Ferric Carboxymaltose Injection 100 mg / 2 ml, 500 mg / 10 ml & 1 g / 20 ml

Feronia FCM 100

Each ml contains :

Ferric Carboxymaltose

equivalent to elemental Iron 50 mg

Water for Injections IP q.s.

Feronia FCM 500

Each ml contains :

Ferric Carboxymaltose

equivalent to elemental Iron 50 mg

Water for Injections IP q.s.

Feronia FCM 1K

Ferric Carboxymaltose

equivalent to elemental Iron 50 mg

Water for Injections IP q.s.

Injection 100 mg / 2 ml

Injection 500 mg / 10 ml

Injection 1 g / 20 ml

For IV Injection / Infusion

4.1 Therapeutic indication

For treatment of iron deficiency when oral iron preparations are ineffective or cannot be used. The diagnosis must be based on laboratory tests.

4.2 Posology and method of administration

Monitor carefully patients for signs and symptoms of hypersensitivity reactions during and following each administration of Ferric Carboxymaltose. Ferric Carboxymaltose Injection should only be administered when staff trained to evaluate and manage anaphylactic reactions is immediately available, in an environment where full resuscitation facilities can be assured. The patient should be observed for adverse effects for at least 30 minutes following each Ferric Carboxymaltose Injection.

Calculation of the cumulative iron dose

The cumulative dose for repletion of iron using Ferric Carboxymaltose is determined based on the patient's body weight and haemoglobin level and must not be exceeded. The following table should be used to determine the cumulative iron dose :

Note :Acumulative iron dose of 500mg should not be exceeded for patientswith bodyweight<35 kg.

Maximum tolerated single dose

A single Ferric Carboxymaltose administration should not exceed :

• 15 mg iron/kg body weight (for administration by intravenous injection) or 20 mg iron/kg body weight (for administration by intravenous infusion).
• 1,000 mg of iron (20 mL Ferric Carboxymaltose).

Do not administer 1000 mg of iron (20 ml) more than once a week.

Post-iron repletion assessments

Re-assessment should be performed by the clinician based on the individual patient's condition. The Hb level should be re-assessed no earlier than 4 weeks post nal Ferric Carboxymaltose administration to allow adequate time for erythropoiesis and iron utilisation.

Special population

Haemodialysis-dependent chronic kidney disease

A single maximum daily injection dose of 200 mg iron should not be exceeded in haemodialysisdependent chronic kidney disease patients.

Paediatric population

The use of Ferric Carboxymaltose Injection has not been studied in children and therefore is not recommended in children under 14 years.

Method of administration

Ferric Carboxymaltose must only be administered by the intravenous route :

• By injection, or
• By infusion, or
• During a haemodialysis session undiluted directly into the venous limb of the dialyser.

Ferric Carboxymaltose must not be administered by the subcutaneous or intramuscular route.

Intravenous injection

Ferric Carboxymaltose may be administered by intravenous injection using undiluted solution. The maximum single dose is 15 mg iron/kg body weight but should not exceed 1,000 mg iron.

Administration rates for intravenous injection of Ferric Carboxymaltose

Intravenous infusion

Ferric Carboxymaltose Injection may be administered by intravenous infusion, in which case it must be diluted. The maximum single dose is 20 mg iron/kg body weight, but should not exceed 1000 mg iron.

In case of infusion, Ferric Carboxymaltose Injection must be diluted only in sterile 0.9% Sodium Chloride Solution as follows :

Dilution plan of Ferric Carboxymaltose Injection for intravenous drip infusion

Note : For stability reasons, dilutions to concentrations less than 2 mg iron/ml are not permissible. Inspect vials visually for sediment and damage before use. Use only those containing sedimentfree, homogeneous solution.

Each vial of Ferric Carboxymaltose Injection is intended for single use only. Any unused product or waste material should be disposed of in accordance with local requirements. Ferric Carboxymaltose Injection must only be mixed with sterile 0.9% Sodium Chloride Solution. No other intravenous dilution solutions and therapeutic agents should be used, as there is the potential for precipitation and/or interaction.

From a microbiological point of view, preparations for parenteral administration should be used immediately after dilution with sterile 0.9% Sodium Chloride Solution.

4.3 Contraindications

The use is contraindicated in cases of :

• Hypersensitivity to the active substance, to Ferric Carboxymaltose Injection or any of its Excipients.
• Known serious hypersensitivity to other parenteral iron products.
• Anaemia not attributed to iron deficiency, e.g. other microcytic anaemia.
• Evidence of iron overload or disturbances in the utilisation of iron.
• First trimester of pregnancy.

4.4 Warning and precautions

Parenterally administered iron preparations can cause hypersensitivity reactions including anaphylactoid reactions which may be potentially fatal. Therefore, facilities for cardio-pulmonary resuscitation must be available. Hypersensitivity reactions have also been reported after previously uneventful doses of parenteral iron complexes.

The risk is enhanced for patients with known allergies including drug allergies, including patients with a history of severe asthma, eczema or other atopic allergy. There is also an increased risk of hypersensitivity reactions to parenteral iron complexes in patients with immune or inammator y conditions (e.g. systemic lupus erythematosus, rheumatoid arthritis). Ferric Carboxymaltose Injection should only be administered when staff trained to evaluate and manage anaphylactic reactions is immediately available, in an environment where full resuscitation facilities can be assured. Each patient should be observed for adverse effects for at least 30 minutes following each Ferric Carboxymaltose Injection. If hypersensitivity reactions or signs of intolerance occur during administration, the treatment must be stopped immediately. Facilities for cardio respiratory resuscitation and equipment for handling acute anaphylactic / anaphylactoid reactions should be available, including an injectable 1:1000 adrenaline solution. Additional treatment with antihistamines and/or corticosteroids should be given as appropriate.

In patients with liver dysfunction, parenteral iron should only be administered after careful risk/benet assessment. Parenteral iron administration should be avoided in patients with hepatic dysfunction where iron overload is a precipitating factor, in particular Porphyria Cutanea Tarda (PCT). Careful monitoring of iron status is recommended to avoid iron overload. No safety data on haemodialysis-dependent chronic kidney disease patients receiving single doses of more than 200 mg iron are available.

Parenteral iron must be used with caution in cases of acute or chronic infection, asthma, eczema or atopic allergies. It is recommended that the administration of Ferric Carboxymaltose Injection is stopped in patients with ongoing bacteremia. In patients with chronic infection a risk/benet evaluation has to be performed, taking into account the suppression of erythropoiesis. Caution should be exercised to avoid paravenous leakage when administering Ferric Carboxymaltose Injection. Paravenous leakage of Ferric Carboxymaltose Injection at the injection site may lead to brown discolouration and irritation of the skin. In case of paravenous leakage, the administration of Ferric Carboxymaltose Injection must be stopped immediately. As with all parenteral iron preparations the absorption of oral iron is reduced when administered concomitantly.

4.5 Drug interactions

As with all parenteral iron preparations the absorption of oral iron is reduced when administered concomitantly. Therefore, if required, oral iron therapy should not be started for at least 5 days after the last injection of Ferric Carboxymaltose.

4.6 Special populations

Pregnancy

There are no adequate and well-controlled trials of Ferric Carboxymaltose in pregnant women. A careful benet/risk evaluation is required before use during pregnancy and Ferric Carboxymaltose should not be used during pregnancy unless clearly necessary. Treatment with Ferric Carboxymaltose should be conned to the second and third trimester if the benet is judged to outweigh the potential risk for both the mother and the foetus. Animal data suggest that iron released from Ferric Carboxymaltose can cross the placental barrier and that its use during pregnancy may influence skeletal development in the fetus.

Lactation

Clinical studies showed that transfer of iron from Ferric Carboxymaltose to human milk was negligible (≤ 1%). Based on limited data on breast-feeding women it is unlikely that Ferric Carboxymaltose represents a risk to the breast-fed child.

Fertility

There are no data on the effect of Ferric Carboxymaltose on human fertility. Fertility was unaffected following Ferric Carboxymaltose treatment in animal studies.

Pediatric use

The use of Ferric Carboxymaltose Injection has not been studied in children.

4.7 Effects on ability to drive and use machines

Ferric Carboxymaltose Injection is unlikely to impair the ability to drive and use machines.

4.8 Undesirable effects

The most commonly reported ADR is nausea (occurring in 3.2% of the subjects), followed by

injection/infusion site reactions, hypophosphataemia, headache, ushing, dizziness and hypertension. Injection/infusion site reactions comprise several ADRs which individually are either uncommon or rare. The most serious ADR is anaphylactic reactions (rare); fatalities have been reported.

The following denitions of frequencies are used : Common (≥ 1/100 to < 1/10), Uncommon (≥ 1/1,000 to <1/100) and Rare (≥ 1/10,000 to < 1/1,000).

Immune system disorders

Uncommon : Hypersensitivity

Rare : Anaphylactoid reactions

Metabolism and nutritional disorders

Common : Hypophosphataemia

Nervous system disorders

Common : Headache, dizziness

Uncommon : Paraesthesia, dysgeusia

Frequency not known (estimated as rare) : Loss of consciousness

Psychiatric disorders

Rare : Anxiety

Cardiac disorders

Uncommon : Tachycardia

Frequency not known (estimated as rare) : Kounis syndrome

Vascular disorders

Common : Hypotension, flushing

Uncommon : Hypertension

Rare : Phlebitis, syncope, presyncope

Respiratory, thoracic and mediastinal disorders

Uncommon : Dyspnoea

Rare : Bronchospasm

Gastrointestinal disorders

Common : Nausea

Uncommon : Vomiting, dyspepsia, abdominal pain, constipation, diarrhoea

Rare : Flatulence

Skin and subcutaneous tissue disorders

Uncommon : Pruritus, urticaria, erythema, rash

Rare : Angioedema, pallor, distant skin discolouration

Frequency not known (estimated as rare) : Face oedema

Musculoskeletal and connective tissue disorders

Uncommon : Myalgia, back pain, arthralgia, muscle spasm

Frequency not known (estimated as rare) : Hypophosphataemic osteomalacia

General disorders and administration site conditions

Common : Injection/infusion site reactions - Includes, but is not limited to, the following preferred terms : injection/infusion site -pain, -haematoma, -discolouration, -extravasation, -irritation, - reaction, (all individual ADRs determined to be uncommon) and -paraesthesia (individual ADR determined to be rare).

Uncommon : Pyrexia, fatigue, chest pain, oedema peripheral, chills, malaise Rare : Rigors, malaise, inuenza like illness (onset may vary from a few hours to several days)

Investigations

Uncommon : Alanine aminotransferase increased, Aspartate aminotransferase increased, gamma-glutamyltransferase increased, blood lactate dehydrogenase increased, blood alkaline phosphatase increased

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

4.9 Overdose

Administration of Ferric Carboxymaltose Injection in quantities exceeding the amount needed to correct iron deficit at the time of administration may lead to accumulation of iron in storage sites eventually leading to hemosiderosis. Monitoring of iron parameters such as serum ferritin and transferrin saturation may assist in recognizing iron accumulation. If iron accumulation has occurred, treat according to standard medical practice, e.g. consider the use of an iron chelator.

5.1 Mechanism of action

Ferric Carboxymaltose is a colloidal iron (III) hydroxide in complex with Carboxymaltose, a carbohydrate polymer that releases iron. The complex is designed to provide, in a controlled way, utilisable iron for the iron transport and storage proteins in the body (transferrin and ferritin, respectively).

5.2 Pharmacodynamic properties

Pharmacotherapeutic group : Iron trivalent, parenteral preparation ATC code : B03AC Using positron emission tomography (PET) it was demonstrated that red cell uptake of 59Fe and 59 52Fe from Ferric Carboxymaltose ranged from 61% to 99%. Red cell utilisation of Fe from radiolabelled Ferric Carboxymaltose ranged from 91% to 99% in subjects with iron deficiency (ID) and 61% to 84% in subjects with renal anaemia at 24 days post-dose. Ferric Carboxymaltose treatment results in an increase in reticulocyte count, serum ferritin levels and TSAT levels to within normal ranges.

