenosis (narrowing of the artery supplying blood to the kidney),
• you have abnormally high levels of a hormone called aldosterone in your blood (primary aldosteronism),
• you have heart failure or any other heart problem, such as minor disturbances in heart rhythm or severe chest pain at rest (Prinzmetal's angina),
• you suffer from a collagen vascular disease (a connective tissue disease) such as systemic lupus erythematosus or scleroderma,
• you are on a low-salt diet or use salt substitutes containing potassium (excess potassium in the blood may cause changes in heart rate),
• you have recently had diarrhea or vomiting, or are dehydrated (Rabisop may cause a drop in blood pressure),
• you are undergoing LDL apheresis (removal of cholesterol from the blood using a machine),
• you are receiving allergy treatment or are about to undergo desensitization therapy to reduce the effects of allergy to bee or wasp stings,
• you are fasting or on a strict diet,
• you are about to undergo anesthesia and/or major surgery,
• you have circulation problems in the limbs,
• you suffer from asthma or chronic lung disease,
• you have (or have had) psoriasis,
• you have a tumor of the adrenal gland (phaeochromocytoma),
• you have thyroid problems (Rabisop may mask symptoms of overactive thyroid),
• you have angioedema (a severe allergic reaction with swelling of the face, lips, tongue or throat causing difficulty swallowing or breathing). This may occur at any time during treatment. If you develop these symptoms, stop taking Rabisop and contact your doctor immediately,
• you are of Black ethnicity, as you may have a higher risk of angioedema and this medicine may be less effective in lowering blood pressure compared to non-Black patients,
• you are taking any of the following medicines used to treat high blood pressure:
• an "angiotensin II receptor antagonist" (AIIRA) (also known as sartans – e.g. valsartan, telmisartan, irbesartan), especially if you have kidney problems related to diabetes.
• aliskiren. Your doctor may monitor your kidney function, blood pressure and blood electrolyte levels (e.g. potassium) at regular intervals. See also information provided under "Do not take Rabisop".
• you are taking any of the following medicines, which increase the risk of angioedema:
• racecadotril (used to treat diarrhea),
• sirolimus, everolimus, temsirolimus and other drugs belonging to the class of so-called mTOR inhibitors (used to prevent rejection of transplanted organs),
• sacubitril (available as a fixed-dose combination with valsartan), used to treat chronic heart failure.

Do not stop taking Rabisop suddenly, as this may cause a serious worsening of your heart condition. Treatment should not be stopped abruptly, especially in patients with coronary artery disease.
You must inform your doctor if you think you are (or might be) pregnant. Rabisop is not recommended during early pregnancy and must not be taken after the first 3 months of pregnancy, as it may cause serious harm to the unborn child if used during this period (see section “Pregnancy”).
For athletes: using this medicine without a therapeutic indication constitutes doping and may lead to a positive anti-doping test.

Children and adolescents
Rabisop is not recommended for use in children and adolescents under 18 years of age.

Other medicines and Rabisop
Talk to your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
Some medicines may alter the effect of Rabisop or their own effect may be altered by Rabisop. These interactions may reduce the effectiveness of one or both medicines or increase the risk or severity of side effects.
Make sure to inform your doctor if you are taking any of the following medicines:

