Ramipril and amlodipine Krka

Patient Information Leaflet

Ramipril and Amlodipine Krka 5 mg/5 mg hard capsules, 5 mg/10 mg hard capsules, 10 mg/5 mg hard capsules, 10 mg/10 mg hard capsules

ramipril/amlodipine
Please read all of this leaflet carefully before you start taking this medicine, as it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• 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 may be harmful.
• If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist (see section 4).

Contents of this leaflet

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

1. What Ramipril and Amlodipine Krka is and what it is used for

Ramipril and Amlodipine Krka contains two active substances called ramipril and amlodipine. Ramipril
belongs to a group of medicines known as ACE inhibitors (Angiotensin Converting Enzyme inhibitors),
whereas amlodipine belongs to a group of medicines called calcium channel blockers.
Ramipril works by:

• Reducing the body's production of substances that can cause an increase in blood pressure.
• Relaxing and widening blood vessels.
• Helping the heart to pump blood around the body more easily.

Amlodipine works by:

• Relaxing and widening blood vessels, allowing blood to flow through more easily.

Ramipril and Amlodipine Krka can be used for the treatment of high blood pressure (hypertension) in
patients who are adequately controlled by taking the individual medicines separately as tablets, but at the same dosage strength as their combination.

2. What you need to know before taking Ramipril and Amlodipine Krka

Do not take Ramipril and Amlodipine Krka:

• If you are allergic to ramipril or amlodipine (the active substances), to any other ACE inhibitor or calcium antagonist, or to any of the other ingredients of this medicine (listed in section 6).
• Signs of an allergic reaction may include rash, difficulty swallowing or breathing, swelling of lips, face, throat or tongue, itching or redness of the skin.
• If you have ever had a severe allergic reaction called "angioedema". Signs include itching, hives, red patches on hands, feet and throat, swelling of throat and tongue, swelling around eyes and lips, difficulty breathing and swallowing.
• If you are undergoing dialysis or any other type of blood filtration. Depending on the machine used, Ramipril and Amlodipine Krka may not be suitable for you.
• If you have kidney problems due to reduced blood flow to the kidneys (renal artery stenosis).
• During the last 6 months of pregnancy (see section below on "Pregnancy and breastfeeding").
• If your blood pressure is abnormally low (hypotension) or unstable. Your doctor will need to assess this.
• If you have diabetes or impaired kidney function and are being treated with a blood pressure-lowering medicine called aliskiren.
• If you have narrowing of the aortic valve (aortic stenosis) or cardiogenic shock (a condition in which the heart is unable to supply enough blood to the body).
• If you suffer from heart failure following a heart attack.
• If you have taken or are currently taking sacubitril/valsartan, a medicine used to treat chronic heart failure in adults, as this increases the risk of angioedema (rapid swelling under the skin, for example in the throat).

Do not take Ramipril and Amlodipine Krka if any of the above apply to you. If you are unsure, consult your doctor before taking Ramipril and Amlodipine Krka.

Warnings and precautions

Talk to your doctor or pharmacist before taking Ramipril and Amlodipine Krka. Inform your doctor if any of the following apply to you:

• If you have heart, liver or kidney problems.
• If you have lost body salts or fluids (due to illness (vomiting), diarrhoea, excessive sweating, following a low-salt diet, taking diuretics (water tablets) for a long time, or having undergone dialysis).
• If you are about to undergo treatment for allergy to bee or wasp stings (desensitisation).
• If you are about to receive an anaesthetic. This may be given during surgery or dental procedures. You may need to stop taking Ramipril and Amlodipine Krka one day before; consult your doctor.
• If you have high levels of potassium in your blood (shown by blood tests).
• If you are taking medicines or have conditions that may reduce sodium levels in your blood. Your doctor may carry out regular blood tests, particularly to monitor blood sodium levels, especially if you are elderly.
• If you think you are (or might become) pregnant. Ramipril and Amlodipine Krka is not recommended during the first 3 months of pregnancy and may cause serious harm to the unborn baby after 3 months of pregnancy (see section below on "Pregnancy and breastfeeding").
• If you have a collagen vascular disease such as scleroderma or systemic lupus erythematosus.
• If you have a severe increase in blood pressure (hypertensive crisis).
• If you are elderly and your dose may need to be reduced.
• If you are taking any of the following medicines used to treat high blood pressure:
  • An angiotensin II receptor blocker (ARBs) (also known as sartans – e.g. valsartan, telmisartan, irbesartan), particularly if you have liver disease due to diabetes.
  • Aliskiren.

If you are taking any of the following medicines, the risk of angioedema (rapid swelling under the skin, for example in the throat) is increased:

• Racecadotril, a medicine used to treat diarrhoea.
• Medicines used to prevent rejection of organ transplants and to treat cancer (such as temsirolimus, sirolimus, everolimus).
• Vildagliptin, a medicine used to treat diabetes.

Your doctor may check your kidney function, blood pressure, and levels of electrolytes (e.g. potassium) in your blood at regular intervals.

See also the information in the section "Do not take Ramipril and Amlodipine Krka".

If you experience sudden swelling of lips and face, tongue and throat, neck, possibly also hands and feet, difficulty swallowing or breathing, hives or hoarseness ('angioedema'), this could be a sign of a serious allergic reaction. This may occur at any time during treatment. People with black skin may have a higher risk of developing this condition. If you develop such symptoms, inform your doctor immediately.

Children and adolescents

The use of Ramipril and Amlodipine Krka is not recommended in children and adolescents under 18 years of age, as the safety and efficacy of Ramipril and Amlodipine Krka have not yet been established.

Other medicines and Ramipril and Amlodipine Krka

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

Inform your doctor if you are taking any of the following medicines:

• Medicines used to relieve pain and inflammation (e.g. non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen or indomethacin, and acetylsalicylic acid).
• Medicines used to treat low blood pressure, shock, heart failure, asthma or allergies, such as ephedrine, noradrenaline or adrenaline. Your doctor must monitor your blood pressure.
• Medicines for cancer (chemotherapy).
• Medicines to prevent organ rejection after transplantation, such as cyclosporine.
• Diuretics (medicines to eliminate fluids) such as furosemide.
• Medicines that may increase potassium levels in the blood such as spironolactone, triamterene, amiloride, potassium salts and heparin (used to make blood less viscous).
• Steroid medicines used to treat inflammation, such as prednisolone.
• Allopurinol (used to lower uric acid levels in the blood).
• Procainamide (for heart rhythm problems).
• Temsirolimus (for cancer).
• Vildagliptin (used for type 2 diabetes).
• Medicines for diabetes such as oral hypoglycaemics and insulin. Ramipril and Amlodipine Krka may lower blood sugar levels. Monitor your blood sugar levels carefully when taking Ramipril and Amlodipine Krka.
• Lithium (for psychiatric conditions). Ramipril and Amlodipine Krka may increase lithium levels in the blood. Your doctor must monitor your blood lithium levels carefully.
• Ketoconazole, itraconazole (antifungal medicines).
• Ritonavir, indinavir, nelfinavir (also known as protease inhibitors used for HIV treatment).
• Rifampicin, erythromycin, clarithromycin (antibiotics used for bacterial infections).
• Hypericum perforatum (St. John's Wort).
• Verapamil, diltiazem (medicines used to treat heart disorders or high blood pressure).
• Dantrolene (infusion for severe abnormalities in body temperature).
• Tacrolimus (used to control the body's immune response, enabling the body to accept organ transplants).
• Simvastatin (a medicine to lower cholesterol).
• Medicines usually used to prevent rejection of transplanted organs (sirolimus, everolimus and other medicines belonging to the class of mTOR inhibitors). See section "Warnings and precautions".
• Potassium supplements (including salt substitutes), potassium-sparing diuretics, and other medicines that may increase potassium levels in the blood (such as trimethoprim and cotrimoxazole for treating bacterial infections; cyclosporine, an immunosuppressive medicine used to prevent rejection of transplanted organs; and heparin, a medicine used to thin the blood and prevent clotting).

Your doctor may need to adjust your dose and/or take other precautions:

• If you are taking an angiotensin II receptor blocker (ARB) or aliskiren (see also information in the section "Do not take Ramipril and Amlodipine Krka" and "Warnings and precautions").

If any of the above conditions occur (or if you have any doubts), consult your doctor before taking Ramipril and Amlodipine Krka.

Ramipril and Amlodipine Krka with food, drinks and alcohol

Ramipril and Amlodipine Krka can be taken with or without food.

• Drinking alcoholic beverages together with Ramipril and Amlodipine Krka may cause dizziness or lightheadedness. If you are concerned about how much alcohol you can drink while taking Ramipril and Amlodipine Krka, discuss this with your doctor, as blood pressure-lowering medicines and alcohol may have additive effects.

Grapefruit and grapefruit juice must not be consumed by people taking Ramipril and Amlodipine Krka.

This is because grapefruit and grapefruit juice can lead to increased levels of the active substance amlodipine in the blood, which may cause an unpredictable drop in blood pressure, thereby enhancing the effect of Ramipril and Amlodipine Krka.

Pregnancy and breastfeeding

Pregnancy

Inform your doctor if you think you may be pregnant (or might become pregnant).

You must not take Ramipril and Amlodipine Krka during the first 12 weeks of pregnancy and must not take it at all after week 13, as it may harm the unborn baby.

If you become pregnant while taking Ramipril and Amlodipine Krka, inform your doctor immediately. Before planning a pregnancy, you must switch to an alternative medicine appropriate for use during pregnancy.

Breastfeeding

You must not take Ramipril and Amlodipine Krka while breastfeeding.

It has been shown that amlodipine passes into breast milk in small amounts. Consult your doctor or pharmacist before taking any medicine.

Driving and using machines

Ramipril and Amlodipine Krka may affect your ability to drive and use machines.

If the capsules make you feel unwell, dizzy or tired, or if you have a headache, do not drive or operate machinery and contact your doctor immediately. This is more likely to occur when you first start taking Ramipril and Amlodipine Krka or when you take a higher dose.

3. How to take Ramipril and Amlodipine Krka

Take this medicine exactly as your doctor or pharmacist has told you. If
you have any doubts, consult your doctor or pharmacist.
Take this medicine by mouth at the same time each day, with or without food.
Swallow the tablets with liquid.
Do not take Ramipril and Amlodipine Krka with grapefruit juice.
Ramipril and Amlodipine Krka should be taken once daily.
Elderly
Your doctor will reduce the initial dose and adjust treatment very slowly.
If you take more Ramipril and Amlodipine Krka than you should
Taking too many capsules may cause low blood pressure or even dangerously low blood pressure. You may experience dizziness, lightheadedness, fainting, or weakness. If the drop in blood pressure is severe, shock may occur. You may feel cold and clammy and may lose consciousness. Inform your doctor or go immediately to the nearest hospital emergency department.
Do not drive yourself to the hospital; ask someone else to take you or call an ambulance. Take the medicine packaging with you. This way the doctor will know what you have taken.
If you forget to take Ramipril and Amlodipine Krka
If you forget to take a capsule, do not worry. Do not take the missed dose. Take your next dose at the usual time.
Do not take a double dose to make up for a forgotten dose.
If you stop taking Ramipril and Amlodipine Krka
Your doctor will advise you how long you should take the medicine. Your condition may return if you stop taking the medicine before being told to do so.
If you have any doubts about how to use this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
Stop taking Ramipril and Amlodipine Krka and contact your doctor immediately if you notice any of the following serious side effects – you may need urgent medical treatment:
Swelling of the face, lips or throat making it difficult to swallow or breathe, as well as itching and skin rashes. This could be a sign of a severe allergic reaction to Ramipril and Amlodipine Krka.
Severe skin reactions including rashes, mouth ulcers, worsening of pre-existing skin disease, redness, blisters or peeling of the skin, itching, blisters, desquamation and swelling of the skin, inflammation of mucous membranes (such as Stevens-Johnson syndrome, toxic epidermal necrolysis or erythema multiforme).
Contact your doctor immediately if you experience:
Rapid heartbeat, irregular or forceful heartbeat (palpitations), chest pain, feeling of chest tightness or more serious problems including heart attack and stroke.
Shortness of breath, cough, sudden breathlessness, chest pain or difficulty breathing. These may be signs of lung problems.
Easy bruising, prolonged bleeding, any signs of bleeding (e.g. bleeding gums), purple spots, skin spots or increased susceptibility to infections, sore throat and fever, feeling tired, weakness, dizziness or pale appearance. These may be signs of circulatory or bone marrow problems.
Severe stomach pain that may extend to the back. This could be a sign of pancreatitis (inflammation of the pancreas).
Fever, chills, fatigue, loss of appetite, stomach pain, feeling unwell, yellowing of the skin or eyes (jaundice). These may be signs of liver problems such as hepatitis (liver inflammation) or liver damage.
Swelling of the eyelids or tongue.
Allergic reactions.

Related to ramipril:
Common (may affect up to 1 in 10 people)
Headache or feeling weak.
Dizziness. This is more likely when you have just started taking Ramipril and Amlodipine Krka or have recently increased the dose.
Fainting and hypotension (unusually low blood pressure), especially when standing up or getting up quickly.
Dry, persistent cough, sinus inflammation (sinusitis) or bronchitis, shortness of breath.
Stomach ache or intestinal pain, diarrhoea, indigestion, feeling sick and vomiting.
Skin rash with or without swelling.
Chest pain.
Muscle cramps or muscle pain.
Blood tests showing higher potassium levels than usual in the blood.

Uncommon (may affect up to 1 in 100 people)
Balance problems (dizziness).
Itching and unusual skin sensations such as numbness, tingling, itching, burning or prickling on the skin (paraesthesia).
Loss or change in taste.
Sleep disturbances.
Depressed mood, anxiety, increased nervousness or restlessness.
Stuffy nose, difficulty breathing or worsening of asthma.
Swelling of the intestine called "intestinal angioedema" presenting with symptoms such as abdominal pain, vomiting and diarrhoea.
Heartburn, constipation or dry mouth.
Increased amount of urine during the day.
Increased sweating.
Loss or decrease in appetite (anorexia).
Increased or irregular heartbeat.
Swollen arms and legs. This may be a sign that your body is retaining more fluid than usual.
Flushing.
Blurred vision.
Joint pain.
Fever.
Impotence in men, reduced sexual desire in men or women.
Decrease in the number of white blood cells in the blood (eosinophilia), detected during blood tests.
Changes in liver, pancreas or kidney function shown by blood tests.

Rare (may affect up to 1 in 1,000 people):
Feeling unsteady and confused.
Redness and swelling of the tongue.
Severe peeling or desquamation of the skin, itching, rashes with lumps.
Nail problems (e.g. loss or separation of a nail from its bed).
Skin rash or bruising.
Spots on the skin and cold extremities.
Red, swollen or watery eyes, itching.
Hearing disturbances and ringing in the ears.
Feeling weak.
Blood tests showing a decrease in the number of red blood cells, white blood cells or platelets, or in the amount of haemoglobin.

Very rare (may affect up to 1 in 10,000 people)
Feeling more sensitive to sunlight than usual.

Not known (frequency cannot be estimated from the available data)
Concentrated urine (dark colour), feeling or being sick, muscle cramps, confusion and seizures which may be due to inadequate secretion of ADH (antidiuretic hormone). If you experience these symptoms, contact your doctor as soon as possible.

Other side effects reported:
Inform your doctor if any of the following conditions become severe or persist for more than a few days.
Difficulty concentrating.
Swollen mouth.
Blood tests showing a decrease in blood cells.
Blood tests showing a decrease in sodium levels in the blood.
Fingers of hands and feet changing colour when cold and tingling or hurting when warmed (Raynaud's phenomenon).
Breast enlargement in men.
Slowed or altered reactions.
Burning sensation.
Altered sense of smell.
Hair loss.

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

• Ankle swelling (oedema)

Common (may affect up to 1 in 10 people)
Headache, dizziness, drowsiness (especially at the beginning of treatment).
Palpitations (awareness of your heartbeat), hot flushes.
Abdominal pain, feeling unwell (nausea).
Altered bowel habits, diarrhoea, constipation, indigestion.
Fatigue, weakness.
Visual disturbances, double vision.
Muscle cramps.

Other side effects that have been reported are included in the following list. If any of these become severe or if you notice any side effect not listed in this leaflet, inform your doctor or pharmacist.

Uncommon (may affect up to 1 in 100 people)
Mood changes, anxiety, depression, insomnia.
Tremor, altered taste, fainting.
Numbness or tingling in limbs, loss of pain sensation.
Ringing in the ears.
Low blood pressure.
Sneezing/runny nose due to inflammation of the nasal mucosa (rhinitis).
Cough.
Dry mouth, vomiting (being sick).
Hair loss, increased sweating, itching, red spots on the skin, skin colour changes.
Urination problems, increased need to urinate at night, increased frequency of urination.
Inability to achieve an erection, discomfort or breast enlargement in men.
Pain, discomfort.
Muscle or joint pain, back pain.
Weight gain or weight loss.

