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Female Sex hormones

Dienogest acts as an agonist at the progesterone receptor (PR) with weak affinity that is comparable to that of progesterone but has a very potent progestagenic effect in the endometrium, causing endometrial atrophy after prolonged use. It promotes antiproliferative, immunologic and antiangiogenic effects on endometrial tissue. Dienogest reduces the level of endogenous production of oestradiol and thereby suppressing the trophic effects of oestradiol on both the eutopic and ectopic endometrium. Continous administration of dienogest results in hyperprogestogenic and moderately hypoestrogenic endocrine environment, which causes initial decidualization of endometrial tissue. It is an antagonist at androgen receptors, improve androgenic symptoms such as acne and hirsutism [A16570].

Tablet-taking can be started on any day of the menstrual cycle. The dosage of Dienogest is 2 mg daily without any break, taken preferably at the same time each day with some liquid as needed. Tablet must be taken continuously without regard to vaginal bleeding. When a pack is finished, the next one should be started without interruption.

In the event of missed tablet(s), the woman should take 2 mg only, as soon as she remembers, and should then continue the next day to take the tablet at her usual time. A tablet not absorbed due to vomiting or diarrhea should likewise be replaced by 2 mg.

Undesirable effects are more common during the 1st months after start of intake of Dienogest, and subside with duration of treatment. The following undesirable effects have been reported in users of Dienogest. The most frequently reported undesirable effects during treatment that were considered at least possibly related to Dienogest were headache (9%), breast discomfort (5.4%), depressed mood (5.1%) and acne (5.1%).

• Nervous System Disorders: Headache, migraine.
• Cardiac Disorders: Uncommon: Unspecified circulatory system disorder, palpitations.
• Vascular Disorders: Uncommon: Hypotension.
• Gastrointestinal Disorders: Common: Nausea, abdominal pain, flatulence.
• Metabolism and nutrition disorders: Weight increase (3.6%)
• Psychiatric Disorders: Depressed mood, irritability, nervousness, altered mood.

Hypersensitivity to dienogest or to any of the excipients of Dienogest. Dienogest should not be used in the presence of any of the conditions such as, Active venous thromboembolic disorder; arterial and cardiovascular disease, (e.g, myocardial infarction, cerebrovascular accident, ischemic heart disease); diabetes mellitus with vascular involvement; presence or history of severe hepatic disease as long as liver function values have not returned to normal; presence or history of liver tumors (benign or malignant); known or suspected sex hormone-dependent malignancies and undiagnosed vaginal bleeding.

Before starting Dienogest treatment, pregnancy must be excluded. During treatment, patients are advised to use nonhormonal methods of contraception (e.g, barrier method) if contraception is required.

As Dienogest is a progestogen-only preparation, it can be assumed that special warnings and special precautions for use of other progestogen-only preparations are also valid for the use of Dienogest .

• Changes in Bleeding Pattern: Dienogest treatment affects the menstrual bleeding pattern in the majority of women.
• Hepatic Impairment: Dienogest is contraindicated in patients with present or past severe hepatic disease.
• Impairment of Fertility: Based on available data, ovulation is inhibited in the majority of patients during treatment with Dienogest. However, Dienogest is not a contraceptive. If contraception is required, a nonhormonal method should be used.

Progestogens including Dienogest are metabolized mainly by the cytochrome P450 3A4 system . Therefore, inducers or inhibitors of CYP3A4 may affect the progestogen drug metabolism. Known CYP3A4 inhibitors like azole antifungals (e.g, ketoconazole, itraconazole, fluconazole), cimetidine, verapamil, macrolides (e.g, erythromycin, clarithromycin and roxithromycin), diltiazem, protease inhibitors (e.g, ritonavir, saquinavir, indinavir, nelfinavir), antidepressants (e.g, nefazodone, fluvoxamine, fluoxetine) may increase plasma levels of progestogens and result in adverse reactions.

There are limited data from the use of Dienogest in pregnant women. Animal studies and data from women exposed to Dienogest during pregnancy reveal no special risks on pregnancy, embryonic/fetal development, birth or development after birth for humans. However, Dienogest should not be administered to pregnant women because there is no need to treat endometriosis during pregnancy.

Treatment with Dienogest during lactation is not recommended. Physiochemical properties and animal data indicate excretion of Dienogest in breast milk. A decision must be made whether to discontinue breastfeeding or to abstain from Dienogest therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Use in Children: Dienogest is not indicated in children prior to menarche. The safety and efficacy of Dienogest in adolescents (menarche to 18 years) has not yet been established.

Use in the Elderly: There is no relevant indication for the use of Dienogest in the geriatric population.

Acute toxicity studies performed with Dienogest did not indicate a risk of acute adverse effects in case of inadvertent intake of a multiple of the daily therapeutic dose. There is no specific antidote. Dienogest 20-30 mg/day (10-15 times higher dose than in Dienogest) over 24 weeks of use were very well tolerated.

Keep in a cool and dry place. Protect from light. Keep out of the reach of children.

Female Sex hormones

Dienogest acts as an agonist at the progesterone receptor (PR) with weak affinity that is comparable to that of progesterone but has a very potent progestagenic effect in the endometrium, causing endometrial atrophy after prolonged use. It promotes antiproliferative, immunologic and antiangiogenic effects on endometrial tissue. Dienogest reduces the level of endogenous production of oestradiol and thereby suppressing the trophic effects of oestradiol on both the eutopic and ectopic endometrium. Continous administration of dienogest results in hyperprogestogenic and moderately hypoestrogenic endocrine environment, which causes initial decidualization of endometrial tissue. It is an antagonist at androgen receptors, improve androgenic symptoms such as acne and hirsutism [A16570].

Tablet-taking can be started on any day of the menstrual cycle. The dosage of Dienogest is 2 mg daily without any break, taken preferably at the same time each day with some liquid as needed. Tablet must be taken continuously without regard to vaginal bleeding. When a pack is finished, the next one should be started without interruption.

In the event of missed tablet(s), the woman should take 2 mg only, as soon as she remembers, and should then continue the next day to take the tablet at her usual time. A tablet not absorbed due to vomiting or diarrhea should likewise be replaced by 2 mg.

Undesirable effects are more common during the 1st months after start of intake of Dienogest, and subside with duration of treatment. The following undesirable effects have been reported in users of Dienogest. The most frequently reported undesirable effects during treatment that were considered at least possibly related to Dienogest were headache (9%), breast discomfort (5.4%), depressed mood (5.1%) and acne (5.1%).

• Nervous System Disorders: Headache, migraine.
• Cardiac Disorders: Uncommon: Unspecified circulatory system disorder, palpitations.
• Vascular Disorders: Uncommon: Hypotension.
• Gastrointestinal Disorders: Common: Nausea, abdominal pain, flatulence.
• Metabolism and nutrition disorders: Weight increase (3.6%)
• Psychiatric Disorders: Depressed mood, irritability, nervousness, altered mood.

Hypersensitivity to dienogest or to any of the excipients of Dienogest. Dienogest should not be used in the presence of any of the conditions such as, Active venous thromboembolic disorder; arterial and cardiovascular disease, (e.g, myocardial infarction, cerebrovascular accident, ischemic heart disease); diabetes mellitus with vascular involvement; presence or history of severe hepatic disease as long as liver function values have not returned to normal; presence or history of liver tumors (benign or malignant); known or suspected sex hormone-dependent malignancies and undiagnosed vaginal bleeding.

Before starting Dienogest treatment, pregnancy must be excluded. During treatment, patients are advised to use nonhormonal methods of contraception (e.g, barrier method) if contraception is required.

As Dienogest is a progestogen-only preparation, it can be assumed that special warnings and special precautions for use of other progestogen-only preparations are also valid for the use of Dienogest .

• Changes in Bleeding Pattern: Dienogest treatment affects the menstrual bleeding pattern in the majority of women.
• Hepatic Impairment: Dienogest is contraindicated in patients with present or past severe hepatic disease.
• Impairment of Fertility: Based on available data, ovulation is inhibited in the majority of patients during treatment with Dienogest. However, Dienogest is not a contraceptive. If contraception is required, a nonhormonal method should be used.

