Zestoretic: detailed information

Patient Information Leaflet

ZESTORETIC 20 mg + 12.5 mg tablets

Lisinopril + Hydrochlorothiazide
Please read all of this leaflet carefully before you start 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 their symptoms are the same as yours, as it could be harmful.
If you experience any side effect, including those not listed in this leaflet, tell your doctor or pharmacist. See section 4.

Contents of this leaflet:

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

1. What Zestoretic is and what it is used for

Zestoretic contains the active substances: lisinopril and hydrochlorothiazide.
Lisinopril belongs to a group of medicines called ACE inhibitors (Angiotensin-Converting Enzyme inhibitors), which work by reducing blood pressure through the dilation of blood vessels.
Hydrochlorothiazide belongs to a group of medicines called diuretics, which work by increasing the production and elimination of urine, thereby lowering blood pressure.
Zestoretic is indicated for the treatment of high blood pressure (primary arterial hypertension) in adults when it cannot be controlled by monotherapy with either lisinopril or hydrochlorothiazide alone.
Talk to your doctor if you do not feel better or if you feel worse.

2. What you should know before taking Zestoretic

Do not take Zestoretic:

if you are allergic to lisinopril or hydrochlorothiazide or to any of the other ingredients of this medicine (listed in section 6)
if you are allergic to medicines similar to Zestoretic (other ACE inhibitors or sulfonamide-derived medicines)
if you are not passing urine (anuria)
if you previously experienced itching, hives, sudden drop in blood pressure, swelling of hands, feet, ankles, face, lips, tongue and/or throat (angioedema) caused by prior treatment with ACE inhibitors
if someone in your family has ever had a severe allergic reaction of unknown cause. This may indicate a condition called hereditary angioedema and may make you more susceptible to the symptoms described above
if you suffer from idiopathic angioedema (without evident cause)
if you have severe kidney problems (creatinine clearance < 30 ml/min)
if you have severe liver problems
if you are more than 3 months pregnant (see section “Pregnancy and breastfeeding”)
if you are taking medicines containing aliskiren (for treating high blood pressure) and you have diabetes or reduced kidney function (see section “Other medicines and Zestoretic”).

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

if you have narrowing (stenosis) of the aortic valve (a heart artery) or of the renal artery
if you have hypertrophic cardiomyopathy (a condition characterized by thickening of the heart muscle) or if you have narrowing of heart valves (mitral valve), or if there are other obstructions to blood flow out of your left ventricle
if you have problems with diarrhoea or vomiting
if you suffer from gout (a disease causing joint pain)
if you suffer from liver problems
if you suffer from kidney problems
if you are undergoing dialysis (a medical treatment to clean the blood when you have severe kidney disease)
if you have had a kidney transplant
if you are on a low-salt diet
if you are taking medicines for treating allergies, for example due to insect stings
if you or someone in your family has previously had allergic reactions with swelling of the hands, feet or ankles, face, lips, tongue and/or throat, with difficulty breathing (see section “Possible side effects”)
if you need to undergo plasmapheresis (a procedure to separate certain components from the blood)
if you suffer from hypotension (low blood pressure, which may manifest as weakness or dizziness)
if you have reduced sugar tolerance or suffer from diabetes
if you are taking any of the following medicines for treating 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
if you are taking medicines for treating breast cancer called mTOR inhibitors (e.g. temsirolimus, everolimus, sirolimus) or medicines containing NEP inhibitors (e.g. racecadotril), as these may increase the risk of angioedema. Symptoms of angioedema include swelling of the face, lips, tongue and/or throat with difficulty swallowing or breathing
if you have previously had skin cancer or are developing an unexpected skin lesion during treatment. Treatment with hydrochlorothiazide, particularly long-term use at high doses, may increase the risk of certain types of skin and lip cancer (non-melanoma skin cancer). Protect your skin from exposure to sunlight and UV rays while taking Zestoretic
If you experience decreased vision or eye pain. These could be symptoms of fluid accumulation in the vascular layer of the eye (choroidal effusion) or increased pressure in the eye and may occur from a few hours to weeks after taking Zestoretic. This may lead to permanent vision loss if not treated. If you previously had an allergy to penicillins or sulfonamides, you may be at higher risk of developing this
If you have previously experienced breathing or lung problems (including inflammation or fluid in the lungs) after taking hydrochlorothiazide. If you develop shortness of breath or severe breathing difficulties after taking Zestoretic, consult a doctor immediately.

