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Naproxen is indicated for the relief of sign and symptoms of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, juvenile arthritis, tendonitis, bursitis & acute gout. It is also indicated for the management of primary dysmenorrhea & pain.

Drugs for Osteoarthritis, Drugs used for Rheumatoid Arthritis, Non-steroidal Anti-inflammatory Drugs (NSAIDs)

Naproxen is a non steroidal anti-inflammatory drug (NSAID) with anti-inflammatory, analgesic & antipyretic properties. It is rapidly absorbed from the gastrointestinal tract and achieves 95% bioavailability.

Naproxen Tablet-

• Rheumatoid arthritis, osteoarthritis and ankylosing spondylitis: The usual dose is 500-1000 mg daily in two divided doses after meals.
• Management of pain, primary dysmenorrhea, acute tendonitis & bursitis: Recommended starting dose is 500 mg followed by 500 mg every 12 hours or 250 mg every 6-8 hours. The initial total daily dose should not exceed 1250 mg and thereafter, the total daily dose should not exceed 1000 mg.
• Acute gout: Recommended starting dose is 750 mg followed by 250 mg every 8 hours until the attack has subsided.

Naproxen Suspension-

• For Juvenile rheumatoid arthritis: The usual dose for children over 2 years is 10 mg/kg/day given as two divided doses at 12-hours intervals. Therapy in children under 2 years of age is not recommended.

Naproxen Gel-

• Is to be applied 2-6 times a day as required and is not recommended for use in children.

Most frequently reported side effects include following:

• Gastrointestinal: Heartburn, abdominal pain, nausea, diarrhea, dyspepsia.
• Central Nervous System: Headache, vertigo, drowsiness.
• Dermatological: Pruritus (itching), purpura.
• Cardiovascular: Edema, palpitation.
• Others: Visual disturbances, hearing disturbances.

Naproxen is contraindicated in patients with known hypersensitivity to Naproxen. It should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. It is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery.

ACE inhibitors: diminish the antihypertensive effect of ACE inhibitors.
Antacids & Sucralfate: delay the absorption of Naproxen.
Aspirin: increase adverse effects.
Diuretics: reduce the natriuretic effect of Furosemide and Thiazides.
Methotrexate: enhance the toxicity of Methotrexate.
Warfarin: increase the risk of GI bleeding.
Selective Serotonin Reuptake Inhibitors (SSRI): increase the risk of GI bleeding.

US FDA pregnancy category of Naproxen is C. So, Naproxen should be avoided in pregnancy & lactation unless the potential benefits to the other outweigh the possible risks to the fetus.

Keep below 30°C temperature, protected from light & moisture. Keep out of the reach of children.

Naproxen & Esomeprazole is indicated for the relief of signs & symptoms of-

• Osteoarthritis
• Rheumatoid arthritis
• Ankylosing spondylitis &
• To decrease the risk of developing gastric ulcers in patients at risk of developing NSAID-associated gastric ulcers.

Drugs for Osteoarthritis, Drugs used for Rheumatoid Arthritis, Non-steroidal Anti-inflammatory Drugs (NSAIDs)

This consists of an immediate release Esomeprazole Magnesium layer & an enteric-coated Naproxen core. As a result, Esomeprazole is released first into the stomach, prior to the dissolution of Naproxen in the small intestine.

Naproxen is a NSAID with analgesic & antipyretic properties. The mechanism of action of Naproxen is to inhibit the prostaglandin synthesis. Esomeprazole is a proton pump inhibitor that suppresses gastric acid secretion by specific inhibition of the H⁺/k⁺ -ATPase in the gastric parietal cell by acting specifically on the proton pump, Esomeprazole blocks the final step in acid production, thus reducing gastric acidity.

Carefully consider the potential benefits & risks of this tablet & other treatment options before deciding to use this tablet. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals. If a dose of Esomeprazole lower than a total daily dose of 40 mg is more appropriate, a different treatment should be considered.

Rheumatoid Arthritis, Osteoarthritis and Ankylosing Spondylitis-

• Adults: One tablet twice daily of either: 375 mg naproxen/20 mg of esomeprazole; or 500 mg naproxen/20 mg of esomeprazole

Juvenile Idiopathic Arthritis in Adolescent Patients 12 Years of Age & Older-

• Weight greater than 50 kg: 375 mg naproxen/20 mg of esomeprazole; or 500 mg naproxen/20 mg of esomeprazole
• Weight 38 kg to less than 50 kg: One tablet twice daily of 375 mg naproxen/20 mg of esomeprazole.

Do not split, chew, crush or dissolve the tablet. This tablet is to be taken at least 30 minutes before meals.

In general, this preparation is well tolerated. The most common adverse reactions in clinical trials (>5%): erosive gastritis, dyspepsia, gastritis, diarrhea, gastric ulcer, upper abdominal pain, nausea etc.

Patients with known CV disease/risk factors may be at greater risk. This tablet should be used with caution in patients with fluid retention or heart failure.

With medicine:

• Concomitant use of NSAIDs may reduce the antihypertensive effect of ACE inhibitors, diuretics & beta-blockers
• Concomitant use of this tablet and warfarin may result in an increased risk of a bleeding complication.
• Esomeprazole inhibits gastric acid secretion & may interfere with the absorption of drugs where gastric pH is an important determinant of bioavailability (eg. Ketoconazole, iron salts and digoxin).

With food & others: Administration of Naproxen & Esomeprazole together with high-fat food in healthy volunteers does not affect the extent of absorption of naproxen but significantly prolongs t_max by 10 hours and decreases peak plasma concentration (C_max) by about 12%

Pregnancy category C. In late pregnancy, it should be avoided because it may cause premature closure of the ductus arteriosus. This tablet should not be used in nursing mothers due to the Naproxen component.

Elderly patients: Studies indicate that although the total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. Use caution when high doses are required & some adjustment of dosage may be required in elderly patients. As with other drugs used in the elderly use the lowest effective dose.

Patients with Moderate to Severe Renal impairment: Naproxen-containing products are not recommended for use in patients with moderate to severe or severe renal impairment (creatinine clearance <30 ml/min).

Hepatic insufficiency: Monitor patients with mild to moderate hepatic impairment closely & consider a possible dose reduction based on the Naproxen component of this tablet. This is not recommended in patients with severe hepatic impairment because Esomeprazole dosage should not exceed 20 mg daily in these patients.

There is no clinical data on overdosage with this tablet.

Overdose of Naproxen: Significant naproxen overdosage may be characterized by lethargy, drowsiness, epigastric pain, abdominal discomfort, heartburn, indigestion, nausea, transient alteration in liver function, hypoprothrombinemia, renal dysfunction, metabolic acidosis, apnea, vomiting etc.

Overdose of Esomeprazole: The major signs of acute toxicity were reduced motor activity, changes in respiratory frequency, tremor and intermittent clonic convulsions etc.

Store at temperature of below 30°C, protect from light & moisture. Keep out of reach of children.

Naproxen & Esomeprazole is indicated for the relief of signs & symptoms of-

• Osteoarthritis
• Rheumatoid arthritis
• Ankylosing spondylitis &
• To decrease the risk of developing gastric ulcers in patients at risk of developing NSAID-associated gastric ulcers.

Drugs for Osteoarthritis, Drugs used for Rheumatoid Arthritis, Non-steroidal Anti-inflammatory Drugs (NSAIDs)

This consists of an immediate release Esomeprazole Magnesium layer & an enteric-coated Naproxen core. As a result, Esomeprazole is released first into the stomach, prior to the dissolution of Naproxen in the small intestine.

Naproxen is a NSAID with analgesic & antipyretic properties. The mechanism of action of Naproxen is to inhibit the prostaglandin synthesis. Esomeprazole is a proton pump inhibitor that suppresses gastric acid secretion by specific inhibition of the H⁺/k⁺ -ATPase in the gastric parietal cell by acting specifically on the proton pump, Esomeprazole blocks the final step in acid production, thus reducing gastric acidity.

Carefully consider the potential benefits & risks of this tablet & other treatment options before deciding to use this tablet. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals. If a dose of Esomeprazole lower than a total daily dose of 40 mg is more appropriate, a different treatment should be considered.

Rheumatoid Arthritis, Osteoarthritis and Ankylosing Spondylitis-

• Adults: One tablet twice daily of either: 375 mg naproxen/20 mg of esomeprazole; or 500 mg naproxen/20 mg of esomeprazole

Juvenile Idiopathic Arthritis in Adolescent Patients 12 Years of Age & Older-

• Weight greater than 50 kg: 375 mg naproxen/20 mg of esomeprazole; or 500 mg naproxen/20 mg of esomeprazole
• Weight 38 kg to less than 50 kg: One tablet twice daily of 375 mg naproxen/20 mg of esomeprazole.

Do not split, chew, crush or dissolve the tablet. This tablet is to be taken at least 30 minutes before meals.

In general, this preparation is well tolerated. The most common adverse reactions in clinical trials (>5%): erosive gastritis, dyspepsia, gastritis, diarrhea, gastric ulcer, upper abdominal pain, nausea etc.

Patients with known CV disease/risk factors may be at greater risk. This tablet should be used with caution in patients with fluid retention or heart failure.

With medicine:

• Concomitant use of NSAIDs may reduce the antihypertensive effect of ACE inhibitors, diuretics & beta-blockers
• Concomitant use of this tablet and warfarin may result in an increased risk of a bleeding complication.
• Esomeprazole inhibits gastric acid secretion & may interfere with the absorption of drugs where gastric pH is an important determinant of bioavailability (eg. Ketoconazole, iron salts and digoxin).

With food & others: Administration of Naproxen & Esomeprazole together with high-fat food in healthy volunteers does not affect the extent of absorption of naproxen but significantly prolongs t_max by 10 hours and decreases peak plasma concentration (C_max) by about 12%

Pregnancy category C. In late pregnancy, it should be avoided because it may cause premature closure of the ductus arteriosus. This tablet should not be used in nursing mothers due to the Naproxen component.

Elderly patients: Studies indicate that although the total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. Use caution when high doses are required & some adjustment of dosage may be required in elderly patients. As with other drugs used in the elderly use the lowest effective dose.

Patients with Moderate to Severe Renal impairment: Naproxen-containing products are not recommended for use in patients with moderate to severe or severe renal impairment (creatinine clearance <30 ml/min).

Hepatic insufficiency: Monitor patients with mild to moderate hepatic impairment closely & consider a possible dose reduction based on the Naproxen component of this tablet. This is not recommended in patients with severe hepatic impairment because Esomeprazole dosage should not exceed 20 mg daily in these patients.

There is no clinical data on overdosage with this tablet.

Overdose of Naproxen: Significant naproxen overdosage may be characterized by lethargy, drowsiness, epigastric pain, abdominal discomfort, heartburn, indigestion, nausea, transient alteration in liver function, hypoprothrombinemia, renal dysfunction, metabolic acidosis, apnea, vomiting etc.

Overdose of Esomeprazole: The major signs of acute toxicity were reduced motor activity, changes in respiratory frequency, tremor and intermittent clonic convulsions etc.

Store at temperature of below 30°C, protect from light & moisture. Keep out of reach of children.

For the treatment of fungal corneal ulcers/ keratitis.

Ophthalmic Anti-fungal Products

Fluconazole is fungistatic in action. It inhibits cytochrome P-450 14-α demethylase in susceptible fungi which leads to accumulation of lanosterol and decreased concentration of ergosterol thereby altering cellular membrane resulting in increased membrane permeability, leakage of essential elements and impaired uptake of precursor molecules to DNA.

Instill 1 drop to be instilled into the affected eye(s) 5 times daily.

This drug is generally well tolerated. Eosinophillia has been reported in some patients.

The drug is contraindicated in patients with hypersensitivity to azoles.

Use of fluconazole may result in overgrowth of non-susceptible strains of candida other than Candida albicans

Fluconazole can alter pharmacokinetics of certain drugs undergoing hepatic metabolism.

Use in pregnancy: Pregnancy category C. There are no adequate and well-controlled studies in pregnant women. Fluconazole should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Use in lactation: Nursing mother should not be given as the drug is excreted in breast milk in concentration similar to plasma.

Keep out of the reach of children. Store in a cool, dry place, away from heat and direct light. Do not use more than 4 weeks after opening the bottle

Acute and chronic non-infectious conjunctivitis, nonspecific conjunctival irritation; also after successful treatment of bacterial and viral conjunctivitis. Irrigation of the tear ducts.

Ophthalmic Non-Steroid drugs

Zinc ions, the active compound of zinc sulphate, have an astringent, i.e. tissue-sealing and slightly anti-septic effect. Naphazoline constricts the blood vessels and reduces the inflammation and swelling of the conjunctiva. This effect of naphazoline, a substance of the benzylimidazoline group, is due to direct binding to a-adrenergic receptor sites on unstriated muscle cells in the blood vessels.

Adults: 1 drop in the conjunctival sac, three to 4 times per day.

Children: Naphazoline nitrate and Zinc sulphate drops has not been studied in children. Generally, in children the dosage of vasoconstrictors should be low and selected with caution.

Mydriasis and a slight increase of intraocular pressure in isolated cases. A slight and transient burning sensation may occur after instillation, which does not affect the success of the treatment. Long term use may result in reactive redness of the eye (rebound effect).

In very rare cases systemic cardiovascular effects, such as hypertension and arrhythmia, may occur. Nonspecific fatigue has been observed in some patients.

Hypersensitivity to zinc sulphate, Naphazoline and other ingredients. Naphazoline & Zinc is contraindicated in patients suffering from narrow-angle glaucoma, dry eye and especially keratoconjunctivits sicca Sjogren's syndrome. Naphazoline & Zinc must not be used in infants.

Uncontrolled use of Naphazoline & Zinc over extended periods of time should be avoided. If no improvement is seen after 2 days, treatment should be discontinued and other therapeutic measures should be considered. If ocular discomfort or visual disturbance occurs during Naphazoline & Zinc treatment, the therapy must be discontinued. Caution is indicated in patients with predisposition to glaucoma and in patients suffering from hypertension, cardiovascular diseases, pheochromocytoma, aneurysm, hyperglycemia, and hyperthyroidism.

Naphazoline containing products should not be administered during treatment with MAO-blockers nor during 10 days after discontinuation of such treatment. The effects of Naphazoline may be increased by concomitant use of tricyclic antidepressants.

Use in pregnancy: There are neither controlled animal studies nor studies in pregnant women available.

Use in lactation: The effects of Naphazoline & Zinc treatment during lactation have not been investigated.

Oxymetazoline Hydrochlorid is indicated for the treatment of nasal congestion associated with acute or chronic rhinitis, common cold, sinusitis, upper respiratory allergies, epistaxis and hay fever. It is also used as nasal decongestant in otitis media.

Nasal Anti-histamine preparations, Nasal Decongestants & Other Nasal Preparations

Oxymetazoline Hydrochloride is an imidazoline derivative sympathomimetic amine. It is a direct agonist at α-adrenoceptors but has no action on β- adrenoceptors. It is used as a topical agent on the nasal mucosa, produces a rapid and long acting vasoconstriction of the arterioles, thus reducing the blood flow and diminishing swelling of the mucosa. This results in improved potency of the airway and better drainage of the nasal sinus.

Oxymetazoline nasal spray-

• Adults and children (6 years of age and older): 2 or 3 sprays in each nostril twice daily for 3-5 days.
• Elderly: There is no need for dosage reduction in the elderly for nasal administration.
• Children below 6 years of age: It is not suitable for children below 6 years of age.

Oxymetazoline nasal drop-

• Adults & children 6 years of age: 2-3 drops of 0.05% Nasal Drops in each nostril twice daily in the morning and evening.
• Children 2-5 years of age: 2-3 drops of 0.025% Nasal Drops in each nostril twice daily in the morning and evening

How to use the Nasal Spray-

• Shake the bottle gently and remove the dust cover.
• Hold the spray with your forefinger and middle finger on either side of the nozzle and your thumb underneath the bottle. Press down until a fine spray appears. If using for the first time or if you have not used it for a week or more, press the nasal applicator several times until a fine moist comes out from the container.
• Gently blow the nose to clear the nostrils.
• Close one nostril and carefully insert the nasal applicator into the open nostril. Tilt your head forward slightly and keep the spray upright. Breathe in through your nose and while breathing in, press the white-collar of nasal applicator firmly down once to release a spray.
• Breathe out through your mouth.
• Repeat the above steps in the same/ other nostril for consecutive doses.

Cleaning: The nasal spray should be cleaned at least once a week. The procedures are as follows-

• Remove the dust cover.
• Gently pull off the nasal applicator.
• Wash the applicator and dust cover in warm water.
• Shake off the excess water and leave to dry in a normal place. Avoid to apply additional heat.
• Gently push the applicator back on the top of the bottle and re-fix the dust cover.

Occasionally it may cause local irritation and dryness of the mouth and throat. Temporarily discomfort such as burning, stinging, sneezing or increase in nasal discharge may occur.

It is contraindicated in patients with cardiovascular disease, hyperthyroidism, prostatic enlargement, angle closure glaucoma and hypersensitivity to any of its ingredients.

Keep away from the eyes. The spray should not be used for longer than seven days without medical advice. Frequent or prolonged use may cause nasal congestion to recur or worsen.

Oxymetazoline Hydrochloride Nasal preparation should not be given to patients being treated with MAO inhibitors or within 14 days of ceasing such treatment.

The safety of Oxymetazoline Hydrochloride Nasal Spray during pregnancy and lactation has not been established, but is not thought to constitute a hazard during those periods.

Overdose may give rise to local irritation and rebound congestion. Treatment need only be symptomatic.

Keep below 30° C temperature in a dry place, protect from light. Do not refrigerate or freeze. Keep out of the reach of children.

Nasal Decongestants & Other Nasal Preparations

Sodium Chloride nasal wash is a non-drug, isotonic saline solution that is used to moisturize nasal membranes. This formulation provides comfort for extensive and continuous use.

Sodium Chloride 0.9% nasal wash moistures inside the nose by dissolving and softening thick or crusty mucus thus helps to remove the mucus from the nose and makes breathing easier. Excess sodium is predominantly excreted by the kidneys with small amounts lost in faeces and sweat.

Nasal Congestion: In infants, 1-2 drops of Sodium Chloride nasal wash in each nostril before feeds will help relieve congestion and allow more effective suckling.

Ear Wax Removal: Allow the Sodium Chloride nasal wash to warm to room temperature before use. It is important to put the drops into the ear carefully. Lie down on one side and fill the ear canal with the drops and wait for a few minutes before standing up. Age: from 6 months onwards. Put 3 to 4 drops into the affected ear(s) 3 to 4 times a day for 3 to 5 days.

How to use the Nasal Spray-

• Shake the bottle gently and remove the dust cover.
• Hold the spray with your forefinger and middle finger on either side of the nozzle and your thumb underneath the bottle. Press down until a fine spray appears. If using for the first time or if you have not used it for a week or more, press the nasal applicator several times until a fine moist comes out from the container.
• Gently blow the nose to clear the nostrils.
• Close one nostril and carefully insert the nasal applicator into the open nostril. Tilt your head forward slightly and keep the spray upright. Breathe in through your nose and while breathing in, press the white-collar of nasal applicator firmly down once to release a spray.
• Breathe out through your mouth.
• Repeat the above steps in the same/ other nostril for consecutive doses.

Cleaning: The nasal spray should be cleaned at least once a week. The procedures are as follows-

• Remove the dust cover.
• Gently pull off the nasal applicator.
• Wash the applicator and dust cover in warm water.
• Shake off the excess water and leave to dry in a normal place. Avoid to apply additional heat.
• Gently push the applicator back on the top of the bottle and re-fix the dust cover.

No side effects are expected to occur. However stinging, sneezing, increased nasal discharge, or salty taste may occur in some cases.

Do not share this medication with others. Doing so may increase the risk of infection.

Tell your doctor about your medical history, especially of heart problems (e.g., congestive heart failure), lung problems (pulmonary edema), kidney problems, low levels of potassium (hypokalemia), high levels of sodium (hypernatremia), and any allergies.

Tell your doctor if you are pregnant before using this medication. It is unknown if this medication passes into breast milk. Consult your doctor before breast-feeding.

There have been no adverse reports of overdose with Sodium Chloride 0.9% nasal wash.

Keep out of the reach of children. Store at room temperature (between 15°C to 30°C), away from light and moisture.

This is indicated in the treatment of topical bacterial infections. This is particularly effective in atopic, contact stasis and infections, eczematoid dermatitis, neurodermatitis, eczema, anogenital pruritus. It may also be useful as an adjunct in certain pyodermas, such as impetigo, during specific systemic antibiotic therapy for these infections.

Ophthalmic and Topical antibacterial products

Bacitracin inhibits bacterial cell wall synthesis and is active against many gram-positive bacteria (e.g. staphylococci, streptococci, corynebacteria and Clostridia) and some gram-negative species (e.g. Neisseria and Haemophilus influenzae). They are often found in combinations in topical preparations as broad spectrum antibacterial agents.

Neomycin, an aminoglyoside with antimicrobial spectrum similar to gentamicin, binds to the 30S subunits of the bacterial ribosome, inhibiting protein synthesis and thereby disrupting DNA synthesis. It is active against many gram negative aerobes and against some strains of staphylococci.

Ointment: Before use, the area for application should be cleaned gently. Derbis such as pus or crusts should be removed from the affected area. Apply two to three times daily to the affected skin area.

Dusting Powder: Antibiotic powder is a non- sterile dusting powder and used for superficial skin infections. A light dusting of the powder to be applied to the affected skin area upto 4 times daily.

This preparation is usually well tolerated. In rare cases, allergic reactions may be occurred.

Hypersensitivity to any of its components.

Bacitracin & Neomycin antibiotic powder should not be used to large open wounds or to severely injured skin or on areas that exude large volumes of fluid as hard crusts may form. Since this skin ointment contains Neomycin, it should not be used for the treatment of otitis external when the eardrum is perforated because of risk of ototoxicity.

Patients considering self-medication with a topical anti-infective for deep or puncture wounds, animal bites, or serious burns should be advised to first consult a physician. Patients using the preparations for the prevention of infection in minor skin injuries (e.g., cuts, scrapes, burns) should be advised to discontinue the topical anti-infective preparation and consult a physician if the condition persists or worsens; it should not be used for longer than 1 week unless directed by a physician.

Bacitracin Zinc: Increased risk of nephrotoxicity when used with other nephrotoxic drugs. May enhance the action of neuromuscular-blocking agents.

Neomycin Sulphate: Additive nephrotoxic and neurotoxic effect with other aminoglycosides, bacitracin, cisplatin, vancomycin, amphotericin B, polymyxin B, colistin and viomycin. Enhanced toxicity with potent diuretics. May impair the absorption of other drugs. May enhance the effect of acarbose. May enhance the effect of non-depolarising muscle relaxants. May antagonise the parasympathomimetic effect of neostigmine and pyridostigmine. May increase the risk of hypocalcaemia in patients receiving bisphosphonates. May alter INR when givenwithanticoagulants. May inactivate oral typhoid vaccine.

The safe use of this preparation during pregnancy & lactation has not been established. Therefore it should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Children and Infants: This ointment is suitable for use in children at the same dose as adults, but the dose should be reduced in infants. This ointment is not recommended for use in neonates.

Keep all medicines out of reach of children. Store in a cool and dry place, protected from light.

This is indicated in the treatment of topical bacterial infections. This is particularly effective in atopic, contact stasis and infections, eczematoid dermatitis, neurodermatitis, eczema, anogenital pruritus. It may also be useful as an adjunct in certain pyodermas, such as impetigo, during specific systemic antibiotic therapy for these infections.

Ophthalmic and Topical antibacterial products

Bacitracin inhibits bacterial cell wall synthesis and is active against many gram-positive bacteria (e.g. staphylococci, streptococci, corynebacteria and Clostridia) and some gram-negative species (e.g. Neisseria and Haemophilus influenzae). They are often found in combinations in topical preparations as broad spectrum antibacterial agents.

Neomycin, an aminoglyoside with antimicrobial spectrum similar to gentamicin, binds to the 30S subunits of the bacterial ribosome, inhibiting protein synthesis and thereby disrupting DNA synthesis. It is active against many gram negative aerobes and against some strains of staphylococci.

Ointment: Before use, the area for application should be cleaned gently. Derbis such as pus or crusts should be removed from the affected area. Apply two to three times daily to the affected skin area.

Dusting Powder: Antibiotic powder is a non- sterile dusting powder and used for superficial skin infections. A light dusting of the powder to be applied to the affected skin area upto 4 times daily.

This preparation is usually well tolerated. In rare cases, allergic reactions may be occurred.

Hypersensitivity to any of its components.

Bacitracin & Neomycin antibiotic powder should not be used to large open wounds or to severely injured skin or on areas that exude large volumes of fluid as hard crusts may form. Since this skin ointment contains Neomycin, it should not be used for the treatment of otitis external when the eardrum is perforated because of risk of ototoxicity.

Patients considering self-medication with a topical anti-infective for deep or puncture wounds, animal bites, or serious burns should be advised to first consult a physician. Patients using the preparations for the prevention of infection in minor skin injuries (e.g., cuts, scrapes, burns) should be advised to discontinue the topical anti-infective preparation and consult a physician if the condition persists or worsens; it should not be used for longer than 1 week unless directed by a physician.

Bacitracin Zinc: Increased risk of nephrotoxicity when used with other nephrotoxic drugs. May enhance the action of neuromuscular-blocking agents.

Neomycin Sulphate: Additive nephrotoxic and neurotoxic effect with other aminoglycosides, bacitracin, cisplatin, vancomycin, amphotericin B, polymyxin B, colistin and viomycin. Enhanced toxicity with potent diuretics. May impair the absorption of other drugs. May enhance the effect of acarbose. May enhance the effect of non-depolarising muscle relaxants. May antagonise the parasympathomimetic effect of neostigmine and pyridostigmine. May increase the risk of hypocalcaemia in patients receiving bisphosphonates. May alter INR when givenwithanticoagulants. May inactivate oral typhoid vaccine.

The safe use of this preparation during pregnancy & lactation has not been established. Therefore it should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Children and Infants: This ointment is suitable for use in children at the same dose as adults, but the dose should be reduced in infants. This ointment is not recommended for use in neonates.

Keep all medicines out of reach of children. Store in a cool and dry place, protected from light.

This is indicated in the treatment of topical bacterial infections. This is particularly effective in atopic, contact stasis and infections, eczematoid dermatitis, neurodermatitis, eczema, anogenital pruritus. It may also be useful as an adjunct in certain pyodermas, such as impetigo, during specific systemic antibiotic therapy for these infections.

Ophthalmic and Topical antibacterial products

Bacitracin inhibits bacterial cell wall synthesis and is active against many gram-positive bacteria (e.g. staphylococci, streptococci, corynebacteria and Clostridia) and some gram-negative species (e.g. Neisseria and Haemophilus influenzae). They are often found in combinations in topical preparations as broad spectrum antibacterial agents.

Neomycin, an aminoglyoside with antimicrobial spectrum similar to gentamicin, binds to the 30S subunits of the bacterial ribosome, inhibiting protein synthesis and thereby disrupting DNA synthesis. It is active against many gram negative aerobes and against some strains of staphylococci.

Ointment: Before use, the area for application should be cleaned gently. Derbis such as pus or crusts should be removed from the affected area. Apply two to three times daily to the affected skin area.

Dusting Powder: Antibiotic powder is a non- sterile dusting powder and used for superficial skin infections. A light dusting of the powder to be applied to the affected skin area upto 4 times daily.

This preparation is usually well tolerated. In rare cases, allergic reactions may be occurred.

Hypersensitivity to any of its components.

Bacitracin & Neomycin antibiotic powder should not be used to large open wounds or to severely injured skin or on areas that exude large volumes of fluid as hard crusts may form. Since this skin ointment contains Neomycin, it should not be used for the treatment of otitis external when the eardrum is perforated because of risk of ototoxicity.

Patients considering self-medication with a topical anti-infective for deep or puncture wounds, animal bites, or serious burns should be advised to first consult a physician. Patients using the preparations for the prevention of infection in minor skin injuries (e.g., cuts, scrapes, burns) should be advised to discontinue the topical anti-infective preparation and consult a physician if the condition persists or worsens; it should not be used for longer than 1 week unless directed by a physician.

Bacitracin Zinc: Increased risk of nephrotoxicity when used with other nephrotoxic drugs. May enhance the action of neuromuscular-blocking agents.

Neomycin Sulphate: Additive nephrotoxic and neurotoxic effect with other aminoglycosides, bacitracin, cisplatin, vancomycin, amphotericin B, polymyxin B, colistin and viomycin. Enhanced toxicity with potent diuretics. May impair the absorption of other drugs. May enhance the effect of acarbose. May enhance the effect of non-depolarising muscle relaxants. May antagonise the parasympathomimetic effect of neostigmine and pyridostigmine. May increase the risk of hypocalcaemia in patients receiving bisphosphonates. May alter INR when givenwithanticoagulants. May inactivate oral typhoid vaccine.

The safe use of this preparation during pregnancy & lactation has not been established. Therefore it should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Children and Infants: This ointment is suitable for use in children at the same dose as adults, but the dose should be reduced in infants. This ointment is not recommended for use in neonates.

Keep all medicines out of reach of children. Store in a cool and dry place, protected from light.

Topical Antibiotic preparations

The combination of Polymyxin B sulfate with Neomycin and Bacitracin zinc most nearly meets the criteria for an ideal topical antibacterial preparation. The spectrum of action encompasses virtually all pathogenic bacteria found topically and the three antibiotics are bactericidal. When used topically Polymyxin B sulphate with Neomycin and Bacitracin zinc are rarely irritating, and absorption from the skin or mucous membrane is insignificant. Polymyxin B sulphate attacks gram-negative bacilli including clinically isolated strains of Pseudomonas aeruginosa. This organism is conspicuously absent from the spectra of most other antibiotic agents, but it is highly susceptible to polymyxin B sulphate, which is acknowledged to be the most effective agent known for the treatment and prophylaxis of Pseudomonas infections. Neomycin provides bactericidal action against various gram-positive organisms and gram-negative organisms including many strains of Proteus. Neomycin is considered by various authorities to be the most effective antibiotic against Staphylococcus aureus which is among the more common aetiological organisms in topical bacterial infections. Bacitracin zinc is highly active against gram-positive bacilli and cocci and extends the spectrum to include haemolytic streptococci, thus completing the anti-bacterial range of this Ointment. There is overlapping of the bactericidal spectra of these three antibiotics, thereby providing increased activity through combined antibiotic action.

Adult: This Ointment should be applied thinly over the affected area after cleaning it.1-3 daily applications should be continued until the infection is controlled and healing completely.

Children and Infants: This Ointment is suitable for use in children at the same dose as adults, but the dose should be reduced in infants. This ointment is not recommended for use in neonates.

Common side effects are Nausea; Vomiting; Pain, burning, or swelling; Skin rashes; Possible kidney problems; Hearing loss; Dizziness; Unusual numbness of the skin; Muscle twitching; Seizures; Pain; Redness; Swelling at the injection site.

This ointment should not be used in individuals who have shown sensitivity to any of the components. A possibility of increased absorption exists in very young children, thus this ointment is not recommended for use in neonates.

It is to be noted that this Ointment is not intended for sterile use in surgical procedures such as those involving abdominal or thoracic cavities as there is evidence that neomycin, when in contact with peritoneal or pleural tissues, can potentiate neuromuscular block in patients under the influence of muscle relaxants, producing respiratory paralysis. As with other antibiotic preparations prolonged use may result in overgrowth of non-susceptible organisms. Ototoxicity to neomycin has been reported. In neonates and infants, absorption by immature skin may be enhanced and renal function may be immature.

There is little information to demonstrate the possible effect of topically applied neomycin in pregnancy and lactation. However, neomycin present in maternal blood can cross the placenta and may give rise to a theoretical risk of foetal toxicity, thus this ointment is not recommended in pregnancy and lactation.

Store below 30˚C. Keep all medicine out of reach of children.

This is indicated in the treatment of topical bacterial infections. This is particularly effective in atopic, contact stasis and infections, eczematoid dermatitis, neurodermatitis, eczema, anogenital pruritus. It may also be useful as an adjunct in certain pyodermas, such as impetigo, during specific systemic antibiotic therapy for these infections.

Ophthalmic and Topical antibacterial products

Bacitracin inhibits bacterial cell wall synthesis and is active against many gram-positive bacteria (e.g. staphylococci, streptococci, corynebacteria and Clostridia) and some gram-negative species (e.g. Neisseria and Haemophilus influenzae). They are often found in combinations in topical preparations as broad spectrum antibacterial agents.

Neomycin, an aminoglyoside with antimicrobial spectrum similar to gentamicin, binds to the 30S subunits of the bacterial ribosome, inhibiting protein synthesis and thereby disrupting DNA synthesis. It is active against many gram negative aerobes and against some strains of staphylococci.

Ointment: Before use, the area for application should be cleaned gently. Derbis such as pus or crusts should be removed from the affected area. Apply two to three times daily to the affected skin area.

Dusting Powder: Antibiotic powder is a non- sterile dusting powder and used for superficial skin infections. A light dusting of the powder to be applied to the affected skin area upto 4 times daily.

This preparation is usually well tolerated. In rare cases, allergic reactions may be occurred.

Hypersensitivity to any of its components.

Bacitracin & Neomycin antibiotic powder should not be used to large open wounds or to severely injured skin or on areas that exude large volumes of fluid as hard crusts may form. Since this skin ointment contains Neomycin, it should not be used for the treatment of otitis external when the eardrum is perforated because of risk of ototoxicity.

Patients considering self-medication with a topical anti-infective for deep or puncture wounds, animal bites, or serious burns should be advised to first consult a physician. Patients using the preparations for the prevention of infection in minor skin injuries (e.g., cuts, scrapes, burns) should be advised to discontinue the topical anti-infective preparation and consult a physician if the condition persists or worsens; it should not be used for longer than 1 week unless directed by a physician.

Bacitracin Zinc: Increased risk of nephrotoxicity when used with other nephrotoxic drugs. May enhance the action of neuromuscular-blocking agents.

Neomycin Sulphate: Additive nephrotoxic and neurotoxic effect with other aminoglycosides, bacitracin, cisplatin, vancomycin, amphotericin B, polymyxin B, colistin and viomycin. Enhanced toxicity with potent diuretics. May impair the absorption of other drugs. May enhance the effect of acarbose. May enhance the effect of non-depolarising muscle relaxants. May antagonise the parasympathomimetic effect of neostigmine and pyridostigmine. May increase the risk of hypocalcaemia in patients receiving bisphosphonates. May alter INR when givenwithanticoagulants. May inactivate oral typhoid vaccine.

The safe use of this preparation during pregnancy & lactation has not been established. Therefore it should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Children and Infants: This ointment is suitable for use in children at the same dose as adults, but the dose should be reduced in infants. This ointment is not recommended for use in neonates.

Keep all medicines out of reach of children. Store in a cool and dry place, protected from light.

This is indicated in the treatment of topical bacterial infections. This is particularly effective in atopic, contact stasis and infections, eczematoid dermatitis, neurodermatitis, eczema, anogenital pruritus. It may also be useful as an adjunct in certain pyodermas, such as impetigo, during specific systemic antibiotic therapy for these infections.

Ophthalmic and Topical antibacterial products

Bacitracin inhibits bacterial cell wall synthesis and is active against many gram-positive bacteria (e.g. staphylococci, streptococci, corynebacteria and Clostridia) and some gram-negative species (e.g. Neisseria and Haemophilus influenzae). They are often found in combinations in topical preparations as broad spectrum antibacterial agents.

Neomycin, an aminoglyoside with antimicrobial spectrum similar to gentamicin, binds to the 30S subunits of the bacterial ribosome, inhibiting protein synthesis and thereby disrupting DNA synthesis. It is active against many gram negative aerobes and against some strains of staphylococci.

Ointment: Before use, the area for application should be cleaned gently. Derbis such as pus or crusts should be removed from the affected area. Apply two to three times daily to the affected skin area.

Dusting Powder: Antibiotic powder is a non- sterile dusting powder and used for superficial skin infections. A light dusting of the powder to be applied to the affected skin area upto 4 times daily.

This preparation is usually well tolerated. In rare cases, allergic reactions may be occurred.

Hypersensitivity to any of its components.

Bacitracin & Neomycin antibiotic powder should not be used to large open wounds or to severely injured skin or on areas that exude large volumes of fluid as hard crusts may form. Since this skin ointment contains Neomycin, it should not be used for the treatment of otitis external when the eardrum is perforated because of risk of ototoxicity.

Patients considering self-medication with a topical anti-infective for deep or puncture wounds, animal bites, or serious burns should be advised to first consult a physician. Patients using the preparations for the prevention of infection in minor skin injuries (e.g., cuts, scrapes, burns) should be advised to discontinue the topical anti-infective preparation and consult a physician if the condition persists or worsens; it should not be used for longer than 1 week unless directed by a physician.

Bacitracin Zinc: Increased risk of nephrotoxicity when used with other nephrotoxic drugs. May enhance the action of neuromuscular-blocking agents.

Neomycin Sulphate: Additive nephrotoxic and neurotoxic effect with other aminoglycosides, bacitracin, cisplatin, vancomycin, amphotericin B, polymyxin B, colistin and viomycin. Enhanced toxicity with potent diuretics. May impair the absorption of other drugs. May enhance the effect of acarbose. May enhance the effect of non-depolarising muscle relaxants. May antagonise the parasympathomimetic effect of neostigmine and pyridostigmine. May increase the risk of hypocalcaemia in patients receiving bisphosphonates. May alter INR when givenwithanticoagulants. May inactivate oral typhoid vaccine.

The safe use of this preparation during pregnancy & lactation has not been established. Therefore it should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Children and Infants: This ointment is suitable for use in children at the same dose as adults, but the dose should be reduced in infants. This ointment is not recommended for use in neonates.

Keep all medicines out of reach of children. Store in a cool and dry place, protected from light.

Nebivolol is indicated in-

• Hypertension
• Treatment of essential hypertension
• Chronic heart failure (CHF)
• Treatment of stable mild and moderate chronic heart failure in addition to standard therapies in elderly patients.

Beta-adrenoceptor blocking drugs, Beta-blockers

Nebivolol is a β adrenergic receptor blocking agent. Nebivolol inhibits both β1 and β1 adrenergic receptors. Nebivolol lacks intrinsic sympathomimetic and membrane stabilizing activity at therapeutically relevant concentrations. At clinically relevant doses, Nebivolol does not demonstrate β1-adrenergic receptor blockade activity. Various metabolites, including glucuronides, contribute to beta-blocking activity.

Mode of Action of Nebivolol involved include:

• decreased heart rate
• decreased myocardia contractility
• diminution of tonic sympathetic outflow to the periphery from cerebral vasomotor centers
• suppression of renin activity and
• vasodilation and decreased peripheral vascular resistance

Pharmacokinetics: Nebivolol is metabolized by a number of routes, including glucuronidation and hydroxylation by CYP2D6. The active isomer (d-nebivolol) has an effective half-life of about 12 hours in CYP2D6 extensive metabolizers (most people), and 19 hours in poor metabolizers and exposure to d-nebivolol is substantially increased in poor metabolizers. This has less importance than usual, however, because the metabolites, including the hydroxyl metabolite and glucuronides (the predominant circulating metabolites), contribute to b blocking activity.

Absorption and Distribution: Absorption of Nebivolol is similar to an oral solution. Mean peak plasma nebivolol concentrations occur approximately 1.5 to 4 hours post-dosing in EMs and PMs. Food does not alter the pharmacokinetics of nebivolol. Nebivolol may be administered without regard to meals. The in vitro human plasma protein binding of nebivolol is approximately 98%, mostly to albumin, and is independent of nebivolol concentrations.

Metabolism and Excretion: Nebivolol is predominantly metabolized via direct glucuronidation of parent and to a lesser extent via N-dealkylation and oxidation via cytochrome P450 2D6. After a single oral administration of 14C-nebivolol, 38% of the dose was recovered in urine and 44% in feces for EMs and 67% in urine and 13% in feces for PMs.

Digoxin: Concomitant administration of Nebivolol (10 mg once daily) and digoxin (0.25 mg once daily) for 10 days in 14 healthy adult individuals resulted in no significant changes in the pharmacokinetics of digoxin or nebivolol.

Warfarin: Administration of Nebivolol (10 mg once daily for 10 days) led to no significant changes in the pharmacokinetics of nebivolol or R- or S-warfarin following a single 10 mg dose of warfarin. Similarly, nebivolol has no significant effects on the anticoagulant activity of warfarin, as assessed by Prothrombin time and INR profiles from 0 to 144 hours after a single 10 mg warfarin dose in 12 healthy adult volunteers. The starting dose should be reduced in patients with moderate hepatic impairment. No formal studies have been performed in patients with severe hepatic impairment and nebivolol should be contraindicated for these patients.

The dose of Nebivolol should be individualized to the needs of the patient. For most patients, the recommended starting dose is 5 mg once daily, with or without food, as monotherapy or in combination with other agents. For patients requiring further reduction in blood pressure, the dose can be increased at 2-week intervals up to 40 mg. A more frequent dosing regimen is unlikely to be beneficial.

Headache, nausea and bradycardia.

Nebivolol is contraindicated in patients with severe bradycardia, heart block greater than first degree, cardiogenic shock, decompensated cardiac failure, sick sinus syndrome (unless a permanent pacemaker is in place), or severe hepatic impairment (Child-Pugh >B), and in patients who are hypersensitive to any component of this product.

Abrupt Cessation of Therapy: Patients with coronary artery disease treated with Nebivolol should be advised against abrupt discontinuation of therapy. Severe exacerbation of angina and the occurrence of myocardial infarction and ventricular arrhythmias have been reported in patients with coronary artery disease following the abrupt discontinuation of therapy with β-blockers. Myocardial infarction and ventricular arrhythmias may occur with or without preceding exacerbation of the angina pectoris. Even patients without overt coronary artery disease should be cautioned against interruption or abrupt discontinuation of therapy. As with other β-blockers, when discontinuation of Nebivolol is planned, patients should be carefully observed and advised to minimize physical activity. Nebivolol should be tapered over 1 to 2 weeks when possible. If the angina worsens or acute coronary insufficiency develops, it is recommended that Nebivolol be promptly reinstituted, at least temporarily.

Cardiac Failure: Sympathetic stimulation is a vital component supporting circulatory function in the setting of congestive heart failure, and (β-blockade may result in further depression of myocardial contractility and precipitate more severe failure. In patients who have compensated congestive heart failure, Nebivolol should be administered cautiously. If heart failure worsens, discontinuation of Nebivolol should be considered.

Angina and Acute Myocardial Infarction: Nebivolol was not studied in patients with angina pectoris or who had a recent Ml.

Bronchospastic Diseases: In general, patients with bronchospastic diseases should not receive (3-blockers.

Anesthesia and Major Surgery: If Nebivolol is to be continued perioperatively, patients should be closely monitored when anesthetic agents which depress myocardial function, such as ether, cyclopropane, and trichloroethylene, are used. If β-blocking therapy is withdrawn prior to major surgery, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures. The β-blocking effects of Nebivolol can be reversed by β-agonists, e.g., dobutamine or isoproterenol. However, such patients may be subject to protracted severe hypotension. Additionally, difficulty in restarting and maintaining the heartbeat has been reported with (β-blockers).

Diabetes and Hypoglycemia: β-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective β-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. It is not known whether nebivolol has these effects. Patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be advised about these possibilities and nebivolol should be used with caution.

Thyrotoxicosis: β-blockers may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of β-blockers may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate a thyroid storm.

Peripheral Vascular Disease: β-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Caution should be exercised in these patients.

Non-dihydropyridine Calcium Channel Blockers: Because of significant negative inotropic and chronotropic effects in patients treated with β-blockers and calcium channel blockers of the verapamil and diltiazem type, caution should be used in patients treated concomitantly with these agents and ECG and blood pressure should be monitored.

Nebivolol should be used with care when myocardial depressants or inhibitors of AV conduction, such as certain calcium antagonists (particularly of the phenylalkylamine [verapamil] and benzothiazepine [diltiazem] classes), or antiarrhythmic agents, such as disopyramide, are used concurrently. Both digitalis glycosides and β-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.

Nebivolol should not be combined with other β-blockers. Patients receiving catecholamine-depleting drugs, such as reserpine or guanethidine, should be closely monitored, because the added β-blocking action of Nebivolol may produce excessive reduction of sympathetic activity. In patients who are receiving Nebivolol and clonidine, Nebivolol should be discontinued for several days before the gradual tapering of clonidine.

CYP2D6 Inhibitors: Use caution when Nebivolol is co-administered with CYP2D6 inhibitors (quinidine, propafenone, fluoxetine, paroxetine, etc.)

Impaired Renal Function: Nebivolol should be used with caution in patients with severe renal impairment because of decreased renal clearance. Nebivolol has not been studied in patients receiving dialysis.

Impaired Hepatic Function: Nebivolol should be used with caution in patients with moderate hepatic impairment because of decreased metabolism. Since Nebivolol has not been studied in patients with severe hepatic impairment, Nebivolol is contraindicated in this population. 

Risk of Anaphylactic Reactions: While taking β-blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated challenges either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.

Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.

Nebivolol is indicated in-

• Hypertension
• Treatment of essential hypertension
• Chronic heart failure (CHF)
• Treatment of stable mild and moderate chronic heart failure in addition to standard therapies in elderly patients.

Beta-adrenoceptor blocking drugs, Beta-blockers

Nebivolol is a β adrenergic receptor blocking agent. Nebivolol inhibits both β1 and β1 adrenergic receptors. Nebivolol lacks intrinsic sympathomimetic and membrane stabilizing activity at therapeutically relevant concentrations. At clinically relevant doses, Nebivolol does not demonstrate β1-adrenergic receptor blockade activity. Various metabolites, including glucuronides, contribute to beta-blocking activity.

Mode of Action of Nebivolol involved include:

• decreased heart rate
• decreased myocardia contractility
• diminution of tonic sympathetic outflow to the periphery from cerebral vasomotor centers
• suppression of renin activity and
• vasodilation and decreased peripheral vascular resistance

Pharmacokinetics: Nebivolol is metabolized by a number of routes, including glucuronidation and hydroxylation by CYP2D6. The active isomer (d-nebivolol) has an effective half-life of about 12 hours in CYP2D6 extensive metabolizers (most people), and 19 hours in poor metabolizers and exposure to d-nebivolol is substantially increased in poor metabolizers. This has less importance than usual, however, because the metabolites, including the hydroxyl metabolite and glucuronides (the predominant circulating metabolites), contribute to b blocking activity.

Absorption and Distribution: Absorption of Nebivolol is similar to an oral solution. Mean peak plasma nebivolol concentrations occur approximately 1.5 to 4 hours post-dosing in EMs and PMs. Food does not alter the pharmacokinetics of nebivolol. Nebivolol may be administered without regard to meals. The in vitro human plasma protein binding of nebivolol is approximately 98%, mostly to albumin, and is independent of nebivolol concentrations.

Metabolism and Excretion: Nebivolol is predominantly metabolized via direct glucuronidation of parent and to a lesser extent via N-dealkylation and oxidation via cytochrome P450 2D6. After a single oral administration of 14C-nebivolol, 38% of the dose was recovered in urine and 44% in feces for EMs and 67% in urine and 13% in feces for PMs.

Digoxin: Concomitant administration of Nebivolol (10 mg once daily) and digoxin (0.25 mg once daily) for 10 days in 14 healthy adult individuals resulted in no significant changes in the pharmacokinetics of digoxin or nebivolol.

Warfarin: Administration of Nebivolol (10 mg once daily for 10 days) led to no significant changes in the pharmacokinetics of nebivolol or R- or S-warfarin following a single 10 mg dose of warfarin. Similarly, nebivolol has no significant effects on the anticoagulant activity of warfarin, as assessed by Prothrombin time and INR profiles from 0 to 144 hours after a single 10 mg warfarin dose in 12 healthy adult volunteers. The starting dose should be reduced in patients with moderate hepatic impairment. No formal studies have been performed in patients with severe hepatic impairment and nebivolol should be contraindicated for these patients.

The dose of Nebivolol should be individualized to the needs of the patient. For most patients, the recommended starting dose is 5 mg once daily, with or without food, as monotherapy or in combination with other agents. For patients requiring further reduction in blood pressure, the dose can be increased at 2-week intervals up to 40 mg. A more frequent dosing regimen is unlikely to be beneficial.

Headache, nausea and bradycardia.

Nebivolol is contraindicated in patients with severe bradycardia, heart block greater than first degree, cardiogenic shock, decompensated cardiac failure, sick sinus syndrome (unless a permanent pacemaker is in place), or severe hepatic impairment (Child-Pugh >B), and in patients who are hypersensitive to any component of this product.

Abrupt Cessation of Therapy: Patients with coronary artery disease treated with Nebivolol should be advised against abrupt discontinuation of therapy. Severe exacerbation of angina and the occurrence of myocardial infarction and ventricular arrhythmias have been reported in patients with coronary artery disease following the abrupt discontinuation of therapy with β-blockers. Myocardial infarction and ventricular arrhythmias may occur with or without preceding exacerbation of the angina pectoris. Even patients without overt coronary artery disease should be cautioned against interruption or abrupt discontinuation of therapy. As with other β-blockers, when discontinuation of Nebivolol is planned, patients should be carefully observed and advised to minimize physical activity. Nebivolol should be tapered over 1 to 2 weeks when possible. If the angina worsens or acute coronary insufficiency develops, it is recommended that Nebivolol be promptly reinstituted, at least temporarily.

Cardiac Failure: Sympathetic stimulation is a vital component supporting circulatory function in the setting of congestive heart failure, and (β-blockade may result in further depression of myocardial contractility and precipitate more severe failure. In patients who have compensated congestive heart failure, Nebivolol should be administered cautiously. If heart failure worsens, discontinuation of Nebivolol should be considered.

Angina and Acute Myocardial Infarction: Nebivolol was not studied in patients with angina pectoris or who had a recent Ml.

Bronchospastic Diseases: In general, patients with bronchospastic diseases should not receive (3-blockers.

Anesthesia and Major Surgery: If Nebivolol is to be continued perioperatively, patients should be closely monitored when anesthetic agents which depress myocardial function, such as ether, cyclopropane, and trichloroethylene, are used. If β-blocking therapy is withdrawn prior to major surgery, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures. The β-blocking effects of Nebivolol can be reversed by β-agonists, e.g., dobutamine or isoproterenol. However, such patients may be subject to protracted severe hypotension. Additionally, difficulty in restarting and maintaining the heartbeat has been reported with (β-blockers).

Diabetes and Hypoglycemia: β-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective β-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. It is not known whether nebivolol has these effects. Patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be advised about these possibilities and nebivolol should be used with caution.

Thyrotoxicosis: β-blockers may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of β-blockers may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate a thyroid storm.

Peripheral Vascular Disease: β-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Caution should be exercised in these patients.

Non-dihydropyridine Calcium Channel Blockers: Because of significant negative inotropic and chronotropic effects in patients treated with β-blockers and calcium channel blockers of the verapamil and diltiazem type, caution should be used in patients treated concomitantly with these agents and ECG and blood pressure should be monitored.

Nebivolol should be used with care when myocardial depressants or inhibitors of AV conduction, such as certain calcium antagonists (particularly of the phenylalkylamine [verapamil] and benzothiazepine [diltiazem] classes), or antiarrhythmic agents, such as disopyramide, are used concurrently. Both digitalis glycosides and β-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.

Nebivolol should not be combined with other β-blockers. Patients receiving catecholamine-depleting drugs, such as reserpine or guanethidine, should be closely monitored, because the added β-blocking action of Nebivolol may produce excessive reduction of sympathetic activity. In patients who are receiving Nebivolol and clonidine, Nebivolol should be discontinued for several days before the gradual tapering of clonidine.

CYP2D6 Inhibitors: Use caution when Nebivolol is co-administered with CYP2D6 inhibitors (quinidine, propafenone, fluoxetine, paroxetine, etc.)

Impaired Renal Function: Nebivolol should be used with caution in patients with severe renal impairment because of decreased renal clearance. Nebivolol has not been studied in patients receiving dialysis.

Impaired Hepatic Function: Nebivolol should be used with caution in patients with moderate hepatic impairment because of decreased metabolism. Since Nebivolol has not been studied in patients with severe hepatic impairment, Nebivolol is contraindicated in this population. 

Risk of Anaphylactic Reactions: While taking β-blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated challenges either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.

Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.

Nebivolol is indicated in-

• Hypertension
• Treatment of essential hypertension
• Chronic heart failure (CHF)
• Treatment of stable mild and moderate chronic heart failure in addition to standard therapies in elderly patients.

Beta-adrenoceptor blocking drugs, Beta-blockers

Nebivolol is a β adrenergic receptor blocking agent. Nebivolol inhibits both β1 and β1 adrenergic receptors. Nebivolol lacks intrinsic sympathomimetic and membrane stabilizing activity at therapeutically relevant concentrations. At clinically relevant doses, Nebivolol does not demonstrate β1-adrenergic receptor blockade activity. Various metabolites, including glucuronides, contribute to beta-blocking activity.

Mode of Action of Nebivolol involved include:

• decreased heart rate
• decreased myocardia contractility
• diminution of tonic sympathetic outflow to the periphery from cerebral vasomotor centers
• suppression of renin activity and
• vasodilation and decreased peripheral vascular resistance

Pharmacokinetics: Nebivolol is metabolized by a number of routes, including glucuronidation and hydroxylation by CYP2D6. The active isomer (d-nebivolol) has an effective half-life of about 12 hours in CYP2D6 extensive metabolizers (most people), and 19 hours in poor metabolizers and exposure to d-nebivolol is substantially increased in poor metabolizers. This has less importance than usual, however, because the metabolites, including the hydroxyl metabolite and glucuronides (the predominant circulating metabolites), contribute to b blocking activity.

Absorption and Distribution: Absorption of Nebivolol is similar to an oral solution. Mean peak plasma nebivolol concentrations occur approximately 1.5 to 4 hours post-dosing in EMs and PMs. Food does not alter the pharmacokinetics of nebivolol. Nebivolol may be administered without regard to meals. The in vitro human plasma protein binding of nebivolol is approximately 98%, mostly to albumin, and is independent of nebivolol concentrations.

Metabolism and Excretion: Nebivolol is predominantly metabolized via direct glucuronidation of parent and to a lesser extent via N-dealkylation and oxidation via cytochrome P450 2D6. After a single oral administration of 14C-nebivolol, 38% of the dose was recovered in urine and 44% in feces for EMs and 67% in urine and 13% in feces for PMs.

Digoxin: Concomitant administration of Nebivolol (10 mg once daily) and digoxin (0.25 mg once daily) for 10 days in 14 healthy adult individuals resulted in no significant changes in the pharmacokinetics of digoxin or nebivolol.

Warfarin: Administration of Nebivolol (10 mg once daily for 10 days) led to no significant changes in the pharmacokinetics of nebivolol or R- or S-warfarin following a single 10 mg dose of warfarin. Similarly, nebivolol has no significant effects on the anticoagulant activity of warfarin, as assessed by Prothrombin time and INR profiles from 0 to 144 hours after a single 10 mg warfarin dose in 12 healthy adult volunteers. The starting dose should be reduced in patients with moderate hepatic impairment. No formal studies have been performed in patients with severe hepatic impairment and nebivolol should be contraindicated for these patients.

The dose of Nebivolol should be individualized to the needs of the patient. For most patients, the recommended starting dose is 5 mg once daily, with or without food, as monotherapy or in combination with other agents. For patients requiring further reduction in blood pressure, the dose can be increased at 2-week intervals up to 40 mg. A more frequent dosing regimen is unlikely to be beneficial.

Headache, nausea and bradycardia.

Nebivolol is contraindicated in patients with severe bradycardia, heart block greater than first degree, cardiogenic shock, decompensated cardiac failure, sick sinus syndrome (unless a permanent pacemaker is in place), or severe hepatic impairment (Child-Pugh >B), and in patients who are hypersensitive to any component of this product.

Abrupt Cessation of Therapy: Patients with coronary artery disease treated with Nebivolol should be advised against abrupt discontinuation of therapy. Severe exacerbation of angina and the occurrence of myocardial infarction and ventricular arrhythmias have been reported in patients with coronary artery disease following the abrupt discontinuation of therapy with β-blockers. Myocardial infarction and ventricular arrhythmias may occur with or without preceding exacerbation of the angina pectoris. Even patients without overt coronary artery disease should be cautioned against interruption or abrupt discontinuation of therapy. As with other β-blockers, when discontinuation of Nebivolol is planned, patients should be carefully observed and advised to minimize physical activity. Nebivolol should be tapered over 1 to 2 weeks when possible. If the angina worsens or acute coronary insufficiency develops, it is recommended that Nebivolol be promptly reinstituted, at least temporarily.

Cardiac Failure: Sympathetic stimulation is a vital component supporting circulatory function in the setting of congestive heart failure, and (β-blockade may result in further depression of myocardial contractility and precipitate more severe failure. In patients who have compensated congestive heart failure, Nebivolol should be administered cautiously. If heart failure worsens, discontinuation of Nebivolol should be considered.

Angina and Acute Myocardial Infarction: Nebivolol was not studied in patients with angina pectoris or who had a recent Ml.

Bronchospastic Diseases: In general, patients with bronchospastic diseases should not receive (3-blockers.

Anesthesia and Major Surgery: If Nebivolol is to be continued perioperatively, patients should be closely monitored when anesthetic agents which depress myocardial function, such as ether, cyclopropane, and trichloroethylene, are used. If β-blocking therapy is withdrawn prior to major surgery, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures. The β-blocking effects of Nebivolol can be reversed by β-agonists, e.g., dobutamine or isoproterenol. However, such patients may be subject to protracted severe hypotension. Additionally, difficulty in restarting and maintaining the heartbeat has been reported with (β-blockers).

Diabetes and Hypoglycemia: β-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective β-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. It is not known whether nebivolol has these effects. Patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be advised about these possibilities and nebivolol should be used with caution.

Thyrotoxicosis: β-blockers may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of β-blockers may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate a thyroid storm.

Peripheral Vascular Disease: β-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Caution should be exercised in these patients.

Non-dihydropyridine Calcium Channel Blockers: Because of significant negative inotropic and chronotropic effects in patients treated with β-blockers and calcium channel blockers of the verapamil and diltiazem type, caution should be used in patients treated concomitantly with these agents and ECG and blood pressure should be monitored.

Nebivolol should be used with care when myocardial depressants or inhibitors of AV conduction, such as certain calcium antagonists (particularly of the phenylalkylamine [verapamil] and benzothiazepine [diltiazem] classes), or antiarrhythmic agents, such as disopyramide, are used concurrently. Both digitalis glycosides and β-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.

Nebivolol should not be combined with other β-blockers. Patients receiving catecholamine-depleting drugs, such as reserpine or guanethidine, should be closely monitored, because the added β-blocking action of Nebivolol may produce excessive reduction of sympathetic activity. In patients who are receiving Nebivolol and clonidine, Nebivolol should be discontinued for several days before the gradual tapering of clonidine.

CYP2D6 Inhibitors: Use caution when Nebivolol is co-administered with CYP2D6 inhibitors (quinidine, propafenone, fluoxetine, paroxetine, etc.)

Impaired Renal Function: Nebivolol should be used with caution in patients with severe renal impairment because of decreased renal clearance. Nebivolol has not been studied in patients receiving dialysis.

Impaired Hepatic Function: Nebivolol should be used with caution in patients with moderate hepatic impairment because of decreased metabolism. Since Nebivolol has not been studied in patients with severe hepatic impairment, Nebivolol is contraindicated in this population. 

Risk of Anaphylactic Reactions: While taking β-blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated challenges either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.

Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.

Nebivolol is indicated in-

• Hypertension
• Treatment of essential hypertension
• Chronic heart failure (CHF)
• Treatment of stable mild and moderate chronic heart failure in addition to standard therapies in elderly patients.

Beta-adrenoceptor blocking drugs, Beta-blockers

Nebivolol is a β adrenergic receptor blocking agent. Nebivolol inhibits both β1 and β1 adrenergic receptors. Nebivolol lacks intrinsic sympathomimetic and membrane stabilizing activity at therapeutically relevant concentrations. At clinically relevant doses, Nebivolol does not demonstrate β1-adrenergic receptor blockade activity. Various metabolites, including glucuronides, contribute to beta-blocking activity.

Mode of Action of Nebivolol involved include:

• decreased heart rate
• decreased myocardia contractility
• diminution of tonic sympathetic outflow to the periphery from cerebral vasomotor centers
• suppression of renin activity and
• vasodilation and decreased peripheral vascular resistance

Pharmacokinetics: Nebivolol is metabolized by a number of routes, including glucuronidation and hydroxylation by CYP2D6. The active isomer (d-nebivolol) has an effective half-life of about 12 hours in CYP2D6 extensive metabolizers (most people), and 19 hours in poor metabolizers and exposure to d-nebivolol is substantially increased in poor metabolizers. This has less importance than usual, however, because the metabolites, including the hydroxyl metabolite and glucuronides (the predominant circulating metabolites), contribute to b blocking activity.

Absorption and Distribution: Absorption of Nebivolol is similar to an oral solution. Mean peak plasma nebivolol concentrations occur approximately 1.5 to 4 hours post-dosing in EMs and PMs. Food does not alter the pharmacokinetics of nebivolol. Nebivolol may be administered without regard to meals. The in vitro human plasma protein binding of nebivolol is approximately 98%, mostly to albumin, and is independent of nebivolol concentrations.

Metabolism and Excretion: Nebivolol is predominantly metabolized via direct glucuronidation of parent and to a lesser extent via N-dealkylation and oxidation via cytochrome P450 2D6. After a single oral administration of 14C-nebivolol, 38% of the dose was recovered in urine and 44% in feces for EMs and 67% in urine and 13% in feces for PMs.

Digoxin: Concomitant administration of Nebivolol (10 mg once daily) and digoxin (0.25 mg once daily) for 10 days in 14 healthy adult individuals resulted in no significant changes in the pharmacokinetics of digoxin or nebivolol.

Warfarin: Administration of Nebivolol (10 mg once daily for 10 days) led to no significant changes in the pharmacokinetics of nebivolol or R- or S-warfarin following a single 10 mg dose of warfarin. Similarly, nebivolol has no significant effects on the anticoagulant activity of warfarin, as assessed by Prothrombin time and INR profiles from 0 to 144 hours after a single 10 mg warfarin dose in 12 healthy adult volunteers. The starting dose should be reduced in patients with moderate hepatic impairment. No formal studies have been performed in patients with severe hepatic impairment and nebivolol should be contraindicated for these patients.

The dose of Nebivolol should be individualized to the needs of the patient. For most patients, the recommended starting dose is 5 mg once daily, with or without food, as monotherapy or in combination with other agents. For patients requiring further reduction in blood pressure, the dose can be increased at 2-week intervals up to 40 mg. A more frequent dosing regimen is unlikely to be beneficial.

Headache, nausea and bradycardia.

Nebivolol is contraindicated in patients with severe bradycardia, heart block greater than first degree, cardiogenic shock, decompensated cardiac failure, sick sinus syndrome (unless a permanent pacemaker is in place), or severe hepatic impairment (Child-Pugh >B), and in patients who are hypersensitive to any component of this product.

Abrupt Cessation of Therapy: Patients with coronary artery disease treated with Nebivolol should be advised against abrupt discontinuation of therapy. Severe exacerbation of angina and the occurrence of myocardial infarction and ventricular arrhythmias have been reported in patients with coronary artery disease following the abrupt discontinuation of therapy with β-blockers. Myocardial infarction and ventricular arrhythmias may occur with or without preceding exacerbation of the angina pectoris. Even patients without overt coronary artery disease should be cautioned against interruption or abrupt discontinuation of therapy. As with other β-blockers, when discontinuation of Nebivolol is planned, patients should be carefully observed and advised to minimize physical activity. Nebivolol should be tapered over 1 to 2 weeks when possible. If the angina worsens or acute coronary insufficiency develops, it is recommended that Nebivolol be promptly reinstituted, at least temporarily.

Cardiac Failure: Sympathetic stimulation is a vital component supporting circulatory function in the setting of congestive heart failure, and (β-blockade may result in further depression of myocardial contractility and precipitate more severe failure. In patients who have compensated congestive heart failure, Nebivolol should be administered cautiously. If heart failure worsens, discontinuation of Nebivolol should be considered.

Angina and Acute Myocardial Infarction: Nebivolol was not studied in patients with angina pectoris or who had a recent Ml.

Bronchospastic Diseases: In general, patients with bronchospastic diseases should not receive (3-blockers.

Anesthesia and Major Surgery: If Nebivolol is to be continued perioperatively, patients should be closely monitored when anesthetic agents which depress myocardial function, such as ether, cyclopropane, and trichloroethylene, are used. If β-blocking therapy is withdrawn prior to major surgery, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures. The β-blocking effects of Nebivolol can be reversed by β-agonists, e.g., dobutamine or isoproterenol. However, such patients may be subject to protracted severe hypotension. Additionally, difficulty in restarting and maintaining the heartbeat has been reported with (β-blockers).

Diabetes and Hypoglycemia: β-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective β-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. It is not known whether nebivolol has these effects. Patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be advised about these possibilities and nebivolol should be used with caution.

Thyrotoxicosis: β-blockers may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of β-blockers may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate a thyroid storm.

Peripheral Vascular Disease: β-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Caution should be exercised in these patients.

Non-dihydropyridine Calcium Channel Blockers: Because of significant negative inotropic and chronotropic effects in patients treated with β-blockers and calcium channel blockers of the verapamil and diltiazem type, caution should be used in patients treated concomitantly with these agents and ECG and blood pressure should be monitored.

Nebivolol should be used with care when myocardial depressants or inhibitors of AV conduction, such as certain calcium antagonists (particularly of the phenylalkylamine [verapamil] and benzothiazepine [diltiazem] classes), or antiarrhythmic agents, such as disopyramide, are used concurrently. Both digitalis glycosides and β-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.

Nebivolol should not be combined with other β-blockers. Patients receiving catecholamine-depleting drugs, such as reserpine or guanethidine, should be closely monitored, because the added β-blocking action of Nebivolol may produce excessive reduction of sympathetic activity. In patients who are receiving Nebivolol and clonidine, Nebivolol should be discontinued for several days before the gradual tapering of clonidine.

CYP2D6 Inhibitors: Use caution when Nebivolol is co-administered with CYP2D6 inhibitors (quinidine, propafenone, fluoxetine, paroxetine, etc.)

Impaired Renal Function: Nebivolol should be used with caution in patients with severe renal impairment because of decreased renal clearance. Nebivolol has not been studied in patients receiving dialysis.

Impaired Hepatic Function: Nebivolol should be used with caution in patients with moderate hepatic impairment because of decreased metabolism. Since Nebivolol has not been studied in patients with severe hepatic impairment, Nebivolol is contraindicated in this population. 

Risk of Anaphylactic Reactions: While taking β-blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated challenges either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.

Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.

Nebivolol is indicated in-

• Hypertension
• Treatment of essential hypertension
• Chronic heart failure (CHF)
• Treatment of stable mild and moderate chronic heart failure in addition to standard therapies in elderly patients.

Beta-adrenoceptor blocking drugs, Beta-blockers

Nebivolol is a β adrenergic receptor blocking agent. Nebivolol inhibits both β1 and β1 adrenergic receptors. Nebivolol lacks intrinsic sympathomimetic and membrane stabilizing activity at therapeutically relevant concentrations. At clinically relevant doses, Nebivolol does not demonstrate β1-adrenergic receptor blockade activity. Various metabolites, including glucuronides, contribute to beta-blocking activity.

Mode of Action of Nebivolol involved include:

• decreased heart rate
• decreased myocardia contractility
• diminution of tonic sympathetic outflow to the periphery from cerebral vasomotor centers
• suppression of renin activity and
• vasodilation and decreased peripheral vascular resistance

Pharmacokinetics: Nebivolol is metabolized by a number of routes, including glucuronidation and hydroxylation by CYP2D6. The active isomer (d-nebivolol) has an effective half-life of about 12 hours in CYP2D6 extensive metabolizers (most people), and 19 hours in poor metabolizers and exposure to d-nebivolol is substantially increased in poor metabolizers. This has less importance than usual, however, because the metabolites, including the hydroxyl metabolite and glucuronides (the predominant circulating metabolites), contribute to b blocking activity.

Absorption and Distribution: Absorption of Nebivolol is similar to an oral solution. Mean peak plasma nebivolol concentrations occur approximately 1.5 to 4 hours post-dosing in EMs and PMs. Food does not alter the pharmacokinetics of nebivolol. Nebivolol may be administered without regard to meals. The in vitro human plasma protein binding of nebivolol is approximately 98%, mostly to albumin, and is independent of nebivolol concentrations.

Metabolism and Excretion: Nebivolol is predominantly metabolized via direct glucuronidation of parent and to a lesser extent via N-dealkylation and oxidation via cytochrome P450 2D6. After a single oral administration of 14C-nebivolol, 38% of the dose was recovered in urine and 44% in feces for EMs and 67% in urine and 13% in feces for PMs.

Digoxin: Concomitant administration of Nebivolol (10 mg once daily) and digoxin (0.25 mg once daily) for 10 days in 14 healthy adult individuals resulted in no significant changes in the pharmacokinetics of digoxin or nebivolol.

Warfarin: Administration of Nebivolol (10 mg once daily for 10 days) led to no significant changes in the pharmacokinetics of nebivolol or R- or S-warfarin following a single 10 mg dose of warfarin. Similarly, nebivolol has no significant effects on the anticoagulant activity of warfarin, as assessed by Prothrombin time and INR profiles from 0 to 144 hours after a single 10 mg warfarin dose in 12 healthy adult volunteers. The starting dose should be reduced in patients with moderate hepatic impairment. No formal studies have been performed in patients with severe hepatic impairment and nebivolol should be contraindicated for these patients.

The dose of Nebivolol should be individualized to the needs of the patient. For most patients, the recommended starting dose is 5 mg once daily, with or without food, as monotherapy or in combination with other agents. For patients requiring further reduction in blood pressure, the dose can be increased at 2-week intervals up to 40 mg. A more frequent dosing regimen is unlikely to be beneficial.

Headache, nausea and bradycardia.

Nebivolol is contraindicated in patients with severe bradycardia, heart block greater than first degree, cardiogenic shock, decompensated cardiac failure, sick sinus syndrome (unless a permanent pacemaker is in place), or severe hepatic impairment (Child-Pugh >B), and in patients who are hypersensitive to any component of this product.

Abrupt Cessation of Therapy: Patients with coronary artery disease treated with Nebivolol should be advised against abrupt discontinuation of therapy. Severe exacerbation of angina and the occurrence of myocardial infarction and ventricular arrhythmias have been reported in patients with coronary artery disease following the abrupt discontinuation of therapy with β-blockers. Myocardial infarction and ventricular arrhythmias may occur with or without preceding exacerbation of the angina pectoris. Even patients without overt coronary artery disease should be cautioned against interruption or abrupt discontinuation of therapy. As with other β-blockers, when discontinuation of Nebivolol is planned, patients should be carefully observed and advised to minimize physical activity. Nebivolol should be tapered over 1 to 2 weeks when possible. If the angina worsens or acute coronary insufficiency develops, it is recommended that Nebivolol be promptly reinstituted, at least temporarily.

Cardiac Failure: Sympathetic stimulation is a vital component supporting circulatory function in the setting of congestive heart failure, and (β-blockade may result in further depression of myocardial contractility and precipitate more severe failure. In patients who have compensated congestive heart failure, Nebivolol should be administered cautiously. If heart failure worsens, discontinuation of Nebivolol should be considered.

Angina and Acute Myocardial Infarction: Nebivolol was not studied in patients with angina pectoris or who had a recent Ml.

Bronchospastic Diseases: In general, patients with bronchospastic diseases should not receive (3-blockers.

Anesthesia and Major Surgery: If Nebivolol is to be continued perioperatively, patients should be closely monitored when anesthetic agents which depress myocardial function, such as ether, cyclopropane, and trichloroethylene, are used. If β-blocking therapy is withdrawn prior to major surgery, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures. The β-blocking effects of Nebivolol can be reversed by β-agonists, e.g., dobutamine or isoproterenol. However, such patients may be subject to protracted severe hypotension. Additionally, difficulty in restarting and maintaining the heartbeat has been reported with (β-blockers).

Diabetes and Hypoglycemia: β-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective β-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. It is not known whether nebivolol has these effects. Patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be advised about these possibilities and nebivolol should be used with caution.

Thyrotoxicosis: β-blockers may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of β-blockers may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate a thyroid storm.

Peripheral Vascular Disease: β-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Caution should be exercised in these patients.

Non-dihydropyridine Calcium Channel Blockers: Because of significant negative inotropic and chronotropic effects in patients treated with β-blockers and calcium channel blockers of the verapamil and diltiazem type, caution should be used in patients treated concomitantly with these agents and ECG and blood pressure should be monitored.

Nebivolol should be used with care when myocardial depressants or inhibitors of AV conduction, such as certain calcium antagonists (particularly of the phenylalkylamine [verapamil] and benzothiazepine [diltiazem] classes), or antiarrhythmic agents, such as disopyramide, are used concurrently. Both digitalis glycosides and β-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.

Nebivolol should not be combined with other β-blockers. Patients receiving catecholamine-depleting drugs, such as reserpine or guanethidine, should be closely monitored, because the added β-blocking action of Nebivolol may produce excessive reduction of sympathetic activity. In patients who are receiving Nebivolol and clonidine, Nebivolol should be discontinued for several days before the gradual tapering of clonidine.

CYP2D6 Inhibitors: Use caution when Nebivolol is co-administered with CYP2D6 inhibitors (quinidine, propafenone, fluoxetine, paroxetine, etc.)

Impaired Renal Function: Nebivolol should be used with caution in patients with severe renal impairment because of decreased renal clearance. Nebivolol has not been studied in patients receiving dialysis.

Impaired Hepatic Function: Nebivolol should be used with caution in patients with moderate hepatic impairment because of decreased metabolism. Since Nebivolol has not been studied in patients with severe hepatic impairment, Nebivolol is contraindicated in this population. 

Risk of Anaphylactic Reactions: While taking β-blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated challenges either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.

Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.

Nebivolol is indicated in-

• Hypertension
• Treatment of essential hypertension
• Chronic heart failure (CHF)
• Treatment of stable mild and moderate chronic heart failure in addition to standard therapies in elderly patients.

Beta-adrenoceptor blocking drugs, Beta-blockers

Nebivolol is a β adrenergic receptor blocking agent. Nebivolol inhibits both β1 and β1 adrenergic receptors. Nebivolol lacks intrinsic sympathomimetic and membrane stabilizing activity at therapeutically relevant concentrations. At clinically relevant doses, Nebivolol does not demonstrate β1-adrenergic receptor blockade activity. Various metabolites, including glucuronides, contribute to beta-blocking activity.

Mode of Action of Nebivolol involved include:

• decreased heart rate
• decreased myocardia contractility
• diminution of tonic sympathetic outflow to the periphery from cerebral vasomotor centers
• suppression of renin activity and
• vasodilation and decreased peripheral vascular resistance

Pharmacokinetics: Nebivolol is metabolized by a number of routes, including glucuronidation and hydroxylation by CYP2D6. The active isomer (d-nebivolol) has an effective half-life of about 12 hours in CYP2D6 extensive metabolizers (most people), and 19 hours in poor metabolizers and exposure to d-nebivolol is substantially increased in poor metabolizers. This has less importance than usual, however, because the metabolites, including the hydroxyl metabolite and glucuronides (the predominant circulating metabolites), contribute to b blocking activity.

Absorption and Distribution: Absorption of Nebivolol is similar to an oral solution. Mean peak plasma nebivolol concentrations occur approximately 1.5 to 4 hours post-dosing in EMs and PMs. Food does not alter the pharmacokinetics of nebivolol. Nebivolol may be administered without regard to meals. The in vitro human plasma protein binding of nebivolol is approximately 98%, mostly to albumin, and is independent of nebivolol concentrations.

Metabolism and Excretion: Nebivolol is predominantly metabolized via direct glucuronidation of parent and to a lesser extent via N-dealkylation and oxidation via cytochrome P450 2D6. After a single oral administration of 14C-nebivolol, 38% of the dose was recovered in urine and 44% in feces for EMs and 67% in urine and 13% in feces for PMs.

Digoxin: Concomitant administration of Nebivolol (10 mg once daily) and digoxin (0.25 mg once daily) for 10 days in 14 healthy adult individuals resulted in no significant changes in the pharmacokinetics of digoxin or nebivolol.

Warfarin: Administration of Nebivolol (10 mg once daily for 10 days) led to no significant changes in the pharmacokinetics of nebivolol or R- or S-warfarin following a single 10 mg dose of warfarin. Similarly, nebivolol has no significant effects on the anticoagulant activity of warfarin, as assessed by Prothrombin time and INR profiles from 0 to 144 hours after a single 10 mg warfarin dose in 12 healthy adult volunteers. The starting dose should be reduced in patients with moderate hepatic impairment. No formal studies have been performed in patients with severe hepatic impairment and nebivolol should be contraindicated for these patients.

The dose of Nebivolol should be individualized to the needs of the patient. For most patients, the recommended starting dose is 5 mg once daily, with or without food, as monotherapy or in combination with other agents. For patients requiring further reduction in blood pressure, the dose can be increased at 2-week intervals up to 40 mg. A more frequent dosing regimen is unlikely to be beneficial.

Headache, nausea and bradycardia.

Nebivolol is contraindicated in patients with severe bradycardia, heart block greater than first degree, cardiogenic shock, decompensated cardiac failure, sick sinus syndrome (unless a permanent pacemaker is in place), or severe hepatic impairment (Child-Pugh >B), and in patients who are hypersensitive to any component of this product.

Abrupt Cessation of Therapy: Patients with coronary artery disease treated with Nebivolol should be advised against abrupt discontinuation of therapy. Severe exacerbation of angina and the occurrence of myocardial infarction and ventricular arrhythmias have been reported in patients with coronary artery disease following the abrupt discontinuation of therapy with β-blockers. Myocardial infarction and ventricular arrhythmias may occur with or without preceding exacerbation of the angina pectoris. Even patients without overt coronary artery disease should be cautioned against interruption or abrupt discontinuation of therapy. As with other β-blockers, when discontinuation of Nebivolol is planned, patients should be carefully observed and advised to minimize physical activity. Nebivolol should be tapered over 1 to 2 weeks when possible. If the angina worsens or acute coronary insufficiency develops, it is recommended that Nebivolol be promptly reinstituted, at least temporarily.

Cardiac Failure: Sympathetic stimulation is a vital component supporting circulatory function in the setting of congestive heart failure, and (β-blockade may result in further depression of myocardial contractility and precipitate more severe failure. In patients who have compensated congestive heart failure, Nebivolol should be administered cautiously. If heart failure worsens, discontinuation of Nebivolol should be considered.

Angina and Acute Myocardial Infarction: Nebivolol was not studied in patients with angina pectoris or who had a recent Ml.

Bronchospastic Diseases: In general, patients with bronchospastic diseases should not receive (3-blockers.

Anesthesia and Major Surgery: If Nebivolol is to be continued perioperatively, patients should be closely monitored when anesthetic agents which depress myocardial function, such as ether, cyclopropane, and trichloroethylene, are used. If β-blocking therapy is withdrawn prior to major surgery, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures. The β-blocking effects of Nebivolol can be reversed by β-agonists, e.g., dobutamine or isoproterenol. However, such patients may be subject to protracted severe hypotension. Additionally, difficulty in restarting and maintaining the heartbeat has been reported with (β-blockers).

Diabetes and Hypoglycemia: β-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective β-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. It is not known whether nebivolol has these effects. Patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be advised about these possibilities and nebivolol should be used with caution.

Thyrotoxicosis: β-blockers may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of β-blockers may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate a thyroid storm.

Peripheral Vascular Disease: β-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Caution should be exercised in these patients.

Non-dihydropyridine Calcium Channel Blockers: Because of significant negative inotropic and chronotropic effects in patients treated with β-blockers and calcium channel blockers of the verapamil and diltiazem type, caution should be used in patients treated concomitantly with these agents and ECG and blood pressure should be monitored.

Nebivolol should be used with care when myocardial depressants or inhibitors of AV conduction, such as certain calcium antagonists (particularly of the phenylalkylamine [verapamil] and benzothiazepine [diltiazem] classes), or antiarrhythmic agents, such as disopyramide, are used concurrently. Both digitalis glycosides and β-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.

Nebivolol should not be combined with other β-blockers. Patients receiving catecholamine-depleting drugs, such as reserpine or guanethidine, should be closely monitored, because the added β-blocking action of Nebivolol may produce excessive reduction of sympathetic activity. In patients who are receiving Nebivolol and clonidine, Nebivolol should be discontinued for several days before the gradual tapering of clonidine.

CYP2D6 Inhibitors: Use caution when Nebivolol is co-administered with CYP2D6 inhibitors (quinidine, propafenone, fluoxetine, paroxetine, etc.)

Impaired Renal Function: Nebivolol should be used with caution in patients with severe renal impairment because of decreased renal clearance. Nebivolol has not been studied in patients receiving dialysis.

Impaired Hepatic Function: Nebivolol should be used with caution in patients with moderate hepatic impairment because of decreased metabolism. Since Nebivolol has not been studied in patients with severe hepatic impairment, Nebivolol is contraindicated in this population. 

Risk of Anaphylactic Reactions: While taking β-blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated challenges either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.

Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.

Nebivolol is indicated in-

• Hypertension
• Treatment of essential hypertension
• Chronic heart failure (CHF)
• Treatment of stable mild and moderate chronic heart failure in addition to standard therapies in elderly patients.

Beta-adrenoceptor blocking drugs, Beta-blockers

Nebivolol is a β adrenergic receptor blocking agent. Nebivolol inhibits both β1 and β1 adrenergic receptors. Nebivolol lacks intrinsic sympathomimetic and membrane stabilizing activity at therapeutically relevant concentrations. At clinically relevant doses, Nebivolol does not demonstrate β1-adrenergic receptor blockade activity. Various metabolites, including glucuronides, contribute to beta-blocking activity.

Mode of Action of Nebivolol involved include:

• decreased heart rate
• decreased myocardia contractility
• diminution of tonic sympathetic outflow to the periphery from cerebral vasomotor centers
• suppression of renin activity and
• vasodilation and decreased peripheral vascular resistance

Pharmacokinetics: Nebivolol is metabolized by a number of routes, including glucuronidation and hydroxylation by CYP2D6. The active isomer (d-nebivolol) has an effective half-life of about 12 hours in CYP2D6 extensive metabolizers (most people), and 19 hours in poor metabolizers and exposure to d-nebivolol is substantially increased in poor metabolizers. This has less importance than usual, however, because the metabolites, including the hydroxyl metabolite and glucuronides (the predominant circulating metabolites), contribute to b blocking activity.

Absorption and Distribution: Absorption of Nebivolol is similar to an oral solution. Mean peak plasma nebivolol concentrations occur approximately 1.5 to 4 hours post-dosing in EMs and PMs. Food does not alter the pharmacokinetics of nebivolol. Nebivolol may be administered without regard to meals. The in vitro human plasma protein binding of nebivolol is approximately 98%, mostly to albumin, and is independent of nebivolol concentrations.

Metabolism and Excretion: Nebivolol is predominantly metabolized via direct glucuronidation of parent and to a lesser extent via N-dealkylation and oxidation via cytochrome P450 2D6. After a single oral administration of 14C-nebivolol, 38% of the dose was recovered in urine and 44% in feces for EMs and 67% in urine and 13% in feces for PMs.

Digoxin: Concomitant administration of Nebivolol (10 mg once daily) and digoxin (0.25 mg once daily) for 10 days in 14 healthy adult individuals resulted in no significant changes in the pharmacokinetics of digoxin or nebivolol.

Warfarin: Administration of Nebivolol (10 mg once daily for 10 days) led to no significant changes in the pharmacokinetics of nebivolol or R- or S-warfarin following a single 10 mg dose of warfarin. Similarly, nebivolol has no significant effects on the anticoagulant activity of warfarin, as assessed by Prothrombin time and INR profiles from 0 to 144 hours after a single 10 mg warfarin dose in 12 healthy adult volunteers. The starting dose should be reduced in patients with moderate hepatic impairment. No formal studies have been performed in patients with severe hepatic impairment and nebivolol should be contraindicated for these patients.

The dose of Nebivolol should be individualized to the needs of the patient. For most patients, the recommended starting dose is 5 mg once daily, with or without food, as monotherapy or in combination with other agents. For patients requiring further reduction in blood pressure, the dose can be increased at 2-week intervals up to 40 mg. A more frequent dosing regimen is unlikely to be beneficial.

Headache, nausea and bradycardia.

Nebivolol is contraindicated in patients with severe bradycardia, heart block greater than first degree, cardiogenic shock, decompensated cardiac failure, sick sinus syndrome (unless a permanent pacemaker is in place), or severe hepatic impairment (Child-Pugh >B), and in patients who are hypersensitive to any component of this product.

Abrupt Cessation of Therapy: Patients with coronary artery disease treated with Nebivolol should be advised against abrupt discontinuation of therapy. Severe exacerbation of angina and the occurrence of myocardial infarction and ventricular arrhythmias have been reported in patients with coronary artery disease following the abrupt discontinuation of therapy with β-blockers. Myocardial infarction and ventricular arrhythmias may occur with or without preceding exacerbation of the angina pectoris. Even patients without overt coronary artery disease should be cautioned against interruption or abrupt discontinuation of therapy. As with other β-blockers, when discontinuation of Nebivolol is planned, patients should be carefully observed and advised to minimize physical activity. Nebivolol should be tapered over 1 to 2 weeks when possible. If the angina worsens or acute coronary insufficiency develops, it is recommended that Nebivolol be promptly reinstituted, at least temporarily.

Cardiac Failure: Sympathetic stimulation is a vital component supporting circulatory function in the setting of congestive heart failure, and (β-blockade may result in further depression of myocardial contractility and precipitate more severe failure. In patients who have compensated congestive heart failure, Nebivolol should be administered cautiously. If heart failure worsens, discontinuation of Nebivolol should be considered.

Angina and Acute Myocardial Infarction: Nebivolol was not studied in patients with angina pectoris or who had a recent Ml.

Bronchospastic Diseases: In general, patients with bronchospastic diseases should not receive (3-blockers.

Anesthesia and Major Surgery: If Nebivolol is to be continued perioperatively, patients should be closely monitored when anesthetic agents which depress myocardial function, such as ether, cyclopropane, and trichloroethylene, are used. If β-blocking therapy is withdrawn prior to major surgery, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures. The β-blocking effects of Nebivolol can be reversed by β-agonists, e.g., dobutamine or isoproterenol. However, such patients may be subject to protracted severe hypotension. Additionally, difficulty in restarting and maintaining the heartbeat has been reported with (β-blockers).

Diabetes and Hypoglycemia: β-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective β-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. It is not known whether nebivolol has these effects. Patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be advised about these possibilities and nebivolol should be used with caution.

Thyrotoxicosis: β-blockers may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of β-blockers may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate a thyroid storm.

Peripheral Vascular Disease: β-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Caution should be exercised in these patients.

Non-dihydropyridine Calcium Channel Blockers: Because of significant negative inotropic and chronotropic effects in patients treated with β-blockers and calcium channel blockers of the verapamil and diltiazem type, caution should be used in patients treated concomitantly with these agents and ECG and blood pressure should be monitored.

Nebivolol should be used with care when myocardial depressants or inhibitors of AV conduction, such as certain calcium antagonists (particularly of the phenylalkylamine [verapamil] and benzothiazepine [diltiazem] classes), or antiarrhythmic agents, such as disopyramide, are used concurrently. Both digitalis glycosides and β-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.

Nebivolol should not be combined with other β-blockers. Patients receiving catecholamine-depleting drugs, such as reserpine or guanethidine, should be closely monitored, because the added β-blocking action of Nebivolol may produce excessive reduction of sympathetic activity. In patients who are receiving Nebivolol and clonidine, Nebivolol should be discontinued for several days before the gradual tapering of clonidine.

CYP2D6 Inhibitors: Use caution when Nebivolol is co-administered with CYP2D6 inhibitors (quinidine, propafenone, fluoxetine, paroxetine, etc.)

Impaired Renal Function: Nebivolol should be used with caution in patients with severe renal impairment because of decreased renal clearance. Nebivolol has not been studied in patients receiving dialysis.

Impaired Hepatic Function: Nebivolol should be used with caution in patients with moderate hepatic impairment because of decreased metabolism. Since Nebivolol has not been studied in patients with severe hepatic impairment, Nebivolol is contraindicated in this population. 

Risk of Anaphylactic Reactions: While taking β-blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated challenges either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.

Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.