Each vial contains :

Artesunate IP (Sterile) 60 mg

This pack contains 1 ml ampoule of Sodium Bicarbonate

Injection IP 5% w/v & 5 ml ampoule of Sodium Chloride

Injection IP 0.9% w/v.

Each vial contains :

Artesunate IP (Sterile) 120 mg

This pack contains 2 ml ampoule of Sodium Bicarbonate

Injection IP 5% w/v & 10 ml ampoule of Sodium Chloride

Injection IP 0.9% w/v.

Chemical formula : C₁₉H₂₈O₈

Molecular weight : 384.421 g/mol

Artesunate is the water insoluble hemisuccinate ester of dihydroartemisinin, (Qinghaosu) an anti malarial principle extracted from leaves of the plant Artemisia annua. Artesunate is a white crystalline powder, odorless and almost tasteless. The chemical structure of Artesunate contains a sesquiterpene lactone ring with an endoperoxide bridge. Artesunate is active against multidrug resistant Plasmodium falciparum as well as the sensitive strains. It is also highly active against P. vivax. WHO recommends the use of Artesunate as an injectable preparation for severe malaria.

Mechanism of Action

The endoperoxide bridge is essential for the antimalarial activity of Artesunate. This endoperoxide bridge interacts with heme in the parasite. Intra parasitic iron catalyses the cleavage of the endoperoxide bridge of Artesunate within the infected erythrocyte, generating free radicals (singlet oxygen). These highly reactive free radical species binds to membrane proteins, causes lipid peroxidation, damages endoplasmic reticulum, inhibit protein synthesis and ultimately results in lysis of the parasite. Artesunate acts rapidly against asexual erythrocytic stage of plasmodia. Artesunate has gametocytocidal activity but shows no action on hepatic forms (hypnozoites).

Pharmacokinetics

Artesunate is extensively converted to dihydroartemisinin (DHA) by blood esterases.

Falcinil Injection

In patients with severe malaria, the Cmax of DHA ranges from 513 - 5789 nmol/L. The median elimination half-life (t1/2) is 0.34 h (range 0.18 - 0.87 h) and the time to last detectable DHA in blood is around 2 h.

Falcinil Forte Injection

In patients with severe malaria, Artesunate shows a volume of distribution (Vd) of 0.08 liter/kg, clearance (CL) of 1.63 liters/h/kg and a short elimination half-life (t1/2) of 2.3 min. The peak concentration of DHA (Cmax) of 8.5 µmol/liter is reached within 10.4 min (Tmax). The mean AUC of DHA in patients with severe malaria is around 7.3 µmol.h/liter. DHA shows a Vd of 0.77 liter/kg and a t1/2 of 40 min.

Severe malaria including cerebral malaria.

Contradictions :

Prior hypersensitivity to Artesunate or any other artemisinin derivative

Special Population :

Pediatrics

Parenteral Artesunate is recommended by WHO for severe malaria in children, but it should be used with caution.

Pregnancy

WHO recommends using parenteral Artesunate in severe malaria in patients with second and third trimester pregnancy. Parenteral Artesunate can be considered as an option in first trimester pregnancy by taking into account the risk-benefit ratio.

Lactating mother

Breast feeding should be stopped while using artemisinin derivatives in lactating mothers.

Geriatrics

No special precautions are required when administering parenteral Artesunate to geriatric population.

Patients with renal or hepatic failure

There is no information available regarding the use of Artesunate in patients with renal or hepatic failure. Parenteral Artesunate should be used with caution in such patient population.

Patients with cardiac disorders

Since artemisinin has induced cardio toxic effects in experimental animals and transient first degree block has been documented, it should be used with caution in patients with chronic cardiac disorders.

Dosage :

For adults

Artesunate 2.4 mg/kg body weight; I.V. or I.M. given on admission (time = 0), then at 12 h and 24 h, then once a day until patient is able to tolerate medication when an ACT (artemisinin combination therapy) is given.

For children

<20 kg : 3.0 mg/kg, >20 kg : 2.4 mg/kg; I.V. or I.M. given on admission (time = 0), then at 12 h and 24 h, then once a day until patient is able to tolerate medication when an ACT (artemisinin combination therapy) is given.

Administration :

Falcinil Injection

The powder for injection should be reconstituted with 1 ml of 5% Sodium Bicarbonate Injection IP and Shake vigorously for 5 minutes to get clear solution.

For I.V. use : Add 5 ml of normal saline or 5% w/v Dextrose Injection IP and mix again to prepare final concentration of 10 mg/ml for I.V.

The required amount of drug for I.V. use should be administered slowly over a period of 2 to 3 minutes.

For I.M. use : Add 2 ml of normal saline or 5% w/v Dextrose Injection IP and mix again to prepare final concentration of 20 mg/ml for I.M. use.

Falcinil Forte Injection

The powder for injection should be reconstituted with 2 ml of 5% Sodium Bicarbonate Injection IP and Shake vigorously for 5 minutes to get clear solution.

For I.V. use : Add 10 ml of normal saline or 5% w/v Dextrose Injection IP and mix again to prepare final concentration of 10 mg/ml for I.V. The required amount of drug for I.V. use should be administered slowly over a period of 4 to 6 minutes

For I.M. use : Add 4 ml of normal saline or 5% w/v Dextrose Injection IP and mix again to prepare final concentration of 20 mg/ml for I.M. use.

• The powder for Injection is difficult to dissolve and care should be taken to ensure that it is completely dissolved before parenteral administration.
• Prepare a fresh solution for each administration.
• The formulation should be used immediately after reconstitution. Discard any unused solution after the use.
• If the solution is cloudy or a precipitate is present, the parenteral solution should be discarded.

Artemisinin and its derivatives appear to be generally well tolerated, although there have been reports of mild gastrointestinal disturbances including nausea, vomiting, headache, tinnitus and neutropenia. Other reported adverse reactions are transient and reversible reticulocytopenia, fever, rash, bradycardia, transient first degree heart block, QT prolongation and transient & reversible elevation of serum transaminases. Evidence of neurotoxicity has been seen in animals when given in high doses.

• Artesunate alters the pharmacokinetics of mefloquine, i.e. the peak concentration of mefloquine is reduced and the volume of distribution is expanded.
• Since Artesunate prolonged PR and QT intervals in some experimental animals, some adverse drug interactions could get induced when Artesunate is administered with other antimalarials that have cardiac reactions viz. quinine, quinidine, mefloquine, halofantrine etc.
• Drugs known to prolong QT interval, viz. erythromycin, terfenadine, astemizole, quinidine, tricyclic antidepressants, neuroleptics etc. should not be co-prescribed with Artesunate.

Store below 25°C. Protect from light & moisture.

Keep out of reach of children.

After reconstitution, do not use in case any foreign particulate matter is observed inside the vial. Use immediately after reconstitution.

Refer on the pack.

Presentation :

Falcinil Injection

A vial of 60 mg along with 1 ml ampoule of Sodium Bicarbonate Injection IP 5% w/v & 5 ml ampoule of Sodium Chloride Injection IP 0.9% w/v.

Falcinil Forte Injection

A vial of 120 mg along with 2 ml ampoule of Sodium Bicarbonate Injection IP 5% w/v & 10 ml ampoule of Sodium Chloride Injection IP 0.9% w/v.

Probiotic Vaginal Tablets

Each vaginal tablet contains:

At least 1 Billion CFU of Mix Lactobacilli: L. brevis CD2, L. salivarius FV2 & L. plantarum FV9.

Vaginal tablet

1 Billion CFU

4.1 Therapeutic Indication 

• Helps to maintain normal vaginal flora and restore healthy vaginal pH, in general, and after clinical treatment of opportunistic infections (Vulvovaginal candidiasis, protozoal and viral infections).
• Treatment of Bacterial Vaginosis and prevention of relapse of Bacterial Vaginosis.

4.2 Posology and method of administration

1 tablet intra-vaginal at bedtime for 8 days every month preferably from 8 day of menstrual cycle for 3 consecutive months.

Method of Administration:

• Wash your hands with soap.

• Remove the tablet from the pack.

• Do not break or crush the tablet

• insert the tablet inside the vagina while lying in a recumbent position.

4.3 Contraindications

Known hypersensitivity to any of the ingredients mentioned under COMPOSITION section.

4.4 Special warnings and precautions for use

• Do not use if the packaging is broken or damaged
• Avoid douching during treatment
• Do not ingest (Only for Vaginal Use).
• Avoid use of intra-vaginal antibiotics during treatment.
• Compatible with condoms and other physical barrier methods without any interference in intercourse.

4.5 Drugs interactions

EvaNew vaginal tablet can be taken with any other pharmaceutical products without interference.

4.6 Use in special populations

Pregnancy and Lactation:

No adverse events have been reported with usage of EvaNew vaginal tablet in pregnant and lactating women.

4.7 Effects on ability to drive and use machines

None Anticipated

4.8 Undesirable effects

• Non-teratogenic.
• No adverse effects reported on reproductive health and fertility in animals.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com

Website: https://www.zuventus.co.in/drug-safety-reporting

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

No over dosage has been reported for EvaNew vaginal tablet.

5.1 Pharmacodynamic Properties

EvaNew vaginal tablet is a novel product, possessing anti-microbial and anti-inflammatory activities. An optimal concentration of the three strains in EvaNew vaginal tablet is designed based on their adhesive properties, H2O2 1 production, pathogen inhibition and co-aggregation with Candida albicans and Gardnerella vaginalis.

The female lower genital tract is an ecological niche where several microorganisms coexist in a dynamic balance. This ecosystem is dynamic with changes in structure and composition being influenced by age, menarche, time in menstrual cycle, pregnancy, infections, methods of birth control, sexual activity, use of medications and hygiene. In healthy women, the vaginal ecosystem is dominated by Lactobacillus spp. Some of the undesirable organisms are yeasts (Candida albicans, C. Tropicalis, C. krusei), anaerobic bacteria responsible of vaginosis (Gardnerella vaginalis, Atopobium vaginae, Prevotella, Veillonella), uropathogens (E. coli, Proteus, Klebsiella, Serratia), and sexually transmitted viruses (HIV, Herpes virus). Lactobacilli are involved in maintaining the normal vaginal microflora by preventing overgrowth of pathogenic and opportunistic organisms.

The rationale for use of EvaNew vaginal tablet in women is based on the genitourinary regulatory role played by the vaginal microbiota and the need for restoration of this microbial ecosystem after insult. Lactobacilli are commonly used as probiotics. The use of lactobacilli to re-establish a physiological microbial flora of the female urogenital tract dates back to early 1900s. Because antimicrobial treatment of urogenital infections is not always effective, and problems remain due to bacterial and yeast resistance, recurrent infection, as well as side effects, it is not surprising that alternative remedies are of interest to patients and their caregivers.

Mechanism of Action

The principle mechanisms by which EvaNew vaginal tablet exerts its protective functions are (1) stimulation of the local immune system (2) competition with other microorganisms for the nutrients and for adherence to the vaginal epithelium, (3) reduction of the vaginal pH by the production of the organic acids, especially lactic acid, and (4) production of antimicrobial substances, such as bacteriocins and hydrogen peroxide.

The different mechanisms of action of the individual strains are as given below:

• L. brevis possesses strong adherence characteristics and as a virtue of its larger morphology size exerts 1 competitive exclusion of vaginal opportunistic pathogens.
• L. salivarius and L. plantarum produce high amounts of lactic acid maintaining a healthy vaginal pH which is 1 inhibitory to growth of vaginal pathogens including HSV-2 and HIV-1
• Peroxidase, hydrogen peroxide and halides constitute a strong anti-microbial system in phagocytes and in tissue fluids. Peroxidase and halide ions are present in the vaginal fluid while L. salivarius and L. plantarum secrete H₂O₂ which has anti-bacterial and anti-viral properties. In vitro, hydrogen peroxide producing Lactobacillus strains have a strong inhibitory activity against Gardnerella vaginalis, Prevotella bivia, Neisseria gonorrhoeae, and HIV-1
• The probiotic strains in EvaNew vaginal tablet co-aggregate very efficiently with both Gardnerella vaginalis and Candida albicans, producing a microenvironment around the pathogens, where the concentration of inhibiting substances, produced by lactobacilli, is exacerbated.
• Lactobacillus brevis is rich in arginine deiminase, which uses arginine as a substrate for the production of citrulline, thus preventing its use for the synthesis of polyamines. Arginine deiminase can also act as anti-viral agent suppressing HIV-1 replication in CD4+ cells.
• L. brevis contains high concentration of sphingomyelinase. Sphingomyelin present in the vaginal secretion can be metabolized by sphingomyelinase to generate ceramide. Ceramide inhibits viral infections by membrane-lipid rafts organization and structure. EvaNew tablet therefore may prevent entry of HSV-2 and HIV
• The bacterial strain, L. brevis, in particular has been reported to prevent the binding / entry of HSV-2 in vitro.