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

if changes in blood cell counts (white blood cells, red blood cells, and platelets) occur during treatment with Zestoretic
if you develop a marked decrease in certain types of white blood cells, leading to increased susceptibility to infections and severe general symptoms (agranulocytosis)

Changes in blood salt levels (electrolyte imbalance)
Due to the diuretic in Zestoretic, levels of sodium and potassium in the blood may decrease. This may cause dry mouth, thirst, weakness, drowsiness, irritability, fatigue, muscle pain, hypotension, nausea, rapid heartbeat, and stomach and/or intestinal disturbances.
The diuretic may also cause a decrease in chloride and magnesium levels, while possibly increasing calcium levels.
Therefore, your doctor may prescribe blood tests to monitor your salt levels.

Cough
During treatment, you may develop a dry, persistent cough.
This cough resolves upon discontinuation of treatment.
If you need to undergo tests to assess respiratory function during treatment, inform your doctor that you are taking Zestoretic.

Sudden drop in blood pressure
The initial dose may cause a more pronounced drop in blood pressure than occurs later during continued treatment. You may therefore experience weakness or dizziness; lying down may help in such cases. If symptoms persist, consult your doctor.

Anaesthesia
If you are admitted to hospital, you must inform medical staff that you are being treated with Zestoretic, and particularly inform the anaesthetist (the doctor administering anaesthesia) if undergoing surgery. You should also inform your dentist if local anaesthesia is administered for dental procedures.

Ethnicity
If you are of African origin, you may be more likely to develop “angioedema” (characterized by swelling of the face, lips, tongue, throat, or sudden breathing difficulty).

For athletes
Using this medicine without therapeutic need constitutes doping and may lead to a positive result in anti-doping tests.

Children and adolescents
The safety and efficacy of Zestoretic in children and adolescents has not been established; therefore, this medicine is not recommended for children and adolescents.

Other medicines and Zestoretic
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
In particular, before starting treatment with Zestoretic, inform your doctor if you are taking:

other diuretic medicines (including a type of diuretics called “potassium-sparing diuretics”), as they may increase the effect of this medicine when taken together with Zestoretic
other antihypertensive medicines (for treating high blood pressure) known as sartans (e.g. valsartan, telmisartan, irbesartan), especially if you have kidney problems or diabetes
other antihypertensive medicines (for treating high blood pressure), including those containing aliskiren (for treating high blood pressure), as they may increase the effect of this medicine when taken together with Zestoretic. In particular, do not take Zestoretic if you are taking aliskiren and have kidney problems or diabetes (see section “Do not take Zestoretic”)
indomethacin (an analgesic, medicine for pain and inflammation) or other medicines for treating joint inflammation or muscle pain
lithium (used for treating mental illnesses)
injectable gold (for treating rheumatoid arthritis, a chronic inflammation of the joints)
NSAIDs (Non-Steroidal Anti-Inflammatory Drugs, medicines for pain and inflammation), as they may reduce the effect of Zestoretic when taken together. Moreover, if you have reduced kidney function, these medicines may further reduce your kidney function
allopurinol (for treating gout, a disease causing joint pain), as taking it together with Zestoretic may increase the risk of leucopenia (reduced number of white blood cells in the blood)
cytostatic agents (used to reduce tumour growth), e.g. cyclophosphamide, methotrexate, everolimus, and medicines used to prevent rejection of transplanted organs, e.g. kidney or liver (such as temsirolimus, sirolimus), as they may increase the risk of leucopenia when taken together with Zestoretic
racecadotril, used to treat diarrhoea
tissue plasminogen activator (TPA), used to dissolve blood clots formed in blood vessels
immunosuppressants (medicines that reduce immune response), which may increase the risk of leucopenia when taken together with Zestoretic
procainamide and sotalol (medicines for heart rhythm disorders, antiarrhythmics)
medicines for treating diabetes (including insulin), as your doctor may need to adjust the dose of your diabetes medicine if you have diabetes
potassium supplements or potassium-containing salt substitutes, or other medicines that increase potassium levels in the blood (e.g. heparin, cotrimoxazole)
salicylate derivatives, used to treat various types of pain (e.g. headache, menstrual pain, muscle or bone pain), to reduce fever, and to treat inflammatory diseases
calcium or vitamin D supplements
vasodilators, nitroglycerin and other nitrates (used to reduce blood pressure and/or treat heart problems)
medicines to relax muscles during general anaesthesia and intensive care (including tubocurarine chloride and anaesthetics)
medicines for treating mood disorders, such as tricyclic antidepressants and antipsychotics
sympathomimetics (medicines acting mainly on the sympathetic nervous system, which controls internal organs, particularly blood circulation and the heart)
amphotericin B (administered intravenously), for treating fungal infections
carbenoxolone (for treating ulcers or inflammation of the oesophagus or around the mouth)
corticotropin (a hormone)
stimulant laxatives (medicines for treating constipation)
digoxin (for treating heart problems, including heart rhythm disorders)
medicines for treating high cholesterol levels, such as cholestyramine and colestipol
trimethoprim, for treating bacterial infections
medicines to prevent organ rejection after transplantation, such as cyclosporine
medicines with anti-inflammatory activity (corticosteroids), as they increase the excretion of certain salts normally dissolved in blood and body fluids, particularly potassium
medicines such as adrenaline (a medicine that stimulates the heart), as their effect may be reduced
barbiturates and narcotics (substances that reduce brain activity), as they may cause excessive drop in blood pressure when standing
diazoxide (used to treat low blood sugar levels)
amantadine (used to treat viral infections), as its toxicity may increase