5.3 Pharmacokinetic properties

Distribution

Positron emission tomography demonstrated that Fe and Fe from Ferric Carboxymaltose was rapidly eliminated from the blood, transferred to the bone marrow, and deposited in the liver and spleen.

After administration of a single dose of Ferric Carboxymaltose of 100 to 1,000 mg of Iron in iron decient subjects, maximum total serum iron levels of 37 µg/mL up to 333 µg/mL are obtained after 15 minutes to 1.21 hours respectively. The volume of distribution was estimated to be 3 L.

Elimination

The iron injected or infused was rapidly cleared from the plasma, the terminal half-life ranged from 7 to 12 hours, the mean residence time (MRT) from 11 to 18 hours. Renal elimination of iron was negligible.

6.1 Animal toxicology or pharmacology

Preclinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeat dose toxicity and genotoxicity. Preclinical studies indicate that iron released from Ferric Carboxymaltose does cross the placental barrier and is excreted in milk in limited, controlled amounts. In reproductive toxicology studies using iron replete rabbits Ferric Carboxymaltose was associated with minor skeletal abnormalities in the fetus. In a fertility study in rats, there were no effects on fertility for either male or female animals. No long-term studies in animals have been performed to evaluate the carcinogenic potential of Ferric Carboxymaltose. No evidence of allergic or immunotoxic potential has been observed. A controlled in-vivo test demonstrated no cross-reactivity of Ferric Carboxymaltose with anti-dextran antibodies. No local irritation or intolerance was observed after intravenous administration.

Ferric Carboxymaltose, an iron replacement product, is an iron carbohydrate complex with the chemical name of polynuclear iron (III)-hydroxide4(R)-(poly-(1→4)-O-α-Dglucopyranosyl)-oxy2(R),3(R),5(R), 6-tetrahydroxy-hexanoate. It has a relative molecular weight of approximately 150,000 Da corresponding to the following empirical formula :

[FeOx(OH)y(H2O)z]n [{(C6H10O5)m (C6H12O7)}l]k where n ≈ 103, m ≈ 8, l≈ 11 and k ≈ 4 (l represents the mean 

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

Feronia FCM 100 : A vial of 2 ml.

Feronia FCM 500 : A Vial of 10 ml.

Feronia FCM 1K : A vial of 20 ml.

8.4 Storage and handing instructions

Store in a cool & dark place (8°C to 25°C). Do not refrigerate

Keep out of reach of children.

Before using, check for absence of sediments

Advise the patient to read the patient information leaflet and discuss with the patient the etiology of the iron deficiency anemia and the patient’s iron deficiency anemia treatment options. Advise patients of the risks associated with Ferric Carboxymaltose Injection.

Prior history of reactions to parenteral iron products

Question patients regarding any prior history of reactions to parenteral iron products.

Serious hypersensitivity reactions

Advise patients to report any signs and symptoms of hypersensitivity that may develop during and following Ferric Carboxymaltose Injection administration, such as rash, itching, dizziness, lightheadedness, swelling, and breathing problems.

Pregnancy

Advise pregnant women about the risk of hypersensitivity reactions which may have serious consequences for the fetus. Advise patients who may become pregnant to inform their healthcare provider of a known or suspected pregnancy.

Deflazacort Tablets 6 mg/12mg/24 mg/30 mg

Each uncoated tablet contains

Deflazacort 6 mg/12 mg/24 mg/30 mg.

Excipients q.s.

Tablets for oral administration.

6 mg/12 mg/24 mg/30 mg

4.1. Therapeutic indication

For asthma, rheumatoid arthritis when glucocorticosteriod therapy is warranted.

4.2.Posology and method of administration

Deflazacort is a glucocorticoid derived from prednisolone and 6mg of deflazacort has approximately the same anti-inflammatory potency as 5mg prednisolone or prednisone. Doses vary widely in different diseases and different patients. In more serious and lifethreatening conditions, high doses of deflazacort may need to be given. When deflazacort is used long term in relatively benign chronic diseases, the maintenance dose should be kept as low as possible. Dosage may need to be increased during periods of stress or in exacerbation of illness. The dosage should be individually titrated according to diagnosis, severity of disease and patient response and tolerance. The lowest dose that will produce an acceptable response should be used.

Adults

For acute disorders, up to 120 mg/day deflazacort may need to be given initially. Maintenance doses in most conditions are within the range 3-18 mg/day. The following regimens are for guidance only

Rheumatoid arthritis: The maintenance dose is usually within the range 3 - 18 mg/day. The smallest effective dose should be used and increased if necessary.

Bronchial asthma: In the treatment of an acute attack, high doses of 48-72 mg/day may be needed depending on severity and gradually reduced once the attack has been controlled. For maintenance in chronic asthma, doses should be titrated to the lowest dose that controls symptoms.

Other conditions: The dose of deflazacort depends on clinical need titrated to the lowest effective dose for maintenance. Starting doses may be estimated on the basis of ratio of 5mg prednisone or prednisolone to 6mg deflazacort.

Hepatic Impairment

In patients with hepatic impairment, blood levels of deflazacort may be increased. Therefore, the dose of deflazacort should be carefully monitored and adjusted to the minimum effective dose.

Renal Impairment

In renally impaired patients, no special precautions other than those usually adopted in patients receiving glucocorticoid therapy are necessary.

Elderly

In elderly patients, no special precautions other than those usually adopted in patients receiving glucocorticoid therapy are necessary. The common adverse effects of systemic corticosteroids may be associated with more serious consequences in old age.

Paediatric Population

There has been limited exposure of children to deflazacort in clinical trials. In children, the indications for glucocorticoids are the same as for adults, but it is important that the lowest effective dosage is used. Alternate day administration may be appropriate.

Doses of deflazacort usually lie in the range 0.25 - 1.5 mg/kg/day. The following ranges provide general guidance:

Juvenile chronic arthritis: The usual maintenance dose is between 0.25 - 1.0 mg/kg/day

Nephrotic syndrome: Initial dose of usually 1.5 mg/kg/day followed by down titration according to clinical need.

Bronchial asthma: On the basis of the potency ratio, the initial dose should be between 0.25 - 1.0 mg/kg deflazacort on alternate days.

Deflazacort withdrawal

In patients who have received more than physiological doses of systemic corticosteroids (approximately 9mg per day or equivalent) for greater than 3 weeks, 3 withdrawal should not be abrupt. How dose reduction should be carried out depends largely on whether the disease is likely to relapse as the dose of systemic corticosteroids is reduced. Clinical assessment of disease activity may be needed during withdrawal. If the disease is unlikely to relapse on withdrawal of systemic corticosteroids but there is uncertainty about HPA suppression, the dose of systemic corticosteroids may be reduced rapidly to physiological doses. Once a daily dose equivalent to 9mg deflazacort is reached, dose reduction should be slower to allow the HPA-axis to recover. Abrupt withdrawal of systemic corticosteroid treatment, which has continued up to 3 weeks is appropriate if it is considered that the disease is unlikely to relapse. Abrupt withdrawal of doses up to 48 mg daily of deflazacort, or equivalent for 3 weeks is unlikely to lead to clinically relevant HPA-axis suppression, in the majority of patients. In the following patient groups, gradual withdrawal of systemic corticosteroid therapy should be considered even after courses lasting 3 weeks or less:

•  Patients who have had repeated courses of systemic corticosteroids, particularly if taken for greater than 3 weeks.
• When a short course has been prescribed within one year of cessation of long-term therapy (months or years).
• Patients who may have reasons for adrenocortical insufficiency other than exogenous corticosteroid therapy.
• Patients receiving doses of systemic corticosteroid greater than 48 mg daily of deflazacort (or equivalent),
• Patients repeatedly taking doses in the evening

4.3.Contraindications

Systemic infection unless specific anti-infective therapy is employed. Hypersensitivity to the active substance, deflazacort or any of the excipients. Patients receiving live virus immunisation.

4.4.Special warnings and precautions for use

Patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption should not take this medicine. Undesirable effects may be minimised by using the lowest effective dose for the minimum period, and by administering the daily requirement as a single morning dose or whenever possible as a single morning dose on alternate days. Frequent patient review is required to appropriately titrate the dose against disease activity.

Adrenal suppression

Adrenal cortical atrophy develops during prolonged therapy and may persist for years after stopping treatment. Withdrawal of corticosteroids after prolonged therapy must therefore always be gradual to avoid acute adrenal insufficiency which could be fatal, being tapered off over weeks or months according to the dose and duration of treatment. During prolonged therapy, any intercurrent illness, trauma or surgical procedure will require a temporary increase in dosage; if corticosteroids have been stopped following prolonged therapy, they may need to be temporarily re-introduced. Patients should carry 'Steroid treatment' cards which give clear guidance on the precautions to be taken to minimise risk and which provide details of prescriber, drug, dosage and the duration of treatment.

Anti-inflammatory/immunosuppressive effects and infection

Suppression of the inflammatory response and immune function increases the susceptibility to infections and their severity. The clinical presentation may often be atypical and serious infections such as septicaemia and tuberculosis may be masked and may reach an advanced stage before being recognised. Chickenpox is of particular concern since this normally minor illness may be fatal in immunosuppressed patients. Patients (or parents of children) without a definite history of chicken pox should be advised to avoid close personal contact with chickenpox or herpes zoster and, if exposed, they should seek urgent medical attention. Passive immunisation with varicella zoster immunoglobulin (VZIG) is needed by exposed non-immune patients who are receiving systemic corticosteroids or who have used them within the previous 3 months; this should be given within 10 days of exposure to chickenpox. If a diagnosis of chickenpox is confirmed, the illness warrants specialist care and urgent treatment. Corticosteroids should not be stopped and the dose may need to be increased. Patients should be advised to take particular care to avoid exposure to measles and to seek immediate medical advice if exposure occurs. Prophylaxis with intramuscular normal immunoglobulin may be needed. Live vaccines should not be given to individuals with impaired responsiveness. The antibody response to other vaccines may be diminished.

Visual disturbance

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids. Prolonged use of glucocorticoids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves and may enhance the establishment of secondary ocular infections due to fungi or viruses. Use in active tuberculosis should be restricted to those cases of fulminating and disseminated tuberculosis in which deflazacort is used for management with appropriate antituberculosis regimen. If glucocorticoids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged glucocorticoid therapy, these patients should receive chemoprophylaxis. Tendonitis and tendon rupture are known class effect of glucocorticoids. The risk of such reactions may be increased by co-administration of quinolones. Pheochromocytoma crisis, which can be fatal, has been reported after administration of systemic corticosteroids. Corticosteroids should only be administered to patients with suspected or identified pheochromocytoma after an appropriate risk/benefit evaluation.

Special precautions

The following clinical conditions require special caution and frequent patient monitoring is necessary: -

• Cardiac disease or congestive heart failure (except in the presence of active rheumatic carditis), hypertension, thromboembolic disorders. Glucocorticoids can cause salt and water retention and increased excretion of potassium. Dietary salt restriction and potassium supplementation may be necessary.
• Gastritis or oesophagitis, diverticulitis, ulcerative colitis if there is probability of impending perforation, abscess or pyogenic infections, fresh intestinal anastomosis, active or latent peptic ulcer.
• Diabetes mellitus or a family history, osteoporosis, myasthenia gravis, renal insufficiency.
• Emotional instability or psychotic tendency, epilepsy. 
• Previous corticosteroid-induced myopathy.
• Liver failure.
• Hypothyroidism and cirrhosis, which may increase glucocorticoid effect.
• Ocular herpes simplex because of possible corneal perforation.