5.2 Pharmacokinetic Properties

Lactobacilli are present in most of the dairy products e.g. milk, curd and cheese. In human beings these microorganisms are present in mouth, intestinal tract and vagina. No specific pharmacokinetics data is available for EvaNew vaginal tablet. It acts through local action.

6.1 Animal Toxicology or Pharmacology

No known animal toxicology data

EvaNew vaginal tablet is a mixture of three lactobacilli probiotic strains namely, L. brevis CD2, L. salivarius Fv2 and L. plantarum FV9 which colonize in the vagina and restore a healthy vaginal flora and pH.

8.1 Incompatibilities

Not-applicable

8.2 Shelf-life

Please see Mfg. Date/Expiry Date printed on pack. Do not use the product after the expiry date, which is stated on the packaging. The expiry date refers to the last day of that month. The expiry date refers to the product kept unopened in its original packing

8.3 Packaging information

A blister strip of 8 tablets.

8.4 Storage and handing instructions

Store between 2⁰C to 8⁰C. Do not freeze.

Keep out of reach of children.

Any discoloration or spotting on the tablet will not affect its efficacy.

• EvaNew vaginal tablets helps to maintain normal vaginal flora and restore healthy vaginal pH, in general, and after clinical treatment of opportunistic infections.
• Advice to the patients: Evanew Vaginal Tablet is inserted into the vagina, preferably at night before going to bed.
• Do not skip any doses and finish the full course of treatment even if you feel better.
• Tell the patients if they get any side effects, talk to the doctor. This includes any possible side effects not listed in this leaflet. Advice patients if they have any further questions, ask the doctor or pharmacist.

02-07-2024

Eslo Met 2.5

Each modified release uncoated bilayered tablet contains :

S (-) Metoprolol Succinate 23.75 mg

equivalent to S (-) Metoprolol Tartrate 25 mg

(As prolonged release)

S (-) Amlodipine Besylate IP equivalent to S (-) Amlodipine 2.5 mg

(As immediate release)

Excipients q.s.

Colour : Lake of Indigo Carmine

Eslo Met 5

Each modified release uncoated bilayered tablet contains :

S (-) Metoprolol Succinate 23.75 mg

equivalent to S (-) Metoprolol Tartrate 25 mg

(As prolonged release)

S (-) Amlodipine Besylate IP equivalent to S (-) Amlodipine 5 mg

(As immediate release)

Excipients q.s

Colour : Lake of Quinoline Yellow

S (-) Metoprolol is a selective β1-receptor blocker and it is the active form of the racemate Metoprolol. The β1 receptor affinity of S (-) Metoprolol is about 500 times greater than that of R (+) Metoprolol. S (-) Amlodipine is a dihydropyridine calcium channel blocker with vasodilating properties. S (-) Amlodipine is 1000 times more potent than the R (+) isomer in binding to the dihydropyridine receptor. S (-) Amlodipine is the active form of the racemate Amlodipine.

S (-) Metoprolol is a selective β1-receptor blocking agent. Blockade of β1-receptors results in reduction of heart rate, cardiac output and blood pressure. The beneficial effects of β-blocking agents in angina are related primarily to their hemodynamic effects i.e. decreased heart rate, blood pressure, and contractility-which decrease myocardial oxygen requirement.

S (-) Amlodipine is a dihydropyridine calcium channel antagonist that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. S (-) Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure. Reduction in the peripheral vascular resistance benefits the patients with angina of effort. In cardiac muscle, blockade of calcium channel results in reduction in the contractility of the heart and decrease in sinus node pacemaker rate and decrease in atrioventricular node conduction velocity. Cardiac output is also reduced. The reduction in cardiac mechanical function reduces the oxygen requirement in patients with angina. Reduction in coronary arterial tone has been demonstrated in patients with variant angina.

In humans absorption of S (-) Metoprolol is rapid and complete. Metoprolol is eliminated by several pathways, including benzylic hydroxylation (alphahydroxylation) which accounts for ~ 10% of the dose. This pathway is stereoselective for S (-) Metoprolol. The major pathway is O-demethylation that favours R (+) Metoprolol and accounts for 65% of the dose of racemic Metoprolol.

Administration of S (-) Amlodipine 2.5 mg as a single dose in the fasting state produced maximum plasma concentration (Cmax) of 8.30 ± 1.071 ng/ml in 2.73 ± 0.88 hours (Tmax). The mean AUC0-t value (t=48 hours) of S (-) Amlodipine (2.5 mg) was 95.33 ± 14.45 ng-hour/ml. The AUC0-∞value recorded was 140.91± 28.06 ng-hour/ml.

Eslo Met is indicated for the treatment of essential hypertension and angina pectoris in adults.

In patients who have shown hypersensitivity to any component of the product or to other beta-blockers or calcium channel blockers.

In atrioventricular block of second or third degree, patients with unstable decompensated cardiac heart failure (pulmonary oedema, hypoperfusion or hypotension), patients with continuous or intermittent inotropic therapy acting through beta-receptor agonism, marked clinically relevant sinus bradycardia, sick-sinus syndrome, cardiogenic shock and severe peripheral arterial circulatory disorder

S (-) Metoprolol should not be given to patients with suspected acute myocardial infarction as long as the heart rate is <45 beats/min, the PQ-interval is >0.24sec orthe systolic blood pressure is<100mmHg.

One tablet to be taken once daily, orally. The dose may be titrated as per requirement.

In case of Eslo Met overdosage, unabsorbed drug should removed by induction of emesis and / or gastric lavage.

Potential signs and symptoms associated with overdosage of S (-) Metoprolol are bradycardia, hypotension, bronchospasm and cardiac failure. There is no specific antidote. Symptoms of S (-) Metoprolol overdosage should be treated with atropine, vasopressors, β2-stimulating agents and drugs for cardiac failure.

Overdose with S (-) Amlodipine may result in excessive peripheral vasodilatation. Marked and probably prolonged systemic hypotension up to and including shock with fatal outcome have been reported. The patient should be closely monitored, and the treatment should be symptomatic and supportive. Management depends on the time since ingestion and the severity of the symptoms. Serum electrolytes and creatinine should be monitored frequently.

Intravenous administration of calcium antagonists of the verapamil-type should not be given to patients treated with beta-blockers

Patients suffering from heart failure should have their decompensation treated both before and during treatment. Abrupt interruption of the medication is to be avoided.

Sudden withdrawal of beta blockade is hazardous, especially in high-risk patients, and may aggravate chronic heart failure as well as increase the risk of myocardial infarction and sudden death. Any withdrawal of the product should therefore, if possible, be made gradually over at least two weeks when the dose is reduced by half in each step, down to the final dose. The final dose should be given for at least four days before discontinuation. If symptoms occur, a slower withdrawal rate is recommended.

Though clinical studies in patients with normal liver function have shown that there is no elevation in the hepatic enzymes with the use of S (-) Amlodipine, caution should be taken while administering S (-) Amlodipine to patients with hepatic and renal impairment.

Pregnant women & Nursing Mothers

No data available; the product should be administered only when the potential benefits outweighs the risk to the patient.

Safety and effectiveness not established.

Gingival Hypertrophy & Alopecia have been reported with S (-) Amlodipine use. On the basis of clinical data available, the following adverse events have been reported in less than 2% of patients with S (-) Amlodipine : vertigo (0.05%), tachycardia (0.05%), cough (0.05%), headache (0.43%), difficulty in breathing (0.1%), and facial puffiness (0.05%). Fatigue, dry mouth, dizziness, dyspnoea and mild rash have been reported with S (-) Metoprolol.

Store below 30°C. Protect from light & moisture

Presentation:

Eslo Met 2.5 : A blister strip of 10 tablets.

Eslo Met 5 : A blister strip of 10 tablets.

Each uncoated tablet contains :

S (-) Amlodipine Besylate IP

equivalent to S (-) Amlodipine 2.5 mg

Hydrochlorothiazide IP 12.5 mg

Excipients q.s.

Colour : Lake of Sunset Yellow

S (-) Amlodipine, the chirally pure form of Amlodipine is a calcium channel antagonist belonging to the dihydropyridine class. Hydrochlorothiazide is a diuretic which produces the antihypertensive activity.

The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) states that drug treatment for hypertension should begin with a thiazide-type diuretic in most patients, either alone or in combination with an ACE inhibitor, an ARB, or a CCB. Various studies have been conducted using calcium channel blockers along with the Hydrochlorothiazide and the combination has found to be superior than the individual drugs and there are no adverse drug interactions recorded with the usage of the combination. Therefore combination of S (-) Amlodipine along with a thiazide diuretic is a rationale combination which can be used as a first line treatment of the hypertension.

S (-) Amlodipine, the chirally pure form of Amlodipine is a calcium channel antagonist belonging to the dihydropyridine class. The S (-) isomer of Amlodipine is found to possess greater pharmacological effects than R (+) Amlodipine. S (-) Amlodipine is 1000 times more potent than the R (+) isomer in binding to the dihydropyridine receptor. Therefore this is the only form which produces its therapeutic effects. In humans, the dominant effects of Amlodipine are consequent to vasodilation. S (-) Amlodipine lowers peripheral vascular resistance without causing a reflex tachycardia. In patients with angina pectoris S (-) Amlodipine reduces the myocardial oxygen demand by causing a direct vasodilation of the coronary artery and arterioles. Thiazides are moderately potent diuretics and exert their diuretic effect by reducing the reabsorption of electrolytes from the renal tubules, thereby increasing the excretion of Sodium and Chloride ions, and consequently of water. They act mainly at the beginning of the distal tubules. They also reduce carbonic-anhydrase activity so that bicarbonate excretion is increased, but this effect is generally small compared with the effect on Chloride excretion and does not appreciably alter the pH of the urine. Their hypotensive effect is probably partly due to a reduction in peripheral resistance : they also enhance the effects of other antihypertensives.

Administration of S (-) Amlodipine 2.5 mg as a single dose in the fasting state produced maximum plasma concentration (Cmax) of 8.30 ± 1.071 ng/ ml in 2.73 ± 0.88 hrs. (Tmax). Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with 10% of the parent compound and 60% of the metabolites excreted in the urine. Ex vivo studies have shown that approximately 93% of the circulating drug is bound to plasma proteins in hypertensive patients. The mean AUC0-t value (t = 48 hrs.) of S (-) Amlodipine (2.5 mg) is 95.33 ± 14.45 ng.hr/ml. The AUC0-∞ value is recorded to be 140.91± 28.06 ng.hr/ml. The plasma elimination half life of S (-) Amlodipine has been found to be 31.09 ± 12.65 hrs. Hydrochlorothiazide is fairly rapidly absorbed from the gastrointestinal tract. It is reported to have a bioavailability of about 65 to 70%. It has been estimated to have a plasma half-life of between about 5 and 15 hours and appears to be preferentially bound to red blood cells. It is excreted mainly unchanged in the urine. Hydrochlorothiazide crossed the placental barrier and is distributed into breast milk.

For the treatment of mild to moderate hypertension.

Hypersensitivity to any of the components listed in the formulation

Dosage and Administration:

One tablet to be administered once daily

There are no reported cases of overdosage with the use of S (-) Amlodipine. Overdosage with racemic Amlodipine may cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. Hence, caution should be taken in case of an overdosage with S (-) Amlodipine. If massive overdose occurs, active cardiac and respiratory monitoring should be instituted. Frequent blood pressure measurements should be performed. Should hypotension occur, cardiovascular support including elevation of the extremities and the judicious administration of fluids should be initiated. If hypotension remains unresponsive to these conservative measures, administration of vasopressors (such as phenylephrine) should be considered with attention to circulating. If massive overdose occurs, gastric lavage should be employed. As this product is highly plasma protein bound, hemodialysis is not likely to be of benefit. Electrolyte depletion (hypokalaemia, hypochloremia, hyponatraemia) and dehydration are the most common signs and symptoms of Hydrochlorothiazide overdosage. If digitalis has been administered, hypokalaemia may accentuate cardiac arrhythmias. The plasma half-life of Hydrochlorothiazide is 5.6 hours with a subsequent longer terminal half-life. Treatment should be symptomatic and supportive. Therapy should be discontinued and the patient watched closely.

