Moduretic - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf life and Storage Composition and pharmaceutical form

Active ingredients: amiloride (amiloride hydrochloride dihydrate), hydrochlorothiazide

MODURETIC 5 mg + 50 mg tablets

Indications Why is Moduretic used? What is it for?

Moduretic contains two active ingredients: hydrochlorothiazide and amiloride.

Hydrochlorothiazide is a diuretic that belongs to a group of medicines called thiazides. It works by stimulating the kidneys to produce more urine (diuretic action) and in doing so lowers blood pressure (antihypertensive action).

Amiloride prevents the excessive loss of potassium that can occur in patients taking a thiazide diuretic, and is therefore called a potassium-sparing agent.

Moduretic combines the diuretic and antihypertensive action of hydrochlorothiazide with the potassium-sparing effect of amiloride.

Moduretic is indicated in the treatment of:

  • patients with excessive accumulation of fluid in body tissues due to cardiovascular disease (edema of cardiac origin);
  • patients with chronic degenerative liver disease with accumulation of fluid in the abdomen (ascitogenic liver cirrhosis);
  • patients with high blood pressure (hypertension).

Contraindications When Moduretic should not be used

Do not take Moduretic if:

  • you are allergic to the active substances (hydrochlorothiazide and amiloride) or to other medicines derived from sulfonamide (a substance chemically related to hydrochlorothiazide), or to any of the other ingredients of this medicine (listed in section 6);
  • have high levels of potassium in the blood (hyperkalaemia), are taking other potassium-sparing medicines or are taking potassium supplements;
  • you have kidney disease;
  • have kidney disease due to diabetes (diabetic nephropathy) with or without impaired kidney function (renal failure).

Moduretic must not be used in children (see section "Children and adolescents").

Precautions for use What you need to know before taking Moduretic

Talk to your doctor or pharmacist before taking Moduretic if:

  • have ever had, or currently have, hypersensitivity reactions (allergic reactions) or asthma. Signs of an allergic reaction may be skin rashes, difficulty swallowing or breathing, swelling of the lips, face, throat or tongue;
  • you usually have high levels of potassium in your blood, particularly if these are associated with heart disease, lung disease, liver or kidney problems, or if you are being treated with other diuretics. In these cases the doctor may deem it necessary to check the hydro-saline balance of the body more frequently (hydroelectrolytic balance) and / or provide for an adjustment of the dose of the medicines taken;
  • you are diabetic, as frequent monitoring of blood electrolytes and kidney function and a possible dose adjustment of diabetes medicines, including insulin, are required during treatment with Moduretic; your doctor will stop your treatment at least three days before a glucose tolerance test
  • has a particular metabolic disorder that causes inflammation, redness and pain in the joints (gout);
  • have an inflammatory disease of the immune system that affects various organs and tissues of the body (lupus erythematosus);
  • you are about to undergo anesthesia for surgery or dental surgery, as you may experience a sudden drop in blood pressure;
  • you must carry out tests to check the functionality of the glands that regulate the levels of calcium in the blood (parathyroid glands). Consult your doctor who will tell you to stop taking Moduretic before taking this test.

Fluid and electrolyte imbalance may occur during treatment with Moduretic, manifesting with signs and symptoms which may include: dry mouth, thirst, weakness, deep sleep (lethargy), drowsiness, agitation, involuntary muscle twitching (seizures), confusion, muscle cramps and pains, muscle fatigue, low blood pressure, reduced urine production, increased heart rate and gastrointestinal disturbances, such as nausea and vomiting. In these cases, notify your doctor promptly.

If you experience excessive vomiting while being treated with Moduretic, contact your doctor promptly, as this may result in water and electrolyte imbalance.

Children and adolescents

Moduretic is not recommended for use in children due to a lack of data on safety and efficacy.

Interactions Which drugs or foods can modify the effect of Moduretic

Other medicines and Moduretic

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

In particular, ask your doctor or pharmacist if you are taking:

  • medicines used to treat high blood pressure belonging to the categories of ACE inhibitors (angiotensin converting enzyme inhibitors) and angiotensin II receptor antagonists;
  • medicines used to suppress the immune system response (immunosuppressants), such as cyclosporine and tacrolimus;
  • potassium-sparing medicines or potassium supplements;
  • medicines that facilitate the elimination of urine (diuretics);
  • insulin or other antidiabetic medicines taken by mouth;
  • medicines used for muscle relaxation, such as tubocurarine;
  • adrenaline or noradrenaline, known as pressor amines;
  • corticosteroids (which modulate anti-inflammatory reactions) and adrenocorticotropic hormone ACTH (used to check if your adrenal glands are working properly);
  • non-steroidal anti-inflammatory drugs (NSAIDs), used to treat joint inflammation (arthritis) or muscle pain;
  • lithium, used to treat some depressive disorders;
  • medicines used to reduce the amount of fat in the blood, such as cholestyramine and colestipol resins;
  • barbiturates which have a sedative effect on the central nervous system, used for example to treat epilepsy;
  • medicines which have an anesthetic effect and induce sleep (narcotics);
  • medicines that help relieve pain (pain relievers).

