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Vitamin-C Preparations

vitamin C, the water-soluble vitamin, is readily absorbed from the gastrointestinal tract and is widely distributed in the body tissues. It is believed to be involved in biological oxidations and reductions used in cellular respiration. It is essential for the synthesis of collagen and intracellular material. Vitamin C deficiency develops when the dietary intake is inadequate and when increased demand is not fulfilled. Deficiency leads to the development of well defined syndrome known as scurvy, which is characterized by capillary fragility, bleeding (especially from small blood vessels and the gums), anaemia, cartilage and bone lesions and slow healing of wounds.

Oral administration-

• For the prevention of scurvy: 1 tablet daily
• For the treatment of scurvy: 1-2 tablets daily; but dose may be increased depending on the severity of the condition.
• For the reduction of risk of stroke in the elderly: 1-2 tablets daily.
• In other cases: 1 tablet daily or as directed by the physician.
• Maximum safe dose is 2000 mg daily in divided doses.

Parenteral administration-

• Vitamin C is usually administered orally. When oral administration is not feasible or when malabsorption is suspected, the drug may be administered IM, IV, or subcutaneously. When given parenterally, utilization of the vitamin reportedly is best after IM administration and that is the preferred parenteral route.
• For intravenous injection, dilution into a large volume parenteral such as Normal Saline, Water for Injection, or Glucose is recommended to minimize the adverse reactions associated with intravenous injection.
• The average protective dose of vitamin C for adults is 70 to 150 mg daily. In the presence of scurvy, doses of 300 mg to 1 g daily are recommended. However, as much as 6 g has been administered parenterally to normal adults without evidence of toxicity.
• To enhance wound healing, doses of 300 to 500 mg daily for a week or ten days both preoperatively and postoperatively are generally considered adequate, although considerably larger amounts have been recommended. In the treatment of burns, doses are governed by the extent of tissue injury. For severe burns, daily doses of 1 to 2 g are recommended. In other conditions in which the need for vitamin C is increased, three to five times the daily optimum allowances appear to be adequate.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever the solution and container permit.

Vitamin C has little toxicity and only mega-doses of vitamin C may cause diarrhoea, abdominal bloating, iron over-absorption that is harmful in patients with thalassaemia, sideroblastic anemia, and haemochromatosis; hyperoxaluria, hyperuricosuria, and hemolysis in patients with glucose-6 phosphate dehydrogenase deficiency. A pregnant woman taking more than 5 gm/day may suffer fetal abortion.

Ingestion of megadose (more than 1000 mg daily) of vitamin C during pregnancy has resulted in scurvy in neonates. Vitamin C in mega-doses has been contraindicated for patients with hyperoxaluria. Vitamin C itself is a reactive substance in the redox system and can give rise to false positive reactions in certain analytical tests for glucose, uric acid, creatine and occult blood.

Potentially hazardous interactions: Ascorbic acid is incompatible in solution with aminophylline, bleomycin, erythromycin, lactobionate, nafcillin, nitrofurantoin sodium, conjugated oestrogen, sodium bicarbonate, sulphafurazole diethanolamine, chloramphenicol sodium succinate, chlorthiazide sodium and hydrocortisone sodium succinate.

Useful interactions: Ascorbic acid increases the apparent half-life of paracetamol and enhances iron absorption from the gastrointestinal tract.

The drug is safe in normal doses in pregnant women, but a daily intake of 5 gm or more is reported to have caused abortion. The drug may be taken safely during lactation.

Should be stored in a dry place below 30˚C.

Cilostazol is indicated for the reduction of symptoms of intermittent claudication, as indicated by an increased walking distance.

Peripheral Vasodilator drugs: Intermittent Claudication

Cilostazol is a preparation of Cilostazol which is a quinolinone derivative. The mechanism of action is to specifically inhibit cellular phosphodiesterase III (PDE III) and suppress cAMP degradation with a resultant increase in cAMP in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation.

The recommended dosage of Cilostazol is 100 mg bid, taken at least half an hour before or two hours after breakfast and dinner. A dose of 50 mg bid should be considered during coadministration of Fluconazole, Ketoconazole, Itraconazole, Erythromycin, Clarithromycin, Fluvoxamine, Fluoxetine, Nefazodone, Sertraline and Diltiazem.

Pediatric use: The safety and effectiveness of Cilostazol in pediatric patients have not been established.

The most common side effects are headache, diarrhoea, vomiting, leg cramps, rash etc. The less frequent side effects are anorexia and edema.

Cilostazol is contraindicated in patients with congestive heart failure of any severity. Cilostazol is also contraindicated in patients with known or suspected hypersensitivity to any of its components.

Cilostazol should be used with caution in patients with any degree of heart failure. There is no information with respect to the efficacy or safety of the concurrent use of Cilostazol and Clopidogrel.

Pharmacokinetic studies have demonstrated that Omeprazole and Erythromycin significantly increased the systemic exposure of Cilostazol and/or its major metabolites. Population pharmacokinetic studies showed higher concentrations of Cilostazol among patients concurrently treated with Diltiazem.

There are no adequate and well controlled studies in pregnant women. Transfer of Cilostazol into milk has been reported in experimental animals. Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue Cilostazol.

Store in a cool & dry place, protected from light and moisture.

Cilostazol is indicated for the reduction of symptoms of intermittent claudication, as indicated by an increased walking distance.

Peripheral Vasodilator drugs: Intermittent Claudication

Cilostazol is a preparation of Cilostazol which is a quinolinone derivative. The mechanism of action is to specifically inhibit cellular phosphodiesterase III (PDE III) and suppress cAMP degradation with a resultant increase in cAMP in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation.

The recommended dosage of Cilostazol is 100 mg bid, taken at least half an hour before or two hours after breakfast and dinner. A dose of 50 mg bid should be considered during coadministration of Fluconazole, Ketoconazole, Itraconazole, Erythromycin, Clarithromycin, Fluvoxamine, Fluoxetine, Nefazodone, Sertraline and Diltiazem.

Pediatric use: The safety and effectiveness of Cilostazol in pediatric patients have not been established.

The most common side effects are headache, diarrhoea, vomiting, leg cramps, rash etc. The less frequent side effects are anorexia and edema.

Cilostazol is contraindicated in patients with congestive heart failure of any severity. Cilostazol is also contraindicated in patients with known or suspected hypersensitivity to any of its components.

Cilostazol should be used with caution in patients with any degree of heart failure. There is no information with respect to the efficacy or safety of the concurrent use of Cilostazol and Clopidogrel.

Pharmacokinetic studies have demonstrated that Omeprazole and Erythromycin significantly increased the systemic exposure of Cilostazol and/or its major metabolites. Population pharmacokinetic studies showed higher concentrations of Cilostazol among patients concurrently treated with Diltiazem.

There are no adequate and well controlled studies in pregnant women. Transfer of Cilostazol into milk has been reported in experimental animals. Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue Cilostazol.

Store in a cool & dry place, protected from light and moisture.

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.

This is indicated in-

• Peripheral arterial occlusive disease (PAOD) of arteriosclerotic or diabetic origin (e.g. with intermittent claudication and rest pain)
• Trophic lesions (e.g. leg ulcers and gangrene)
• Cerebral vascular diseases 
• Circulatory disturbances of the eye in conjunction with degenerative vascular disorders.