• medicines used to control blood pressure or for heart problems (such as amiodarone, amlodipine, clonidine, digitalis glycosides, diltiazem, disopyramide, felodipine, flecainide, lidocaine, methyldopa, moxonidine, procainamide, propafenone, quinidine, rilmenidine, verapamil),
• other medicines used to treat high blood pressure, including angiotensin II receptor antagonists (AIIRAs), aliskiren (see also information under "Do not take Rabisop" and "Warnings and precautions") or diuretics (medicines that increase urine production by the kidneys),
• potassium-sparing agents (e.g. triamterene, amiloride), potassium supplements or potassium-containing salt substitutes, other medicines that may increase potassium levels in the body (such as heparin and co-trimoxazole, also known as trimethoprim/sulfamethoxazole),
• potassium-sparing agents used to treat heart failure: eplerenone and spironolactone at doses between 12.5 mg and 50 mg per day,
• sympathomimetic agents used to treat clinical shock (adrenaline, noradrenaline, dobutamine, isoprenaline, ephedrine),
• estramustine used in cancer therapy,
• medicines often used to treat diarrhea (racecadotril) or to prevent rejection of transplanted organs (sirolimus, everolimus, temsirolimus and other drugs belonging to the class of so-called mTOR inhibitors). See section “Warnings and precautions”,
• sacubitril/valsartan (used for long-term treatment of heart failure). See sections "Do not take Rabisop" and “Warnings and precautions”,
• lithium used to treat mania or depression,
• certain medicines used to treat depression such as imipramine, amitriptyline, monoamine oxidase inhibitors (MAOIs) (except MAO-B inhibitors),
• certain medicines used to treat schizophrenia (antipsychotics),
• certain medicines used to treat epilepsy (phenytoin, barbiturates such as phenobarbital),
• anesthetic medicines used in surgery,
• vasodilators including nitrates (substances that widen blood vessels),
• trimethoprim used to treat infections,
• immunosuppressants (medicines that reduce the body's defense mechanisms) such as cyclosporine, tacrolimus, used to treat autoimmune disorders or after organ transplantation,
• allopurinol used to treat gout,
• parasympathomimetic medicines used to treat conditions such as Alzheimer's disease or glaucoma,
• topical beta-blockers used to treat glaucoma (increased eye pressure),
• mefloquine used to prevent or treat malaria,
• baclofen used to treat muscle stiffness in diseases such as multiple sclerosis,
• gold salts, especially when administered intravenously (used to treat symptoms of rheumatoid arthritis),
• medicines to treat diabetes such as insulin, metformin, linagliptin, saxagliptin, sitagliptin, vildagliptin,
• non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen or diclofenac or high-dose aspirin used to treat arthritis, headache, pain or inflammation.

Rabisop with food, drinks and alcohol
It is preferable to take Rabisop before a meal.

Pregnancy and breastfeeding
If you are pregnant, think you may be pregnant, planning a pregnancy, or breastfeeding, consult your doctor or pharmacist before taking this medicine.

Pregnancy
You must inform your doctor if you think you are pregnant or if there is a possibility of becoming pregnant. Your doctor will usually advise you to stop taking Rabisop before becoming pregnant or as soon as pregnancy is confirmed, and will recommend an alternative medicine. Rabisop is not recommended during early pregnancy and must not be taken beyond the first 3 months of pregnancy, as it may cause serious harm to your baby if taken after the third month of pregnancy.

Breastfeeding
Inform your doctor if you are breastfeeding or planning to breastfeed. Rabisop is not recommended for breastfeeding mothers, and your doctor may choose another treatment for you if you intend to breastfeed, especially if the baby is newborn or was born prematurely.

Driving and using machines
Rabisop generally does not affect alertness and attention (vigilance), but in some patients dizziness or weakness due to low blood pressure may occur, especially at the beginning of treatment or when changing medication, and particularly when combined with alcohol. If this happens to you, your ability to drive or operate machinery may be impaired.

Lactose
Rabisop 2.5 mg / 1.25 mg contains 40.97 mg of lactose (20.49 mg glucose and 20.49 mg galactose) per dose. This should be taken into consideration in patients with diabetes mellitus.
Rabisop 2.5 mg / 2.5 mg contains 40.97 mg of lactose (20.49 mg glucose and 20.49 mg galactose) per dose. This should be taken into consideration in patients with diabetes mellitus.
Rabisop 5 mg / 2.5 mg contains 81.94 mg of lactose (40.97 mg glucose and 40.97 mg galactose) per dose. This should be taken into consideration in patients with diabetes mellitus.
Rabisop 5 mg / 5 mg contains 81.94 mg of lactose (40.97 mg glucose and 40.97 mg galactose) per dose. This should be taken into consideration in patients with diabetes mellitus.
Rabisop 10 mg / 5 mg contains 163.88 mg of lactose (81.94 mg glucose and 81.94 mg galactose) per dose. This should be taken into consideration in patients with diabetes mellitus.
Rabisop 10 mg / 10 mg contains 163.88 mg of lactose (81.94 mg glucose and 81.94 mg galactose) per dose. This should be taken into consideration in patients with diabetes mellitus.