S (-) Amlodipine : Gingival Hypertrophy and Alopecia has been seen with S (-) Amlodipine. On the basis of the clinical data available, only minor side effects have been reported with the use of S (-) Amlodipine. Adverse events reported in less than 5% of the patients included anxiety (0.43%), anorexia (0.43%), irritation (0.43%), headache (2.13%) and facial flushing (2.13%). Caution should be exercised when administering S (-) Amlodipine to patients with impaired hepatic and renal function. Hydrochlorothiazide : Common adverse events seen with Hydrochlorothiazide are as follows : fever, necrotising angiitis (vasculitis, cutaneous vasculitis), jaundice (intrahepatic cholestatic jaundice), pancreatitis, cramping, gastric irritation, glycosuria, hyperglycaemia, hyperuricaemia, hypokalaemia, photosensitivity, sialadenitis, urticaria, toxic epidermal necrolysis, agranulocytosis, aplastic anaemia, haemolytic anaemia, leucopenia, purpura, thrombocytopenia, restlessness, interstitial nephritisrespiratory distress, including pneumonitis, pulmonary oedema, transient blurred vision, xanthopsia, non-melanoma skin cancer (Basal cell carcinoma and Squamous cell carcinoma).

Hepatic impairment and renal impairment : No controlled clinical study of S (-) Amlodipine has been performed in patients with hepatic impairment and renal impairment. Clinical studies in patients with normal liver function have shown that there is no elevation in the hepatic enzymes with the use of S (-) Amlodipine. Approximately 90% of S (-) Amlodipine is metabolised in liver therefore a careful dosage adjustment should be considered in cases of hepatic impairment. Since about 10% of the S (-) Amlodipine is excreted unchanged in urine, no dosage adjustment is required in patients with renal impairment. Hydrochlorothiazide should be avoided in patients with severe hepatic impairment, in whom encephalopathy may be precipitated. Diuretics should be given with caution in patients with renal impairment, since they can further reduce renal impairment.

Pregnant Women & Nursing Mothers : There is no data available on the use of S (-) Amlodipine in pregnant and lactating women. Hydrochlorothiazide may cross placenta, and there have been reports of neonatal jaundice, thrombocytopenia and electrolyte imbalance following maternal use. Treatment with large doses may inhibit lactation.

Since there are no studies available on the use of the combination in pregnant women, it should be administered only when the potential benefits outweighs the risk to the patient.

Children : Safety and effectiveness of this product in children has not been established.

Clinical studies have shown that S (-) Amlodipine when combined with aspirin, nitrates, beta-blockers, statins, ACE inhibitors, H2 blockers, and Proton Pump Inhibitors produced no drug interactions. Usual side effects of S (-) Amlodipine given alone and Hydrochlorothiazide given alone can be expected with the combination, but no known enhancement of the side effect has been observed in the published literature with the combination.

Store below 30°C. Protect from light & moisture.

Keep out of reach of children.

Each uncoated bilayered tablet contains :

S (-) Amlodipine Besylate IP

equivalent to S (-) Amlodipine 2.5 mg

Atenolol IP 50 mg

Excipients q.s

Colour : Lake of Sunset Yellow

Antihypertensive, antianginal agent

Description:

S (-) Amlodipine, the chirally pure form of Amlodipine is a Calcium channel antagonist belonging to the Dihydropyridine class. The chemical name of S (-) Amlodipine is (S)-3-ethyl-5-1-methyl-2-(2- aminoethoxymethyl)-4-(2-chlorophenyl)-1,4-dih-ydro-6-methyl-3,5-pyridinedicarboxylate. Its empirical formula

is C₂₀H₂₅ClN₂O₅  C₆H₆O₃S, with a molecular weight of 567.1 g/mol.

Atenolol is a β1-selective receptor antagonist and produces the antihypertensive activity. It is chemically described as Benzeneacetamide, 4-[2'-hydroxy-3'-[(1-methylethyl) amino] propoxy]. Atenolol has a molecular weight of 266.34 g/mol with molecular formula C₁₄H₂₂N₂O₃

Clinical Pharmacology :

S (-) Amlodipine, the chirally pure form of Amlodipine is a calcium channel antagonist belonging to the Dihydropyridine class. The S (-) isomer of Amlodipine is found to possess greater pharmacological effects than R (+) Amlodipine. S (-) Amlodipine is 1000 times more potent than the R (+) isomer in binding to the Dihydropyridine receptor. In humans, the dominant effects of Amlodipine are consequent to vasodilation. S (-) Amlodipine lowers peripheral vascular resistance without causing a reflex tachycardia. In patients with angina pectoris S (-) Amlodipine reduces the myocardial oxygen demand by causing a direct vasodilation of the coronary artery and arterioles. Atenolol is a β1-selective receptor antagonist and produces the antihypertensive activity. β-adrenergic antagonists slow the heart rate and decrease myocardial contractility. These agents decrease the effect of catecholamines on the determinants of myocardial oxygen consumption thus improving the relationship between cardiac oxygen supply and demand. Combinations of Amlodipine and Atenolol have been used successfully to treat hypertension and angina. Since S (-) Amlodipine is the chirally pure form of Amlodipine, the combination of S (-) Amlodipine and Atenolol is highly beneficial in the treatment of hypertension and angina.

Pharmacokinetics:

Administration of S (-) Amlodipine 2.5 mg as a single dose in the fasting state produced maximum plasma concentration (Cmax) of 8.30 ± 1.071 ng/ ml in 2.73 ± 0.88 hrs. (Tmax). Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with 10% of the parent compound and 60% of the metabolites excreted in the urine. Ex vivo studies have shown that approximately 93% of the circulating drug is bound to plasma proteins in hypertensive patients. The mean AUC0-t value (t= 48 hrs.) of Tablet S (-) Amlodipine (2.5 mg) is 95.33 ± 14.45 ng.hr/ml. The AUC0-∞ value is recorded to be 140.91± 28.06 ng.hr/ml. The plasma elimination half life of (S) - Amlodipine has been found to be 31.09 ± 12.65 hrs.

Approximately 50% of an oral dose of Atenolol is absorbed from the gastro-intestinal tract and the remainder being excreted unchanged in the faeces. Maximum plasma concentrations are reached within two to four hours after a single oral dose and doses of 50 mg and 100 mg produce mean peak plasma concentrations of approximately 300 and 700 ng/mL, respectively. The plasma half-life (t½) is 6-7 hours and Atenolol is effective for at least 24 hours after a single oral dose. Atenolol is 6-16% plasma protein bound and is extensively distributed to extravascular tissues, but only a small amount is found in the central nervous system. Approximately 10% of Atenolol is metabolised in man. Approximately 47% and 53% of an oral dose is eliminated in the urine and faeces respectively.

Indications :

For treatment of Essential Hypertension and Angina Pectoris.

Hypersensitivity to any of the components of the formulation, sinus bradycardia, second and higher degrees of heart block, cardiogenic shock, hypotension and overt cardiac failure

Dosage and Administration :One tablet to be administered once daily.

Gingival hypertrophy and alopecia has been seen with S (-) Amlodipine. On the basis of the clinical data available, only minor side effects have been reported with the use of S (-) Amlodipine. On the basis of clinical data available, adverse events reported in less than 5% of the patients included anxiety (0.43%), anorexia (0.43%), irritation (0.43%), headache (2.13%) and facial flushing (2.13%). Caution should be exercised when administering S (-) Amlodipine to patients with impaired hepatic and renal function. Common adverse events seen with Atenolol are as follows : Sleep disturbances, purpura, thrombocytopenia, leucopenia, mood changes, depression, anxiety, nightmares, confusion, psychosis, hallucinations, dizziness, headache, paraesthesia of extremities, dry eyes, impaired vision, visual disturbances, bradycardia, heart failure deterioration, precipitation of heart block, cold extremities, postural hypotension which may be associated with syncope, bronchospasmm, gastrointestinal disturbances, constipation, dry mouth, elevations of transaminase levels, hepatic toxicity including intrahepatic cholestasis, alopecia, psoriasiform skin reactions, exacerbation of psoriasis, skin rashes, impotence, fatigue, sweating.

Clinical studies have shown that S (-) Amlodipine when combined with aspirin, nitrates, beta-blockers, statins, ACE inhibitors, H2 blockers, and Proton Pump Inhibitors produced no drug interactions. No drug interaction has been reported with the use of Atenolol.

Warnings :

Increased Angina and/or Myocardial Infarction

Rarely, patients, particularly those with severe obstructive coronary artery disease, have developed documented increased frequency, duration and/or severity of angina or acute myocardial infarction on starting calcium channel blocker therapy or at the time of dosage increase. The mechanism of this effect has not been elucidated.

Cardiac Failure

Sympathetic stimulation is necessary in supporting circulatory function in congestive heart failure, and beta blockade carries the potential hazard of further depressing myocardial contractility and precipitating more severe failure. In patients who have congestive heart failure controlled by digitalis and/or diuretics, Atenolol should be administered cautiously. Both digitalis and Atenolol slow AV conduction. In general, calcium channel blockers should also be used with caution in patients with heart failure.

Bronchospastic Diseases

Patients with bronchospastic disease should, in general, not receive beta blockers. Because of its relative β1 selectivity, however, Atenolol may be used with caution in patients with bronchospastic disease who do not respond to, or cannot tolerate, other antihypertensive treatment.

Thyrotoxicosis

Beta-adrenergic blockade may mask certain clinical signs (eg, tachycardia) of hyperthyroidism. Abrupt withdrawal of beta blockade might precipitate a thyroid storm; therefore, patients suspected of developing thyrotoxicosis from which Atenolol therapy is to be withdrawn and should be monitored closely.

Untreated Pheochromocytoma

Atenolol should not be given to patients with untreated pheochromocytoma.

There is no data available on the use of S (-) Amlodipine in pregnant and lactating women. Atenolol can cause fetal harm when administered to a pregnant woman. Atenolol crosses the placental barrier and appears in cord blood. Administration of Atenolol, starting in the second trimester of pregnancy, has been associated with the birth of infants that are small for gestational age. No studies have been performed on the use of Atenolol in the first trimester and the possibility of fetal injury cannot be excluded. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Neonates born to mothers who are receiving Atenolol at parturition or breast-feeding may be at risk for hypoglycemia and bradycardia. Caution should be exercised when Atenolol is administered during pregnancy or to a woman who is breast-feeding.

Hepatic impairment and renal impairment

No controlled clinical study of S (-) Amlodipine has been performed in patients with hepatic impairment and renal impairment. Clinical studies in patients with normal liver function have shown that there is no elevation in the hepatic enzymes with the use of S (-) Amlodipine. Since about 90% of the drug is excreted unchanged in urine, no dosage adjustment is required in patients with hepatic impairment. There is no significant hepatic metabolism of Atenolol and more than 90% of that absorbed reaches the systemic circulation unaltered. Plasma half-life is raised in patients with renal failure with S (-) Amlodipine. Since Atenolol is excreted via the kidneys, the dosage should be adjusted in cases of severe impairment of renal function.

Hence, caution should be taken while administering the combination to such patients.

Safety and effectiveness of this product in children has not been established.

Overdosage with racemic Amlodipine and Atenolol may cause excessive peripheral vasodilation with marked hypotension possibly a reflex tachycardia, acute cardiac insufficiency and bronchospasm. Hence, caution should be taken in case of an overdosage with Eslo AT tablet. If massive overdose occurs, active cardiac and respiratory monitoring should be instituted. Frequent blood pressure measurements should be performed. Should hypotension occur, cardiovascular support including elevation of the extremities and the judicious administration of fluids should be initiated. If hypotension remains unresponsive to these conservative measures, administration of vasopressors (such as phenylephrine) should be considered with attention to circulating volume and urine output. If massive overdose occurs, gastric lavage should be employed. As this product is highly plasma protein bound, hemodialysis is not likely to be of benefit.

Store protected from light & moisture at a temperature not exceeding 30°C.

Keep out of reach of children.

A blister strip of 15 tablets.

Eslo Tel 2.5 mg

Each uncoated bilayered tablet contains :

S (-) Amlodipine Besylate IP

equivalent to S (-) Amlodipine 2.5 mg

Telmisartan IP 40 mg

Excipients q.s.

Colour : Iron Oxide Red

Eslo Tel 5 mg

Each uncoated bilayered tablet contains :

S (-) Amlodipine Besylate IP

equivalent to S (-) Amlodipine 5 mg

Telmisartan IP 40 mg

Excipients q.s.

Colour : Iron Oxide Yellow

Antihypertensive agent

Eslo Tel combines two antihypertensive compounds with complementary mechanisms to control blood pressure in patients with essential hypertension : an angiotensin II receptor antagonist, Telmisartan, and a dihydropyridinic calcium channel blocker, S (-) Amlodipine. The combination of these agents has an additive antihypertensive effect, reducing blood pressure to a greater degree than either component alone. Eslo Tel once daily produces effective and consistent reductions in blood pressure across the 24-hour therapeutic dose range.

