Composition: Each tablet contains:
Nebivolol (as Nebivolol HCl). . . . . . . . . . . . . 5 mg
Hydrochlorothiazide . . . . . . . . . . . . . . . .12.5 mg
3 blisters of 10 tablets in a carton box.
Treatment of hypertension.

Additional information

Dosage and administration

Adults: 1 tablet daily.
Patients with renal insufficiency: Nicarlol Plus is not recommended in patients with severe renal impairment (creatinine clearance < 30 ml/ min).
Patients with hepatic insufficiency: The use of Nicarlol Plus in these patients is contraindicated.
Elderly: In view of the limited experience in patients above 75 years, caution must be exercised and these patients monitored closely.
Children and adolescents: The efficacy and safety of Nicarlol Plus in children and adolescents aged below 18 years have not been established. Therefore, use in children and adolescents is not recommended.
Nicarlol Plus tablets may be taken with meals, preferably at the same time of the day.


Hypersensitivity to nebivolol, hydrochlorothiazide or any excipients of the product.
Liver insufficiency or liver function impairment.
Anuria, severe renal insufficiency (creatinine clearance < 30 ml/min).
Acute heart failure, cardiogenic shock or episodes of heart failure decompensation requiring I.V. inotropic therapy.
Sick sinus syndrome, including sino-atrial block.
Second and third-degree heart block (without a pacemaker).
History of bronchospasm and bronchial asthma.
Untreated phaeochromocytoma.
Metabolic acidosis.
Bradycardia (heart rate < 60bpm prior to starting the therapy).
Hypotension (systolic blood pressure < 90mmHg).
Severe peripheral circulatory disturbances.
Hypokalaemia, hyponatraemia, hypercalcaemia.
Hyperuricemia, as in patients with gout.

Warnings and precautions for use

Continuation of beta blockade reduces the risk of arrhythmias during induction and intubation. If beta blockade is interrupted in preparation for surgery, the beta-adrenergic antagonist should be discontinued at least 24 hours beforehand. Caution should be observed with certain anaesthetics that cause myocardial depression. The patient can be protected against vagal reactions by intravenous administration of atropine.
In general, beta-adrenergic antagonists should not be used in patients with untreated congestive heart failure (CHF), unless their condition has been stabilised.
In patients with ischaemic heart disease, treatment with a beta-adrenergic antagonist should be discontinued gradually over 1-2 weeks. If necessary, replacement therapy should be initiated at the same time to prevent exacerbation of angina pectoris.
Beta-adrenergic antagonists may induce bradycardia: If the pulse rate drops below 50-55 bpm at rest and/or the patient experiences symptoms suggestive of bradycardia, the dosage should be reduced.
Beta-adrenergic antagonists should be used with caution in the following conditions:
Patients with peripheral circulatory disorders (Raynaud's disease or syndrome, intermittent claudication), as aggravation of these disorders may occur upon use of beta blockers.
Patients with first-degree heart block, because of the negative effect of beta-blockers on conduction time.
Patients with Prinzmetal's angina due to unopposed alpha-receptor mediated coronary artery vasoconstriction, beta-adrenergic antagonists may increase the number and duration of anginal attacks.
Nebivolol does not affect glucose levels in diabetic patients. However, care should be taken in diabetic patients, as nebivolol may mask certain symptoms of hypoglycaemia (tachycardia, palpitations). Beta-adrenergic blocking agents may mask tachycardic symptoms in hyperthyroidism. Abrupt withdrawal may aggravate symptoms.
This medicine contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Caution should be exercised when treating patients with a history of psoriasis with beta-adrenergic antagonists as they may increase the sensitivity to allergens and the severity of anaphylactic reactions.
The initiation of CHF treatment with nebivolol necessitates regular monitoring. Treatment discontinuation should not be done abruptly unless clearly indicated.
Renal impairment:
Full benefit from thiazide diuretics can be derived only if the kidney function is not altered. In patients with renal disease, thiazides may increase azotaemia. Cumulative effects of this active substance may develop in patients with impaired renal function. If progressive renal impairment becomes evident, as indicated by a rising non-protein nitrogen, careful reappraisal of therapy is necessary, with consideration given to discontinuing diuretic therapy.
Metabolic and endocrine effects:
Thiazide therapy may impair glucose tolerance. Dosage adjustments of insulin or oral hypoglycaemic agents may be required. Latent diabetes mellitus may become manifest during thiazide therapy. Increases in cholesterol and triglyceride levels have been associated with thiazide diuretic therapy. Thiazide therapy may reduce renal excretion of uric acid, precipitate hyperuricaemia and/or gout in certain patients.
Electrolyte imbalance:
As for any patients receiving diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals. Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (especially hypokalaemia, hyponatraemia, and hypochloraemic alkalosis). Warning signs of fluid or electrolyte imbalance are dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea or vomiting.
The risk of hypokalaemia is greatest in patients with cirrhosis of the liver, in patients experiencing brisk diuresis, in patients who are receiving inadequate oral intake of electrolytes and in patients receiving concomitant therapy with corticosteroids or ACTH. Patients with long QT syndrome, either congenital or iatrogenic, are particularly at high risk in case of hypokalaemia. Hypokalaemia increases the cardiotoxicity of digitalis glycosides and the risk of cardiac arrhythmia. More frequent plasma potassium monitoring is indicated in patients at risk of hypokalaemia, starting within the week after initiation of therapy.
Dilutional hyponatraemia may occur in oedematous patients in hot weather. Decreased serum sodium level is generally mild and usually does not require treatment. Thiazides may decrease urinary calcium excretion and may cause an intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. A marked hypercalcaemia may be the evidence of a hidden hyperparathyroidism. Thiazides should be discontinued before carrying out test for parathyroid function.
Thiazides have been shown to increase the urinary excretion of magnesium, which may result in hypomagnesaemia.
Lupus erythematosus:
Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazides.
Anti-doping test:
Hydrochlorothiazide contained in this medication could produce a positive analytic result in an anti-doping test.
Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma. Photosensitivity reactions have been reported with thiazide diuretics in rare case. If photosensitivity reactions occur during treatment, it is recommended to stop the treatment. If a re-administration of treatment is deemed necessary, it is recommended to protect exposed areas from the sun or artificial UVA-light.
Protein bound iodine:
Thiazides may decrease serum protein bound iodine levels without signs of thyroid disturbance.
This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp-lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Recommendation for pregnancy and breastfeeding

