CARVEDEXXON 6.25

Israel - English - Ministry of Health

Buy It Now

Active ingredient:
CARVEDILOL
Available from:
DEXCEL LTD, ISRAEL
ATC code:
C07AG02
Pharmaceutical form:
TABLETS
Composition:
CARVEDILOL 6.25 MG
Administration route:
PER OS
Prescription type:
Required
Manufactured by:
DEXCEL LTD, ISRAEL
Therapeutic group:
CARVEDILOL
Therapeutic area:
CARVEDILOL
Therapeutic indications:
Treatment of symptomatic congestive heart failure. Carvedexxon may be used as adjunct to standard therapy, but may also be used in those patients unable to tolerate an ACE inhibitor, or those who are not receiving digitalis, hydralazine or nitrate therapy.
Authorization number:
127 19 30614 00
Authorization date:
2012-11-30

Documents in other languages

Patient Information leaflet Patient Information leaflet - Hebrew

07-11-2017

SUMMARY OF PRODUCT CHARACTERITICS

CARVEDEXXON 6.25, 12.5 mg Tablets

1.

NAME OF THE MEDICINAL PRODUCT

Carvedexxon 6.25

Carvedexxon 12.5

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains Carvedilol 6.25 mg or 12.5 mg respectively

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Tablet.

White to off white, round, biconvex tablets, scored on one side.

The tablet can be divided into equal doses.

4.

CLINICAL PARTICULARS

4.1 Therapeutic indications

Treatment of symptomatic congestive heart failure.

Carvedexxon may be used as adjunct to standard therapy, but may also be used in those

patients unable to tolerate an ACE inhibitor, or those who are not receiving digitalis,

hydralazine or nitrate therapy.

4.2 Posology and method of administration

The tablets should be taken with fluid. Carvedexxon should be given with food to slow the

rate of absorption and reduce the incidence of orthostatic effects.

Symptomatic congestive heart failure

The dosage must be titrated to individual requirements and monitored during up-titration.

For those patients receiving diuretics and/or digoxin and/or ACE inhibitors, dosing of these

other drugs should be stabilized prior to initiation of Carvedexxon treatment.

Adults

The recommended dose for the initiation of therapy is 3.125 mg twice a day for two weeks. If

this dose is tolerated, the dosage should be increased subsequently, at intervals of not less

than two weeks, to 6.25 mg twice daily, followed by 12.5 mg twice daily and thereafter 25

mg twice daily. Dosing should be increased to the highest level tolerated by the patient.

The recommended maximum daily dose is 25 mg given twice daily in patients weighing less

than 85kg and 50 mg twice daily in patients weighing more than 85 kg.

Before each dose increase the patient should be evaluated by the physician for symptoms of

worsening heart failure or vasodilation. Transient worsening of heart failure, vasodilation or

fluid retention may be treated with increased doses of diuretics or ACE inhibitors or by

modifying or temporarily discontinuing Carvedexxon treatment. Under these circumstances,

the dose of Carvedexxon should not be increased until symptoms of worsening heart failure

or vasodilation have been stabilized.

If Carvedexxon is discontinued for more than two weeks, therapy should be recommenced at

3.125 mg twice daily and up-titrated in line with the above dosing recommendation.

Elderly

As for adults.

Children

Safety and efficacy in children (under 18 years) has not been established.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Unstable/decompensated heart failure requiring intravenous inotropic support.

Clinically manifest liver dysfunction.

As with other beta-blocking agents:

History of bronchospasm or asthma

2nd and 3rd degree atrioventricular (AV) heart block, (unless a permanent pacemaker is in

place)

Severe bradycardia (< 50 bpm)

Cardiogenic shock

Sick sinus syndrome (including sino-atrial block)

Severe hypotension (systolic blood pressure < 85 mmHg).

4.4 Special warnings and precautions for use

Chronic congestive heart failure: In congestive heart failure patients, worsening cardiac

failure or fluid retention may occur during up-titration of Carvedexxon. If such symptoms

occur, diuretics should be increased and the Carvedexxon dose should not be further

increased until clinical stability resumes. Occasionally it may be necessary to lower the

Carvedexxon dose or, in rare cases, temporarily discontinue it. Such episodes do not

preclude subsequent successful up-titration of Carvedexxon.

Carvedexxon should be used with caution in combination with digitalis glycosides, since

both drugs slow A-V conduction (see section 4.5).

Renal function in congestive heart failure: Reversible deterioration of renal function has been

observed with Carvedilol therapy in chronic heart failure patients with low blood pressure

(systolic BP < 100 mmHg), ischaemic heart disease and diffuse vascular disease, and/or

underlying renal insufficiency. In CHF patients with these risk factors, renal function should

be monitored during up-titration of Carvedexxon and the drug discontinued or dosage

reduced if worsening of renal failure occurs.

Chronic obstructive pulmonary disease: Carvedilol should be used with caution, in patients

with chronic obstructive pulmonary disease (COPD) with a bronchospastic component who

are not receiving oral or inhaled medication, and only if the potential benefit outweighs the

potential risk. In patients with a tendency to bronchospasm, respiratory distress can occur as a

result of a possible increase in airway resistance. Patients should be closely monitored during

initiation and up-titration of carvedilol and the dose of Carvedexxon should be reduced if

any evidence of bronchospasm is observed during treatment.

Diabetes: Care should be taken in the administration of Carvedexxon to patients with

diabetes mellitus, as it may be associated with worsening control of blood glucose, or the

early signs and symptoms of acute hypoglycemia may be masked or attenuated. Alternatives

to beta-blocking agents are generally preferred in insulin-dependent patients. Therefore,

regular monitoring of blood glucose is required in diabetics when Carvedexxon is initiated

or up-titrated and hypoglycemic therapy adjusted accordingly (see section 4.5).

Peripheral vascular disease and Raynaurd's phenomenon: Carvedexxon should be used with

caution in patients with peripheral vascular disease (e.g. Raynaud's phenomenon) as beta-

blockers can precipitate or aggravate symptoms of arterial insufficiency.

Thyrotoxicosis: Carvedexxon may obscure the symptoms of thyrotoxicosis.

Bradycardia: Carvedexxon may induce bradycardia. If the patient's pulse rate decreases to

less than 55 beats per minute, the dosage of Carvedexxon should be reduced.

Hypersensitivity: Care should be taken in administering Carvedexxon to patients with a

history of serious hypersensitivity reactions and in patients undergoing desensitization

therapy as beta-blockers may increase both the sensitivity towards allergens and the severity

of hypersensitivity reactions.

Severe cutaneous adverse reactions (SCARs): Very rare cases of severe cutaneous adverse

reactions such as toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS)

have been reported during treatment with Carvedexxon (see section 4.8). Carvedexxon

should be permanently discontinued in patients who experience severe cutaneous adverse

reactions possibly attributable to Carvedexxon.

Psoriasis: Patients with a history of psoriasis associated with beta-blocker therapy should be

given Carvedexxon only after consideration of the risk-benefit ratio.

Interactions with other medicinal products: There are a number of important pharmacokinetic

and pharmacodynamics interactions with other drugs (e.g., digoxin, ciclosporin, rifampicin,

anesthetic drugs, anti-arrhythmic drug. See section 4.5).

Pheochromocytoma: In patients with pheochromocytoma, an alpha-blocking agent should be

initiated prior to the use of any beta-blocking agent. Although Carvedexxon has both alpha

and beta blocking pharmacological activities, there is no experience of the use of carvedilol

in this condition. Therefore, caution should be taken in the administration of Carvedexxon to

patients suspected of having pheochromocytoma.

Prinzmetal's variant angina: Agents with non-selective beta-blocking activity may provoke

chest pain in patients with Prinzmetal's variant angina. There is no clinical experience with

carvedilol in these patients, although the alpha-blocking activity of Carvedexxon may

prevent such symptoms. Caution should be taken in the administration of Carvedexxon to

patients suspected of having Prinzmetal's variant angina.

Contact lenses: Wearers of contact lenses should be advised of the possibility of reduced

lacrimation.

Withdrawal syndrome: Although angina has not been reported on stopping treatment,

discontinuation should be gradual (over a period of 2 weeks), particularly in patients with

ischemic heart disease, as Carvedexxon has beta-blocking activity.

Usage of carvedilol in patients with symptomatic congestive heart failure has not been shown

to reduce mortality.

4.5 Interaction with other medicinal products and other forms of interaction

Pharmacokinetic interactions:

Effects of Carvedilol on the pharmacokinetics of other drugs

Carvedilol is a substrate as well as an inhibitor of P-glycoprotein. Therefore the

bioavailability of drugs transported by P-glycoprotein may be increased with concomitant

administration of carvedilol. In addition, the bioavailability of carvedilol can be modified by

inducers or inhibitors of P-glycoprotein.

Inhibitors as well as inducers of CYP2D6 and CYP2C9 can modify the systemic and/or

presystemic metabolism of carvedilol stereoselectively, leading to increased or decreased

plasma concentrations of R and S-carvedilol. (see section 5.2). Some examples observed in

patients or in healthy subjects are listed below but the list is not exhaustive.

Digoxin: An increased exposure of digoxin of up to 20% has been shown in some studies in

healthy subjects and patients with heart failure. A significantly larger effect has been seen in

male patients compared to female patients. Therefore monitoring of digoxin levels is

recommended when initiating, adjusting or discontinuing carvedilol (see section 4.4).

Carvedilol had no effect on digoxin administered intravenously.

Ciclosporin: Two studies in renal and cardiac transplant patients receiving oral ciclosporin

have shown an increase in ciclosporin plasma concentration following the initiation of

carvedilol. It appears that carvedilol increases exposure to oral ciclosporin by around 10 to

20%. In an attempt to maintain therapeutic ciclosporin levels, an average 10-20% reduction

of the ciclosporin dose was necessary. The mechanism for the interaction is not known but

inhibition of intestinal P glycoprotein by carvedilol may be involved. Due to wide

interindividual variability of ciclosporin levels, it is recommended that ciclosporin

concentrations are monitored closely after initiation of carvedilol therapy and that the dose of

ciclosporin be adjusted as appropriate. In case of IV administration of ciclosporin, no

interaction with carvedilol is expected.