Patients and/or carers should be warned that potentially severe psychiatric adverse reactions may occur with systemic steroids. Symptoms typically emerge within a few days or weeks of starting the treatment. Risks may be higher with high doses/systemic exposure, although dose levels do not allow prediction of the onset, type, severity or duration of reactions. Most reactions recover after either dose reduction or withdrawal, although specific treatment may be necessary. Patients/carers should be encouraged to seek medical advice if worrying psychological symptoms develop, especially if depressed mood or suicidal ideation is suspected. Patients/carers should also be alert to possible psychiatric disturbances that may occur either during or immediately after dose tapering/withdrawal of systemic steroids, although such reactions have been reported infrequently.

Particular care is required when considering the use of systemic corticosteroids in patients with existing or previous history of severe affective disorders in themselves or in their first degree relatives. These would include depressive or manic-depressive illness and previous steroid psychosis. Glucocorticoids are known to cause irregular menstruation and leukocytosis, care should be taken with deflazacort.

Paediatric population

Corticosteroids cause dose-related growth retardation in infancy, childhood and adolescence which may be irreversible. Hypertrophic cardiomyopathy has been reported after systemic administration of glucocorticosteroids in preterm infants. In infants receiving administration of systemic glucocorticosteroids, echocardiograms should be performed to monitor myocardial structure and function.

Use in Elderly

The common adverse effects of systemic corticosteroids may be associated with more serious consequences in old age, especially osteoporosis, hypertension, hypokalaemia, diabetes, susceptibility to infection and thinning of the skin. Close clinical supervision is required to avoid life-threatening reactions. Since complications of glucocorticoid therapy are dependent on dose and duration of therapy, the lowest possible dose must be given and a risk/benefit decision must be made as to whether intermittent therapy should be used.

4.5.Interaction with other medicinal products and other forms of interaction

• The same precautions should be exercised as for other glucocorticoids. Deflazacort is metabolised in the liver. It is recommended to increase the maintenance dose of deflazacort if drugs which are liver enzyme inducers are co-administered, e.g. rifampicin, rifabutin, carbamazepine, phenobarbitone, phenytoin, primidone and aminoglutethimide. For drugs which inhibit liver enzymes, e.g. ketoconazole it may be possible to reduce the maintenance dose of deflazacort.
• In patients taking estrogens, corticosteroid requirements may be reduced.
• The desired effects of hypoglycaemic agents (including insulin), anti-hypertensives and diuretics are antagonised by corticosteroids and the hypokalaemic effects of acetazolamide, loop diuretics, thiazide diuretics, beta 2-agonists, xanthines and carbenoxolone are enhanced.
• The efficacy of coumarin anticoagulants may be enhanced by concurrent corticosteroid therapy and close monitoring of the INR or prothrombin time is required to avoid spontaneous bleeding.
• In patients treated with systemic corticosteroids, use of non-depolarising muscle relaxants can result in prolonged relaxation and acute myopathy. Risk factors for this include prolonged and high dose corticosteroid treatment, and prolonged duration of muscle paralysis. This interaction is more likely following prolonged ventilation (such as in the ITU setting).
• The renal clearance of salicylates is increased by corticosteroids and steroid withdrawal may result in salicylate intoxication.
• As glucocorticoids can suppress the normal responses of the body to attack by micro-organisms, it is important to ensure that any anti-infective therapy is effective and it is recommended to monitor patients closely. Concurrent use of glucocorticoids and oral contraceptives should be closely monitored as plasma levels of glucocorticoids may be increased. This effect may be due to a change in metabolism or binding to serum proteins. Antacids may reduce bioavailability; leave at least 2 hours between administration of deflazacort and antacids. 8
• Co-treatment with CYP3A inhibitors, including cobicistat-containing products, is expected to increase the risk of systemic side-effects. The combination should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid side-effects, in which case patients should be monitored for systemic corticosteroid side-effects.

4.6.Fertility, pregnancy and lactation

Pregnancy

The ability of corticosteroids to cross the placenta varies between individual drugs, however, deflazacort does cross the placenta. Administration of corticosteroids to pregnant animals can cause abnormalities of foetal development including cleft palate, intra-uterine growth retardation and effects on brain growth and development. There is no evidence that corticosteroids result in an increased incidence of congenital abnormalities, such as cleft palate/lip in man. However, when administered for prolonged periods or repeatedly during pregnancy, corticosteroids may increase the risk of intra-uterine growth retardation. Hypoadrenalism may, in theory, occur in the neonate following prenatal exposure to corticosteroids but usually resolves spontaneously following birth and is rarely clinically important. As with all drugs, corticosteroids should only be prescribed when the benefits to the mother and child outweigh the risks. When corticosteroids are essential however, patients with normal pregnancies may be treated as though they were in the non-gravid state.

Breast-feeding

Corticosteroids are excreted in breast milk, although no data are available for deflazacort. Doses of up to 50 mg daily of deflazacort are unlikely to cause systemic effects in the infant. Infants of mothers taking higher doses than this may have a degree of adrenal suppression but the benefits of breast feeding are likely to outweigh any theoretical risk.

Fertility

No data is available on Deflazacort and its effects on fertility.

4.7.Effects on ability to drive and use machines

The effect of corticosteroids on the ability to drive or use machinery has not been systematically evaluated. Vertigo is a possible undesirable effect after treatment with deflazacort. If affected, patients should not drive or operate machinery.

4.8.Undesirable effects

The incidence of predictable undesirable effects, including hypothalamic-pituitaryadrenal suppression correlates with the relative potency of the drug, dosage; timing of administration and the duration of treatment. The following CIOMS frequency rating is used: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10000 to <1/1000); very rare (<1/10000), not known (cannot be estimated from the available data).

Endocrine disorders

Uncommon: Suppression of the hypothalamic-pituitary-adrenal axis, amenorrhoea, Cushingoid facies. Not known: Growth suppression in infancy, childhood and adolescence.

Metabolism and nutrition disorders

Common: Weight gain. Uncommon: impaired carbohydrate tolerance with increased requirement for antidiabetic therapy, sodium and water retention with hypertension, potassium loss and hypokalaemic alkalosis when co-administered with beta 2-agonist and xanthines. Not known: Negative protein and calcium balance, increased appetite.

Infections and Infestations

Uncommon: Increased susceptibility and severity of infections with suppression of clinical symptoms and signs, opportunistic infections, recurrence of dormant tuberculosis. Not known: candidiasis.

Musculoskeletal and connective tissue disorders

Uncommon: Osteoporosis, vertebral and long bone fractures. Rare: Muscle wasting. Not known: avascular osteonecrosis, tendonitis and tendon rupture when coadministered with quinolones, myopathy (acute myopathy may be precipitated by nondepolarising muscle relaxants, negative nitrogen balance.

Reproductive system and breast disorders

Not known: Menstrual irregularity.

Cardiac disorders

Not known: Heart failure, hypertrophic cardiomyopathy in preterm infants.

Nervous system disorders

Uncommon: Headache, vertigo.

Not known: restlessness, Increased intra-cranial pressure with papilloedema in children (pseudotumour cerebri), usually after treatment withdrawal, aggravation of epilepsy.

Psychiatric disorders

A wide range of psychiatric reactions including affective disorders such as: Uncommon: depressed and labile mood. Not known: irritable, euphoric, suicidal thoughts. Psychotic reactions including: Not known: mania, delusions, hallucinations, aggravation of schizophrenia Other reactions including: Uncommon: behavioural disturbances. Not known: anxiety, sleep disturbances, and cognitive dysfunction including confusion and amnesia have been reported. Reactions are common and may occur in both adults and children. In adults, the frequency of severe reactions has been estimated to be 5-6%. Psychological effects have been reported on withdrawal of corticosteroids; the frequency is unknown.

Eye disorders

Not known: Vision blurred, increased intra-ocular pressure, glaucoma, papilloedema, posterior subcapsular cataracts especially in children, chorioretinopathy, corneal or scleral thinning, exacerbation of ophthalmic viral or fungal diseases.

Gastrointestinal disorders

Uncommon: Dyspepsia, peptic ulceration, haemorrhage, nausea. Not known: perforation of peptic ulcer, acute pancreatitis (especially in children), candidiasis.

Skin and subcutaneous tissue disorders

Uncommon: hirsutism, striae, acne.

Rare: bruising.

Not known: Skin atrophy, telangiectasia.

General disorders and administration site conditions

Uncommon: Oedema.

Not known: impaired healing.

Immune system disorders

Uncommon: Hypersensitivity including anaphylaxis has been reported.

Blood and lymphatic system disorders

Not known: Leukocytosis.

Vascular disorders

Not known: Thromboembolism in particular in patients with underlying conditions associated with increased thrombotic tendency, rare incidence of benign intracranial hypertension.

Withdrawal symptoms and signs

Not known: Too rapid a reduction of corticosteroid dosage following prolonged treatment can lead to acute adrenal insufficiency, hypotension and death. A 'withdrawal syndrome' may also occur including fever, myalgia, arthralgia, rhinitis, conjunctivitis, painful itchy skin nodules and loss of weight. This may occur in patients even without evidence of adrenal insufficiency.

Class effect

Pheochromocytoma crisis has been reported with other systemic corticosteroids and is a known class effect.

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

4.9. Overdose

It is unlikely that treatment is needed in cases of acute overdosage. The LD50 for the oral dose is greater than 4000 mg/kg in laboratory animals.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: corticosteroids for systemic use; Glucocorticoids. ATC code: H02AB13. Deflazacort is a glucocorticoid. Its anti-inflammatory and immunosuppressive effects are used in treating a variety of diseases and are comparable to other antiinflammatory steroids. Clinical studies have indicated that the average potency ratio of deflazacort to prednisolone is 0.69-0.89.

5.2 Pharmacokinetic properties

Absorption: Orally administered deflazacort appears to be well absorbed.

Distribution: The active metabolite D 21-OH achieves peak plasma concentrations in 1.5 to 2 hours. It is 40% protein-bound and has no affinity for corticosteroid-binding-globulin (transcortin).

Biotransformation: Orally administered deflazacort is immediately converted by plasma esterases to the pharmacologically active metabolite (D 21-OH). Metabolism of D 21-OH is extensive. The metabolite of D 21-OH is deflazacort 6- beta-OH.

Elimination: Its elimination plasma half-life is 1.1 to 1.9 hours. Elimination takes place primarily through the kidneys; 70% of the administered dose is excreted in the urine. The remaining 30% is eliminated in the faeces. Metabolism of D 21-OH is extensive; only 18% of urinary excretion represents D 21-OH. The metabolite of D 21-OH, deflazacort 6-beta-OH, represents one third of the urinary elimination.

Safety studies have been carried out in the rat, dog, mouse and monkey. The findings are consistent with other glucocorticoids at comparable doses. Teratogenic effects demonstrated in rodents and rabbits are typical of those caused by other glucocorticoids. Deflazacort was not found to be carcinogenic in the mouse, but studies in the rat produced carcinogenic findings consistent with the findings with other glucocorticoids.

Deflazacort, is an oxaline derivative of Prednisolone.

Figure: Structure of Deflazacort

IUPAC Name: (11β,16β)-21-(acetyloxy)-11-hydroxy-2'-methyl-5'H-pregna-1,4- dieno[17,16-d]oxazole-3,20-dione Molecular Formula: C₂₅H₃₁NO₆ Molecular Weight: 441.5 g/mol

1. Incompatibilities Not applicable.

2. Shelf-life

3. Packaging information

4. Storage and handing instructions

• Keep out of reach of children. Keep out of the sight and reach of children. Store in a dry place at a temperature not exceeding 25°C.

A patient information leaflet is available for this product.

Administration

Warn patients and/or caregivers to not stop taking Cortimax abruptly or without first checking with their healthcare providers as there may be a need for gradual dose reduction to decrease the risk of adrenal insufficiency.

Cortimax may be taken with or without food. Do not take Cortimax with grapefruit juice.

Tablets

Cortimax Tablets may be taken whole or crushed and taken immediately after mixing with applesauce.

Increased Risk of Infection

Tell patients and/or caregivers to inform their healthcare provider if the patient has had recent or ongoing infections or if they have recently received a vaccine. Medical advice should be sought immediately if the patient develops fever or other signs of infection. Patients and/or caregivers should be made aware that some infections can potentially be severe and fatal. Warn patients who are on corticosteroids to avoid exposure to chickenpox or measles and to alert their healthcare provider immediately if they are exposed.