Zestoretic and alcohol
Drinking alcohol together with Zestoretic may cause excessive drop in blood pressure when standing.

Pregnancy and breastfeeding
If you are pregnant, think you might be pregnant, planning to become pregnant, or breastfeeding, consult your doctor or pharmacist before taking this medicine.

Pregnancy
The use of Zestoretic is not recommended during the first 3 months of pregnancy.
Do not take Zestoretic after the first 3 months of pregnancy (see section “Do not take Zestoretic”).
You must inform your doctor if you think you are pregnant (or if there is a possibility of becoming pregnant).
Treatment with Zestoretic should not be started during pregnancy.
Your doctor will usually advise you to stop taking Zestoretic before becoming pregnant or as soon as pregnancy is confirmed, and will recommend an alternative medicine unless continued treatment with an ACE inhibitor is considered essential.
Zestoretic is not recommended in early pregnancy, as there may be a slight increase in the risk of fetal toxicity.
Zestoretic must not be taken if you are more than three months pregnant, as it may cause serious harm to the baby if taken after the third month of pregnancy (see section “Do not take Zestoretic”).
If exposure to an ACE inhibitor occurs after the first trimester of pregnancy, your doctor will recommend an ultrasound to assess fetal kidney and skull development, and will subsequently monitor the newborn for risk of hypotension (low blood pressure).

Breastfeeding
Inform your doctor if you are breastfeeding or planning to breastfeed.
Breastfeeding of newborns (first weeks after birth), and especially of premature infants, is not recommended while taking Zestoretic. Your doctor will evaluate the benefits to you and the risks to the newborn associated with taking Zestoretic during breastfeeding, and may recommend an alternative treatment if you wish to breastfeed.

Driving and using machines
During treatment with Zestoretic, you may experience dizziness or fatigue.
Therefore, avoid driving or operating machinery requiring special attention until your response to this medicine is known.

3. How to take Zestoretic

Take this medicine exactly as directed by your doctor or pharmacist. If you have
any doubts, consult your doctor or pharmacist.
Adults and elderly
The recommended dose is 1 tablet once daily. In general, if the desired effect is not achieved after 2-4 weeks, your doctor may increase the dosage up to 2 tablets taken together as a single daily dose.
If you have reduced kidney function (renal impairment)
If you suffer from renal impairment, your doctor, after assessing your kidney function, may decide not to prescribe Zestoretic for initial treatment of hypertension, as this medicine may be ineffective. When used alone, the recommended starting dose of lisinopril in renal impairment is 5–10 mg.
If you have previously been treated with diuretics (medicines that work by increasing the amount of urine produced by the kidneys)
If you have previously been treated with diuretics before starting Zestoretic, you may experience symptomatic hypotension (reduction in blood pressure causing symptoms such as nausea, weakness, headache, drowsiness, mental confusion). This is especially likely if you have a reduced blood volume (hypovolemia) and/or low sodium levels in the blood due to prior diuretic therapy.
If you are taking diuretics, your doctor will stop your diuretic treatment for 2–3 days before starting Zestoretic. If this is not possible, your doctor will start treatment with lisinopril alone at a dose of 5 mg.
Use in children and adolescents
The safety and efficacy of Zestoretic in children and adolescents has not been established; therefore, this medicine is not recommended for use in children and adolescents.
How to take
Take the tablets with a glass of water at the same time each day, preferably in the early morning.
If you take more Zestoretic than you should
In case of accidental overdose, contact your doctor or the nearest hospital immediately.
If you take an excessive dose of this medicine, you may experience the following symptoms: low blood pressure, syncope (fainting), electrolyte imbalances (levels of sodium, potassium and other substances in the blood), kidney problems, rapid and deep breathing, fast heartbeat, palpitations, slow heartbeat, dizziness, anxiety, cough, increased urination, seizures, paresis, irregular heartbeat, and severe kidney problems.
If you forget to take Zestoretic
If you forget to take a dose, take it as soon as possible. Do not take two doses at the same time.
Do not take a double dose to make up for a forgotten tablet.
If you stop taking Zestoretic
Do not stop treatment because you feel better, unless your doctor tells you to do so.
If you have any doubts about how to use this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
Zestoretic is generally well tolerated.