Effects of other drugs on the pharmacokinetics of Carvedilol

Rifampicin: In a study in 12 healthy subjects, exposure to carvedilol decreased by around

60% during concomitant administration with rifampicin and a decrease effect of carvedilol on

the systolic blood pressure was observed. The mechanism for the interaction is not known but

it may be due to the induction of the intestinal P glycoprotein by rifampicin. A close

monitoring of the β-blockade activity in patients receiving concomitant administration of

carvedilol and rifampicin is appropriate.

Amiodarone: An in vitro study with human liver microsomes has shown that amiodarone and

desethylamiodarone inhibited the oxidation of R and S-carvedilol. The trough concentration

of R and S-carvedilol was significantly increased by 2.2-fold in heart failure patients

receiving carvedilol and amiodarone concomitantly as compared to patients receiving

carvedilol monotherapy. The effect on S-carvedilol was attributed to desethylamiodarone, a

metabolite of amiodarone, which is a strong inhibitor of CYP2C9. A monitoring of the β-

blockade activity in patients treated with the combination carvedilol and amiodarone is

advised.

Fluoxetine and Paroxetine: In a randomized, cross-over study in 10 patients with heart

failure, coadministration of fluoxetine, a strong inhibitor of CYP2D6, resulted in

stereoselective inhibition of carvedilol metabolism with a 77% increase in mean R(+)

enantiomer's AUC, and a non-statistically 35% increase of the S(-) enantiomer's AUC as

compared to the placebo group. However, no differences in adverse events, blood pressure or

heart rate were noted between treatment groups. The effect of single dose paroxetine, a strong

CYP2D6 inhibitor, on carvedilol pharmacokinetics was investigated in 12 healthy subjects

following single oral administration. Despite significant increase in R and S-carvedilol

exposure, no clinical effects were observed in these healthy subjects.

Pharmacodynamic interactions:

Insulin or oral hypoglycemics: Agents with beta-blocking properties may enhance the blood-

sugar-reducing effect of insulin and oral hypoglycemic. The signs of hypoglycemia may be

masked or attenuated (especially tachycardia). In patients taking insulin or oral

hypoglycemic, regular monitoring of blood glucose is therefore recommended (see section

4.4).

Catecholamine-depleting agents: Patients taking both agents with beta-blocking properties

and a drug that can deplete catecholamines (e.g. reserpine and monoamine oxidase inhibitors)

should be observed closely for signs of hypotension and/or severe bradycardia.

Digoxin: The combined use of beta-blockers and digoxin may result in additive prolongation

of atrioventricular (AV) conduction time.

Non-dihydropyridines calcium channel blockers or other antiarrhythmics: In combination

with carvedilol can increase the risk of AV conduction disturbances (see section 4.4). Isolated

cases of conduction disturbance (rarely with hemodynamic compromise) have been observed

when carvedilol is co-administered with diltiazem. As with other agents with β-blocking

properties, if carvedilol is to be administered orally with non-dihydropyridines calcium

channel blockers of the verapamil or diltiazem type, amiodarone or other antiarrhythmics it is

recommended that ECG and blood pressure be monitored.

Clonidine: Concomitant administration of clonidine with agents with beta-blocking properties

may potentiate blood pressure and heart rate lowering effects. When concomitant treatment

with agents with beta-blocking properties and clonidine is to be terminated, the beta-blocking

agent should be discontinued first. Clonidine therapy can then be discontinued several days

later by gradually decreasing the dosage.

Antihypertensives: As with other agents with beta-blocking activity, Carvedilol may

potentiate the effect of other concomitantly administered drugs that are anti-hypertensive in

action (e.g. alpha1-receptor antagonists) or have hypotension as part of their adverse effect

profile.

Anaesthetic agents: Careful attention must be paid during general anesthesia to the

synergistic negative inotropic and hypotensive effects of carvedilol and anesthetic drugs (see

section 4.4).

NSAIDs: The concurrent use of non-steroidal anti-inflammatory drugs (NSAIDs) and beta-

adrenergic blockers may result in an increase in blood pressure and impairment of blood

pressure control.

Beta-agonist bronchodilators: Non-cardioselective beta blockers oppose the bronchodilator

effects of beta-agonist bronchodilators.

4.6 Fertility, pregnancy and lactation

Pregnancy

There is no adequate clinical experience with carvedilol in pregnant women.

Animal studies are insufficient with respect to effects on pregnancy, embryonal/fetal

development, parturition and postnatal development (see section 5.3). The potential risk for

humans is unknown.

Carvedilol should not be used during pregnancy unless the potential benefit outweighs the

potential risk.

Beta blockers reduce placental perfusion which may result in intrauterine fetal death and

immature and premature deliveries.

In addition, adverse effects (especially hypoglycemia and bradycardia) may occur in the fetus

and neonate. There may be an increased risk of cardiac and pulmonary complications in the

neonate in the postnatal period. Animal studies have not shown substantive evidence of

teratogenicity with carvedilol (see also section 5.3).

Lactation

Animal studies demonstrated that carvedilol and/or its metabolites are excreted in rat breast

milk. The excretion of carvedilol in human milk has not been established. However, most β-

blockers, in particular lipophilic compounds, will pass into human breast milk although to a

variable extent. Breast feeding is therefore not recommended following administration of

carvedilol.

4.7 Effects on ability to drive and use machines

No studies of the effects on ability to drive and use machines have been performed.

As for other drugs which produce changes in blood pressure, patients taking carvedilol should

be warned not to drive or operate machinery if they experience dizziness or related

symptoms. This applies particularly when starting or changing treatment and in conjunction

with alcohol.

4.8 Undesirable effects

The following undesirable effects have been reported to occur when carvedilol is

administered:

Frequency categories are as follows:

Table 1 Adverse Drug Reactions

Very common ≥1/10

Common ≥1/100 and <1/10

Uncommon ≥1/1,000 and <1/100

Rare ≥1/10,000 and <1/1,000

Very rare <1/10,000

Table 1 Adverse Drug Reactions

System Organ Class

Adverse Reaction

Frequency

Blood and Lymphatic System

Disorders

Anaemia

Common

Thrombocytopenia

Rare

Leukopenia

Very rare

Cardiac Disorders

Cardiac failure

Very common

Bradycardia

Common

Hypervolemia

Common

Fluid overload

Common

Edema

Common

Atrioventricular block

Uncommon

Angina pectoris

Uncommon

Eye Disorders

Visual impairment

Common

Lacrimation decreased (dry

eye)

Common

Eye irritation

Common

Gastrointestinal Disorders

Nausea

Common

Diarrhea

Common

Vomiting

Common

Dyspepsia

Common

Abdominal pain

Common

Constipation

Uncommon

Dry mouth

Rare

General Disorders and

Administration Site

Asthenia (fatigue)

Very common

Edema

Common

Conditions

Pain

Common

Hepatobiliary disorders

Alanine aminotransferase

(ALT), aspartate

aminotransferase (AST) and

gamma-glutamyltransferase

(GGT) increased

Very rare

Immune System Disorders

Hypersensitivity (allergic

reactions)

Very rare

Infections and Infestations

Pneumonia

Common

Bronchitis

Common

Upper respiratory tract

infection

Common

Urinary tract infection

Common

Metabolism and Nutrition

Disorders

Weight increase

Common

Hypercholesterolemia

Common

Impaired blood glucose

control (hyperglycemia,

hypoglycemia) in patients

with pre-existing diabetes

Common

Musculoskeletal and

Connective Tissue Disorders

Pain in extremities

Common

Nervous System Disorders

Dizziness

Very common

Headache

Very Common

Syncope, presyncope

Common

Paraesthesia

Uncommon

Psychiatric Disorders

Depression, depressed mood

Common

Sleep disorders

Uncommon

Renal and urinary disorders

Renal failure and renal

function abnormalities in

patients with diffuse vascular

disease and/or underlying

renal insufficiency

Common

Micturition disorders

Rare

Urinary incontinence in

women

Very rare

Reproductive system and

breast disorders

Erectile dysfunction

Uncommon

Respiratory, Thoracic and

Dyspnea

Common

Mediastinal Disorders

Pulmonary edema

Common

Asthma in predisposed

patients

Common

Nasal congestion, flu-like

symptoms

Rare

Skin and Subcutaneous

Disorders

Skin reactions (e.g. allergic

exanthema, dermatitis,

urticaria, pruritus, psoriatic

and lichen planus like skin

lesions), alopecia

Uncommon

Vascular Disorders

Hypotension

Very common

Orthostatic hypotension

Common

Disturbances of peripheral

circulation (cold extremities,

peripheral vascular disease,

exacerbation of intermittent

claudication and Reynaud's

phenomenon)

Common

Hypertension

Common

Description of selected adverse reactions

The frequency of adverse reactions is not dose-dependent, with the exception of dizziness,

abnormal vision and bradycardia. Dizziness, syncope, headache and asthenia are usually mild

and are more likely to occur at the beginning of treatment.

In patients with congestive heart failure, worsening cardiac failure and fluid retention may

occur during up-titration of carvedilol dose (see section 4.2 Warnings and Precautions).

Cardiac failure was a very commonly reported adverse event in both placebo (14.5%) and

carvedilol-treated (15.4%) patients, in patients with left ventricular dysfunction following

acute myocardial infarction.

Reversible deterioration of renal function has been observed with carvedilol therapy in

chronic heart failure patients with low blood pressure, ischemic heart disease and diffuse

vascular disease and/or underlying renal insufficiency (see section 4.2 Warnings and

Precautions).

The following adverse events have been identified during post-marketing use of carvedilol.

Because these events are reported from a population of uncertain size, it is not always

possible to reliably estimate their frequency and/or establish a causal relationship to drug

exposure:

As a class, beta-adrenergic receptor blockers may cause latent diabetes to become manifest,

manifest diabetes to be aggravated, and blood glucose counter-regulation to be inhibited.

Severe cutaneous adverse reactions (Toxic epidermal necrolysis, Stevens-Johnson syndrome

(see section 4.4).

Carvedilol may cause urinary incontinence in women which resolves upon discontinuation of

the medication.

Reporting suspected adverse reactions after authorisation of the medicinal product is

important. It allows continued monitoring of the benefit/risk balance of the medicinal

product.