Clinical Pharmacology:

Pharmacodynamics

S (-) Amlodipine

Amlodipine is a racemic mixture of R and S enantiomers in 1:1 ratio. S-enantiomer of Amlodipine is active and R-enantiomer is inactive. The S (-) isomer of Amlodipine is found to possess greater pharmacological effects than R (+) Amlodipine. S (-) Amlodipine is 1000 times more potent than the R (+) isomer in binding to the dihydropyridine receptor. Therefore this is the only form which produces its therapeutic effects. In humans, the dominant effects of S (-) Amlodipine are consequent to vasodilation. S (-) Amlodipine lowers peripheral vascular resistance without causing a reflex tachycardia. In patients with angina pectoris S (-) Amlodipine reduces the myocardial oxygen demand by causing a direct vasodilation of the coronary artery and arterioles.

Telmisartan

Telmisartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. There is also an AT2 receptor found in many tissues, but AT2 is not known to be associated with cardiovascular homeostasis. Telmisartan has much greater affinity (>3,000 fold) for the AT1 receptor than for the AT2 receptor. Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE.

Because Telmisartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Telmisartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

Pharmacokinetics:

Paediatric population (age below 18 years)

No pharmacokinetic data are available in the paediatric population.

Elderly

The pharmacokinetics of Telmisartan does not differ in young and elderly patients. In elderly patients, Amlodipine clearance tends to decline with resulting increases in AUC and elimination half-life.

Renal impairment

In patients with mild to moderate and severe renal impairment, doubling of plasma concentrations of Telmisartan was observed. However, lower plasma concentrations were observed in patients with renal insufficiency undergoing dialysis. Telmisartan is highly bound to plasma protein in renal-insufficient subjects and cannot be removed by dialysis. The elimination half-life is not changed in patients with renal impairment. The pharmacokinetics of S (-) Amlodipine is not significantly influenced by renal impairment.

Hepatic impairment

Pharmacokinetic studies in patients with hepatic impairment showed an increase in absolute bioavailability of Telmisartan up to nearly 100%. The elimination half-life of Telmisartan is not changed in patients with hepatic impairment. Patients with hepatic insufficiency have decreased clearance of Amlodipine with resulting increase of approximately 40-60% in AUC.

Treatment of essential hypertension

Hypersensitivity to the active substances, to dihydropyridine derivatives or to any of the excipients.

Second and third trimesters of pregnancy

Biliary obstructive disorders and severe hepatic impairment

Shock (including cardiogenic shock)

Obstruction of the outflow tract of the left ventricle (e.g. high grade aortic stenosis)

Haemodynamically unstable heart failure after acute myocardial infarction The concomitant use of Eslo Tel with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 2 60 ml/min/1.73 m )

Posology

The recommended dose of this medicinal product is one tablet per day.

The maximum recommended dose is one tablet 80 mg Telmisartan / 5 mg S (-) Amlodipine per day.

This medicinal product is indicated for long term treatment.

Add on therapy

Eslo Tel 40 mg/2.5 mg may be administered in patients whose blood pressure is not adequately controlled with S (-) Amlodipine 2.5 mg alone. Individual dose titration with the components (i.e. S (-) Amlodipine and Telmisartan) is recommended before changing to the fixed dose combination. When clinically appropriate, direct change from monotherapy to the fixed combination may be considered. Patients treated with 5 mg S (-) Amlodipine who experience any dose limiting adverse reactions, may be switched to Eslo-Tel 40 mg/2.5 mg once daily, reducing the dose of S (-) Amlodipine without reducing the overall expected antihypertensive response.

Replacement therapy

Patients receiving Telmisartan and S (-) Amlodipine from separate tablets can instead receive tablets of Eslo Tel containing the same component doses in one tablet once daily.

Elderly patients (> 65 years)

No dose adjustment is necessary for elderly patients.

Limited experience is available in patients with severe renal impairment or haemodialysis. Caution is advised when using Eslo Tel in such patients as S (-) Amlodipine and Telmisartan are not dialysable. No dosage adjustment is required for patients with mild to moderate renal impairment. When Eslo Tel is used in patients with impaired renal function, a periodic monitoring of potassium and creatinine serum levels is recommended. There is no experience regarding the administration of Eslo Tel in patients with a recent kidney transplant. Telmisartan and S (-) Amlodipine are not dialysable.

Patients with renal impairment

In most patients, initiate S (-) Amlodipine therapy at 1.25 mg. Titrate slowly in patients with hepatic impairment. In patients with mild to moderate hepatic impairment, Eslo Tel should be administered with caution. For Telmisartan the dose should not exceed 40 mg once daily. Eslo Tel is contraindicated in patients with severe hepatic impairment

Paediatric population

No data are available.

Method of administration

Oral use. Eslo Tel can be taken with or without food. It is recommended to take Eslo Tel with some liquid.

Symptoms

Signs and symptoms of overdose are expected to be in line with exaggerated pharmacological effects of individual drugs. The most prominent manifestations of Telmisartan overdose are expected to be hypotension and tachycardia; bradycardia, dizziness, increase in serum creatinine, and acute renal failure have also been reported. Overdose with S (-) Amlodipine may 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.

The patient should be closely monitored, and the treatment should be symptomatic and supportive. Management depends on the time since ingestion and the severity of the symptoms. Suggested measures include induction of emesis and / or gastric lavage. Activated charcoal may be useful in the treatment of overdose of both Telmisartan and S (-) Amlodipine. Serum electrolytes and creatinine should be monitored frequently. If hypotension occurs, the patient should be placed in a supine position with elevation of extremities, with salt and volume replacement given quickly. Supportive treatment should be instituted. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade. Telmisartan and S (-) Amlodipine are not removed by haemodialysis.

Pregnancy

Pregnancy Category D

When pregnancy is detected, discontinue Eslo Tel as soon as possible. Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

Breast-feeding

Because no information is available regarding the use of Telmisartan and/or Amlodipine during breastfeeding, Eslo Tel is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while breast-feeding a newborn or preterm infant.

Adverse Reactions

S (-) Amlodipine

Gingival Hypertrophy & Alopecia have been reported with S (-) Amlodipine use. No adverse drug reactions were observed in the Randomized Controlled Trials of S (-) Amlodipine. Post Marketing Surveillance studies of S (-) Amlodipine involving 4089 patients further confirmed the safety and tolerability of S (-) Amlodipine. On the basis of clinical data available, the following adverse events have been reported in less than 2% of patients : vertigo (0.05%), tachycardia (0.05%), cough (0.05%), headache (0.43%), difficulty in breathing (0.1%), and facial puffiness (0.05%).

Telmisartan

Telmisartan is usually well tolerated. The side effects have been mild and transient in nature and have only infrequently required discontinuation of therapy. The commonly observed side effects are back pain, diarrhea, pharyngitis, headache, dizziness, pain, fatigue and nausea. Uncommon adverse effects seen were anaemia, hyperkalaemia, dyspnoea, flatulence, hyperhidrosis, renal impairment including acute renal failure, and increased blood creatinine.

No interactions between the two components of this fixed dose combinations have been observed in clinical studies. No drug interaction studies have been performed for this combination.

To be taken into account with concomitant use :

Other antihypertensive medicinal products The blood pressure lowering effect of Eslo Tel can be increased by concomitant use of other antihypertensive medicinal products.

Medicinal products with blood pressure lowering potential

Based on their pharmacological properties it can be expected that the following medicinal products may potentiate the hypotensive effects of all antihypertensives including this medicinal product, e.g. baclofen, amifostine, neuroleptics or antidepressants. Furthermore, orthostatic hypotension may be aggravated by alcohol.

Reduction of the antihypertensive effect

Warnings & Precautions

Store below 25°C. Protect from light & moisture.

Keep out of reach of children. Moisture sensitive tablets, do not remove from blister strip until immediately before administration.

Shelf-life:

Refer on the pack.

Presentation

Eslo Tel 2.5 mg : Alu-Alu blister strip of 15 tablets.

Eslo Tel 5 mg : Alu-Alu blister strip of 15 tablets.

Each uncoated bilayered tablet contains :

S (-) Amlodipine Besylate IP

equivalent to S (-) Amlodipine 5 mg

Atenolol IP 50 mg

Excipients q.s.

Colour : Lake of Sunset Yellow

THERAPEUTIC CATEGORY :

Antihypertensive, antianginal agent

S (-) Amlodipine, the chirally pure form of Amlodipine is a calcium channel antagonist belonging to the dihydropyridine class. The chemical name of S (-) Amlodipine is (S)-3-ethyl5-1-methyl-2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)- 1,4-dih-ydro-6-methyl-3,5-pyridinedicarboxylate. Its empirical l formula is C₂₀H₂₅ClN₂O₅C₆H₆O₃ S,with a molecular 20 25 2 5 6 6 3 weight of 567.1

Atenolol is a β1-selective receptor antagonist and produces the antihypertensive activity. It is chemically described as benzeneacetamide, 4-[2'-hydroxy-3'-[(1-methylethyl) amino] propoxy]. Atenolol has a molecular weight of 266.34 with molecular formula C₁₄H ₂₂N₂O₃ .

Clinical Pharmacology :

S (-) Amlodipine, the chirally pure form of Amlodipine is a calcium channel antagonist belonging to the dihydropyridine class. The S (-) isomer of Amlodipine is found to possess greater pharmacological effects than R (+) Amlodipine. S (-) Amlodipine is 1000 times more potent than the R (+) isomer in binding to the dihydropyridine receptor. In humans, the dominant effects of Amlodipine are consequent to vasodilation. S (-) Amlodipine lowers peripheral vascular resistance without causing a reflex tachycardia. In patients with angina pectoris S (-) Amlodipine reduces the myocardial oxygen demand by causing a direct vasodilation of the coronary artery and arterioles. Atenolol is a β1-selective receptor antagonist and produces the antihypertensive activity. β-adrenergic antagonists slow the heart rate and decrease myocardial contractility. These agents decrease the effect of catecholamines on the determinants of myocardial oxygen consumption thus improving the relationship between cardiac oxygen supply and demand. Combinations of Amlodipine and Atenolol have been used successfully to treat hypertension and angina. Since S (-) Amlodipine is the chirally pure form of Amlodipine, the combination of S (-) Amlodipine and Atenolol is highly beneficial in the treatment of hypertension and angina.

Pharmacokinetics:

Administration of S (-) Amlodipine 2.5 mg as a single dose in the fasting state produced maximum plasma concentration (Cmax) of 8.30 ± 1.071 ng/ ml in 2.73 ± 0.88 hrs. (Tmax). Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with 10% of the parent compound and 60% of the metabolites excreted in the urine. Ex vivo studies have shown that approximately 93% of the circulating drug is bound to plasma proteins in hypertensive patients. The mean AUC0-t value (t= 48 hrs.) of Tablet S (-) Amlodipine (2.5 mg) is 95.33 ± 14.45 ng.hr/ml. The AUC0-∞ value is recorded to be 140.91± 28.06 ng.hr/ml. The plasma elimination half life of S (-) Amlodipine has been found to be 31.09 ± 12.65 hrs.

Approximately 50% of an oral dose of Atenolol is absorbed from the gastro-intestinal tract and the remainder being excreted unchanged in the faeces. Maximum plasma concentrations are reached within two to four hours after a single oral dose and doses of 50 mg and 100 mg produce mean peak plasma concentrations of approximately 300 and 700 ng/mL, respectively. The plasma half-life (t½) is 6-7 hours and Atenolol is effective for at least 24 hours after a single oral dose. Atenolol is 6-16% plasma protein bound and is extensively distributed to extravascular tissues, but only a small amount is found in the central nervous system. Approximately 10% of Atenolol is metabolised in man. Approximately 47% and 53% of an oral dose is eliminated in the urine and faeces respectively.

For treatment of Essential Hypertension & Angina Pectoris.

Hypersensitivity to any of the components of the formulation, sinus bradycardia, second and higher degrees of heart block, cardiogenic shock, hypotension and overt cardiac failure.

One tablet to be administered once daily.

Gingival hypertrophy and alopecia has been seen with S (-) Amlodipine. On the basis of the clinical data available, only minor side effects have been reported with the use of S (-) Amlodipine. On the basis of clinical data available, adverse events reported in less than 5% of the patients included anxiety (0.43%), anorexia (0.43%), irritation (0.43%), headache (2.13%) and facial flushing (2.13%). Caution should be exercised when administering S (-) Amlodipine to patients with impaired hepatic and renal function.

Common adverse events seen with Atenolol are as follows : Sleep disturbances, purpura, thrombocytopenia, leucopenia, mood changes, depression, anxiety, nightmares, confusion, psychosis, hallucinations, dizziness, headache, paraesthesia of extremities, dry eyes, impaired vision, visual disturbances, bradycardia, heart failure deterioration, precipitation of heart block, cold extremities, postural hypotension which may be associated with syncope, bronchospasmm, gastrointestinal disturbances, constipation, dry mouth, elevations of transaminase levels, hepatic toxicity including intrahepatic cholestasis, alopecia, psoriasiform skin reactions, exacerbation of psoriasis, skin rashes, impotence, fatigue, sweating.