Sodium
This medicine contains less than 1 mmol (23 mg) of sodium per capsule, i.e. essentially 'sodium-free'.

3. How to take Rabisop

Take this medicine exactly as your doctor or pharmacist has told you. If you are unsure, consult your doctor or pharmacist.
The recommended dose is one capsule once daily. Take the capsule with a glass of water in the morning before food.

Patients with kidney disease
If you have moderate kidney disease, your doctor will adjust the dose of Rabisop. Rabisop is not recommended if you have severe kidney disease.

Patients with liver impairment
Your doctor will carefully monitor the initiation of treatment with Rabisop if you have mild to moderate liver disease.

Use in children and adolescents
Use in children and adolescents is not recommended.

If you take more Rabisop than you should
If you take more capsules than prescribed, contact your doctor or pharmacist immediately.
The most likely effects of overdose are low blood pressure, which may make you feel dizzy or cause fainting (if this occurs, lying down with your legs raised may help), severe breathing difficulties, tremor (due to low blood sugar), and slow heart rate.

If you forget to take Rabisop
It is important to take the medicine every day, as regular treatment is more effective. However, if you forget to take a dose of Rabisop, take the next dose at your usual time.
Do not take a double dose to make up for the forgotten dose.

If you stop taking Rabisop
Do not stop treatment with Rabisop suddenly or change the dose without consulting your doctor, as this may cause a significant worsening of your heart condition. Treatment should not be stopped abruptly, especially in patients with coronary heart disease.

If you have any questions about the use of this medicine, consult your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
Stop taking Rabisop and contact your doctor immediately if you experience any of the following side effects:

• severe dizziness or lightheadedness, or fainting due to low blood pressure (common – may affect up to 1 in 10 people),
• worsening of heart failure causing increased shortness of breath and/or fluid retention (common – may affect up to 1 in 10 people),
• swelling of the face, lips, mouth, tongue or throat, difficulty breathing (angioedema) (uncommon – may affect up to 1 in 100 people),
• sudden breathing difficulty, chest pain, shortness of breath or trouble breathing (bronchospasm) (uncommon – may affect up to 1 in 100 people),
• unusually slow or irregular heartbeat, chest pain (angina) or heart attack (uncommon – may affect up to 1 in 100 people),
• weakness in arms or legs, or difficulty speaking, which could be signs of a possible stroke (not known – frequency cannot be estimated from available data),
• inflamed pancreas which may cause severe abdominal pain and back pain accompanied by a general feeling of severe illness (very rare – may affect up to 1 in 10,000 people),
• yellowing of the skin or eyes (jaundice), which could be a sign of hepatitis (rare – may affect up to 1 in 1,000 people),
• skin rash that often starts with itchy red spots on the face, arms or legs (erythema multiforme) (not known – frequency cannot be estimated from available data).

Rabisop is generally well tolerated, but as with any medicine, people may experience other side effects, especially at the beginning of treatment.

If you notice any of the following side effects listed below or not listed, inform your doctor or pharmacist immediately:
Very common (may affect more than 1 in 10 people):

• slow heartbeat.

Common (may affect up to 1 in 10 people):

• headache,
• dizziness,
• fainting, hypotension (abnormally low blood pressure), especially when standing up or rising quickly,
• numbness in hands or feet,
• sensation of cold hands or feet,
• cough,
• shortness of breath,
• sinus inflammation (sinusitis) or bronchitis,
• chest pain,
• gastrointestinal disorders such as nausea, vomiting, abdominal pain, indigestion or dyspepsia, diarrhoea, constipation,
• allergic reactions such as skin rash, itching,
• muscle cramps, muscle pain (myalgia),
• feeling of tiredness,
• fatigue,
• blood tests showing higher than normal potassium levels in the blood.