Any suspected adverse events should be reported to the Ministry of Health according to the

National Regulation by using an online form

http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic

@moh.gov.il

4.9 Overdose

Symptoms and signs:

In the event of overdose, there may be severe hypotension, bradycardia, heart failure,

cardiogenic shock and cardiac arrest. There may also be respiratory problems, bronchospasm,

vomiting, disturbed consciousness and generalized seizures.

Treatment:

The patients should be monitored for the above mentioned signs and symptoms and managed

according to the best judgment of the treating physicians and according to standard practice

for patients with β-blocker overdose (e.g. atropine, transvenous pacing, glucagon,

phosphodiesterase inhibitor such as amrinone or milrinone, β-sympathomimetics).

Gastric lavage or induced emesis may be useful in the first few hours after ingestion.

In cases of severe overdose with symptoms of shock, supportive treatment as described

should be continued for a sufficiently long period of time, i.e. until the patient stabilizes,

since prolonged elimination half-life and redistribution of carvedilol from deeper

compartments can be expected.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Alpha and beta blocking agents. ATC code: C07AG02.

Carvedilol is a vasodilating non-selective beta blocking agent. Vasodilation is predominantly

mediated through alpha1 receptor antagonism.

Carvedilol reduces the peripheral vascular resistance through vasodilation and suppresses the

renin-angiotensin-aldosterone system through beta blockade. The activity of plasma renin is

reduced and fluid retention is rare. Some of the limitations of traditional β-blockers do not

appear to be shared by some of the vasodilating β-blockers, such as carvedilol.

Carvedilol has no intrinsic sympathomimetic activity and like propranolol, it has membrane

stabilizing properties.

Clinical studies have shown that the balance of vasodilation and beta-blockade provided by

carvedilol results in the following effects:

In hypertensive patients, a reduction in blood pressure is not associated with a concomitant

increase in total peripheral resistance, as observed with pure beta-blocking agents. Heart rate

is slightly decreased. Renal blood flow and renal function are maintained. Peripheral blood

flow is maintained; therefore cold extremities (often observed with drugs possessing beta-

blocking activity) are rarely seen.

In patients with left ventricular dysfunction or congestive heart failure, carvedilol has

demonstrated favorable effects on hemodynamics and improvements in left ventricular

ejection fraction and dimensions.

Clinical efficacy

Renal impairment

Carvedilol reduces morbidity and mortality in dialysis patients with dilated cardiomyopathy.

A meta-analysis of placebo-controlled clinical trials including a large number of patients

(>4000) with mild to moderate chronic kidney disease supports carvedilol treatment of

patients with left ventricular dysfunction with or without symptomatic heart failure to reduce

rates of all cause of mortality as well as heart failure related events.

In patients with stable angina, carvedilol has demonstrated anti-ischemic and anti-anginal

properties. Acute hemodynamic studies demonstrated that carvedilol reduces both cardiac

pre-load and after-load with consequent improvement in left ventricular systolic and diastolic

function without substantial changes in the cardiac output.

Carvedilol has no adverse effects on the metabolic risk factors of coronary heart disease. It

does not impair the normal serum lipid profile and in hypertensive patients with dyslipidemia

favorable effects on the serum lipids have been reported after six months of oral therapy.

5.2 Pharmacokinetic properties

Absorption

Following oral administration of a 25 mg capsule to healthy subjects, carvedilol is rapidly

absorbed with a peak plasma concentration C

of 21 mg/L reached after approximately 1.5

hour (t

). The C

values are linearly related to the dose.

Following oral administration, carvedilol undergoes extensive first pass metabolism that

results in an absolute bioavailability of about 25% in healthy male subjects.

Carvedilol is a racemate and the S-(-)- enantiomer appears to be metabolized more rapidly

than the R-(+)- enantiomer, showing an absolute oral bioavailability of 15% compared to

31% for the R-(+)- enantiomer . The maximal plasma concentration of R-carvedilol is

approximately 2 fold higher than that of S-carvedilol.

In vitro studies have shown that carvedilol is a substrate of the efflux transporter P-

glycoprotein. The role of P-glycoprotein in the disposition of carvedilol was also confirmed

in vivo in healthy subjects. Food does not affect bioavailability, residence time or the

maximum serum concentration, although the time to reach maximum serum concentration is

delayed.

Distribution

Carvedilol is highly lipophilic, showing a plasma protein of around 95%. The distribution

volume ranges between 1.5 and 2L/kg and increased in patients with liver cirrhosis.

Metabolism

In humans, carvedilol is extensively metabolized in the liver via oxidation and conjugation

into a variety of metabolites that are eliminated mainly in the bile.

Pharmacokinetic studies in human have shown that the oxidative metabolism of carvedilol is

stereoselective. The results of an in vitro study suggested that different cytochrome P450

isoenzymes may be involved in the oxidation and hydroxylation processes including

CYP2D6, CYP3A4, CYP2E1, CYP2C9, as well as CYP1A2.

Studies in healthy volunteers and in patients have shown that the R-enantiomer is

predominantly metabolized by CYP2D6. The S-enantiomer is mainly metabolized by

CYP2D6 and CYP2C9.

Genetic polymorphism

The results of clinical pharmacokinetic studies in human subjects have shown that CYP2D6

plays a major role in the metabolism of R and of S-carvedilol. As a consequence plasma

concentrations of R and S-carvedilol are increased in CYP2D6 slow metabolizers. The

importance of CYP2D6 genotype in the pharmacokinetics of R and S-carvedilol was

confirmed in population pharmacokinetics studies, whereas other studies did not confirm this

observation. It was concluded that CYP2D6 genetic polymorphism may be of limited clinical

significance.

Elimination

Following a single oral administration of 50 mg carvedilol, around 60% are secreted into the

bile and eliminated with the faeces in the form of metabolites within 11 days. Following a

single oral dose, only about 16% are excreted into the urine in form of carvedilol or its

metabolites. The urinary excretion of unaltered drug represents less than 2%. After

intravenous infusion of 12.5 mg to healthy volunteers, the plasma clearance of carvedilol

reaches around 600 mL/min and the elimination half-life around 2.5 hours. The elimination

half-life of a 50 mg capsule observed in the same individuals was 6.5 hours corresponding

indeed to the absorption half-life from the capsule. Following oral administration, the total

body clearance of the S-carvedilol is approximately two times larger than that of the R-

carvedilol.

Special populations

Elderly: Age has no statistically significant effect on the pharmacokinetics of carvedilol in

hypertensive patients

Children: Investigation in pediatrics has shown that the weight-adjusted clearance is

significantly larger in pediatrics as compared to adults.

Hepatic impairment: In a study in patients with cirrhotic liver disease, the bioavailability of

carvedilol was four times greater and the peak plasma level five times higher than in healthy

subjects.

Renal impairment: Since carvedilol is primarily excreted via the feces, significant

accumulation in patients with renal impairment is unlikely.

Heart failure: In a study in 24 Japanese patients with heart failure, the clearance of R-and S-

carvedilol was significantly lower than previously estimated in healthy volunteers. These

results suggested that the pharmacokinetics of R-and S-carvedilol is significantly altered by

heart failure in Japanese patients.

5.3 Preclinical safety data

There is no evidence from animal studies that carvedilol has any teratogenic effects.

Embryotoxicity was observed only after large doses in rabbits. The relevance of these

findings for humans is uncertain. In addition, animal studies have shown that carvedilol

crosses the placental barrier and therefore the possible consequences of alpha and beta

blockade in the human fetus and neonate should also be borne in mind (although see section

4.6).

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipient(s)

Microcrystalline Cellulose, Povidone, Sodium starch glycolate (type A), Magnesium stearate,

Silica colloidal anhydrous.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

36 months

6.4 Special precautions for storage

Do not store above 25

C. Store in the original package. Store in a dry and dark place.

6.5 Nature and contents of container

Blister.

Pack size: 7, 10, 14, 28, 30, 50 or 100 tablets.

Not all pack sizes may be marketed.

7. MARKETING AUTHORISATION HOLDER

Dexcel ltd.

1 Dexcel street, Or Akiva, 3060000, Israel

8. MANUFACTURER

Dexcel ltd.

1 Dexcel street, Or Akiva, 3060000, Israel

The format of this leaflet was determined by the Ministry of Health (MOH) and its content

was checked and approved by the MOH in 03/2017

לע העדוה ( הרמחה

עדימ ל ןולעב )תוחיטב אפור

ןכדועמ(

.102.50

ךיראת

2200052

:םושירה רפסמו תילגנאב רישכת םש

(

127 19 30614 00

(

Carvedexxon 6.25

(

127 20 30615 00

(

Carvedexxon 12.5

םושירה לעב םש

.

Dexcel Ltd

ה טורפל דעוימ הז ספוט דבלב תורמחה

מחהה תושקובמה תור

ןולעב קרפ

יחכונ טסקט

שדח טסקט

Indication

Contraindications

Carvedilol is contra-

indicated in patients with

marked fluid retention or

overload requiring

intravenous inotropic

support.

Patients with obstructive

airways disease, liver

dysfunction,

hypersensitivity to

carvedilol or any other

constituents of the tablets.

As with other beta-blocking

agents:

History of

bronchospasm or asthma,

2nd and 3rd degree A-V

heart block, severe

bradycardia (< 50 bpm),

cardiogenic shock, sick

sinus syndrome

(including sino-atrial

block), severe hypotension

(systolic blood pressure <

85mmHg),

Hypersensitivity to the active substance or to any of

the excipients listed in section 6.1.

Marked fluid retention or overload

Unstable/decompensated heart failure requiring

intravenous inotropic support.

Clinically manifest liver dysfunction.

As with other beta-blocking agents:

History of bronchospasm or asthma

2nd and 3rd degree atrioventricular (AV) heart block,

(unless a permanent pacemaker is in place)

Severe bradycardia (< 50 bpm)

Cardiogenic shock

Sick sinus syndrome (including sino-atrial block)

Severe hypotension (systolic blood pressure < 85

mmHg).

metabolic acidosis and phaeochromocytoma (unless

adequately controlled by alpha blockade).

metabolic acidosis and

phaeochromocytoma

(unless adequately

controlled by alpha

blockade).

Posology, dosage

& administration

tablets should be taken

with food. The tablets are

intended for oral use.

The recommended dose

for the initiation therapy is

3.125mg twice a day for

two weeks. If this dose is

tolerated, the dosage

should be increased

subsequently, at intervals

of not less than two weeks,

to 6.25mg twice daily,

followed by 12.5mg twice

daily and thereafter 25mg

twice daily. Dosing should

be increased to the highest

level tolerated by the

patient. The

recommended maximum

daily dose is 25mg given

twice daily in patients

weighing less than 85kg

and 50mg twice daily in

patient weighing more than

85kg.

Prior to each dose

increase, the patient

should be examined by a

physician with regard to

any symptoms relating to

deteriorating heart failure

The tablets should be taken with fluid. Carvedexxon

should be given with food to slow the rate of

absorption and reduce the incidence of orthostatic

effects.

Symptomatic congestive heart failure

The dosage must be titrated to individual

requirements and monitored during up-titration.

For those patients receiving diuretics and/or digoxin

and/or ACE inhibitors, dosing of these other drugs

should be stabilized prior to initiation of

Carvedexxon treatment.

Adults

The recommended dose for the initiation of therapy

is 3.125 mg twice a day for two weeks. If this dose is

tolerated, the dosage should be increased

subsequently, at intervals of not less than two weeks,

to 6.25 mg twice daily, followed by 12.5 mg twice

daily and thereafter 25 mg twice daily. Dosing should

be increased to the highest level tolerated by the

patient.

The recommended maximum daily dose is 25 mg

given twice daily in patients weighing less than 85kg

and 50 mg twice daily in patients weighing more than

85 kg.

Before each dose increase the patient should be

evaluated by the physician for symptoms of

worsening heart failure or vasodilation. Transient

worsening of heart failure, vasodilation or fluid

retention may be treated with increased doses of

diuretics or ACE inhibitors or by modifying or

temporarily discontinuing Carvedexxon treatment.

Under these circumstances, the dose of Carvedexxon

should not be increased until symptoms of worsening

heart failure or vasodilation have been stabilized.

Sometimes it may become necessary to decrease the

dose of Carvedilol or temporarally discontinue

Carvedilol treatment.

If Carvedexxon is discontinued for more than two

weeks, therapy should be recommenced at 3.125 mg

twice daily and up-titrated in line with the above

dosing recommendation.

Elderly

and/or vascular dilation.

Occasional deterioration of

heart failure or increased

fluid retention should be

treated with increased

dosage of diuretics. Under

these circumstances, the

dose of Carvedexxon

should not be increased

until symptoms of

worsening heart failure or

vasodilatation have been

established.

Sometimes it may become

necessary to decrease the

dose of Carvedilol or

temporally discontinue

Carvedilol treatment. If

Carvedilol is discontinued

for more than two weeks,

therapy should be

recommenced at 3.125 mg

twice daily and up-titrated

in line with the above

dosing recommendation.

Elderly

As for adults.

Children

Safety and efficacy in

children (under 18 years)

has not been established.

Patients with co-existing

hepatic disease

Carvedilol is contra-

indicated in patients with

hepatic dysfunction (see

sections

4.3

As for adults.

Children

Safety and efficacy in children (under 18 years) has

not been established.

Patients with co-existing hepatic disease

Carvedilol is contra-indicated in patients with

hepatic dysfunction (see sections

4.3

Contraindications

5.2 Pharmacokinetic

properties

Patients with co-existing renal dysfunction

No dose adjustment is anticipated as long as

systolic blood pressure is above 100mmHg (see

also sections

4.4 Special warnings and precautions

for use

5.2 Pharmacokinetic properties

Contraindications

5.2

Pharmacokinetic properties

Patients with co-existing

renal dysfunction

No dose adjustment is

anticipated as long as

systolic blood pressure is

above 100mmHg (see also

sections

4.4 Special

warnings and precautions for

use

5.2 Pharmacokinetic

properties

Special Warnings

and Special

Precautions for

Use

In chronic heart failure

patients, worsening

cardiac failure or fluid

retention may occur during

up-titration of carvedilol. If

such symptoms occur, the

dose of diuretic should be

adjusted and the carvedilol

dose should not be

advanced until clinical

stability resumes.

Occasionally it may be

necessary to lower the

Carvedilol dose or

temporarily discontinue it.

Such episodes do not

preclude subsequent

successful titration of

Carvedilol

In hypertensive patients

who have chronic heart

failure controlled with

digoxin, diuretics and/or an

ACE inhibitor, Carvedilol

should be used with

Chronic congestive heart failure: In congestive heart

failure patients, worsening cardiac failure or fluid

retention may occur during up-titration of

Carvedexxon. If such symptoms occur, diuretics

should be increased and the Carvedexxon dose

should not be further increased until clinical stability

resumes. Occasionally it may be necessary to lower

the Carvedexxon dose or, in rare cases, temporarily

discontinue it. Such episodes do not preclude

subsequent successful up-titration of Carvedexxon.

In hypertensive patients who have chronic heart

failure controlled with digoxin, diuretics

and/or an ACE inhibitor, Carvedilol should be

used with caution since both digoxin and

Carvedilol may slow A-V conduction.

Carvedexxon should be used with caution in

combination with digitalis glycosides, since both

drugs slow A-V conduction (see section 4.5).

Renal function in congestive heart failure: Reversible

deterioration of renal function has been observed

with Carvedilol therapy in chronic heart failure

patients with low blood pressure (systolic BP < 100

mmHg), ischaemic heart disease and diffuse vascular

disease, and/or underlying renal insufficiency. In

CHF patients with these risk factors, renal function

should be monitored during up-titration of

Carvedexxon and the drug discontinued or dosage

reduced if worsening of renal failure occurs.

Chronic obstructive pulmonary disease: Carvedilol

should be used with caution, in patients with chronic

obstructive pulmonary disease (COPD) with a

bronchospastic component who are not receiving oral

or inhaled medication, and only if the potential

caution since both digoxin

and Carvedilol may slow

A-V conduction.

As with other drugs with

beta-blocking activity,

Carvedilol may mask the

early signs of acute

hypoglycaemia in patients

with diabetes mellitus.

Alternatives to beta-

blocking agents are

generally preferred in

insulin-dependent patients.

In patients with diabetes,

the use of Carvedilol may

be associated with

worsening control of blood

glucose. Therefore, regular

monitoring of blood

glucose is required in

diabetics when Carvedilol

is initiated or up-titrated

and hypoglycaemic

therapy adjusted

accordingly.

Reversible deterioration of

renal function has been

observed with Carvedilol

therapy in chronic heart

failure patients with low

blood pressure (systolic

BP < 100mmHg),

ischaemic heart disease

and diffuse vascular

disease, and/or underlying

renal insufficiency. In CHF

benefit outweighs the potential risk. In patients with a

tendency to bronchospasm, respiratory distress can

occur as a result of a possible increase in airway

resistance. Patients should be closely monitored

during initiation and up-titration of carvedilol and the

dose of Carvedexxon should be reduced if any

evidence of bronchospasm is observed during

treatment.

Diabetes: Care should be taken in the administration

of Carvedexxon to patients with diabetes mellitus, as

it may be associated with worsening control of blood

glucose, or the early signs and symptoms of acute

hypoglycemia may be masked or attenuated.

Alternatives to beta-blocking agents are generally

preferred in insulin-dependent patients. Therefore,

regular monitoring of blood glucose is required in

diabetics when Carvedexxon is initiated or up-

titrated and hypoglycemic therapy adjusted

accordingly (see section 4.5).

Peripheral vascular disease and Raynaurd's

phenomenon:

Carvedilol may be used in patients

with peripheral vascular disease

. Carvedexxon

should be used with caution in patients with

peripheral vascular disease (e.g. Raynaud's

phenomenon) as pure beta-blockers can precipitate or

aggravate symptoms of arterial insufficiency.

However as Carvedilol also has alpha-blocking

properties this effect is largely counterbalanced.

Thyrotoxicosis: Carvedexxon may obscure the

symptoms of thyrotoxicosis.

Bradycardia: Carvedexxon may induce bradycardia.

If the patient's pulse rate decreases to less than 55

beats per minute, the dosage of Carvedexxon should

be reduced.

Hypersensitivity: Care should be taken in

administering Carvedexxon to patients with a

history of serious hypersensitivity reactions and in

patients undergoing desensitization therapy as beta-

blockers may increase both the sensitivity towards

allergens and the severity of hypersensitivity

anaphylactic reactions.

Severe cutaneous adverse reactions (SCARs): Very

rare cases of severe cutaneous adverse reactions such

as toxic epidermal necrolysis (TEN) and Stevens-

Johnson syndrome (SJS) have been reported during

treatment with Carvedexxon (see section 4.8).

Carvedexxon should be permanently discontinued in

patients who experience severe cutaneous adverse

reactions possibly attributable to Carvedexxon.

Psoriasis: Patients with a history of psoriasis

patients with these risk

factors, renal function

should be monitored

during up-titration of

Carvedilol and the drug

discontinued or dosage

reduced if worsening of

renal failure occurs

Wearers of contact lenses

should be advised of the

possibility of reduced

lacrimation.

Although angina has not

been reported on stopping

treatment, discontinuation

should be gradual (1 - 2

weeks) particularly in

patients with ischaemic

heart disease, as

Carvedilol has beta-

blocking activity.

Carvedilol may be used in

patients with peripheral

vascular disease. Pure

beta-blockers can

precipitate or aggravate

symptoms of arterial

insufficiency. However as

Carvedilol also has alpha-

blocking properties this

effect is largely

counterbalanced.

Carvedilol, as with other

agents with beta-blocking

activity, may mask the

symptoms of

associated with beta-blocker therapy should be given

Carvedexxon only after consideration of the risk-

benefit ratio.

Interactions with other medicinal products: There are

a number of important pharmacokinetic and

pharmacodynamics interactions with other drugs

(e.g., digoxin, ciclosporin, rifampicin, anesthetic

drugs, anti-arrhythmic drug. See section 4.5).

Pheochromocytoma: In patients with

pheochromocytoma, an alpha-blocking agent should

be initiated prior to the use of any beta-blocking

agent. Although Carvedexxon has both alpha and

beta blocking pharmacological activities, there is no

experience of the use of carvedilol in this condition.