Alterations in Cardiovascular/Renal Function

Inform patients and/or caregivers that Cortimax can cause an increase in blood pressure and water retention. If this occurs, dietary salt restriction and potassium supplementation may be needed.

Behavioral and Mood Disturbances

Advise patients and/or caregivers about the potential for severe behavioral and mood changes with Cortimax and encourage them to seek medical attention if psychiatric symptoms develop.

Decreases in Bone Mineral Density

Advise patients and/or caregivers about the risk of osteoporosis with prolonged use of Cortimax, which can predispose the patient to vertebral and long bone fractures.

Ophthalmic Effects

Inform patients and/or caregivers that Cortimax may cause cataracts or glaucoma and advise monitoring if corticosteroid therapy is continued for more than 6 weeks.

Vaccination

Advise patients and/or caregivers to bring immunizations up-to-date according to immunization guidelines prior to starting therapy with Cortimax. Live-attenuated or live vaccines should be administered at least 4 to 6 weeks prior to starting Cortimax. Inform patients and/or caregivers that they may receive concurrent vaccinations with use of Cortimax, except for live-attenuated or live vaccines.

Serious Skin Rashes

Instruct patients and/or caregivers to seek medical attention at the first sign of a rash.

Drug Interactions

Certain medications can cause an interaction with Cortimax. Advise patients and/or caregivers to inform their healthcare provider of all the medicines the patient is taking, including over-the-counter medicines (such as insulin, aspirin or other NSAIDS), dietary supplements, and herbal products. Inform patients and/or caregivers that alternate therapy, dosage adjustment, and/or special test(s) may be needed during the treatment.

Cefpodoxime Proxetil Dispersible Tablets / Cefpodoxime Proxetil Tablets IP

Polares-100 DT

Each uncoated dispersible tablet contains :

Cefpodoxime Proxetil IP

equivalent to Cefpodoxime 100 mg

Excipients

Colour : Quinoline Yellow

Flavour added

Polares-200

Each film coated tablet contains :

Cefpodoxime Proxetil IP

equivalent to Cefpodoxime 200 mg

Excipients q.s

Colours : Titanium Dioxide IP and

Quinoline Yellow

Dispersible tablet 100 mg, Film coated tablet 200 mg

4.1 Therapeutic indications

Acute bronchitis, exacerbations of chronic bronchitis, bronchiolitis pneumonia, sinusitis, recurrent chronic tonsillitis, pharyngitis, acute otitis.

4.2 Posology and method of administration

Polares - 100 DT Tablets

Direction for use

Disperse the tablet in one teaspoonful of previously boiled and cooled water before administration. Cefpodoxime Proxetil 100 DT, should be administered orally with food to enhance absorption. The recommended dosages, durations of treatment, and applicable patient population are as described in the following chart. Infants and Pediatric Patients (age 2 months through 12 years)

Polares-200 Tablets

Cefpodoxime Proxetil Tablets, should be administered orally with food to enhance absorption. The recommended dosages, durations of treatment, and applicable patient population are as described in the following chart. Adults and Adolescents (age 12 years and older)

Patients with Renal Dysfunction

For patients with severe renal impairment (<30 mL/min creatinine clearance), the dosing intervals should be increased to Q 24 hours. In patients maintained on hemodialysis, the dose frequency should be 3 times/week after hemodialysis.

Patients with Cirrhosis

Cefpodoxime pharmacokinetics in cirrhotic patients (with or without ascites) are similar to those in healthy subjects. Dose adjustment is not necessary in this population

4.3 Contraindications

• patients with a known allergy to cefpodoxime or to the cephalosporin group of antibiotics.

• previous history of immediate and / or severe hypersensitivity reaction (anaphylaxis) to penicillin or other betalactam antibiotic.

4.4 Special warnings and precautions for use

Before therapy with cefpodoxime proxetil is instituted, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to cefpodoxime, other cephalosporins, penicillins, or other drugs. If cefpodoxime is to be administered to penicillin sensitive patients, caution should be exercised because cross hypersensitivity among beta-lactam antibiotics has been clearly documented and may occur in up to 10% of patients with a history of penicillin allergy. If an allergic reaction to cefpodoxime proxetil occurs, discontinue the drug. Serious acute hypersensitivity reactions may require treatment with epinephrine and other emergency measures, including oxygen, intravenous fluids, intravenous antihistamine, and airway management, as clinically indicated.

General precautions

In patients with transient or persistent reduction in urinary output due to renal insufficiency, the total daily dose of cefpodoxime proxetil should be reduced because high and prolonged serum antibiotic concentrations can occur in such individuals following usual doses. Cefpodoxime, like other cephalosporins, should be administered with caution to patients receiving concurrent treatment with potent diuretics. As with other antibiotics, prolonged use of cefpodoxime proxetil may result in overgrowth of non-susceptible organisms. Repeated evaluation of the patient’s condition is essential. If superinfection occurs during therapy, appropriate measures should be taken. Prescribing Cefpodoxime Proxetil, in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug resistant bacteria.

4.5 Interaction with other medicinal products and other forms of interaction

Antacids

Concomitant administration of high doses of antacids (sodium bicarbonate and aluminum hydroxide) or H2 blockers reduces peak plasma levels by 24% to 42% and the extent of absorption by 27% to 32%, respectively. The rate of absorption is not altered by these concomitant medications. Oral anticholinergics (e.g., propantheline) delay peak plasma levels (47% increase in Tmax), but do not affect the extent of absorption (AUC).

Probenecid

As with other beta-lactam antibiotics, renal excretion of cefpodoxime was inhibited by probenecid and resulted in an approximately 31% increase in AUC and 20% increase in peak cefpodoxime plasma levels.

Nephrotoxic drugs

Although nephrotoxicity has not been noted when cefpodoxime proxetil was given alone, close monitoring of renal function is advised when cefpodoxime proxetil is administered concomitantly with compounds of known nephrotoxic potential.

Drug/Laboratory Test Interactions

Cephalosporins, including cefpodoxime proxetil, are known to occasionally induce a positive direct Coombs’ test

4.6 Fertility, pregnancy and lactation

Pregnancy

There are, however, no adequate and well-controlled studies of cefpodoxime proxetil use in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Labor and Delivery

Cefpodoxime proxetil has not been studied for use during labor and delivery.

Lactation

Cefpodoxime is excreted in human milk. Because of the potential for serious reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

4.7 Effects on ability to drive and use machines

It may cause dizziness. Driving or operating machinery is to be avoided

4.8 Undesirable effects

In clinical trials using multiple doses of cefpodoxime proxetil granules for oral drop, 2128 pediatric patients (93% of whom were less than 12 years of age) were treated with the recommended dosages of cefpodoxime (10 mg/kg/day Q 24 hours or divided Q 12 hours to a maximum equivalent adult dose). There were no deaths or permanent disabilities in any of the patients in these studies. Twenty-four patients (1.1%) discontinued medication due to adverse events thought possibly- or probably-related to study drug. Primarily, these discontinuations were for gastrointestinal disturbances, usually diarrhea, vomiting, or rashes. Adverse events thought possibly- or probably-related, or of unknown relationship to cefpodoxime proxetil for oral drop in multiple dose clinical trials (N=2128 patients treated with cefpodoxime) were:

Incidence Greater Than 1% were:

Incidence Less Than 1%

Body: Localized abdominal pain, abdominal cramp, headache, monilla, generalized abdominal pain, asthenia, fever, fungal infection.

Digestive: Nausea, monilia, anorexia, dry mouth, stomatitis, pseudomembranous colitis. Hemic & Lymphatic: Thrombocythemia, positive direct

Coombs' test, eosinophilla, leukocytosis, leukopenia, prolonged partial thromboplastin time, thrombocytopenic purpura. Metabolic & Nutritional: Increased SGPT Musculo-Skeletal: Myalgia. Nervous: Hallucination, hyperkinesia, nervousness, somnolence. Respiratory: Epistaxis, rhinitis, Skin: Fixed drug eruption (FDE), skin moniliasis, urticaria, fungal dermatitis, acne, exfoliative dermatitis, maculopapular rash. Special Senses: Taste perversion. Laboratory Changes Significant laboratory changes that have been reported in adult and pediatric patients in clinical trials of cefpodoxime proxetil, without regard to drug relationship, were: Hepatic: Transient Increases in AST (SGOT), ALT (SGPT), GGT, alkaline phosphatase, bilirubin, and LDH. Hematologic: Eosinophilia, leukocytosis, lymphocytosis, granulocytosis, basophilia, mono- cytosis, thrombocytosis, decreased hemoglobin, decreased hematocrit, leukopenia, neu- tropenia, lymphocytopenia, thrombocytopenia, thrombocythemia, positive Coombs' test, and prolonged PT, and PTT. Serum Chemistry: Hyperglycemia, hypoglycemia, hypoalbuminemia, hypoproteinemia, hyperkalemia, and hyponatremia. Renal: Increases in BUN and creatinine. Most of these abnormalities were transient and not clinically significant. 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  By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

In acute rodent toxicity studies, a single 5 g/kg oral dose produced no adverse effects. In the event of serious toxic reaction from overdosage, hemodialysis or peritoneal dialysis may aid in the removal of cefpodoxime from the body, particularly if renal function is compromised. The toxic symptoms following an overdose of beta-lactam antibiotics may include nausea, vomiting, epigastric distress, and diarrhea.

5.1 Mechanism of action

Cefpodoxime is a bactericidal agent that acts by inhibition of bacterial cell wall synthesis. Cefpodoxime has activity in the presence of some betalactamases, both penicillinases and cephalosporinases, of Gram-negative and Gram-positive bacteria.

5.2 Pharmacodynamic properties

Resistance to Cefpodoxime is primarily through hydrolysis by beta-lactamase, alteration of penicillin-binding proteins (PBPs), and decreased permeability. Cefpodoxime has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections

Gram-positive Bacteria

Staphylococcus aureus (methicillin-susceptible strains, including those producing penicillinases) Staphylococcus saprophyticus Streptococcus pneumoniae (excluding penicillin-resistant isolates) Streptococcus pyogenes

Gram-negative Bacteria

Escherichia coli Klebsiella pneumoniae Proteus mirabilis Haemophilus influenzae (including beta-lactamase producing isolates) Moraxella catarrhalis Neisseria gonorrhoeae (including penicillinase-producing isolates) The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for cefpodoxime. However, the efficacy of cefpodoxime in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled clinical trials.

Gram-positive Bacteria

Streptococcus agalactiae Streptococcus spp. (Groups C, F, G)

Gram-negative Bacteria

Citrobacter diversus Klebsiella oxytoca Proteus vulgaris Providencia rettgeri Haemophilus parainfluenzae

Anaerobic Gram-positive Bacteria

Peptostreptococcus magnus

5.3 Pharmacokinetic properties

In adult subjects, a 100 mg dose of oral suspension produced an average peak cefpodoxime concentration of approximately 1.5 mcg/mL (range: 1.1 to 2.1 mcg/mL), which is equivalent to that reported following administration of the 100 mg tablet. Time to peak plasma concentration and area under the plasma concentration-time curve (AUC) for the oral suspension were also equivalent to those produced with film-coated tablets in adults following a 100 mg oral dose. The pharmacokinetics of cefpodoxime were investigated in 29 patients aged 1 to 17 years. Each patient received a single, oral, 5 mg/kg dose of cefpodoxime oral suspension. Plasma and urine samples were collected for 12 hours after dosing. The plasma levels reported from this study are as follows:

Dose did not exceed 200 mg.