If you experience any of the following side effects while taking Zestoretic, contact your doctor immediately, who will STOP treatment with Zestoretic:

allergic reactions. Signs may include: swelling of the face, hands, feet, ankles, lips, tongue and/or throat (angioedema) (see section “Warnings and precautions”);
jaundice (yellowing of the skin and whites of the eyes);
marked increase in liver enzymes (assessed by blood test). Elevated liver enzymes are signs of impaired liver function: hepatitis (liver inflammation), liver failure (severe liver disease).

If you experience the following side effect while taking Zestoretic, contact your doctor immediately:

severe eye pain accompanied by redness and sudden blurred vision. If untreated, this condition could lead to permanent loss of vision.

Additionally, the following side effects have been observed and reported during treatment with Zestoretic, with the following frequencies:
Common (may affect up to 1 in 10 people):

dizziness
headache
paresthesia (tingling)
orthostatic effects, including hypotension (low blood pressure when standing up, accompanied by symptoms such as dizziness/light-headedness)
syncope (fainting)
cough
diarrhea
nausea
vomiting
rash (skin eruptions)
muscle cramps
inability to achieve an erection (impotence)
fatigue
asthenia (weakness)
changes in blood tests to monitor kidney function (increased urea and creatinine)
changes in blood tests to monitor liver function (increased liver enzymes)
changes in blood tests assessing hemoglobin (decreased hemoglobin).

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

gout (a disease causing joint pain)
depressive symptoms
palpitations (sensation of increased heart rate)
dry mouth
chest tightness
alteration in a laboratory test: decreased hematocrit (a test measuring the amount of red blood cells in the blood).

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

anemia (reduced hemoglobin in the blood, the substance that carries oxygen)
inadequate production of a hormone that reduces the amount of urine produced by the kidneys, called “antidiuretic hormone”
increased blood sugar levels (hyperglycemia)
reduced potassium levels in the blood (hypokalemia)
increased uric acid levels in the blood (hyperuricemia)
increased potassium levels in the blood (hyperkalemia)
disturbances in smell
pancreatitis (inflammation of the pancreas, a gland located near the stomach)
muscle weakness
increased bilirubin (a substance produced by the body, whose increase may be due to liver disorder) in the blood.

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

bone marrow depression (reduced activity of the bone marrow, where blood cells are produced)
hemolytic anemia (a disease caused by destruction of certain blood cells, red blood cells)
thrombocytopenia (reduced number of platelets in the blood)
leucopenia (reduced number of white blood cells in the blood)
agranulocytosis (increase in the number of granulocytes in the blood, a type of blood cell)
intestinal angioedema (swelling of the intestinal walls that may cause severe abdominal pain, vomiting and diarrhea)
pseudolymphoma cutis (a disease manifesting with a complex set of symptoms which may include one or more of the following: fever, vasculitis (inflammation of blood vessels), myalgia (muscle pain), arthralgia/arthritis (joint pain/inflammation), positive laboratory tests for certain immune reactions (positive antinuclear antibodies, ANA), elevated erythrocyte sedimentation rate (ESR, a laboratory marker of inflammation), eosinophilia and leukocytosis (increased levels of eosinophils and leukocytes in the blood), rash (skin eruptions), photosensitivity (sensitivity to sunlight), and other skin-related manifestations)
Acute respiratory distress (signs include severe shortness of breath, fever, weakness and confusion).

Not known (frequency cannot be estimated from available data)

Severe allergic reactions
Skin and lip cancer (non-melanoma skin cancer)

Other side effects reported with other medicines containing the same active substances as Zestoretic (hydrochlorothiazide and lisinopril), and which may therefore also potentially occur with Zestoretic.

