Karvidil®

Therapeutic indications
Hypertension, angina.

Contra-indications
Hypersensitivityto carvedilol or any other constituents of themedicine;                    history of asthma  (2 death reports) orbronchospasm, Prinzmetal’s angina, marked bradycardia  or hypotension,sick sinus syndrome, second- or third-  degree AV block, cardiogenic shock, severe chronic heart failure (NYHA class IV), cor pulmonale;hepatic insufficiency, metabolic acidosis, severe peripheralvasoconstriction; patients who are receiving monoamine oxidaseinhibitors (MAOIs).

Posology and method of administration
Karvidil  should be taken with food.
Hypertension.
Thedose for initiation of therapy is 12.5 mg once daily, increased after 2days to usual dose of 25 mg once daily. If necessary, the dose may beincreased at interval of at least 2 weeks to maximum dose of 50 mgdaily used in single or divided doses.
For elderly patients dose of 12.5 mg provides satisfactory control.

Angina.
The dose for initiation of therapy is 12.5 mg twice daily, increased after 2 days to 25 mg twice daily. 
According to data found in literature dose, of Karvedil is advised 50 mg twice daily  in treating of stable angina.
Karvidilshould not be given to children and adolescent (under 18 years)because  safety and efficiency in these groups has not beenestablished.

Special warnings and precautions for use
In patients with phaeochromocytoma an alpha-blocking agent should be initiated prior to the use of any  beta-blocking agent.
Aswith other drugs with beta-blocking activity, Karvidil should not beenstopped suddenly. Abrupt withdrawal of Karvidil may cause acutesymptoms of angina in the patients with heart failure, enhances therisk of myocardial infarction and ventricular arrythmias, as well asaggravates the symptoms in patients with thyrotoxicosis.  Karvidildiscontinuation should be gradual an interval 1-2 weeks. If thesymptoms of the angina pectoris worse, Karvidil should be restartedimmediately (at least short time). The dosage must be titrated toindividual requirements.
Karvidil should be indicated with care to patients with slow AV conduction, especially  with first degree AV block.
Karvidildose should be reduced in the patients with liver diseases. Beta-adrenoblocking agents worse liver function in patients with portalhypertensia. Reduced initial dose is required for patients with renalinsufficiency, too.
Beta-blockers may praecipitate or aggravatesymptoms of arterial insufficienci in patients with peripheral vasculardisease.          
Karvidil should be used with care in thepatients with diabetes mellitus; the medicine may mask early signs ofacute hypoglycaemia. Therefore, regular monitoring of blood glucose isrequired when Karvidil is initiated or uptitrated. Karvidil may maskclinical symptoms of hyperthyroidism and depress signs of Myastheniagravis. 
Karvidil should be used with caution in the patients with psoriasis (see Undesirable effects).          
Duringgeneral anaesthesia, attention should be paid to the potentialsynergistic negative inotropic and hypotensive effects of Karvidil andanaesthetic drugs, when  Karvidil administration have not been stoppedbefore. 
Patients with history of serious hypersensitivity orallergic disease may increase both sensitivity towards allergens andthe seriousness of anaphylactic reactions. The response to adrenalineinjection may be decreased.
Medicine should be used with cautionin the patients with obstructive lung disease, the dose to be reducedto minimal effective one.
Wearers of contact lenses should be advised of the possibility of reduced lacrimation.
Patientswith lactose intolerance should be warned that Karvidil tablets containlactose following: 50 mg lactose in 6,25 mg Karvidil tablet, 100 mg in12,6 mg Karvedil tablet, 200 mg in 25 mg Karvidil tablet.
 