Distribution

Protein binding of cefpodoxime ranges from 22 to 33% in serum and from 21 to 29% in plasma

Effects of Decreased Renal Function

Elimination of cefpodoxime is reduced in patients with moderate to severe renal impairment (<50 mL/min creatinine clearance). In subjects with mild impairment of renal function (50 to 80 mL/min creatinine clearance), the average plasma half-life of cefpodoxime was 3.5 hours. In subjects with moderate (30 to 49 mL/min creatinine clearance) or severe renal impairment (5 to 29 mL/mincreatinine clearance), the half-life increased to 5.9 and 9.8 hours, respectively. Approximately 23% of the administered dose was cleared from the body during a standard 3-hour hemodialysis procedure.

6.1 Animal Toxicology or Pharmacology

No known animal toxicology data

Cefpodoxime proxetil is an orally administered, extended spectrum, semisynthetic antibiotic of the cephalosporin class. The chemical name is (RS)-1(isopropoxycarbonyloxy) ethyl (+) (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2- {(Z)methoxyimino} acetamido]-3-methoxymethyl-8-oxo-5-thia-1-azabicyclo [4.2.0]oct-2-ene-2-carboxylate. Its empirical formula is C₂₁H₂₇N₅O₉S₂ and its structural formula is represented below:

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

Polares 100 DT : A strip of 10 tablets each.

Polares 200 : A strip of 10 tablets each.

8.4 Storage and handing instructions

Polares 100 DT : Store below 30°C. Protect from moisture.

Polares 200 : Store protected from moisture, at a temperature not exceeding 30°C.

Keep out of reach of children

Patients should be counseled that antibacterial drugs including Cefpodoxime Proxetil, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Cefpodoxime Proxetil, is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Cefpodoxime Proxetil, or other antibacterial drugs in the future. Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible

Cefpodoxime Oral Suspension IP

Polares Dry Suspension

Each 5 ml of reconstituted suspension contains :

Cefpodoxime Proxetil IP

equivalent to Cefpodoxime 50 mg

Excipients q.s

Colour : Quinoline Yellow WS

Polares-100 Dry Suspension

Each 5 ml of reconstituted suspension contains :

Cefpodoxime Proxetil IP

equivalent to Cefpodoxime 100 mg

Excipients q.s.

Colour : Quinoline Yellow WS

Dry Suspension, 50 / 100 mg

4.1 Therapeutic indication

Acute bronchitis, exacerbations of chronic bronchitis, bronchiolitis pneumonia, sinusitis, recurrent chronic tonsillitis, pharyngitis, acute otitis

4.2 Posology and method of administration

The recommended dosages, durations of treatment, and applicable patient population are as described in the following chart:

Adults and Adolescents (age 12 years and older)

 

Patients with Renal Insufficiency: For patients with severe renal impairment (<30 mL/min creatinine clearance), the dosing intervals should be increased to every 24 hours. In patients maintained on haemodialysis, the dose frequency should be 3 times/week after hemodialysis. Geriatric use: Dose adjustment in elderly patients with normal renal function is not necessary.

Patients with Hepatic Disease: No dose adjustment is necessary for cirrhotic patients (with or without ascites). Directions for reconstitution Shake the bottle well to loosen the granules. Add freshly boiled and cooled water upto the ring mark on the bottle and shake well. Add more water if necessary to adjust the volume upto the mark. Any unused reconstituted suspension should be discarded after 14 days. Store the constituted oral suspension in a refrigerator.

4.3 Contraindications

• known allergy to cefpodoxime or to the cephalosporin group of antibiotics or to any of the excipients.

• previous history of immediate and / or severe hypersensitivity reaction (anaphylaxis) to penicillin or other betalactam antibiotic.

4.4 Special warnings and precautions for use

Before therapy with cefpodoxime proxetil is instituted, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to cefpodoxime, other cephalosporin, penicillin, or other drugs. If cefpodoxime is to be administered to penicillin sensitive patients, caution should be exercised because cross hypersensitivity among beta-lactam antibiotics has been clearly documented and may occur in up to 10% of patients with a history of penicillin allergy. If an allergic reaction to cefpodoxime proxetil occurs, discontinue the drug. Serious acute hypersensitivity reactions may require treatment with epinephrine and other emergency measures, including oxygen, intravenous fluids, intravenous antihistamine, and airway management. Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Cefpodoxime, and may range in severity from mild diarrhea to fatal colitis. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. In patients with transient or persistent reduction in urinary output due to renal insufficiency, the total daily dose of cefpodoxime proxetil should be reduced because high and prolonged serum antibiotic concentrations can occur in such individuals following usual doses. Cefpodoxime, like other cephalosporin, should be administered with caution to patients receiving concurrent treatment with potent diuretics.

4.5 Drugs interactions

Antacids: Concomitant administration of high doses of antacids (sodium bicarbonate and aluminum hydroxide) or H2 blockers (e.g. ranitidine) reduce peak plasma levels and the extent of absorption but do not alter the rate of absorption. Probenecid: Inhibits renal excretion of Cefpodoxime, resulting in an increase in AUC and peak plasma levels. Nephrotoxic drugs: Close monitoring of renal function is advised when cefpodoxime proxetil is administered concomitantly with compounds of known nephrotoxic potential.

4.6 Use in special populations

Pregnancy

Pregnancy Category B There are, however, no adequate and well-controlled studies of cefpodoxime proxetil use in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing mothers

Cefpodoxime is excreted in human milk. Because of the potential for serious reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

4.7 Effects on ability to drive and use machines

Dizziness has been reported during treatment with cefpodoxime and may affect the ability to drive and use machines.

4.8 Undesirable effects

In clinical trials using multiple doses of cefpodoxime proxetil granules for oral suspension, 2128 pediatric patients (93% of whom were less than 12 years of age) were treated with the recommended dosages of cefpodoxime (10 mg/kg/day Q 24 hours or divided Q 12 hours to a maximum equivalent adult dose). There were no deaths or permanent disabilities in any of the patients in these studies. Twenty-four patients (1.1%) discontinued medication due to adverse events thought possibly- or probably-related to study drug. Primarily, these discontinuations were for gastrointestinal disturbances, usually diarrhea, vomiting, or rashes. Adverse events thought possibly- or probably-related, or of unknown relationship to cefpodoxime proxetil for oral suspension in multiple dose clinical trials (N=2128 patients treated with cefpodoxime) were:

Incidence Less Than 1%

Body: Localized abdominal pain, abdominal cramp, headache, monilla, generalized abdominal pain, asthenia, fever, fungal infection. Digestive: Nausea, monilia, anorexia, dry mouth, stomatitis, pseudomembranous colitis. Hemic & Lymphatic: Thrombocythemia, positive direct Coombs' test, eosinophilla, leukocytosis, leukopenia, prolonged partial thromboplastin time, thrombocytopenic purpura. Metabolic & Nutritional: Increased SGPT Musculo-Skeletal: Myalgia. Nervous: Hallucination, hyperkinesia, nervousness, somnolence. Respiratory: Epistaxis, rhinitis, Skin: Fixed drug eruption (FDE), skin moniliasis, urticaria, fungal dermatitis, acne, exfoliative dermatitis, maculopapular rash. Special Senses: Taste perversion. Laboratory Changes Significant laboratory changes that have been reported in adult and pediatric patients in clinical trials of cefpodoxime proxetil, without regard to drug relationship, were: Hepatic: Transient Increases in AST (SGOT), ALT (SGPT), GGT, alkaline phosphatase, bilirubin, and LDH. Hematologic: Eosinophilia, leukocytosis, lymphocytosis, granulocytosis, basophilia, mono- cytosis, thrombocytosis, decreased hemoglobin, decreased hematocrit, leukopenia, neu- tropenia, lymphocytopenia, thrombocytopenia, thrombocythemia, positive Coombs' test, and prolonged PT, and PTT. Serum Chemistry: Hyperglycemia, hypoglycemia, hypoalbuminemia, hypoproteinemia, hyperkalemia, and hyponatremia. Renal: Increases in BUN and creatinine. Most of these abnormalities were transient and not clinically significant.

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

4.9 Overdose

The toxic symptoms following an overdose of beta-lactam antibiotics may include nausea, vomiting, epigastric distress, and diarrhea. In the event of serious toxic reaction from overdosage, hemodialysis or peritoneal dialysis may aid in the removal of cefpodoxime from the body.

5.1 Mechanism of Action

Cefpodoxime is a bactericidal agent that acts by inhibition of bacterial cell wall synthesis. Cefpodoxime has activity in the presence of some betalactamases, both penicillinases and cephalosporinases, of Gram-negative and Gram-positive bacteria.

5.2 Pharmacodynamic properties

Resistance to Cefpodoxime is primarily through hydrolysis by beta-lactamase, alteration of penicillin-binding proteins (PBPs), and decreased permeability. Cefpodoxime has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections

Gram-positive Bacteria

Staphylococcus aureus (methicillin-susceptible strains, including those producing penicillinases) Staphylococcus saprophyticus Streptococcus pneumoniae (excluding penicillin-resistant isolates) Streptococcus pyogenes

Gram-negative Bacteria

Escherichia coli Klebsiella pneumoniae Proteus mirabilis Haemophilus influenzae (including beta-lactamase producing isolates) Moraxella catarrhalis Neisseria gonorrhoeae (including penicillinase-producing isolates) The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for cefpodoxime. However, the efficacy of cefpodoxime in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled clinical trials.

Gram-positive Bacteria

Streptococcus

agalactiae

Streptococcus spp.

(Groups C, F, G)

Gram-negative Bacteria

Citrobacter diversus

Klebsiella oxytoca

Proteus vulgaris

Providencia rettgeri

Haemophilus parainfluenzae

Anaerobic Gram-positive Bacteria

Peptostreptococcus magnus

5.3 Pharmacokinetic properties

Absorption

Following oral administration of 100 mg of cefpodoxime proxetil to fasting subjects, approximately 50% of the administered cefpodoxime dose was absorbed systemically. Over the recommended dosing range (100 to 400 mg), the rate and extent of cefpodoxime absorption exhibited dose-dependency. Over the recommended dosing range, the Tmaxwas approximately 2 to 3 hours and the T½ ranged from 2.09 to 2.84 hours. Mean Cmax was 1.4 mcg/mL for the 100 mg dose, 2.3 mcg/mL for the 200 mg dose, and 3.9 mcg/mL for the 400 mg dose. In patients with normal renal function, neither accumulation nor significant changes in other pharmacokinetic parameters were noted following multiple oral doses of up to 400 mg Q 12 hours.

Distribution

Protein binding of cefpodoxime ranges from 22 to 33% in serum and from 21 to 29% in plasma.

Skin Blister

Following multiple-dose administration every 12 hours for 5 days of 200 mg or 400 mg cefpodoxime proxetil, the mean maximum cefpodoxime concentration in skin blister fluid averaged 1.6 and 2.8 mcg/mL, respectively.

Tonsil Tissue

Following a single, oral 100 mg cefpodoxime proxetil film-coated tablet, the mean maximum cefpodoxime concentration in tonsil tissue averaged 0.24 mcg/g at 4 hours post-dosing and 0.09 mcg/g at 7 hours post-dosing. These results demonstrated that concentrations of cefpodoxime exceeded the MIC90 of S. pyogenes for at least 7 hours after dosing of 100 mg of cefpodoxime proxetil.

Lung Tissue

Following a single, oral 200 mg cefpodoxime proxetil film coated tablet, the mean maximum cefpodoxime concentration in lung tissue averaged 0.63 mcg/g at 3 hours post-dosing, 0.52 mcg/g at 6 hours post-dosing, and 0.19 mcg/g at 12 hours post-dosing. The results of this study indicated that cefpodoxime penetrated into lung tissue and produced sustained drug concentrations for at least 12 hours after dosing at levels that exceeded the MIC90 for S. pneumoniae and H. influenzae.