Therefore, caution should be taken in the

administration of Carvedexxon to patients suspected

of having pheochromocytoma.

Prinzmetal's variant angina: Agents with non-

selective beta-blocking activity may provoke chest

pain in patients with Prinzmetal's variant angina.

There is no clinical experience with carvedilol in

these patients, although the alpha-blocking activity of

Carvedexxon may prevent such symptoms. Caution

should be taken in the administration of

Carvedexxon to patients suspected of having

Prinzmetal's variant angina.

Contact lenses: Wearers of contact lenses should be

advised of the possibility of reduced lacrimation.

Withdrawal syndrome: Although angina has not been

reported on stopping treatment, discontinuation

should be gradual (over a period of 2 weeks),

particularly in patients with ischemic heart disease,

as Carvedexxon has beta-blocking activity.

Usage of carvedilol in patients with symptomatic

congestive heart failure has not been shown to reduce

mortality.

thyrotoxicosis.

If Carvedilol induces

bradycardia, with a

decrease in pulse rate to

less than 55 beats per

minute, the dosage of

Carvedilol tablets should

be reduced.

Care should be taken in

administering Carvedilol to

patients with a history of

serious hypersensitivity

reactions and in those

undergoing desensitisation

therapy as beta-blockers

may increase both the

sensitivity towards

allergens and the

seriousness of

anaphylactic reactions.

In patients suffering from

the peripheral circulatory

disorder Raynaud's

phenomenon, there may

be exacerbation of

symptoms.

Patients with a history of

psoriasis associated with

beta-blocker therapy

should be given Carvedilol

only after consideration of

the risk-benefit ratio.

In patients with

phaeochromocytoma, an

alpha-blocking agent

should be initiated prior to

the use of any beta-

blocking agent. There is no

experience of the use of

carvedilol in this condition.

Therefore, caution should

be taken in the

administration of Carvedilol

to patients suspected of

having

phaeochromocytoma.

Agents with non-selective

beta-blocking activity may

provoke chest pain in

patients with Prinzmetal's

variant angina. There is no

clinical experience with

Carvedilol in these

patients, although the

alpha-blocking activity of

Carvedilol may prevent

such symptoms. However,

caution should be taken in

the administration of

Carvedilol to patients

suspected of having

Prinzmetal's variant

angina.

In patients with a tendency

to bronchospastic

reactions, respiratory

distress can occur as a

result of a possible

increase in airway

resistance.

Interaction with

Other

Medicaments and

As with other agents with

beta-blocking activity,

Pharmacokinetic interactions:

Effects of Carvedilol on the pharmacokinetics of

Other Forms of

Interaction

Carvedilol may potentiate

the effect of other

concomitantly

administered drugs that

are anti-hypertensive in

action (e.g. alpha

-receptor

antagonists) or have

hypotension as part of their

adverse effect profile.

Isolated cases of

conduction disturbance

(rarely with haemodynamic

disruption) have been

observed when Carvedilol

and diltiazem were given

concomitantly. Therefore,

as with other drugs with

beta-blocking activity,

careful monitoring of ECG

and blood pressure should

be undertaken when co-

administering calcium

channel blockers of the

verapamil or diltiazem

type, or class I anti-

arrhythmic drugs. These

types of drugs should not

be co-administered

intravenously in patients

receiving Carvedilol.

The effects of insulin or

oral hypoglycaemics may

be intensified. Regular

monitoring of blood

glucose is therefore

recommended.

other drugs

Carvedilol is a substrate as well as an inhibitor of P-

glycoprotein. Therefore the bioavailability of drugs

transported by P-glycoprotein may be increased with

concomitant administration of carvedilol. In addition,

the bioavailability of carvedilol can be modified by

inducers or inhibitors of P-glycoprotein.

Inhibitors as well as inducers of CYP2D6 and

CYP2C9 can modify the systemic and/or presystemic

metabolism of carvedilol stereoselectively, leading to

increased or decreased plasma concentrations of R

and S-carvedilol. (see section 5.2). Some examples

observed in patients or in healthy subjects are listed

below but the list is not exhaustive.

Digoxin: An increased exposure of digoxin of up to

16 20% has been shown in some studies in healthy

subjects and patients with heart failure. A

significantly larger effect has been seen in male

patients compared to female patients. Therefore

monitoring of digoxin levels is recommended when

initiating, adjusting or discontinuing carvedilol (see

section 4.4). Carvedilol had no effect on digoxin

administered intravenously.

Ciclosporin: Two studies in renal and cardiac

transplant patients receiving oral ciclosporin have

shown an increase in ciclosporin plasma

concentration following the initiation of carvedilol. It

appears that carvedilol increases exposure to oral

ciclosporin by around 10 to 20%. In an attempt to

maintain therapeutic ciclosporin levels, an average

10-20% reduction of the ciclosporin dose was

necessary. The mechanism for the interaction is not

known but inhibition of intestinal P glycoprotein by

carvedilol may be involved. Due to wide

interindividual variability of ciclosporin levels, it is

recommended that ciclosporin concentrations are

monitored closely after initiation of carvedilol

therapy and that the dose of ciclosporin be adjusted

as appropriate. In case of IV administration of

ciclosporin, no interaction with carvedilol is

expected.

Effects of other drugs on the pharmacokinetics of

Carvedilol

Rifampicin: In a study in 12 healthy subjects,

exposure to carvedilol decreased by around 60%

during concomitant administration with rifampicin

and a decrease effect of carvedilol on the systolic

blood pressure was observed. The mechanism for the

interaction is not known but it may be due to the

induction of the intestinal P glycoprotein by

rifampicin. A close monitoring of the β-blockade

activity in patients receiving concomitant

Trough plasma digoxin

levels may be increased by

approximately 16% in

hypertensive patients co-

administered Carvedilol

and digoxin. Increased

monitoring of digoxin levels

is recommended when

initiating, adjusting or

discontinuing Carvedilol.

Concomitant

administration of Carvedilol

and cardiac glycosides

may prolong AV

conduction time.

When treatment with

Carvedilol and clonidine

together is to be

terminated, Carvedilol

should be withdrawn first,

several days before

gradually decreasing the

dosage of clonidine.

Care may be required in

those receiving inducers of

mixed function oxidases

e.g. rifampicin, as serum

levels of carvedilol may be

reduced or inhibitors of

mixed function oxidases

e.g. cimetidine, as serum

levels may be increased.

During general

anaesthesia, attention

should be paid to the

potential synergistic

administration of carvedilol and rifampicin is

appropriate.

Amiodarone: An in vitro study with human liver

microsomes has shown that amiodarone and

desethylamiodarone inhibited the oxidation of R and

S-carvedilol. The trough concentration of R and S-

carvedilol was significantly increased by 2.2-fold in

heart failure patients receiving carvedilol and

amiodarone concomitantly as compared to patients

receiving carvedilol monotherapy. The effect on S-

carvedilol was attributed to desethylamiodarone, a

metabolite of amiodarone, which is a strong inhibitor

of CYP2C9. A monitoring of the β-blockade activity

in patients treated with the combination carvedilol

and amiodarone is advised.

Fluoxetine and Paroxetine: In a randomized, cross-

over study in 10 patients with heart failure,

coadministration of fluoxetine, a strong inhibitor of

CYP2D6, resulted in stereoselective inhibition of

carvedilol metabolism with a 77% increase in mean

R(+) enantiomer's AUC, and a non-statistically 35%

increase of the S(-) enantiomer's AUC as compared

to the placebo group. However, no differences in

adverse events, blood pressure or heart rate were

noted between treatment groups. The effect of single

dose paroxetine, a strong CYP2D6 inhibitor, on

carvedilol pharmacokinetics was investigated in 12

healthy subjects following single oral administration.

Despite significant increase in R and S-carvedilol

exposure, no clinical effects were observed in these

healthy subjects.

Care may be required in those receiving

inducers of mixed function oxidases e.g.

rifampicin,

as serum levels of carvedilol may be reduced or

inhibitors of mixed function oxidases e.g.

cimetidine, as serum levels may be increased.

Pharmacodynamic interactions:

Insulin or oral hypoglycemics: Agents with beta-

blocking properties may enhance the blood-sugar-

reducing effect of insulin and oral hypoglycemic.

The signs of hypoglycemia may be masked or

attenuated (especially tachycardia). In patients taking

insulin or oral hypoglycemic, regular monitoring of

blood glucose is therefore recommended (see section

4.4).

Catecholamine-depleting agents: Patients taking both

agents with beta-blocking properties and a drug that

can deplete catecholamines (e.g. reserpine and

negative inotropic effects

of carvedilol and

anaesthetic drugs.

monoamine oxidase inhibitors) should be observed

closely for signs of hypotension and/or severe

bradycardia.

Digoxin: The combined use of beta-blockers and

digoxin cardiac glycosides may result in additive

prolongation of atrioventricular (AV) conduction

time.

Non-dihydropyridines calcium channel blockers or

other antiarrhythmics: In combination with

carvedilol can increase the risk of AV conduction

disturbances (see section 4.4). Isolated cases of

conduction disturbance (rarely with hemodynamic

compromise) have been observed when carvedilol is

co-administered with diltiazem. As with other agents

with β-blocking properties, if carvedilol is to be

administered orally with non-dihydropyridines

calcium channel blockers of the verapamil or

diltiazem type, amiodarone or other antiarrhythmics

class I anti-arrhythmic drugs it is recommended that

ECG and blood pressure be monitored.

These types

of drugs should not be co-administered

intravenously in patients receiving Carvedilol.

Clonidine: Concomitant administration of clonidine

with agents with beta-blocking properties may

potentiate blood pressure and heart rate lowering

effects. When concomitant treatment with agents

with beta-blocking properties carvedilol and

clonidine is to be terminated, the beta-blocking agent

should be discontinued first, several days before

gradually decreasing the dosage of clonidine.

Clonidine therapy can then be discontinued several

days later by gradually decreasing the dosage.

Antihypertensives: As with other agents with beta-

blocking activity, Carvedilol may potentiate the

effect of other concomitantly administered drugs that

are anti-hypertensive in action (e.g. alpha1-receptor

antagonists) or have hypotension as part of their

adverse effect profile.

Anaesthetic agents: Careful attention must be paid

during general anesthesia to the synergistic negative

inotropic and hypotensive effects of carvedilol and

anesthetic drugs (see section 4.4).