Interaction with other medicaments and other forms of interactions
Both pharmacodinamic and pharmacokinetic interactions have been reported with beta-blockers.
Pharmacodynamicinteractions may occur with the drugs whose action enhance orantagonise the various effects of beta blockers at beta1 and beta2receptors, including their antihypertensive effect, cardiodepressanteffect, effect on carbohydrate metabolism, or effect on bronchialbeta-2-adrenoreceptors. Therefore, periodical monitoring of bloodpressure should be undertaken when Karvidil is administeredconcurrently with ACE inhibitors, diuretics, calcium channel blockers,clonidine or alprostadil. When concomitant treatment with clonidine isto be terminated, Karvidil should be withdrawn first, several daysbefore gradually decreasing the dosage of clonidine. Anaesthetics,hypnotics, anxiolytics, alcohol potentates the hypotensive effect ofKarvidil while non-steroidal analgesics and corticosteroids antagonisethe hypotensive effect.
MAOIs, reserpine may cause markedbradycardia and enhance the hypotensive effect of Karvidil,antimalarials increase risk of bradycaria, but amiodarone enhances riskof ventricular arrhythmias.
Severe bradycardia or heart block isobserved when Karvidil and calcium channel blockers of the verapamil ordiltiazem type, or class I anti-arrhytmic drugs are givenconcomitantly. Verapamil injection may produce markedly hypotension andasystoles. Beta adrenoblockers enhance bradycardia caused by digoxin.Сoncurrent use of Karvidil and ergotamine or ergometrine increaseperipheral vasoconstriction. The combination of Karvidil andantidiabetics may enhance hypoglycaemic effect and mask warning signsof hypoglycaemia such as tremor.
Medicine may increase thecyclosporin blood concentration, therefore the dose of cyclosporinshould be reduced. It is recommended that cyclosporin concentration bemonitored after initiation of Karvidil therapy. 
Medicine mayincrease the pressor effect of adrenaline. Prolonged treatment ofbeta-adrenoblockers may decrease the effect of adrenaline used to treatanaphylaxis.
Pharmacokinetic interactions are observed by concurrentuse of aluminium hydroxide or colestyramine, Karvidil absorption isslowed.
Metabolism of Karvidil may be increased by concomitanttreatment with barbiturates and rifampicin thereby action of Karvidil is decreased.     
On the other hand cimetidine, erythromycin,fluvoxamine, and hydralazine decrease Karvidil metabolism and in resultenhanced effect of Karvidil is observed.
Concomitant use of beta-blocking agents with chlorpromazine may increase blood concentrations of both medicines.

Pregnancy and lactation
 Beta-blockersreduce placental perfusion, which may result in intrauterine foetalimmature and premature deliveries. Growth retardation, bradycardia,hypoglycaemia and hypotension may occur in human foetus and neonate.
 Karvidil should be used in pregnancy only if the potential benefits justifies the potential risks to the foetus.
 Karvidil is excreted in breast milk therefore breast-feeding should be discontinued for the period of treatment.
 
Effects on ability to drive and use machines
Patients taking Karvidil should not drive or operate machinery if they experience dizziness or fatigue.

Undesirable effects
Posturalhypotension, dizziness, fatigue, lapses of consciousness on theinitiation of therapy, headache, gastro-intestinal disturbances(nausea, vomiting, diarrhoea, constipation), bradycardia may beobserved, particularly during the first few days of therapy.  
Occasionallydiminished peripheral circulation (coldness of the palms and feet),peripheral oedema (oedema of the legs and ankles), thrill or painfulpalms and feet, dry mouth or dry eyes, eye irritation or disturbedvision occurs.
Impotence has been rarely reported. Other undesirableeffects include flu-like symptoms; disturbances of micturition causedby reversible deterioration of renal function.
Chest pain andother symptoms of angina are occasionally observed, heart failure maybe precipitated, Raynaud’s phenomenon, allergic skin reactions,exacerbation of psoriasis may occur. Depressed mood, sleepdisturbances, nasal stuffiness, wheezing, increased liver enzymes,thrombocytopenia, and leucopenia, weight increase have beenoccasionally reported. Karvidil may change blood glucose level(hypoglycaemia or hyperglycaemia).              
Patients should consult their doctor, if a rash, urticaria, or allergic reactions are developed.

Pharmacodynamic properties
Karvidil (carvedilol)is a combined alpha- and non-selective beta-blocker. Karvidil hasmultiple action that makes it a useful cardiovascular drug.
Medicineshows prevalent beta-adrenoreceptors blocking activity. Karvidil hasbeta1-blocking activity like propranolol, but stronger than labetalol.However, duration of action is longer than mention above drugs.       
Vasodilationis predominantly mediated through alpha1 receptor antagonism. Karvedilreduces the peripheral vascular resistance trough vasodilation.  Hypotensive effect of Karvidil is equivalent to metoprolol activity.  Medicine dilates both arteries and veins. Karvidil lowers standingblood pressure more than supine, however orthostatic hypotension shouldbe less of Karvidil than labetalol. Reflex  tachycardia does not occurdue to beta-blockade. 
In addition the alpha1-blocking propertiesoffset peripheral vasoconstriction, that might be expected with betablockade. Karvidil has no intrinsic sympathomimetic  activity. 
Karvidilalso possesses antioxidant properties and free radical scavengingeffects. During long term treatment Karvidil does not decreaseglomerular filtration rate or renal blood plasma flow, nor doessignificantly alter glucose tolerance test in non  insulin-dependentdiabetics without heart failure. Karvidil is appropriate therapy fortreating hypertension in patients with renal disease or diabetesmellitus.      
Long-term Karvidil therapy  has a beneficial effect on serum lipids by decreasing  total cholesterol, low-densitylipoproteins and triglycerides and increasing high-densitylipoproteins.  Carvedilol is also used in the management of heartfailure. The beneficial effect in heart failure primarily result fromits blockade of beta1 receptors. Beta1-blockade causes an upregulationof myocardial beta1-receptors, which restores the response to increasedsympathetic stimulation. Due to its alpha-blocking effects(vasodilatation), carvedilol also counterbalances the negativeinotropic effects resulting from beta-blockade. Carvedilol alsosupresses the renin-angiotensin-aldosterone  system.  There are somereports in literature that carvedilol may reduce left ventricularhypertrophy.    

Pharmacokinetics 
Carvedilolis well absorbed from the gastrointestinal tract and it undergoesextensive first-past metabolism in liver. The absolute bioavailabilityof active substance   is approximately 25 %.  A peak plasma level isreached in 1 - 2 hours after an oral dose.  Food decreases the rate butnot the extent of absorption. Carvedilol is highly lipophilic. Thedistribution volume (Vd) that is approximately 1,5-2,0 l/kg body weightevidences about distribution of carvedilol in all body tissues. Over 98% carvedilol is bound with plasma proteins. Carvedilol is extensivemetabolised in liver, the metabolites are excreted primarily via thebile. Average elimination half–life ranges from 7 to 10 hours.
 Animal studies have shown that carvedilol is excreted in breast milk.   

Pharmaceutical form
Tablets for oral use.
6.25 mg tablets – round biconvex tablets with score on one side, yellowish coloured with dark pink spots;
12.5 mg tablets – round biconvex tablets with score on one side, pink coloured with dark pink spots;
25 mg tablets – white round biconvex tablets with score on one side.

Excipients:lactose, microcrystalline cellulose, crospovidone, silica, coloidalanhydrous, magnesium stearate, yellow iron oxide (6,25 and 12,5 mgtablets), red iron oxide (12,5 mg tablets).

Pharmaceutical incompatibilities
Not applicable.     

Self- life
2 years.

Storage
Store at temperature bellow 25oC, protect from light.
Do not use after the expiry date stated on the label!

MARKETING AUTHORISATION HOLDER AND MANUFACTURER
JSC «Grindeks»
53, Krustpils St., Riga, LV-1057 Latvia
Phone: 371 7083205
Fax: 371 7083505

MARKETING AUTHORISATION NUMBER
03-0345 (6. 25 mg)
03-0346 (12.5 mg) 
03-0347 (25 mg) (Latvia)

DATE OF THE FIRST REGISTRATION
24.10.2003 (Latvia)