Effects of Decreased Renal Function

Elimination of cefpodoxime is reduced in patients with moderate to severe renal impairment (<50 mL/min creatinine clearance). In subjects with mild impairment of renal function (50 to 80 mL/min creatinine clearance), the average plasma half-life of cefpodoxime was 3.5 hours. In subjects with moderate (30 to 49 mL/min creatinine clearance) or severe renal impairment (5 to 29 mL/min creatinine clearance), the half-life increased to 5.9 and 9.8 hours, respectively. Approximately 23% of the administered dose was cleared from the body during a standard 3-hour hemodialysis procedure. Effect of Hepatic Impairment (cirrhosis) Absorption was somewhat diminished and elimination unchanged in patients with cirrhosis. The mean cefpodoxime Trot and renal clearance in cirrhotic patients were similar to those derived in studies of healthy subjects. Pharmacokinetics in Elderly Subjects Elderly subjects do not require dosage adjustments unless they have diminished renal function.

6.1 Animal Toxicology or Pharmacology

No known animal toxicology data

Cefpodoxime proxetil is an orally administered, extended spectrum, semi-synthetic antibiotic of the cephalosporin class. The chemical name is (RS)-1(isopropoxycarbonyloxy) ethyl (+)-(6R,7R)-7-[2- (2-amino-4-thiazolyl)-2-{(Z)methoxyimino} acetamido]-3- methoxymethyl-8-oxo-5-thia-1-azabicyclo [4.2.0]oct-2-ene-2- carboxylate. Its structural formula is represented below:

Molecular Formula: C₂₁H₂₇N₅O₉S₂

Molecular Weight: 557.6

8.1 Incompatibilities

Not Applicable

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

Polares Dry Suspension : A bottle of 7.5 g / 30 ml.

Polares-100 Dry Suspension : A bottle of 15 g / 30 ml.

8.4 Storage and handing instructions Store below 30°C. Protect from moisture

Keep out of reach of children.

Store the reconstituted oral suspension in a refrigerator (at 2°C to 8°C).

Patients should be counseled that antibacterial drugs including Cefpodoxime Proxetil Suspension, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Cefpodoxime Proxetil Suspension, is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed.

Skipping doses or not completing the full course of therapy may

(1) decrease the effectiveness of the immediate treatment and

(2) increase the likelihood that bacteria will develop resistance and will not be treatable by Cefpodoxime Proxetil Suspension, or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible

Cefpodoxime Oral Suspension IP

Each ml of reconstituted suspension contains :

Cefpodoxime Proxetil IP

equivalent to Cefpodoxime 25 mg

Excipients q.s.

Colour : Quinoline Yellow WS

This pack contains Sterile Water for Injections IP 10 ml for reconstitution.

Dry Suspension, 25 mg

4.1 Therapeutic indications

Acute bronchitis, exacerbations of chronic bronchitis, bronchiolitis pneumonia, sinusitis, recurrent chronic tonsillitis, pharyngitis, acute otitis.

4.2 Posology and method of administration

Posology

Cefpodoxime Proxetil Drop, should be administered orally with food to enhance absorption.

The recommended dosages, durations of treatment, and applicable patient population are as described in the following chart.

Infants and Pediatric Patients (age 2 months through 12 years)

Patients with Renal Dysfunction

For patients with severe renal impairment (<30 mL/min creatinine clearance), the dosing intervals should be increased to Q 24 hours. In patients maintained on hemodialysis, the dose frequency should be 3 times/week after hemodialysis.

Patients with Cirrhosis

Cefpodoxime pharmacokinetics in cirrhotic patients (with or without ascites) are similar to those in healthy subjects. Dose adjustment is not necessary in this population

4.3 Contraindications

• Cefpodoxime is contraindicated in patients with a known allergy to cefpodoxime or to the cephalosporin group of antibiotics.

• previous history of immediate and / or severe hypersensitivity reaction (anaphylaxis) to penicillin or other betalactam antibiotic.

4.4 Special warnings and precautions for use

Before therapy with cefpodoxime proxetil is instituted, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to cefpodoxime, other cephalosporins, penicillins, or other drugs. If cefpodoxime is to be administered to penicillin sensitive patients, caution should be exercised because cross hypersensitivity among beta-lactam antibiotics has been clearly documented and may occur in up to 10% of patients with a history of penicillin allergy. If an allergic reaction to cefpodoxime proxetil occurs, discontinue the drug. Serious acute hypersensitivity reactions may require treatment with epinephrine and other emergency measures, including oxygen, intravenous fluids, intravenous antihistamine, and airway management, as clinically indicated.

General precautions

In patients with transient or persistent reduction in urinary output due to renal insufficiency, the total daily dose of cefpodoxime proxetil should be reduced because high and prolonged serum antibiotic concentrations can occur in such individuals following usual doses. Cefpodoxime, like other cephalosporins, should be administered with caution to patients receiving concurrent treatment with potent diuretics. As with other antibiotics, prolonged use of cefpodoxime proxetil may result in overgrowth of non-susceptible organisms. Repeated evaluation of the patient’s condition is essential. If superinfection occurs during therapy, appropriate measures should be taken. Prescribing Cefpodoxime Proxetil, in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug resistant bacteria.

4.5 Interaction with other medicinal products and other forms of interaction

Antacids

Concomitant administration of high doses of antacids (sodium bicarbonate and aluminum hydroxide) or H2 blockers reduces peak plasma levels by 24% to 42% and the extent of absorption by 27% to 32%, respectively. The rate of absorption is not altered by these concomitant medications. Oral anti-cholinergics (e.g., propantheline) delay peak plasma levels (47% increase in Tmax), but do not affect the extent of absorption (AUC).

Probenecid

As with other beta-lactam antibiotics, renal excretion of cefpodoxime was inhibited by probenecid and resulted in an approximately 31% increase in AUC and 20% increase in peak cefpodoxime plasma levels.

Nephrotoxic drugs

Although nephrotoxicity has not been noted when cefpodoxime proxetil was given alone, close monitoring of renal function is advised when cefpodoxime proxetil is administered concomitantly with compounds of known nephrotoxic potential.

Drug/Laboratory Test Interactions

Cephalosporins, including cefpodoxime proxetil, are known to occasionally induce a positive direct Coombs’ test

4.6 Fertility, pregnancy and lactation

Pregnancy

There are, however, no adequate and well-controlled studies of cefpodoxime proxetil use in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Labor and Delivery

Cefpodoxime proxetil has not been studied for use during labor and delivery

Lactation

Cefpodoxime is excreted in human milk. Because of the potential for serious reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

4.7 Effects on ability to drive and use machines

It may cause dizziness. Driving or operating machinery is to be avoided

4.8 Undesirable effects

In clinical trials using multiple doses of cefpodoxime proxetil granules for oral drop, 2128 pediatric patients (93% of whom were less than 12 years of age) were treated with the recommended dosages of cefpodoxime (10 mg/kg/day Q 24 hours or divided Q 12 hours to a maximum equivalent adult dose). There were no deaths or permanent disabilities in any of the patients in these studies. Twenty-four patients (1.1%) discontinued medication due to adverse events thought possibly- or probably-related to study drug. Primarily, these discontinuations were for gastrointestinal disturbances, usually diarrhea, vomiting, or rashes.

Adverse events thought possibly- or probably-related, or of unknown relationship to cefpodoxime proxetil for oral drop in multiple dose clinical trials (N=2128 patients treated with cefpodoxime) were:

Incidence Greater Than 1% were:

Incidence Less Than 1%

Body: Localized abdominal pain, abdominal cramp, headache, monilla, generalized abdominal pain, asthenia, fever, fungal infection

Digestive: Nausea, monilia, anorexia, dry mouth, stomatitis, pseudomembranous colitis. Hemic & Lymphatic: Thrombocythemia, positive direct Coombs' test, eosinophilla, leukocytosis, leukopenia, prolonged partial thromboplastin time, thrombocytopenic purpura.

Metabolic & Nutritional: Increased SGPT

Musculo-Skeletal: Myalgia

Nervous: Hallucination, hyperkinesia, nervousness, somnolence. Respiratory: Epistaxis, rhinitis

Skin: Fixed drug eruption (FDE), skin moniliasis, urticaria, fungal dermatitis, acne, exfoliative dermatitis, maculopapular rash.

Special Senses: Taste perversion.

Laboratory Changes

Significant laboratory changes that have been reported in adult and pediatric patients in clinical trials of cefpodoxime proxetil, without regard to drug relationship, were:

Hepatic: Transient Increases in AST (SGOT), ALT (SGPT), GGT, alkaline phosphatase, bilirubin, and LDH

Hematologic: Eosinophilia, leukocytosis, lymphocytosis, granulocytosis, basophilia, mono- cytosis, thrombocytosis, decreased hemoglobin, decreased hematocrit, leukopenia, neu- tropenia, lymphocytopenia, thrombocytopenia, thrombocythemia, positive Coombs' test, and prolonged PT, and PTT.

Serum Chemistry: Hyperglycemia, hypoglycemia, hypoalbuminemia, hypoproteinemia, hyperkalemia, and hyponatremia.

Renal: Increases in BUN and creatinine.

Most of these abnormalities were transient and not clinically significant

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

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

4.9 Overdose

In acute rodent toxicity studies, a single 5 g/kg oral dose produced no adverse effects. In the event of serious toxic reaction from overdosage, hemodialysis or peritoneal dialysis may aid in the removal of cefpodoxime from the body, particularly if renal function is compromised.

The toxic symptoms following an overdose of beta-lactam antibiotics may include nausea, vomiting, epigastric distress, and diarrhea.

5.1 Mechanism of action

Cefpodoxime is a bactericidal agent that acts by inhibition of bacterial cell wall synthesis. Cefpodoxime has activity in the presence of some betalactamases, both penicillinases and cephalosporinases, of Gram-negative and Gram-positive bacteria.

5.2 Pharmacodynamic properties

Resistance to Cefpodoxime is primarily through hydrolysis by beta-lactamase, alteration of penicillin-binding proteins (PBPs), and decreased permeability.

Cefpodoxime has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections

Gram-positive Bacteria

Staphylococcus aureus (methicillin-susceptible strains, including those producing penicillinases)

Staphylococcus saprophyticus

Streptococcus pneumoniae (excluding penicillin-resistant isolates)

Streptococcus pyogenes

Gram-negative Bacteria

Escherichia coli

Klebsiella pneumoniae

Proteus mirabilis

Haemophilus influenzae (including beta-lactamase producing isolates)

Moraxella catarrhalis

Neisseria gonorrhoeae (including penicillinase-producing isolates)

The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for cefpodoxime. However, the efficacy of cefpodoxime in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled clinical trials.

Gram-positive Bacteria

Streptococcus agalactiae

Streptococcus spp. (Groups C, F, G)

Gram-negative Bacteria

Citrobacter diversus

Klebsiella oxytoca

Proteus vulgaris

Providencia rettgeri

Haemophilus parainfluenzae

Anaerobic Gram-positive Bacteria

Peptostreptococcus magnus

5.3 Pharmacokinetic properties

In adult subjects, a 100 mg dose of oral suspension produced an average peak cefpodoxime concentration of approximately 1.5 mcg/mL (range: 1.1 to 2.1 mcg/mL), which is equivalent to that reported following administration of the 100 mg tablet. Time to peak plasma concentration and area under the plasma concentration-time curve (AUC) for the oral suspension were also equivalent to those produced with film-coated tablets in adults following a 100 mg oral dose.

The pharmacokinetics of cefpodoxime were investigated in 29 patients aged 1 to 17 years. Each patient received a single, oral, 5 mg/kg dose of cefpodoxime oral suspension. Plasma and urine samples were collected for 12 hours after dosing. The plasma levels reported from this study are as follows:

Cefpodoxime Plasma Levels (mcg/mL) In Fasted Patients (1 to 17 Years of Age) After Suspension Administration

Dose did not exceed 200 mg

Distribution

Protein binding of cefpodoxime ranges from 22 to 33% in serum and from 21 to 29% in plasma

Effects of Decreased Renal Function

Elimination of cefpodoxime is reduced in patients with moderate to severe renal impairment (<50 mL/min creatinine clearance). In subjects with mild impairment of renal function (50 to 80 mL/min creatinine clearance), the average plasma half-life of cefpodoxime was 3.5 hours. In subjects with moderate (30 to 49 mL/min creatinine clearance) or severe renal impairment (5 to 29 mL/mincreatinine clearance), the half-life increased to 5.9 and 9.8 hours, respectively. Approximately 23% of the administered dose was cleared from the body during a standard 3-hour hemodialysis procedure.