Moduretic with food, drink and alcohol

Moduretic should not be taken together with alcohol, as excessive lowering of blood pressure can occur.

Warnings It is important to know that:

Pregnancy and breastfeeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before using this medicine.

Pregnancy

Moduretic is not recommended in pregnant women; if you need antihypertensive therapy, your doctor will evaluate the possibility of an alternative treatment. If you are taking Moduretic if you are pregnant or suspected of being pregnant, tell your doctor who will assess whether the possible benefits of treatment for you outweigh the potential risks to the baby.

Feeding time

Moduretic is not recommended in women who are breastfeeding. The hydrochlorothiazide contained in Moduretic is found in breast milk; if Moduretic is considered essential, your doctor will tell you to stop breastfeeding.

Driving and using machines

There are no data suggesting effects of Moduretic on the ability to drive and use machines.

Although rarely, Moduretic can cause side effects that may affect the ability to drive and use machines, such as sleepiness, dizziness and temporary disturbances in vision (see section 4 "Possible side effects"). Therefore, exercise caution when driving and using machines.

Moduretic contains lactose

If you have been told by your doctor that you have "intolerance to some sugars, contact your doctor before taking this medicinal product.

For those who practice sports

The use of the drug without therapeutic necessity constitutes doping and can in any case determine positive anti-doping tests.

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

Always take this medicine exactly as your doctor or pharmacist has told you. If you are unsure, consult your doctor or pharmacist. The optimal dose and duration of treatment for Moduretic will be determined by your doctor based on your clinical condition and taking into account the medicines you are already taking.

Edema of cardiac origin

The recommended starting dose is 1 tablet per day. If necessary, your doctor may increase the dose to a maximum of 2 tablets per day. Once diuresis is achieved, the doctor may reduce the dose for maintenance therapy. Maintenance therapy can be carried out on a non-continuous basis.

Ascitogenic liver cirrhosis

The minimum recommended starting dose is 1 tablet per day. If necessary, your doctor may gradually increase the dose until effective diuresis is obtained, up to a maximum of 2 tablets per day.

Maintenance therapy may be performed at a dose lower than that required to initiate diuresis.

Hypertension

The usual recommended dose is 1 tablet per day, given as a single dose or in divided doses (half a tablet twice a day). It may be sufficient to take only half a tablet of Moduretic a day.

Overdose What to do if you have taken too much Moduretic

If you take more Moduretic than you should

If you accidentally take an overdose of Moduretic, notify your doctor immediately or go to the nearest hospital.

Symptoms of an overdose could be: light-headedness or dizziness due to too low blood pressure, excessive thirst, mental confusion, decreased urine production, increased heart rate.

Method of treatment in case of taking an overdose of Moduretic

There are no special instructions for treatment in case of overdose of Moduretic and there is no specific substance that can counteract the effect of Moduretic overdose.

It is not known whether Moduretic is disposable by dialysis.

If an excessive dose of Moduretic is taken, treatment should be stopped, symptoms should be treated appropriately and the patient monitored closely. Recommended measures in the event of overdose include induction of vomiting and / or gastric lavage and appropriate supportive care.

If you forget to use Moduretic

Do not take a double dose to make up for a forgotten tablet. If in doubt, contact your doctor.

If you stop using Moduretic

For it to be effective, Moduretic must be taken regularly every day and for the duration of treatment, as prescribed by your doctor.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Side Effects What are the side effects of Moduretic

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

The undesirable effects seen with Moduretic are generally those known to be associated with thiazide therapy, or related to the underlying disease being treated, or to diuresis. Clinical studies have shown that the combination of amiloride-hydrochlorothiazide does not increase the risk of undesirable effects compared to the separate administration of the two active ingredients.

Stop taking Moduretic and see your doctor immediately if you notice any serious side effects, such as:

  • severe allergic reaction (anaphylactic reaction);
  • severe skin reactions including more or less pruritic rash (urticaria), skin disease leading to peeling of the skin (toxic epidermal necrolysis).