Clinical studies have shown that S (-) Amlodipine when combined with aspirin, nitrates, beta-blockers, statins, ACE inhibitors, H blockers, and Proton Pump Inhibitors produced no drug interactions. No drug interaction has been reported 2 with the use of Atenolol.

Increased Angina and/or Myocardial Infarction

Rarely, patients, particularly those with severe obstructive coronary artery disease, have developed documented increased frequency, duration and/or severity of angina or acute myocardial infarction on starting calcium channel blocker therapy or at the time of dosage increase. The mechanism of this effect has not been elucidated.

Cardiac Failure

Sympathetic stimulation is necessary in supporting circulatory function in congestive heart failure, and beta blockade carries the potential hazard of further depressing myocardial contractility and precipitating more severe failure. In patients who have congestive heart failure controlled by digitalis and/or diuretics, Atenolol should be administered cautiously. Both digitalis and Atenolol slow AV conduction. In general, calcium channel blockers should also be used with caution in patients with heart failure.

Bronchospastic Diseases

Patients with bronchospastic disease should, in general, not receive beta blockers. Because of its relative β1 selectivity, however, Atenolol may be used with caution in patients with bronchospastic disease who do not respond to, or cannot tolerate, other antihypertensive treatment.

Thyrotoxicosis

Beta-adrenergic blockade may mask certain clinical signs (eg, tachycardia) of hyperthyroidism. Abrupt withdrawal of beta blockade might precipitate a thyroid storm; therefore, patients suspected of developing thyrotoxicosis from which Atenolol therapy is to be withdrawn and should be monitored closely.

Untreated Pheochromocytoma

Atenolol should not be given to patients with untreated pheochromocytoma

Pregnancy and Fetal Injury

There is no data available on the use of S (-) Amlodipine in pregnant and lactating women. Atenolol can cause fetal harm when administered to a pregnant woman. Atenolol crosses the placental barrier and appears in cord blood. Administration of Atenolol, starting in the second trimester of pregnancy, has been associated with the birth of infants that are small for gestational age. No studies have been performed on the use of Atenolol in the first trimester and the possibility of fetal injury cannot be excluded. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Neonates born to mothers who are receiving Atenolol at parturition or breast-feeding may be at risk for hypoglycemia and bradycardia. Caution should be exercised when Atenolol is administered during pregnancy or to a woman who is breast-feeding.

Precautions :

Hepatic impairment and renal impairment

No controlled clinical study of S (-) Amlodipine has been performed in patients with hepatic impairment and renal impairment. Clinical studies in patients with normal liver function have shown that there is no elevation in the hepatic enzymes with the use of S (-) Amlodipine. Since about 90% of the drug is excreted unchanged in urine, no dosage adjustment is required in patients with hepatic impairment. There is no significant hepatic metabolism of Atenolol and more than 90% of that absorbed reaches the systemic circulation unaltered. Plasma half-life is raised in patients with renal failure with S (-) Amlodipine. Since Atenolol is excreted via the kidneys, the dosage should be adjusted in cases of severe impairment of renal function. Hence, caution should be taken while administering the combination to such patients.

Children

Safety and effectiveness of this product in children has not been established.

Overdosage with racemic Amlodipine and Atenolol may cause excessive peripheral vasodilation with marked hypotension possibly a reflex tachycardia, acute cardiac insufficiency and bronchospasm. Hence, caution should be taken in case of an overdosage with Eslo-5AT tablet. If massive overdose occurs, active cardiac and respiratory monitoring should be instituted. Frequent blood pressure measurements should be performed. Should hypotension occur, cardiovascular support including elevation of the extremities and the judicious administration of fluids should be initiated. If hypotension remains unresponsive to these conservative measures, administration of vasopressors (such as phenylephrine) should be considered with attention to circulating volume and urine output. If massive overdose occurs, gastric lavage should be employed. As this product is highly plasma protein bound, hemodialysis is not likely to be of benefit.

Store protected from light & moisture, at a temperature not exceeding 30°C.

Keep out of reach of children.

Refer on the pack.

A blister strip of 10 tablets.

Ondansetron Injection

Emigo injection 4 mg/8 mg

Each ml contains:

Ondansetron Hydrochloride IP

equivalent to Ondansetron………………………………………… 2 mg

Water for Injections IP q.s.

Injection 4 mg/8 mg

4.1 Therapeutic indication

In the treatment and management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy.

4.2 Posology and method of administration

Chemotherapy and radiotherapy induced nausea and vomiting

Adults

The emetogenic potential of cancer treatment varies according to the doses and combinations of chemotherapy and radiotherapy regimens used. The dose range of ondansetron solution for injection or infusion is 8-32 mg a day and selected as shown below.

Emetogenic chemotherapy and radiotherapy

For patients receiving emetogenic chemotherapy or radiotherapy ondansetron can be given either by intravenous or other routes of administration, however this product is for intravenous use only.

The recommended intravenous dose of ondansetron is 8 mg administered as a slow injection (in not less than 30 seconds) or as an infusion over 15 minutes immediately before treatment, followed by treatment with dosage forms other than intravenous.

Treatment with dosage forms other than intravenous is recommended to protect against delayed or prolonged emesis after the first 24 hours.

Highly emetogenic chemotherapy

For patients receiving highly emetogenic chemotherapy, e.g. high-dose cisplatin, ondansetron can be given by intravenous or other routes of administration, however this product is for intravenous use only

Ondansetron has been shown to be equally effective in the following intravenous dose schedules over the first 24 hours of chemotherapy:

• A single dose of 8 mg by slow intravenous injection (in not less than 30 seconds) immediately before chemotherapy.
• A dose of 8 mg by slow intravenous injection (in not less than 30 seconds) or as a short
• time intravenous infusion over 15 minutes immediately before chemotherapy, followed by two further intravenous doses of 8 mg four hours apart, or by a constant infusion of 1 mg/hour for up to 24 hours.
• A maximum initial intravenous dose of 16 mg diluted in 50-100 ml of sodium chloride 9 mg/ml (0.9 % w/v) solution or other compatible infusion fluid and infused over not less than 15 minutes immediately before chemotherapy. The initial dose of Ondansetron may be followed by two additional 8 mg intravenous doses (in not less than 30 seconds) four hours apart. A single dose greater than 16 mg must not be given due to dose dependent increase of QT-prolongation risk.

The selection of dose regimen should be determined by the severity of the emetogenic challenge.

The efficacy of ondansetron in highly emetogenic chemotherapy may be enhanced by the addition of a single intravenous dose of dexamethasone sodium phosphate, 20 mg administered prior to chemotherapy.

To protect against delayed or prolonged emesis after the first 24 hours, ondansetron treatment with dosage forms other than intravenous should be continued after a course of treatment.

Paediatric Population:

CINV in children aged ≥ 6 months and adolescents

The dose for CINV can be calculated based on body surface area (BSA) or weight. Weightbased dosing results in higher total daily doses compared to BSA-based dosing.

Ondansetron injection should be diluted in 5% glucose or 0.9% sodium chloride or other compatible infusion fluid and infused intravenously over not less than 15 minutes. There are no data from controlled clinical trials on the use of Ondansetron in the prevention of delayed or prolonged CINV. There are no data from controlled clinical trials on the use of Ondansetron for radiotherapy-induced nausea and vomiting in children.

Dosing by BSA:

Ondansetron should be administered immediately before chemotherapy as a single intravenous dose of 5 mg/m2. The intravenous dose must not exceed 8 mg.

Oral dosing can commence twelve hours later and may be continued for up to 5 days (Table 1).

The total daily dose must not exceed adult dose of 32 mg.

Table 1: BSA-based dosing for Chemotherapy - Children aged ≥ 6 months and adolescents

a The intravenous dose must not exceed 8mg

b The total daily dose must not exceed adult dose of 32 mg

Dosing by bodyweight:

Weight-based dosing results in higher total daily doses compared to BSA-based dosing.

Ondansetron should be administered immediately before chemotherapy as a single intravenous dose of 0.15 mg/kg. The intravenous dose must not exceed 8 mg. Two further intravenous doses may be given in 4-hourly intervals. The total daily dose must not exceed adult dose of 32 mg

Oral dosing can commence twelve hours later and may be continued for up to 5 days (Table 2)

Table 2: Weight-based dosing for Chemotherapy - Children aged ≥ 6 months and adolescents

a The intravenous dose must not exceed 8mg.

b The total daily dose must not exceed adult dose of 32 mg.

Elderly

In patients 65 to 74 years of age, the dose schedule for adults can be followed. All intravenous doses should be diluted in 50-100 ml of saline or other compatible infusion fluid and infused over 15 minutes.

In patients 75 years of age or older, the initial intravenous dose should not exceed 8 mg. All intravenous doses should be diluted in 50-100 ml of saline or other compatible infusion fluid and infused over 15 minutes. The initial dose of 8 mg may be followed by two further intravenous doses of 8 mg, infused over 15 minutes and given no less than four hours apart.

Post-operative nausea and vomiting (PONV)

Prevention of PONV

Adults: For the prevention of PONV ondansetron can be administered by intravenous injection or other dosage forms.

Ondansetron may be administered as a single dose of 4 mg given by slow intravenous injection at induction of anaesthesia.

Treatment of established PONV

For treatment of established PONV a single dose of 4 mg given by slow intravenous injection is recommended.

Paediatric population

PONV in children aged ≥ 1 month and adolescents

For prevention of PONV in paediatric patients having surgery performed under general anaesthesia, a single dose of ondansetron may be administered by slow intravenous injection (not less than 30 seconds) at a dose of 0.1 mg/kg up to a maximum of 4 mg either prior to, at or after induction of anaesthesia.

For the treatment of PONV after surgery in paediatric patients having surgery performed under general anaesthesia, a single dose of ondansetron may be administered by slow intravenous injection (not less than 30 seconds) at a dose of 0.1 mg/kg up to a maximum of 4 mg. There are no data on the use of ondansetron in the treatment of PONV in children below 2 years of age.

For treatment of established PONV in paediatric patients and adolescents, ondansetron may be administered by slow intravenous injection at a dose of 0.1 mg/kg up to a maximum of 4 mg.

Elderly

There is limited experience in the use of ondansetron in the prevention and treatment of PONV in the elderly, however ondansetron is well tolerated in patients over 65 years receiving chemotherapy.

Special Populations

Patients with renal impairment

No alteration of daily dosage or frequency of dosing, or route of administration is required.

Patients with hepatic impairment

Clearance of ondansetron is significantly reduced and serum half-life significantly prolonged in subjects with moderate or severe impairment of hepatic function. In such patients a total daily dose of 8 mg should not be exceeded.

Patients with poor sparteine/debrisoquine metabolism

The elimination half-life of ondansetron is not altered in subjects classified as poor metabolisers of sparteine and debrisoquine. Consequently, in such patients repeat dosing will give drug exposure levels no different from those of the general population. No alteration of daily dosage or frequency of dosing is required.

4.3 Contraindications

• Hypersensitivity to the active substance or to other selective 5-HT3 receptor antagonists (e.g. granisetron, dolasetron) or to any of the excipients listed in the formulation.
• Concomitant use with apomorphine.

4.4 Special warnings and precautions for use

Hypersensitivity reactions have been reported in patients who have exhibited hypersensitivity to other selective 5-HT3 receptor antagonists.

Respiratory events should be treated symptomatically and clinicians should pay particular attention to them as precursors of hypersensitivity reactions.

Ondansetron prolongs the QT interval in a dose-dependent manner. In addition, postmarketing cases of Torsade de Pointes have been reported in patients using ondansetron. Avoid ondansetron in patients with congenital long QT syndrome. Ondansetron should be administered with caution to patients who have or may develop prolongation of QTc. These conditions include patients with electrolyte abnormalities, congestive heart failure,bradyarrhythmias or patients taking other medicinal products that lead to QT prolongation or electrolyte abnormalities.

Cases of myocardial ischemia have been reported in patients treated with ondansetron. In some patients, especially in the case of intravenous administration, symptoms appeared immediately after administration of ondansetron. Patients should be alerted to the signs and symptoms of myocardial ischaemia.

Hypokalaemia and hypomagnesaemia should be corrected prior to ondansetron administration.

There have been post-marketing reports describing patients with serotonin syndrome (including altered mental status, autonomic instability and neuromuscular abnormalities) following the concomitant use of ondansetron and other serotonergic drugs (including selective serotonin reuptake inhibitors (SSRI) and serotonin noradrenaline reuptake inhibitors (SNRIs)). If concomitant treatment with ondansetron and other serotonergic drugs is clinically warranted, appropriate observation of the patient is advised.