Peripheral Vasodilator drugs: Intermittent Claudication

Pentoxifylline and its metabolites improve the flow properties of blood by decreasing its viscosity. In patients with chronic peripheral arterial disease, this increases blood flow to the affected microcirculation and enhances tissue oxygenation. The precise mode of action of pentoxifylline and the sequence of events leading to clinical improvement are still to be defined. Pentoxifylline administration has been shown to produce dose-related hemorrheologic effects, lowering blood viscosity, and improving erythrocyte flexibility. Leukocyte properties of hemorrheologic importance have been modified in animal and in vitro human studies. Pentoxifylline has been shown to increase leukocyte deformability and to inhibit neutrophil adhesion and activation. Tissue oxygen levels have been shown to be significantly increased by therapeutic doses of pentoxifylline in patients with peripheral arterial disease.

In principle, dosage is based on the type and severity of the circulatory disorders and on how the individual patient tolerates the drug. Usual dosage is 400 mg pentoxifylline 2 to 3 times daily. Tablets are to be swallowed whole during or shortly after a meal with sufficient amounts of liquid (approx. ½ glass).

These adverse reactions have been reported in clinical trials or post-marketing-

• Investigations: Transaminases increased (Transaminase elevation), Blood pressure decreased (Fall in blood pressure)
• Cardiac disorders: Arrhythmia (Cardiac arrhythmia), Tachycardia, Angina Pectoris
• Blood and lymphatic system disorders: Thrombocytopenia (Thrombopenia), Leucopenia/neutropenia
• Nervous system disorders: Dizziness, headache, meningitis aseptic (Aseptic meningitis)
• Gastrointestinal disorders: Gastrointestinal disorder (Gastrointestinal complaints), Epigastric discomfort (Gastric pressure), Abdominal distension (Fullness), Nausea, Vomiting, Diarrhoea, Constipation, Hypersalivation
• Skin and subcutaneous tissue disorders: Pruritus, Erythema (Reddening of the skin), Urticaria, Rash
• Vascular disorders: Hot fush (Flushes), Haemorrhage (Bleedings)
• Immune system disorders: Anaphylactic reaction, Anaphylactoid reaction, Angioedema (Angioneurotic edema), Bronchospasm, Anaphylactic shock (shock)
• Hepatobiliary disorders: Cholestasis (Intrahepatic cholestasis)
• Psychiatric disorders: Agitation, Sleep disorder (Sleep disturbances)

Pentoxifylline must not be used:

• in patients with hypersensitivity to pentoxifylline, other methylxanthines or any of the excipients of Pentoxifylline.
• in patients with massive bleeding (risk of increased bleeding).
• in patients with extensive retinal bleeding (risk of increased bleeding).

At the first signs of an anaphylactic/anaphylactoid reaction, Pentoxifylline must be discontinued or the infusion be halted immediately, and a physician must be informed. Particularly careful monitoring is required:

• in patients with severe cardiac arrhythmias
• in patients with myocardial infarction
• in hypotensive patients
• in patients with impaired renal function (creatinine clearance below 30 ml/min)
• in patients with severely impaired liver function
• in patients with increased bleeding
• in patients treated concomitantly with pentoxifylline and anti-vitamin K or platelet aggregation inhibitors
• in patients treated concomitantly with pentoxifylline and antidiabetic agents
• in patients treated concomitantly with pentoxifylline and ciprofoxacin
• in patients treated concomitantly with pentoxifylline and theophylline

Insufficient experience has been gained concerning use in pregnancy. Therefore, it is recommended that Pentoxifylline is not used during pregnancy. Pentoxifylline passes into breast milk in minute quantities. Because insufficient experience has been gained, the physician must carefully weigh the possible risks and benefits before administering Pentoxifylline in breast-feeding women.

Hepatic impairment: A dose reduction- guided by individual tolerance- is necessary in patients with severely impaired liver function.

Renal impairment: In patients with impairment of renal function (creatinine clearance below 30 mL/min) a dose reduction by approx. 30% to 50% may be necessary guided by individual tolerance.

Other: Treatment must be started at low-dose levels in hypotensive patients or patients whose circulation is unstable as well as in patients, who would be at particular risk from a reduction in blood pressure (e.g. patients with severe coronary heart disease or relevant stenoses of blood vessels supplying the brain); in such cases, the dose must only be increased gradually.

Initial symptoms of acute overdose with pentoxifylline may be nausea, dizziness, tachycardia or a fall in blood pressure. Furthermore, signs such as fever, agitation, flush, loss of consciousness, areflexia, tonic -clonic convulsions and as a sign of gastrointestinal bleeding - coffee-ground vomiting may occur. No specific antidote is known. If ingestion has only just taken place, attempts may be made to prevent further systemic absorption of the active ingredient by primary elimination of the toxin (e.g. gastric lavage) or by delaying its absorption (e.g. activated charcoal).

Keep in a cool and dry place, away from light. Do not use later than date of expiry. Keep all medicine out of the reach of children. To be dispensed only on the prescription of a registered physician.

Calcium-channel blockers

Amlodipine is a dihydropyridine calcium-channel blocker, with a long duration of action, used for the treatment of hypertension and angina pectoris. Amlodipine influences the myocardial cells, the cells within the specialized conducting system of the heart, and the cells of vascular smooth muscle. Administration of Amlodipine results primarily in vasodilation, with reduced peripheral resistance, blood pressure and afterload, increased coronary blood flow and a reflex increase in coronary heart rate. This in turn results in an increase in myocardial oxygen supply and cardiac output.

Hypertension: Usual dose is 5 mg once daily. The maximum dose is 10 mg once daily. Elderly patients with hepatic insufficiency may be started on 2.5 mg once daily; this dose may also be used when adding Amlodipine to other antihypertensive therapy.

Angina (Chronic stable or Vasospastic): 5 to 10 mg, using the lower dose for elderly and in patients with hepatic insufficiency. Most patients require 10 mg.

Administrations: May be taken without regard to meals.

The most common adverse effects of amlodipine are associated with vasodilatory action, such as dizziness, flushing, headache, hypotension and peripheral edema. Gastrointestinal disturbances, increased micturition frequency, lethargy, eye pain and mental depression may also occur. A paradoxical increase in ischaemic chest pain may occur at the start of the treatment and in a few patients excessive fall in blood pressure has led to cerebral or myocardial ischaemia or transient blindness. Rashes, fever and abnormalities in liver function due to hypersensitivity reaction of Amlodipine may occur.

Hypersensitivity to dihydropyridine derivatives. Pregnant woman.

Precaution should be taken in patients with hepatic impairment and during pregnancy and breast feeding.

Drug Interactions-

• Potentially hazardous interactions: Little or no data are available in patients with markedly impaired cardiac left ventricular function; however, as with other calcium antagonist drugs, the combination of Amlodipine and p-blockers should be avoided in such patients.

Other Significant Interactions-

• Digoxin: Absence of any interaction between Amlodipine and Digoxin in healthy volunteers has been documented in a controlled clinical study.
• Cimetidine: An unpublished clinical study indicated no interaction between, Amlodipine and Cimetidine in healthy volunteers.
• Warfarin: An unpublished clinical study in healthy volunteers indicates that Amlodipine did not significantly alter the effect of Warfarin on prothrombin time.
• Food: Food does not alter the rate or extent of absorption of Amlodipine.

Pregnancy Category C. There are no adequate and well-controlled studies of Amlodipine in pregnant women. Amlodipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is not known whether Amlodipine is excreted in human milk. In the absence of this information, it is recommended that nursing be discontinued while Amlodipine is administered.

Children with hypertension from 6 years to 17 years of age: 2.5 mg once daily as a starting dose, up-titrated to 5 mg once daily if blood pressure goal is not achieved after 4 weeks. Doses in excess of 5 mg daily have not been studied in pediatric patients.

Children under 6 years old:  The effect of amlodipine on blood pressure in patients less than 6 years of age is not known.

Elderly: Amlodipine used at similar doses in elderly or younger patients is equally well tolerated. Normal dosage regimens are recommended in the elderly, but increase of the dosage should take place with care.

Renal impairment: Changes in amlodipine plasma concentrations are not correlated with degree of renal impairment, therefore the normal dosage is recommended. Amlodipine is not dialysable.

Hepatic impairment: Dosage recommendations have not been established in patients with mild to moderate hepatic impairment; therefore dose selection should be cautions and should start at the lower end of the dosing range. The pharmacokinetics of Amlodipine have not been studied in severe hepatic impairment. Amlodipine should be initiated at the lowest dose (2.5 mg once daily) and titrated slowly in patients with severe hepatic impairment.

Symptoms: Available data suggest that large overdosage could result in excessive peripheral vasodilatation and possibly reflex tachycardia. Marked and probably prolonged systemic hypotension up to and including shock with fatal outcome have been reported.

Management: Clinically significant hypotension due to amlodipine overdosage calls for active cardiovascular support including frequent monitoring of cardiac and respiratory function, elevation of extremities, and attention to circulating fluid volume and urine output. 

A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade. Gastric lavage may be worthwhile in some cases. In healthy volunteers the use of charcoal up to 2 hours after administration of amlodipine 10 mg has been shown to reduce the absorption rate of amlodipine. Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit.

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

Calcium-channel blockers

Amlodipine is a dihydropyridine calcium-channel blocker, with a long duration of action, used for the treatment of hypertension and angina pectoris. Amlodipine influences the myocardial cells, the cells within the specialized conducting system of the heart, and the cells of vascular smooth muscle. Administration of Amlodipine results primarily in vasodilation, with reduced peripheral resistance, blood pressure and afterload, increased coronary blood flow and a reflex increase in coronary heart rate. This in turn results in an increase in myocardial oxygen supply and cardiac output.

Hypertension: Usual dose is 5 mg once daily. The maximum dose is 10 mg once daily. Elderly patients with hepatic insufficiency may be started on 2.5 mg once daily; this dose may also be used when adding Amlodipine to other antihypertensive therapy.

Angina (Chronic stable or Vasospastic): 5 to 10 mg, using the lower dose for elderly and in patients with hepatic insufficiency. Most patients require 10 mg.

Administrations: May be taken without regard to meals.

The most common adverse effects of amlodipine are associated with vasodilatory action, such as dizziness, flushing, headache, hypotension and peripheral edema. Gastrointestinal disturbances, increased micturition frequency, lethargy, eye pain and mental depression may also occur. A paradoxical increase in ischaemic chest pain may occur at the start of the treatment and in a few patients excessive fall in blood pressure has led to cerebral or myocardial ischaemia or transient blindness. Rashes, fever and abnormalities in liver function due to hypersensitivity reaction of Amlodipine may occur.

Hypersensitivity to dihydropyridine derivatives. Pregnant woman.

Precaution should be taken in patients with hepatic impairment and during pregnancy and breast feeding.

Drug Interactions-

• Potentially hazardous interactions: Little or no data are available in patients with markedly impaired cardiac left ventricular function; however, as with other calcium antagonist drugs, the combination of Amlodipine and p-blockers should be avoided in such patients.

Other Significant Interactions-

• Digoxin: Absence of any interaction between Amlodipine and Digoxin in healthy volunteers has been documented in a controlled clinical study.
• Cimetidine: An unpublished clinical study indicated no interaction between, Amlodipine and Cimetidine in healthy volunteers.
• Warfarin: An unpublished clinical study in healthy volunteers indicates that Amlodipine did not significantly alter the effect of Warfarin on prothrombin time.
• Food: Food does not alter the rate or extent of absorption of Amlodipine.

Pregnancy Category C. There are no adequate and well-controlled studies of Amlodipine in pregnant women. Amlodipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is not known whether Amlodipine is excreted in human milk. In the absence of this information, it is recommended that nursing be discontinued while Amlodipine is administered.

Children with hypertension from 6 years to 17 years of age: 2.5 mg once daily as a starting dose, up-titrated to 5 mg once daily if blood pressure goal is not achieved after 4 weeks. Doses in excess of 5 mg daily have not been studied in pediatric patients.

Children under 6 years old:  The effect of amlodipine on blood pressure in patients less than 6 years of age is not known.

Elderly: Amlodipine used at similar doses in elderly or younger patients is equally well tolerated. Normal dosage regimens are recommended in the elderly, but increase of the dosage should take place with care.

Renal impairment: Changes in amlodipine plasma concentrations are not correlated with degree of renal impairment, therefore the normal dosage is recommended. Amlodipine is not dialysable.

Hepatic impairment: Dosage recommendations have not been established in patients with mild to moderate hepatic impairment; therefore dose selection should be cautions and should start at the lower end of the dosing range. The pharmacokinetics of Amlodipine have not been studied in severe hepatic impairment. Amlodipine should be initiated at the lowest dose (2.5 mg once daily) and titrated slowly in patients with severe hepatic impairment.

Symptoms: Available data suggest that large overdosage could result in excessive peripheral vasodilatation and possibly reflex tachycardia. Marked and probably prolonged systemic hypotension up to and including shock with fatal outcome have been reported.

Management: Clinically significant hypotension due to amlodipine overdosage calls for active cardiovascular support including frequent monitoring of cardiac and respiratory function, elevation of extremities, and attention to circulating fluid volume and urine output. 

A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade. Gastric lavage may be worthwhile in some cases. In healthy volunteers the use of charcoal up to 2 hours after administration of amlodipine 10 mg has been shown to reduce the absorption rate of amlodipine. Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit.

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

This is indicated in-

• Patients with essential hypertension
• Patients with angina pectoris & hypertension as co-existing diseases
• ln post Ml patients
• ln patients with refractory angina pectoris where nitrate therapy has failed.

Combined antihypertensive preparations

This is a fixed-dose combination of Amlodipine and Atenolol. Amlodipine is a dihydropyridine calcium antagonist that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle; it has a greater effect on vascular smooth muscle than on cardiac muscle. Amlodipine is a peripheral vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure. Amlodipine reduces tone, decreases coronary vasoreactivity and lowers cardiac demand by reducing afterload.

Atenolol is a cardioselective beta-blocker. The cardio-selectivity is dose-related. Atenolol causes a reduction in blood pressure by lowering cardiac output, decreasing the plasma renin activity and sympathetic outflow from CNS. Atenolol also causes a reduction in myocardial oxygen demand by virtue of its negative inotropic and negative chronotropic effects.

The recommended dosage is Amlodipine and Atenolol 5/25 mg tablet once daily. If necessary, the dosage may be increased to 5/25 mg two tablets daily or as advised by the physicians. The dosage however should be individualized.

The combination of Amlodipine and Atenolol is well tolerated. Overall side-effects include
fatigue, headache, edema, nausea, drowsiness, anxiety and depression.

Hypersensitivity to either component, sinus bradycardia, second and higher degrees of heart block, cardiogenic shock, hypotension, congestive heart failure, poor left ventricular function.

Bronchospasm: The combination should be used with caution in patients with airway obstruction.

Renal impairment: The combination can be used in patients with renal impairment. However, caution may be necessary if the creatinine clearance is less than 30 ml/min because of possible reduction in the excretion of unchanged Atenolol.

Hepatic impairment: Caution may be necessary in the use of the combination in patients with severe liver damage because of prolongation of the elimination half-life of Amlodipine.

Drug withdrawal: Since coronary heart disease may exist without being recognized, patients should be warned against stopping the drug suddenly. Any discontinuation should be gradual and under observation.

Disopyramide: Atenolol reduces the clearance of disopyramide by 20%. Additive negative inotropic effects on the heart may be produced.

Ampicillin: at doses of 1 gm and above may reduce Atenolol levels.

Oral antidiabetics and insulin: Beta-blockers may decrease tissue sensitivity to insulin and inhibit insulin secretion e.g. in response to oral antidiabetics. Atenolol has less potential for these actions.

The combination should be used during pregnancy only if the expected benefit outweighs the potential fetal risk. The combination should not be used by nursing mothers. If its use is considered necessary, breast-feeding should be stopped.

Though not documented, hypotension and less frequently congestive cardiac failure may occur in cases of overdosage. Unabsorbed drugs may be removed by gastric lavage or administration of activated charcoal. Symptomatic treatment is suggested.

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

Calcium Dobesilate is indicated for the treatment of hemorrhoidal syndrome, microcirculation disorders of arteovenous origin, clinical signs of chronic venous insufficiency in the lower limbs (pain, cramps, paresthesia, edema, stasis, dermotosis) and in the particular microangiopathy like diabetic retinopathy. It is also indicated in superficial thrombophlebitis as adjuvant therapy.

Vaso Protective

Calcium dobesilate acts selectively on the capillary walls regulating their physiological functions of resistance and permeability. It lowers blood viscosity and restores normal blood flow. This action is beneficial in all cases of capillary fragility due to metabolic disturbances (constitutional or acquired), and surgical stress or induced by certain medicines.

Calcium Dobesilate capsule once or twice daily should be taken with the main meal. Treatment duration, which generally between a few weeks to several months, depends on the disease and its evolution. Dosage should be adapted individually according to the severity of the disease.

Rarely gastrointestinal disorders including nausea and diarrhea, skin reactions, fever, articular pain and in very rare cases agranulocytosis have been reported. These reactions are generally spontaneously reversible after treatment withdrawal.

Hypersensitivity. Pregnancy and lactation.

Dosage should be reduced in case of severe renal insufficiency requiring dialysis. In patient with agranulocytosis, this medication can decrease the number of white blood cells which affect the body’s ability to fight against various infections. If patients experience flu-like symptoms such as cough, sore throat, fever and others, they are advised to seek medical care as soon as possible.

The safety of Calcium Dobesilate during pregnancy and lactation has not been established. As it is not known whether calcium dobesilate crosses the placental barrier in humans, the drug should be administered during pregnancy only if the benefit to the mother outweighs the potential risk to the fetus. Avoid breastfeeding while using this medicine.

The clinical signs of a possible overdose are not known. If overdose occurs, seek medical advice immediately.

Store in a cool and dry place, away from light. Keep out of the reach of children.

Preparations for Ophthalmic diagnosis

Tropicamide binds to and blocks the receptors in the muscles of the eye (muscarinic receptor M4). Tropicamide acts by blocking the responses of the iris sphincter muscle to the iris and ciliary muscles to cholinergic stimulation, producing dilation of the pupil and paralysis of the ciliary muscle.

Phenylephrine Hydrochloride is a selective alpha-1 agonist, which causes mydriasis without cycloplegia. It tends to reduce intraocular lesion by vasoconstrictor action.

Uveitis: 1-2 drops bid-qid or as required.

Diagnostic purpose/Pre-operative purpose: Instill 1-2 drops in the eye(s) 15-20 minutes before examination. If examination is not conducted within 20–30 minutes, an additional drop may be placed in the eye(s) to prolong the effect.

Elevated IOP (occasionally), stinging, blurred vision, tachycardia, photophobia, headache, parasympathetic stimulation and allergic reactions. Systemic effects include arrhythmias, hypertension and coronary artery spasm.

This medication is contraindicated in these following cases

• Patients with hypersensitivity to any of the components and narrow angles or narrow angle glaucoma.
• Low birth weight infants and some elderly adults with severe arteriosclerotic cardiovascular or cerebrovascular disease.
• During intraocular operative procedures when the corneal epithelial barrier has been disturbed.

Caution should be taken when administered with, or upto 21days after administration of monoamine oxidase (MAO) inhibitors as exaggerated adrenergic effects may result.

The possibility of psychotic reactions and behavioral disturbances should be considered in patients who are hypersensitive to anticholinergic drugs.

Use with extreme caution in infants.

Tropicamide may interfere with the antihypertensive action of carbachol, pilocarpine or ophthalmic cholinesterase inhibitors.

The safety of this medication during pregnancy or lactation has not been established.

Excessive use in children and in certain susceptible individuals may produce systemic toxic symptoms.

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. 

Trimetazidine Dihydrochloride is indicated in adults as add-on therapy for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled by or intolerant to first-line antianginal therapies.

Other Anti-anginal & Anti-ischaemic drugs

Trimetazidine Dihydrochloride is the first 3- keto acyl CoA thiolase inhibitor (KAT), a metabolic anti-ischemic agent with proven benefits for all coronary patients. Trimetazidine Dihydrochloride inhibits fatty acid pathway by inhibiting 3-keto acyl CoA thiolase enzyme and transfers oxygen to glucose pathway. Since glucose pathway is more efficient in producing energy, the same oxygen produces more energy and makes the heart more active. Moreover, the aerobic oxidation of glucose stops production of lactic acid, which prevents angina pectoris.

The recommended dose of Trimetazidine is 35 mg twice daily or 20 mg tablet thrice daily during meals. The benefit of the treatment should be assessed after three months and Trimetazidine should be discontinued if there is no treatment response.

Trimetazidine is safe and well tolerated. The Common side effects associated with Trimetazidine are dizziness, headache, abdominal pain, diarrhoea, dyspepsia, nausea, vomiting, rash, pruritus, urticaria and asthenia

Trimetazidine is contraindicated in patients who have hypersensitivity to the active substance or to any of the excipients. It is also is contraindicated in patients with Parkinson’s disease, parkinsonian symptoms, tremors, restless legs movement disorders, severe renal impairment.

Trimetazidine is not a curative treatment for angina attacks, nor an initial treatment for unstable angina pectoris. It is also not a treatment for myocardial infarction.

No drug interaction so far has been reported. In particular, no interaction has been reported with beta-blockers, calcium antagonists, nitrates, heparin, hypolipidemic agents or digitalis preparation.

There is no data on the use of Trimetazidine in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. As a precautionary measure, it is preferable to avoid the use of Trimetazidine during pregnancy. It is unknown whether Trimetazidine is excreted in human milk. A risk to the newborns/infants cannot be excluded. Trimetazidine should not be used during breast-feeding.

Keep in a dry place away from light and heat. Keep out of the reach of children.

Regional anesthesia

Bupivacaineis a long acting anaesthetic agent of the amide type. Bupivacaine & Dextrosehas a rapid onset of action and long duration. The duration of analgesia in the T10-T12 segments is 2-3 hours. Bupivacaine Hydrochloride produces a moderate muscular relaxation of the lower extremities lasting 2-2.5 hours. The motor blockade of the abdominal muscles makes the solution suitable for performance of abdominal surgery lasting 45-60 minutes.

The doses recommended below should be regarded as a guide for use in the average adult. Spinal anaesthesia for surgery: 2-4 ml (10-20 mg Bupivacaine hydrochloride). The spread of anaesthesia obtained with Bupivacaine depends on several factors including the volume of the solutions and the position if the patients during and following the injection. When injected in the L3-L4 intervertebral space with the patient in the sitting position, 3 ml of Bupivacaine spreads to the T7- T10 spinal segments. With the patient receiving the injection in the horizontal position and then turned supine, the blockade spine spreads to T4-T7 spinal segments. It should be understood that the level of spinal anaesthetic can be unpredictable in a given patient.

The adverse reaction profile for Bupivacaine is similar to those for other long acting local anesthetics administered intrathecally. Adverse reactions caused by the drug are difficult to distinguish from the physiological effects of the nerve block (e.g. decrease in blood pressure, bradycardia, temporary urinary retention), events caused directly (e.g. nerve trauma) or indirectly (e.g. epidural abscess) by the needle puncture or events associated to cerebrospinal leakage (eg. postdural puncture headache).

Bupivacaine in Dextrose is contraindicated in patients with a known hypersensitivity to it or to any local anaesthetic agent of the amide type. The following conditions preclude the use of spinal anaesthesia: Severe hemorrhage, severe hypotension or shock and arrhythmias, such as complete heart block, which severely restrict cardiac output,Local infection at the site of proposed lumbar puncture ,Septicemia.

Bupivacaine should be given cautiously to the elderly, the debilitated patients and to children, to patients with epilepsy, respiratory impairment, impaired cardiac conduction, bradycardia, severe shock; porphyria; myasthenia gravis. Myocardial depression may be more severe and more resistant to treatment.

Bupivacaine should be used with care in patients receiving antiarrhythmic drugs with local anaesthetic activity, as their toxic effects may be additive. Phenothiazines and Butyrophenones may reduce or reverse the pressor effect of epinephrine.

It is reasonable to assume that a large number of pregnant women and women of child-bearing age have been given Bupivacaine. No specific disturbances to the reproductive process have so far been reported, e.g. no increased incidence of malformations. It should be noted that the dose should be reduced in patients in the late stages of pregnancy

With recommended doses, Bupivacaine enters breast milk in such small quantities that there is generally no risk of affecting the breast feed child. At maternal serum levels of up to 0.45 µg/ml produced by the epidural use of Bupivacaine for vaginal delivery, Bupivacaine could not be detected in breast milk during the first 24 hours after delivery (detection limit 0.02 µg/ml).

Use in children: Bupivacaine Hydrochloride is not recommended in patients younger than 18 years of age.

Use in elderly and renal impairment: Patients in poor general condition due to ageing or other compromising factors such as partial or complete heart conduction block, advanced liver or renal dysfunction require special attention, although regional anesthesia may be the optimal choice for surgery in these patients.

Acute emergencies from local anaesthetics are generally related to high plasma levels encountered during therapeutic use or to underventilation (and perhaps apnea) secondary to upward extension of spinal anaesthesia. Hypotension is commonly encountered during the conduct of spinal anaesthesia due to relaxation of sympathetic tone, and sometimes, contributory mechanical obstruction of venous return.

Store in a cool and dry place. Protect from light.

Other Anti-anginal & Anti-ischaemic drugs, Statins

Atorvastatin is a selective inhibitor of HMG-CoA reductase. This enzyme is the rate-limiting enzyme responsible for the conversion of HMG-CoA to mevalonate, a precursor of sterols, including cholesterol. Atorvastatin lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and increases the number of hepatic LDL receptors on the cell surface for enhanced uptake and catabolism of LDL.

Primary hypercholesterolaemia and combined hyperlipidaemia-

• Adults: Usually 10 mg once daily; if necessary, may be increased at intervals of at least 4 weeks to max. 80 mg once daily.
• Child (10-18 years): Initially 10 mg once daily, increased if necessary at intervals of at least 4 weeks to usual max. 20 mg once daily.

Familial hypercholesterolaemia-

• Adults: Initially 10 mg daily, increased at intervals of at least 4 weeks to 40 mg once daily; if necessary, further increased to max. 80 mg once daily (or 40 mg once daily combined with anion-exchange resin in heterozygous familial hypercholesterolaemia).
• Child (10-18 years): Initially 10 mg once daily, increased if necessary at intervals of at least 4 weeks to usual max. 80 mg once daily.

Prevention of cardiovascular events-

• Adults: Initially 10 mg once daily adjusted according to response.

Atorvastatin is generally well-tolerated. The most frequent side effects related to Atorvastatin are constipation, flatulence, dyspepsia, abdominal pain. Other side effects includes infection, headache, back pain, rash, asthenia, arthralgia, myalgia.

Atorvastatin should not be used in patient with hypersensitivity to any component of this medication. Atorvastatin is contraindicated in active liver disease or unexplained persistent elevations of serum transaminases. It is also contraindicated in patient with history of serious adverse reaction to prior administration of HMG-CoA reductase inhibitors.

Liver effects: Liver function tests should be performed before the initiation of treatment and periodically thereafter. Atorvastatin should be used with caution in patients who consume substantial quantities of alcohol or have a history of liver disease. Atorvastatin therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected.

The risk of myopathy during treatment with Atorvastatin is increased with concurrent administration of cyclosporin, fibric acid derivatives, erythromycin, azole antifungals and niacin. No clinically significant interactions were seen when Atorvastatin was administered with antihypertensives or hypoglycemic agents. Patients should be closely monitored if Atorvastatin is added to digoxin, erythromycin, oral contraceptives, colestipol, antacid and warfarin.

Pregnancy: Atorvastatin is contraindicated during pregnancy. Safety in pregnant women has not been established. No controlled clinical trials with atorvastatin have been conducted in pregnant women. Rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors have been received. Animal studies have shown toxicity to reproduction. Maternal treatment with atorvastatin may reduce the fetal levels of mevalonate which is a precursor of cholesterol biosynthesis. Atorvastatin should not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with atorvastatin should be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant

Lactation: It is not known whether atorvastatin or its metabolites are excreted in human milk. In rats, plasma concentrations of atorvastatin and its active metabolites are similar to those in milk. Because of the potential for serious adverse reactions, women taking atorvastatin should not breastfeed their infants. Atorvastatin is contraindicated during breastfeeding.

Hepatic impairment: Atorvastatin should be used with caution in patients with hepatic impairment.

Pediatric use: For patients aged 10 years and above, the recommended starting dose of atorvastatin is 10 mg per day with titration up to 20 mg per day. Atorvastatin is not indicated in the treatment of patients below the age of 10 years.

Specific treatment is not available for atorvastatin overdose. The patient should be treated symptomatically and supportive measures instituted, as required. Liver function tests should be performed and serum CK levels should be monitored. Due to extensive atorvastatin binding to plasma proteins, hemodialysis is not expected to significantly enhance atorvastatin clearance.

Keep in a dry place away from light and heat. Keep out of the reach of children.

Other Anti-anginal & Anti-ischaemic drugs, Statins

Atorvastatin is a selective inhibitor of HMG-CoA reductase. This enzyme is the rate-limiting enzyme responsible for the conversion of HMG-CoA to mevalonate, a precursor of sterols, including cholesterol. Atorvastatin lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and increases the number of hepatic LDL receptors on the cell surface for enhanced uptake and catabolism of LDL.

Primary hypercholesterolaemia and combined hyperlipidaemia-

• Adults: Usually 10 mg once daily; if necessary, may be increased at intervals of at least 4 weeks to max. 80 mg once daily.
• Child (10-18 years): Initially 10 mg once daily, increased if necessary at intervals of at least 4 weeks to usual max. 20 mg once daily.

Familial hypercholesterolaemia-

• Adults: Initially 10 mg daily, increased at intervals of at least 4 weeks to 40 mg once daily; if necessary, further increased to max. 80 mg once daily (or 40 mg once daily combined with anion-exchange resin in heterozygous familial hypercholesterolaemia).
• Child (10-18 years): Initially 10 mg once daily, increased if necessary at intervals of at least 4 weeks to usual max. 80 mg once daily.

Prevention of cardiovascular events-

• Adults: Initially 10 mg once daily adjusted according to response.

Atorvastatin is generally well-tolerated. The most frequent side effects related to Atorvastatin are constipation, flatulence, dyspepsia, abdominal pain. Other side effects includes infection, headache, back pain, rash, asthenia, arthralgia, myalgia.

Atorvastatin should not be used in patient with hypersensitivity to any component of this medication. Atorvastatin is contraindicated in active liver disease or unexplained persistent elevations of serum transaminases. It is also contraindicated in patient with history of serious adverse reaction to prior administration of HMG-CoA reductase inhibitors.

Liver effects: Liver function tests should be performed before the initiation of treatment and periodically thereafter. Atorvastatin should be used with caution in patients who consume substantial quantities of alcohol or have a history of liver disease. Atorvastatin therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected.

The risk of myopathy during treatment with Atorvastatin is increased with concurrent administration of cyclosporin, fibric acid derivatives, erythromycin, azole antifungals and niacin. No clinically significant interactions were seen when Atorvastatin was administered with antihypertensives or hypoglycemic agents. Patients should be closely monitored if Atorvastatin is added to digoxin, erythromycin, oral contraceptives, colestipol, antacid and warfarin.

Pregnancy: Atorvastatin is contraindicated during pregnancy. Safety in pregnant women has not been established. No controlled clinical trials with atorvastatin have been conducted in pregnant women. Rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors have been received. Animal studies have shown toxicity to reproduction. Maternal treatment with atorvastatin may reduce the fetal levels of mevalonate which is a precursor of cholesterol biosynthesis. Atorvastatin should not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with atorvastatin should be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant

Lactation: It is not known whether atorvastatin or its metabolites are excreted in human milk. In rats, plasma concentrations of atorvastatin and its active metabolites are similar to those in milk. Because of the potential for serious adverse reactions, women taking atorvastatin should not breastfeed their infants. Atorvastatin is contraindicated during breastfeeding.

Hepatic impairment: Atorvastatin should be used with caution in patients with hepatic impairment.

Pediatric use: For patients aged 10 years and above, the recommended starting dose of atorvastatin is 10 mg per day with titration up to 20 mg per day. Atorvastatin is not indicated in the treatment of patients below the age of 10 years.

Specific treatment is not available for atorvastatin overdose. The patient should be treated symptomatically and supportive measures instituted, as required. Liver function tests should be performed and serum CK levels should be monitored. Due to extensive atorvastatin binding to plasma proteins, hemodialysis is not expected to significantly enhance atorvastatin clearance.

Keep in a dry place away from light and heat. Keep out of the reach of children.

Trimetazidine Dihydrochloride is indicated in adults as add-on therapy for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled by or intolerant to first-line antianginal therapies.

Other Anti-anginal & Anti-ischaemic drugs

Trimetazidine Dihydrochloride is the first 3- keto acyl CoA thiolase inhibitor (KAT), a metabolic anti-ischemic agent with proven benefits for all coronary patients. Trimetazidine Dihydrochloride inhibits fatty acid pathway by inhibiting 3-keto acyl CoA thiolase enzyme and transfers oxygen to glucose pathway. Since glucose pathway is more efficient in producing energy, the same oxygen produces more energy and makes the heart more active. Moreover, the aerobic oxidation of glucose stops production of lactic acid, which prevents angina pectoris.

The recommended dose of Trimetazidine is 35 mg twice daily or 20 mg tablet thrice daily during meals. The benefit of the treatment should be assessed after three months and Trimetazidine should be discontinued if there is no treatment response.

Trimetazidine is safe and well tolerated. The Common side effects associated with Trimetazidine are dizziness, headache, abdominal pain, diarrhoea, dyspepsia, nausea, vomiting, rash, pruritus, urticaria and asthenia

Trimetazidine is contraindicated in patients who have hypersensitivity to the active substance or to any of the excipients. It is also is contraindicated in patients with Parkinson’s disease, parkinsonian symptoms, tremors, restless legs movement disorders, severe renal impairment.

Trimetazidine is not a curative treatment for angina attacks, nor an initial treatment for unstable angina pectoris. It is also not a treatment for myocardial infarction.

No drug interaction so far has been reported. In particular, no interaction has been reported with beta-blockers, calcium antagonists, nitrates, heparin, hypolipidemic agents or digitalis preparation.

There is no data on the use of Trimetazidine in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. As a precautionary measure, it is preferable to avoid the use of Trimetazidine during pregnancy. It is unknown whether Trimetazidine is excreted in human milk. A risk to the newborns/infants cannot be excluded. Trimetazidine should not be used during breast-feeding.

Keep in a dry place away from light and heat. Keep out of the reach of children.

Trimetazidine Dihydrochloride is indicated in adults as add-on therapy for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled by or intolerant to first-line antianginal therapies.

Other Anti-anginal & Anti-ischaemic drugs

Trimetazidine Dihydrochloride is the first 3- keto acyl CoA thiolase inhibitor (KAT), a metabolic anti-ischemic agent with proven benefits for all coronary patients. Trimetazidine Dihydrochloride inhibits fatty acid pathway by inhibiting 3-keto acyl CoA thiolase enzyme and transfers oxygen to glucose pathway. Since glucose pathway is more efficient in producing energy, the same oxygen produces more energy and makes the heart more active. Moreover, the aerobic oxidation of glucose stops production of lactic acid, which prevents angina pectoris.

The recommended dose of Trimetazidine is 35 mg twice daily or 20 mg tablet thrice daily during meals. The benefit of the treatment should be assessed after three months and Trimetazidine should be discontinued if there is no treatment response.

Trimetazidine is safe and well tolerated. The Common side effects associated with Trimetazidine are dizziness, headache, abdominal pain, diarrhoea, dyspepsia, nausea, vomiting, rash, pruritus, urticaria and asthenia

Trimetazidine is contraindicated in patients who have hypersensitivity to the active substance or to any of the excipients. It is also is contraindicated in patients with Parkinson’s disease, parkinsonian symptoms, tremors, restless legs movement disorders, severe renal impairment.

Trimetazidine is not a curative treatment for angina attacks, nor an initial treatment for unstable angina pectoris. It is also not a treatment for myocardial infarction.

No drug interaction so far has been reported. In particular, no interaction has been reported with beta-blockers, calcium antagonists, nitrates, heparin, hypolipidemic agents or digitalis preparation.

There is no data on the use of Trimetazidine in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. As a precautionary measure, it is preferable to avoid the use of Trimetazidine during pregnancy. It is unknown whether Trimetazidine is excreted in human milk. A risk to the newborns/infants cannot be excluded. Trimetazidine should not be used during breast-feeding.

Keep in a dry place away from light and heat. Keep out of the reach of children.

Symptomatic treatment of mild to moderately severe Alzheimer's dementia. Symptomatic treatment of mild to moderately severe dementia in patients with Idiopathic Parkinson's disease.

Drugs for Dementia

Rivastigmine is a carbamate derivative that is structurally related to physostigmine, but not to donepezil and tacrine. The precise mechanism of rivastigmine has not been fully determined, but it is suggested that rivastigmine binds reversibly with and inactivates chlolinesterase (eg. acetylcholinesterase, butyrylcholinesterase), preventing the hydrolysis of acetycholine, and thus leading to an increased concentration of acetylcholine at cholinergic synapses. The anticholinesterase activity of rivastigmine is relatively specific for brain acetylcholinesterase and butyrylcholinesterase compared with those in peripheral tissues.

Rivastigmine capsule-

• Initial dose: Rivastigmine 1.5 mg twice a day.
• Dose titration: The starting dose is Rivastigmine 1.5 mg twice a day. If this dose is well tolerated after a minimum of two weeks of treatment, the dose may be increased to Rivastigmine 3 mg twice a day. Subsequent increases to 4.5 mg and then 6 mg twice a day should also be based on good tolerability of the current dose and may be considered after a minimum of two weeks of treatment at that dose level.
• Maintenance dose: The effective dose is 3 mg to 6 mg twice a day; to achieve maximum therapeutic benefit patients should be maintained on their highest well tolerated dose. The recommended maximum daily dose is 6 mg twice a day. Maintenance treatment can be continued for as long as a therapeutic benefit for the patient exists. 
• Re-initiation of therapy: If treatment is interrupted for more than several days, it should be re-initiated at 1.5 mg twice daily. Dose titration should then be carried out as described above.

Rivastigmine transdermal patch: Apply patch on intact skin for a 24-hour period; replace with a new patch every 24 hours.

• Initial Dose: Initiate treatment with 4.6 mg/24 hours Rivastigmine transdermal patch.
• Dose Titration: After a minimum of 4 weeks, if tolerated, increase dose to 9.5 mg/24 hours, which is the minimum effective dose. Following a minimum additional 4 weeks, may increase dosage to maximum dosage of 13.3 mg/24 hours.
• Mild to Moderate Alzheimer's Disease and Parkinson’s Disease Dementia: Rivastigmine transdermal patch 9.5 mg/24 hours or 13.3 mg/24 hours once daily.
• Severe Alzheimer’s Disease: Rivastigmine transdermal patch 13.3 mg/24 hours once daily.
• For treatment interruption longer than 3 days, retitrate dosage starting at 4.6 mg per 24 hours.

Rivastigmine should be administered twice a day, with morning and evening meals.

The most commonly reported adverse reactions are gastrointestinal, including nausea (38%) and vomiting (23%), especially during titration. Female patients in clinical studies were found to be more susceptible than male patients to gastrointestinal adverse reactions and weight loss.

The use of this medicinal product is contraindicated in patients with hypersensitivity to the active substance or other carbamate derivatives.

Patients with sick sinus syndrome or conduction defects, resp diseases. Cholinergic stimulation may increase gastric acid secretion. May exacerbate urinary obstruction and seizures. Pregnancy. Renal impairment, mild to moderate hepatic impairment. Monitor body wt. Asthma or obstructive pulmonary disease. May worsen extrapyramidal symptoms. Lactation.

As a cholinesterase inhibitor, Rivastigmine may exaggerate the effects of succinylcholine-type muscle relaxants during anaesthesia. Caution is recommended when selecting anaesthetic agents. Possible dose adjustments or temporarily stopping treatment can be considered if needed. In view of its pharmacodynamic effects, rivastigmine should not be given concomitantly with other cholinomimetic substances and might interfere with the activity of anticholinergic medicinal products. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam or fluoxetine in studies in healthy volunteers. The increase in prothrombin time induced by warfarin is not affected by administration of rivastigmine. No untoward effects on cardiac conduction were observed following concomitant administration of digoxin and Rivastigmine.

For Rivastigmine no clinical data are available. Rivastigmine should not be used during pregnancy unless clearly necessary. In animals, rivastigmine is excreted into milk. It is not known if rivastigmine is excreted into human milk. Therefore, women on rivastigmine should not breast-feed.

Renal and hepatic impairment: Due to increased exposure in moderate renal and mild to moderate hepatic impairment, dosing recommendations to titrate according to individual tolerability should be closely followed

Use in children: Rivastigmine is not recommended for use in children.

Most cases of accidental overdose have not been associated with any clinical signs or symptoms and almost all of the patients concerned continued rivastigmine treatment. Where symptoms have occurred, they have included nausea, vomiting and diarrhoea, hypertension or hallucinations. Due to the known vagotonic effect of cholinesterase inhibitors on heart rate, bradycardia and/or syncope may also occur. Ingestion of 46 mg occurred in one case; following conservative management the patient fully recovered within 24 hours. As rivastigmine has a plasma half-life of about 1 hour and a duration of acetylcholinesterase inhibition of about 9 hours, it is recommended that in cases of asymptomatic overdose no further dose of rivastigmine should be administered for the next 24 hours. In overdose accompanied by severe nausea and vomiting, the use of antiemetics should be considered. Symptomatic treatment for other adverse reactions should be given as necessary. In massive overdose, atropine can be used. An initial dose of 0.03 mg/kg intravenous atropine sulphate is recommended, with subsequent doses based on clinical response. Use of scopolamine as an antidote is not recommended.

Store in a cool and dry place, protected from light.

Symptomatic treatment of mild to moderately severe Alzheimer's dementia. Symptomatic treatment of mild to moderately severe dementia in patients with Idiopathic Parkinson's disease.

Drugs for Dementia

Rivastigmine is a carbamate derivative that is structurally related to physostigmine, but not to donepezil and tacrine. The precise mechanism of rivastigmine has not been fully determined, but it is suggested that rivastigmine binds reversibly with and inactivates chlolinesterase (eg. acetylcholinesterase, butyrylcholinesterase), preventing the hydrolysis of acetycholine, and thus leading to an increased concentration of acetylcholine at cholinergic synapses. The anticholinesterase activity of rivastigmine is relatively specific for brain acetylcholinesterase and butyrylcholinesterase compared with those in peripheral tissues.

Rivastigmine capsule-

• Initial dose: Rivastigmine 1.5 mg twice a day.
• Dose titration: The starting dose is Rivastigmine 1.5 mg twice a day. If this dose is well tolerated after a minimum of two weeks of treatment, the dose may be increased to Rivastigmine 3 mg twice a day. Subsequent increases to 4.5 mg and then 6 mg twice a day should also be based on good tolerability of the current dose and may be considered after a minimum of two weeks of treatment at that dose level.
• Maintenance dose: The effective dose is 3 mg to 6 mg twice a day; to achieve maximum therapeutic benefit patients should be maintained on their highest well tolerated dose. The recommended maximum daily dose is 6 mg twice a day. Maintenance treatment can be continued for as long as a therapeutic benefit for the patient exists. 
• Re-initiation of therapy: If treatment is interrupted for more than several days, it should be re-initiated at 1.5 mg twice daily. Dose titration should then be carried out as described above.

Rivastigmine transdermal patch: Apply patch on intact skin for a 24-hour period; replace with a new patch every 24 hours.

• Initial Dose: Initiate treatment with 4.6 mg/24 hours Rivastigmine transdermal patch.
• Dose Titration: After a minimum of 4 weeks, if tolerated, increase dose to 9.5 mg/24 hours, which is the minimum effective dose. Following a minimum additional 4 weeks, may increase dosage to maximum dosage of 13.3 mg/24 hours.
• Mild to Moderate Alzheimer's Disease and Parkinson’s Disease Dementia: Rivastigmine transdermal patch 9.5 mg/24 hours or 13.3 mg/24 hours once daily.
• Severe Alzheimer’s Disease: Rivastigmine transdermal patch 13.3 mg/24 hours once daily.
• For treatment interruption longer than 3 days, retitrate dosage starting at 4.6 mg per 24 hours.

Rivastigmine should be administered twice a day, with morning and evening meals.

The most commonly reported adverse reactions are gastrointestinal, including nausea (38%) and vomiting (23%), especially during titration. Female patients in clinical studies were found to be more susceptible than male patients to gastrointestinal adverse reactions and weight loss.

The use of this medicinal product is contraindicated in patients with hypersensitivity to the active substance or other carbamate derivatives.

Patients with sick sinus syndrome or conduction defects, resp diseases. Cholinergic stimulation may increase gastric acid secretion. May exacerbate urinary obstruction and seizures. Pregnancy. Renal impairment, mild to moderate hepatic impairment. Monitor body wt. Asthma or obstructive pulmonary disease. May worsen extrapyramidal symptoms. Lactation.

As a cholinesterase inhibitor, Rivastigmine may exaggerate the effects of succinylcholine-type muscle relaxants during anaesthesia. Caution is recommended when selecting anaesthetic agents. Possible dose adjustments or temporarily stopping treatment can be considered if needed. In view of its pharmacodynamic effects, rivastigmine should not be given concomitantly with other cholinomimetic substances and might interfere with the activity of anticholinergic medicinal products. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam or fluoxetine in studies in healthy volunteers. The increase in prothrombin time induced by warfarin is not affected by administration of rivastigmine. No untoward effects on cardiac conduction were observed following concomitant administration of digoxin and Rivastigmine.

For Rivastigmine no clinical data are available. Rivastigmine should not be used during pregnancy unless clearly necessary. In animals, rivastigmine is excreted into milk. It is not known if rivastigmine is excreted into human milk. Therefore, women on rivastigmine should not breast-feed.

Renal and hepatic impairment: Due to increased exposure in moderate renal and mild to moderate hepatic impairment, dosing recommendations to titrate according to individual tolerability should be closely followed

Use in children: Rivastigmine is not recommended for use in children.

Most cases of accidental overdose have not been associated with any clinical signs or symptoms and almost all of the patients concerned continued rivastigmine treatment. Where symptoms have occurred, they have included nausea, vomiting and diarrhoea, hypertension or hallucinations. Due to the known vagotonic effect of cholinesterase inhibitors on heart rate, bradycardia and/or syncope may also occur. Ingestion of 46 mg occurred in one case; following conservative management the patient fully recovered within 24 hours. As rivastigmine has a plasma half-life of about 1 hour and a duration of acetylcholinesterase inhibition of about 9 hours, it is recommended that in cases of asymptomatic overdose no further dose of rivastigmine should be administered for the next 24 hours. In overdose accompanied by severe nausea and vomiting, the use of antiemetics should be considered. Symptomatic treatment for other adverse reactions should be given as necessary. In massive overdose, atropine can be used. An initial dose of 0.03 mg/kg intravenous atropine sulphate is recommended, with subsequent doses based on clinical response. Use of scopolamine as an antidote is not recommended.

Store in a cool and dry place, protected from light.

Symptomatic treatment of mild to moderately severe Alzheimer's dementia. Symptomatic treatment of mild to moderately severe dementia in patients with Idiopathic Parkinson's disease.

Drugs for Dementia

Rivastigmine is a carbamate derivative that is structurally related to physostigmine, but not to donepezil and tacrine. The precise mechanism of rivastigmine has not been fully determined, but it is suggested that rivastigmine binds reversibly with and inactivates chlolinesterase (eg. acetylcholinesterase, butyrylcholinesterase), preventing the hydrolysis of acetycholine, and thus leading to an increased concentration of acetylcholine at cholinergic synapses. The anticholinesterase activity of rivastigmine is relatively specific for brain acetylcholinesterase and butyrylcholinesterase compared with those in peripheral tissues.

Rivastigmine capsule-

• Initial dose: Rivastigmine 1.5 mg twice a day.
• Dose titration: The starting dose is Rivastigmine 1.5 mg twice a day. If this dose is well tolerated after a minimum of two weeks of treatment, the dose may be increased to Rivastigmine 3 mg twice a day. Subsequent increases to 4.5 mg and then 6 mg twice a day should also be based on good tolerability of the current dose and may be considered after a minimum of two weeks of treatment at that dose level.
• Maintenance dose: The effective dose is 3 mg to 6 mg twice a day; to achieve maximum therapeutic benefit patients should be maintained on their highest well tolerated dose. The recommended maximum daily dose is 6 mg twice a day. Maintenance treatment can be continued for as long as a therapeutic benefit for the patient exists. 
• Re-initiation of therapy: If treatment is interrupted for more than several days, it should be re-initiated at 1.5 mg twice daily. Dose titration should then be carried out as described above.

Rivastigmine transdermal patch: Apply patch on intact skin for a 24-hour period; replace with a new patch every 24 hours.

• Initial Dose: Initiate treatment with 4.6 mg/24 hours Rivastigmine transdermal patch.
• Dose Titration: After a minimum of 4 weeks, if tolerated, increase dose to 9.5 mg/24 hours, which is the minimum effective dose. Following a minimum additional 4 weeks, may increase dosage to maximum dosage of 13.3 mg/24 hours.
• Mild to Moderate Alzheimer's Disease and Parkinson’s Disease Dementia: Rivastigmine transdermal patch 9.5 mg/24 hours or 13.3 mg/24 hours once daily.
• Severe Alzheimer’s Disease: Rivastigmine transdermal patch 13.3 mg/24 hours once daily.
• For treatment interruption longer than 3 days, retitrate dosage starting at 4.6 mg per 24 hours.

Rivastigmine should be administered twice a day, with morning and evening meals.

The most commonly reported adverse reactions are gastrointestinal, including nausea (38%) and vomiting (23%), especially during titration. Female patients in clinical studies were found to be more susceptible than male patients to gastrointestinal adverse reactions and weight loss.

The use of this medicinal product is contraindicated in patients with hypersensitivity to the active substance or other carbamate derivatives.

Patients with sick sinus syndrome or conduction defects, resp diseases. Cholinergic stimulation may increase gastric acid secretion. May exacerbate urinary obstruction and seizures. Pregnancy. Renal impairment, mild to moderate hepatic impairment. Monitor body wt. Asthma or obstructive pulmonary disease. May worsen extrapyramidal symptoms. Lactation.

As a cholinesterase inhibitor, Rivastigmine may exaggerate the effects of succinylcholine-type muscle relaxants during anaesthesia. Caution is recommended when selecting anaesthetic agents. Possible dose adjustments or temporarily stopping treatment can be considered if needed. In view of its pharmacodynamic effects, rivastigmine should not be given concomitantly with other cholinomimetic substances and might interfere with the activity of anticholinergic medicinal products. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam or fluoxetine in studies in healthy volunteers. The increase in prothrombin time induced by warfarin is not affected by administration of rivastigmine. No untoward effects on cardiac conduction were observed following concomitant administration of digoxin and Rivastigmine.

For Rivastigmine no clinical data are available. Rivastigmine should not be used during pregnancy unless clearly necessary. In animals, rivastigmine is excreted into milk. It is not known if rivastigmine is excreted into human milk. Therefore, women on rivastigmine should not breast-feed.

Renal and hepatic impairment: Due to increased exposure in moderate renal and mild to moderate hepatic impairment, dosing recommendations to titrate according to individual tolerability should be closely followed

Use in children: Rivastigmine is not recommended for use in children.

Most cases of accidental overdose have not been associated with any clinical signs or symptoms and almost all of the patients concerned continued rivastigmine treatment. Where symptoms have occurred, they have included nausea, vomiting and diarrhoea, hypertension or hallucinations. Due to the known vagotonic effect of cholinesterase inhibitors on heart rate, bradycardia and/or syncope may also occur. Ingestion of 46 mg occurred in one case; following conservative management the patient fully recovered within 24 hours. As rivastigmine has a plasma half-life of about 1 hour and a duration of acetylcholinesterase inhibition of about 9 hours, it is recommended that in cases of asymptomatic overdose no further dose of rivastigmine should be administered for the next 24 hours. In overdose accompanied by severe nausea and vomiting, the use of antiemetics should be considered. Symptomatic treatment for other adverse reactions should be given as necessary. In massive overdose, atropine can be used. An initial dose of 0.03 mg/kg intravenous atropine sulphate is recommended, with subsequent doses based on clinical response. Use of scopolamine as an antidote is not recommended.

Store in a cool and dry place, protected from light.