Progestogens including Dienogest are metabolized mainly by the cytochrome P450 3A4 system . Therefore, inducers or inhibitors of CYP3A4 may affect the progestogen drug metabolism. Known CYP3A4 inhibitors like azole antifungals (e.g, ketoconazole, itraconazole, fluconazole), cimetidine, verapamil, macrolides (e.g, erythromycin, clarithromycin and roxithromycin), diltiazem, protease inhibitors (e.g, ritonavir, saquinavir, indinavir, nelfinavir), antidepressants (e.g, nefazodone, fluvoxamine, fluoxetine) may increase plasma levels of progestogens and result in adverse reactions.

There are limited data from the use of Dienogest in pregnant women. Animal studies and data from women exposed to Dienogest during pregnancy reveal no special risks on pregnancy, embryonic/fetal development, birth or development after birth for humans. However, Dienogest should not be administered to pregnant women because there is no need to treat endometriosis during pregnancy.

Treatment with Dienogest during lactation is not recommended. Physiochemical properties and animal data indicate excretion of Dienogest in breast milk. A decision must be made whether to discontinue breastfeeding or to abstain from Dienogest therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Use in Children: Dienogest is not indicated in children prior to menarche. The safety and efficacy of Dienogest in adolescents (menarche to 18 years) has not yet been established.

Use in the Elderly: There is no relevant indication for the use of Dienogest in the geriatric population.

Acute toxicity studies performed with Dienogest did not indicate a risk of acute adverse effects in case of inadvertent intake of a multiple of the daily therapeutic dose. There is no specific antidote. Dienogest 20-30 mg/day (10-15 times higher dose than in Dienogest) over 24 weeks of use were very well tolerated.

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

Flupentixol and Melitracen tablet is indicated in-

• Anxiety
• Depression
• Apathy
• Psychogenic depression.
• Depressive neurosses.
• Masked depression.
• Psychosomatic affections accompanied by anxiety and apathy.
• Menopausal depressions.
• Dysphoria and depression in alcoholics and drug addicts.

Combined anxiolytics & anti-depressant drugs

This consists of two well known and well proven compounds: flupentixol-a neuroleptic with anxiolytic and antidepressant properties of its own when given in small doses, and melitracen-a bipolar thymoleptic with activating properties in low doses. In combination the compounds render a preparation with antidepressant, anxiolytic and activating properties. Maximal serum concentration is reached in about 4 hours after oral administration of flupentixol and in about 4 hours after oral administration of melitracen. The biological half-life of flupentixol is about 35 hours and that of melitracen is about 19 hours. The combination of flupentixol and melitracen does not seem to influence the pharmacokinetic properties of the individual compounds.

Adults: Usually 2 tablets orally daily in the morning and noon. In severe cases, the morning dose may be increased to 2 tablets.

Elderly patients: 1 tablet in the morning.

Maintenance dose: Usually 1 tablet orally in the morning. In cases of insomnia or severe restlessness, additional treatment with a sedative in the acute phase is recommended.

In the recommended doses side effects are rare. These could be transient restlessness and insomnia.

If previously the patient has been treated with tranquillizers with sedative effect these should be withdrawn gradually.

This tablet may enhance the response to alcohol, barbiturates and other CNS depressants. Simultaneous administration of MAO-inhibitors may cause hypertensive crises. Neuroleptics and thymoleptics reduce the antihypertensive effect of guanethidine and similar acting compounds and thymoleptics enhance the effects of adrenaline and noradrenaline.

This tablet should preferably not be given during pregnancy and lactation.

In cases of overdosage the symptoms of intoxications by melitracen, especially of anticholinergic nature, dominate. More rarely extrapyramidal symptoms due to flupentixol occur. Symptomatic and Supportive. Gastric lavage should be carried out as soon as possible and activated charcoal may be administered. Measures aimed at supporting the respiratory and cardiovascular systems should be instituted. Epinephrine (adrenaline) must not be used for such patients. Convulsions may be treated with diazepam and extrapyramidal symptoms with biperiden.

Store at a temperature not exceeding 30°C in a dry place. Protect from light. Keep out of reach of children.

Bisoprolol is indicated in-

• Hypertension
• Angina
• Moderate to severe heart failure

Bisoprolol is not recommended for the emergency treatment of hypertensive crises.

Anti adrenergic agent (Beta blockers), Beta-adrenoceptor blocking drugs, Beta-blockers

Bisoprolol Hemifumarate is the most selective ß1 blocker. It displays highest level of affinity for the ß1 receptor than any other beta-blocker available up to now. Selectively blocks ß1 adrenergic receptor in the heart and vascular smooth muscle and reduces heart rate and cardiac output resulting in decrease of arterial hypertension. Lipid metabolism can be adversely affected by ß-blockers, in patients with non-ß1 selective ß1-blocker, but Bisoprolol does not cause any change in the cholesterol fraction including the cardioprotective HDL-cholesterol, in long-term therapy.

Adult: In the treatment of mild to moderate hypertension, Bisoprolol fumarate must be individualized to the needs of the patient. The usual starting dose is 5 mg once daily either added to a diuretic or alone. If the response to 5 mg is inadequate, the dose may be increased to 10 mg and then, if necessary, to 20 mg once daily. An appropriate interval for dose titration is 2 weeks. Increasing the dose beyond 20 mg once daily produces only a small incremental benefit.

Children: Safety and effectiveness in children have not been established.

Patients With Renal or Hepatic Impairment: In patients with hepatic impairment (hepatitis or cirrhosis) or renal dysfunction (creatinine clearance less than 40 mL/min) as in other patients, the initial daily dose should be 5 mg. Because of the possibility of accumulation, caution must be used in dose titration. Since limited data suggest that bisoprolol fumarate is not dialysable, drug replacement is not necessary in patients undergoing dialysis.

Geriatrics: In the elderly, it is not usually necessary to adjust the dose, unless there is also significant renal or hepatic dysfunction

Bisoprolol, like any medication, may have some side effects. It is important that you keep your doctor informed of all side effects especially if you experience one of the following for several days. The most common side effects, whether or not caused by Bisoprolol, are: headache, fatigue, urinary tract infection, rhinitis or sinusitis (inflammation in the nose), diarrhea, dizziness, peripheral edema (swelling of the ankles), joint pain, cough, insomnia (trouble sleeping), nausea (feeling like vomiting), and sore throat. You must seek medical attention immediately if you experience an allergic reaction with symptoms of rash, itching, swelling, dizziness or trouble breathing.

Medicines affect different people in different ways. Just because side effects have occurred in other patients does not mean you will get them. Discuss how you feel on Bisoprolol with your doctor or pharmacist. Do not stop or restart Bisoprolol on your own.

In patients with cardiogenic shock, overt heart failure, second or third degree A-V block, right ventricular failure secondary to pulmonary hypertension and sinus bradycardia.

Monitoring of renal, hepatic and hematopoietic function should be performed at regular intervals during long-term treatment with bisoprolol.

Other β-blocking Agents: Bisoprolol fumarate should not be combined with other β-blocking agents.

Catecholamine-Depleting Drugs: Patients receiving catecholamine-depleting drugs, such as reserpine or guanethidine, should be monitored closely because the added β-adrenergic blocking action of bisoprolol fumarate may produce excessive reduction of sympathetic activity.

Centrally Active Antihypertensive Agents: β-blockers may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. If the two drugs are coadministered, the β-blocker should be withdrawn several days before discontinuing clonidine. If replacing clonidine by β-blocker therapy, the introduction of β-blockers should be delayed for several days after clonidine administration has stopped (see also prescribing information for clonidine).

Antiarrhythmic Agents: Bisoprolol fumarate should be used with care when myocardial depressants or inhibitors of A-V conduction, such as certain calcium antagonists (particularly of the phenyl alkylamine (verapamil) and benzothiazepine (diltiazem) classes), or antiarrhythmic agents, such as disopyramide, are used concurrently.

Calcium Channel Blockers: Combined use of β-blockers and calcium channel blockers with negative inotropic effects can lead to prolongation of S-A and A-V conduction, particularly in patients with impaired ventricular function or conduction abnormalities. This may result in severe hypotension, bradycardia and cardiac failure.

