Diclofenac Diethylamine Transdermal Patch

Each 50 cm2 Transdermal Patch contains:

Diclofenac Diethylamine IP 100 mg

Transdermal Patch

Diclofenac Diethylamine 100 mg/50 cm²

FOR EXTERNAL USE ONLY

4.1 Therapeutic indications

DicloPLAST® is indicated for the treatment of mild to moderate pain due to osteoarthritis or soft tissue injury.

4.2 Posology and method of administration

Adults and adolescents from 16 years

One Patch to be applied for one day or as directed by the physician

Duration of use

DicloPLAST® is for short-term treatment. The duration of use should not exceed 7 days. The therapeutic benefit of longer use has not been established.

If there is no improvement, during the recommended duration of treatment or a worsening of symptoms, a doctor should be consulted.

DicloPLAST® is to be used for the shortest duration necessary to control symptoms depending on the indication.

Elderly patients and patients with renal or hepatic impairment

This medication should be used with caution in elderly patients who are more prone to adverse events.

Paediatric population

Safety and effectiveness of DicloPLAST® has not been established in pediatric patients.

Method of administration

Cutaneous (Transdermal) use only.

Instructions for using DicloPlast Transdermal Patch:

• DicloPLAST® should be applied on non-hairy area.
• DicloPLAST® should be applied only to intact non-diseased skin and should not be worn when bathing or showering.
• Clean the application area with water & dry it before applying DicloPLAST®.
• Do not cut DicloPLAST®. This may reduce the efficacy.
• If necessary, the medicated patch can be held in place using a net bandage.
• The DicloPLAST® must not be used together with an occlusive dressing.

4.3 Contraindications

• Hypersensitivity to the active substance or to any of the excipients.
• In patients with hypersensitivity to acetylsalicylic acid or other non-steroidal anti-
• inflammatory drugs [NSAIDs].
• In patients who have previously experienced asthma, angioedema, urticaria or acute rhinitis
• when taking acetylsalicylic acid or any other NSAIDs.
• In patients with active peptic ulcer.
• On damaged skin, whatever the lesion involved: exudative dermatitis, eczema, infected
• lesion, burn or wound.
• During the last trimester of pregnancy.
• Children: The use in children is contraindicated.

4.4 Special warnings and precautions for use

DicloPLAST® must not come into contact with or be applied to the eyes or mucous membranes. It should be applied only to intact non-diseased skin, and not to skin wounds or open injuries. Topical diclofenac can be used with non-occlusive bandages but should not be used with an airtight occlusive dressing. Undesirable effects can be reduced by using the lowest effective dose for the shortest possible period of time. Bronchospasm can occur in patients who suffer or have previously suffered from bronchial asthma or allergies. Treatment must be stopped immediately if a skin rash develops after applying the medicated patches. Patients should be warned against exposure to sunlight or solarium radiation after removal of the DicloPLAST® in order to reduce the risk of photosensitisation. The possibility of systemic adverse events from application of diclofenac medicated patch cannot be excluded if the preparation is used on large areas of skin and over a prolonged period. Although the systemic effects are expected to be minimal, the medicated patch should be used with caution in patients with impaired renal, cardiac or hepatic function, or a history of peptic ulcer, inflammatory bowel disease or haemorrhagic diathesis. Non-steroidal anti-inflammatory drugs should be used with caution in elderly patients as they are more likely to experience undesirable effects. No other medicinal products containing diclofenac or any other non-steroidal anti-inflammatory drugs (NSAIDs) should be used concomitantly, neither topically nor systemically. Paediatric population DicloPLAST® is not recommended for use in children.

4.5 Drug Interactions

Non-steroidal anti-inflammatory drugs may interact with blood pressure lowering drugs, and may possibly enhance the effects of anticoagulants, although the chance of either of these occurring with a topically administered preparation is extremely remote. Concurrent aspirin or other NSAIDs may result in an increased incidence of adverse reactions. Since systemic absorption of diclofenac during labelled use of the DicloPLAST® is very low, the risk of developing clinically relevant drug-drug interactions is negligible.

4.6 Use in special populations

Fertility

There are no data available on the use of topical formulations of diclofenac and its effects on fertility in humans. The systemic concentration of diclofenac is lower after topical administration, compared to oral formulations. As for other NSAIDs, the oral use of diclofenac may impair female fertility and is not recommended in women attempting to conceive.

Pregnancy

As the safety of Diclofenac in pregnant women has not been established large dose or long-term use of this drug in pregnant women should be avoided.