NSAIDs: The concurrent use of non-steroidal anti-

inflammatory drugs (NSAIDs) and beta-adrenergic

blockers may result in an increase in blood pressure

and impairment of blood pressure control.

Beta-agonist bronchodilators: Non-cardioselective

beta blockers oppose the bronchodilator effects of

beta-agonist bronchodilators.

Pregnancy and

Fertility, Lactation

There is no adequate

experience with Carvedilol

in pregnant women.

Carvedilol should not be

used in pregnancy or in

breast feeding mothers

unless the anticipated

benefits outweigh the

potential risks. There is no

evidence from animal

studies that carvedilol has

any teratogenic effects.

Embryotoxicity was

observed only after large

doses in rabbits.

The relevance of these

findings for humans is

uncertain. Beta blockers

reduce placental perfusion

which may result in

intrauterine foetal death

and immature and

premature

deliveries. In

addition, animal studies

have shown that carvedilol

crosses the placental

barrier and is excreted in

breast milk and therefore

the possible consequences

of alpha and beta blockade

in the human foetus and

neonate should also be

borne in mind. With other

alpha and beta blocking

agents, effects have

included perinatal and

Pregnancy

There is no adequate clinical experience with

carvedilol in pregnant women.

Animal studies are insufficient with respect to effects

on pregnancy, embryonal/fetal development,

parturition and postnatal development (see section

5.3). The potential risk for humans is unknown.

There is no evidence from animal studies that

carvedilol has any teratogenic effects.

Embryotoxicity was observed only after large

doses in rabbits.

The relevance of these findings for humans is

uncertain

Carvedilol should not be used during pregnancy

unless the potential benefit outweighs the potential

risk.

Beta blockers reduce placental perfusion which may

result in intrauterine fetal death and immature and

premature deliveries.

In addition, animal studies have shown that

carvedilol crosses the placental barrier and is

excreted in breast milk and therefore the

possible consequences of alpha and beta

blockade in the human foetus and neonate

should also be borne in mind. With other alpha

and beta blocking agents, effects have included

perinatal and neonatal distress (bradycardia,

hypotension, respiratory depression,

hypoglycaemia, hypothermia).

In addition, adverse effects (especially hypoglycemia

and bradycardia) may occur in the fetus and neonate.

There is may be an increased risk of cardiac and

pulmonary complications in the neonate in the

postnatal period. Animal studies have not shown

substantive evidence of teratogenicity with carvedilol

(see also section 5.3).

Lactation

Animal studies demonstrated that carvedilol and/or

its metabolites are excreted in rat breast milk. The

excretion of carvedilol in human milk has not been

established. However, most β-blockers, in particular

lipophilic compounds, will pass into human breast

milk although to a variable extent. Breast feeding is

neonatal distress

(bradycardia, hypotension,

respiratory depression,

hypoglycaemia,

hypothermia). There is an

increased risk of cardiac

and pulmonary

complications in the

neonate in the postnatal

period.

therefore not recommended following administration

of carvedilol.

Adverse events

Symptomatic postural

hypotension, mainly on the

initiation of therapy or

when increasing the dose,

may occur but the

incidence is minimised

when the drug is used as

recommended.

Commonly dizziness,

headache, fatigue,

gastrointestinal upset

(nausea, abdominal pain,

diarrhoea, hyperglycemia,

hypercholesterolemia;

infrequently constipation

and vomiting),

bradycardia and

hypotension (infrequently

syncope) have been

observed. These effects

are usually mild, transient

and occur early in the

course of treatment. Other

common effects have

included pain in the

extremities and reduced

Symptomatic postural hypotension, mainly on

the initiation of therapy or when increasing the

dose, may occur but the incidence is minimised

when the drug is used as recommended.

Commonly dizziness, headache, fatigue,

gastrointestinal upset (nausea, abdominal pain,

diarrhoea, hyperglycemia,

hypercholesterolemia; infrequently constipation

and vomiting),

bradycardia and hypotension (infrequently

syncope) have been observed. These effects

are usually mild, transient and occur early in the

course of treatment. Other common effects have

included pain in the extremities and reduced

lacrimation and, in predisposed patients, there

may be asthma and dyspnoea.

Infrequently there may be depressed mood,

sleep disturbance, paraesthesia, wheezing, flu-

like symptoms, rare or isolated cases of skin

reactions (e.g. allergic exanthema, in isolated

cases urticaria, pruritus and lichen planus-like

reactions). Psoriatic skin lesions may occur or

existing lesions may be exacerbated.

Diminished peripheral circulation (cold

extremities) or peripheral oedema may occur

infrequently. Rarely there may be A-V block,

lacrimation and, in

predisposed patients, there

may be asthma and

dyspnoea.

Infrequently there may be

depressed mood, sleep

disturbance, paraesthesia,

wheezing, flu-like

symptoms, rare or isolated

cases of skin reactions

(e.g. allergic exanthema, in

isolated cases urticaria,

pruritus and lichen planus-

like reactions). Psoriatic

skin lesions may occur or

existing lesions may be

exacerbated.

Diminished peripheral

circulation (cold

extremities) or peripheral

oedema may occur

infrequently. Rarely there

may be A-V block,

syncope, angina pectoris,

acute renal failure.

Renal abnormalities in

patients with diffuse

vascular disease and/or

impaired renal function has

been reported. Rarely

there can be exacerbation

of symptoms in patients

suffering from intermittent

claudication, Raynaud's

phenomenon, or

progression of heart

syncope, angina pectoris, acute renal failure.

Renal abnormalities in patients with diffuse

vascular disease and/or impaired renal function

has been reported. Rarely there can be

exacerbation of symptoms in patients suffering

from intermittent claudication, Raynaud's

phenomenon, or progression of heart failure.

Stuffy nose may occur infrequently.

Isolated cases of changes in serum

transaminases, thrombocytopenia and

leucopenia have been reported.

There have also been rare cases of sexual

impotence, disturbed vision, eye irritation,

dryness of the mouth and disturbances of

micturition.

Due to the beta-blocking properties it is also

possible for latent diabetes mellitus to become

manifest, manifest diabetes to be aggravated,

and blood glucose counter-regulation to be

inhibited.

The following undesirable effects have been reported

to occur when carvedilol is administered:

Frequency categories are as follows:

Table 1 Adverse Drug Reactions

Very common ≥1/10

Common ≥1/100 and <1/10

Uncommon ≥1/1,000 and <1/100

Rare ≥1/10,000 and <1/1,000

Very rare <1/10,000

Table 1 Adverse Drug Reactions

System Organ Class

Adverse Reaction

Frequency

Blood and Lymphatic System

Disorders

Anaemia

Common

Thrombocytopenia

Rare

Leukopenia

Very rare

Cardiac Disorders

Cardiac failure

Very

common

Bradycardia

Common

Hypervolemia

Common

failure.

Stuffy nose may occur

infrequently.

Isolated cases of changes

in serum transaminases,

thrombocytopenia and

leucopenia have been

reported.

There have also been rare

cases of sexual impotence,

disturbed vision, eye

irritation, dryness of the

mouth and disturbances of

micturition.

Due to the beta-blocking

properties it is also

possible for latent diabetes

mellitus to become

manifest, manifest

diabetes to be aggravated,

and blood glucose counter-

regulation to be inhibited.

Fluid overload

Common

Edema

Common

Atrioventricular block

Uncommon

Angina pectoris

Uncommon

Eye Disorders

Visual impairment

Common

Lacrimation decreased (dry eye)

Common

Eye irritation

Common

Gastrointestinal Disorders

Nausea

Common

Diarrhea

Common

Vomiting

Common

Dyspepsia

Common

Abdominal pain

Common

Constipation

Uncommon

Dry mouth

Rare

General Disorders and Administration

Site Conditions

Asthenia (fatigue)

Very

common

Edema

Common

Pain

Common

Hepatobiliary disorders

Alanine aminotransferase (ALT), aspartate

aminotransferase (AST) and gamma-

glutamyltransferase (GGT) increased

Very rare

Immune System Disorders

Hypersensitivity (allergic reactions)

Very rare

Infections and Infestations

Pneumonia

Common

Bronchitis

Common

Upper respiratory tract infection

Common

Urinary tract infection

Common

Metabolism and Nutrition Disorders

Weight increase

Common

Hypercholesterolemia

Common

Impaired blood glucose control

(hyperglycemia, hypoglycemia) in patients

with pre-existing diabetes

Common

Musculoskeletal and Connective Tissue

Disorders

Pain in extremities

Common

Nervous System Disorders

Dizziness

Very

common

Headache

Very

Common

Syncope, presyncope

Common

Paraesthesia

Uncommon

Psychiatric Disorders

Depression, depressed mood

Common

Sleep disorders

Uncommon

Renal and urinary disorders

Renal failure and renal function

abnormalities in patients with diffuse

vascular disease and/or underlying renal

insufficiency

Common

Micturition disorders

Rare

Urinary incontinence in women

Very rare

Reproductive system and breast

disorders

Erectile dysfunction

Uncommon

Respiratory, Thoracic and

Mediastinal Disorders

Dyspnea

Common

Pulmonary edema

Common

Asthma in predisposed patients

Common

Nasal congestion, flu-like symptoms

Rare

Skin and Subcutaneous Disorders

Skin reactions (e.g. allergic exanthema,

dermatitis, urticaria, pruritus, psoriatic and

lichen planus like skin lesions), alopecia

Uncommon

Vascular Disorders

Hypotension

Very

common

Orthostatic hypotension

Common

Disturbances of peripheral circulation

(cold extremities, peripheral vascular

disease, exacerbation of intermittent

claudication and Reynaud's phenomenon)

Common

Hypertension

Common

Description of selected adverse reactions

The frequency of adverse reactions is not dose-

dependent, with the exception of dizziness, abnormal

vision and bradycardia. Dizziness, syncope, headache

and asthenia are usually mild and are more likely to

occur at the beginning of treatment.

In patients with congestive heart failure, worsening

cardiac failure and fluid retention may occur during

up-titration of carvedilol dose (see section 4.2

Warnings and Precautions).

Cardiac failure was a very commonly reported

adverse event in both placebo (14.5%) and

carvedilol-treated (15.4%) patients, in patients with

left ventricular dysfunction following acute

myocardial infarction.