Pregnancy: Bisoprolol fumarate was not teratogenic in rats at doses up to 150 mg/kg/day, which is 375 times the maximum recommended human daily dose. Bisoprolol fumarate was fetotoxic (increased late resorptions) at 50 mg/kg/day and maternotoxic (decreased food intake and body-weight gain) at 150 mg/kg/day. Bisoprolol fumarate was not teratogenic in rabbits at doses up to 12.5 mg/kg/day, which is 31 times the maximum recommended human daily dose, but was embryolethal (increased early resorptions) at 12.5 mg/kg/day. There are no studies in pregnant women. Bisoprolol fumarate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lactation: Small amounts of bisoprolol fumarate (<2% of the dose) have been detected in the milk of lactating rats. It is not known whether this drug is excreted in human milk. If use of bisoprolol fumarate is considered essential, then mothers should stop nursing.

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

It is indicated in the treatment of-

• Acute hemorrhoidal attacks.
• Chronic hemorrhoidal disease.
• Organic and functional chronic venous insufficiency of the lower limbs with the following symptoms: heavy legs, pain, nocturnal cramps.

Phlebotonic & Vascular protecting preparation

Diosmin and Hesperidin is a phlebotonic drug and a vascular protecting agent. It reinforces venous tone by prolonging the activity of parietal noradrenaline. Thus Diosmin and Hesperidin decreases venous capacitance, venous distensibility, and venous emptying time.

Diosmin and Hesperidin protects the microcirculation by fighting the microcirculation damaging process; It combats venous inflammation by decreasing leukocyte activation, and as a consequence, by inhibiting the release of inflammatory mediators, principally free radicals and prostaglandin. Thus Diosmin and Hesperidin normalizes capillary permeability and strengthens capillary resistance.

Diosmin and Hesperidin acts on the lymphatic system, It improves lymphatic drainage by increasing lymph flow and lymph oncotic pressure.

Diosmin 450 mg & Hesperidin 50 mg-

• Acute hemorrhoidal attacks: 3 tablets twice daily for the first 4 days, then 2 tablets twice daily for three days and if required 1 tablet twice daily as a maintenance dosage.
• Chronic hemorrhoids: 1 tablet twice daily.
• Chronic venous insufficiency: 1 tablet twice daily initially for seven days. Duration may be increased depending on severity.

Diosmin 900 mg & Hesperidin 100 mg-

• Acute Hemorrhoid: 1 tablet thrice daily for first 4 days, followed by 1 tablet twice daily for 3 days & then 1 tablet once daily as maintenance dose.
• Relapse of Internal Hemorrhoid & Chronic Hemorrhoid: 1 tablet once daily for 3 months.
• Chronic venous insufficiency: 1 tablet once daily for 2-6 months.
• Leg Wounds: 1 tablet once daily for 2 months.

Tablet should be taken at meal times.

Some cases of routine gastric disorders and neurovegetative disorders (feeling of discomfort) have been reported. In this cases discontinuation of treatment is not required.

Chronic venous insufficiency and its complications should be diagnosed and management monitored by a physician. It is contraindicated for anyone having a hypersensitivity to any ingredient in the product.

If the hemorrhoidal symptoms do not disappear within 15 days, patient should ask doctor for advice. Diosmin (up to 900 mg/day) has been administered to a small number of breast cancer patients who were experiencing lymphedema following surgical and nodal irradiation treatment with resultant reduction of arm edema but no effect on the cancer. Animal studies and more than 20 years of clinical use in Europe have not found any evidence of carcinogenicity or mutagenicity when the components of Diosmin & Hesperidin are used as recommended. As a precaution, Diosmin & Hesperidin is not recommended for patients with a history of cancer since no specific studies have been performed in this population.

No evidence of drug incompatibility (drug interaction) has been reported in clinical trials.

Experimental studies have not shown any teratogenic effect in animals. In human beings, no harmful effect has so far been reported. In the absence of data concerning excretion into breast milk, breast feeding is not recommended during treatment.

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

It is indicated in the treatment of-

• Acute hemorrhoidal attacks.
• Chronic hemorrhoidal disease.
• Organic and functional chronic venous insufficiency of the lower limbs with the following symptoms: heavy legs, pain, nocturnal cramps.

Phlebotonic & Vascular protecting preparation

Diosmin and Hesperidin is a phlebotonic drug and a vascular protecting agent. It reinforces venous tone by prolonging the activity of parietal noradrenaline. Thus Diosmin and Hesperidin decreases venous capacitance, venous distensibility, and venous emptying time.

Diosmin and Hesperidin protects the microcirculation by fighting the microcirculation damaging process; It combats venous inflammation by decreasing leukocyte activation, and as a consequence, by inhibiting the release of inflammatory mediators, principally free radicals and prostaglandin. Thus Diosmin and Hesperidin normalizes capillary permeability and strengthens capillary resistance.

Diosmin and Hesperidin acts on the lymphatic system, It improves lymphatic drainage by increasing lymph flow and lymph oncotic pressure.

Diosmin 450 mg & Hesperidin 50 mg-

• Acute hemorrhoidal attacks: 3 tablets twice daily for the first 4 days, then 2 tablets twice daily for three days and if required 1 tablet twice daily as a maintenance dosage.
• Chronic hemorrhoids: 1 tablet twice daily.
• Chronic venous insufficiency: 1 tablet twice daily initially for seven days. Duration may be increased depending on severity.

Diosmin 900 mg & Hesperidin 100 mg-

• Acute Hemorrhoid: 1 tablet thrice daily for first 4 days, followed by 1 tablet twice daily for 3 days & then 1 tablet once daily as maintenance dose.
• Relapse of Internal Hemorrhoid & Chronic Hemorrhoid: 1 tablet once daily for 3 months.
• Chronic venous insufficiency: 1 tablet once daily for 2-6 months.
• Leg Wounds: 1 tablet once daily for 2 months.

Tablet should be taken at meal times.

Some cases of routine gastric disorders and neurovegetative disorders (feeling of discomfort) have been reported. In this cases discontinuation of treatment is not required.

Chronic venous insufficiency and its complications should be diagnosed and management monitored by a physician. It is contraindicated for anyone having a hypersensitivity to any ingredient in the product.

If the hemorrhoidal symptoms do not disappear within 15 days, patient should ask doctor for advice. Diosmin (up to 900 mg/day) has been administered to a small number of breast cancer patients who were experiencing lymphedema following surgical and nodal irradiation treatment with resultant reduction of arm edema but no effect on the cancer. Animal studies and more than 20 years of clinical use in Europe have not found any evidence of carcinogenicity or mutagenicity when the components of Diosmin & Hesperidin are used as recommended. As a precaution, Diosmin & Hesperidin is not recommended for patients with a history of cancer since no specific studies have been performed in this population.

No evidence of drug incompatibility (drug interaction) has been reported in clinical trials.

Experimental studies have not shown any teratogenic effect in animals. In human beings, no harmful effect has so far been reported. In the absence of data concerning excretion into breast milk, breast feeding is not recommended during treatment.

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

Other beta-lactam Antibiotics

Doripenem is a synthetic broad-spectrum carbapenem β-lactam antibiotic with potent in vitro antibacterial activity against aerobic and anaerobic gm+ve and gm-ve bacteria including Pseudomonas aeruginosa. It inhibits bacterial cell wall synthesis by binding to several penicillin-binding proteins, which in turn inhibits the final transpeptidase step of peptidoglycan synthesis in bacterial cell walls.

Intravenous-

• Complicated intra-abdominal infections: 500 mg 8 hrly infused over 1 hr for 5-14 days. May switch to an appropriate oral therapy, after at least 3 days of parenteral therapy.
• Complicated UTI, Pyelonephritis: 500 mg 8 hrly infused over 1 hr for 10 days. May switch to an appropriate oral therapy, after at least 3 days of parenteral therapy.
• Patient with concurrent bacteraemia: Duration can be extended up to 14 days.

