Patient Information Leaflet

Enefin 20 mg + 12.5 mg tablets

enalapril maleate + hydrochlorothiazide
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 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 could be harmful.
If you experience any side effects, including those not listed in this leaflet, contact your doctor or pharmacist. See section 4.

Contents of this leaflet:

What Enefin is and what it is used for
What you need to know before taking Enefin
How to take Enefin
Possible side effects
How to store Enefin
Contents of the pack and other information

1. What Enefin is and what it is used for

Enefin contains two active substances: enalapril maleate and hydrochlorothiazide.
Enalapril maleate belongs to a group of medicines known as angiotensin-converting enzyme inhibitors (ACE inhibitors). ACE inhibitors work by relaxing blood vessels, thereby making it easier for blood to flow through them. ACE inhibitors are used to treat high blood pressure (hypertension).
Hydrochlorothiazide belongs to a group of medicines called thiazide diuretics. It works by stimulating the kidneys to produce more urine (diuretic effect), thereby reducing blood pressure (antihypertensive effect).
Enefin is used to treat high blood pressure and is indicated in patients whose blood pressure is not adequately controlled with enalapril maleate or hydrochlorothiazide given alone.

2. What you should know before taking Enefin

Do not take Enefin:

if you are allergic to the active substances (enalapril maleate and hydrochlorothiazide) or to other sulfonamide-derived medicines (chemically related to hydrochlorothiazide), or to any of the other ingredients of this medicine (listed in section 6);
if you have had an allergic reaction causing swelling of the hands, feet, ankles, or even the face, lips, tongue and/or throat, leading to difficulty in swallowing or breathing (angioedema) after taking ACE inhibitors;
if you suffer from hereditary angioedema (due to a familial predisposition);
if you suffer from idiopathic angioedema, i.e. angioedema of unknown cause;
if you have severe kidney problems (severe renal failure);
if you are unable to urinate (anuria);
if you are in the second or third trimester of pregnancy (see section "Pregnancy and breastfeeding");
if you suffer from severe liver problems (severe hepatic failure);
if you have diabetes or impaired kidney function and are being treated with a blood pressure-lowering medicine containing aliskiren (see section "Other medicines and Enefin");
if you are being treated with sacubitril/valsartan, a medicine for heart failure.

Warnings and precautions
Talk to your doctor or pharmacist before taking Enefin.
In particular, consult your doctor or pharmacist before taking Enefin if:

you are taking medicines that increase urine production (diuretics), are on a low-salt diet, or have experienced vomiting or diarrhoea. In these cases, you are at risk of excessive drop in blood pressure (hypotension), which may manifest as weakness or dizziness. Your doctor will prescribe regular monitoring of electrolyte levels in your blood.
you have disorders of blood flow to the heart (ischaemic heart disease) or brain (ischaemic cerebrovascular disease), or other heart problems, with or without kidney involvement. In such cases, excessive lowering of blood pressure may be particularly dangerous. If you experience symptoms of hypotension during treatment with Enefin, lie down and contact your doctor immediately;
you have previously had skin cancer or are developing unexpected skin lesions during treatment. Treatment with hydrochlorothiazide, especially long-term use at high doses, may increase the risk of certain types of non-melanoma skin cancer and lip cancer. Protect your skin from exposure to sunlight and UV rays while taking Enefin;
inform your doctor if you are taking a medicine containing a neprilysin inhibitor such as sacubitril (available as a fixed-dose combination with valsartan), used in patients with heart failure, or racecadotril, used in patients with acute diarrhoea;
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), particularly 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 in section "Do not take Enefin";
you are at risk of increased potassium levels in the blood (hyperkalemia) due to:
renal failure, worsening kidney function, age over 70 years, diabetes, dehydration, acute heart failure causing inadequate blood circulation, increased blood acidity (metabolic acidosis);
concomitant use of medicines that promote urine elimination while preserving potassium (potassium-sparing diuretics, e.g. spironolactone, eplerenone, triamterene or amiloride), potassium supplements, potassium-containing salt substitutes, or other medicines that may increase blood potassium levels (e.g., heparin [a medicine used to prevent blood clots], trimethoprim-containing products such as co-trimoxazole [medicines used to treat infections]) (see section "Other medicines and Enefin"). In such cases, your doctor will frequently monitor your blood potassium levels;
you suffer from narrowing (stenosis) of the aortic artery or have thickening of the heart walls (hypertrophic cardiomyopathy);
you suffer from severe heart problems (severe heart failure);
you have kidney problems, e.g. narrowing (stenosis) of one or both renal arteries, as there is an increased risk of hypotension and renal failure. In such cases, your doctor will closely monitor your kidney function;
you have recently undergone a kidney transplant. In this case, use of this medicine is not recommended;
you are undergoing dialysis (blood purification therapy) due to kidney failure. In this case, your doctor will consider an alternative treatment (see section "Do not take Enefin");
you have liver problems or suffer from a disease that could lead to destruction of liver cells (progressive liver disease) (see sections "Do not take Enefin" and "Stop taking Enefin and inform your doctor if");
you have chronic degenerative liver disease (hepatic cirrhosis), marked urine production, inadequate oral intake of electrolytes, or are being treated with corticosteroids or adrenocorticotropic hormone (hormonal medicines). In such cases, the risk of low blood potassium levels (hypokalemia) is highest;
you suffer from a connective tissue disease affecting blood vessels, are taking medicines that suppress the immune system (immunosuppressants), suffer from gout or are taking allopurinol (used to treat gout) or procainamide (used to treat heart rhythm disorders), or have a combination of these risk factors, especially if you also have kidney problems. In such cases, severe infections may occur that may not respond to antibiotic therapy. If you need to take Enefin under these conditions, your doctor will prescribe specific blood tests. Report any signs or symptoms of infection to your doctor;
you have diabetes and are taking oral antidiabetic medicines or insulin. In this case, your doctor will advise blood tests to monitor glucose levels, especially during the first month of treatment with Enefin, and may adjust the dose of your antidiabetic medicines;
you are taking lithium (a medicine for the treatment of mood disorders) (see section "Other medicines and Enefin");
you are of Black race. Enefin may be less effective in lowering blood pressure in Black patients compared to non-Black patients. In addition, you may have a higher risk of developing angioedema;
you have developed a persistent dry cough for a long time after starting treatment with an ACE inhibitor;
if you have a history of allergies or bronchial asthma, as sensitivity reactions may occur with the use of Enefin;
if you suffer from a disorder called systemic lupus erythematosus (an autoimmune disease), which may develop or worsen with the use of Enefin;
if you experience vision loss or eye pain. These may be symptoms of fluid accumulation in the vascular layer of the eye (choroidal effusion) or increased eye pressure and may occur from a few hours to weeks after taking ENEFIN. This condition may lead to permanent vision loss if not treated. If you have previously experienced allergy to penicillin or sulfonamide, you may be at higher risk of developing this condition.

If you are about to undergo any of the following procedures, inform your doctor that you are
taking Enefin:

any surgical intervention or if you are to receive anaesthetic therapy;
a treatment called dextran-sulfate LDL (low-density lipoprotein) apheresis, to remove cholesterol from the blood using machines. Your doctor may temporarily discontinue Enefin to prevent a possible allergic reaction;
a treatment to reduce the effects of an allergy, for example following an insect sting (desensitization therapy). If you take Enefin during this treatment, you may experience a severe allergic reaction; therefore, temporary interruption of therapy is advisable;
you need to undergo tests to assess parathyroid gland function. Consult your doctor, who will advise you to stop taking Enefin before this test.

Stop taking Enefin and inform your doctor if you experience:

swelling of the hands, feet, ankles, or of the face, lips, tongue and/or throat, causing difficulty in swallowing or breathing (angioedema);
yellowing of the skin and whites of the eyes (jaundice), indicating liver problems or increased levels of transaminases (liver enzymes) in the blood;
increased levels of nitrogen and creatinine in the blood, which may suggest possible renal artery stenosis;
increased calcium levels in the blood (hypercalcemia). During treatment with Enefin, an electrolyte imbalance may occur, manifesting with signs and symptoms such as:
dry mouth, thirst, weakness, pathological state of deep sleep (lethargy), drowsiness, agitation, muscle pain or cramps, muscle fatigue, low blood pressure, reduced urine output, increased heart rate (tachycardia), and gastrointestinal disturbances such as nausea and vomiting. In such cases, contact your doctor promptly. This medicine must be used under regular medical supervision. Therefore, strictly follow all laboratory tests and check-ups as prescribed by your doctor.

Children and adolescents
The use of Enefin is not recommended in children due to lack of data on safety and efficacy.
Other medicines and Enefin
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
In particular, consult your doctor or pharmacist if you are taking:

an angiotensin II receptor antagonist (AIIRA) or aliskiren (see also section "Do not take Enefin" and "Warnings and precautions"). Your doctor may consider it necessary to adjust the dose and/or take other precautions;
other medicines that lower blood pressure (antihypertensives), including vasodilators, nitroglycerin and other nitrates, as excessive reduction in blood pressure may occur;
lithium, used to treat certain mood disorders, as excessive increase in lithium concentration in the blood and consequent lithium toxicity may occur;
medicines that promote urine elimination while preserving potassium (potassium-sparing diuretics, e.g. spironolactone, triamterene or amiloride), potassium supplements, potassium-containing salt substitutes, or other medicines that may increase blood potassium levels (e.g., heparin [a medicine used to prevent blood clots], trimethoprim-containing products such as co-trimoxazole [medicines used to treat infections]) (see section "Warnings and precautions");
medicines that promote diuresis (diuretics), such as thiazides or loop diuretics, as they may cause a reduction in blood pressure;
anaesthetics, antipsychotics and tricyclic antidepressants (used to treat mental disorders), as further reduction in blood pressure may occur;
medicines acting on the autonomic nervous system (sympathomimetics) such as ephedrine, pseudoephedrine, salbutamol found in some nasal decongestants, cough and cold remedies, asthma treatments, low blood pressure treatments, and heart condition treatments. These medicines may reduce the antihypertensive effects of Enefin;
insulin or other oral antidiabetic medicines. Blood glucose levels must be carefully monitored, especially during the first weeks of treatment with Enefin and in patients with kidney problems;
medicines used to treat stiffness and inflammation associated with painful conditions, particularly those affecting muscles, bones and joints, including:
gold-containing medicines administered by injection, e.g. sodium aurothiomalate, as they may cause facial flushing, nausea, vomiting and low blood pressure when taken with Enefin;
non-steroidal anti-inflammatory drugs (NSAIDs), including COX-2 inhibitors, as they may reduce the effectiveness of Enefin, increase blood potassium levels and worsen kidney function;
carbenoxolone (a medicine used to treat stomach problems such as ulcers), kaliuretic diuretics (e.g. furosemide) or excessive use of laxatives. Taking Enefin with these medicines may further reduce potassium and/or magnesium levels in the blood;
tubocurarine, used to relax muscles during surgery (muscle relaxant), as Enefin may enhance its effects;
barbiturates, which have a sedative effect on the central nervous system, used, for example, to treat epilepsy, or opioid analgesics, medicines used to reduce pain. These medicines may worsen dizziness upon standing due to low blood pressure (orthostatic hypotension);
medicines used to reduce blood fat levels, such as cholestyramine or colestipol resins, as they may reduce the absorption of Enefin;
medicines used to treat irregular heartbeat (antiarrhythmics such as quinidine, procainamide, amiodarone, sotalol), as they may cause heart rhythm problems (torsades de pointes);
medicines used to treat heart failure (digitalis medicines);
corticosteroids (which modulate anti-inflammatory responses) and adrenocorticotropic hormone (ACTH) (used to check adrenal gland function), as they may further reduce blood electrolyte levels, particularly potassium (hypokalemia);
pressor amines (e.g. noradrenaline), as Enefin may reduce their effects;
cancer medicines such as cyclophosphamide or methotrexate, as Enefin may increase their toxicity;
medicines used to treat gout, such as allopurinol (see section "Warnings and precautions");
immunosuppressive medicines;
mTOR inhibitors (e.g., temsirolimus, sirolimus, everolimus), as concomitant administration may increase the risk of an allergic reaction called angioedema (see section "Stop taking Enefin and inform your doctor if");
a medicine containing a neprilysin inhibitor such as sacubitril (available as a fixed-dose combination with valsartan) and racecadotril. The risk of angioedema (swelling of the face, lips, tongue or throat with difficulty swallowing or breathing) may be increased. See also information in sections "Do not take ENEFIN" and "Warnings and precautions".

Enefin and alcohol
Enefin must not be taken with alcohol, as excessive lowering of blood pressure may occur.
Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, plan to become pregnant, or are breastfeeding, consult your doctor or pharmacist before using this medicine.
Pregnancy
Enefin is not recommended during pregnancy and must not be taken if you are more than 3 months pregnant, as it may cause serious harm to the unborn child if taken after the third month of pregnancy (see section "Do not take Enefin").
You must inform your doctor if you think you are pregnant (or if you are planning a pregnancy). Your doctor will advise you to stop taking Enefin immediately before becoming pregnant or as soon as you learn you are pregnant, and will recommend an alternative medicine.
Breastfeeding
Inform your doctor if you are breastfeeding or intend to breastfeed. Enefin is not recommended for breastfeeding women, especially if your baby was born prematurely and during the first few weeks after delivery.
Driving and using machines
Enefin may cause side effects that may affect your ability to drive and use machines, such as dizziness or fatigue, which may occur occasionally.
Therefore, exercise caution when driving or operating machinery.
Enefin contains lactose
If your doctor has diagnosed you with an intolerance to certain sugars, contact him/her before taking this medicine.
For those engaged in sports
Using this medicine without therapeutic need constitutes doping and may result in a positive anti-doping test.