There are no adequate data from the use of nebivolol/hydrochlorothiazide in pregnant women.
Animal studies on the two individual components are insufficient with respect to the effects of the combination of nebivolol and hydrochlorothiazide on reproduction.
Insufficient data exist on the use of nebivolol in human pregnancy to determine its potential harmfulness. However, nebivolol has pharmacological effects that may cause harmful effects on pregnancy and/or the foetus/newborn. In general, beta-adrenoceptor blockers reduce placental perfusion, which has been associated with growth retardation, intrauterine death, abortion or early labour. Adverse effects (e.g. hypoglycaemia and bradycardia) may occur in the foetus and newborn infant. If treatment with beta-adrenoceptor blockers is necessary, beta-1-selective adrenoceptor blockers are preferable.
Nebivolol should not be used during pregnancy unless clearly necessary. If treatment with nebivolol is considered necessary, the uteroplacental blood flow and the foetal growth should be monitored. In case of harmful effects on pregnancy or the foetus alternative treatment should be considered. The newborn infant must be closely monitored. Symptoms of hypoglycaemia and bradycardia are generally to be expected within the first 3 days.
There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient.
Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide, its use during the second and third trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia.
Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or preeclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without a beneficial effect on the course of the disease.
Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare situations where no other treatment could be used.
It is unknown whether nebivolol is excreted into human breast milk. Animal studies have shown that nebivolol is excreted into breast milk. Most beta-blockers, particularly lipophilic compounds like nebivolol and its active metabolites, pass into breast milk although to a variable extent. Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit the milk production. The use of Nicarlol Plus during breast feeding is not recommended. If Nicarlol Plus is used during breast feeding, doses should be kept as low as possible.

Effects on ability to drive and use machines

Nicarlol Plus may cause headache, dizziness. If affected, caution should be taken when driving vehicles or operating machines.