The most frequently reported effects with Moduretic in clinical trials were:

  • decreased or lack of appetite (anorexia);
  • dizziness, headache (headache);
  • nausea;
  • appearance of spots or bumps on the skin (rash);
  • asthenia.

Other side effects include:

  • altered appetite, dehydration, electrolyte imbalance, gout, decreased sodium levels in the blood (hyponatremia - see section "Warnings and precautions"); hyponatremia with accentuation of symptoms;
  • depression, insomnia, mental confusion, nervousness, drowsiness;
  • altered taste, pins and needles (paraesthesia), decreased attention, orientation and change in understanding (stupor), temporary loss of consciousness (syncope);
  • vision disturbances;
  • vertigo;
  • chest pain caused by reduced oxygen and blood supply to the heart (angina pectoris), changes in heart beat (arrhythmias), increased heart rate (tachycardia);
  • flushing, decrease in blood pressure following a sudden transition from sitting or lying to standing (orthostatic hypotension);
  • cough and difficulty in breathing (dyspnoea), stuffy nose (nasal congestion);
  • feeling of fullness in the abdomen, abdominal pain, difficulty passing stool (constipation), diarrhea, increased production of intestinal gas (flatulence), gastrointestinal bleeding, hiccups, vomiting;
  • increased sweating (diaphoresis), itching;
  • back pain (low back pain), joint pain, leg pain, involuntary muscle contraction (muscle cramps);
  • difficulty urinating (dysuria), incontinence, need to get up more times during the night to urinate (nocturia), kidney dysfunction including renal failure;
  • difficulty in men to achieve or maintain an erection (impotence);
  • chest pain, decreased resistance to muscle strain (fatigue), malaise, thirst;
  • high blood potassium levels (> 5.5 mEq per liter);
  • toxicity due to medicines used to treat heart failure (digitalis medicines).

Undesirable effects related to amiloride

  • insufficient production of blood cells by the bone marrow (aplastic anemia), decrease in the number of specific blood cells called neutrophils (neutropenia);
  • decreased sex drive (decreased libido);
  • brain dysfunction (encephalopathy), sleepiness, tremors;
  • annoying sensation of ringing or ringing in the ears (tinnitus);
  • partial cardiac arrest that has turned into total cardiac arrest (in 1 patient), irregular or strengthened heartbeat (palpitations);
  • cough;
  • activation of lesions of the mucous membrane of the digestive system (peptic ulcer) probably pre-existing, dry mouth, pain in the upper half of the abdomen (dyspepsia);
  • yellowing of the skin and whites of the eyes (jaundice), changes in liver function;
  • hair loss (alopecia);
  • neck / shoulder pain, pain in extremities;
  • involuntary contractions of the bladder (bladder spasm), increased amount of urine passed (polyuria), increased frequency of passing small amounts of urine (pollakiuria);
  • changes in kidney function, increased pressure in the eye (intraocular pressure).

Undesirable effects related to hydrochlorothiazide

  • inflammation of the salivary glands (sialoadenitis);
  • severe reduction in the number of granulocytes (a type of white blood cell) in the blood (agranulocytosis), insufficient production of blood cells by the bone marrow (aplastic anemia), excessive destruction of red blood cells (haemolytic anemia), abnormal reduction in white blood cells ( leukopenia), rupture of the capillaries below the surface of the skin (purpura), reduction in the number of platelets in the blood (thrombocytopenia);
  • increased blood sugar (hyperglycaemia), high concentration of uric acid in the blood (hyperuricaemia), deficiency of potassium in the blood (hypokalaemia);
  • restlessness;
  • temporary blurring of vision, disturbance in color vision (xanthopsia);
  • necrotic inflammation of the wall of the skin vessels (necrotizing angioit, vasculitis);
  • difficulty in breathing also due to inflammation of the lungs (pneumonia) or due to the presence of fluid in the lungs (pulmonary edema);
  • involuntary muscle contraction (cramps), stomach irritation, inflammation of the pancreas (pancreatitis);
  • yellowing of the skin and whites of the eyes (jaundice), mainly due to liver disease (intrahepatic colostatic jaundice);
  • sensitivity of the skin to a light source (photosensitivity);
  • presence of sugar in the urine (glycosuria), inflammatory disease of one of the kidney tissues (interstitial nephritis); - fever.

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. You can also report side effects directly via 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

Keep this medicine out of the sight and reach of children. Store in the original package to protect the medicine from light.

