Ranitidine Hydrochloride

Ranitidine Hydrochloride

75mg Tablet

150mg Tablet

300mg Tablet

Drug Category: H₂ Receptor Antagonist

Structure and Chemical Name:

N[2-[[[5-[9dimethylamino)methyl]-2-furanyl]methyl]thio]ethyl]-N-methyl-2-nitro-1,1-ethenediamine, hydrochloride. C₁₃H₂₂N₄S.HCl

Pharmacology:

Ranitidine is a specific rapidly acting histamine H₂-antagonist. It inhibits basal and stimulated secretions of gastric acid, reducing both the volume and the acid and pepsin content of the secretion. Ranitidine has a long duration of action and a single 75-mg dose suppresses gastric acid secretion for up to twelve hours.

Clinical studies have shown that Ranitidine can relieve the symptoms of excess acid production for up to twelve hours.

Pharmacokinetics:

Ranitidine HCl is 50% absorbed after oral administration. Absorption is not significantly impaired by the administration of food or antacids. Following a single dose of 150mg, serum concentrations of ranitidine HCl are in this range up to 12 hours. However, blood levels bear no consistent relationship to dose or degree of acid inhibition.

The principal route of excretion is the urine, with approximately 30% of the orally administered dose collected in the urine as unchanged drug in 24 hours. Renal clearance is about 410ml per minute, indicating active tubular excretion.

In man, the N-oxide is the principal metabolite in he urine; however, this amounts to <4% of the dose. Other metabolites are the S-oxide (1%) and the desmethyl ranitidine (1%). The remainder of the administered dose is found in the stool.

The volume of distribution is about 1.4L/kg. Serum protein binding averages 15%.

Indications:

• Short-term treatments of active duodenal ulcer
• Maintenance therapy for duodenal ulcer patients at reduced dosage after healing of acute ulcers
• The treatment of pathological hypersectory conditions (e.g. Zollinger-Ellison syndrome and systemic mastocytosis)
• Short-term treatment of active, benign gastric ulcer
• Maintenance therapy for gastric ulcer patients at reduced dosage after healing of acute ulcers
• Treatment of GERD
• Treatment of endoscopically diagnosed erosive esophagitis
• Maintenance of healing of erosive esophagitis

Contraindications:

Ranitidine is contraindicated for patients known to be hypersensitivity to the drug or any of the ingredients of the product.

Precautions and Warnings:

• Ranitidine excreted via the kidney and so plasma levels of the drug are increased in patients with severe renal impairment. Ranitidine is not suitable for these patients.
• Patients who are taking non-steroidal anti-inflammatory drugs especially in the elderly should be referred to their doctor before taking ranitidine.
• Although clinical reports of acute intermittent porphyria associated with ranitidine administration have been rare and inconclusive; ranitidine should be avoided in patients with a history of this conditions.
• Treatment with histamine H₂-antagonist may mask symptoms associated with carcinoma of the stomach and may therefore delay diagnosis of the condition.

Use in Pregnancy and Lactation:

Ranitidine crosses the placenta but therapeutic doses administered to obstetric patients in labor or undergoing cesarean section have been without any adverse effect in labor, delivery or subsequent neonatal progress. Therefore, ranitidine should not be taken during pregnancy without consulting a doctor.

Ranitidine is also excreted in human breast milk and women who are breast feeding will be advised to speak to their doctor before taking Ranitidine.

Drug Interactions:

• Although ranitidine has been reported to bind weakly to cytochrome P-450 in vitro, recommended doses of the drug do not inhibit the action of the cytochrome P-450-linked oxygenase enzymes in the liver. However, ranitidine may affect the bioavailability of certain drugs by some mechanism.
• Increased or decreased prothrombin times have been reported during concurrent use of ranitidine and warfarin. However, in human pharmacokinetic studies with dosages of ranitidine up to 400mg per day, no interaction occurred; ranitidine had no effect on warfarin clearance or prothrombin time.
• Reduced gastric acidity due to ranitidine may result in an increase in the availability of triazolam, when used concurrently. The clinical significance of triazolam and ranitidine pharmacokinetic interaction is unknown.