As ondansetron is known to increase large bowel transit time, patients with signs of subacute intestinal obstruction should be monitored following administration.

In patients with adenotonsillar surgery prevention of nausea and vomiting with ondansetron may mask occult bleeding. Therefore, such patients should be followed carefully after ondansetron.

Paediatric Population:

Paediatric patients receiving ondansetron with hepatotoxic chemotherapeutic agents should be monitored closely for impaired hepatic function.

4.5 Drugs interactions

Effects of ondansetron on other medicinal products

There is no evidence that ondansetron either induces or inhibits the metabolism of other drugs commonly co administered with it. Specific studies have shown that ondansetron does not interact with alcohol, temazepam, furosemide, alfentanil, morphine, lignocaine, propofol and thiopental.

Effects of other medicinal products on ondansetron

Ondansetron is metabolised by multiple hepatic cytochrome P-450 enzymes: CYP3A4, CYP2D6 and CYP1A2. Due to the multiplicity of metabolic enzymes capable of metabolising ondansetron, enzyme inhibition or reduced activity of one enzyme (e. g. CYP2D6 genetic deficiency) is normally compensated by other enzymes and should result in little or no significant change in overall ondansetron clearance or dose requirement.

Caution should be exercised when ondansetron is co administered with drugs that prolong the QT interval and/or cause electrolyte abnormalities.

Use of ondansetron with QT prolonging drugs may result in additional QT prolongation. Concomitant use of ondansetron with cardiotoxic drugs (e.g. anthracyclines such as doxorubicin, daunorubicin or trastuzimab), antibiotics (such as erythromycin or ketoconazole), antiarrhythmics (such as amiodarone) and beta blockers (such as atenolol or timolol) may increase the risk of arrhythmias.

There have been post-marketing reports describing patients with serotonin syndrome (including altered mental status, autonomic instability and neuromuscular abnormalities) following the concomitant use of ondansetron and other serotonergic drugs (including SSRIs and SNRIs).

Apomorphine: Based on reports of profound hypotension and loss of consciousness when ondansetron was administered with apomorphine hydrochloride, concomitant use with apomorphine is contraindicated.

Phenytoin, carbamazepine and rifampicin: In patients treated with potent inducers of CYP3A4 (i.e. phenytoin, carbamazepine and rifampicin), the oral clearance of ondansetron was increased and ondansetron blood concentrations were decreased.

Tramadol: Data from small studies indicate that ondansetron may reduce the analgesic effect of tramadol.

4.6 Use in special populations

Women of childbearing potential

Women of childbearing potential should consider the use of contraception.

Pregnancy

Based on human experience from epidemiological studies, ondansetron is suspected to cause orofacial malformations when administered during the first trimester of pregnancy.

In one cohort study including 1.8 million pregnancies, first trimester ondansetron use was associated with an increased risk of oral clefts (3 additional cases per 10 000 women treated; adjusted relative risk, 1.24, (95% CI 1.03-1.48)).

The available epidemiological studies on cardiac malformations show conflicting results.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. However, Ondansetron should not be used during the first trimester of pregnancy.

Lactation

Tests have shown that ondansetron passes into the milk of lactating animals. It is therefore recommended that mothers receiving ondansetron should not breast-feed their babies.

4.7 Effects on ability to drive and use machines

Ondansetron has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Immune system disorders

Rare:

Immediate hypersensitivity reactions, sometimes severe including anaphylaxis. Anaphylaxis may be fatal. Hypersensitivity reactions were also observed in patients, who were sensitive towards other selective 5-HT3 receptor antagonists.

Nervous system disorders

Very common: Headache.

Uncommon:

There have been reports suggestive of involuntary movement disorders such as extrapyramidal reactions, e.g. oculogyric crisis/dystonic reactions and dyskinesia without definitive evidence of persistent clinical sequelae and seizures (e.g. epileptic spasms) have been observed although no known pharmacological mechanism can account for ondansetron causing these effects.

Rare:

Dizziness during rapid intravenous administration.

Very rare:

Depression.

Eye disorders

Rare:

Transient visual disturbances (e.g. blurred vision) during rapid intravenous administration.

Very rare:

In individual cases transitory blindness was reported in patients receiving chemotherapeutic agents including cisplatin. Most reported cases were resolved within 20 minutes. Some cases of transient blindness were reported as cortical in origin.

Cardiac disorders

Uncommon:

Chest pain with or without ST segment depression, cardiac arrhythmias and bradycardia. Chest pain and cardiac arrhythmias may be fatal in individual cases.

Rare:

Transitory changes in the electrocardiogram, QTc prolongation (including Torsades de Pointes)

Unknown:

Vascular disorders

Common: Sensations of flushing or warmth.

Uncommon: Hypotension.

Respiratory, thoracic and mediastinal disorders

Uncommon: Hiccups.

Gastrointestinal disorders

Common:  Ondansetron is known to increase the large bowel transit time and may cause constipation in some patients.

Hepatobiliary disorders

Uncommon: Asymptomatic increases in liver function tests were observed. These reactions were frequently observed in patients under chemotherapy with cisplatin.

Skin and subcutaneous tissue disorders

Uncommon: Hypersensitivity reactions around the injection site (e.g. rash, urticaria, itching) may occur, sometimes extending along the drug administration vein.

General disorders and administration site conditions

Common: Local reactions at the IV injection site.

Paediatric population

The adverse event profile in children and adolescents was comparable to that seen in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com

Website: https://www.zuventus.com/drug-safety-reporting

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

Little is known at present about overdosage with ondansetron, however, a limited number of patients received overdoses. In the majority of cases, symptoms were similar to those already reported in patients receiving recommended doses. Manifestations that have been reported include visual disturbances, severe constipation, hypotension and a vasovagal episode with transient second degree AV block. In all instances, the events resolved completely. Ondansetron prolongs the QT interval in a dose-dependent fashion. ECG monitoring is recommended in cases of overdose.

There is no specific antidote for ondansetron, therefore in all cases of suspected overdose, symptomatic and supportive therapy should be given as appropriate. The use of ipecacuanha to treat overdose with ondansetron is not recommended, as patients are unlikely to respond due to the anti-emetic action of ondansetron itself.

Paediatric population

Paediatric cases consistent with serotonin syndrome have been reported after inadvertent oral overdoses of ondansetron (exceeded estimated ingestion of 4 mg/kg) in infants and children aged 12 months to 2 years.

5.1 Mechanism of action

Ondansetron is a potent, highly selective 5HT3 receptor-antagonist.

Its precise mode of action in the control of nausea and vomiting is not known. Chemotherapeutic agents and radiotherapy may cause release of 5HT in the small intestine initiating a vomiting reflex by activating vagal afferents via 5HT3 receptors. Ondansetron blocks the initiation of this reflex. Activation of vagal afferents may also cause a release of 5HT in the area postrema, located on the floor of the fourth ventricle, and this may also promote emesis through a central mechanism. Thus, the effect of ondansetron in the management of the nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy is probably due to antagonism of 5HT3 receptors on neurons located both in the peripheral and central nervous system. The mechanisms of action in post-operative nausea and vomiting are not known but there may be common pathways with cytotoxic induced nausea and vomiting.

5.2 Pharmacodynamic properties

The effect of ondansetron on the QTc interval was evaluated in a double blind, randomised, placebo and positive (moxifloxacin) controlled, crossover study in 58 healthy adult men and women. Ondansetron doses included 8 mg and 32 mg infused intravenously over 15 minutes. At the highest tested dose of 32 mg, the maximum mean (upper limit of 90% CI) difference in QTcF from placebo after baseline-correction was 19.6 (21.5) msec. At the lower tested dose of 8 mg, the maximum mean (upper limit of 90% CI) difference in QTcF from placebo after baseline-correction was 5.8 (7.8) msec. In this study, there were no QTcF measurements greater than 480 msec and no QTcF prolongation was greater than 60 msec. No significant changes were seen in the measured electrocardiographic PR or QRS intervals.

5.3 Pharmacokinetic properties

Absorption

Following oral administration, ondansetron is passively and completely absorbed from the gastrointestinal tract and undergoes first pass metabolism (Bioavailability is about 60%.). Peak plasma concentrations of about 30 ng/ml are attained approximately 1.5 hours after an 8 mg dose. For doses above 8 mg the increase in ondansetron systemic exposure with dose is greater than proportional; this may reflect some reduction in first pass metabolism at higher oral doses. Bioavailability, following oral administration, is slightly enhanced by the presence of food but unaffected by antacids.

A 4 mg intravenous infusion of ondansetron given over 5 minutes results in peak plasma concentrations of about 65 ng/ml. Following intramuscular administration of ondansetron, peak plasma concentrations of about 25 ng/ml are attained within 10 minutes of injection.

Distribution

The disposition of ondansetron following oral, intramuscular (IM) and intravenous (IV) dosing is similar with a steady state volume of distribution of about 140 L. Equivalent systemic exposure is achieved after IM and IV administration of ondansetron.

Ondansetron is not highly protein bound (70-76%).

Metabolism

Ondansetron is cleared from the systemic circulation predominantly by hepatic metabolism through multiple enzymatic pathways. The absence of the enzyme CYP2D6 (the debrisoquine polymorphism) has no effect on ondansetron's pharmacokinetics.

Excretion

Less than 5% of the absorbed dose is excreted unchanged in the urine. Terminal half-life is about 3 hours.

6.1 Animal Toxicology or Pharmacology

Preclinical data revealed no special hazard for humans based on conventional studies of safety, pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction.

Ondansetron and its metabolites accumulate in the milk of rats, milk/plasma-ratio was 5.2:1. A study in cloned human cardiac ion channels has shown ondansetron has the potential to affect cardiac repolarisation via blockade of HERG potassium channels. The clinical relevance of this finding is uncertain.

The active ingredient of Ondansetron Injection, is ondansetron hydrochloride, a selective blocking agent of the serotonin 5-HT3 receptor type. Its chemical name is (±) 1, 2, 3, 9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4- one, monohydrochloride, dihydrate.

Rare : Immediate hypersensitivity reactions, sometimes severe including anaphylaxis. Anaphylaxis may be fatal.

Hypersensitivity reactions were also observed in patients, who were sensitive towards other selective 5- HT receptor antagonists.

Nervous system disorders

Very common : Headache

Uncommon : There have been reports suggestive of involuntary movement disorders such as extrapyramidal reactions, e.g. oculogyric crisis/dystonic reactions and dyskinesia without definitive evidence of persistent clinical sequelae and seizures (e.g. epileptic spasms) have been observed although no known pharmacological mechanism can account for ondansetron causing these effects.

Rare : Dizziness during rapid intravenous administration.

Very rare : Depression.

Eye disorders

Rare : Transient visual disturbances (e.g. blurred vision) during rapid intravenous administration.

Very rare : In individual cases transitory blindness was reported in patients receiving chemotherapeutic agents including cisplatin. Most reported cases were resolved within 20 minutes. Some cases of transient blindness were reported as cortical in origin.

8.3 Storage and handing instructions

Store below 30°C. Protect from light.

Keep out of reach of children.

Do not freeze. Do not use if solution is not clear or has suspended matter.

QT Prolongation

Patients should be informed that Ondansetron Injection may cause serious cardiac arrhythmias such as QT prolongation. Patients should be instructed to tell their healthcare provider right away if they perceive a change in their heart rate, if they feel lightheaded, or if they have a syncopal episode.

Patients should be informed that the chances of developing severe cardiac arrhythmias such as QT prolongation and Torsade de Pointes are higher in the following people:

• Patients with a personal or family history of abnormal heart rhythms, such as congenital long QT syndrome
• Patients who take medications, such as diuretics, which may cause electrolyte abnormalities.
• Patients with hypokalemia or hypomagnesemia.

Ondansetron Injection should be avoided in these patients, since they may be more at risk for cardiac arrhythmias such as QT prolongation and Torsade de Pointes.

Hypersensitivity Reactions

Inform patients that Ondansetron Injection may cause hypersensitivity reactions, some as severe as anaphylaxis and bronchospasm. The patient should report any signs and symptoms of hypersensitivity reactions, including fever, chills, rash, or breathing problems.

Masking of Progressive Ileus and Gastric Distension

Inform patients following abdominal surgery or those with chemotherapy-induced nausea and vomiting that Ondansetron Injection may mask signs and symptoms of bowel obstruction. Instruct patients to immediately report any signs or symptoms consistent with a potential bowel obstruction to their healthcare provider.