3. How to take Enefin

Take this medicine exactly as directed by your doctor. If you have any doubts, consult your doctor.

It is recommended to start therapy with ½ tablet daily. The recommended dose may then be increased to 1 tablet daily. If necessary, your doctor may increase the dose up to a maximum of 2 tablets, taken once daily.

Previous diuretic therapy
If you are already taking another medicine that increases diuresis, the use of enalapril contained in Enefin may lead to an excessive reduction in blood pressure. In such cases, if your doctor considers Enefin nevertheless necessary, they will instruct you to stop taking the diuretic a few days before starting Enefin. If this is not possible, your doctor may decide to start therapy with lower doses of enalapril, using separate tablets containing the same active substances as Enefin (enalapril and hydrochlorothiazide). Enefin may be used later, once your doctor has determined that you require the fixed dose of enalapril and hydrochlorothiazide contained in the Enefin tablet.

Patients with kidney problems (renal impairment)
You must not use Enefin if you suffer from severe kidney problems (see section "Do not take Enefin").
If you have kidney problems, your doctor will monitor your kidney function and determine the appropriate dose of Enefin.

Use in children and adolescents
The use of Enefin is not recommended in children.

Use in the elderly
Dosage adjustment is not required in elderly patients.

If you take more Enefin than you should
If you accidentally take too much Enefin, contact your doctor immediately or go to the nearest hospital and stop treatment.
Symptoms of overdose may include: feeling faint or dizzy due to excessive lowering of blood pressure, severe circulatory problems (circulatory shock), kidney failure, hyperventilation, increased heart rate (tachycardia), palpitations, decreased heart rate (bradycardia), anxiety, cough, electrolyte disturbances such as low levels of potassium (hypokalaemia), chloride (hypochloraemia), and sodium (hyponatraemia) in the blood, and dehydration due to excessive diuresis.

If you forget to take Enefin
Do not take a double dose to make up for the missed tablet. If in doubt, contact your doctor.

If you stop taking Enefin
Do not stop treatment with Enefin unless instructed by your doctor.

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

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody will get them.
Stop taking Enefin and contact your doctor immediately if you experience symptoms of angioedema during treatment, such as:

allergic reaction accompanied by swelling of the hands, feet, ankles, or also of the face, lips, tongue and/or throat, leading to difficulty swallowing or breathing (angioedema).

The side effects observed with the use of Enefin are as follows:
Very common (may affect more than 1 in 10 people)

blurred vision;
dizziness;
cough;
nausea;
loss of strength (asthenia).

Common (may affect up to 1 in 10 people)

low blood potassium levels (hypokalaemia) or high blood potassium levels (hyperkalaemia), increased blood cholesterol, triglycerides, uric acid (hyperuricaemia) and creatinine levels;
headache (cephalalgia), depression, temporary loss of consciousness (syncope), altered taste;
low blood pressure (hypotension), drop in blood pressure upon sudden change from sitting or lying down to standing (orthostatic hypotension), irregular heart rhythm, chest pain with a sensation of tightness and pressure (angina pectoris), increased heart rate (tachycardia);
difficulty breathing (dyspnoea);
diarrhoea, abdominal pain;
skin rash (exanthema);
involuntary muscle contractions (muscle cramps);
chest pain, fatigue.

Uncommon (may affect up to 1 in 100 people)

reduced number of red blood cells (anaemia, including aplastic and haemolytic anaemia);
low blood sugar (hypoglycaemia), low blood magnesium levels (hypomagnesaemia), joint pain and swelling (gout);
confusion, drowsiness, insomnia, nervousness, tingling sensation in legs, arms or other body parts (paraesthesia), sensation of dizziness (vertigo);
reduced sexual desire, impotence;
unpleasant sensation of ringing or buzzing in the ears (tinnitus);
flushing and sensation of warmth, mainly in the face, awareness of irregular or forceful heartbeat (palpitations), heart attack (myocardial infarction) or stroke (cerebrovascular accident), possibly secondary to a sharp drop in blood pressure in high-risk patients (see section “Warnings and precautions”);
runny nose (rhinorrhoea), throat burning (laryngodynia) and hoarseness, sensation of chest tightness causing difficult and noisy breathing (bronchospasm/asthma);
reduced intestinal movements (ileus), inflammation of the pancreas (pancreatitis), vomiting, difficulty digesting (dyspepsia), constipation (stipsis), loss of appetite (anorexia), stomach irritation, dry mouth, stomach lesions (peptic ulcer), increased intestinal gas production (flatulence);
increased sweating (diaphoresis), itching, urticaria, hair loss (alopecia);
joint pain (arthralgia);
impaired kidney function, kidney failure, presence of protein in urine (proteinuria);
malaise, fever;
increased blood urea levels (uraemia), low sodium concentration in blood (hyponatraemia).