Adverse Effects:

• Transient and reversible changes in liver function tests can occur. There have been occasional reports of reversible hepatitis (hepatocellular, hepatocanalicular or mixed) with or without jaundice.
• Leucopenia and thrombocytopenia have occurred rarely in patients. The are usually reversible.
• Rare cases of agranulocytosis or of pancytopenia, sometimes with marrow hypoplasia, or aplasia have been reported.
• Hypersensitivity reactions (urticaria, angioneurotic edema, fever, bronchospasm, hypotension, anaphylactic shock) have been seen rarely following oral administration of ranitidine. These reactions have occasionally occurred after a single dose.
• As with other H₂ receptor antagonist there have been rare reports of bradycardia and AV block.
• Headache, sometimes severe and dizziness have been reported in a very small proportion of patients. Rare cases of vasculitis and alopecia have been reported rarely.
• Reversible impotence has been reported rarely.
• Musculoskeletal symptoms such as arthralgia and myalgia have been reported rarely.
• There have been a few reports of breast symptoms (swelling and/or discomfort) in men taking ranitidine; some cases have resolved on continued ranitidine treatment.

Dosage and Administration:

Usual dosage of Ranitidine is 150mg twice daily. Alternatively, it can be given as a single bedtime dose of 300mg. Treatment should be continued for up to 4-8 weeks in most cases of duodenal ulcer, gastric ulcer and post operative ulcer and reflux esophagitis. In cases of NSAIDs induced ulceration, 150mg twice daily at bedtime should be given. In patient with Zollinger-Ellison syndrome, the starting dose is 150m twice or three times daily and this may be increased as necessary. Patients with this syndrome have been given increasing doses up to 6g/day and these doses have been well tolerated; or as prescribed by the physician.

Overdosage:

Ranitidine is very specific in action and accordingly no particular problems are expected following overdosage with the drug. Symptomatic and supportive therapy should be given as appropriate. However, in case of overdose, symptomatic treatment with gastric lavage should employed. If need be, the drug may be removed form the plasma by hemodialysis.

Storage Condition:

Store at temperatures not exceeding 30^oC.

Protect from direct sunlight.

Keep out or reach of children.

Amlodipine besilate

Amlodipine besilate

5mg Tablet

10mg Tablet

Drug Category: Anti-hypertensive / Calcium Channel Blocker

Pharmacodynamic Properties

Mechanism of Action:

Amlodipine is a calcium ion influx inhibitor of the dihydropyridine group (slow channel blocker or calcium ion antagonist) and inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle.

The mechanism of the antihypertensive action of amlodipine is due to a direct relaxant effect on vascular smooth muscle. The precise mechanism by which amlodipine relieves angina has not been fully determined but amlodipine reduces total ischemic burden by the following two actions.

1. Amlodipine dilates peripheral arterioles and thus, reduces the total peripheral resistance (afterload) against which the heart works. Since the heart rate remains stable, this unloading of the heart reduces myocardial energy consumption and oxygen requirements.
2. The mechanism of action of amlodipine also probably invovles dilation of the main coronary arteries and coronary arterioles, both in normal and ischemic regions. This dilation increases myocardial oxygen delivery in patients with coronary artery spasm (Prinzmetal's or variant angina).

In patients with hypertension, once daily dosing provides clinical significant reductions of blood pressure in both the supine and standing positions throughout the 24 hour interval. Due to the slow onset of action, acute hypotension is not a feature of amlodipine administration.

In patients with angina, once daily administration of amlodipine increases total exercise time, time to angina onset, and time to 1mm ST segment depression, and decreases both angina attack frequency and glyceryl trinitrate tablet consumption.

Amlodipine has not been associated with any adverse metabolic effects or changes in plasma lipids and is suitable for use in patients with asthma, diabetes and gout.

Use in Patients with Heart Failure: Hemodynamic studies and exercise based controlled clinical trials in NYHA Class II-IV heart failure patients have shown that amlodipine did not lead to clinical deterioration as measured by exercise tolerance, left ventricular ejection fraction and clinical symptomatology.

A placebo controlled study designed to evaluate patients in NYHA Class III-IV heart failure receiving digoxin, diuretics and ACE inhibitors has shown that amlodipine did not lead to an increase in risk of mortality or combined mortality and morbidity with heart failure.

In a follow-up, long term, placebo controlled study of amlodipine in patients with NYHA III and IV heart failure without clinical symptoms or objective finding suggestive or underlying ischemic disease, on stable doses of ACE inhibitors, digitalis and diuretics, amlodipine had no effect on total cardiovascular mortality. In this same population amlodipine was associated with increased reports of pulmonary edema despite no significant difference in the incidence of worsening heart failure as compared to placebo.

The long-term effects of amlodipine on growth, puberty and general development have not been studied. The long-term efficacy of amlodipine on therapy in childhood to reduce cardiovascular morbidity and mortality in adulthood have also not been established.

Pharmacokinetic Properties:

Amlodipine is well absorbed following oral administration with peak plasma blood concentrations occurring after 6 12 hours. It has prolonged terminal elimination half-life of 35 to 50 hours and steady state plasma concentrations are not achieved until 7 to 8 days of administration.

Amlodipine is extensively metabolized; metabolites are mostly excreted in urine together with less than 10% of a dose as unchanged drug.

Amlodipine is reported to be about 97.5% bound to plasma protein.

Use in the elderly:

The time to reach peak plasma concentrations of amlodipine is similar in elderly and younger subjects. Amlodipine clearance tends to be decreased with resulting increases in AUC and elimination half-life in elderly patients. Increases in AUC and elimination half-life in patients with congestive heart failure were as expected for the patient age group studied.

Indication

Management of Hypertension.

Management of stable and vasopastic angina pectoris.

Dosage and Administration

For Adults:

For both hypertension and angina the usual initial dose is 5mg amlodipine once daily which may be increased to a maximum dose of 10mg depending on the individual patient's response.

No dose adjustment of amlodipine is required upon concomitant administration of thiazide diuretics, beta blockers, and angiotensin-converting enzyme inhibitors.

Use in the elderly: Amlodipine is used at similar doses in elderly or younger patients, is equally well tolerated. Therefore normal dosage regimens are recommended.

Patients with 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.

For Children and infants by age groups: Not recommended.

Contraindication

• Amlodipine is contraindicated in patients with known sensitivity to dihydropyridines, amlodipine or any of the excipients.
• Amlodipine should not be used in cardiogenic shock, clinically significant aortic stenosis, unstable angina (excluding Prinzmetal's angina)
• Pregnancy and lactation

Warning and Precautions

Use in patients with Heart Failure: In a long-term, placebo controlled study of amlodipine in patients with NYHA III and IV heart failure or non-ischemic etiology, amlodipine was associated with increased reports of pulmonary edema despite no significant difference in the incidence of worsening heart failure as compared to placebo.

Use in patients with impaired hepatic function: As with all calcium antagonists, amlodipine's half-life is prolonged in patients with impaired liver function and dosage recommendations have not been established. The drug should therefore be administered with caution in these patients.

There are no data to support the use of amlodipine alone, during or within one month of myocardial infarction.

The safety and efficacy of amlodipine in hypertensive crisis has not been established.

Pregnancy and Lactation

Although some dihydropyridine compounds have been found to be teratogenic in animals, data in the rat and rabbit for amlodipine provide no evidence for a teratogenic effect. There is, however, no clinical experience with the preparation in pregnancy or lactation. Accordingly, amlodipine should not be administered during pregnancy, or lactation, or to women of childbearing potential unless effective concentration is used.

Adverse Drug Reactions

The most commonly reported side effects of amlodipine are headache, edema, rash, fatigue, nausea, flushing, and dizziness.

Other reported side effects are:

Blood and lymphatic system disorders

Very rare: thrombocytopenia, leucocytopenia

Immune system disorders

Very rare: allergic reaction

Metabolic and nutrition disorders

Very rare: hyperglycemia

Psychiatric disorders

Uncommon: mood changes, insomnia

Nervous system disorders

Common: somnolence

Uncommon: tremor, taste pervesion, syncope, hypoaesthesia, paresthesia

Very rare: peripheral neuropathy

Eye disorders

Uncommon: visual disturbances

Ear and Labyrinth disorders

Uncommon: tinnitus

Cardiac disorders

Common: palpitations

Rare: syncope

Very rare: Myocardial infarction, arrhythmia, ventricular tachycardia and atrial fibrillation

Vascular disorders

Uncommon: hypotension

Very rare: vasculitis

Respiratory, thoracic and mediastinal disorders

Uncommon: Dyspnea, rhinitis

Very rare: coughing

Gastrointestinal disorders

Common: Abdominal pain

Uncommon: Vomiting, dyspnea, altered bowel habits, dry mouth

Very rare: Pancreatitis, gastritis, gingival hyperplasia

Hepato-biliary disorders

Very rare: Abnormal liver function tests, hepatitis, jaundice

Skin and subcutaneous tissue disorders

Uncommon: alopecia, pruritus, perpura, skin discoloration, increased sweating

Very rare: erythema multiforme, angioedema and urticaria

Musculoskeletal, connective tissue and bone disorders

Uncommon: Myalgia, arthralgia, muscle cramps and back pain

Renal and urinary disorders

Uncommon: Increased urinary frequency, micturition disorder, nocturia

Reproductive system and breast disorders

Uncommon: Impotence, gynecomastia

General disorders and administration site conditions

Uncommon: Chest pain, asthenia, pain, malaise, increase or decrease in weight

Drug Interactions

Amlodipine has been safely administered with thiazide diuretics, alpha blockers, beta blockers, angiotensin-converting enzyme inhibitors, long acting nitrates, sublingual glyceryl trinitrate, non-steroidal anti-inflammatory drugs (NSAIDs), antibiotics and oral hypoglycemic drugs.

Special Studies: Effect of Other agents on amlodipine

Cimetidine: Co-administration of amlodipine with cimetidine did not alter the pharmacokinetics of amlodipine.

Grapefruit Juice: Co-administration of 240ml of grapefruit juice with a single oral dose of amlodipine 10mg in 20 healthy volunteers had no significant effect on the pharmacokinetics of amlodipine.

Sildenafil: When amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect.

Special Studies: Effect of amlodipine on other agents

Atorvastatin: Co-administration of multiple 10mg doses of amlodipine with 80mg of atorvastatin resulted in no significant change in the steady state pharmacokinetics parameters of atorvastatin.

Digoxin: Co-administration of amlodipine with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers.

Warfarin: In healthy male volunteers, the co-administration of amlodipine does not significantly alter the effect of warfarin on prothrombin response time. Co-administration of amlodipine with warfarin did not change the warfarin prothrombin response time.

Ciclosporin: Pharmacokinetics studies with ciclosporin have demostrated that amlodipine does not significantly alter the pharmacokinetics of ciclosporin.

Drug/Laboratory test Interactions: None known.

Known symptoms of overdosage and particular of its treatment:

There is no documented experience with amlodipine overdosage. Gastric lavage may be of benefit. Gross overdosage could result in excessive peripheral vasodilation, resulting in marked and probably prolonged systemic hypotension. Clinically significant hypotension due to amlodipine over-dosage requires active cardiovascular support. Intravenous calcium gluconate may be of benefit in reversing the effects of calcium channel blockade. Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit. TREATMENT IS SYMPTOMATIC AND SUPPORTIVE.

Storage Conditions:

Store at temperatures not exceeding 30^oC.

Terbutaline Sulfate

Terbutaline Sulfate

2.5mg Tablet

1.5mg/5ml Syrup

Drug Category: β-adrenergic Receptor Agonist (Anti-asthma)

Pharmacologic Action:

Terbutaline sulfate contains a sympathomimetic substance which stimulates β-adrenergic receptors of the sympathetic nervous system. Its main effect is relaxation of smooth muscles of the bronchial tree and peripheral vaculature.

Indications:

For the relief of reversible bronchospasm in patients with obstructive airway disease, e.g., asthma, bronchitis, and emphysema.

Dosage and Administration:

Adults: 2.5mg three times daily to be increased to 5mg three times daily as necessary.