Uncommon (may affect up to 1 in 100 people):

• dizziness,
• altered taste,
• tingling sensation (paraesthesia),
• vision disturbances,
• tinnitus (ringing or noise in the ears),
• stuffy nose, difficulty breathing or worsening of asthma,
• rhinitis, nasal congestion,
• hot flushes,
• mood changes,
• sleep disorders,
• depression,
• dry mouth,
• sweating,
• kidney problems,
• increased urine production during the day,
• impotence,
• elevated eosinophils (a type of white blood cells in the blood),
• drowsiness,
• palpitations,
• tachycardia,
• irregular heartbeat (atrioventricular conduction disturbances),
• muscle weakness,
• arthralgia (joint pain),
• localized swelling (peripheral oedema),
• fever,
• loss or reduced appetite (anorexia),
• changes in laboratory parameters: increased number of certain white blood cells in the blood (eosinophilia), increased blood urea, increased blood creatinine, elevated liver enzymes, increased serum bilirubin levels,
• increased protein levels in urine,
• mouth ulcers,
• breast enlargement in men.

Rare (may affect up to 1 in 1,000 people):

• nightmares, hallucinations,
• reduced tear production (dry eyes),
• red, itchy, swollen or watery eyes,
• hearing problems,
• liver inflammation which may cause yellowing of the skin or whites of the eyes,
• inflammation of blood vessels (vasculitis),
• changes in laboratory parameters: abnormal lipid levels, decreased number of red blood cells, white blood cells or platelets, or reduced haemoglobin levels in the blood.

Very rare (may affect up to 1 in 10,000 people):

• confusion,
• inflammation of the pancreas (which may cause severe abdominal and back pain),
• hair loss,
• onset or worsening of scaly skin rash (psoriasis), or psoriasis-like rash,
• increased sensitivity of the skin to sunlight (photosensitivity reaction).

Frequency not known (frequency cannot be estimated from available data):

• changes in colour, numbness and pain in fingers of hands or feet (Raynaud's phenomenon),
• low sodium levels, very low blood sugar levels (hypoglycaemia) in diabetic patients,
• inflammation of the tongue.

With the use of ACE inhibitors, very concentrated (dark-coloured) urine, a feeling or state of malaise, muscle cramps, confusion and seizures may occur, probably due to inappropriate secretion of ADH (antidiuretic hormone). If you experience these symptoms, contact your doctor immediately.

Reporting of side effects
If you get any side effects, including those not listed in this leaflet, talk to your doctor, pharmacist or nurse. You can also report side effects directly via the national reporting system at the following website:
https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Rabisop

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the blister and the carton after "Exp".
The expiry date refers to the last day of that month.
Do not store above 30 °C. Do not refrigerate or freeze.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to
dispose of medicines you no longer use. This will help protect the environment.

6. Package Contents and Other Information

What Rabisop Contains

• The active substances are ramipril and bisoprolol fumarate.
• The other components are: Capsule contents: lactose monohydrate, polyvinyl alcohol, sodium croscarmellose (E468), sodium stearil fumarate, microcrystalline cellulose, anhydrous dicalcium phosphate, crospovidone type A, anhydrous colloidal silica, magnesium stearate.