Renal impairment-

• CrCI (30-50 ml/min): 250 mg every 8 hr by IV infusion over 1 hr
• CrCI (11 -29 ml/min): 250 mg every 12 hr by IV infusion over 1 hr

Headache, nausea, diarrhoea, rash, pruritus, phlebitis, elevated hepatic enzymes, oral candidiasis, anaemia, vulvomycotic infection, thrombocytopenia, neutropenia.

Hypersensitivity to doripenem, other carbapenem antibacterial agents; history of anaphylactic reaction to β-lactams (e.g. penicillins, cephalosporins).

Patient with known or suspected CNS disorders (e.g. brain lesions, history of seizures). Not intended for treatment of any type of pneumonia. Renal impairment. Pregnancy and lactation. Monitoring Parameters Monitor renal function and for signs of anaphylaxis during 1st dose. Consider haematologic assessment during prolonged therapy.

Increased plasma concentration with probenecid. May decrease plasma levels of valproic acid thus, increasing the risk of seizures.

Pregnancy Category B. Either animal-reproduction studies have not demonstrated a fetal risk but there are no controlled studies in pregnant women or animal-reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the 1st trimester (and there is no evidence of a risk in later trimesters).

Reconstituted suspension may be held for 1 hr prior to dilution in infusion bag. Following dilution of the suspension with NaCl 0.9%, stability is 8 hr at room temperature or 24 hr between 2-8°C. Stability of solution when diluted with dextrose 5% injection is 4 hr at room temperature or 24 hr between 2-8°C.

It is indicated in the treatment of-

• Acute hemorrhoidal attacks.
• Chronic hemorrhoidal disease.
• Organic and functional chronic venous insufficiency of the lower limbs with the following symptoms: heavy legs, pain, nocturnal cramps.

Phlebotonic & Vascular protecting preparation

Diosmin and Hesperidin is a phlebotonic drug and a vascular protecting agent. It reinforces venous tone by prolonging the activity of parietal noradrenaline. Thus Diosmin and Hesperidin decreases venous capacitance, venous distensibility, and venous emptying time.

Diosmin and Hesperidin protects the microcirculation by fighting the microcirculation damaging process; It combats venous inflammation by decreasing leukocyte activation, and as a consequence, by inhibiting the release of inflammatory mediators, principally free radicals and prostaglandin. Thus Diosmin and Hesperidin normalizes capillary permeability and strengthens capillary resistance.

Diosmin and Hesperidin acts on the lymphatic system, It improves lymphatic drainage by increasing lymph flow and lymph oncotic pressure.

Diosmin 450 mg & Hesperidin 50 mg-

• Acute hemorrhoidal attacks: 3 tablets twice daily for the first 4 days, then 2 tablets twice daily for three days and if required 1 tablet twice daily as a maintenance dosage.
• Chronic hemorrhoids: 1 tablet twice daily.
• Chronic venous insufficiency: 1 tablet twice daily initially for seven days. Duration may be increased depending on severity.

Diosmin 900 mg & Hesperidin 100 mg-

• Acute Hemorrhoid: 1 tablet thrice daily for first 4 days, followed by 1 tablet twice daily for 3 days & then 1 tablet once daily as maintenance dose.
• Relapse of Internal Hemorrhoid & Chronic Hemorrhoid: 1 tablet once daily for 3 months.
• Chronic venous insufficiency: 1 tablet once daily for 2-6 months.
• Leg Wounds: 1 tablet once daily for 2 months.

Tablet should be taken at meal times.

Some cases of routine gastric disorders and neurovegetative disorders (feeling of discomfort) have been reported. In this cases discontinuation of treatment is not required.

Chronic venous insufficiency and its complications should be diagnosed and management monitored by a physician. It is contraindicated for anyone having a hypersensitivity to any ingredient in the product.

If the hemorrhoidal symptoms do not disappear within 15 days, patient should ask doctor for advice. Diosmin (up to 900 mg/day) has been administered to a small number of breast cancer patients who were experiencing lymphedema following surgical and nodal irradiation treatment with resultant reduction of arm edema but no effect on the cancer. Animal studies and more than 20 years of clinical use in Europe have not found any evidence of carcinogenicity or mutagenicity when the components of Diosmin & Hesperidin are used as recommended. As a precaution, Diosmin & Hesperidin is not recommended for patients with a history of cancer since no specific studies have been performed in this population.

No evidence of drug incompatibility (drug interaction) has been reported in clinical trials.

Experimental studies have not shown any teratogenic effect in animals. In human beings, no harmful effect has so far been reported. In the absence of data concerning excretion into breast milk, breast feeding is not recommended during treatment.

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

Valsartan is indicated:

• For hypertension
• To reduce hospitalizations in patients with congestive heart failure
• To reduce death in patients who developed congestive heart failure after myocardial infarction

Angiotensin-ll receptor blocker

Valsartan is an oral medication that belongs to a class of drugs called angiotensin receptor blockers (ARBs). It is orally active and specific angiotensin II antagonist acting on the AT1 subtype. Angiotensin's attachment to the receptors cause the blood vessels to narrow (vasoconstrict) which leads to an increase in blood pressure (hypertension). Valsartan blocks the angiotensin II receptor. By blocking the action of angiotensin, Valsartan dilates blood vessels and reduces blood pressure without affecting pulse rate. Valsartan has much greater affinity (about 20,000-fold) for the AT1 receptor than for the AT2 receptor. It does not bind or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

Hypertension: The usual dose of Valsartan is 80 to 160 mg once daily. The maximum dose is 320 mg daily. Maximum blood pressure reduction occurs within 4 weeks. 

Heart failure: The usual dose is 40 mg twice daily and may be increased to 80-160 mg twice daily. 

Post-Myocardial Infarction: The initial dose after myocardial infarction is 20 mg twice daily. The dose should be increased with a target of 160 mg daily if tolerated without side effects.

Administration of Valsartan with food decreases the absorption of Valsartan by about 40%, so it should be taken on an empty stomach. No initial dosage adjustment is required for elderly patients with mild to moderate renal and hepatic insufficiency.

Valsartan is generally well tolerated and side effects are rare. The most common side effects include headache, dizziness, fatigue, abdominal pain, cough, diarrhea and nausea. Patient may also experience hyperkalemia, impotency, reduced renal function, allergic reactions, dyspnea, constipation, back pain, muscle cramps, rash, anxiety, insomnia and vertigo. Hypotension may also occur if patient have been taking diuretics along with Valsartan.

Valsartan is contraindicated in patients who are hypersensitive to any component of this product.

Impaired Hepatic Function: As the majority of Valsartan is eliminated in the bile, care should be exercised in patients with mild to moderate hepatic impairment including biliary obstructive disorder.

Impaired Renal Function: Dosage reduction or discontinuation may be required with patients having pre-existing renal impairment.

Heart Failure and Myocardial Infarction: Caution should be exercised when initiating therapy in patients with heart failure and post-myocardial infarction patients.

No drug interactions of clinical significance have been found. Compounds which have been studied in clinical trials include Cimetidine, Warfarin, Furosemide, Digoxin, Atenolol, Indomethacin, Hydrochlorothiazide, Amlodipine and Glibenclamide

As Valsartan is not metabolized to a significant extent, clinically relevant drug-drug interactions in the form of metabolic induction or inhibition of the cytochrome P450 system are not expected with Valsartan. Although valsartan is highly bound to plasma proteins, in vitrostudies have not shown any interaction at this level with a range of molecules which are also highly protein bound, such as Diclofenac, Furosemide, and Warfarin. Concomitant use of potassium sparing diuretics (e.g., Spironolactone, Triamterene, Amiloride) potassium supplements, or salt substitutes containing potassium may lead to increase in serum potassium. If co medication is considered necessary, caution is advisable

Pregnancy: Valsartan should not be used in pregnancy, as in 2nd and 3rd trimester it can cause injury and even death to fetus. When pregnancy is detected, Valsartan should be stopped as soon as possible.

Nursing mothers: It is not known whether Valsartan is excreted in human milk. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric use: Safety and effectiveness in paediatric patients have not been established.

Geriatric use: No overall difference in the efficacy or safety of Valsartan was observed in this patient population, but greater sensitivity of some elderly persons cannot be ruled out.

Hepatic Impairment:

• Mild to moderate: Max: 80 mg once daily.
• Severe: Contraindicated.

