Regiam

Patient Information Leaflet

Regiam 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 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 others, even if they have the same symptoms as you, because it could be harmful.
• If you experience any side effect, including those not listed in this leaflet, contact your doctor, pharmacist, or nurse. See section 4.

Contents of this leaflet:

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

1. What Regiam is and what it is used for

Regiam 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, thereby making it easier for the heart to pump blood around the body.
• 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.

Regiam 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 supply to the heart is reduced or blocked) and in those who have already had a heart attack and/or a procedure to improve blood supply to the heart by dilating the vessels that supply it.
Instead of taking bisoprolol fumarate and ramipril in separate capsules, you will take only one capsule of Regiam containing both active substances at the same dosage.

2. What you should know before taking Regiam

Do not take Regiam 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 hospital treatment;
• 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 and toes or make them pale or blue;
• you have untreated phaeochromocytoma, a rare tumour of the adrenal gland (medulla);
• you have metabolic acidosis, a condition in which there is too much 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 previous 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 (Regiam 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, Regiam may not be suitable for you;
• you have kidney problems due to reduced blood flow 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 Regiam”).

Warnings and precautions
Talk to your doctor or pharmacist before taking Regiam 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 hyperaldosteronism);
• you have heart failure or any other heart problems, such as minor heart rhythm disturbances 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 (too much potassium in the blood may cause changes in heart rate);
• you have recently had diarrhoea or vomiting, or are dehydrated (Regiam may cause a drop in blood pressure);
• you are undergoing LDL apheresis (removal of cholesterol from the blood using a machine);
• you are receiving allergen immunotherapy or are about to undergo desensitisation treatment to reduce the effects of allergy to bee or wasp stings;
• you are fasting or on a strict diet;
• you are about to undergo anaesthesia 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 tumour of the adrenal gland (phaeochromocytoma);
• you have thyroid problems (Regiam may mask symptoms of overactive thyroid);
• you have angioedema (a severe allergic reaction with swelling of the face, lips, tongue or throat causing difficulty in swallowing or breathing). This may occur at any time during treatment. If you develop these symptoms, stop taking Regiam immediately and contact your doctor;
• 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 under "Do not take Regiam".
• you are taking any of the following medicines, which increase the risk of angioedema:
• racecadotril (used to treat diarrhoea);
• 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 combination with valsartan), used to treat chronic heart failure.

Do not stop taking Regiam suddenly, as this may cause a serious worsening of 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 could be) pregnant. Regiam is not recommended during early pregnancy and must not be taken after the first 3 months of pregnancy, as it may cause severe harm to the unborn child if used during this period (see section “Pregnancy”).
For athletes: using this medicine without therapeutic need constitutes doping and may lead to a positive anti-doping test.

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

Other medicines and Regiam
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 Regiam or their effect may be altered by Regiam. Such interactions may reduce the effect 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, cardiac 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 Regiam" 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 daily;
• sympathomimetic agents used to treat clinical shock (adrenaline, noradrenaline, dobutamine, isoprenaline, ephedrine);
• estramustine used in cancer therapy;
• medicines often used to treat diarrhoea (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 Regiam" 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);
• anaesthetic medicines used in surgery;
• vasodilators including nitrates (substances that widen blood vessels);
• trimethoprim used to treat infections;
• immunosuppressants (medicines that reduce the body's defence 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 for 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.

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

Pregnancy and breastfeeding
If you are pregnant, think you may be pregnant or are planning to become pregnant, or if you are 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 Regiam before becoming pregnant or as soon as pregnancy is confirmed, and will recommend an alternative medicine to Regiam. Regiam is not recommended during early pregnancy and must not be taken after the first 3 months of pregnancy, as it may cause severe harm to your baby if taken after the third month of pregnancy.

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

Driving and using machines
Regiam generally does not affect alertness and attention (vigilance), but some patients may experience dizziness or weakness due to low blood pressure, especially at the beginning of treatment, when changing medication, or when consuming alcohol. If this occurs, your ability to drive or operate machinery may be impaired.