Do not use this medicine after the expiry date which is stated on the carton and blister after "EXP". The expiry date refers to the last day of that month.

Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Composition and pharmaceutical form

What Moduretic contains

  • The active substances are amiloride hydrochloride dihydrate and hydrochlorothiazide. Each tablet contains 5.7 mg of amiloride hydrochloride dihydrate (equivalent to 5.0 mg of anhydrous amiloride hydrochloride) and 50 mg of hydrochlorothiazide.
  • The other ingredients are dibasic calcium phosphate dihydrate, lactose monohydrate, maize starch, pregelatinised starch, guar gum, magnesium stearate.

Description of what Moduretic looks like and contents of the pack

Moduretic comes in the form of tablets contained in a PVC and aluminum blister.

Each pack contains 20 tablets.

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 Moduretic 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 interaction 04.6 Pregnancy and lactation 04.7 Effects on ability to drive and use machines 04.8 Undesirable effects 04.9 Overdose 05.0 PHARMACOLOGICAL PROPERTIES 05.1 Pharmacodynamic properties 05.2 Pharmacokinetic properties 05.3 Preclinical safety data 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 primary packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER 08.0 MARKETING AUTHORIZATION NUMBER CIO 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIO DRUGS, FULL 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

MODURETIC 5 MG + 50 MG TABLETS

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains: amiloride hydrochloride dihydrate 5.7 mg (equivalent to anhydrous amiloride hydrochloride 5.0 mg) and hydrochlorothiazide 50 mg.

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Tablets.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

MODURETIC is indicated in the treatment of patients with edema of cardiac origin, with ascitogenic liver cirrhosis and in hypertensive patients.

04.2 Posology and method of administration

The appropriate posology should be defined by the physician. Unless otherwise indicated, the following dosage guidelines apply.

Moduretic usually starts to work within 2-4 hours of taking.

Edema of cardiac origin

MODURETIC therapy can be started with 1 tablet per day. If necessary, the dose may be increased, but the maximum dosage should not exceed 2 MODURETIC tablets per day. Once diuresis is achieved, an attempt should be made to reduce the dosage for maintenance therapy. Maintenance therapy can be carried out on a non-continuous basis.

Hypertension

The usual dosage is 1 tablet per day, once or in divided doses. Some patients may only need half a MODURETIC tablet per day.

Ascitogenic liver cirrhosis

Treatment should begin with a minimal dosage of MODURETIC (one tablet once a day). If necessary, the dosage can be gradually increased until effective diuresis is obtained. The dosage should not exceed two tablets per day. The maintenance dosage may be lower than that required to induce diuresis; consequently, an attempt should be made to reduce the daily dose when the patient's weight has stabilized. Gradual weight reduction of cirrhotic patients is particularly desirable to reduce the likelihood of adverse reactions associated with diuretic therapy.

Administration and duration of treatment

The duration of treatment is determined by the doctor.

04.3 Contraindications

- Hypersensitivity to the active substances, to other drugs derived from sulfonamide or to any of the excipients

- Hyperkalaemia (greater than 5.5 mEq / l).

- Simultaneous administration of other potassium-sparing drugs or potassium salts (see section 4.4).

- Renal function disorders: anuria, acute renal failure, severe progressive nephropathies and diabetic nephropathy are contraindications to the use of MODURETIC. Patients in whom BUN exceeds 60 mg / 100 ml, serum creatinine exceeds 1.5 mg / 100 ml, or urea nitrogen exceeds 30 mg / 100 ml or patients with diabetes mellitus should not be treated with MODURETIC without careful and frequent monitoring of serum electrolyte levels, serum creatinine and blood urea nitrogen. Potassium retention associated with the use of an antikaliuretic agent is accentuated in the presence of renal damage and can cause the rapid development of hyperkalaemia.

- In children.

- Diabetic nephropathy, with or without renal insufficiency.

04.4 Special warnings and appropriate precautions for use

Diabetes mellitus

In diabetic patients, hyperkalaemia has been reported with the use of all potassium-sparing diuretics, including amiloride hydrochloride, even in patients with no evidence of diabetic nephropathy. MODURETIC should therefore be avoided, if possible, in diabetic patients and, if used. , serum electrolytes and renal function should be monitored frequently.

MODURETIC will need to be stopped at least three days before a glucose tolerance test.