6.1 Animal Toxicology or Pharmacology

No known animal toxicology data

Cefpodoxime proxetil is an orally administered, extended spectrum, semi-synthetic antibiotic of the cephalosporin class. The chemical name is (RS)-1(iso-propoxycarbonyloxy) ethyl (+) (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2- {(Z)methoxyimino} acetamido]-3-methoxymethyl-8-oxo-5-thia-1-azabicyclo [4.2.0]oct-2-ene-2-carboxylate. Its empirical formula is C21H27N5O9S2 and its structural formula is represented below:

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

A bottle of 4 g / 10 ml.

8.4 Storage and handing instructions

Preserve in tight containers, at a temperature not exceeding 30°C

Keep out of reach of children.

Store the reconstituted oral suspension in a refrigerator (at 2°C to 8°C).

Patients should be counseled that antibacterial drugs including Cefpodoxime Proxetil, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Cefpodoxime Proxetil, is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed.

Skipping doses or not completing the full course of therapy may

(1) decrease the effectiveness of the immediate treatment and

(2) increase the likelihood that bacteria will develop resistance and will not be treatable by Cefpodoxime Proxetil, or other antibacterial drugs in the future. Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible

Aceclofenac & Paracetamol Tablets [100 mg + 325 mg]

Each film coated tablet contains :

Aceclofenac IP 100 mg

Paracetamol IP 325 mg

Excipients q.s.

Colour : Titanium Dioxide IP

Film-coated tablet, 100 mg of Aceclofenac and 325 mg of Paracetamol.

4.1 Therapeutic indications

For acute painful conditions in adults only

4.2 Posology and method of administration

Posology

The maximum recommended dose of Mahadol is two tablets daily, taken as one tablet in the morning and one in the evening.

Method of administration

Mahadol tablets are supplied for oral administration in adults and should be swallowed whole with sufficient amount of liquid. It should be taken preferably with or after food.

4.3 Contraindications

Mahadol is contraindicated in the following situations :

• Patients sensitive to Aceclofenac, Paracetamol or to any of the excipients of the product.

• Patients with active or history of recurrent peptic ulcer / haemorrhage (two or more distinct episodes of proven ulceration or bleeding).

• Patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, angioedema or urticaria) in response to Ibuprofen, Aspirin, or other non-steroidal anti-inflammatory drugs.

• Patients with severe heart failure, hypertension, hepatic or renal insufficiency should not be prescribed.

• During pregnancy, especially during the last trimester of pregnancy, unless there are compelling reasons for doing so. The lowest effective dosage should be used.

4.4 Special warnings and precautions for use

Undesirable effects may be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms. Concomitant use with NSAIDs including cyclooxygenase- 2 selective inhibitors should be avoided. It should not be combined with other analgesic medications that contain Paracetamol and should be given with care to patients with impaired kidney or liver function. The administration of an NSAID may cause a dose dependent reduction in prostaglandin formation and precipitate renal failure. Patients at greatest risk of this reaction are those with impaired renal function, cardiac impairment, liver dysfunction, those taking diuretics and the elderly. Renal function should be monitored in these patients.

Respiratory disorders

Caution is required if administered to patients suffering from, or with a previous history of, bronchial asthma since NSAIDs have been reported to precipitate bronchospasm in such patients.

Hepatic toxicity

Paracetamol may cause liver damage if taken more than the recommended dose. Allergic reactions like swelling of the face, mouth and throat, difficulty in breathing, itching or rash may occur due to high doses of Paracetamol. Severe liver damage may occur if :

• Adult takes more than 4000 mg in 24 hours, which is the maximum daily amount.

• Child takes more than 5 doses in 24 hours.

• Taken with other drugs containing Paracetamol.

• Adult has 3 or more alcoholic drinks every day while using this product.

Cardiovascular and cerebrovascular effects

Appropriate monitoring and advice are required for patients with a histor y of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy. Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). There are insufficient data to exclude such a risk for Aceclofenac. Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

Gastrointestinal bleeding, ulceration and perforation

GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI events. Close medical surveillance is imperative in patients with symptoms indicative of gastro-intestinal disorders, with a history suggestive of gastro-intestinal ulceration, with ulcerative colitis or with Crohn's disease, bleeding diathesis or haematological abnormalities.

The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation, and in the elderly. These patients should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant low dose Aspirin, or other drugs likely to increase gastrointestinal risk.

Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment. Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or antiplatelet agents such as Aspirin. When GI bleeding or ulceration occurs the treatment should be withdrawn. NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) as these conditions may be exacerbated.

SLE and mixed connective tissue disease

In patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders there may be an increased risk of aseptic meningitis.

Dermatological

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs. Patients appear to be at highest risk for these reactions early in the course of therapy : the onset of the reaction occurring in the majority of cases within the first month of treatment. Discontinuation should be done at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity. Doses higher than those recommended involve a risk of very severe liver damage. If liver damage is suspected, then liver function tests should be performed.

Hypersensitivity reactions

As with other NSAIDs, allergic reactions, including anaphylactic / anaphylactoid reactions, can also occur without earlier exposure to the drug.

Haematological

May cause reversibly inhibit platelet aggregation.

Long-term treatment

Individuals receiving long-term treatment should be regularly monitored for renal function tests, liver function tests and blood counts.

It is to be used with caution in hepatic porphyria, coagulation disorders, history of peptic ulcers, ulcerative colitis, Crohn's disease, cerebrovascular bleeding, pregnancy and lactation. Caution should be exercised in patients with mild to moderate impairment of cardiac, hepatic or renal function and in elderly patients who are more likely to be suffering from these conditions. Caution is also required in patients on diuretic therapy or otherwise at risk of hypovolemia.

4.5 Interaction with other medicinal products and other forms of interaction

Other analgesics including cyclooxygenase-2 selective inhibitors

Avoid concomitant use of two or more NSAIDs (including Aspirin) as this may increase the risk of adverse effects, including GI bleeding.

Anti-hypertensives

Reduced anti-hypertensive effect. The risk of acute renal insufficiency, which is usually reversible, may be increased in some patients with compromised renal function (e.g. dehydrated patients or elderly patients) when ACE- inhibitors or angiotensin II receptor antagonists are combined with NSAIDs. Therefore, the combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy, and periodically thereafter

Diuretics

Reduced diuretic effect. Diuretics can increase the risk of nephrotoxicity of NSAIDs. Although it was not shown to affect blood pressure control when co-administered with Bendrofluazide, interactions with other diuretics cannot be ruled out. When concomitant administration with Potassium-sparing diuretics is employed, serum potassium should be monitored.

Cardiac glycosides like Digoxin

NSAIDs may exacerbate cardiac failure, reduce GFR (glomerular filtration rate) and increase plasma glycoside levels. The combination should be avoided unless frequent monitoring of glycoside levels can be performed.

Lithium

Several NSAIDs drugs inhibit the renal clearance of Lithium, resulting in increased serum concentration of Lithium. The combination should be avoided unless frequent monitoring of Lithium can be performed.

Methotrexate

The possible interaction between NSAIDs and Methotrexate should be born in mind also when low doses of Methotrexate are used, especially in patients with decreased renal function. When combination therapy has to be used, the renal function should be monitored. Caution should be exercised if NSAIDs and Methotrexate are administered within 24 hours of each other, since NSAIDs may increase plasma levels, resulting in increased toxicity.

Mifepristone

NSAIDs should not be used for 8 - 12 days after Mifepristone administration as NSAIDs can reduce the effect of Mifepristone

Corticosteroids

Increased risk of gastrointestinal ulceration or bleeding.

Anti-coagulants

NSAIDs may enhance the effects of anti-coagulants, such as Warfarin. Close monitoring of patients on combined anticoagulants and Aceclofenac 100 mg Film-coated Tablets therapy should be undertaken.

Quinolone antibiotics

Animal data indicate that NSAIDs can increase the risk of convulsions associated with Quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.

Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs)

Increased risk of gastrointestinal bleeding.

Ciclosporin and Tacrolimus

Administration of NSAID drugs together with Cyclosporin or Tacrolimus is thought to increase the risk of nephrotoxicity due to decreased synthesis of prostacyclin in the kidney. During combination therapy it is therefore important to carefully monitor renal function.

Zidovudine

Increased risk of haematological toxicity when NSAIDs are given with Zidovudine. There is evidence of an increased risk of haemarthroses and haematoma in HIV(+) haemophiliacs receiving concurrent treatment with Zidovudine and Ibuprofen.

Antidiabetic agents

Clinical studies have shown that Diclofenac can be given together with oral antidiabetic agents without influencing their clinical effect. However, there have been isolated reports of hypoglycaemic and hyperglycaemic effects. Thus with Aceclofenac 100 mg Film-coated Tablets, consideration should be given to adjustment of the dosage of hypoglycaemic agents.

Other NSAIDs

Concomitant therapy with Aspirin or other NSAIDs may increase the frequency of adverse reactions, including the risk of GI bleeding.

4.6 Fertility, pregnancy and lactation

Aceclofenac

Other analgesics including cyclooxygenase-2 selective inhibitors

Avoid concomitant use of two or more NSAIDs (including Aspirin) as this may increase the risk of adverse effects.

Anti-hypertensives

Reduced anti-hypertensive effect.

Diuretics

Reduced diuretic effect. Diuretics can increase the risk of nephrotoxicity of NSAIDs. Although it was not shown to affect blood pressure control when co-administered with Bendrofluazide, interactions with other diuretics cannot be ruled out. When concomitant administration with Potassium-sparing diuretics is employed, serum potassium should be monitored.

Cardiac glycosides

NSAIDs may exacerbate cardiac failure, reduce GFR (glomerular filtration rate) and increase plasma glycoside levels.

Lithium

Decreased elimination of Lithium.

Methotrexate

Decreased elimination of Methotrexate. Caution should be exercised if NSAIDs and Methotrexate are administered within 24 hours of each other, since NSAIDs may increase plasma levels, resulting in increased toxicity.

Ciclosporin

Increased risk of nephrotoxicity.

Mifepristone

NSAIDs should not be used for 8 - 12 days after Mifepristone administration as NSAIDs can reduce the effect of Mifepristone.

Corticosteroids

Increased risk of gastrointestinal ulceration or bleeding.

Anti-coagulants

NSAIDs may enhance the effects of anti-coagulants, such as Warfarin. Close monitoring of patients on combined anticoagulants and Aceclofenac therapy should be undertaken.

Quinolone antibiotics

Animal data indicate that NSAIDs can increase the risk of convulsions associated with Quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.

Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs)

Increased risk of gastrointestinal bleeding.

Tacrolimus

Possible increased risk of nephrotoxicity when NSAIDs are given with Tacrolimus.

Zidovudine

Increased risk of haematological toxicity when NSAIDs are given with Zidovudine. There is evidence of an increased risk of haemarthroses and haematoma in HIV(+) haemophiliacs receiving concurrent treatment with Zidovudine and Ibuprofen.

Antidiabetic agents

Clinical studies have shown that diclofenac can be given together with oral antidiabetic agents without influencing their clinical effect. However, there have been isolated reports of hypoglycaemic and hyperglycaemic effects. Thus with Aceclofenac, consideration should be given to adjustment of the dosage of hypoglycaemic agents.

Other NSAIDs

Concomitant therapy with Aspirin or other NSAIDs may increase the frequency of adverse reactions, including the risk of GI bleeding.