Drug Interactions

• Instruct the patient to report the use of all medications, especially apomorphine, to their healthcare provider. Concomitant use of apomorphine and Ondansetron Injection may cause a significant drop in blood pressure and loss of consciousness.
• Advise patients of the possibility of serotonin syndrome with concomitant use of Ondansetron Injection and another serotonergic agent such as medications to treat depression and migraines. Advise patients to seek immediate medical attention if the following symptoms occur: changes in mental status, autonomic instability, neuromuscular symptoms with or without gastrointestinal symptoms.

18.09.2022

ENOXARIN 40

Each Pre-filled syringe contains :

Enoxaparin Sodium IP 40 mg

Water for Injections IP q.s. to 0.4 ml

ENOXARIN 60

Each Pre-filled syringe contains :

Enoxaparin Sodium IP 60 mg

Water for Injections IP q.s. to 0.6 ml

ENOXARIN Injection is a sterile aqueous solutions containing Enoxaparin Sodium, a low molecular weight heparin. The average molecular weight is about 4,500 daltons.

Pharmacodynamics

In humans, Enoxaparin given at a dose of 1.5 mg/kg subcutaneously (SC) is characterized by a higher ratio of anti-Factor Xa to anti-Factor IIa activity (mean±SD, 14.0±3.1) (based on areas under anti-Factor activity versus time curves) compared to the ratios observed for heparin (mean±SD, 1.22±0.13). Increases of up to 1.8 times the control values were seen in the thrombin time (TT) and the activated partial thromboplastin time (aPTT). Enoxaparin at a 1 mg/kg dose (100 mg/mL concentration), administered SC every 12 hours to patients in a large clinical trial resulted in aPTT values of 45 seconds or less in the majority of patients (n =1607). A 30 mg IV bolus immediately followed by a 1 mg/kg SC administration resulted in aPTT post-injection values of 50 seconds. The average aPTT prolongation value on Day 1 was about 16% higher than on Day 4.

Pharmacokinetics

Absorption : Pharmacokinetic trials were conducted using the 100 mg/mL formulation. Maximum anti Factor Xa and anti-thrombin (anti-Factor IIa) activities occur 3 to 5 hours after SC injection of Enoxaparin. Mean peak anti-Factor Xa activity was 0.16 IU/mL (1.58 mcg/mL) and 0.38 IU/mL (3.83 mcg/mL) after the 20 mg and the 40 mg clinically tested SC doses, respectively. Mean (n = 46) peak anti-Factor Xa activity was 1.1 IU/mL at steady state in patients with unstable angina receiving 1 mg/kg SC every 12 hours for 14 days. Mean absolute bioavailability of Enoxaparin, after 1.5 mg/kg given SC, based on anti-Factor Xa activity is approximately 100% in healthy subjects. A 30 mg IV bolus immediately followed by a 1 mg/kg SC every 12 hours provided initial peak anti-Factor Xa levels of 1.16 IU/mL (n=16) and average exposure corresponding to 84% of steady-state levels. Steady state is achieved on the second day of treatment. Enoxaparin pharmacokinetics appear to be linear over the recommended dosage ranges. After repeated subcutaneous administration of 40 mg once daily and 1.5 mg/kg once daily regimens in healthy volunteers, the steady state is reached on day 2 with an average exposure ratio about 15% higher than after a single dose. Steady-state Enoxaparin activity levels are well predicted by single-dose pharmacokinetics. After repeated subcutaneous administration of the 1 mg/kg twice daily regimen, the steady state is reached from day 4 with mean exposure about 65% higher than after a single dose and mean peak and trough levels of about 1.2 and 0.52 IU/mL, respectively. Based on Enoxaparin Sodium pharmacokinetics, this difference in steady state is expected and within the therapeutic range.

Distribution : The volume of distribution of anti-Factor Xa activity is about 4.3 L.

Elimination : Following intravenous (IV) dosing, the total body clearance of Enoxaparin is 26 mL/min. After IV dosing of Enoxaparin labeled with the gamma-emitter, 99m Tc, 40% of radioactivity and 8 to 20% of anti-Factor Xa activity were recovered in urine in 24 hours. Elimination half-life based on antiFactor Xa activity was 4.5 hours after a single SC dose to about 7 hours after repeated dosing. Significant anti-Factor Xa activity persists in plasma for about 12 hours following a 40 mg SC once a day dose. Following SC dosing, the apparent clearance (CL/F) of Enoxaparin is approximately 15 mL/min.

Metabolism : Enoxaparin Sodium is primarily metabolized in the liver by desulfation and/or depolymerization to lower molecular weight species with much reduced biological potency. Renal clearance of active fragments represents about 10% of the administered dose and total renal excretion of active and non-active fragments 40% of the dose.

Indications :

Prophylaxis of Deep Vein Thrombosis

Enoxaparin Sodium Injection is indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE)

• In patients undergoing abdominal surgery who are at risk for thromboembolic complications.
• In patients undergoing hip replacement surgery, during and following hospitalization.
• In patients undergoing knee replacement surgery.
• In medical patients who are at risk for thromboembolic complications due to severely restricted mobility during acute illness.

Treatment of Acute Deep Vein Thrombosis

Enoxaparin Sodium Injection is indicated for

• The inpatient treatment of acute deep vein thrombosis with or without pulmonary embolism, when administered in conjunction with warfarin Sodium.
• The outpatient treatment of acute deep vein thrombosis without pulmonary embolism when administered in conjunction with warfarin Sodium.

Prophylaxis of Ischemic Complications of Unstable Angina and Non-Q-Wave Myocardial Infarction

Treatment of Acute ST-Segment Elevation Myocardial Infarction

Contraindications:

• Active major bleeding
• Thrombocytopenia associated with a positive in vitro test for anti-platelet antibody in the presence of Enoxaparin Sodium
• Known hypersensitivity to Enoxaparin Sodium (e.g., pruritus, urticaria, anaphylactic/ anaphylactoid reactions)
• Known hypersensitivity to heparin or pork products

Dosage & Administration :

Abdominal Surgery : In patients undergoing abdominal surgery who are at risk for thromboembolic complications, the recommended dose of Enoxaparin Sodium Injection is 40 mg once a day administered by SC injection with the initial dose given 2 hours prior to surgery. The usual duration of administration is 7 to 10 days; up to 12 days administration has been administered in clinical trials.

Hip or Knee Replacement Surgery : In patients undergoing hip or knee replacement surgery, the recommended dose of Enoxaparin Sodium Injection is 30 mg every 12 hours administered by SC injection. Provided that hemostasis has been established, the initial dose should be given 12 to 24 hours after surgery. For hip replacement surgery, a dose of 40 mg once a day SC, given initially 12 (±3) hours prior to surgery, may be considered. Following the initial phase of thromboprophylaxis in hip replacement surgery patients, it is recommended that continued prophylaxis with Enoxaparin Sodium Injection 40 mg once a day be administered by SC injection for 3 weeks. The usual duration of administration is 7 to 10 days; up to 14 days administration has been administered in clinical trials.

Medical Patients During Acute Illness : In medical patients at risk for thromboembolic complications due to severely restricted mobility during acute illness, the recommended dose of Enoxaparin Sodium Injection is 40 mg once a day administered by SC injection. The usual duration of administration is 6 to 11 days; up to 14 days of Enoxaparin Sodium Injection has been administered in the controlled clinical trial.

Treatment of Deep Vein Thrombosis with or without Pulmonary Embolism : In outpatient treatment, patients with acute deep vein thrombosis without pulmonary embolism who can be treated at home, the recommended dose of Enoxaparin Sodium Injection is 1 mg/kg every 12 hours administered SC. In inpatient (hospital) treatment, patients with acute deep vein thrombosis with pulmonary embolism or patients with acute deep vein thrombosis without pulmonary embolism (who are not candidates for outpatient treatment), the recommended dose of Enoxaparin Sodium Injection is 1 mg/kg every 12 hours administered SC or 1.5 mg/kg once a day administered SC at the same time every day. In both outpatient and inpatient (hospital) treatments, warfarin Sodium therapy should be initiated when appropriate (usually within 72 hours of Enoxaparin Sodium Injection). Enoxaparin Sodium Injection should be continued for a minimum of 5 days and until a therapeutic oral anticoagulant effect has been achieved (International Normalization Ratio 2.0 to 3.0). The average duration of administration is 7 days; up to 17 days of Enoxaparin Sodium Injection administration has been administered in controlled clinical trials.

Unstable Angina and Non-Q-Wave Myocardial Infarction : In patients with unstable angina or non-Q-wave myocardial infarction, the recommended dose of Enoxaparin Sodium Injection is 1 mg/kg administered SC every 12 hours in conjunction with oral aspirin therapy (100 to 325 mg once daily). Treatment with Enoxaparin Sodium Injection should be prescribed for a minimum of 2 days and continued until clinical stabilization. The usual duration of treatment is 2 to 8 days; up to 12.5 days of Enoxaparin Sodium Injection has been administered in clinical trials.

Treatment of Acute ST-Segment Elevation Myocardial Infarction : In patients with acute ST-segment elevation myocardial infarction, the recommended dose of Enoxaparin Sodium Injection is a single IV bolus of 30 mg plus a 1 mg/kg SC dose followed by 1 mg/kg administered SC every 12 hours (maximum 100 mg for the first two doses only, followed by 1 mg/kg dosing for the remaining doses). Dosage adjustments are recommended in patients ≥75 years of age. All patients should receive aspirin as soon as they are identified as having STEMI and maintained with 75 to 325 mg once daily unless contraindicated. When administered in conjunction with a thrombolytic (fibrin-specific or non-fibrin specific), Enoxaparin Sodium Injection should be given between 15 minutes before and 30 minutes after the start of fibrinolytic therapy. In the pivotal clinical study, the Enoxaparin Sodium Injection treatment duration was 8 days or until hospital discharge, whichever came first. An optimal duration of treatment is not known, but it is likely to be longer than 8 days. For patients managed with percutaneous coronary intervention (PCI) : If the last Enoxaparin Sodium Injection SC administration was given less than 8 hours before balloon inflation, no additional dosing is needed. If the last Enoxaparin Sodium Injection SC administration was given more than 8 hours before balloon inflation, an IV bolus of 0.3 mg/kg of Enoxaparin Sodium Injection should be administered.

Renal impairment : Although no dose adjustment is recommended in patients with moderate (creatinine clearance 30–50 mL/min) and mild (creatinine clearance 50–80 mL/min) renal impairment, all such patients should be observed carefully for signs and symptoms of bleeding. The recommended prophylaxis and treatment dosage regimens for patients with severe renal impairment (creatinine clearance < 30 mL/min) are described in the table below

For treatment of acute ST-segment elevation myocardial infarction in geriatric patients ≥75 years of age, do not use an initial intravenous bolus. Initiate dosing with 0.75 mg/kg subcutaneously every 12 hours (maximum 75 mg for the first two doses only, followed by 0.75 mg/kg dosing for the remaining doses). No dose adjustment is necessary for other indications in geriatric patients unless kidney function is impaired.

In clinical studies, haemorrhages, thrombocytopenia and thrombocytosis were the most commonly reported reactions Other adverse reactions observed in clinical studies and reported in post-marketing experience (* indicates reactions from post-marketing experience) are detailed below. Frequencies are defined as follows : very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to <1/1,000); and very rare (< 1/10,000) or not known (cannot be estimated from available data). Within each system organ class, adverse reactions are presented in order of decreasing seriousness.

Blood and the lymphatic system disorders

• Common : Haemorrhage, haemorrhagic anaemia*, thrombocytopenia, thrombocytosis
• Rare : Eosinophilia*, cases of immuno-allergic thrombocytopenia with thrombosis; in some of them thrombosis was complicated by organ infarction or limb ischaemia (see section 4.4).

Immune system disorders

• Common : Allergic reaction
• Rare : Anaphylactic/Anaphylactoid reactions including shock*

Nervous system disorders

• Common : Headache*

Vascular disorders

• Rare : Spinal haematoma* (or neuraxial haematoma). These reactions have resulted in varying degrees of neurologic injuries including long-term or permanent paralysis (see section 4.4).

Hepato-biliary disorders

• Very common : Hepatic enzyme increases (mainly transaminases > 3 times the upper limit of normality)
• Uncommon : Hepatocellular liver injury *
• Rare : Cholestatic liver injury*

Skin and subcutaneous tissue disorders

• Common : Urticaria, pruritus, erythema
• Uncommon : Bullous dermatitis
• Rare : Alopecia, cutaneous vasculitis*, skin necrosis* usually occurring at the injection site (these phenomena have been usually preceded by purpura or erythematous plaques, infiltrated and painful).
• Injection site nodules* (inflammatory nodules, which were not cystic enclosure of Enoxaparin). They resolve after a few days and should not cause treatment discontinuation.