Metabolic or respiratory acidosis

Antikaliuretic treatment should be initiated with caution in severely ill patients in whom respiratory or metabolic acidosis may occur, such as patients with cardiopulmonary disease or patients with decompensated diabetes. Variations in the acid-base balance alter the balance between extracellular potassium and intracellular potassium, and rapid increases in potassium values ​​can be followed by acidosis.

Hyperkalemia

Hyperkalaemia (serum potassium levels> 5.5 mEq / l) has been observed in patients treated with amiloride hydrochloride, either alone or in combination with other diuretics. In particular, this phenomenon has been observed in elderly patients, in patients diabetics and in patients admitted to hospital with liver cirrhosis or edema of cardiac origin, who had known renal impairment or were seriously ill or were receiving vigorous diuretic treatment. These patients should be carefully monitored for clinical, electrocardiographic or biochemical signs of hyperkalaemia Some deaths have occurred in this group of patients.

Supplemental potassium supplements in the form of drugs or a potassium-rich diet should not be used with MODURETIC except in cases of severe and / or refractory hypokalaemia. If potassium supplements are given, careful monitoring of blood potassium is recommended. Signs of hyperkalaemia are: paraesthesia, muscle weakness, fatigue, flaccid paralysis of the extremities, bradycardia, shock, abnormalities in blood potassium and ECG. It is important to monitor the serum potassium level closely, since hyperkalaemia is not always accompanied by electrocardiographic changes.

Treatment of hyperkalemia

Whenever hyperkalaemia occurs during treatment with MODURETIC, the drug should be stopped immediately and, if necessary, vigorous measures should be taken to reduce the serum potassium level. Discontinuation of antikaliurietic treatment should be followed by intravenous administration of molar sodium lactate, or oral or parenteral glucose associated with fast-acting insulin. If necessary, a cation exchange resin can be administered orally or by enteroclysis, e.g. sodium polystyrenesulfonate. In patients whose hyperkalaemia persists, hemodialysis may be required.

Electrolyte imbalance and elevation of azotemia

Although the likelihood of electrolyte imbalance is decreased with MODURETIC, signs of electrolyte imbalance such as hyponatremia, hypochloraemic alkalosis, hypokalaemia and hypomagnesaemia should be carefully monitored. It is especially important to perform quantitative serum electrolyte and urine tests when the patient vomits excessively or is injecting fluids. Warning signs and symptoms of fluid and electrolyte imbalance include: dry mouth, thirst, weakness, lethargy, drowsiness, agitation, convulsions, confusion, muscle cramps or pains, muscle fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

Hypokalaemia can develop with hydrochlorothiazide as well as with any other strong diuretic, especially with intense diuresis, after prolonged treatment or in the presence of severe cirrhosis. Hypokalaemia can sensitize or increase the heart's response to the toxic effects of digitalis (eg . increased ventricular irritability).

Diuretic-induced hyponatremia is usually mild and asymptomatic. In some patients it may become severe or symptomatic; such patients require immediate attention and appropriate treatment.

Elevations of urea nitrogen levels have been observed with amiloride hydrochloride and hydrochlorothiazide. These elevations are usually associated with intense fluid elimination, especially when diuretic treatment is used for seriously ill patients, such as those suffering from ascitogenic liver cirrhosis and metabolic alkalosis, or for those suffering from refractory edema. Consequently, when MODURETIC is administered to such patients, careful monitoring of serum electrolyte and urea nitrogen levels is important.

BUN levels may be increased by hydrochlorothiazide. Cumulative effects of the drug may develop in patients with impaired renal function. If elevated BUN and oliguria occur during treatment of severe progressive kidney disease, treatment should be discontinued.

Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, as minor disturbances in fluid and electrolyte balance can precipitate hepatic coma.

Metabolic and endocrine effects

Thiazides can reduce serum levels of protein bound iodine with no signs of thyroid disorders.

Due to the hydrochlorothiazide component, insulin requirements may be increased, reduced or unchanged in diabetic patients. Latent diabetes mellitus may become manifest during administration of thiazide diuretics.

Since calcium excretion is reduced by hydrochlorothiazide, MODURETIC will have to be discontinued before performing parathyroid function tests. Pathological changes in the parathyroid glands with hypercalcaemia and hypophosphataemia have been observed in some patients undergoing prolonged treatment with thiazides. Common complications of hyperparathyroidism such as renal lithiasis, bone resorption and gastric ulcer have been observed.

Hyperuricaemia or gout may occur in some patients taking thiazides.

Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.

Hypersensitivity reactions

They can occur in patients with and without a history of allergies or bronchial asthma. The possibility of exaggeration or activation of systemic lupus erythematosus has been reported with the use of thiazides.

Use in children

Safety and efficacy in children have not been established.

For those who play sports:

The use of the drug without therapeutic necessity constitutes doping and can in any case determine positive anti-doping tests.

This medicine contains lactose: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

04.5 Interactions with other medicinal products and other forms of interaction

Lithium: diuretics reduce the clearance renal lithium, carrying a high risk of lithium toxicity; concomitant use is not recommended. Read the technical data sheet of the lithium-based preparation carefully before using these preparations.

Non-steroidal anti-inflammatory agents including selective cyclooxygenase-2 (COX-2) inhibitors

Non-steroidal anti-inflammatory drugs (NSAIDs) including selective cyclooxygenase-2 (COX-2) inhibitors may decrease the effect of antihypertensive drugs, including the diuretic, natriuretic and antihypertensive effects of diuretics.

In some patients with impaired renal function (such as the elderly or patients who are volume depleted, including those on diuretic therapy) who are being treated with non-steroidal anti-inflammatory drugs, including selective cyclooxygenase-2 inhibitors, concomitant administration of Angiotensin II receptor antagonists or ACE inhibitors may cause further deterioration of renal function. Therefore, concomitant administration should be used with caution in patients with impaired renal function.

Concomitant administration of NSAIDs and potassium-sparing agents, including amiloride hydrochloride, may cause hyperkalaemia, especially in elderly patients. Therefore, if amiloride hydrochloride is administered concomitantly with NSAIDs, serum potassium levels should be closely monitored.

Amiloride hydrochloride

When amiloride hydrochloride is used concomitantly with angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, cyclosporine or tacrolimus, the risk of hyperkalaemia may be increased. Therefore, if concomitant use of these agents is indicated due to established hypokalaemia, they should be used with caution and with frequent monitoring of serum potassium.

Hydrochlorothiazide

The following drugs, when administered concomitantly, may interact with thiazide diuretics.

Alcohol, barbiturates or narcotics: Potentiation of orthostatic hypotension may occur.

Antidiabetic drugs (oral agents and insulin): the dosage of the antidiabetic drug may need to be adjusted.

Other antihypertensive drugs: additive effect. Diuretic therapy should be discontinued 2-3 days prior to initiating therapy with an ACE inhibitor in order to reduce the chances of first-dose hypotension.

Colestyramine and colestipol resins: the absorption of hydrochlorothiazide is compromised by the presence of anionic exchange resins. Single doses of cholestyramine or colestipol bind with hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively.

Corticosteroids, ACTH: may intensify electrolyte depletion, particularly hypokalaemia.

Pressor amines (e.g. norepinephrine): a reduction in the response to pressor amines is possible, but not such as to preclude their administration.

Muscle relaxants, non-depolarizing (e.g. tubocurarine): an enhancement of the responsiveness to the muscle relaxant is possible.

Drug / laboratory interactionsDue to their effects on calcium metabolism, thiazides may interfere with tests for parathyroid function (see section 4.4).

04.6 Pregnancy and lactation

The usual use of diuretics in healthy pregnant women, with or without mild edema, is not recommended and exposes both mother and fetus to unnecessary risks. Diuretics do not prevent the development of toxaemia of pregnancy and there is no satisfactory evidence of their usefulness in the treatment of toxemia. Thiazides cross the placental barrier and appear in the umbilical cord blood.Consequently, in the case of administration of MODURETIC during a certain or suspected pregnancy, the potential benefits of the drug must be carefully weighed against the possible risks to the fetus. These risks include fetal or neonatal jaundice, thrombocytopenia and possibly other adverse effects that have occurred in adults.

Thiazides have been detected in breast milk. If the use of MODURETIC is considered indispensable, the patient should stop breastfeeding.

04.7 Effects on ability to drive and use machines

There are no data suggesting effects of MODURETIC on the ability to drive and use machines. However, patients should be advised that, although rarely, treatment with MODURETIC may cause drowsiness, dizziness and temporary disturbances in vision.

04.8 Undesirable effects

The undesirable effects observed with MODURETIC are generally those well known associated with diuresis, thiazide therapy or the underlying disease being treated. Clinical studies have not shown that the combination of amiloride-hydrochlorothiazide increases the risk of undesirable effects beyond those seen with the separate administration of the two substances.

The following adverse reactions have been reported with MODURETIC:

Disorders of the immune system

anaphylactic reaction.

Metabolism and nutrition disorders

anorexia*,

altered appetite,

dehydration,

electrolyte imbalance,

gout,

hyponatraemia (see section 4.4),

symptomatic hyponatremia.

Psychiatric disorders

depression,

insomnia,

mental confusion,

nervousness,

drowsiness.

Nervous system disorders

change in taste,

dizziness*,

headache *,

paraesthesia,

stupor,

syncope.

Eye disorders

vision disturbances.

Ear and labyrinth disorders

vertigo.

Cardiac pathologies

angina pectoris,

arrhythmias,

tachycardia.

Vascular pathologies

hot flashes,

orthostatic hypotension.

Respiratory, thoracic and mediastinal disorders

dyspnea,

nasal congestion.

Gastrointestinal disorders

sense of abdominal fullness,

abdominal pain,

constipation,

diarrhea,

flatulence,

gastrointestinal bleeding,

hiccup,

nausea*,

He retched.

Skin disorders of the subcutaneous tissue

diaphoresis,

itch,

rash*.

Disorders of the musculoskeletal system, connective tissue and bone tissue

low back pain,

joint pain,

leg pain,

muscle cramps.

Renal and urinary disorders

dysuria,

incontinence,

nocturia,

renal dysfunction including renal failure.

Diseases of the reproductive system and breast

impotence.

General disorders and administration site conditions

chest pain,

fatigue,

malaise,

thirst,

asthenia*.

Diagnostic tests

elevated serum potassium levels (> 5.5 mEq per liter).

Injury and poisoning

digitalis toxicity.

Other side effects have also been reported with separate administration of the two substances.

AMILORIS

Disorders of the blood and lymphatic system

aplastic anemia,

neutropenia.

Psychiatric disorders

decreased libido.

Nervous system disorders

encephalopathy,

drowsiness,

tremors.

Ear and labyrinth disorders

tinnitus.

Cardiac pathologies

a patient with partial cardiac arrest developed total cardiac arrest,

palpitations.

Respiratory, thoracic and mediastinal disorders

cough.

Gastrointestinal disorders

activation of a possibly pre-existing peptic ulcer,

dryness of the mucous membrane of the oral cavity,

dyspepsia.

Hepatobiliary disorders

jaundice,

liver function disorders.

Skin disorders of the subcutaneous tissue

alopecia.

Disorders of the musculoskeletal system, connective tissue and bone tissue

neck / shoulder pain,

pain in extremities.

Renal and urinary disorders

bladder spasm,

polyuria,

pollakiuria.

Diagnostic tests

abnormal kidney function,

increased intraocular pressure.

HYDROCHLOROTHIAZIDE

Infections and infestations

sialoadenitis.

Disorders of the blood and lymphatic system

agranulocytosis,

aplastic anemia,

haemolytic anemia,

leukopenia,

purple,

thrombocytopenia.

Metabolism and nutrition disorders

hyperglycemia,

hyperuricemia,

hypokalaemia.

Psychiatric disorders

restlessness.

Eye disorders

transient blurring of vision,

xanthpsia.

Vascular pathologies

necrotizing angitis (vasculitis, cutaneous vasculitis).

Respiratory, thoracic and mediastinal disorders

respiratory distress including pneumonia and pulmonary edema.

Gastrointestinal disorders

cramps,

gastric irritation,

pancreatitis.

Hepatobiliary disorders

intrahepatic colostatic jaundice.

Skin disorders of the subcutaneous tissue

photosensitivity,

toxic epidermal necrolysis,

urticaria.

Renal and urinary disorders

glycosuria,

interstitial nephritis.

General disorders and administration site conditions

fever.

04.9 Overdose

No data are available on overdose in humans. The oral LD50 of the combination of the two substances is 189 and 422 mg / kg in female mice and male rats, respectively. It is not known whether the drug is dialysable.

There are no special indications for the treatment of overdose with MODURETIC and no specific antidote is available. Treatment is symptomatic and supportive. Treatment with MODURETIC should be discontinued and the patient observed carefully. Recommended recommended measures in case of overdose include vomiting and / or gastric lavage.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: diuretics and potassium-sparing drugs.

ATC: C03EA01

MODURETIC is an antihypertensive diuretic which combines the powerful natriuretic action of hydrochlorothiazide with the potassium-saving effect of amiloride hydrochloride. MODURETIC provides a diuretic and antihypertensive activity (mainly due to the hydrochlorothiazide component) while through the amiloride component it prevents the excessive loss of potassium that can occur in patients receiving a thiazide diuretic. Due to the effect of amiloride, MODURETIC has less urinary excretion of magnesium than a thiazide or a loop diuretic used alone. diuretic and antihypertensive of amiloride hydrochloride are additive to the natriuretic, diuretic and antihypertensive activity of thiazide while minimizing the loss of potassium and bicarbonate reducing the possibility of an acid-base imbalance.

Amiloride hydrochloride is a potassium-sparing drug that has mild natriuretic, diuretic and antihypertensive activity. The main use is to preserve potassium in patients receiving diuretic drugs in whom excessive potassium losses are present or expected.

Hydrochlorothiazide generally does not cause clinically important changes in normal blood pressure.

05.2 Pharmacokinetic properties

The onset of the diuretic action of MODURETIC occurs within 2 hours and this action appears to last for approximately 24 hours.

Amiloride hydrochloride

Amiloride hydrochloride generally begins to act within 2 hours of an oral dose. Its effect on electrolyte excretion peaks in 6-10 hours and lasts for approximately 24 hours. Maximum plasma levels are obtained in 3-4 hours and the plasma half-life ranges from 6 to 9 hours.

Amiloride hydrochloride is not metabolised by the liver, but is eliminated unchanged by the kidneys. It has little effect on glomerular filtration volume and renal blood flow. As amiloride hydrochloride is not metabolised by the liver, accumulation of the substance is not expected. patients with liver dysfunction, but accumulation may occur if hepatorenal syndrome develops.

Hydrochlorothiazide

The diuretic effect of hydrochlorothiazide begins within two hours after oral administration, peaks after approximately 4 hours and lasts approximately 6-12 hours. Hydrochlorothiazide is rapidly eliminated by the kidneys.

05.3 Preclinical safety data

Amiloride hydrochloride

The acute oral LD50 of amiloride (calculated as a basis) is 56 mg / kg in mice and 36-85 mg / kg in rats, depending on race. In a 78-week chronic toxicity study conducted in rats, the maximum tolerated dose over a period of more than a few weeks was 10 mg / kg / day (calculated as amiloride hydrochloride). a reduction in body weight and serum sodium and an increase in serum potassium.

No carcinogenic effect was observed when amiloride hydrochloride was administered for 92 weeks to mice at a dosage of up to 10 mg / kg / day (25 times the maximum daily human dose). Amiloride hydrochloride was also administered for 104 weeks to male and female rats at doses up to 6-8 mg / kg / day (15 and 20 times the maximum daily human dose, respectively). No carcinogenic effects were observed.

Amiloride hydrochloride is devoid of mutagenic activity in numerous strains of Salmonella typhimurium with or without microsomal mammalian liver activation (Ames test). Teratology studies have been conducted with combinations of amiloride hydrochloride and hydrochlorothiazide in rabbits and mice at doses up to 25 times the maximum daily dose used in humans; no fetal harm was detected.

Hydrochlorothiazide

In acute and chronic toxicology studies hydrochlorothiazide was observed to be relatively low toxic. In acute animal toxicology studies the LD50 in mice is greater than 10,000 mg / kg in suspension orally and 884 mg / kg intravenously. rats the acute LD50 is greater than 10,000 mg / kg in suspension orally and 3,130 mg / kg in suspension intraperitoneally. In rabbits the acute intravenous LD50 is 461 mg / kg and in dogs about 1,000 mg / kg. Dogs tolerate up to at 2,000 mg / kg orally with no signs of toxicity. In chronic oral toxicology studies in rats, using doses up to 2,000 mg / kg / day for 5 days a week for 26 weeks, no signs of drug effect were observed. , nor drug-related alterations at autopsy. 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.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

Calcium dibasic phosphate dihydrate, lactose monohydrate, maize starch, pregelatinised starch, guar gum, magnesium stearate.

06.2 Incompatibility

Not relevant.

06.3 Period of validity

3 years.

06.4 Special precautions for storage

Store in the original packaging. Keep the container in the outer carton to protect the medicine from light.

06.5 Nature of the immediate packaging and contents of the package

PVC and aluminum blisters.

Pack of 20 tablets 5 mg + 50 mg.

06.6 Instructions for use and handling

No special instructions.

07.0 MARKETING AUTHORIZATION HOLDER

MSD Italia S.r.l.

Via Vitorchiano, 151 - 00189 Rome

08.0 MARKETING AUTHORIZATION NUMBER

20 tablets 5 mg + 50 mg AIC n.023070016

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION

February 1974

10.0 DATE OF REVISION OF THE TEXT

February 2011

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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