Limited data are available related to overdosage in humans. The most likely manifestations of overdosage would be hypotension and tachycardia, bradycardia could occur from parasympathetic (vagal) stimulation. If excessive hypotension occurs, the patient should be placed in the supine position and if necessary, has to be given an intravenous infusion of normal saline.

Store between 15-30° C. Protect from moisture and heat.

Valsartan is indicated:

• For hypertension
• To reduce hospitalizations in patients with congestive heart failure
• To reduce death in patients who developed congestive heart failure after myocardial infarction

Angiotensin-ll receptor blocker

Valsartan is an oral medication that belongs to a class of drugs called angiotensin receptor blockers (ARBs). It is orally active and specific angiotensin II antagonist acting on the AT1 subtype. Angiotensin's attachment to the receptors cause the blood vessels to narrow (vasoconstrict) which leads to an increase in blood pressure (hypertension). Valsartan blocks the angiotensin II receptor. By blocking the action of angiotensin, Valsartan dilates blood vessels and reduces blood pressure without affecting pulse rate. Valsartan has much greater affinity (about 20,000-fold) for the AT1 receptor than for the AT2 receptor. It does not bind or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

Hypertension: The usual dose of Valsartan is 80 to 160 mg once daily. The maximum dose is 320 mg daily. Maximum blood pressure reduction occurs within 4 weeks. 

Heart failure: The usual dose is 40 mg twice daily and may be increased to 80-160 mg twice daily. 

Post-Myocardial Infarction: The initial dose after myocardial infarction is 20 mg twice daily. The dose should be increased with a target of 160 mg daily if tolerated without side effects.

Administration of Valsartan with food decreases the absorption of Valsartan by about 40%, so it should be taken on an empty stomach. No initial dosage adjustment is required for elderly patients with mild to moderate renal and hepatic insufficiency.

Valsartan is generally well tolerated and side effects are rare. The most common side effects include headache, dizziness, fatigue, abdominal pain, cough, diarrhea and nausea. Patient may also experience hyperkalemia, impotency, reduced renal function, allergic reactions, dyspnea, constipation, back pain, muscle cramps, rash, anxiety, insomnia and vertigo. Hypotension may also occur if patient have been taking diuretics along with Valsartan.

Valsartan is contraindicated in patients who are hypersensitive to any component of this product.

Impaired Hepatic Function: As the majority of Valsartan is eliminated in the bile, care should be exercised in patients with mild to moderate hepatic impairment including biliary obstructive disorder.

Impaired Renal Function: Dosage reduction or discontinuation may be required with patients having pre-existing renal impairment.

Heart Failure and Myocardial Infarction: Caution should be exercised when initiating therapy in patients with heart failure and post-myocardial infarction patients.

No drug interactions of clinical significance have been found. Compounds which have been studied in clinical trials include Cimetidine, Warfarin, Furosemide, Digoxin, Atenolol, Indomethacin, Hydrochlorothiazide, Amlodipine and Glibenclamide

As Valsartan is not metabolized to a significant extent, clinically relevant drug-drug interactions in the form of metabolic induction or inhibition of the cytochrome P450 system are not expected with Valsartan. Although valsartan is highly bound to plasma proteins, in vitrostudies have not shown any interaction at this level with a range of molecules which are also highly protein bound, such as Diclofenac, Furosemide, and Warfarin. Concomitant use of potassium sparing diuretics (e.g., Spironolactone, Triamterene, Amiloride) potassium supplements, or salt substitutes containing potassium may lead to increase in serum potassium. If co medication is considered necessary, caution is advisable

Pregnancy: Valsartan should not be used in pregnancy, as in 2nd and 3rd trimester it can cause injury and even death to fetus. When pregnancy is detected, Valsartan should be stopped as soon as possible.

Nursing mothers: It is not known whether Valsartan is excreted in human milk. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric use: Safety and effectiveness in paediatric patients have not been established.

Geriatric use: No overall difference in the efficacy or safety of Valsartan was observed in this patient population, but greater sensitivity of some elderly persons cannot be ruled out.

Hepatic Impairment:

• Mild to moderate: Max: 80 mg once daily.
• Severe: Contraindicated.

Limited data are available related to overdosage in humans. The most likely manifestations of overdosage would be hypotension and tachycardia, bradycardia could occur from parasympathetic (vagal) stimulation. If excessive hypotension occurs, the patient should be placed in the supine position and if necessary, has to be given an intravenous infusion of normal saline.

Store between 15-30° C. Protect from moisture and heat.

Valsartan is indicated:

• For hypertension
• To reduce hospitalizations in patients with congestive heart failure
• To reduce death in patients who developed congestive heart failure after myocardial infarction

Angiotensin-ll receptor blocker

Valsartan is an oral medication that belongs to a class of drugs called angiotensin receptor blockers (ARBs). It is orally active and specific angiotensin II antagonist acting on the AT1 subtype. Angiotensin's attachment to the receptors cause the blood vessels to narrow (vasoconstrict) which leads to an increase in blood pressure (hypertension). Valsartan blocks the angiotensin II receptor. By blocking the action of angiotensin, Valsartan dilates blood vessels and reduces blood pressure without affecting pulse rate. Valsartan has much greater affinity (about 20,000-fold) for the AT1 receptor than for the AT2 receptor. It does not bind or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

Hypertension: The usual dose of Valsartan is 80 to 160 mg once daily. The maximum dose is 320 mg daily. Maximum blood pressure reduction occurs within 4 weeks. 

Heart failure: The usual dose is 40 mg twice daily and may be increased to 80-160 mg twice daily. 

Post-Myocardial Infarction: The initial dose after myocardial infarction is 20 mg twice daily. The dose should be increased with a target of 160 mg daily if tolerated without side effects.

Administration of Valsartan with food decreases the absorption of Valsartan by about 40%, so it should be taken on an empty stomach. No initial dosage adjustment is required for elderly patients with mild to moderate renal and hepatic insufficiency.

Valsartan is generally well tolerated and side effects are rare. The most common side effects include headache, dizziness, fatigue, abdominal pain, cough, diarrhea and nausea. Patient may also experience hyperkalemia, impotency, reduced renal function, allergic reactions, dyspnea, constipation, back pain, muscle cramps, rash, anxiety, insomnia and vertigo. Hypotension may also occur if patient have been taking diuretics along with Valsartan.

Valsartan is contraindicated in patients who are hypersensitive to any component of this product.

Impaired Hepatic Function: As the majority of Valsartan is eliminated in the bile, care should be exercised in patients with mild to moderate hepatic impairment including biliary obstructive disorder.

Impaired Renal Function: Dosage reduction or discontinuation may be required with patients having pre-existing renal impairment.

Heart Failure and Myocardial Infarction: Caution should be exercised when initiating therapy in patients with heart failure and post-myocardial infarction patients.

No drug interactions of clinical significance have been found. Compounds which have been studied in clinical trials include Cimetidine, Warfarin, Furosemide, Digoxin, Atenolol, Indomethacin, Hydrochlorothiazide, Amlodipine and Glibenclamide

As Valsartan is not metabolized to a significant extent, clinically relevant drug-drug interactions in the form of metabolic induction or inhibition of the cytochrome P450 system are not expected with Valsartan. Although valsartan is highly bound to plasma proteins, in vitrostudies have not shown any interaction at this level with a range of molecules which are also highly protein bound, such as Diclofenac, Furosemide, and Warfarin. Concomitant use of potassium sparing diuretics (e.g., Spironolactone, Triamterene, Amiloride) potassium supplements, or salt substitutes containing potassium may lead to increase in serum potassium. If co medication is considered necessary, caution is advisable

Pregnancy: Valsartan should not be used in pregnancy, as in 2nd and 3rd trimester it can cause injury and even death to fetus. When pregnancy is detected, Valsartan should be stopped as soon as possible.

Nursing mothers: It is not known whether Valsartan is excreted in human milk. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric use: Safety and effectiveness in paediatric patients have not been established.

Geriatric use: No overall difference in the efficacy or safety of Valsartan was observed in this patient population, but greater sensitivity of some elderly persons cannot be ruled out.