Interactions, incompatibilities of medicine

Pharmacodynamic interactions:
Followings are the commonly seen interactions with beta-blocker group.
Combinations that are not recommended:
Class I anti-arrhythmics (quinidine, hydroquinidine, cibenzoline, flecainide, disopyramide, lidocaine, mexiletine, propafenone): Effect on atrio-ventricular conduction time may be potentiated and the negative inotropic effect increased.
Calcium channel antagonists of verapamil/diltiazem type: Negative influence on contractility and atrio-ventricular conduction. Intravenous administration of verapamil in patients with beta-blocker treatment may lead to profound hypotension and atrio-ventricular block.
Centrally-acting antihypertensives (clonidine, guanfacine, moxonidine, methyldopa, rilmenidine): Concomitant use of centrally acting antihypertensive drugs may worsen heart failure by a decrease in the central sympathetic tonus (reduction of heart rate and cardiac output, vasodilation). Abrupt withdrawal, particularly if prior to beta-blocker discontinuation, may increase risk of “rebound hypertension”.
Combinations used with caution:
Class III anti-arrhythmic drugs (amiodarone): Effect on atrio-ventricular conduction time may be potentiated.
Volatile halogenated anaesthetics: Concomitant use of beta-adrenergic antagonists and anaesthetics may attenuate reflex tachycardia and increase the risk of hypotension. For a general rule, sudden withdrawal of beta-blocker treatment should be avoided. The anaesthesiologist should be informed when the patient is receiving Nicarlol Plus tablets.
Insulin and oral anti-diabetic drugs: Although nebivolol does not affect glucose levels, concomitant use may mask symptoms of hypoglycaemia (palpitations, tachycardia).
Baclofen (antispastic agent), amifostine (antineoplastic adjunt): Concomitant use with antihypertensives is likely to increase the fall in blood pressure. Therefore, the dosage of the antihypertensive medication should be adjusted accordingly.
Combinations to be used only after careful consideration:
Digitalis glycosides: Concomitant use may increase atrio-ventricular conduction time. Clinical trials with nebivolol have not shown any clinical evidence of an interaction. Nebivolol does not influence pharmacokinetics of digoxin.
Calcium antagonists of the dihydropyridine type (amlodipine, felodipine, lacidipine, nifedipine, nicardipine, nimodipine, nitrendipine): Concomitant use may increase the risk of hypotension, and an increase in the risk of a further deterioration of the ventricular pump function in patients with heart failure cannot be excluded.
Antipsychotics and antidepressants (tricyclics, barbiturates and phenotiazines): Concomitant use may enhance the hypotensive effect of the beta-blockers (additive effect).
Nonsteroidal anti-inflammatory drugs (NSAIDs) have no effect on the blood pressure lowering effect of nebivolol.
Sympathomimetic agents: Concomitant use may counteract the effect of beta-adrenergic antagonists. Beta-adrenergic agents may lead to unopposed alpha-adrenergic activity of sympathomimetic agents with both alpha- and beta-adrenergic effects (risk of hypertension, severe bradycardia and heart block).
Pharmacokinetic interactions:
As nebivolol metabolism involves the CYP2D6 isoenzyme, co-administration with substances inhibiting this enzyme, especially paroxetine, fluoxetine, thioridazine, and quinidine may lead to increased plasma levels of nebivolol associated with an increased risk of excessive bradycardia and other adverse events.
Co-administration of nebivolol with cimetidine increased the plasma levels of nebivolol, without changing the clinical effect.
Co-administration of nebivolol with ranitidine did not affect the pharmacokinetics of nebivolol. Provided nebivolol is taken with the meal, and an antacid between meals, the two treatments can be co-prescribed.
Combining nebivolol with nicardipine slightly increased the plasma levels of both drugs, without changing the clinical effect. Co-administration of alcohol, furosemide or hydrochlorothiazide did not affect the pharmacokinetics of nebivolol. Nebivolol does not affect the pharmacokinetics and pharmacodynamics of warfarin.
The following medications may interact with hydrochlorothiazide:
Alcohol, barbiturates or narcotic drugs: Potentiation of postural hypotension may occur.
Antidiabetic drugs (oral agents and insulin): Dose adjustment of the antidiabetic drug may be required because of increased blood glucose level.
Corticosteroids, ACTH: Increased electrolyte depletion, particularly hypokalaemia.
Pressor amines (e.g., norepinephrine): Possible decreased response to pressor amines but not sufficient to preclude their use.
Skeletal muscle relaxants (e.g., tubocurarine): Possible increased responsiveness to the muscle relaxant.
Lithium: Avoid concomitant use with diuretics because of decreased lithium clearance and increased risk of lithium toxicity.
Non-steroidal anti-inflammatory drugs: In some patients, the administration of a non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of thiazide diuretics. Therefore, when hydrochlorothiazide and non-steroidal anti-inflammatory agents are used concomitantly, the patients should be monitored closely to determine if the desired effect of the diuretics is attained.
Quinidine: Concomitant use may induce torsade de pointes leading to lethal ventricular fibrillation.
Thiazides reduce the effect of anticoagulants and antigout medications.
Thiazides increase the effect of anaesthetics, glycosides, vitamin D.
Both cholestyramine and colestipol resins have the potential of binding thiazide diuretics and reducing diuretic absorption from GI tract.
Thiazides increase the toxicity of digitalis.
Thiazides increase the risk of cardiac arrhythmias with QT prolonging medications such as astemizole, terfenadine, halofantrine, pimozide and sotalol.
To avoid drug-drug interactions, inform your physician or pharmacist of the drugs you are taking.