Reversible deterioration of renal function has been

observed with carvedilol therapy in chronic heart

failure patients with low blood pressure, ischemic

heart disease and diffuse vascular disease and/or

underlying renal insufficiency (see section 4.2

Warnings and Precautions).

The following adverse events have been identified

during post-marketing use of carvedilol. Because

these events are reported from a population of

uncertain size, it is not always possible to reliably

estimate their frequency and/or establish a causal

relationship to drug exposure:

As a class, beta-adrenergic receptor blockers may

cause latent diabetes to become manifest, manifest

diabetes to be aggravated, and blood glucose counter-

regulation to be inhibited.

Severe cutaneous adverse reactions (Toxic epidermal

necrolysis, Stevens-Johnson syndrome (see section

4.4).

Carvedilol may cause urinary incontinence in women

which resolves upon discontinuation of the

medication.

Overdose

Symptoms and signs

Profound cardiovascular

effects such as

hypotension and

bradycardia would be

expected after massive

overdose. Heart failure,

cardiogenic shock and

Symptoms and signs:

In the event of massive overdose, there may be

profound cardiovascular effects such as severe

hypotension, bradycardia, heart failure, cardiogenic

shock and cardiac arrest. There may also be

respiratory problems, bronchospasm, vomiting,

disturbed consciousness and generalized seizures.

Treatment:

The patients should be monitored for the above

mentioned signs and symptoms and managed

according to the best judgment of the treating

cardiac arrest may follow.

There may also be

respiratory problems,

bronchospasm, vomiting,

disturbed consciousness

generalised seizures.

Treatment

Gastric lavage or induced

emesis may be useful in

the first few hours after

ingestion.

In addition to general

procedures, vital signs

must be monitored and

corrected, if necessary

under intensive care

conditions.

Patients should be placed

in the supine position.

Atropine, 0.5mg to 2mg i.v.

and/or glucagon 1 to 10mg

i.v. (followed by a slow i.v.

infusion of 2 to 5mg/hour if

necessary) may be given

when bradycardia is

present. Pacemaker

therapy may be necessary.

For excessive

hypotension, intravenous

fluids may be

administered. In addition,

norepinephrine may be

given, either 5 to 10

micrograms i.v., repeated

according to blood

physicians and according to standard practice for

patients with β-blocker overdose (e.g. atropine,

transvenous pacing, glucagon, phosphodiesterase

inhibitor such as amrinone or milrinone, β-

sympathomimetics).

Gastric lavage or induced emesis may be useful in

the first few hours after ingestion.

In addition to general procedures, vital signs

must be monitored and corrected, if necessary

under intensive care conditions.

Patients should be placed in the supine position.

Atropine, 0.5mg to 2mg i.v. and/or glucagon

1 to 10mg i.v. (followed by a slow i.v. infusion of

2 to 5mg/hour if necessary) may be given when

bradycardia is present. Pacemaker therapy may

be necessary. For excessive hypotension,

intravenous fluids may be administered. In

addition, norepinephrine may be given, either 5

to 10 micrograms i.v., repeated according to

blood pressure response, or 5 micrograms per

minute by infusion titrated to blood pressure.

Bronchospasm may be treated using salbutamol

or other beta

-agonists given as aerosol or, if

necessary, by the intravenous route. In the

event of seizures, slow i.v. injection of diazepam

or clonazepam is recommended.

In cases of severe overdose with symptoms of shock,

supportive treatment as described should be

continued for a sufficiently long period of time, i.e.

until the patient stabilizes, since prolonged

elimination half-life and redistribution of carvedilol

from deeper compartments can be expected.

pressure response, or 5

micrograms per minute by

infusion titrated to blood

pressure. Bronchospasm

may be treated using

salbutamol or other beta

agonists given as aerosol

or, if necessary, by the

intravenous route. In the

event of seizures, slow i.v.

injection of diazepam or

clonazepam is

recommended.

In cases of severe

overdose with symptoms

of shock, supportive

treatment as described

should be continued for a

sufficiently long period of

time, i.e. until the patient

stabilises, since

prolonged elimination half

life and redistribution of

carvedilol from deeper

compartments can be

expected.

Preclinical

safety data

Animal studies reveales no

special findings relevant to

clinical use (also see

section

4.6 Pregnancy and

lactation

Animal studies reveales no special findings

relevant to clinical use (also see section

4.6

Pregnancy and lactation

There is no evidence from animal studies that

carvedilol has any teratogenic effects.

Embryotoxicity was observed only after large doses

in rabbits. The relevance of these findings for

humans is uncertain. In addition, animal studies have

shown that carvedilol crosses the placental barrier

and therefore the possible consequences of alpha and

beta blockade in the human fetus and neonate should

also be borne in mind (although see section 4.6).

לע העדוה ( הרמחה

עדימ ןכרצל ןולעב )תוחיטב

ןכדועמ(

.102.50

ךיראת

6102

.

4

.

00

םושירה רפסמו תילגנאב רישכת םש

(

127 19 30614 00

(

6.25

Carvedexxon

(

30615 00

20

127

(

Carvedexxon 12.5

םושירה לעב םש

.

Dexcel Ltd

ה טורפל דעוימ הז ספוט דבלב תורמחה

חהה תושקובמה תורמ

ןולעב קרפ

יחכונ טסקט

שדח טסקט

תויוותה

ןיא יתמ שמתשהל ?רישכתב

יביכרממ דחאל תושיגר העודי םא .רישכתה

תוחיפנ( םילזונ תריצאמ ת/לבוס ךנה םא )םיילגרב וא םיילוסרק ,םיידיב ךרד תונתינה תופורת י"ע תלפוטמה .דירוה

דל ,בלב תויעבמ ת/לבוס ךניה םא אמגו ( בל םסח

heart block

ךומנ בל בצק ,)

וא ףירח םד ץחל תתמ ת/לבוס ךניה םא .דבכב תויעבמ

רבעב תלבסש וא ת/לבוס ךניה םא תולחמ וא המטסאמ האצותכ םיפוצפצמ .תורחא המישנ

תילובטמ תצמחמ ת/לבוס ךניה םא

וא םדב תויצמוח תומר ןוזיא רסוח לנרדאה תטולב לש לודיגמ טיצומורכואפ( .)המו

שיגר התא )יגרלא( ליעפה רמוחל

רק וו לוליד

וא הליכמ רשא םיפסונה םיביכרמהמ דחא לכל הפורתה

ףיעס האר(

האצותכ םיפוצפצמ רבעב תלבסש וא לבוס ךנה סאמ

המ

תורחא המישנ תולחמ וא

ךנה לבוס

הרומח בל תקיפס יא

םילזונ תריצא

,םיידיב תוחיפנ(

ב וא םיילוסרק ה תופכ לגר םיי

תלפוט ידי לע תופורת

תונתינה

ךרד

דירוה

לבוס ךנה דבכב תויעבמ

בלב תויעבמ לבוס ךנה

אמגודל

( בל םסח

heart

block

וא

.יטיא קפוד םיאתמ וניא ןוסקדברק .תומיוסמ בל תויעב םע םילוחהמ קלחב לופיטל

לבוס ךנה

םד ץחל תתמ רומח

תילובטמ תצמחמ לבוס ךנה

ר רוזיא רסוח תומ לנרדאה תטולב לש לודיגמ וא םדב תויצמוח .)המוטיצומורכואפ(

םיבצמהמ דחאמ לבוס התא םא םירכזומה ןיא ,הלעמ וא אפורב ץעוויה ,חוטב ךניא םא .הפורתה תא תחקל .הפורתה תליטנ ינפל חקורב

תורהזא תודחוימ תועגונה שומישל :הפורתב

:תורהזא

ךיילע בל תקיפס יאמ ת/לבוס ךניה םא

ןמיסה תעפוהב לפטמה אפורל חוודל לקשמב הילע( ךבצמב הערהל ןושארה .)המישנ רצוק וא

וא והשלכ ןוזמל ה/שיגר ךנה םא ךכ לע עידוהל ךילע ,יהשלכ הפורתל .הפורתה תליטנ ינפל אפורל

,ןופליעב הוולמ םדה ץחלב הדירי ןכתית וא הביכש לש בצממ המיק תעב דחוימב יושע תיטיא המיק .הבישי

.רוזעל הצק לע י/בש ,הביכש לש בצממ ךמוקב ךשמב תודנדנתמ םיילגרהשכ הטימה

שי ןכמ רחאל .תוקד

תויטיאב רובעל הניא היעבה םא .הדימע לש בצמל תונפל שי ,הפירחמ וא תכשמנ תפלוח .ךלש אפורל

ללוכ( ,חותינ רובעל ת/דמוע ךנה םא ,המדרהב הכורכה הלועפ לכ וא )ילאטנד ורל חווד תליטנ לע םידרמה אפ

הפורת .וז

נה םא חותינ רובעל דמוע ך

לכ וא )ילטנד ללוכ( המדרהב הכורכה הלועפ אפורל חווד , םידרמה

לטונ התאש

ןוסקדברק

םימיוסמ המדרה ירמוח לולע אוהו ךלש םדה ץחל תא דירוהל םילולע .ידמ ךומנ תויהל

אפורל חוודל ךילע בל תקיפס יאמ לבוס ךניה םא ךבצמב הערהל ןושארה ןמיסה תעפוהב לפטמה לע( .)המישנ רצוק וא לקשמב היי

דחוימב ,ןופליעב הוולמ םדה ץחלב הדירי ןכתית המיק .הבישי וא הביכש לש בצממ המיק תעב בש ,הביכש לש בצמ ךמוקב .רוזעל היושע תיטיא ךשמב תודנדנתמ םיילגרהשכ הטימה הצק לע

לש בצמל תויטיאב רובעל שי ןכמ רחאל .תוקד תפלוח הניא היעבה םא .הדימע וא תכשמנ , .ךלש אפורל תונפל שי ,הפירחמ