Possible side effects with hydrochlorothiazide
Frequency not known (cannot be estimated from available data)

anorexia (loss of appetite)
gastric irritation (stomach inflammation)
constipation
sialadenitis (inflammation of the glands producing saliva)
dizziness
xanthopsia (visual disturbance characterized by yellow vision of white objects)
aplastic anemia (inadequate production of all types of blood cells by the bone marrow)
purpura (a condition where the skin turns red due to abnormal accumulation of blood)
photosensitivity (sensitivity to sunlight)
urticaria (skin redness accompanied by itching)
inflammation of blood vessels (necrotizing angiitis: vasculitis, cutaneous vasculitis)
fever
exanthema (skin eruption with pustules, blisters and bullae, typical of some childhood diseases)
breathing difficulties including pneumonia and pulmonary edema (accumulation of fluid in the lungs)
glycosuria (presence of sugar in urine)
electrolyte imbalances including hyponatremia (decreased sodium levels in blood), hypomagnesemia (decreased magnesium levels in blood)
agitation, depression, dizziness, sleep disturbances
kidney disorders (renal dysfunction and interstitial nephritis)
activation or worsening of symptoms of lupus (an immune system disease presenting with fatigue, joint pain, skin rashes, swelling, flushing, weight gain or loss, etc.)
toxic epidermal necrolysis and Stevens-Johnson syndrome (severe skin lesions characterized by skin irritation, blistering and areas of skin detachment)
hypochloremic alkalosis (loss of chloride from the body)
increased cholesterol and triglyceride levels in blood
hypercalcemia (increased calcium in blood); if you develop increased calcium levels in blood, your doctor will prescribe tests to evaluate for a condition called “hyperparathyroidism” (a disorder in the production of a hormone regulating blood calcium levels)
cardiac arrhythmias (abnormal heart rhythm, i.e. change in beats per minute)
sudden-onset difficulty seeing at a distance (acute myopia)
acute angle-closure glaucoma (a severe form of glaucoma, i.e. eye disease caused by increased pressure of the fluid inside the eye)
decreased vision or eye pain due to high pressure (possible signs of fluid accumulation in the vascular layer of the eye (choroidal effusion)
transient visual disturbances including transient blurred vision.

Possible side effects with lisinopril
Common (may affect up to 1 in 10 people):

kidney dysfunction.

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

taste disturbances
sleep disorders
mood changes
myocardial infarction (heart attack) or cerebrovascular event (stroke), possibly due in predisposed individuals to excessive reduction in blood pressure
tachycardia (increased heart rate)
Raynaud's syndrome (pain in fingers of hands and feet which first turn pale, then bluish, then reddish)
rhinitis (irritation or inflammation of nasal mucosa)
stomach ache (abdominal pain and indigestion)
itching.

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

mental confusion
alopecia (hair loss)
urticaria (skin redness accompanied by itching)
psoriasis (a chronic non-infectious, non-contagious inflammatory skin disease)
uremia (presence of urea in blood)
acute renal failure (severe kidney disease)
gynecomastia (development of breasts in men)
low sodium levels in blood.

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

lymphadenopathy (enlargement of lymph nodes – organs of the body's defense system)
autoimmune disease (disorder of the body's defense system)
low blood sugar levels (hypoglycemia)
sinusitis (inflammation of the sinuses)
bronchospasm (narrowing of the bronchi causing severe breathing difficulty due to reduced airflow)
breathing difficulties caused by an allergic reaction including allergic alveolitis/eosinophilic pneumonia
severe skin disorders including pemphigus (a blistering skin disease), toxic epidermal necrolysis and Stevens-Johnson syndrome (severe skin lesions characterized by erythema, blistering and areas of skin detachment), and erythema multiforme (a condition characterized by red spots on the skin with "target" appearance associated with itching)
diaphoresis (excessive sweating)
oliguria/anuria (reduced or absent urine output).

Frequency not known (cannot be estimated from available data)

hot flushes
visual and/or auditory hallucinations (perception of non-existent things and/or voices).

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 https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
By reporting side effects, you help provide more information on the safety of this medicine.

5. How to store Zestoretic

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

6. Pack contents and other information

The active substances are: lisinopril dihydrate (each tablet contains 21.8 mg of lisinopril dihydrate, equivalent to 20 mg of anhydrous lisinopril), hydrochlorothiazide (each tablet contains 12.5 mg of hydrochlorothiazide).
The other components are: mannitol, dibasic calcium phosphate dihydrate, maize starch, pregelatinized starch, magnesium stearate.

Description of the appearance of Zestoretic and pack contents
Tablets packed in blisters containing 14 tablets, 28 tablets, and 42 tablets.
Not all pack sizes may be marketed.

Marketing Authorization Holder and Manufacturer
Atnahs Pharma Netherlands B.V.
Copenhagen Towers, Ørestands Boulevard 108, 5.tv DK-2300, København S, Denmark

Manufacturers
AstraZeneca Reims Production, Parc Industriel de la Pompelle, Chemin de Vrilly, 51100 Reims, France