Undesirable effects (ADRs)

Adverse events are listed separately for hypertension and chronic heart failure (CHF) because of differences in the background diseases.
The adverse reactions reported, which are in most of the cases of mild to moderate intensity are tabulated below, classified by system organ class and ordered by frequency.
Common (1/100 ≤ ADR< 1/10)
Uncommon (1/1000 ≤ ADR< 1/100)
Very rare (ADR<1/10, 000)
Not Known
– Immune system disorders:
+ Not Known: angioneurotic oedema, hypersensitivity
– Psychiatric disorders:
+ Uncommon: nightmares, depression
– Nervous system disorders:
+ Common: headache, dizziness, paraesthesia
+ Very rare: syncope
– Eye disorders:
+ Uncommon: impaired vision
– Cardiac disorders:
+ Uncommon: bradycardia, heart failure, slowed AV conduction/AV-block
– Vascular disorders:
+ Uncommon: hypotension, (increase of) intermittent claudication
– Respiratory, thoracic and mediastinal disorders:
+ Common: dyspnoea
+ Uncommon: bronchospasm
– Gastrointestinal disorders:
+ Common: constipation, nausea, diarrhoea
+ Uncommon: dyspepsia, flatulence, vomiting
– Skin and subcutaneous tissue disorders:
+ Uncommon: pruritus, rash, erythematous
+ Very rare: psoriasis aggravated
– Reproductive system and breast disorders:
+ Uncommon: impotence
– General disorders:
+ Common: tiredness, oedema
The following adverse reactions have also been reported with some beta-adrenergic antagonists: Hallucinations, psychoses, confusion, cold/cyanotic extremities, Raynaud phenomenon, dry eyes, and oculo-mucocutaneous toxicity of the practolol-type.
Chronic heart failure:
Data on adverse reactions in CHF patients are available from one placebo-controlled clinical trial involving 1067 patients taking nebivolol and 1061 patients taking placebo. In this study, a total of 449 nebivolol patients (42.1%) reported at least possibly causally related adverse reactions compared to 334 placebo patients (31.5%). The most commonly reported adverse reactions in nebivolol patients were bradycardia and dizziness, both occurring in approximately 11% of patients. The corresponding frequencies among placebo patients were 2% and 7%, respectively.
The following incidences were reported for adverse reactions (at least possibly drug-related) which are considered specifically relevant in the treatment of chronic heart failure.
Aggravation of cardiac failure occurred in 5.8% of nebivolol patients compares to 5.2% of the placebo patients.
Orthostatic hypotension was reported in 2.1% of nebivolol patients compared to 1.0% of placebo patients.
Drug intolerance occurred in 1.6% of the nebivolol patients compared to 0.8% of the placebo patients.
First degree atrio-ventricular block occurred in 1.4% of nebivolol patients compared to 0.9% of placebo patients.
Oedema of the lower limb were reported in 1.0% of nebivolol patients compared to 0.2% of placebo patients.
Hydrochlorothiazide may cause excessive potassium loss. This effect is dose-dependent and can be reduced with low-dose (12.5 mg/ day), the optimal dose for treatment of hypertension, concurrently minimizing the adverse effects.
Common, ADR > 1/100
Body as a whole: Fatigue, vertigo, dizziness, headache.
Circulatory system: Postural hypotension.
Metabolism: Hypokalaemia, hyperuricemia, hyperglycemia, hyperlipidemia (high doses).
Uncommon, 1/1000 < ADR < 1/100
Circulatory system: Postural hypotension, arrhythmia.
Gastrointestinal: Nausea, vomitting, anorexia, constipation, diarrhea, intestinal spasms.
Skin: Urticaria, rash, photosensitivity.
Metabolism: Hypomagnesemia, hyponatraemia, hypercalcaemia, hypochloremic alkalosis, hypophosphatemia.
Rare, ADR < 1/1000
Body as a whole: Anaphylactic reactions, fever
Blood: Leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia, hemolytic anemia.
Nervous system: Paraesthesia, sleep disorders, depression.
Skin: Vasculitis, rash, hemorrhage.
Hepatic: Hepatitis, intrahepatic cholestasis or jaundice, pancreatitis.
Respiratory: Dyspnea, pneumonia, pulmonary edema (anaphylactic reaction).
Renal and urinary disorders: Renal failure, interstitial nephritis, impotence.
Eye: Vision blurred.
Elevated uric acid levels can trigger potential gouty attack. Orthostatic hypotension may occur when this medication is administered concomitantly with alcohol, anesthetics and sedatives.
Guidelines for ADR management:
Dehydration and electrolyte can cause hypotension, metabolic alkalosis, hypokalemia, hyponatraemia. The electrolyte should be checked, dehydration and electrolyte should be compensated.
People with coronary artery disease, ischemic heart disease is very sensitive to potassium loss and risk of arrhythmias. Serum potassium levels below 30 mEq/ L are associated with high risk. These patients should be carefully checked about electrolyte balance and potassium compensation. Taking low doses of diuretics is very important to limit this harm.
Patients on digitalis are at risk of digitalis toxicity when blood potassium is reduced. Potassium should be added when using diuretics. Patients on quinidine treatment are at risk of arrhythmias when hypokalemia occurs. Electrolytogram and potassium supplementation should be examined. Caution should also be exercised in patients who are being treated with any medication that affects ventricular repolarization, such as phenothiazines and tricyclic antidepressants.
Inform your doctor about any side effects that you may experience while using the medicine.

Overdose and management

Symptoms: Symptoms of overdose with beta-adrenergic antagonists include bradycardia, hypotension, bronchospasm and acute cardiac insufficiency.
In case of overdose or hypersensitivity to nebivolol, the patient should be transfered to healthcare facility for special care and treatment. Blood glucose levels should be checked. Absorption of any drug residues still present in the gastrointestinal tract can be prevented by gastric lavage and the administration of activated charcoal and a laxative. Artificial respiration may be required.
Bradycardia or extensive vagal reactions should be treated by administering atropine or methylatropine. Hypotension and shock should be treated with plasma/plasma substitutes and, if necessary, catecholamines should be used. The beta-blocking effect can be counteracted by slow intravenous administration of isoprenaline hydrochloride, starting with a dose of approximately 5 μg/minute, or dobutamine, starting with a dose of 2.5 μg/minute, until the required effect has been obtained. In refractory cases, isoprenaline can be combined with dopamine. If this does not produce the desired effect either, intravenous administration of glucagon 50-100 μg/kg may be considered. If required, the injection should be repeated within one hour, to be followed -if required- by an i.v. infusion of glucagon 70 μg/kg/h. In extreme cases of treatment-resistant bradycardia, a pacemaker may be inserted.
Overdose symptoms: Water and electrolyte disorders caused by excessive diuresis are main symptoms.
If the drug is recently taken, gastric lavage, activated charcoal may be given.
Interference in blood alkalinization: Ammonium chloride is used, except patients with liver disease.
Water and electrolytes loss must be compensated rapidly.
Peritoneal dialysis may be performed to adjust water and electrolytes balance. In case of hypotension that does not respond to these above interventions, intravenous infusion of norepinephrine at the dose of 4 mg/liter or dopamine with initial dose of 5 micrograms/kg/ min is required.

Pharmacodynamic properties

Nebivolol: Nebivolol is a racemic mixture of two stereoisomers: d-nebivolol (SRRR) and l-nebivolol (RSSS). Its effect is the combination of two different pharmacological activities of two enantiomers in a unique beta-blocker.
Nebivolol is a competitive and selective beta-receptor antagonist, due to the SRRR-enantiomer (d-nebivolol).
Nebivolol has mild vasodilating properties due to an interaction with the L-arginine/nitric oxide pathway.
Hydrochlorothiazide: Hydrochlorothiazide increases the excretion of sodium chloride and water by blocking the reabsorption of sodium and chloride ions in the distal tubule. The excretion of other electrolytes, particularly potassium and magnesium, also increases, whereas calcium excretion is decreased. Hydrochlorothiazide also reduces the activity of carbonic anhydrase. Therefore, it increases the excretion of bicarbonate, but this effect is usually weaker than the effect on Cl- excretion and does not significantly alter the pH of urine. Thiazide diuretics may also reduce glomerular filtration rates. Thiazides have moderate diuretic effect, because about 90% of the sodium ion is reabsorbed prior to reaching the distal tubule where thiazides exhibit their effects.
Hydrochlorothiazide has antihypertensive effect, perhaps, firstly due to the reduction of plasma volume and extracellular fluid related to urinary sodium excretion. Thereafter, during therapeutic process, effect on lowering blood pressure depends on the reduction of peripheral resistance through the gradual adaptation of the blood vessels to sodium ion level reduction. Thus, hypotensive effect of hydrochlorothiazide exhibits slowly after 1-2 weeks, whereas diuretic effect can occur quickly and may be observed after a few hours. Hydrochlorothiazide increases the effect of other antihypertensive drugs.
The combination of nebivolol 5 mg and hydrochlorothiazide 12.5 mg in Nicarlol Plus 5 mg/ 12.5 mg increased the antihypertensive effect of the drug.

Pharmacokinetic properties

Both nebivolol enantiomers are rapidly absorbed after oral administration. The absorption of nebivolol is not affected by food; therefore, it can be given with or without meals.
The oral bioavailability of nebivolol averages 12% in fast metabolizing patients and is virtually complete in slow metabolisers. At steady state and at the same dose level, the peak plasma concentration of unchanged nebivolol is about 23 times higher in poor metabolisers than in extensive metabolisers. When unchanged drug plus active metabolites are considered, the difference in peak plasma concentrations is 1.3 to 1.4 fold. Because of the variation in rates of metabolism, the dose of nebivolol should always be adjusted to the individual requirements of the patient: Poor metabolisers may require lower doses.
Plasma concentrations are dose-proportional between 1 and 30 mg. The pharmacokinetics of nebivolol are not affected by age.
Steady-state plasma levels in most subjects (fast metabolisers) are reached within 24 hours for nebivolol and within a few days for the hydroxy-metabolites. In plasma, both enantiomers of nebivolol are mostly combined with albumin. Plasma protein binding is 98.1% for SRRR-nebivolol and 97.9% for RSSS-nebivolol.
Nebivolol is extensively metabolised, partly to active hydroxy-metabolites. Nebivolol is metabolised via alicyclic and aromatic hydroxylation, N-dealkylation and glucuronidation. In addition, glucuronides of the hydroxy-metabolites are formed. The metabolism of nebivolol by aromatic hydroxylation is subject to the CYP2D6 dependent genetic oxidative polymorphism.
The oral bioavailability of nebivolol averages 12% in fast metabolizing patients and is virtually complete in slow metabolisers.
Because of the variation in rates of metabolism, the dose of nebivolol should always be adjusted to the individual requirements of the patient: Poor metabolisers may require lower doses. In fast metabolisers, elimination half-lives of the nebivolol enantiomers average 10 hours. In slow metabolisers, they are 3-5 times longer. In fast metabolisers, elimination half-lives of the hydroxy-metabolites of both enantiomers average 24 hours, and are about twice as long in slow metabolisers.
One week after administration, 38% of the dose is excreted in the urine and 48% in the faeces. Urinary excretion of unchanged nebivolol is less than 0.5% of the dose.
Hydrochlorothiazide is well absorbed (65 to 75%) following oral administration. Plasma concentrations are linearly related to the administered dose. The absorption of hydrochlorothiazide is dependent on intestinal transit time, being increased when the intestinal transit time is slow, for example when given with food. When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours and peak plasma levels were observed within 1 and 5 hours after dosing.
Hydrochlorothiazide is 68% protein bound in the plasma and its apparent volume of distribution is 0.83 – 1.14 L/kg. Hydrochlorothiazide crosses the placental but not the blood-brain barrier.
Hydrochlorothiazide is not significantly metabolized, and majority is excreted in the urine unchanged.
Hydrochlorothiazide is eliminated primarily by the renal pathway. More than 95% of hydrochlorothiazide appears unchanged in the urine within 3-6 hours after an oral dose. In patients with renal disease, plasma concentrations of hydrochlorothiazide are increased and elimination half-life is prolonged.

Storage conditions, shelf-life, quality specification of the medicine

Storage conditions: Protect from humidity and light, below 30 degrees C.
Shelf – life: 36 months from the manufacture date.
Quality specification: In house specification.