Hepatic Impairment:

• Mild to moderate: Max: 80 mg once daily.
• Severe: Contraindicated.

Limited data are available related to overdosage in humans. The most likely manifestations of overdosage would be hypotension and tachycardia, bradycardia could occur from parasympathetic (vagal) stimulation. If excessive hypotension occurs, the patient should be placed in the supine position and if necessary, has to be given an intravenous infusion of normal saline.

Store between 15-30° C. Protect from moisture and heat.

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

Dexibuprofen (S (+)-ibuprofen) is considered as the pharmacologically active enantiomer of racemic ibuprofen. Like racemic ibuprofen, Dexibuprofen is a non-steroidal anti-inflammatory drug with analgesic action. Like ibuprofen, Dexibuprofen acts by inhibiting prostaglandin synthesis.

Pharmacokinetics: Dexibuprofen is absorbed primarily from the small intestine. After metabolic transformation in the liver (hydroxylation, carboxylation) the pharmacologically inactive metabolites are completely excreted, mainly by the kidneys (90%), but also in the bile. The elimination half-life is 1.8-3.5 hours; the plasma protein binding is about 99%. Maximum plasma levels are reached about 2 hours after oral administration. The administration of dexibuprofen with a meal delays the time to reach maximum concentrations (from 2.1 hours after fasting conditions to 2.8 hours after non-fasting conditions) and decreases the maximum plasma concentrations (from 20.6 to 18.1 mcg/ml, which is of no clinical relevance), but has no effect on the extent of absorption.

The dosage must be adjusted to the seriousness of the syndrome and the complaints of the patient. During chronic pain, the dosage must be adapted to the lowest effective dose.

The recommended dosage: 600-900 mg Dexibuprofen per day, at 2-3 divided doses. The dosage can be raised temporarily up to 1200 mg Dexibuprofen per day in patients with acute disorders or exacerbations. The maximum daily dose is 1200 mg.

At dysmenorrhea: A dosage of 600 up to 900 mg Dexibuprofen per day, at a divided dose.

Clinical experience has shown that adverse effects of Dexibuprofen are similar to those of racemic ibuprofen. Common side-effects are dyspepsia, diarrhea, fatigue, and headache, nausea, vomiting, abdominal pain, hypersensitivity reactions - bleeding, ulcer.

Dexibuprofen is contraindicated in patients with previous history of hypersensitivity to Dexibuprofen, or another NSAID, or any other component of the product. Patients, who experience attack of asthma, arouse bronchospasm, acute rhinitis, urticaria or edema after use of similar drugs (e.g. aspirin or other NSAID's). It is also contraindicated in patients with active or suspected hemorrhage, Crohn's disease or ulcerative colitis, patients with serious heart diseases, kidney function impairment (GFR <30ml/min), and liver function impairment.

Dexibuprofen should be used with particular caution in patients with bronchial asthma or other chronic diseases of the pulmonary tract as well as in persons prone to allergy. The drug should be used in patients with hepatic, renal or cardiac insufficiency and with hypertension not responding to any treatment. Consultation with a doctor is recommended for patients with systemic lupus or with other autoimmunological disease before beginning therapy using the drug. Dexibuprofen should be used with extreme cautions in active and suspected hemorrhagic conditions such as gastro-duodenal ulcers, ulcerative colitis, Crohn's disease, alcoholism. Allergic reactions to the drug may appear even for the first-time user and in such case, it should immediately be stopped.

The reported drug interactions of Dexibuprofen are similar to that of racemic mixture of ibuprofen. Drug interactions is noticed with simultaneous use of anticoagulant, hydantoine and sulfonamide, ticlopidine, lithium, other NSAID's, ACE inhibitors, beta blockers, cyclosporine, tacrolimus, corticosteroids, digoxin, methotrexate, pentoxyfiline, phenytoine, probenecid, sulfinpyrazon, sulfonylurea, thiazide and thiazide type diuretics, and zidovudine.

Pregnancy: Although no teratogennic impact has been observed in the animal-experimental research with dexibuprofen or ibuprofen, the use should be avoided during the pregnancy. However, animal reproduction studies are not always predictive of human response. Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during late pregnancy should be avoided.

Lactation: Studies at people have shown that racimic ibuprofen proceed in small to negligible degree in mother milk. So, Dexibuprofen should be used with cautions in nursing mothers.

Hepatic impairment: Patients with mild to moderate liver function impairments must start with low amounts, and must closely be monitored. Dexibuprofen should not be used in patients with serious liver function impairments.

Renal impairment: The start amount must be reduced at patients with mild to moderate kidney function impairments. Dexibuprofen cannot be used patients with serious kidney function impairments.

Children Dose: Although Dexibuprofen is not licensed for use in children under 18 years of age in the UK, some countries permit such use. For example, in Switzerland, Dexibuprofen has been given to children aged 6 years and over at a dose of 10 to 15 mg/kg daily in 2-4 divided doses.

For elderly people: Lowest effective dose is recommended. The dosage can be raised to adult dosage if well tolerated.

Dexibuprofen has low acute toxicities. Symptoms of toxicity occur at doses between 80 and 100 mg/kg body weight. Mild symptoms are abdominal pain, nausea, vomiting, lethargy, headache, tinnitus and ataxia. Moderate to serious symptoms, such as flatulence, hypotension, hypothermia, metabolic acidosis, reduced kidney function, coma, and apnoea. The treatment must be symptomatic: there is no specific antidote. In case of large quantities of Dexibuprofen, activated charcoal should be administered. Vomiting can be induced only when life-threatening quantities of the substance ingested and the procedure can be carried out within 60 minutes after ingestion. Dialysis and hemodialysis are of little value as Dexibuprofen binds strongly to plasma protein.

Do not store above 30°C. Keep away from light and out of the reach of children

Rupatadine is indicated for the symptomatic treatment of Seasonal & Perennial Allergic Rhinitis and Urticaria.

Non-sedating antihistamines

Rupatadine is a long-acting, non-sedative antagonist of histamine H1-receptors. It also antagonizes the platelet activating factor (PAF). Both histamine and PAF cause broncho constriction which leads to an increase in the vascular permeability and act as a mediator in the inflammatory process. With the dual mode of action, Rupatadine shows better therapeutic effect than an isolated antihistamine. Rupatadine possesses other anti allergic properties such as the inhibition of the degranulation of mast cells induced by immunological and non immunological stimuli and inhibition of the release of cytokines, particularly of the tumor necrosis factor alpha (TNF α) in human mastocytes and monocytes.

Adults and adolescents (over 12 years): The recommended dose is 10 mg once a day. Rupatadine may be taken with or without food.

Children aged 2 to 11 years:

• Children weighing 25 kg or more: 1 teaspoonful (5 ml) of the oral solution once daily with or without food.
• Children weighing equal or more than 10 kg to less than 25 kg: 1/2 teaspoonful (2.5 ml) oral solution once daily with or without food.

Common: Asthenia, dizziness, drowsiness. Uncommon: Appetite increased, arthralgia, back pain, concentration impaired, constipation, cough, diarrhea, dry throat, epistaxis, fever, gastrointestinal discomfort, increased risk of infection, irritability, malaise, myalgia, nasal dryness, nausea, oropharyngeal pain, rash, thirst, vomiting, weight increased. Rare: Palpitations, tachycardia.

Hypersensitivity to Rupatadine or to any of the excipients.

Rupatadine should be used with caution in patients with known prolongation of the QT interval, patients with uncorrected hypokalemia, and patients with ongoing proarrhythmic conditions, such as clinically significant bradycardia or acute myocardial ischemia. Rupatadine should be used with caution in elderly patients (65 years and older). As there is no clinical experience in patients with impaired kidney or liver function, the use of Rupatadine 10 mg tablets is at present not recommended in these patients.

With medicine: The concomitant administration of Rupatadine 20 mg and ketoconazole or erythromycin increases the systemic exposure. Rupatadine should be used with caution when it is administered concomitantly with these drug substances and other inhibitors of the isozyme CYP3A4. Rupatadine should be used with caution when it is co-administered with statins, CNS depressants or alcohol.