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

Very rare (may affect up to 1 in 10,000 people)
Decrease in the number of white blood cells, decrease in blood platelets which may cause bruising or easy bleeding (damage to red blood cells).
High blood sugar (hyperglycaemia).
Nerve disorders which may cause weakness, tingling or numbness.
Gum swelling.
Abdominal swelling (gastritis).
Abnormal liver function, liver inflammation (hepatitis), yellowing of the skin (jaundice), increased liver enzymes which may affect certain medical tests.
Increased muscle tension.
Inflammation of blood vessels, often with skin rash.
Sensitivity to light.
Conditions involving stiffness, tremor, and/or movement disorders.

Not known (frequency cannot be estimated from the available data)
Tremor, rigid posture, mask-like face, slow and shuffling movements, unbalanced gait.

Reporting of side effects
If you get any side effects, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the national reporting system at 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 Ramipril and Amlodipine Krka

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the packaging after EXP.
The expiry date refers to the last day of that month.
Do not store above 30°C.
Store in the original packaging to protect the medicine from light and moisture.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer used. This will help protect the environment.

6. Contents of the pack and other information

What Ramipril and Amlodipine Krka contains

• The active substances are ramipril and amlodipine (as amlodipine besilate).
  5 mg/5 mg hard capsules: Each hard capsule contains 5 mg of ramipril and 5 mg of amlodipine (as amlodipine besilate).
  5 mg/10 mg hard capsules: Each hard capsule contains 5 mg of ramipril and 10 mg of amlodipine (as amlodipine besilate).
  10 mg/5 mg hard capsules: Each hard capsule contains 10 mg of ramipril and 5 mg of amlodipine (as amlodipine besilate).
  10 mg/10 mg hard capsules: Each hard capsule contains 10 mg of ramipril and 10 mg of amlodipine (as amlodipine besilate).
• The other ingredients are hypromellose 6cP, pregelatinized maize starch, microcrystalline cellulose, magnesium stearate (E470b) inside the capsule.
  Other ingredients of the 5 mg/5 mg and 10 mg/5 mg hard capsules: titanium dioxide (E171), yellow iron oxide (E172), red iron oxide (E172), black iron oxide (E172), gelatin, black ink (shellac (E904), propylene glycol (E1520), potassium hydroxide (E525), black iron oxide (E172)) in the capsule coating.
  Other ingredients of the 5 mg/10 mg hard capsules: titanium dioxide (E171), red iron oxide (E172), gelatin, black ink (shellac (E904), propylene glycol (E1520), potassium hydroxide (E525), black iron oxide (E172)) in the capsule coating.
  Other ingredients of the 10 mg/10 mg hard capsules: titanium dioxide (E171), red iron oxide (E172), gelatin, white ink (shellac (E904), propylene glycol (E1520), potassium hydroxide (E525), titanium dioxide (E171)) in the capsule coating.

Description of the appearance of Ramipril and Amlodipine Krka and contents of the pack
5 mg/5 mg capsules (capsules): the capsule body is orange-brown with the black imprint 0505. The capsule cap is orange-brown. The capsule content is white to almost white powder, possibly with crystals. Capsule size No. 2.
5 mg/10 mg capsules (capsules): the capsule body is white to almost white with the grey imprint 0510. The capsule cap is red-brown. The capsule content is white to almost white powder, possibly with crystals. Capsule size No. 0.
10 mg/5 mg capsules (capsules): the capsule body is white to almost white with the black imprint 1005. The capsule cap is orange-brown. The capsule content is white to almost white powder, possibly with crystals. Capsule size No. 0.
10 mg/10 mg capsules (capsules): the capsule body is red-brown with the white imprint 1010. The capsule cap is red-brown. The capsule content is white to almost white powder, possibly with crystals. Capsule size No. 0.
Ramipril and Amlodipine Krka is available in packs containing:

• 30, 50, 60, 90 and 100 hard capsules in blisters,
• 30 x 1, 50 x 1, 60 x 1, 90 x 1 and 100 x 1 hard capsules in unit dose blisters.

Not all pack sizes may be marketed.
Marketing Authorisation Holder
KRKA, d. d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia
Local representative in Italy:
KRKA Farmaceutici Milano S.r.l. – Italy
Responsible manufacturers for batch release
KRKA, d. d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia
TAD Pharma GmbH, Heinz-Lohmann-Straße 5, 27472 Cuxhaven, Germany
This medicinal product is authorised in the European Economic Area countries with the following names:

More detailed information on this medicinal product is available on the website of the Italian Medicines Agency, http://www.aifa.gov.it