Lactose
Regiam 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 considered in patients with diabetes mellitus.
Regiam 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 considered in patients with diabetes mellitus.
Regiam 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 considered in patients with diabetes mellitus.
Regiam 5 mg / 5 mg contains 81.94 mg of lactose (40.97 mg glucose and 40.97 mg galactose) per dose. This should be considered in patients with diabetes mellitus.
Regiam 10 mg / 5 mg contains 163.88 mg of lactose (81.94 mg glucose and 81.94 mg galactose) per dose. This should be considered in patients with diabetes mellitus.
Regiam 10 mg / 10 mg contains 163.88 mg of lactose (81.94 mg glucose and 81.94 mg galactose) per dose. This should be considered 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 Regiam

Take this medicine exactly as instructed by your doctor or pharmacist. If
you have any doubts, 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 renal disease
If you have moderate renal disease, your doctor will adjust the dose of Regiam. Regiam is not
recommended if you have severe renal disease.

Patients with hepatic impairment
Your doctor will carefully monitor the start of treatment with Regiam 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 Regiam 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 Regiam
It is important to take the medicine every day, as regular treatment is more effective. However,
if you forget to take a dose of Regiam, take the next dose at your usual time.
Do not take a double dose to make up for a forgotten dose.

If you stop taking Regiam
Do not stop treatment with Regiam 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 artery disease.

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

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.

Stop taking Regiam and contact your doctor immediately if you notice any of the following side effects:

• Severe dizziness, 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 speech problems, 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, often starting with itchy red spots on the face, arms or legs (erythema multiforme) (not known – frequency cannot be estimated from available data).

Regiam 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 or any not listed below, inform your doctor or pharmacist immediately:

Very common (may affect more than 1 in 10 people):

• Slowed 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 from a sitting or lying position,
• Numbness of hands or feet,
• Sensation of cold hands or feet,
• Cough,
• Shortness of breath,
• Inflammation of the sinuses (sinusitis) or bronchitis,
• Chest pain,
• Gastrointestinal disturbances 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):

• Lightheadedness,
• Taste disturbances,
• Tingling sensations (paraesthesia),
• Vision disorders,
• Tinnitus (sensation of 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 heart rate (atrio-ventricular conduction disorders),
• Muscle weakness,
• Arthralgia (joint pain),
• Localised swelling (peripheral oedema),
• Fever,
• Loss or decrease of 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 levels of protein in the 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,
• Inflammation of the liver which may cause yellowing of the skin or whites of the eyes,
• Inflammation of blood vessels (vasculitis),
• Changes in laboratory parameters: abnormal levels of fats in the blood, decreased number of red blood cells, white blood cells or platelets, or decreased 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), psoriasis-like skin 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 or toes (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, highly concentrated (dark-coloured) urine, feeling unwell, 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 experience 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 Regiam

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the blister and 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 medicines 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 Regiam contains

• The active substances are ramipril and bisoprolol fumarate.
• The other components are: Capsule contents: monohydrate lactose, 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 of
10 mg/10 mg, 10 mg/5 mg, 5 mg/5 mg, 5 mg/2.5 mg], yellow iron oxide (E172) [in capsules of
10 mg/5 mg, 5 mg/5 mg, 5 mg/2.5 mg, 2.5 mg/2.5 mg, 2.5 mg/1.25 mg], quinoline yellow (E104) [in
capsules of 5 mg/2.5 mg, 2.5 mg/2.5 mg, 2.5 mg/1.25 mg].
Printing ink: shellac (E904), black iron oxide (E172), propylene glycol, concentrated ammonia solution, potassium hydroxide.

Description of the appearance of Regiam and package contents

Regiam 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.

Regiam 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.

Regiam 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.

Regiam 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.

Regiam 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.

Regiam 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.

Capsule contents: white or almost white powder of ramipril and a yellow, round, biconvex coated tablet of bisoprolol fumarate.

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

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder
Bruno Farmaceutici S.P.A.
Via delle Ande, 15
00144 Roma (RM),
Italy

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

This medicinal product is authorised in the European Economic Area Member States under the following names: