Zestoretic - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf Life and Storage

Active ingredients: Lisinopril, Hydrochlorothiazide

ZESTORETIC 20 mg + 12.5 mg tablets

Why is Zestoretic used? What is it for?

PHARMACOTHERAPEUTIC CATEGORY

ACE inhibitor (angiotensin converting enzyme inhibitor) and diuretic, in combination.

THERAPEUTIC INDICATIONS

Zestoretic is indicated for the treatment of essential hypertension in patients for whom combination therapy is appropriate.

Contraindications When Zestoretic should not be used

Hypersensitivity to lisinopril, to any of the excipients or to other inhibitors of the angiotensin converting enzyme (ACE

Hypersensitivity to hydrochlorothiazide and to other sulfonamide-derived drugs.

Anuria.

History of angioedema related to previous treatment with angiotensin converting enzyme inhibitors

Hereditary or idiopathic angioedema.

Second and third trimester of pregnancy (see Special warnings).

Severe renal impairment (creatinine clearance <30 ml / min).

Severe hepatic impairment.

The concomitant use of Zestoretic with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR <60 ml / min / 1.73 m2)

Precautions for use What you need to know before taking Zestoretic

Before starting therapy, report to your doctor if:

  • you have aortic or mitral valve stenosis / hypertrophic cardiomyopathy or renal artery stenosis;
  • you have problems such as diarrhea or vomiting, gout, liver or kidney problems, if you are undergoing dialysis or kidney transplantation or low-salt diets or are taking desensitizing treatments for some allergy, for example for insect bites;
  • you have had allergic reactions possibly with swelling of the hands, feet or ankles, face, lips, tongue and / or throat with difficulty in breathing. Inform your doctor if a similar reaction has ever occurred to a family member for any reason.
  • blood separation treatment (apheresis) is needed
  • you are taking any of the following medicines used to treat high blood pressure:
  • an 'angiotensin II' receptor antagonist (AIIRA) (also known as sartans eg valsartan, telmisartan, irbesartan), particularly if you have diabetes-related kidney problems.
  • aliskiren.

Your doctor may check your kidney function, blood pressure, and the amount of electrolytes (such as potassium) in your blood at regular intervals. See also what is reported under the heading "Contraindications".

Also report to your doctor if you have hypotension (low blood pressure which may manifest as a feeling of weakness or dizziness).

Ethnicity

Converting enzyme inhibitors (ACE inhibitors) cause angioedema more frequently in black patients than in non-black patients. As with other ACE inhibitors, lisinopril may be less effective in lowering blood pressure in black patients than in black patients. non-blacks, possibly due to a higher prevalence of low renin concentrations in the black hypertensive population.

Lithium

The combination of ACE inhibitors and lithium and lisinopril is generally not recommended (see Interactions).

Electrolyte imbalance

As with any patient on diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals.

Thiazides, including hydrochlorothiazide, can cause fluid and electrolyte imbalance (hypokalaemia, hyponatremia and hypochloraemic alkalosis). Indicator signs of water or electrolyte imbalance are dry mouth, thirst, weakness, lethargy, drowsiness, cramps or muscle pain, fatigue muscle, hypotension, oliguria, tachycardia and gastrointestinal disorders such as nausea and vomiting.

Dilutional hyponatraemia can occur in oedematous patients in hot weather. A chloride deficiency is usually mild and does not require treatment. Thiazides have been shown to increase urinary excretion of magnesium, which can result in hypomagnesaemia.

Thiazides can decrease urinary calcium excretion and cause mild and intermittent increases in calcium. Marked hypercalcaemia can reveal asymptomatic hyperparathyroidism. Thiazide therapy must be discontinued before parathyroid function tests are performed.

Hyperkalaemia

Elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including lisinopril. Patients at risk of developing hyperkalaemia include those with renal insufficiency, diabetes mellitus, or those on concomitant treatment with potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes, or those patients on other drugs with which an increase in serum potassium (eg heparin). If concomitant use of the above agents is considered necessary, regular monitoring of serum potassium is recommended (see Interactions).

Diabetic patients

In diabetic patients being treated with oral antidiabetic drugs or insulin, glycemic control should be closely monitored during the first month of treatment with an ACE inhibitor (see Interactions).

Neutropenia and agranulocytosis

Neutropenia / agranulocytosis, thrombocytopenia and anemia have been reported in patients receiving ACE inhibitors. In patients with normal renal function and in the absence of other complicating factors, neutropenia rarely occurs. Neutropenia and agranulocytosis disappear after discontinuation of treatment with ACE inhibitors.

Lisinopril should be administered with extreme caution to patients with collagen disease, those on immunosuppressive therapy, allopurinol or procainamide, or who have a combination of these complicating factors, especially in previous renal impairment. Some of these patients developed severe infections, which in a few cases did not respond to intensive antibiotic therapy. If these patients are treated with lisinopril, periodic monitoring of white blood cell counts is recommended and patients should be instructed to report any episodes of infection.

Cough

Cough has been reported with the use of ACE inhibitors. This is characteristically nonproductive, persistent and resolves upon discontinuation of therapy.

ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.

The initial dose may cause a fall in blood pressure greater than that which subsequently occurs with continued treatment. A feeling of weakness or dizziness may occur; in these cases it may be helpful to lie down. If symptoms persist, consult your doctor.

Interactions Which drugs or foods may change the effect of Zestoretic

Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, even those without a prescription.

In particular, before starting therapy, report to your doctor if:

  • you are taking other drugs, especially diuretics (including potassium sparing), other antihypertensive drugs (for the treatment of high blood pressure), including those containing aliskiren, which when administered concomitantly may increase the antihypertensive effect, indomethacin (or other drugs for the treatment of arthritis or muscle aches), lithium (for certain psychiatric problems), injectable gold (for the treatment of rheumatoid arthritis), NSAIDs (non-steroidal anti-inflammatory drugs) which when administered concomitantly with ACE inhibitors may decrease the antihypertensive effect and in patients with impaired renal function may lead to a "further reduction in renal function; allopurinol, cytostatic, immunosuppressive agents and procainamide which when given together with ACE inhibitors may increase the risk of leukopenia;
  • you have diabetes, as thiazide diuretics may cause the need to adjust the dose of antidiabetic drugs, including insulin;
  • are taking blood pressure medicines containing aliskiren and have diabetes mellitus;
  • you are taking potassium supplements or potassium-containing salt substitutes;
  • you are taking blood pressure medicines containing aliskiren and have kidney problems;
  • are taking drugs that induce torsades de pointes (some antiarrhythmics, some antipsychotics),
  • are taking nitroglycerin and other nitrates or other vasodilators;
  • are taking muscle relaxants (for example, tubocurarine chloride)
  • are taking tricyclic antidepressants, antipsychotics and anesthetics,
  • are taking sympathomimetics;
  • you are taking amphotericin B (parenteral), carbenoxolone or stimulant laxatives;
  • you are taking calcium salts;
  • are taking cardiac glycosides;
  • you are taking cholestyramine and colestipol;
  • you are taking trimethoprim;
  • you are taking sotalol;
  • you are taking cyclosporine.

When given together, the following drugs can interact with thiazide diuretics: Alcohol - Barbiturates - Narcotics: Potentiation of the pressure drop in standing position may occur.

Corticosteroids, ACTH: intensified electrolyte depletion especially hypokalaemia.

Pressor amines (eg adrenaline): a decreased response to pressor amines is possible, but not such as to preclude their use.

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

  • If you are taking an angiotensin II receptor antagonist (AIIRA) or aliskiren (see also information under Contraindications and "Precautions for use").

Warnings It is important to know that:

In the event of hospitalization, inform the medical staff and in particular the anesthetist, in the event of surgery, of the current treatment with Zestoretic. It will also be advisable to inform your dentist if a dental anesthetic is being administered.

The safety and efficacy of Zestoretic in children has not been established, therefore the drug should not be given to children.

The drug is for personal use only and should never be taken by others.

Fertility, pregnancy and breastfeeding

Ask your doctor or pharmacist for advice before taking any medicine.

Tell your doctor if you are pregnant or want to become pregnant or if you are breastfeeding or want to breastfeed.

Pregnancy

ACE inhibitors:

The use of ACE inhibitors is not recommended during the first trimester of pregnancy. The use of ACE inhibitors is contraindicated during the second and third trimester of pregnancy (see Contraindications).

ACE inhibitor therapy should not be initiated during pregnancy.

Epidemiological evidence on the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however, a small increase in risk cannot be excluded, particularly for the cardiovascular and central nervous systems. If lisinopril is used during the first trimester of pregnancy, patients should be informed of the potential risks to the fetus.

For patients planning pregnancy, the physician should be informed immediately as alternative antihypertensive treatments with a proven safety profile for use in pregnancy should be used, unless continued therapy with a drug is considered essential. ACE inhibitor.

When pregnancy is diagnosed the physician should be informed immediately as treatment with ACE inhibitors should be stopped immediately and, if appropriate, alternative therapy should be started. Should exposure to an ACE inhibitor have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Neonates whose mothers have received ACE inhibitors should be closely monitored for hypotension, oliguria and hyperkalaemia (see Contraindications).

Hydrochlorothiazide:

There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient.

Hydrochlorothiazide crosses the placenta. Based on its mechanism of action, the use of hydrochlorothiazide during the second and third trimester of pregnancy can compromise fetal placental perfusion and can cause fetal and neonatal effects such as jaundice, electrolyte disturbances and thrombocytopenia.

Hydrochlorothiazide should not be used for the treatment of gestational edema, gestational hypertension or preeclampsia due to the risk of decreased plasma volume and placental hypoperfusion without a beneficial effect on the course of the disease.

Hydrochlorothiazide should not be used for the treatment of essential hypertension in pregnant women except in rare situations where no other treatment could be used.

Feeding time

ACE inhibitors:

Since no data are available regarding the use of lisinopril / hydrochlorothiazide during lactation, lisinopril / hydrochlorothiazide is not recommended and alternative treatments with a proven safety profile for use during lactation are preferred, especially if breastfeeding. newborns or premature babies.

Hydrochlorothiazide:

Hydrochlorothiazide is excreted in breast milk in small quantities. High-dose thiazide diuretics cause intense diuresis which can inhibit milk production. The use of Zestoretic while breastfeeding is not recommended. If Zestoretic is taken during breastfeeding, doses should be kept as low as possible. Due to the possible serious reactions caused by hydrochlorothiazide in breastfed babies, a decision must be made whether it is more appropriate to discontinue breastfeeding or Zestoretic while taking in consideration of the importance of the drug for the mother.

Effects on ability to drive and use machines

As with other antihypertensives, the combination of lisinopril / hydrochlorothiazide may have a mild to moderate effect on the ability to drive and use machines. "association is taken with alcohol, but these effects are related to the sensitivity of the individual subject.

When driving vehicles or machines it should be taken into account that dizziness or tiredness may occur.

However, it is preferable not to carry out these activities, which require particular attention, until it is known how the drug is tolerated.

For those who carry out sporting activities The use of the drug without therapeutic need constitutes doping and can in any case determine positive anti-doping tests.

Dose, Method and Time of Administration How to use Zestoretic: Posology

You should follow your doctor's instructions regarding how and how often you take the tablets.

Take the tablets with a little water, at about the same time, preferably early in the morning.

Improved health should not lead to discontinuation of treatment, unless requested by the doctor

Essential hypertension

The usual dosage is one tablet administered once a day. In general, if the desired therapeutic effect is not achieved within 2-4 weeks, the dosage can be increased to 2 tablets administered in a single daily dose.

Dosage in renal insufficiency

Thiazides may be inappropriate diuretics for use in patients with renal impairment and are ineffective at creatinine clearance values ​​of 30 ml / min or less (ie in the presence of moderate or severe renal impairment). Zestoretic should not be used as therapy. initial in patients with renal insufficiency.

In patients with creatinine clearance> 30 and <80 ml / min Zestoretic should only be used after titration of the individual components.

When used alone, the recommended starting dose of lisinopril in mild renal insufficiency is 5-10 mg.

Previous diuretic therapy

Symptomatic hypotension may occur after the initial dose of Zestoretic; this is more likely to occur in hypovolaemic and / or sodium-depleted patients as a result of previous diuretic therapy. Diuretic therapy should be suspended for 2-3 days before starting Zestoretic therapy. If this is not possible, treatment should be started with lisinopril alone at a dose of 5 mg.

Children

The safety and efficacy of Zestoretic in children has not been established.

Use in the elderly

The efficacy and tolerability of the product in the elderly do not differ from that in adults and therefore no dose adjustments are necessary.

Overdose What to do if you have taken too much Zestoretic

In case of accidental ingestion / intake of an excessive dose of Zestoretic, immediately contact your doctor or the nearest hospital

What to do if you have forgotten to take one or more doses

In the event that, due to forgetfulness, the intake of a dose is omitted, therapy must be continued according to the scheduled frequency without taking any additional dose.

Side Effects What are the side effects of Zestoretic

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

Zestoretic is generally well tolerated.

In clinical studies, undesirable effects were generally mild and transient in nature; in most cases it was not necessary to interrupt therapy. The undesirable effects that were observed were limited to those previously reported with lisinopril or hydrochlorothiazide.

The most commonly reported undesirable effects (ADRs) are dizziness, which generally responded to dose reduction and rarely required discontinuation of therapy, headache, cough, and hypotension including orthostatic hypotension which may occur in 1-10. % of treated patients.

Even less common were: diarrhea, nausea, vomiting, dry mouth, rash, gout, palpitations, chest discomfort, muscle cramps and weakness, paraesthesia, asthenia, impotence, acute renal failure and syncope

The following undesirable effects have been observed and reported during treatment with lisinopril / hydrochlorothiazide with the following frequencies: very common (> 10%), common (> 1%, 0.1%, 0.01%,

Disorders of the blood and lymphatic system

Rare: anemia.

Very rare: bone marrow depression, thrombocytopenia, leukopenia, agranulocytosis, haemolytic anemia.

Endocrine pathologies

Rare: Inappropriate antidiuretic hormone secretion.

Metabolism and nutrition disorders

Uncommon: gout.

Rare: hyperglycemia, hypokalaemia, hyperuricaemia, hyperkalaemia.

Nervous system disorders and psychiatric disorders

Common: dizziness, headache, paraesthesia.

Rare: olfactory disturbances.

Uncommon: depressive symptoms.

Cardiac and vascular pathologies

Common: orthostatic effects (including hypotension), syncope.

Uncommon: palpitations.

Respiratory, thoracic and mediastinal disorders

Common: cough.

Gastrointestinal disorders

Common: diarrhea, nausea, vomiting.

Uncommon: dry mouth.

Rare: pancreatitis.

Very rare: intestinal angioedema.

Hepatobiliary disorders

Very rare: both hepatocellular and cholestatic hepatitis, jaundice, hepatic failure. Cases of hepatitis have very rarely been reported to have progressed to hepatic failure in some patients. Patients receiving Zestoretic who experience jaundice or marked elevation of liver enzymes should discontinue treatment with Zestoretic and receive appropriate medical supervision.

Skin and subcutaneous tissue disorders

Common: skin rash.

Uncommon: hypersensitivity / angioneurotic edema: angioneurotic edema of the face, extremities, lips, tongue, glottis, and / or larynx (see "Precautions for use" section).

Very rare: cutaneous pseudolymphoma. Complex symptoms have been reported which may include one or more of the following: fever, vasculitis, myalgia, arthralgia / arthritis, antinuclear antibody (ANA) positivity, increased erythrocyte sedimentation rate (ESR), eosinophilia and leukocytosis, rash, photosensitivity and other dermatological manifestations.

Musculoskeletal and connective tissue disorders

Common: muscle cramps.

Rare: muscle weakness.

Diseases of the reproductive system and breast

Common: impotence.

General disorders and administration site conditions

Common: fatigue, asthenia.

Uncommon: chest tightness.

Laboratory tests

Common: increased blood urea, increased serum creatinine, increased liver enzymes, decreased hemoglobin

Uncommon: decreased hematocrit.

Rare: increase in serum bilirubin.

Other side effects that have been reported with the individual components and which may be potential side effects of Zestoretic are:

Hydrochlorothiazide (frequencies not known):

Infections and infestations Sialodenite System disordersblood and lymphatic Leukopenia, neutropenia / agranulocytosis, thrombocytopenia, aplastic anemia, haemolytic anemia, bone marrow depression Disorders of metabolism andnutrition Anorexia, hyperglycaemia, glucosuria, hyperuricaemia, electrolyte imbalance (including hyponatremia, hypokalaemia, hypochloraemic alkalosis and hypomagnesaemia), elevated cholesterol and triglyceride levels, gout Psychiatric disorders Restlessness, depression, sleep disturbances Nervous system disorders Loss of appetite, paraesthesia, lightheadedness Eye disorders Xanthopsia, transient blurred vision Disorders of the ear and of thelabyrinth Dizziness Cardiac pathologies Postural hypotension Vascular pathologies Necrotizing angiitis (vasculitis, cutaneous vasculitis) Respiratory, thoracic disorders and mediastinal Respiratory distress (including pneumonia and pulmonary edema) Gastrointestinal disorders Gastric irritation, diarrhea, constipation, pancreatitis Hepatobiliary disorders Jaundice (intrahepatic cholestatic jaundice) Skin and skin disorders subcutaneous tissue Photosensitivity reactions, rash, lupus erythematosus-like skin reactions, cutaneous lupus erythematosus reactivation, urticaria, anaphylactic reactions, toxic epidermal necrolysis System disordersmusculoskeletal and tissueconnective Muscle spasms, muscle weakness Renal and urinary disorders Renal dysfunction, interstitial nephritis Systemic pathologies Fever, weakness

Other side effects: purpura, rash.

In very rare cases, Stevens-Johnson syndrome may arise.

In isolated cases: hypercalcemia, the latter making diagnostic tests necessary to highlight a possible hyperparathyroidism. Cardiac arrhythmias, acute myopia and acute angle-closure glaucoma are possible.

Transient visual disturbances, severe eye pain accompanied by redness are possible. Patients with acute pain and red eyes should seek immediate medical attention; if left untreated this condition could cause permanent vision loss

Lisinopril

Disorders of the blood and lymphatic system Rare Decrease in hemoglobin, decrease in hematocrit Very rare Bone marrow depression, anemia, thrombocytopenia, leukopenia, neutropenia, agranulocytosis (see section 4.4), haemolytic anemia, lymphadenopathy, autoimmune disease Metabolism and nutrition disorders Very rare Hypoglycemia Nervous system disorders and psychiatric disorders Common Dizziness, headache, syncope Uncommon Paresthesia, dizziness, altered taste, sleep disturbances, mood alterations, olfactory disturbances. Rare Mental confusion Frequency not known Depressive symptoms Cardiac and vascular disorders Common Orthostatic effects (including orthostatic hypotension) Uncommon Myocardial infarction or cerebrovascular accident, sometimes secondary to excessive hypotension in high-risk patients (see section 4.4), palpitations, tachycardia, Raynaud's syndrome Frequency not known Hot flashes Respiratory, thoracic and mediastinal disorders Common Cough (see section 4.4) Uncommon Rhinitis Very rare Bronchospasm, sinusitis, allergic alveolitis / eosinophilic pneumonia Gastrointestinal disorders Common Diarrhea, vomiting Uncommon Nausea, abdominal pain and indigestion Rare Dry mouth Very rare Pancreatitis, intestinal angioedema Hepatobiliary disorders Uncommon Elevated liver enzymes and bilirubin Very rare Hepatocellular or cholestatic hepatitis, jaundice, hepatic failure (see section 4.4) * Skin and subcutaneous tissue disorders Uncommon Skin rash, itching Rare Hypersensitivity / angioneurotic edema, angioneurotic edema of the face, extremities, lips, tongue, glottis and / or larynx (see section 4.4), urticaria, alopecia, psoriasis. Very rare Diaphoresis, pemphigus, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, cutaneous pseudolymphoma ** Renal and urinary disorders Common Renal dysfunction Rare Uremia, acute renal failure Very rare Oliguria / anuria Diseases of the reproductive system and breast Uncommon Impotence Rare Gynecomastia Endocrine pathologies Rare Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) General disorders and administration site conditions Uncommon Asthenia, fatigue Diagnostic tests Uncommon Blood urea increases, serum creatinine increases, hyperkalaemia Rare Hyponatremia

* Very rarely, it has been reported that in some patients the undesirable development of hepatitis has progressed to hepatic failure. Patients receiving lisinopril / hydrochlorothiazide and who develop jaundice or marked elevation of liver enzymes should stop lisinopril / hydrochlorothiazide and receive a appropriate medical treatment.

** A symptom complex has been reported which may include one or more of the following: fever, vasculitis, myalgia, arthralgia / arthritis, antinuclear antibody (ANA) positivity, high red blood cell sedimentation rate (ESR), eosinophilia and leukocytosis, rash, photosensitivity or other dermatological manifestations.

As with other ACE inhibitors, visual and / or auditory hallucinations have been reported.

Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. Undesirable effects can also be reported directly through the national reporting system at the address: 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.

Expiry and Retention

Expiry: see the expiry date printed on the package.

The expiry date indicated is intended for the product in intact packaging, correctly stored.

Warning: do not use the medicine after the expiry date which is stated on the blister and carton.

Special precautions for storage

The tablets should be stored in their packaging to keep them away from light.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Keep this medicine out of the reach and sight of children.

COMPOSITION

Each tablet contains: active ingredients: 21.8 mg lisinopril dihydrate (equivalent to 20 mg of anhydrous lisinopril), 12.5 mg hydrochlorothiazide.

Excipients: mannitol, dibasic calcium phosphate dihydrate, maize starch, pregelatinised starch, magnesium stearate.

PHARMACEUTICAL FORM AND CONTENT

Tablets.

Pack of 14 tablets.

Pack of 28 tablets.

Pack of 42 tablets.

Not all pack sizes may be marketed.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

Further information on Zestoretic can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction04.6 Pregnancy and lactation04.7 Effects on the ability to drive and use machines04.8 Undesirable effects04.9 Overdose05.0 PHARMACOLOGICAL PROPERTIES05.1 Pharmacodynamic properties05.2 Pharmacokinetic properties05.3 Preclinical data of 06.0 PHARMACEUTICAL PARTICULARS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 HOLDER OF THE ALL AUTHORIZATION "PLACING ON MARKETING 08.0 MARKETING AUTHORIZATION NUMBER 09.0 DATE OF PR IMA AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIOPharmaceuticals, COMPLETE DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON PREPARATION AND QUALITY CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

ZESTORETIC 20 MG + 12.5 MG TABLETS

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains:

active ingredients: lisinopril dihydrate 21.8 mg (equivalent to 20 mg of anhydrous lisinopril) + 12.5 mg hydrochlorothiazide.

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Tablets.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Zestoretic is indicated for the treatment of primary arterial hypertension in patients for whom combination therapy is appropriate.


04.2 Posology and method of administration

Primary arterial hypertension

The usual dosage is one tablet administered once a day. As with other medicines given once a day, Zestoretic should be taken at approximately the same time.

In general, if the desired therapeutic effect is not achieved within 2-4 weeks, the dosage can be increased to 2 tablets administered in a single daily dose.

Dosage in renal insufficiency

Thiazides may be inappropriate diuretics for use in patients with renal impairment and are ineffective at creatinine clearance values ​​of 30 ml / min or less (ie in the presence of moderate or severe renal impairment). Zestoretic should not be used as therapy. initial in patients with renal insufficiency.

In patients with creatinine clearance> 30 and titration of the individual components.

When used alone, the recommended starting dose of lisinopril in mild renal insufficiency is 5-10 mg.

Previous diuretic therapy

Symptomatic hypotension may occur after the initial dose of Zestoretic; this is more likely to occur in hypovolaemic and / or sodium-depleted patients as a result of previous diuretic therapy. Diuretic therapy should be suspended for 2-3 days before starting Zestoretic therapy. If this is not possible, treatment should be started with lisinopril alone, at a dose of 5 mg.

Pediatric population

The safety and efficacy of Zestoretic in children has not been established.

Use in the elderly

In clinical studies, the efficacy and tolerability of lisinopril and hydrochlorothiazide administered together were similar in both the elderly and younger hypertensive patients.

Lisinopril, within a daily dosage range of 20-80 mg, was equally effective in elderly (65 years or older) and non-elderly hypertensive patients. In elderly hypertensive patients, lisinopril monotherapy was as effective in reducing diastolic blood pressure as that with hydrochlorothiazide or atenolol.

In clinical studies, age did not affect the tolerability of lisinopril.


04.3 Contraindications

Zestoretic is contraindicated

• in patients hypersensitive to lisinopril, to any of the excipients listed in section 6.1, or to other angiotensin converting enzyme (ACE) inhibitors.

• in patients hypersensitive to hydrochlorothiazide or to other sulfonamide-derived drugs.

• in patients with anuria.

• in patients with a history of angioedema related to previous treatment with angiotensin converting enzyme inhibitors.

• in patients with hereditary or idiopathic angioedema.

• in the second and third trimester of pregnancy (see sections 4.4. And 4.6).

• in patients with severe renal impairment (creatinine clearance

• in patients with severe hepatic impairment.

• the concomitant use of Zestoretic with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR 2) (see sections 4.5 and 5.1).


04.4 Special warnings and appropriate precautions for use

Symptomatic hypotension

Symptomatic hypotension has rarely been observed in patients with uncomplicated hypertension, but is more likely to occur in the patient who has experienced decreased blood volume or hypomagnesaemia due to previous diuretic therapy, dietary salt restriction, dialysis, diarrhea or vomiting, or with severe renin-dependent hypertension (see sections 4.5 and 4.8). In such patients, regular serum electrolyte checks should be performed at appropriate intervals.

In patients at increased risk for symptomatic hypotension, initiation of therapy and dose adjustment should be carefully monitored.

Particular consideration should be applied to patients with heart disease or ischemic cerebropathy, since an excessive drop in blood pressure could cause a myocardial infarction or a cerebrovascular event.

If hypotension occurs, the patient should be placed in a supine position and, if necessary, infused with saline intravenously. A transient hypotensive response is not a contraindication to further doses of the drug. By restoring effective blood volume and arterial pressure, therapy can be re-established at a reduced dosage; otherwise it is possible to use one or the other member of the association individually.

In some patients with heart failure and normal or low blood pressure, further lowering of blood pressure may occur with lisinopril. This effect is expected and does not usually constitute a reason to discontinue treatment. If hypotension becomes symptomatic, dose reduction or discontinuation of Zestoretic may be necessary.

Aortic or mitral valve stenosis / hypertrophic cardiomyopathy

As with other ACE inhibitors, Zestoretic should be administered with caution to patients with mitral valve stenosis and left ventricular outflow obstruction such as aortic stenosis or hypertrophic cardiomyopathy.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

There is evidence that concomitant use of ACE inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of the RAAS through the combined use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren is therefore not recommended (see sections 4.3 and 4.5).

If dual block therapy is considered absolutely necessary, this should only be done under the supervision of a specialist and with close and frequent monitoring of kidney function, electrolytes and blood pressure.

ACE inhibitors and angiotensin II receptor antagonists should not be used concomitantly in patients with diabetic nephropathy.

Surgery / anesthesia

In patients undergoing major surgery or during anesthesia with agents that produce hypotension, lisinopril may block angiotensin II formation secondary to compensatory renin release. If hypotension attributable to this mechanism occurs, this can be corrected by volume expansion.

Impaired renal function

Thiazides may not be the appropriate diuretics in the treatment of patients with renal impairment and are ineffective at creatinine clearance values ​​of 30 ml / min or less (i.e. in the presence of moderate or severe renal impairment).

Zestoretic should not be administered to patients with renal insufficiency (creatinine clearance ≤ 80 ml / min) until the titration of the individual components has first demonstrated the need for the dosages present in the combination tablet.

In patients with heart failure, hypotension following initiation of ACE inhibitor therapy may lead to further impairment of renal function. Acute renal failure, usually reversible, has been reported in this situation.

In some patients with bilateral renal artery stenosis or monorene renal artery stenosis, increases in blood urea nitrogen and creatinine have been observed with angiotensin converting enzyme (ACE) inhibitors, usually reversible after discontinuation of therapy. This is especially true in patients with renal insufficiency. If renovascular hypertension is also present, there is an increased risk of severe hypotension and renal insufficiency. In these patients, treatment should be initiated under close medical supervision at low doses and after adequate dose titration. Since diuretic treatment may contribute to the above, renal function should be monitored during the first weeks of therapy with Zestoretic.

Some hypertensive patients with no apparent vascular renal disease have developed usually mild and transient increases in blood urea nitrogen and blood creatinine when lisinopril was administered concomitantly with a diuretic.

This is more likely to occur in patients with pre-existing renal impairment. It may be necessary to reduce the dosage and / or discontinue the diuretic and / or lisinopril.

In patients with severe heart failure whose renal function may be dependent on the renin-angiotensin-aldosterone system, treatment with ACE inhibitors may be associated with oliguria and / or progressive azotaemia and, rarely, with acute renal failure and / or death. In these patients, treatment with ACE inhibitors should be introduced with particular caution.

Hepatopathy

Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, as minimal changes in the water and electrolyte balance can precipitate hepatic coma (see section 4.3). Rarely, ACE inhibitors have been associated with a syndrome which begins with cholestatic jaundice or hepatitis and progresses to fulminant necrosis and (sometimes) death. The mechanism of this syndrome is unknown. Patients treated with lisinopril / hydrochlorothiazide who develop jaundice or marked elevation of liver enzymes should discontinue treatment with lisinopril / hydrochlorothiazide and undergo appropriate medical follow-up.

Hypersensitivity / angioedema

Angioedema of the face, extremities, lips, tongue, glottis and / or larynx has been reported uncommonly in patients treated with angiotensin converting enzyme inhibitors, including lisinopril. This can happen at any time during therapy. In such cases, lisinopril administration should be discontinued promptly and appropriate monitoring instituted to ensure complete remission of symptoms before the patient is discharged. Even in those cases where swelling only affects the tongue without respiratory distress, patients should be observed for an extended period as treatment with antihistamines and corticosteroids may not be sufficient.

Fatal events due to angioedema associated with edema of the larynx or tongue have been reported very rarely. Airway obstruction may occur in patients with involvement of the tongue, glottis, or larynx, especially in people with a history of airway surgery. In these cases, emergency therapy should be given promptly. This may include the administration of epinephrine and / or measures to maintain a patent airway. The patient should be kept under close medical observation until complete and persistent resolution of symptoms. .

Conversion enzyme inhibitors (ACE inhibitors) cause angioedema more frequently in black patients than in non-black patients.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while taking an ACE inhibitor (see also section 4.3).

In patients taking thiazides, hypersensitivity reactions may occur with or without a history of allergic episodes or bronchial asthma. Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazides.

Metabolic and endocrine effects

In diabetic patients treated with oral antidiabetic agents or with insulin, blood glucose levels should be closely monitored during the first month of treatment with an ACE inhibitor.

Thiazide therapy can impair glucose tolerance; therefore, adjustment of the dosage of antidiabetic agents, including insulin, may be necessary.

Increases in cholesterol and triglyceride levels have been associated with diuretic therapy with thiazides.

In some patients, treatment with thiazides can precipitate hyperuricaemia and / or gout. Lisinopril may, however, induce an increase in uric acid in the urine and consequently attenuate the hyperuricaemic effect of hydrochlorothiazide.

Desensitization

Patients who received ACE inhibitors during a desensitizing treatment (eg hymenoptera venom) have suffered from anaphylactoid reactions. In the same patients, these reactions were avoided when the ACE inhibitor was temporarily withdrawn, but they reappeared after the drug was inadvertently re-administered.

Anaphylactoid reactions in hemodialysis patients

The use of lisinopril-hydrochlorothiazide is not indicated in patients requiring dialysis for renal insufficiency.

Anaphylactotide reactions have been reported in patients undergoing certain hemodialysis procedures (e.g. with high flux membranes AN 69 and during low density lipoprotein (LDL) apheresis performed with dextran sulfate columns) treated concomitantly with ACE inhibitors. The use of different types of dialysis membranes or different types of antihypertensive agents should be considered for these patients.

Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis

On rare occasions, patients taking ACE inhibitors during low-density lipoprotein (LDL) apheresis with dextran sulfate have developed life-threatening anaphylactoid reactions. These symptoms could be avoided by temporarily withholding ACE-treatment. inhibitors before each apheresis session.

Ethnicity

Conversion enzyme inhibitors (ACE inhibitors) cause angioedema more frequently in black patients than in non-black patients.

As with other ACE inhibitors, lisinopril may be less effective in lowering blood pressure in black patients than in non-black patients, possibly due to a higher prevalence of low renin concentrations in the black hypertensive population.

Cough

Cough has been reported with the use of ACE inhibitors. This is characteristically nonproductive, persistent and resolves upon discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.

Neutropenia and agranulocytosis

Neutropenia / agranulocytosis, thrombocytopenia and anemia have been reported in patients receiving ACE inhibitors. In patients with normal renal function and in the absence of other complicating factors, neutropenia rarely occurs. Neutropenia and agranulocytosis disappear after discontinuation of treatment with ACE inhibitors.

Lisinopril should be administered with extreme caution to patients with collagen disease, those on immunosuppressive therapy, allopurinol or procainamide, or who have a combination of these complicating factors, especially in previous renal impairment. Some of these patients developed severe infections, which in a few cases did not respond to intensive antibiotic therapy. If these patients are treated with lisinopril, periodic monitoring of white blood cell counts is recommended and patients should be instructed to report any episodes of infection.

Pregnancy

ACE inhibitor therapy should not be initiated during pregnancy.

For patients planning to become pregnant, alternative antihypertensive treatments with a proven safety profile for use in pregnancy should be used unless continued ACE inhibitor therapy is considered essential. When pregnancy is diagnosed. , treatment with ACE inhibitors should be stopped immediately and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

Previous diuretic therapy

Diuretic therapy should be suspended for 2-3 days before starting treatment with lisinopril / hydrochlorothiazide. If this is not possible, treatment should be started with lisinopril alone, at a dose of 5 mg.

Renal transplant patients

As there is no experience with patients who have recently undergone a kidney transplant, this combination should not be used.

Electrolyte imbalance

As with any patient on diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals.

Thiazides, including hydrochlorothiazide, can cause fluid and electrolyte imbalance (hypokalaemia, hyponatremia and hypochloraemic alkalosis). Indicator signs of water or electrolyte imbalance are dry mouth, thirst, weakness, lethargy, drowsiness, cramps or muscle pain, fatigue muscle, hypotension, oliguria, tachycardia and gastrointestinal disorders such as nausea and vomiting.

Dilutional hyponatraemia can occur in oedematous patients in hot weather. A chloride deficiency is usually mild and does not require treatment. Thiazides have been shown to increase urinary excretion of magnesium, which can result in hypomagnesaemia.

Thiazides can decrease urinary calcium excretion and cause mild and intermittent increases in calcium. Marked hypercalcaemia can reveal asymptomatic hyperparathyroidism. Thiazide therapy must be discontinued before parathyroid function tests are performed.

Hyperkalaemia

Elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including lisinopril. Patients at risk of developing hyperkalaemia include those with renal insufficiency, diabetes mellitus, or those on concomitant treatment with potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes, or those patients on other drugs with which an increase in serum potassium (eg heparin). If concomitant use of the above agents is considered necessary, regular monitoring of serum potassium is recommended (see section 4.5).

Diabetic patients

In diabetic patients being treated with oral antidiabetic drugs or insulin, glycemic control should be closely monitored during the first month of treatment with an ACE inhibitor (see section 4.5).

Lithium

The combination of ACE inhibitors, lithium and lisinopril is generally not recommended (see section 4.5).

Doping test

The hydrochlorothiazide contained in this medicinal product may give a positive test result in the doping test.


04.5 Interactions with other medicinal products and other forms of interaction

Dual blockade of the renin-angiotensin-aldosterone system

Clinical trial data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) through the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared with the use of a single agent active on the RAAS system (see sections 4.3, 4.4 and 5.1). Closely monitor blood pressure, renal function and electrolytes in patients treated with lisinopril and other agents affecting the RAAS. Do not administer aliskiren with lisinopril in patients with diabetes. Avoid the use of aliskiren with lisinopril in patients with renal impairment (GFR 2) (see section 4.3).

Other antihypertensives

Concomitant administration of these drugs may increase the hypotensive effect of lisinopril / hydrochlorothiazide. Concomitant administration of nitroglycerin and other nitrates or other vasodilators may further reduce blood pressure.

The combination of lisinopril with aliskiren-containing drugs should be avoided (see sections 4.3 and 4.4).

Potassium supplements, potassium-sparing diuretics, or salt substitutes containing potassium and other drugs that may increase serum potassium levels

The potassium depletion induced by thiazide diuretics is usually attenuated by the potassium-sparing effect of lisinopril.

The use of potassium supplements, potassium-sparing agents or potassium-containing salt substitutes and other drugs that may increase serum potassium levels (eg, heparin, co-trimoxazole), may lead to a significant increase in serum potassium, especially in patients with impaired renal function or diabetes mellitus. If concomitant use of lisinopril / hydrochlorothiazide and any of these agents is required, they should be used with caution and with frequent monitoring of serum potassium (see section 4.4).

Lithium

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium and ACE inhibitors.

Diuretic agents and ACE inhibitors reduce the renal clearance of lithium, leading to a high risk of its toxicity.

Therefore, the use of lisinopril / hydrochlorothiazide in combination with lithium is not recommended, but, if the combination is necessary, careful monitoring of serum lithium levels should be performed (see section 4.4). Before using lithium-containing products, consult the relevant Summary of Product Characteristics.

Gold

Nitritoid reactions (symptoms of vasodilation including flushing, nausea, dizziness and hypotension, which can be very severe) have been reported more frequently in patients treated with ACE inhibitors following administration of injectable gold (e.g. sodium aurothiomalate).

Other concomitant therapies

Indomethacin may decrease the antihypertensive efficacy of concomitantly administered lisinopril and hydrochlorothiazide.

Concomitant treatment with tissue plasminogen activators may increase the risk of developing angioedema.

Non-steroidal anti-inflammatory drugs (NSAIDs) including acetylsalicylic acid

Chronic administration of NSAIDs including selective cyclooxygenase-2 inhibitors may reduce the antihypertensive effect of an ACE inhibitor.

ACE inhibitors and NSAIDs may exert an additive effect on the worsening of renal function. These effects are usually reversible.

Rarely, acute renal failure may occur, especially in patients with impaired renal function such as the elderly or dehydrated subjects. The combination should be administered with caution especially in the elderly. Patients should be adequately hydrated and monitoring of blood pressure should be considered. renal function at the start of concomitant therapy.

Non-depolarizing muscle relaxants (for example, tubocurarine chloride)

The effect of these drugs can be intensified by hydrochlorothiazide.

Allopurinol

Concomitant administration of ACE inhibitors and allopurinol increases the risk of renal damage and may lead to an increased risk of leukopenia.

Cytostatic and immunosuppressive agents, procainamide, cyclophosphamide, methotrexate

Concomitant administration of ACE inhibitors may increase the risk of leukopenia. Thiazides may potentiate their myelosuppressive effect by reducing the renal excretion of cytotoxic drugs (see section 4.4).

Drugs that induce torsades de pointes

Due to the risk of hypokalaemia, administration of hydrochlorothiazide and drugs that induce torsades de pointes, for example some antiarrhythmics, some antipsychotics and other drugs known to induce torsades de pointes, should be used with caution.

Tricyclic antidepressants / antipsychotics / anesthetics

The concomitant administration of certain anesthetics, tricyclic antidepressants and antipsychotics with ACE inhibitors may result in a "further decrease in blood pressure (see section 4.4).

Sympathomimetics

Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.

Potential drug interactions

Other antihypertensive agents: additive effects may occur.

When given together, the following drugs can interact with thiazide diuretics: Alcohol - Barbiturates - Narcotics: Potentiation of the pressure drop in standing position may occur.

Antidiabetic drugs

Treatment with a thiazide diuretic may impair glucose tolerance Epidemiological studies have indicated that concomitant administration of ACE inhibitors and antidiabetics (oral hypoglycemic agents and insulin) may cause an increase in the blood glucose lowering effect with risk of hypoglycaemia. are most likely to occur during the first few weeks of combination treatment and in patients with renal impairment. In diabetic patients, dosage adjustment of antidiabetic drugs may be required and the need for other antidiabetic drugs, including insulin, may remain unchanged or be increased or decreased.

Other kaliuretic diuretics, amphotericin B (parenteral), carbenoxolone, corticosteroids, corticotropin (ACTH) or stimulating laxatives, derivatives of salicylic acid

The potassium-depleting effect of hydrochlorothiazide may be intensified by drugs that cause potassium loss and hypokalaemia. Hypokalaemia may develop during concomitant use of steroids or adrenocorticotropics (ACTH).

Calcium salts (calcium or vitamin D supplements)

When administered concomitantly with thiazide diuretics, they can cause an increase in serum calcium levels resulting in decreased excretion.

If calcium or vitamin D supplements are required, serum calcium levels should be monitored and their dose adjusted accordingly.

Cardiac glycosides

There is an increased risk of digitalis intoxication associated with thiazide-induced hypokalaemia. Hypokalaemia may sensitize or increase the heart's response to digitalis toxic effects (eg, increased ventricular irritability).

Cholestyramine and colestipol

They can reduce or slow down the absorption of hydrochlorothiazide. Therefore, sulfonamide diuretics should be taken at least one hour before or 4-6 hours after taking these drugs.

Trimethoprim

Concomitant administration of ACE inhibitors and thiazides with trimethoprim increases the risk of hyperkalaemia.

Sotalol

Thiazide-induced hypokalaemia may increase the risk of sotalol-induced arrhythmias.

Ciclosporine

Concomitant administration of ACE inhibitors with cyclosporine increases the risk of renal damage, hyperkalaemia, hyperuricaemia and gout-like complications.

Pressor amines (e.g. adrenaline)

Thiazides may decrease the arterial response to noradrenaline, but not such as to preclude its use in therapy as a pressure agent.

Diazoxide

Thiazides may increase the hyperglycemic effect of diazoxide.

Amantadina

Thiazides may increase the risk of adverse reactions caused by amantadine.


04.6 Pregnancy and breastfeeding

Pregnancy

ACE inhibitors:

The use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section 4.4). The use of ACE inhibitors is contraindicated during the second and third trimester of pregnancy (see sections 4.3 and 4.4).

Epidemiological evidence on the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however, a small increase in risk cannot be excluded, particularly for the cardiovascular and central nervous systems. If lisinopril is used during the first trimester of pregnancy, patients should be informed of the potential risks to the fetus.

For patients planning to become pregnant, alternative antihypertensive treatments with a proven safety profile for use in pregnancy should be used unless continued ACE inhibitor therapy is considered essential.

When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately and, if appropriate, alternative therapy should be started.

Exposure to ACE inhibitors during the second and third trimesters is known to induce fetal toxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) in women (see also paragraph 5.3).

Maternal oligodramniosis occurred, presumably representing decreased renal function of the fetus and which can result in limb contracture, craniofacial deformations and hypoplastic lung development.

Should exposure to an ACE inhibitor have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.

Neonates whose mothers have taken ACE inhibitors should be closely monitored for hypotension (see sections 4.3 and 4.4).

In those rare cases where use during pregnancy is considered essential, serial ultrasound scans should be performed to check for intra-amniotic conditions if exposure to Zestoretic has occurred during the second or third trimester of pregnancy. In the event that oligodramniosis is found, lisinopril should be discontinued unless considered lifesaving for the mother.

Doctors and patients must be aware, however, that oligodramniosis can also be evident only after irreversible damage to the fetus has been established.

Infants whose mothers have taken lisinopril must also be closely observed for oliguria and hyperkalaemia.

Lisinopril, which crosses the placenta, has been removed from the neonatal circulation by intraperitoneal dialysis with some clinical benefit and can theoretically be removed by plasmapheresis.

Hydrochlorothiazide:

There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient.

Hydrochlorothiazide crosses the placenta. Based on its mechanism of action, the use of hydrochlorothiazide during the second and third trimester of pregnancy may impair fetal placental perfusion and may cause fetal and neonatal effects such as jaundice, electrolyte disturbances and thrombocytopenia.

The continued use of diuretics in healthy pregnant women is not recommended and exposes mother and fetus to unnecessary risk including neonatal jaundice, thrombocytopenia and other adverse reactions that have been reported in adults are also possible.

There is no experience with the removal of hydrochlorothiazide, which crosses the placenta, from the neonatal circulation.

Hydrochlorothiazide should not be used for the treatment of gestational edema, gestational hypertension or preeclampsia due to the risk of decreased plasma volume and placental hypoperfusion without a beneficial effect on the course of the disease.

Hydrochlorothiazide should not be used for the treatment of primary arterial hypertension in pregnant women except in rare situations where no other treatment could be used.

Feeding time

ACE inhibitors:

It is not known whether lisinopril is excreted in human milk as no data are available regarding the use of lisinopril / hydrochlorothiazide during lactation. Lisinopril / hydrochlorothiazide is not recommended and alternative treatments with a proven safety profile for use during lactation are preferred, especially when nursing a newborn or preterm infant.

Hydrochlorothiazide:

Hydrochlorothiazide is excreted in breast milk in small quantities. High-dose thiazide diuretics cause intense diuresis which can inhibit milk production. The use of Zestoretic while breastfeeding is not recommended. If Zestoretic is taken while breastfeeding, doses should be kept as low as possible.

Because of the possible serious reactions caused by hydrochlorothiazide in breast-fed babies, a decision must be made whether it is more appropriate to discontinue breastfeeding or Zestoretic, taking into account the importance of the drug to the mother.


04.7 Effects on ability to drive and use machines

As with other antihypertensives, the combination of lisinopril / hydrochlorothiazide may have a mild to moderate effect on the ability to drive and use machines. "association is taken with alcohol, but these effects are related to the sensitivity of the individual subject.

When driving vehicles or machines it should be taken into account that dizziness or tiredness may occur.


04.8 Undesirable effects

Clinical Studies

Zestoretic is generally well tolerated. In clinical studies, undesirable effects were generally mild and transient in nature; in most cases it was not necessary to interrupt therapy. The undesirable effects that were observed were limited to those previously reported with lisinopril or hydrochlorothiazide.

The most commonly reported undesirable effects (ADRs) are dizziness, which generally responded to dose reduction and rarely required discontinuation of therapy, headache, cough and hypotension including orthostatic hypotension which may occur in 1-10%. of treated patients.

Even less common were: diarrhea, nausea, vomiting, dry mouth, rash, gout, palpitations, chest discomfort, muscle cramps and weakness, paraesthesia, asthenia, impotence, acute renal failure and syncope.

Post Marketing

The following undesirable effects have been observed and reported during treatment with lisinopril / hydrochlorothiazide with the following frequencies: very common (≥1 / 10), common (≥1 / 100,

Disorders of the blood and lymphatic system

Rare: anemia.

Very rare: bone marrow depression, thrombocytopenia, leukopenia, agranulocytosis, haemolytic anemia.

Endocrine pathologies

Rare: Inappropriate antidiuretic hormone secretion.

Metabolism and nutrition disorders

Uncommon: gout.

Rare: hyperglycaemia, hypokalaemia, hyperuricaemia, hyperkalaemia.

Nervous system disorders and psychiatric disorders

Common: dizziness, headache, paraesthesia.

Rare: olfactory disturbances.

Uncommon: depressive symptoms.

Cardiac and vascular pathologies

Common: orthostatic effects (including hypotension), syncope.

Uncommon: palpitations.

Respiratory, thoracic and mediastinal disorders

Common: cough.

Gastrointestinal disorders

Common: diarrhea, nausea, vomiting.

Uncommon: dry mouth.

Rare: pancreatitis.

Very rare: intestinal angioedema.

Hepatobiliary disorders

Very rare: both hepatocellular and cholestatic hepatitis, jaundice, hepatic failure. Cases of hepatitis have very rarely been reported to have progressed to hepatic failure in some patients. Patients receiving Zestoretic who experience jaundice or marked elevation of liver enzymes should discontinue treatment with Zestoretic and receive appropriate medical supervision.

Skin and subcutaneous tissue disorders

Common: skin rash.

Uncommon: hypersensitivity / angioneurotic edema: angioneurotic edema of the face, extremities, lips, tongue, glottis and / or larynx (see section 4.4).

Very rare: cutaneous pseudolymphoma.

Complex symptoms have been reported which may include one or more of the following: fever, vasculitis, myalgia, arthralgia / arthritis, antinuclear antibody (ANA) positivity, increased erythrocyte sedimentation rate (ESR), eosinophilia and leukocytosis, rash, photosensitivity and other dermatological manifestations.

Musculoskeletal and connective tissue disorders

Common: muscle cramps.

Rare: muscle weakness.

Diseases of the reproductive system and breast

Common: impotence.

General disorders and site conditions of administration

Common: fatigue, asthenia.

Uncommon: chest tightness.

Laboratory tests

Common: increased blood urea, increased serum creatinine, increased liver enzymes, decreased hemoglobin.

Uncommon: decreased hematocrit.

Rare: increase in serum bilirubin.

Other side effects that have been reported with the individual components and which may be potential side effects of Zestoretic are:

Hydrochlorothiazide (frequencies not known):

Infections and infestations Sialodenite System disordersblood and lymphatic Leukopenia, neutropenia / agranulocytosis, thrombocytopenia, aplastic anemia, haemolytic anemia, bone marrow depression Disorders of metabolism andnutrition Anorexia, hyperglycaemia, glucosuria, hyperuricaemia, electrolyte imbalance (including hyponatremia, hypokalaemia, hypochloraemic alkalosis and hypomagnesaemia), elevated cholesterol and triglyceride levels, gout Psychiatric disorders Restlessness, depression, sleep disturbances Nervous system disorders Loss of appetite, paraesthesia, lightheadedness Eye disorders Xanthopsia, transient blurred vision Disorders of the ear and of thelabyrinth Dizziness Cardiac pathologies Postural hypotension Vascular pathologies Necrotizing angiitis (vasculitis, cutaneous vasculitis) Respiratory, thoracic disorders and mediastinal Respiratory distress (including pneumonia and pulmonary edema) Gastrointestinal disorders Gastric irritation, diarrhea, constipation, pancreatitis Hepatobiliary disorders Jaundice (intrahepatic cholestatic jaundice) Skin and skin disorders subcutaneous tissue Photosensitivity reactions, rash, lupus erythematosus-like skin reactions, cutaneous lupus erythematosus reactivation, urticaria, anaphylactic reactions, toxic epidermal necrolysis System disordersmusculoskeletal and tissueconnective Muscle spasms, muscle weakness Renal and urinary disorders Renal dysfunction, interstitial nephritis Systemic pathologies Fever, weakness

Other side effects: purpura, systemic lupus erymatosus, rash.

In very rare cases, Stevens-Johnson syndrome may arise.

In isolated cases: hypercalcemia, the latter making diagnostic tests necessary to highlight a possible hyperparathyroidism. Cardiac arrhythmias, acute myopia and acute angle-closure glaucoma are possible.

Lisinopril

Disorders of the blood and lymphatic system Rare Decrease in hemoglobin, decrease in hematocrit Very rare Bone marrow depression, anemia, thrombocytopenia, leukopenia, neutropenia, agranulocytosis (see section 4.4), haemolytic anemia, lymphadenopathy, autoimmune disease Metabolism and nutrition disorders Very rare Hypoglycemia Nervous system disorders and psychiatric disorders Common Dizziness, headache, syncope Uncommon Paresthesia, dizziness, altered taste, sleep disturbances, mood alterations, olfactory disturbances. Rare Mental confusion Frequency not known Depressive symptoms Cardiac and vascular disorders Common Orthostatic effects (including orthostatic hypotension) Uncommon Myocardial infarction or cerebrovascular accident, sometimes secondary to excessive hypotension in high-risk patients (see section 4.4), palpitations, tachycardia, Raynaud's syndrome Frequency not known Hot flashes Respiratory, thoracic and mediastinal disorders Common Cough (see section 4.4) Uncommon Rhinitis Very rare Bronchospasm, sinusitis, allergic alveolitis / eosinophilic pneumonia Gastrointestinal disorders Common Diarrhea, vomiting Uncommon Nausea, abdominal pain and indigestion Rare Dry mouth Very rare Pancreatitis, intestinal angioedema Hepatobiliary disorders Uncommon Elevated liver enzymes and bilirubin Very rare Hepatocellular or cholestatic hepatitis, jaundice, hepatic failure (see section 4.4) * Skin and subcutaneous tissue disorders Uncommon Skin rash, itching Rare Hypersensitivity / angioneurotic edema, angioneurotic edema of the face, extremities, lips, tongue, glottis and / or larynx (see section 4.4), urticaria, alopecia, psoriasis. Very rare Diaphoresis, pemphigus, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, cutaneous pseudolymphoma ** Renal and urinary disorders Common Renal dysfunction Rare Uremia, acute renal failure Very rare Oliguria / anuria Diseases of the reproductive system and breast Uncommon Impotence Rare Gynecomastia Endocrine pathologies Rare Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) General disorders and administration site conditions Uncommon Asthenia, fatigue Diagnostic tests Uncommon Blood urea increases, serum creatinine increases, hyperkalaemia Rare Hyponatremia

* Very rarely, it has been reported that in some patients the undesirable development of hepatitis has progressed to hepatic failure. Patients receiving lisinopril / hydrochlorothiazide and who develop jaundice or marked elevation of liver enzymes should stop lisinopril / hydrochlorothiazide and receive a appropriate medical treatment.

** A symptom complex has been reported which may include one or more of the following: fever, vasculitis, myalgia, arthralgia / arthritis, antinuclear antibody (ANA) positivity, high red blood cell sedimentation rate (ESR), eosinophilia and leukocytosis, rash, photosensitivity or other dermatological manifestations.

As with other ACE inhibitors, visual and / or auditory hallucinations have been reported.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.


04.9 Overdose

There are limited data on overdose in humans.

Treatment is symptomatic and supportive. Zestoretic therapy should be discontinued and the patient monitored closely. Therapeutic measures depend on the nature and severity of the symptoms. Measures should be taken to prevent absorption and to accelerate elimination of the drug.

Symptoms associated with ACE inhibitor overdose may include hypotension, circulatory shock, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety and cough. In case of severe hypotension the patient should be placed in the shock position. The recommended treatment for overdose is administration of saline by intravenous infusion. If hypotension occurs, the patient should be placed in the supine position.If available, treatment by infusion of angiotensin II and / or intravenous injection of catecholamines may also be considered. If ingestion is recent, take steps to eliminate lisinopril (for example: vomiting, gastric lavage, drug administration). absorbents and sodium sulfate).

Lisinopril can be removed from the circulation by hemodialysis (see section 4.4). Avoid using high-flux polyacrylonitrile dialysis membranes. Pacemaker therapy is indicated for therapy-resistant bradycardia. Vital signs, serum electrolytes, and creatinine should be monitored frequently.

Additional symptoms of hydrochlorothiazide overdose are increased urine output, depression of consciousness (including coma), convulsions, paresis, cardiac arrhythmias and renal failure.

If digitalis has also been administered, hypokalaemia may accentuate cardiac arrhythmias.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: ACE inhibitors, combinations - ACE inhibitors and diuretics. ATC code: C09BA03

Zestoretic is the fixed-dose combination of lisinopril an angiotensin converting enzyme (ACE) inhibitor and hydrochlorothiazide, a thiazide diuretic. Both components have complementary mechanisms of action and exert an additive antihypertensive effect.

When combined with other antihypertensive agents, a further decrease in blood pressure may occur.

Lisinopril is a peptidyl dipeptidase inhibitor which catalyzes the conversion of angiotensin I to angiotensin II vasoconstrictor peptide.

Angiotensin II also stimulates the secretion of aldosterone by the adrenal cortex. Inhibition of ACE results in a reduction in angiotensin II concentrations resulting in decreased vasopressor activity and aldosterone secretion. elevation of serum potassium concentration.

Although the mechanism by which lisinopril lowers blood pressure appears to be primarily the suppression of the renin-angiotensin-aldosterone system, lisinopril is also effective in patients with low-renin hypertension. ACE is identical to kininase II, an enzyme that degrades bradykinin. It remains unclear whether increased levels of bradykinin, a potent vasodilator, play a role in the therapeutic effect of lisinopril.

Hydrochlorothiazide is a diuretic and antihypertensive agent. It exerts its antihypertensive action on the electrolytic reabsorption mechanism of the distal renal tubule and increases the excretion of chlorides and sodium to an equivalent extent. Natriuresis can be accompanied by loss of potassium and bicarbonates. The mechanism of the antihypertensive effect of thiazide diuretics is not known. Thiazides do not usually affect normal blood pressure. Concomitant administration of other antihypertensive drugs results in an additive reduction in blood pressure.

Two large randomized controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA Nephron-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE inhibitor with an antagonist of the angiotensin II receptor.

ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus associated with evidence of organ damage. VA NEPHRON-D was a study conducted in patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies did not demonstrate any significant beneficial effect on renal and / or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute renal injury and / or hypotension was observed compared to monotherapy.

These results are also relevant for other ACE inhibitors and angiotensin II receptor antagonists, given their similar pharmacodynamic properties.

ACE inhibitors and angiotensin II receptor antagonists should therefore not be used simultaneously in patients with diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study aimed at verifying the advantage of adding aliskiren to standard therapy of an ACE inhibitor or angiotensin II receptor antagonist in patients with diabetes mellitus. type 2 and chronic kidney disease, cardiovascular disease, or both. The study was terminated early due to an increased risk of adverse events. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group, and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were reported more frequently in the aliskiren group than in the placebo group.


05.2 "Pharmacokinetic properties

Concomitant administration of lisinopril and hydrochlorothiazide has little or no effect on the bioavailability of either drug. The pre-established association is bioequivalent to the two drugs administered simultaneously.

Absorption

After oral administration of lisinopril peak plasma concentrations are observed within 7 hours, with a slight delay in patients with acute myocardial infarction. Based on urinary recovery, the extent of absorption of lisinopril is approximately 25%, with interpatient variability of 6-60% at all doses tested (5-80 mg). Absolute bioavailability is reduced by approximately 16% in patients with heart failure. The absorption of Zestoretic is not affected by food.

Distribution

Lisinopril does not appear to be bound to other plasma proteins other than circulating ACE. Studies in rats indicate that lisinopril poorly crosses the blood brain barrier.

Elimination

Lisinopril is not metabolised and is excreted completely unchanged by the kidney. After multiple doses, lisinopril exhibits a storage half-life of 12.6 hours. The clearance of lisinopril in healthy subjects is approximately 50 ml / min. The decrease in serum concentrations shows a prolonged terminal phase that does not contribute to drug accumulation. This terminal phase probably represents the saturable binding at the ACE level and is not proportional to dose.

Hepatic insufficiency

Impaired liver function in cirrhotic patients leads to a decrease in the absorption of lisinopril (approximately 30% based on urinary recovery), but an increase in exposure (approximately 50%) compared to healthy subjects, due to a decrease clearance.

Kidney failure

Impaired renal function reduces the elimination of lisinopril, which is excreted via the kidney, but this reduction becomes clinically important only when the glomerular filtration rate is less than 30 ml / min.

Pharmacokinetic parameters of lisinopril in relation to renal function in different patient groups after administration of a multiple of the 5 mg dose.

Renal function Measured with creatinine clearance No. Cmax (ng / ml) Tmax (hours) AUC (0-24 hours) (ng / hour / ml) t1 / 2 (hours) > 80 ml / min 6 40,3 6 492+/-172 6,0+/-1,1 30-80 ml / min 6 36,6 8 555+/-364 11,8+/-1,9 5-30 ml / min 6 106,7 8 2228+/-938 19,5+/-5,2

With a creatinine clearance of 30-80 mL / min, the mean AUC increased by only 13%, while a 4-5 fold increase was observed with creatinine clearance 5-30 mL / min.

Lisinopril can be removed by dialysis. During a 4-hour hemodialysis, plasma concentrations of lisinopril decrease on average by 60% with a dialysis clearance between 40 and 55 ml / min.

Heart failure

Compared to healthy subjects, heart failure patients have a higher exposure to lisinopril (an average increase in AUC of 125%), but based on urinary recovery of lisinopril, a reduction in absorption of approximately 16% is noted. .

Senior citizens

Compared to young subjects, elderly patients have increases in blood concentrations and AUC (approximate 60% increase).

Hydrochlorothiazide

With monitoring of plasma levels for at least 24 hours, the plasma half-life was observed to vary in the range of 5.6-14.8 hours.

At least 61% of the oral dose is eliminated unchanged within 24 hours. After oral administration of hydrochlorothiazide the diuretic effect begins within 2 hours, peaks in approximately 4 hours and lasts for 6 to 12 hours. Hydrochlorothiazide crosses the placental but not the blood brain barrier.


05.3 Preclinical safety data

Lisinopril

The safety of lisinopril has been extensively studied in laboratory animals. The oral LD ​​of lisinopril was greater than 20 g / kg in mice and rats.

It appears that the toxicity of lisinopril in rats and dogs is mainly related to an exasperation of the pharmacological effects. There was a large gap between the therapeutic dose for humans and toxic doses for animals.

The ratio of the non-toxic dose for dogs (5 mg / kg / day) to that recommended for humans of 40 mg / day was 6 times higher in this sensitive species.

In humans, with a dose of 40 mg / day, a maximum plasma concentration of 468 ng / ml was reached, significantly lower than the 11,370 ng / ml plasma level determined by a nephrotoxic dose in dogs.

The main signs of toxicity in dogs were related to impaired renal function (elevated BUN and creatinine levels), sometimes associated with renal tubular degeneration. The latter was not observed in rats, although increases in azotemia were noted. These changes in renal function probably represent pre-renal changes in drug-induced azotaemia related to the pharmacological activity of lisinopril. An additional saline intake improves or prevents lisinopril toxicity in rats as well as dogs, further supporting the hypothesis of mechanism-based toxicity.

Carcinogenesis, mutagenesis and fertility studies

There was no evidence of oncogenic effects when lisinopril was administered to male and female rats for 105 weeks at doses up to 90 mg / kg / day (approximately 110 times the maximum recommended human daily dose). Lisinopril was also administered to 92 weeks in mice (male and female) at doses up to 135 mg / kg / day (approximately 170 times the maximum recommended human daily dose) and showed no signs of carcinogenicity. Lisinopril did not show mutagenic properties in the Ames microbial mutagenic assay with or without metabolic activation. It tested negative in an early mutation assay using Chinese hamster lung cells. Lisinopril did not produce single-strand DNA breaks in an in vitro alkaline elution assay in rat hepatocytes. Lisinopril also did not produce increased chromosomal aberrations in an in vitro test on Chinese hamster ovary cells and in one. in vivo mouse bone marrow study No adverse effects on reproductive performance occurred in male and female rats treated with lisinopril doses up to 300 mg / kg / day.

Teratogenesis

Lisinopril was not teratogenic in mice treated with doses up to 1000 mg / kg / day (1250 times the maximum recommended human daily dose) from day 6 to day 15 of gestation.

There was no increase in fetal resorptions with doses below 100 mg / kg; at doses of 1000 mg / kg this was prevented by an additional salt intake. There was no fetotoxicity or teratogenicity in rats treated with lisinopril doses up to 300 mg / kg / day (375 times the maximum recommended dose) from day 6 to day 17 of gestation.

In rats that received lisinopril from day 15 of gestation to beyond day 21 postpartum, there was an increase in the incidence of deaths of births between day 2 and day 7 postpartum. 21st day post-partum the average body weight of the births was lower. With an additional supply of salt to the mother there was neither an increase in deaths nor a decrease in weight in the births. In rabbits, lisinopril did not show teratogenicity when administered over the entire organogenetic period at doses up to 1 mg / kg / day in the presence of an additional salt intake.

The latter has been used to eliminate toxic effects in the mother and allow an assessment of the teratogenic potential at the highest possible dose level. The rabbit has been observed to be extremely sensitive to converting enzyme inhibitors (captopril and enalapril) showing maternal and fetal-toxic effects at dose levels equal to or lower than the therapeutic dose recommended for humans.

In rabbits, fetotoxicity occurred with an increased incidence of fetal resorption at doses of 1 mg / kg / day of lisinopril and with an increased incidence of incomplete ossification at the lowest dose tested (0.1 mg / kg / day). . A single 15 mg / kg / day dose of lisinopril administered intravenously to pregnant rabbits during the 16th, 21st and 26th days of gestation resulted in 88 to 100% fetal deaths.

Hydrochlorothiazide

In acute and chronic toxicology studies hydrochlorothiazide was observed to have relatively low toxicity. In acute animal toxicology studies the LD50 in mice was greater than 10 g / kg in suspension per os.

Dogs tolerated at least 2 g / kg orally with no signs of toxicity. Hydrochlorothiazide was administered to rats in a two-litter study, to mice in a 2-generation study, and to rabbits with a positive pregnancy test. None of these studies showed teratogenic effects of hydrochlorothiazide.

Offspring raised to weaning or maturity showed no signs of treatment-related effects.

Carcinogenesis, mutagenesis and fertility studies

Hydrochlorothiazide is currently under study in the US Carcinogenesis Testing Program. Hydrochlorothiazide did not show mutagenic properties in vitro in the Ames microbial mutagenic assay at concentrations of up to 5 mg / plate using strains TA98 and TA100. Urine samples from patients treated with hydrochlorothiazide did not show mutagenic activity in the Ames test. AND The ability of some drugs to induce nondisjunction and crossing-over was measured on Aspergillus nidulans. A large number of drugs, including hydrochlorothiazide, induced nondisjunction.

Teratogenesis

Reproduction studies in rabbits, mice and rats at doses up to 100 mg / kg / day (50 times the maximum human dose) have shown no evidence of external fetal abnormalities due to hydrochlorothiazide.

Hydrochlorothiazide administered in a two-generation study in rats at doses of 4-5-6 mg / kg / day (approximately 1-2 times the maximum recommended human dose) did not alter the fertility or produce abnormalities of the offspring at birth.

Lisinopril / hydrochlorothiazide

Administration of lisinopril with hydrochlorothiazide results in toxic responses at lower doses than those observed with each compound administered alone. Since the toxicity of each component is due to its therapeutic activity (hypotension) and since there is an increase in the pharmacological activity of lisinopril when administered in combination with diuretics (hydrochlorothiazide), the increase in toxicity with the two drugs was expected. Although potentiation of toxicity secondary to potentiation of the pharmacological effect has been observed at high doses, there is no reason to predict a toxic response in humans to therapeutic doses of either drug. The safety of lisinopril and hydrochlorothiazide administered in combination with therapeutic dosages has been demonstrated in clinical studies. Lisinopril in combination with hydrochlorothiazide did not show mutagenic properties in a microbial mutagen test using Salmonella typhimurium (Ames test) or Escherichia coli with either without activation or in a mutation test using Chinese hamster lung cells. Lisinopril-hydrochlorothiazide did not produce DNA monoelic breaks in the alkaline elution fluid in the rat hepatocyte in vitro assay. Furthermore, it did not produce increases in chromosomal aberration in the in vitro Chinese hamster ovary cell test or in the in vivo mouse bone marrow study.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

Mannitol, dibasic calcium phosphate dihydrate, maize starch, pregelatinised starch, magnesium stearate.


06.2 Incompatibility

Not known.


06.3 Period of validity

30 months.


06.4 Special precautions for storage

Store the tablets in the carton in order to protect them from light.


06.5 Nature of the immediate packaging and contents of the package

PVC and aluminum blisters

Pack of 14 tablets.

Pack of 28 tablets.

Pack of 42 tablets.

Not all pack sizes may be marketed.


06.6 Instructions for use and handling

No special precautions are required

07.0 MARKETING AUTHORIZATION HOLDER

AstraZeneca S.p.A.

Ferraris Palace, Via Ludovico il Moro, 6 / C - Basiglio (MI)

08.0 MARKETING AUTHORIZATION NUMBER

"20 mg + 12.5 mg tablets 14 tablets" A.I.C. 027482013

"20 mg + 12.5 mg tablets 28 tablets" A.I.C. 027482025

"20 mg + 12.5 mg tablets 42 tablets" A.I.C. 027482037

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION

29.01.1992/02.2008

10.0 DATE OF REVISION OF THE TEXT

November 2015

11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY

12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL

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