לוהוכלא תכירצו הפורתב שומיש

לולע הפורתב שומישה ו תונרעב םוגפל םורגל תרוחרחסל

דחוימב לוהוכלא םע בולישב

תונוכמב שומישו הגיהנ

םוי םויה ייח לע הפורתה עיפשת ךיא ?ךלש

תונרעב םוגפל לולע וז הפורתב שומישה תוריהז בייחמ ןכ לעו תרוחרחסל םורגלו תונכוסמ תונוכמ תלעפהב ,בכרב הגיהנב דחוימב תונרע תבייחמה תוליעפ לכבו םע בולישבו לופיטה יונישב וא הלחתהב .לוהוכלא

הפורתב שומישה

לולע ו תונרעב םוגפל םורגל תרוחרחסל

,בכרב הגיהנב תוריהז בייחמ ןכ לעו

תבייחמה תוליעפ לכבו תונכוסמ תונוכמ תלעפה תונריע

לופיטה יונישב וא הלחתהב דחוימב

הז םא ליעפהל וא םילכב שמתשהל ,גוהנל ןיא ,ךל הרוק תועפותב ןיחבמ ךניה םא ךלש אפורל רפס .תונוכמ םילכב שומיש ,הגיהנ לע עיפשהל תולולע רשא תופסונ לטונ ךניה רשאכ תונוכמ וא ןוסקדברק

שמתשהל ןיא ילבמ הפורתב אפורב ץעוויהל תלחתה ינפל :לופיטה

ץעווהל ילבמ הפורתב שמתשהל ןיא ךנה םא לופיטה תלחתה ינפל אפורב וא ןוירהל סנכיהל הסנמ ,ןוירהב דוקפתב יוקילמ ת/לבוס ךנה םא ,הקינימ לטמזנירפ גוסמ הניגנאמ ,תרכסמ הילכה םד ילכ תלחממ ,)הזחב באכ לש גוס( רפירפ םד תמירזב תוערפהמ ,תי לשמל( םיילגרהו םיידיה תועבצאל .)סדואנייר תעפות

רבעב תלבסש וא ת/לבוס ךנה םא וא )דיאורית( סירתה תטולבב תויעבמ ימסוח תליטנ תובקעב סיזאירוספמ תיגרלא הבוגתמ וא אטב גוסמ םינטלוק תימואתפ תוחיפנ :אמגודל( הרומח ,העילבב וא המישנב ישוקל תמרוגה

,םיילוסרקב וא םיילגר ,םיידיב תוחיפ ת/רבוע ךניה םא .)הרומח החירפ וא ךניה םא וא ,היצטזיטיסנסד לש לופיט .עגמ תושדע ה/ביכרמ

:םא אפורל רפס ,ןוסקדברקב לופיטה ינפל

.ךלש תואירה םע תויעב ךל שי

לבוס ךנה

.תוילכב תויעבמ

לבוס ךנה תוהובג רכוס תומר( תרכוסמ .)םדב

יכרמ ךנה .עגמ תושדע ב

םד ילכב תויעבמ לבוס ךנה

ילכ תלחמ םד .)תיפקיה

לבוס ךנה

תויעבמ רבעב תלבסש וא )דיאורית( סירתה תטולבב

לבוס ךנה

רבעב תלבסש וא

הבוגתמ ( הרומח תיגרלא תוחיפנ :אמגודל שקל תמרוגה תימואתפ

וא המישנ ,םיידיב תוחיפנ ,העילב ה תופכב םיילגר

ירפ וא ,םיילוסרקב הרומח הח

ךנה ו היגרלאמ לבוס ד לש לופיט רבוע

היצזיטיסנס

ןגרלאל תושיגרה תתחפהל( .)עודי

ךנה לבוס תועבצאל םד תמירזב תוערפהמ ( םיילגרהו םיידיה לשמל

תנומסת

ונייר

וא לבוס ךנה רועב היעבמ רבעב תלבסש תארקנה סיזאירוספ

ימסוח תליטנ תובקעב

םינטלוק

גוסמ

אטב

לבוס ךנה הניגנאמ )הזחב באכ( גוסמ לטמזנירפ

תוטולבמ תחא לע לודיגמ לבוס ךנה .)המוטיצומורכואפ( הילכה תרתוי

הפורתל וא והשלכ ןוזמל שיגר ךנה .יהשלכ

םא מ רתוי וא דחא ךייבגל םינוכנ הלא םיבצמ חקורב וא אפורב ץעוויה ,חוטב ךניא םא וא .הפורתה תליטנ ינפל

ןיב תובוגת :תויתפורת

םא

םא וא ,תפסונ הפורת ת/לטונ ךנה ,תרחא הפורתב לופיטה התע הז תמייס תופורת וא/ו םשרמ אלל תופורת תוברל ידכ לפטמה אפורל חוודל ךילע ,תויחמצ יא וא םינוכיס עונמל

םיעבונה תוליעי יבגל דחוימב ,תויתפורת ןיב תובוגתמ תופורת :תואבה תוצובקהמ תופורת פורת( בללו םד ץחל תדרוהל תו ןוגכ ןדיס תולעת ימסוח ,תונתשמ ,ןיסקוגיד ,לימפרוו וא םזאיטליד ,הובג םד ץחלל( ןידינולק ,)ןורודוימא ,)םישנב רבעמה ליגב לופיטו הנרגימ וא ןילוסניא ןוגכ תרכסב לופיטל תופורת ( ןיציפמאפיר ,ןימרופטמ

flushing

תופורת ,הנורחאל תחקל םא וא ,חקול התא םא רפס ,הנוזת יפסותו םשרמ אלל תופורת ללוכ תורחא .חקורל וא אפורל ךכ לע ברק לולע ןוסקד

לע עיפשהל תופורת ,ןכ ומכ .תומיוסמ תופורת לש ןתוליעפ .ןוסקדברק תוליעפ לע עיפשהל תולולע תומיוסמ

דחוימב חקורל וא אפורל רפס :חקול התא םא

בללו םד ץחל תדרוהל תופורת :ןוגכ םינתשמ

ןדיס תולעת ימסוח

ו וא םזאיטליד ןוגכ לימפר

לשל תנמ לע תונתינה תופורת רידס אל קפוד לע טו לשמל(

ןיסקוגיד )ןוראדוימא ,

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יבכעמו ןימאונומ

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וב וז הפורת לוטיל ןיא

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ימלובב לופיטה םותמ םוי .)ןואכידל( זדיסקואנימאונומ

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באכ :תובורק םיתיעל תועיפומה תועפות השלוחו תופייע ,תרוחרחס ,שאר

תועפות תועיפומו תורומח ןניאש

תליחתב בורל םיבאכ םיללוכ םינמיסה( בל תויעב .לופיטה שנ רצוק ,תופייע ,הזחב תוחפנתהו המי תועורזה

,המישנה יכרדב םימוהיז .)םיילגרהו ,המישנ רצוק ,םיפוצפצ םיללוכ םינמיסה םימוהיז .הזחב ץחל ,ןורג באכ

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מ םיקלח וא ףוגה לכב תופכ ,םיידיה ומכ ונמ הילע ,)םיילגרהו םיילוסרקה ,םיילגרה לורטסלוכ רתי ,לקשמב

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באכ ,ןואכידו ילוח תשוחת

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ורגל לולע

ארקמל להבית לא .םישמתשמהמ קלחב יאוול תועפותל תחא ףאמ לובסת אלו ןכתי .יאוולה תועפות תמישר .ןהמ

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,ןורג

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םינימסת תוימומדא :לולכל םילוכי הוולמ , תובורק םיתיעל

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תויהל לולעש .םייח ןכסמ תוירוע תובוגת

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תופסונ יאוול תועפות

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ו תועורז

)םיילגר

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תועפות

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תווחל תויושע ב ישוק העפותה ,ןתשה תיחופלש לע הטילש .לופיטה תקספהב תפלוח

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:תדחוימ תוסחייתה תובייחמה תועפות

םיללוכ םינמיסה( הרומח תיגרלא הבוגת ,םיילגר ,םיידיה לש תימואתפ תוחפנתה ד ,הפהו םייתפש ,םינפ ,ןורג ,םיילוסרק רב לע וא המישנה לע תושקהל לולעה רצוקב םיוולמה הזחב םיבאכ ;)העילבה העזה ,המישנ

הכומנ תופיכתב ןתש ןתמ ;ילוח תשוחתו לע דיעהל לולע( םיילגרב תוחיפנ םע רתוי םדב דואמ הכומנ רכוס תמר ;)תוילכב היעב רסוח וא םיפקתהל םורגל לולעה רבד !דימ אפורל הנפ :הרכה

ןונימ לש הרקמב

עיפוהל תולולע רתי ,תרוחרחס ,יטא בל בצק :תואבה תועפותה .םיפוצפצו המישנ רצוק ,הפירח תופייע

יאוול תועפות ה/שיגרמ ךנה ובש הרקמ לכב וא יוניש ולח םא וא ,הז ןולעב וניוצ אלש ץעייתהל ךילע תיללכה ךתשגרהב הרמחה .דימ אפורה םע

תוחיכש יאוול תועפות

ב תועיפומש תועפות

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םינמיסה

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לעו

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תועפות מח ןניאש לופיטה תליחתב בורל תועיפומו תורו

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ו תועורז

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תועפות תוחיכש ןניאש יאוול

ב תועיפומש תועפות

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עפוה :ןוגכ םינמיסב אטבתמ ,םדב תויסט טועימ

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הפב שבוי

תועפות

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תוחפב תועיפומש תועפות ךותמ דחא שמתשממ

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האצותכ

תוחיפנ

לש תימואתפ

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םינפ

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םיילוסרק

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לע הטילשב ישוק תווחל תויושע םישנהמ קלח העפותה ,ןתשה תיחופלש תשמ ללכ ךרדב תרפ .לופיטה תקספהב

ינמיס :םיללוכ םינמיסה( הכומנ תויסט תריפס םיפוצפצ ,שודג ףא ,)ףאהמ םימומידו תורובח .הפב שבוי ,תעפש ייומד םימוטפמיסו

ינמיס תוחתפתהל םורגל הלולע הפורתה

תר ס ילעב םילפוטמב

תרכ .המודר

יאוולה תועפותמ תחא םא ,יאוול תעפות העיפוה םא כ ,הרימחמ הניוצ אלש יאוול תעפותמ לבוס התא רשא ,ןולעב תיללכה ךתשגרהב יוניש לח םא וא

ךילע .אפורה םע ץעייתהל

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