Musculoskeletal, connective tissue and bone disorders

• Rare : Osteoporosis* following long term therapy (greater than 3 months)

General disorders and administration site conditions

• Common : Injection site haematoma, injection site pain, other injection site reaction (such as oedema, haemorrhage, hypersensitivity, inflammation, mass, pain, or reaction)
• Uncommon : Local irritation, skin necrosis at injection site

Investigations

• Rare : Hyperkalaemia

Description of selected adverse reactions

Haemorrhages

These included major haemorrhages, reported at most in 4.2% of the patients (surgical patients). Some of these cases have been fatal. In surgical patients, haemorrhage complications were considered major : (1) if the haemorrhage caused a significant clinical event, or (2) if accompanied by haemoglobin decrease ≥ 2 g/dL or transfusion of 2 or more units of blood products. Retroperitoneal and intracranial haemorrhages were always considered major. As with other anticoagulants, haemorrhage may occur in the presence of associated risk factors such as : organic lesions liable to bleed, invasive procedures or the concomitant use of medications affecting haemostasis.

Increased Risk of Hemorrhage

1. Cases of epidural or spinal hemorrhage and subsequent hematomas have been reported with the use of Enoxaparin Sodium Injection and epidural or spinal anesthesia/analgesia or spinal puncture procedures, resulting in long-term or permanent paralysis. The risk of these events is higher with the use of postoperative indwelling epidural catheters, with the concomitant use of additional drugs affecting hemostasis such as NSAIDs, with traumatic or repeated epidural or spinal puncture, or in patients with a history of spinal surgery or spinal deformity.
2. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of Enoxaparin is low. Placement or removal of a catheter should be delayed for at least 12 hours after administration of lower doses (30 mg once or twice daily or 40 mg once daily) of Enoxaparin Sodium Injection, and at least 24 hours after the administration of higher doses (0.75 mg/kg twice daily, 1 mg/kg twice daily, or 1.5 mg/kg once daily) of Enoxaparin Sodium Injection.
3. Patients receiving the 0.75 mg/kg twice daily dose or the 1 mg/kg twice daily dose should not receive the second Enoxaparin dose in the twice daily regimen to allow a longer delay before catheter placement or removal. Likewise, although a specific recommendation for timing of a subsequent Enoxaparin Sodium Injection dose after catheter removal cannot be made, consider delaying this next dose for at least four hours, based on a benefit-risk assessment considering both the risk for thrombosis and the risk for bleeding in the context of the procedure and patient risk factors.
4. For patients with creatinine clearance <30mL/minute, additional considerations are necessary because elimination of Enoxaparin is more prolonged; consider doubling the timing of removal of a catheter, at least 24 hours for the lower prescribed dose of Enoxaparin Sodium Injection (30 mg once daily) and at least 48 hours for the higher dose (1 mg/kg/day).
5. Should the physician decide to administer anticoagulation in the context of epidural or spinal anesthesia/analgesia or lumbar puncture, frequent monitoring must be exercised to detect any signs and symptoms of neurological impairment such as midline back pain, sensory and motor deficits (numbness or weakness in lower limbs), bowel and/or bladder dysfunction
6. Instruct patients to report immediately if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae.
7. Enoxaparin Sodium injection should be used with extreme caution in conditions with increased risk of hemorrhage, such as bacterial endocarditis, congenital or acquired bleeding disorders, active ulcerative and angiodysplastic gastrointestinal disease, hemorrhagic stroke, or shortly after brain, spinal, or ophthalmological surgery, or in patients treated concomitantly with platelet inhibitors. Major hemorrhages including retroperitoneal and intracranial bleeding have been repor ted. Some of these cases have been fatal. Bleeding can occur at any site during therapy with Enoxaparin Sodium injection. An unexplained fall in hematocrit or blood pressure should lead to a search for a bleeding site.

Percutaneous Coronary Revascularization Procedures

To minimize the risk of bleeding following the vascular instrumentation during the treatment of unstable angina, non-Q-wave myocardial infarction, and acute ST-segment elevation myocardial infarction, adhere precisely to the intervals recommended between Enoxaparin Sodium injection doses. It is important to achieve hemostasis at the puncture site after PCI. In case a closure device is used, the sheath can be removed immediately. If a manual compression method is used, sheath should be removed 6 hours after the last IV/SC Enoxaparin Sodium injection. If the treatment with Enoxaparin Sodium is to be continued, the next scheduled dose should be given no sooner than 6 to 8 hours after sheath removal. The site of the procedure should be observed for signs of bleeding or hematoma formation.

Use of Enoxaparin Sodium Injection with Concomitant Medical Conditions

Enoxaparin Sodium injection should be used with care in patients with a bleeding diathesis, uncontrolled arterial hypertension or a history of recent gastrointestinal ulceration, diabetic retinopathy, renal dysfunction and hemorrhage

History of Heparin-Induced Thrombocytopenia

Enoxaparin Sodium injection should be used with extreme caution in patients with a history of heparin induced thrombocytopenia.

Thrombocytopenia

Thrombocytopenia can occur with the administration of Enoxaparin Sodium injection. Thrombocytopenia of any degree should be monitored closely. If the platelet count falls below 100,000/mm3, Enoxaparin Sodium injection should be discontinued. Cases of heparin-induced thrombocytopenia with thrombosis have also been observed in clinical practice. Some of these cases were complicated by organ infarction, limb ischemia, or death

Interchangeability with Other Heparins

Enoxaparin Sodium injection cannot be used interchangeably (unit for unit) with heparin or other low molecular weight heparins as they differ in manufacturing process, molecular weight distribution, anti- Xa and anti-IIa activities, units, and dosage. Each of these medicines has its own instructions for use.

Pregnant Women with Mechanical Prosthetic Heart Valves

The use of Enoxaparin Sodium injection for thromboprophylaxis in pregnant women with mechanical prosthetic heart valves has not been adequately studied. There also have been isolated postmarketing reports of valve thrombosis in pregnant women with mechanical prosthetic heart valves while receiving Enoxaparin for thromboprophylaxis. Women with mechanical prosthetic heart valves may be at higher risk for thromboembolism during pregnancy, and, when pregnant, have a higher rate of fetal loss from stillbirth, spontaneous abortion and premature delivery. Therefore, frequent monitoring of peak and trough anti- Factor Xa levels, and adjusting of dosage may be needed.

Laboratory Tests

Periodic complete blood counts, including platelet count, and stool occult blood tests are recommended during the course of treatment with Enoxaparin Sodium injection. When administered at recommended prophylaxis doses, routine coagulation tests such as Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT) are relatively insensitive measures of Enoxaparin Sodium injection activity and, therefore, unsuitable for monitoring. Anti-Factor Xa may be used to monitor the anticoagulant effect of Enoxaparin Sodium injection in patients with significant renal impairment. If during Enoxaparin Sodium injection therapy abnormal coagulation parameters or bleeding should occur, anti-Factor Xa levels may be used to monitor the anticoagulant effects of Enoxaparin Sodium injection.

Pregnancy

Pregnancy Category B

All pregnancies have a background risk of birth defect, loss, or other adverse outcome regardless of drug exposure. The fetal risk summary below describes the potential of Enoxaparin Sodium injection to increase the risk of developmental abnormalities above the background risk.

Fetal Risk Summary

Enoxaparin Sodium Injection does not cross the placenta, and is not expected to result in fetal exposure to the drug. Human data suggest that Enoxaparin Sodium Injection does not increase the risk of major developmental abnormalities. Based on animal data, Enoxaparin is not predicted to increase the risk of major developmental abnormalities.

Nursing Mothers

It is not known whether Enoxaparin Sodium injection is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Enoxaparin Sodium injection, a decision should be made whether to discontinue nursing or discontinue Enoxaparin Sodium injection, taking into account the importance of Enoxaparin Sodium injection to the mother and the known benefits of nursing.

Pediatric Use

Safety and effectiveness of Enoxaparin Sodium injection in pediatric patients have not been established.

Geriatric Use

Prevention of Deep Vein Thrombosis in Hip, Knee and Abdominal Surgery; Treatment of Deep Vein Thrombosis, Prevention of Ischemic Complications of Unstable Angina and Non-Q-wave

Myocardial Infarction

The incidence of bleeding complications was higher in geriatric patients as compared to younger patients when Enoxaparin Sodium injection was administered at doses of 1.5 mg/kg once a day or 1 mg/kg every 12 hours. The risk of Enoxaparin Sodium injection-associated bleeding increased with age. Serious adverse events increased with age for patients receiving Enoxaparin Sodium injection. Careful attention to dosing intervals and concomitant medications (especially antiplatelet medications) is advised. Enoxaparin Sodium injection should be used with care in geriatric patients who may show delayed elimination of Enoxaparin. Monitoring of geriatric patients with low body weight (<45 kg) and those predisposed to decreased renal function should be considered

Treatment of Acute ST-Segment Elevation Myocardial Infarction

In the clinical study for treatment of acute ST-segment elevation myocardial infarction, there was no evidence of difference in efficacy between patients ≥75 years of age (n = 1241) and patients less than 75 years of age (n = 9015). Patients ≥75 years of age did not receive a 30 mg IV bolus prior to the normal dosage regimen and had their SC dose adjusted to 0.75 mg/kg every 12 hours. The incidence of bleeding complications was higher in patients ≥65 years of age as compared to younger patients (<65 years).

Renal Impairment

In patients with renal impairment, there is an increase in exposure of Enoxaparin Sodium. All such patients should be observed carefully for signs and symptoms of bleeding. Because exposure of Enoxaparin Sodium is significantly increased in patients with severe renal impairment (creatinine clearance <30 mL/min), a dosage adjustment is recommended for therapeutic and prophylactic dosage ranges. No dosage adjustment is recommended in patients with moderate (creatinine clearance 30–50 mL/min) and mild (creatinine clearance 50–80 mL/min) renal impairment. In patients with renal failure, treatment with Enoxaparin has been associated with the development of hyperkalemia.

Hepatic Impairment

The impact of hepatic impairment on Enoxaparin's exposure and antithrombotic effect has not been investigated. Caution should be exercised when administering Enoxaparin to patients with hepatic impairment.

Low-Weight Patients

An increase in exposure of Enoxaparin Sodium with prophylactic dosages (non-weight adjusted) has been observed in low-weight women (<45 kg) and low-weight men (<57 kg). All such patients should be observed carefully for signs and symptoms of bleeding.

Obese Patients

Obese patients are at higher risk for thromboembolism. The safety and efficacy of prophylactic doses of Enoxaparin Sodium Injection in obese patients (BMI >30 kg/m ) has not been fully determined and there is no consensus for dose adjustment. These patients should be observed carefully for signs and symptoms of thromboembolism.

Whenever possible, agents which may enhance the risk of hemorrhage should be discontinued prior to initiation of Enoxaparin Sodium injection therapy. These agents include medications such as : anticoagulants, platelet inhibitors including acetylsalicylic acid, salicylates, NSAIDs (including ketorolac tromethamine), dipyridamole, or sulfinpyrazone. If co-administration is essential, conduct close clinical and laboratory monitoring

Accidental overdosage following administration of Enoxaparin Sodium injection may lead to hemorrhagic complications. Injected Enoxaparin Sodium injection may be largely neutralized by the slow IV injection of protamine sulfate (1% solution). The dose of protamine sulfate should be equal to the dose of Enoxaparin Sodium injection injected : 1 mg protamine sulfate should be administered to neutralize 1 mg Enoxaparin Sodium injection, if Enoxaparin Sodium was administered in the previous 8 hours. An infusion of 0.5 mg protamine per 1 mg of Enoxaparin Sodium may be administered if Enoxaparin Sodium was administered greater than 8 hours previous to the protamine administration, or if it has been determined that a second dose of protamine is required. The second infusion of 0.5 mg protamine sulfate per 1 mg of Enoxaparin Sodium injection may be administered if the aPTT measured 2 to 4 hours after the first infusion remains prolonged. If at least 12 hours have elapsed since the last Enoxaparin Sodium injection, protamine administration may not be required; however, even with higher doses of protamine, the aPTT may remain more prolonged than following administration of heparin. In all cases, the anti-Factor Xa activity is never completely neutralized (maximum about 60%). Particular care should be taken to avoid overdosage with protamine sulfate. Administration of protamine sulfate can cause severe hypotensive and anaphylactoid reactions. Because fatal reactions, often resembling anaphylaxis, have been reported with protamine sulfate, it should be given only when resuscitation techniques and treatment of anaphylactic shock are readily available.

Store below 25°C. Do not freeze

Keep out of reach of children

Shelf-life 

Refer on the pack

Presentation :

ENOXARIN 40 : A pre-filled syringe of 40 mg / 0.4 ml.

ENOXARIN 60 : A pre-filled syringe of 60 mg / 0.6 ml.