Pediatric Dose: Children's doses may be calculated on the basis of the body weight: a dose of 75mcg per kg three times daily. For children over 7 years of age 2.5mg two or three times daily or as prescribed by the physicians.

Contraindications:

Patients who are known to be hypersensitive to sympathomimetic agents.

Precaution:

Terbutaline sulfate should be used with caution in patients with diabetes mellitus, hypertension, hyperthyroidism or cardiac disease especially those with associated arrhythmias. Discontinue use and consult a physician if decreased effectiveness and bronchoconstriction occurs.

Use in pregnancy and lactation:

Although no teratogenic effects have been observed in animals or in patients, caution is recommended during the first trimester of pregnancy. It passes into the maternal milk but the risk of influence on the child is unlikely with therapeutic doses.

Adverse Effect:

The most common observed adverse effects are tremor and nervousness. The frequency of side effects appear to diminish with continual therapy. Other reported reactions are headache, drowsiness, vomiting, nausea, sweating and muscle cramps. There are usually transient and do not require treatment.

Interactions:

Other sympathomimetic bronchodilators or epinephrine should not be used concomitantly with terbutaline sulfate, since their combined effects may be deleterious to the patients. It should be used with caution in patients being treated with MAOI or tricyclic antidepressants, since the action of terbutaline on the cardiovascular system may be potentiated.

Storage Condition:

Store at temperature not exceeding 30^oC.

Rosuvastatin

Rosuvastatin

10mg Tablet

20mg Tablet

40mg Tablet

Drug Category: Antihyperlipidemic

Pharmacokinetics:

Rosuvastatin is incompletely absorbed from the gastrointestinal tract, with bioavailability of about 20%. Peak plasma concentration are achieved about 5 hours after an oral dose. It is taken up extensively by the liver, its primary site of action, and undergoes limited metabolism, mainly by the cytochrome P450 isoenzyme CYP2C9. It is abut 90% bound to plasma proteins. The plasma elimination half-life of rosuvastatin is about 19 hours. About 19% of oral dose of rosuvastatin is excreted in the feces, including absorbed and non-absorbed drug, and the remainder is excreted in the urine; about 5% of a dose is excreted unchanged in urine.

Indication:

For primary hypercholesterolemia (Type IIa including heterozygous familial hypercholesterolemia), mixed dyslipidemia (Type IIb), or homozygous familial hypercholesterolemia in patients who have not responded adequately to diet and other appropriate measure.

Contraindication:

Rosuvastatin is contraindicated in patients with a known hypersensitivity. It is contraindicated in patients with active liver disease or with unexplained persistent elevations of serum transaminases.

Drug Interaction:

Rosuvastatin undergoes limited metabolism, principally by the cytochrome P450 isoenzyme CYP2CP, and may not have the same interactions with enzyme inhibitors as simvastatin. However, increased rosuvastatin plasma concentrations have been reported with ciclosporin and, to a lesser extent, with gemfibrozil, and such combination should be avoided. If they must be given together, lower doses of rosuvastatin should be used.

Adverse Effects:

The most common adverse effects of therapy with rosuvastatin and other statins are gastrointestinal disturbances. Other adverse effects reported include headache, skin rashes, dizziness, blurred vision, insomnia, dysgeusia. Reversible increases in serum-aminotransferase concentration may occur and liver function should be assessed before treatment is initiated and then monitored periodically until one year after the last elevation in dose. Hepatitis and pancreatitis have been reported. Myopathy, characterized by myalgia, and muscle weakness and associated with increased creatinine phosphokinase concentration has been reported, especially in patients taking rosuvastatin concurrently with ciclosporin, fibric acid and derivatives or nicotinic acid. Rarely, rhabdomyolysis with acute renal failure may develop.

Precaution:

Rosuvastatin should not be given to patients with acute liver disease and unexplained persistently raised serum-aminotransferase concentrations. It should be avoided during pregnancy since there is a possibility that it could interfere with fetal sterol synthesis; there have been few reports of congenital abnormalities associated with statins. It should be discontinued if marked or persistent increases in serum-aminotranferase or creatine phosphokinase concentrations occur. It should be used with caution in patients with severe renal impairment.

Dosage and Administration:

Usual initial dose is 10mg once daily. However, a lower initial dose of 5mg once daily may be adequate is also recommended for patients at risk of myopathy. Patients with marked hypercholesterolemia, may be started on 20mg once daily. Or prescribed by the physicians.

Storage Condition:

Store at temperatures not exceeding 30^oC.

Phospholipids

Phospholipids

300mg Hard Gel Capsule

Category: Hepatoprotector

Composition:

Phospholipids as active ingredient. is from soya-bean 300mg

Indications:

Nutritional support in the management of damaged liver (due to chronic liver disease, liver cirrhosis, fatty liver and intoxication by hepatotoxic substances).

Dosage and Administrations:

Age and/or Body Weight : Children from 12 years (approx. 43 kg), Adolescents and adults

Single dose: 2 hard capsules (600mg of soya-bean phospholipids)

Total daily dose: 3 times daily 2 hard capsules (1800mg of soya-bean phospholipids)

Phospholipids 300mg hard gel capsule is taken unchewed with meals with plenty of liquid (e.g. with a glass of water).

Basically, the duration of the application is not limited.

Contraindications:

Known hypersensitivity to soya-bean preparations or to any of the excipients.

Special warnings and precautions for use:

This drug therapy is not a substitute for the avoidance of the noxious agent causing liver damage (e.g. alcohol). In chronic hepatitis the adjuvant therapy with soya-bean phospholipids is justified only when improved subjective well-being becomes manifest during therapy.

Consult your doctor when complaints aggravate or when other unclear complaints occur.

Children:

As information about the administration in children is insufficient, Phospholipids 300mg hard gel capsule should not be given to children under 12 years of age.

Due to the content in soya-bean oil the medicinal product may provoke severe allergic reactions.

Interaction with other medicinal products and other forms of interaction:

An interaction of Phospholipids 300mg hard gel capsule with anti-coagulants cannot be excluded. For this reason, dose adjustment of the anti-coagulants might be necessary.

Consult a doctor in the case of simultaneous application.

Pregnancy and lactation:

Preparation from soya-bean are largely used in human food and so for no clue has appeared that would suggest any risk during pregnancy. Results from investigation are insufficient. For this reason, the use of Phospholipids 300mg hard gel capsule is not recommended during pregnancy and lactation.

Effects on ability to drive and use machines:

Phospholipids 300mg hard gel capsule has no effect on the ability to drive and to use machines.

Side Effects:

For the evaluation of any adverse effects the following incidences are considered:

very frequent (≥1/10)

frequent (≥1/100 to ≥1/10)

occasional (≥1/1,000 to ≥1/1,00)

rare (≥1/10,000 to ≥1/1,000)

very rare (<1/10,000)

Occasionally the administration of Phospholipids 300mg hard gel capsule may provoke gastrointestinal disorders, such as stomach complaints, soft stools and diarrhea. On very rare occasions allergic reactions may occur, such as exanthema and urticaria. The doctor or pharmacist should be informed about any undesirable effect not listed.

The administration of Phospholipids 300mg hard gel capsule should be discontinued in the event of one of the above mentioned undesirable effects, especially in hypersensitivity reactions. The patient should consult who may decide the severity and any measures that might be necessary.

Overdose:

No overdose reaction nor symptom of intoxication has been reported to date with Phospholipids 300mg hard gel capsule.

The listed undesirable effects may be reinforced.

The patient should consult the doctor who may decide about the severity and any measures that might be necessary.

Clinical Pharmacology

Pharmacodynamic:

Among the pharmacodynamic properties reported were hepatoprotective effects found in numerous experimental models in acute liver damage (induced by ethanol, alcyl alcohol, carbon tetrachloride, paracetamol and galactosamine). Furthermore, it was also seen to inhibit steatosis and fibrosis in chronic liver damage models (induced by ethanol, thioacetamide, and organic solvents). Its suggested principal actions have been through accelerated membrane regeneration and stabilization, inhibited lipid peroxidation and inhibited collagen synthesis.

Pharmacokinetic:

Animal experiments into the pharmacokinetics showed that more than 90% of the orally applied soya-bean phospholipids are absorbed in the small intestines. Most of it is split by phospholipase A to 1-acyl-lysophosphatidylcholine, 50% of which reacylated immediately into polyunsaturated phosphotidylcholine still during the process of absorption in the intestinal mucosa. This polyunsaturated phosphatidylcholine reaches the blood via the lymph pathway and from there – mainly bound to HDL – it passes in particular to the liver.

Tests into human pharmacokinetics were performed with radioactively labeled dilinoleoyl-phosphatidlcholine (³H and ¹⁴C). The choline moiety was ³H-labeled and the linoleic acid had the ¹⁴C-label. The maximum ¹⁴C concentration was achieved after 4 to 12 hours and amounted to 27.9% of the dose. The half-life for this component was 32 hours.

In the feces were found 2% of the ³H and 4.5% of the ¹⁴C label,in the urine 6% of the ³H and only minor amounts of the ¹⁴C label.

These results show that both isotopes are absorbed to over 90% in the intestines.

Storage Conditions:

Store in the original container, not above 25^oC

Store in the original container in order to protect from humidity.

Do not use after the expiry date.

Shelf life: 2 years

Amikacin Sulfate

Amikacin Sulfate

100mg/2ml

250mg/2ml

500mg/2ml

Description: Amikacin Sulfate is a semisynthetic aminoglycoside antibiotic derived from kanamycin. It is C₂₂H₄₃N₅O₁₃.2H₂SO₄. D-Streptamine, 0-3-amino-3deoxy-a-D-glycopyranosyl-(1→6)-)(6-aamino-6deoxy-a-d-glucopyranosyl-(1→ 4)-N1-(4-amino-2-hydroxyl-oxobuty)2-deoxy-, (S)-, sulfate (1:2) (salt).

Clinical Pharmacology:

Intramuscular Administration – Amikacin is rapidly absorbed after intramuscular administration. In normal adult volunteers, average peak serum concentration about 12, 16 and locally, following repeated intramuscular dosing, and when given at maximally recommended doses, no ototoxicity or nephrotoxicity has been reported. There is no evidence of drug accumulation with repeated dosing for 10 days when administered according to recommended doses.

With normal function, 91.9% of the intramuscular dose is excreted unchanged in the urine in the first 8 hours, and 98.2% within 24 hours. Mean urine concentrations for 6 hours are 563 mcg/ml following a 250mg dose. 697 mcg/ml following a 375 mg dose, and 832mcg/ml, following a 500mg dose.

Preliminary intramuscular studies in newborns of different weights (less than 1.5kg, 1.5 to 2.0 kg) at dose of 7.5mg/kg revealed that like other aminoglycosides, serum half-life values were correlated inversely with postnatal age and renal clearances of amikacin. The volume of distribution that amikacin, like other aminoglycosides remains primarily in the extracellular fluid space in neonates. Repeated dosing every 12 hours in all the above groups not demonstrate accumulation after 5 days.

Intravenous Administration – Single doses of 500mg (7.5mg/kg0 administered to normal adults as an infusion over a period of 30 minutes produced a peak serum concentration of 38mcg/ml at the end of the infusion, and levels of 24mcg/ml, 18mcg/ml and 0.75mcg/ml at 30 minutes. 1 hour an 10 hours, post infusion, respectively. Eighty four percent of the administered dose was excreted in the urine in 9 hours and about 94% within 24 hours. Repeated infusions of 7.5mg/kg every 12hours in normal adults were tolerated and caused no drug accumulation.

General – Pharmacokinetics studies in normal adult subjects reveal the mean serum half-life to be slightly over 2 hours with a mean total apparent volume of distribution of 24 liters (28% of the body weight). By the ultrafiltration technique, reports of protein binding range from 0 to 11%. The Mean serum clearance rate is about 100ml/min and the renal clearance rate is 94ml/min in subjects with normal renal function.

Indication and dosage:

Amikacin is indicated in short-treatment of serious infection due to susceptible strains of Gram negative bacteria, including Pseudomonas species, Escherichia coli, species of indole positive and indole-negative, Proteus, Providencia species, Klebsiella – Enterobacter – Seratia species and Acinobacter (mima-Herella) species.

Amikacin is effective in bacteria septecemia (including neonatal sepsis); serious infection of the respiratory tract, bones, joints, central nervous system (including meningitis) and skin and soft tissue intra-abdominal infections (including peritonitis); and in burns and post-operative infections (including postvascular surgery). Aminoglycosides are not indicated in the uncomplicated initial episodes of urinary tract infection, unless the causative organisms are not susceptible to antibiotics having less potential toxicity.

Amikacin is also effective in staphylococcal disease such as, severe infections, where the causative organisms may either Gram negative (-) bacterium or a staphylococcus, infections due to susceptible strains of staphylococci in patients allergic to other antibiotics, and in mixed staphylococcal/Gram negative (-) infections.

Contraindications:

A history of hypersensitivity to amikacin is contraindicated for its use. A history of hypersensitivity of serious toxic reactions to aminoglycosides may containdicate the use of any other aminoglycosides, because of the known cross-sensitivities of patients to drugs in this class.

Dosage and Adminstration:

The patient's pre-treatment body weight should be obtained for calculation of correct dosage. Amikacin may be given intramuscularly or intravenously.

Intramuscular Administration For Patients With Normal Renal Function:

Recommended dosage for adults, children and other infant – 15mg/kg/day divided into 2 to 3 equal doses administered at equally divided intervals i.e., 7.5mg/kg every 12 hours or 5 mg/kg every 8 hours. Treatment of patients in the heavier weight classes should not exceed 1.5g/day. When amikacin is indicated in newborns, it is recommended that a loading dose of 10mg/kg be administered initially to be followed with 7.5mg/kg every 12 hours.

The usual duration of treatment is 7 to 10 days. It is desirable to limit the duration of treatment to short term whenever feasible.

Intramuscular Administration For Patients with Impaired Renal Function:

Whenever possible, serum amikacin concentration should be monitored by appropriate assay procedures. Doses may be adjusted in patients with impaired renal function either by administering normal doses at prolonged intervals or by administering reduced doses at a fixed intervals.

Intravenous Administration:

The individual dose, the total daily dose, and the total cumulative dose of amikacin are identical to the dose recommended for intramuscular administration. The solution of intravenous use is prepared by adding the contents of 500mg vial to 100 or 200 ml of sterile diluent such as Normal Saline or 5% Dextrose in Water or any of the compatible solutions listed below.

The solution is administered to adults over 30 to 60 minutes period. The total daily dose should not exceed 15mg/kg/day and may be divided into, either 2 to 3 equally – divided doses at equally divided intervals.

Stability in IV Fluid : Aminkacin is stable for 24 hours at room temperature at concentrations of 0.25 and 5.0mg/ml in the following solutions:

5% Dextrose Injection

5% Dextrose Solution and 0.2% Sodium Chloride Injection

5% Dextrose Solution and 0.45% Sodium Chloride Injection

0.9% Sodium Chloride Injection

Lactated Ringer's Injection

Normosol R in 5% Dextrose Injection

In the above solutions with amikacin concentrations of 0.25 and 5.0mg/ml, solutions aged for 60 days at 4^oC and then stored at 25^oC had utility time of 24 hours.

At the same concentrations, solutions frozen and aged for 30 days at -15^oC and stored at 25^oC had utility time of 24 hours.

Warnings:

Patients treated with parenteral Aminoglycosides should be under close clinical observation because of the potential ototoxicity and nephrotoxicity associated with their use.

Neurotoxicity manifested as vestibular and permanent bilateral auditory ototoxicity can occur in patients with preexisting renal damage and in patients with normal renal function treated higher doses and for those longer than recommended.

Aminoglycosides are potentially nephortoxic. The risk of nephrotoxicity is greated in patients with impaired renal function and in those who receive higher doses or prolonged the therapy.

Most amikacin contains Sodium Metabisulfite, which may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible persons.

Storage Condition: Store at temperature not exceeding 30^oC.