Film coating - AquaPolish P yellow: hypromellose (E464), hydroxypropylcellulose (E463),
medium-chain triglycerides, talc (E553b), titanium dioxide (E171), yellow iron oxide (E172).
Capsule shell: titanium dioxide (E171), gelatin, red iron oxide (E172) [in capsules
10mg/10mg, 10mg/5mg, 5mg/5mg, 5mg/2.5mg], yellow iron oxide (E172) [in capsules
10mg/5mg, 5mg/5mg, 5mg/2.5mg, 2.5mg/2.5mg, 2.5mg/1.25mg], quinoline yellow (E104) [in
capsules 5mg/2.5mg, 2.5mg/2.5mg, 2.5mg/1.25mg].
Printing ink: shellac (E904), black iron oxide (E172), propylene glycol, concentrated ammonia solution, potassium hydroxide.

Description of the Appearance of Rabisop and Contents of the Package

Rabisop 2.5 mg/1.25 mg hard capsules
The capsule has a yellow cap with '2.5 mg' printed in black and a white body with '1.25 mg' printed in black.
Contents of the 2.5 mg/1.25 mg capsule: white or almost white powder of ramipril and a yellow, round, biconvex coated tablet of bisoprolol fumarate.

Rabisop 2.5 mg/2.5 mg hard capsules
The capsule has a yellow cap with '2.5 mg' printed in black and a yellow body with '2.5 mg' printed in black.
Contents of the 2.5 mg/2.5 mg capsule: white or almost white powder of ramipril and a yellow, round, biconvex coated tablet of bisoprolol fumarate.

Rabisop 5 mg/2.5 mg hard capsules
The capsule has an orange cap with '5 mg' printed in black and a yellow body with '2.5 mg' printed in black.
Contents of the 5 mg/2.5 mg capsule: white or almost white powder of ramipril and a yellow, round, biconvex coated tablet of bisoprolol fumarate.

Rabisop 5 mg/5 mg hard capsules
The capsule has an orange cap with '5 mg' printed in black and an orange body with '5 mg' printed in black.
Contents of the 5 mg/5 mg capsule: white or almost white powder of ramipril and a yellow, round, biconvex coated tablet of bisoprolol fumarate.

Rabisop 10 mg/5 mg hard capsules
The capsule has a reddish-brown cap with '10 mg' printed in black and an orange body with '5 mg' printed in black.
Contents of the 10 mg/5 mg capsule: white or almost white powder of ramipril and a yellow, round, biconvex coated tablet of bisoprolol fumarate.

Rabisop 10 mg/10 mg hard capsules
The capsule has a reddish-brown cap with '10 mg' printed in black and a reddish-brown body with '10 mg' printed in black.
Contents of the 10 mg/10 mg capsule: white or almost white powder of ramipril and two yellow, round, biconvex coated tablets of bisoprolol fumarate.

Blister packs made of laminated BOPA/ALU/PVC and aluminum foil.
The blisters and the package leaflet are packed in a cardboard box.
Capsules are available in packs of 10, 30, 60 or 100 capsules.
Not all pack sizes may be marketed.

Marketing Authorization Holder and Manufacturer

Marketing Authorization Holder
Adamed s.r.l.
Via G. Mazzini 20
20123 Milan (Italy)

Manufacturer
Adamed Pharma S.A.
ul. Marszałka Józefa Piłsudskiego 5
95-200 Pabianice
Poland

This medicinal product is authorized in the Member States of the European Economic Area under the following names:
Poland: Ramizek Plus
Italy: Rabisop
Spain: Rabidux 2.5 mg/1.25mg Cápsula duras
Rabidux 2.5 mg/2.5 Cápsula duras
Rabidux 5 mg/2.5 Cápsula duras
Rabidux 5 mg/5 Cápsula duras
Rabidux 10 mg/5 Cápsula duras
Rabidux 10 mg/10 Cápsula duras
Germany: RamiBiso APONTIS 2.5 mg/1.25 mg Hartkapseln
RamiBiso APONTIS 2.5 mg/2.5 mg Hartkapseln
RamiBiso APONTIS 5 mg/2.5 mg Hartkapseln
RamiBiso APONTIS 5 mg/5 mg Hartkapseln
RamiBiso APONTIS 10 mg/5 mg Hartkapseln
RamiBiso APONTIS 10 mg/10 mg Hartkapseln