Paracetamol

Drugs which induce hepatic microsomal enzymes such as alcohol, barbiturates and other anticonvulsants, may increase the hepatotoxicity of Paracetamol, particularly after over dosage. The anti-coagulant effect of Warfarin and other coumarins may be enhanced by prolonged regular use of Paracetamol with increased risk of bleeding. The effect appears to increase as the dose of Paracetamol is increased, but can occur with doses as low as 1.5 - 2 g Paracetamol per day for at least 5 - 7 days. Occasional doses have no significant effect. Probenicid inhibits the glucuronidation of Paracetamol which can affect the clearance of Paracetamol. This should be considered when these medicines are administered concomitantly. Paracetamol may affect the pharmacokinetics of chloramphenicol. This interaction should be considered when these medications are administered concomitantly, especially in malnourished patients. Enzyme-inducing medicines, such as some antiepileptic drugs (Phenytoin, Phenobarbital, Carbamazepine) have been shown in pharmacokinetic studies to reduce the plasma AUC of Paracetamol to approx. 60%. Other substances with enzyme inducing properties, e.g. Rifampicin and St. John's wort (hypericum) are also suspected of causing lowered concentrations of Paracetamol. In addition, the risk of liver damage during treatment with maximum recommended doses of Paracetamol will be higher in patients being treated with enzyme-inducing agents.

Renal impairment

It should be avoided in patients with moderate and severe renal impairment. The importance of prostaglandins in maintaining renal blood flow should be taken into account in patients with impaired cardiac or renal function, those being treated with diuretics or recovering from major surgery. Effects on renal function are usually reversible on withdrawal.

Hepatic impairment

In patients with hepatic impairment, dosage reductions are recommended. If abnormal liver function tests persist or worsen, clinical signs or symptoms consistent with liver disease develop or if other manifestations occur (eosinophilia, rash), it should be discontinued. Close medical surveillance is necessary in patients suffering from mild to moderate impairment of hepatic function. Hepatitis may occur without prodromal symptoms. Use in patients with hepatic porphyria may trigger an attack.

Pregnancy

Congenital abnormalities have been reported in association with NSAID administration in man; however, these are low in frequency and do not appear to follow any discernible pattern. In view of the known effects of NSAIDs on the foetal cardiovascular system (risk of closure of the ductus arteriosus) and on the possible risk of persistent pulmonary hypertension of the new born, use in the last trimester of pregnancy is contraindicated. The regular use of NSAIDs during the last trimester of pregnancy may decrease uterine tone and contraction. The onset of labour may be delayed and the duration increased with an increased bleeding tendency in both mother and child. NSAIDs should not be used during the first two trimesters of pregnancy or labour unless the potential benefit to the patient outweighs the potential risk to the foetus. The drug in not recommended in pregnant women.

Lactation

In limited studies so far available, NSAIDs can appear in breast milk in very low concentrations. NSAIDs should, if possible, be avoided when breastfeeding. The use of Aceclofenac should therefore be avoided in pregnancy and lactation unless the potential benefits to the other outweigh the possible risks to the foetus. The drug in not recommended in breast-feeding women.

Geriatric

As with other NSAIDs and combinations, caution is advised in elderly patients who are more likely to have concomitant renal, hepatic or cardiovascular impairment or receiving concurrent medication. The elderly has an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal.

4.7 Effects on ability to drive and use machines

It may cause dizziness. Driving or operating machinery is to be avoided.

4.8 Undesirable effects

Renal

Nephrotoxicity in various forms, including interstitial nephritis, nephritic syndrome and renal failure.

Hepatic

Abnormal liver function, hepatitis and jaundice.

Neurological and special senses

Visual disturbances, optic neuritis, headaches, paraesthesia, reports of aseptic meningitis (especially in patients with existing auto-immune disorders, such as systemic lupus erythematosus, mixed connective tissue disease), with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation, depression, confusion, hallucinations, tinnitus, vertigo, dizziness, malaise, fatigue and drowsiness.

Haematological

Thrombocytopenia, neutropenia, agranulocytosis, aplastic anaemia and haemolytic anaemia.

Dermatological

Bullous reactions including Stevens Johnson Syndrome and Toxic Epidermal Necrolysis (very rare), Photosensitivity. Fixed drug eruption (FDE) is associated with Paracetamol use. Within the system organ classes, undesirable effects are listed under headings of frequency, using the following categories : Very common (1/10); Common (1/100 to < 1/10); Uncommon (1/1,000 to < 1/100); Rare (1/10,000 to < 1/1,000); Very rare (< 1/10,000), Not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness

Most of the adverse events are minor and reversible with treatment discontinuation. As with other NSAIDs, severe mucocutaneous skin reactions may also occur

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

4.9 Overdose

Liver damage is possible in adults who have taken 10 g or more of Paracetamol. Ingestion of 5 g or more of Paracetamol may lead to liver damage if the patient has risk factors. Management of acute poisoning with NSAIDs essentially consists of supportive and symptomatic measures. Symptoms Symptoms include headache, nausea, vomiting, epigastric pain, gastrointestinal irritation, gastrointestinal bleeding, rarely diarrhoea, disorientation, excitation, coma, drowsiness, dizziness, tinnitus, hypotension, respirator y depression, fainting, occasionally convulsions. In cases of significant poisoning acute renal failure and liver damage are possible. Therapeutic measure Patients should be treated symptomatically as required. Within one hour of ingestion of a potentially toxic amount, activated charcoal should be considered. Alternatively, in adults, gastric lavage should be considered within one hour of ingestion of a potentially life-threatening overdose. Specific therapies such as dialysis or haemoperfusion are probable of no help in eliminating NSAIDs due to their high rate of protein binding and extensive metabolism. Good urine output should be ensured. Renal and liver function should be closely monitored. Patients should be observed for at least four hours after ingestion of potentially toxic amounts.

In case of frequent or prolonged convulsions, patients should be treated with intravenous diazepam. Other measures may be indicated by the patient's clinical condition. Management of acute poisoning with oral Aceclofenac essentially consists of supportive and symptomatic measures for complications such as hypotension, renal failure, convulsions, gastro-intestinal irritation, and respiratory depression.

5.1 Pharmacodynamic properties

Aceclofenac

Aceclofenac is a non-steroidal agent with marked anti-inflammatory and analgesic properties. The mode of action of Aceclofenac is largely based on the inhibition to prostaglandin synthesis. Aceclofenac is a potent inhibitor of the enzyme cyclo-oxygenase, which is involved in the production of prostaglandins. Aceclofenac relieves pain and inflammation through a variety of mechanisms and in addition exerts stimulatory effects on cartilage matrix synthesis.

Anti-inflammatory activity

The anti-inflammatory effects of Aceclofenac have been shown in both acute and chronic inflammation. It inhibits various mediators of pain and inflammation including :

• PGE2 via cyclooxygenase inhibition (COX-1 and COX-2) after intracellular metabolism to 4-hydroxyaceclofenac and diclofenac in human rheumatoid synovial cells and other inflammatory cells.

• IL-1β, IL-6 and tumor necrosis factor in human osteoarthritic synovial cells and human articular chondrocytes.

• Reactive oxygen species (which plays a role in joint damage) has also been observed in patients with osteoarthritis of knee.

• Expression of cell adhesion molecules (which is implicated in cell migration and inflammation) has also been shown in human neutrophils.

Stimulatory effects on cartilage matrix synthesis

Aceclofenac stimulates glycosaminoglycan synthesis in human osteoarthritic cartilage by inhibition of IL-1 and suppresses cartilage degeneration by inhibiting IL-1 mediated promatrix metalloproteinase production and proteoglycan release.

Paracetamol

Paracetamol is an aniline derivative with analgesic and antipyretic actions similar to those of Aspirin but with no demonstrable anti-inflammatory activity. Paracetamol is less irritant to the stomach than Aspirin. It does not affect thrombocyte aggregation or bleeding time. Paracetamol is generally well tolerated by patients hypersensitive to Acetylsalicylic acid.

Analgesic action

The central analgesic action of Paracetamol resembles that of Aspirin. It produces analgesia by raising pain threshold

Antipyretic effect

The antipyretic effect of Paracetamol is attributed to its ability to inhibit COX in the brain where peroxide tone is low. Recent evidence suggests inhibition of COX-3 (believed to be splice variant product of the COX-1 gene) could represent a primary central mechanism by which Paracetamol decreases pain and possibly fever.

5.2 Pharmacokinetic properties

Aceclofenac

Absorption

After oral administration, Aceclofenac is rapidly and completely absorbed as unchanged drug. Peak plasma concentrations are reached approximately 1.25 to 3.00 hours following ingestion.

Distribution

Aceclofenac penetrates into the synovial fluid, where the concentrations reach approximately 57% of those in plasma. The volume of distribution is approximately 25 L. Aceclofenac is highly protein- bound (> 99%). Aceclofenac circulates mainly as unchanged drug.

Metabolism

4'hydroxyaceclofenac is the main metabolite detected in plasma.

Elimination

The mean plasma elimination half-life is around 4 hours. Approximately two-thirds of the administered dose is excreted via the urine, mainly as hydroxymetabolites.

Paracetamol

Absorption

Paracetamol is well absorbed by oral route. The plasma half-life is about 2 hours.

Distribution

Plasma protein binding is negligible at usual therapeutic concentration but increases with increasing concentrations. Acetaminophen is relatively uniformly distributed throughout most body fluids. The plasma half-life is (t1/2) 2 - 3 hours and the effect after oral dose lasts for 3 - 5 hours.

Metabolism

Paracetamol is primarily metabolized in the liver by conjugation to glucuronide and sulphate. A small amount (about 3 - 10% of a therapeutic dose) is metabolized by oxidation and the reactive intermediate metabolite thus formed is bound preferentially to the liver glutathione and excreted as cysteine and mercapturic acid conjugates.

Elimination

Excretion occurs via the kidneys. 2 - 3% of a therapeutic dose is excreted unchanged; 80 - 90% as glucuronide and sulphate and a smaller amount as cystein and mercapturic acid derivatives.

6.1 Animal toxicology or pharmacology

The results from preclinical studies conducted with Aceclofenac are consistent with those expected for NSAIDs. The principal target organ was the gastro-intestinal tract. No unexpected findings were recorded. Aceclofenac was not considered to have any mutagenic activity in three in vitro studies and an in vivo study in the mouse. Aceclofenac was not found to be carcinogenic in either the mouse or rat. Animal studies indicate that there was no evidence of teratogenesis in rats although the systemic exposure was low and in rabbits treatment with Aceclofenac (10 mg/kg/day) resulted in a series of morphological changes in some fetuses.

Mahadol is a fixed dose combination of Aceclofenac 100 mg and Paracetamol 325 mg. This combination offers the advantage of peripheral effects of Aceclofenac and Central effect of Paracetamol for pain management. Aceclofenac is an orally administered Phenylacetic acid derivative with effects on a variety of inflammatory mediators. Through its analgesic and anti-inflammatory properties, Aceclofenac provides symptomatic relief in a variety of painful conditions. Due to its preferential COX-2 blockade, it has better safety than conventional NSAIDs with respect to adverse effects on gastrointestinal and cardiovascular system. Paracetamol acts predominantly by inhibiting prostaglandin synthesis in the central nervous system and to lesser extent, through a peripheral action by blocking pain impulse generation. Paracetamol is one of the effective mild analgesics, suitable for treating mild to moderate pain.

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

Alu-Alu blister strip of 10 tablets.

8.4 Storage and handing instructions

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

Keep out of reach of children.

• You have been prescribed this combination medicine for relieving pain and inflammation.

• Take Mahadol Tablet it with food to avoid getting an upset stomach.

• Do not take Mahadol Tablet with any other medicine containing Paracetamol (drugs for pain/fever or cough-andcold) without asking your doctor first.

• It may cause dizziness and sleepiness. Do not drive or do anything that requires mental focus until you know how it affects you.

• Avoid consuming alcohol when taking Mahadol Tablet as it may cause excessive drowsiness and increase the risk of liver damage.

• In case of muscle pain, your doctor might advise you to undergo physiotherapy to get relief along with taking Mahadol Tablet.

• Inform your doctor if you have a history of stomach ulcers before taking this medicine