With food: Grapefruit and Grapefruit juice should not be taken simultaneously with Rupatadine

There is no clinical data available on the exposure of Rupatadine during pregnancy. Pregnant women should therefore not use Rupatadine unless the potential benefit outweighs the potential risk for the infant. No information is available, whether Rupatadine is excreted in the mother's milk. Therefore, it should not be used during lactation, unless the potential benefits for the mother justify the potential risk to the infant.

Elderly: Rupatadine should be used with caution in elderly. No information is available that indicates the requirement of any dose adjustment in this population.

Children: Neither the safety nor the efficacy of Rupatadine has been established in patients less than 12 years of age.

Patients with renal or hepatic insufficiency: Use of Rupatadine is not recommended in patients with renal or hepatic insufficiency. As no relevant clinical data is available.

The most common adverse reaction was somnolence. If accidental ingestion of very high doses occurs, symptomatic treatment together with the required supportive measures should be given.

Store in cool & dry place below 30°C, protect from light & moisture. Keep out of reach of children.

Parenteral Phenytoin is indicated for the treatment of generalized tonic-clonic status epilepticus, and prevention and treatment of seizures occurring during neurosurgery. Intravenous Phenytoin can also be substituted, as short-term use, for oral phenytoin. Parenteral Phenytoin should be used only when oral Phenytoin administration is not possible

Adjunct anti-epileptic drugs

Phenytoin acts as an anticonvulsant by increasing efflux or decreasing influx of sodium ions across cell membranes in the motor cortex during generation of nerve impulses; thus stabilising neuronal membranes and decreasing seizure activity. It acts as an antiarrhythmic by extending the effective refractory period and suppressing ventricular pacemaker automaticity, shortening action potential in the heart.

Oral: Epilepsy:

• Adult: Initially, 3-4 mg/kg daily as single dose or in divided doses. Alternatively, 150-300 mg daily increased gradually to 600 mg daily if necessary. Maintenance: 200-500 mg daily.
• Child: Initially, 5 mg/kg daily in 2-3 divided doses. Maintenance: 4-8 mg/kg daily in divided doses. Max dose: 300 mg daily.

Intravenous: Tonic-clonic status epilepticus:

• Adult: Adjunctive therapy with a benzodiazepine (e.g. diazepam): 10-15 mg/kg by slow inj or intermittent infusion at a max rate of 50 mg/min. Maintenance: 100 mg IV (or orally) given every 6-8 hr.
• Child: Neonates: 20 mg/kg as a loading dose, then 2.5-5 mg/kg bid; 1 mth-12 yr: 18 mg/kg as a loading dose, then 2.5-5 mg/kg bid; >12 yr: 18 mg/kg as a loading dose, then up to 100 mg 3-4 times daily.

Should be taken with food. When administering to patients on nasogastric or other enteral feeds, do not administer feeds 2 hr before or after a dose. Be consistent throughout therapy in relation to feed times. Do not switch dosage forms/brands w/o prior consideration.

Hypersensitivity, lack of appetite, headache, dizziness, tremor, transient nervousness, insomnia, GI disturbances (e.g. nausea, vomiting, constipation), tenderness and hyperplasia of the gums, acne, hirsutism, coarsening of the facial features, rashes, osteomalacia. Phenytoin toxicity as manifested as a syndrome of cerebellar, vestibular, ocular effects, notably nystagmus, diplopia, slurred speech, and ataxia; also with mental confusion, dyskinesias, exacerbations of seizure frequency, hyperglycaemia. Solutions for inj may cause local irritation or phlebitis. Prolonged use may produce subtle effects on mental function and cognition, especially in children.

Phenytoin Sodium is contraindicated in patients with:

• A history of hypersensitivity to phenytoin, its inactive ingredients, or other hydantoins 
• Sinus bradycardia, sino-atrial block, second and third degree A-V block, and Adams-Stokes syndrome because of the effect of parenteral phenytoin on ventricular automaticity.
• A history of prior acute hepatotoxicity attributable to phenytoin 
• Coadministration with delavirdine because of the potential for loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors.

Cardiovascular disease, e.g. sinus bradycardia, heart blocks; DM; hepatic impairment; hypoalbuminemia; porphyria; seizures (may increase frequency of petit mal seizures); debilitated patients; elderly. Caution in IV admin in hypotension, heart failure or MI, monitor BP and ECG during therapy. IV must be given slowly (too rapid admin may cause hypotension, CNS depression, cardiac arrhythmias and impaired heart conduction). Extravasation and intra-arterial admin must be avoided. Do not discontinue abruptly (may increase seizure frequency), unless safety concerns require a more rapid withdrawal. May impair ability to drive or operate machinery.

Effects with other sedative drugs or ethanol may be potentiated. Enhances toxic effects of paracetamol, lithium. Increased risk of osteomalacia with acetazolamide. Decreased serum levels/effects with acyclovir, antineoplastics, benzodiazeines, ciprofloxacin, CYP2C9 inducers (e.g. carbamazepine), CYP2C19 inducers (e.g. rifampin), folic acid, vigabatrin. Increased serum concentrations with allopurinol, capecitabine, cimetidine, CYP2C9 inhibitors (e.g. fluconazole), CYP2C19 inhibitors (e.g. delavirdine), disulfiram, methylphenidate, metronidazole, omeprazole, SSRI, trazodone, trimethoprim. Increases metabolism of antiarrhythmics, anticonvulsants, antipsychotics, beta-blockers, calcium channel blockers, chloramphenicol, corticosteroids, doxycycline, oestrogens, HMG-CoA reductase inhibitors, methadone, theophylline, TCAs. Decreases levels/effects of clozapine, ciclosporin, tacrolimus, CYP2B6 substrates (e.g. bupropion, selegiline), CYP2C8 substrates (e.g. amiodarone), CYP2C9 substrates (e.g. celecoxib), CYP2C19 substrates (e.g. citalopram), CYP3A4 substrates (e.g. benzodiazepines), digoxin, itraconazole, levodopa, neuromuscular-blocking agents, thyroid hormones, topiramate. Increases levels/effect of dopamine, ticlopidine. Valproic acid may displace phenytoin from binding sites; and affect phenytoin serum concentrations. Transiently increases the hypothrombinaemia response to warfarin initially, followed by an inhibition of the response.

Category D: There is positive evidence of human foetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Pediatric Use: A loading dose of 15 to 20 mg/kg of Phenytoin intravenously will usually produce serum concentrations of phenytoin within the generally accepted serum total concentrations between 10 and 20 mcg/mL (unbound phenytoin concentrations of 1 to 2 mcg/mL). Because of the increased risk of adverse cardiovascular reactions associated with rapid administration Phenytoin should be injected slowly intravenously at a rate not exceeding 1 to 3 mg/kg/min or 50 mg per minute, whichever is slower

Geriatric Use: Phenytoin clearance tends to decrease with increasing age. Lower or less frequent dosing may be required 

Renal and Hepatic Impairment Or Hypoalbuminemia: The liver is the site of biotransformation. Patients with impaired liver function, elderly patients, or those who are gravely ill may show early toxicity. Because the fraction of unbound phenytoin is increased in patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of phenytoin serum levels should be based on the unbound fraction in those patients.

The lethal dose in pediatric patients is not known. The lethal dose in adults is estimated to be 2 to 5 grams. The initial symptoms are nystagmus, ataxia, and dysarthria. Other signs are tremor, hyperreflexia, lethargy, slurred speech, blurred vision, nausea, and vomiting. The patient may become comatose and hypotensive. Death is caused by respiratory and circulatory depression.

There are marked variations among individuals with respect to phenytoin serum levels where toxicity may occur. Nystagmus, on lateral gaze, usually appears at 20 mcg/mL, ataxia at 30 mcg/mL, dysarthria and lethargy appear when the serum concentration is over 40 mcg/mL, but as high a concentration as 50 mcg/mL has been reported without evidence of toxicity. As much as 25 times the therapeutic dose has been taken to result in a serum concentration over 100 mcg/mL with complete recovery. Irreversible cerebellar dysfunction and atrophy have been reported.