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

reduced number of certain white blood cells (neutropenia, leucopenia and agranulocytosis), reduced haemoglobin levels, reduced total volume of red blood cells (low haematocrit), reduced platelets (thrombocytopenia), or reduced counts of all types of blood cells (pancytopenia), bone marrow depression (when bone marrow fails to produce sufficient blood cells), swelling of glands called lymph nodes (lymphadenopathy), immune system disorders (autoimmune diseases);
increased blood sugar levels;
abnormal dreams, sleep disturbances, partial reduction in mobility (paresis due to hypokalaemia);
reduced blood flow to fingers of hands and feet causing redness and pain (Raynaud's phenomenon);
lung problems including pulmonary infiltrates, severe respiratory failure (respiratory distress syndrome), lung inflammation (pneumonitis) and fluid accumulation in the lungs (pulmonary oedema), allergic (hypersensitivity) reaction in the lungs (allergic alveolitis), lung disease (eosinophilic pneumonia);
irritation or inflammation of the nose (rhinitis);
inflammation of the mouth lining (stomatitis) with ulcerations or aphthae, inflammation of the tongue (glossitis);
liver problems such as liver failure, liver damage (hepatic necrosis, potentially fatal), inflammation of the liver or bile ducts (hepatocellular or cholestatic hepatitis), yellowing of the skin and whites of the eyes (jaundice), inflammation of the gallbladder (cholecystitis, particularly in patients with pre-existing gallstones);
severe skin diseases with blistering, redness and peeling, including erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, purpura, cutaneous lupus erythematosus (an autoimmune disease causing skin inflammation), pemphigus and erythroderma (skin redness);
decreased urine output (oliguria), kidney disease (interstitial nephritis);
breast enlargement in men (gynaecomastia);
increased liver enzymes, increased blood bilirubin levels (bilirubinaemia).

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

increased blood calcium levels (hypercalcaemia);
swelling of the intestinal mucosa (intestinal angioedema).

Not known (frequency cannot be estimated from the available data):

syndrome of inappropriate antidiuretic hormone secretion (SIADH);
decreased vision or eye pain due to high pressure (possible signs of fluid accumulation in the vascular layer of the eye (choroidal effusion) or acute angle-closure glaucoma);
cancer of the skin and lips (non-melanoma skin cancer).

Other side effects
A complex disorder including one or more of the following symptoms has been reported, with unknown frequency:

fever, serositis (inflammation of the membranes lining body cavities such as chest and abdomen), vasculitis (inflammation of blood vessels), muscle pain or inflammation (myalgia/myositis), joint pain or inflammation (arthralgia/arthritis), positive test for antinuclear antibodies, increased erythrocyte sedimentation rate (ESR), increased white blood cell count (eosinophilia, leucocytosis), skin rash, skin sensitivity to light (photosensitivity), and other skin problems.

Reporting of side effects
If you experience any side effect, 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 the website
http://www.agenziafarmaco.gov.it/content/come-segnalare-una-sospetta-reazione-avversa.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Enefin

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the carton and on the blister after "Exp". The expiry date refers to the last day of that month.
Store below 30°C.
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. Pack contents and other information

What Enefin contains

The active substances are enalapril maleate and hydrochlorothiazide. Each tablet contains 20 mg of enalapril maleate and 12.5 mg of hydrochlorothiazide.
The other excipients are: sodium bicarbonate, monohydrate lactose, yellow iron oxide, maize starch, pregelatinized starch, magnesium stearate.

Description of the appearance of Enefin and contents of the pack
Enefin is presented as tablets contained in an aluminium blister pack.
Each pack contains 14 tablets.
Marketing Authorisation Holder and manufacturer
Marketing Authorisation Holder
LANOVA FARMACEUTICI S.r.l.
Via Conca D’oro, 212 – 00141 Roma
00189 Roma
Manufacturer
FARMAR ITALIA Via Zambelletti, 25 – Baranzate (Milan)
LACHIFARMA S.r.l. Laboratorio Chimico Farmaceutico Salentino
S.S. 16 Zona Industriale
73010 Zollino (LE)