Treatment: Treatment is nonspecific since there is no known antidote. The adequacy of the respiratory and circulatory systems should be carefully observed and appropriate supportive measures employed. Hemodialysis can be considered since phenytoin is not completely bound to plasma proteins. Total exchange transfusion has been used in the treatment of severe intoxication in pediatric patients. In acute overdosage the possibility of other CNS depressants, including alcohol, should be borne in mind.

Intravenous: Store at room temperature of 15-30°C.
Oral: 

• Tablet/capsule: Store below 30°C. Protect from light and moisture;
• Oral suspension: Store at room temperature of 20-25°C, do not freeze, protect from light.

Parenteral Phenytoin is indicated for the treatment of generalized tonic-clonic status epilepticus, and prevention and treatment of seizures occurring during neurosurgery. Intravenous Phenytoin can also be substituted, as short-term use, for oral phenytoin. Parenteral Phenytoin should be used only when oral Phenytoin administration is not possible

Adjunct anti-epileptic drugs

Phenytoin acts as an anticonvulsant by increasing efflux or decreasing influx of sodium ions across cell membranes in the motor cortex during generation of nerve impulses; thus stabilising neuronal membranes and decreasing seizure activity. It acts as an antiarrhythmic by extending the effective refractory period and suppressing ventricular pacemaker automaticity, shortening action potential in the heart.

Oral: Epilepsy:

• Adult: Initially, 3-4 mg/kg daily as single dose or in divided doses. Alternatively, 150-300 mg daily increased gradually to 600 mg daily if necessary. Maintenance: 200-500 mg daily.
• Child: Initially, 5 mg/kg daily in 2-3 divided doses. Maintenance: 4-8 mg/kg daily in divided doses. Max dose: 300 mg daily.

Intravenous: Tonic-clonic status epilepticus:

• Adult: Adjunctive therapy with a benzodiazepine (e.g. diazepam): 10-15 mg/kg by slow inj or intermittent infusion at a max rate of 50 mg/min. Maintenance: 100 mg IV (or orally) given every 6-8 hr.
• Child: Neonates: 20 mg/kg as a loading dose, then 2.5-5 mg/kg bid; 1 mth-12 yr: 18 mg/kg as a loading dose, then 2.5-5 mg/kg bid; >12 yr: 18 mg/kg as a loading dose, then up to 100 mg 3-4 times daily.

Should be taken with food. When administering to patients on nasogastric or other enteral feeds, do not administer feeds 2 hr before or after a dose. Be consistent throughout therapy in relation to feed times. Do not switch dosage forms/brands w/o prior consideration.

Hypersensitivity, lack of appetite, headache, dizziness, tremor, transient nervousness, insomnia, GI disturbances (e.g. nausea, vomiting, constipation), tenderness and hyperplasia of the gums, acne, hirsutism, coarsening of the facial features, rashes, osteomalacia. Phenytoin toxicity as manifested as a syndrome of cerebellar, vestibular, ocular effects, notably nystagmus, diplopia, slurred speech, and ataxia; also with mental confusion, dyskinesias, exacerbations of seizure frequency, hyperglycaemia. Solutions for inj may cause local irritation or phlebitis. Prolonged use may produce subtle effects on mental function and cognition, especially in children.

Phenytoin Sodium is contraindicated in patients with:

• A history of hypersensitivity to phenytoin, its inactive ingredients, or other hydantoins 
• Sinus bradycardia, sino-atrial block, second and third degree A-V block, and Adams-Stokes syndrome because of the effect of parenteral phenytoin on ventricular automaticity.
• A history of prior acute hepatotoxicity attributable to phenytoin 
• Coadministration with delavirdine because of the potential for loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors.

Cardiovascular disease, e.g. sinus bradycardia, heart blocks; DM; hepatic impairment; hypoalbuminemia; porphyria; seizures (may increase frequency of petit mal seizures); debilitated patients; elderly. Caution in IV admin in hypotension, heart failure or MI, monitor BP and ECG during therapy. IV must be given slowly (too rapid admin may cause hypotension, CNS depression, cardiac arrhythmias and impaired heart conduction). Extravasation and intra-arterial admin must be avoided. Do not discontinue abruptly (may increase seizure frequency), unless safety concerns require a more rapid withdrawal. May impair ability to drive or operate machinery.

Effects with other sedative drugs or ethanol may be potentiated. Enhances toxic effects of paracetamol, lithium. Increased risk of osteomalacia with acetazolamide. Decreased serum levels/effects with acyclovir, antineoplastics, benzodiazeines, ciprofloxacin, CYP2C9 inducers (e.g. carbamazepine), CYP2C19 inducers (e.g. rifampin), folic acid, vigabatrin. Increased serum concentrations with allopurinol, capecitabine, cimetidine, CYP2C9 inhibitors (e.g. fluconazole), CYP2C19 inhibitors (e.g. delavirdine), disulfiram, methylphenidate, metronidazole, omeprazole, SSRI, trazodone, trimethoprim. Increases metabolism of antiarrhythmics, anticonvulsants, antipsychotics, beta-blockers, calcium channel blockers, chloramphenicol, corticosteroids, doxycycline, oestrogens, HMG-CoA reductase inhibitors, methadone, theophylline, TCAs. Decreases levels/effects of clozapine, ciclosporin, tacrolimus, CYP2B6 substrates (e.g. bupropion, selegiline), CYP2C8 substrates (e.g. amiodarone), CYP2C9 substrates (e.g. celecoxib), CYP2C19 substrates (e.g. citalopram), CYP3A4 substrates (e.g. benzodiazepines), digoxin, itraconazole, levodopa, neuromuscular-blocking agents, thyroid hormones, topiramate. Increases levels/effect of dopamine, ticlopidine. Valproic acid may displace phenytoin from binding sites; and affect phenytoin serum concentrations. Transiently increases the hypothrombinaemia response to warfarin initially, followed by an inhibition of the response.

Category D: There is positive evidence of human foetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Pediatric Use: A loading dose of 15 to 20 mg/kg of Phenytoin intravenously will usually produce serum concentrations of phenytoin within the generally accepted serum total concentrations between 10 and 20 mcg/mL (unbound phenytoin concentrations of 1 to 2 mcg/mL). Because of the increased risk of adverse cardiovascular reactions associated with rapid administration Phenytoin should be injected slowly intravenously at a rate not exceeding 1 to 3 mg/kg/min or 50 mg per minute, whichever is slower

Geriatric Use: Phenytoin clearance tends to decrease with increasing age. Lower or less frequent dosing may be required 

Renal and Hepatic Impairment Or Hypoalbuminemia: The liver is the site of biotransformation. Patients with impaired liver function, elderly patients, or those who are gravely ill may show early toxicity. Because the fraction of unbound phenytoin is increased in patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of phenytoin serum levels should be based on the unbound fraction in those patients.

The lethal dose in pediatric patients is not known. The lethal dose in adults is estimated to be 2 to 5 grams. The initial symptoms are nystagmus, ataxia, and dysarthria. Other signs are tremor, hyperreflexia, lethargy, slurred speech, blurred vision, nausea, and vomiting. The patient may become comatose and hypotensive. Death is caused by respiratory and circulatory depression.

There are marked variations among individuals with respect to phenytoin serum levels where toxicity may occur. Nystagmus, on lateral gaze, usually appears at 20 mcg/mL, ataxia at 30 mcg/mL, dysarthria and lethargy appear when the serum concentration is over 40 mcg/mL, but as high a concentration as 50 mcg/mL has been reported without evidence of toxicity. As much as 25 times the therapeutic dose has been taken to result in a serum concentration over 100 mcg/mL with complete recovery. Irreversible cerebellar dysfunction and atrophy have been reported.

Treatment: Treatment is nonspecific since there is no known antidote. The adequacy of the respiratory and circulatory systems should be carefully observed and appropriate supportive measures employed. Hemodialysis can be considered since phenytoin is not completely bound to plasma proteins. Total exchange transfusion has been used in the treatment of severe intoxication in pediatric patients. In acute overdosage the possibility of other CNS depressants, including alcohol, should be borne in mind.

Intravenous: Store at room temperature of 15-30°C.
Oral: 

• Tablet/capsule: Store below 30°C. Protect from light and moisture;
• Oral suspension: Store at room temperature of 20-25°C, do not freeze, protect 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.

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.