The systemic concentration of diclofenac is lower after topical administration, compared to oral formulations. With reference to experience from treatment with pharmaceutical forms with systemic uptake, the following is recommended:

Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1%, up to approximately 1.5 %. The risk is believed to increase with dose and duration of therapy. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryo-foetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period.

During the first and second trimester of pregnancy, diclofenac should not be given unless clearly necessary. If diclofenac is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to:

• cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
• renal dysfunction, which may progress to renal failure with oligo-hydroamniosis; the mother and the neonate, at the end of pregnancy, to:
• possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses.
• inhibition of uterine contractions resulting in delayed or prolonged labour. Consequently, diclofenac is contraindicated during the third trimester of pregnancy.

Breastfeeding

Like other NSAIDs, diclofenac is excreted into breast milk in small amounts. However, at therapeutic doses of diclofenac medicated patches no effects on the suckling child are anticipated.

Because of a lack of controlled studies in lactating women, the product should only be used during lactation under advice from a healthcare professional. Under this circumstance, DicloPLAST® should not be applied on the breasts of nursing mothers, nor elsewhere on large areas of skin or for a prolonged period of time.

4.7 Effects on ability to drive and use machines

DicloPLAST® has no influence on the ability to drive and use machines.

4.8 Undesirable effects

The following frequency categories are used for reporting undesirable effects:

Systemic plasma diclofenac levels measured during labelled use of the transdermal patches are very low compared to those obtained after oral intake of diclofenac. The risk of developing systemically induced side effects (like gastric, hepatic and renal disorders) during use of the patch therefore appears to be low. However, in particular when the transdermal patch is used on a large area of skin and over a prolonged period of time, systemic side effects may 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
• Website: https://www.zuventus.com/drug-safety-reporting

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

4.9 Overdose

The low systemic absorption of topical diclofenac renders overdoses unlikely. Should significant systemic undesirable effects occur following incorrect use or accidental overdose (e.g. in children), the precautions appropriate for poisoning with non-steroidal anti-inflammatory drugs should be taken.

Pharmacotherapeutic group: Topical products for joint and muscular pain; Anti-inflammatory preparations, non-steroids for topical use ATC code: M02AA15

5.1 Mechanism of Action

Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID). In pharmacologic studies, diclofenac has shown anti-inflammatory, analgesic, and antipyretic activity. As with other NSAIDs, its ability to inhibit prostaglandin synthesis, is involved in its anti-inflammatory activity, as well as contribute to its efficacy in relieving pain associated with inflammation.

5.2 Pharmacodynamic properties

DicloPLAST® Patch applied to intact skin provides local analgesia by releasing diclofenac Diethylamine from the patch into the skin.

5.3 Pharmacokinetic properties

Absorption

Diclofenac is absorbed slowly and incompletely from cutaneous formulations. The plasma concentrations of diclofenac at steady state are characterised by continuous absorption of diclofenac from the patch, regardless of whether the patch is applied in the morning or in the evening. Following cutaneous application, diclofenac may be absorbed into a dermal depot, from where it is released slowly into the central compartment. The systemic absorption of topical products is about 2-10% of that obtained with same dose administered orally. The mean peak plasma concentration is approximately 1 ng/ml. The observed therapeutic efficacy is mainly explained by therapeutically relevant drug tissue concentrations beneath the site of application. Penetration to the site of action may vary with the extent and nature of the condition and depending on the site of application and action.

Distribution

Plasma protein binding of diclofenac is high at 99%.

Biotransformation and Elimination

Metabolism and elimination are similar after cutaneous and oral use. Following rapid hepatic metabolism (hydroxylation and binding to glucuronic acid), ⅔ of the active substance is eliminated renally and ⅓ by the biliary route.

6.1 Animal Toxicology or Pharmacology

Non-clinical data based on conventional studies of safety pharmacology, genotoxicity and carcinogenic potential reveal no special hazards for humans beyond those already outlined in other sections of this prescribing information. In animal studies, chronic toxicity of diclofenac following systemic administration mainly manifested as gastrointestinal lesions and ulcers. In a 2-year toxicity study, rats treated with diclofenac showed a dose-related increase in thrombotic occlusion of the cardiac vessels.

In animal studies on reproductive toxicity, systemically administered diclofenac caused inhibition of ovulation in rabbits and impairment of implantation and early embryonic development in rats. The gestational period and duration of parturition were prolonged by diclofenac. The embryotoxic potential of diclofenac was studied in three animal species (rat, mouse, rabbit). Foetal death and growth retardation occurred at maternotoxic dose levels. Based on the available non-clinical data, diclofenac is regarded as non-teratogenic. Doses below the maternotoxic threshold had no impact on the postnatal development of the offspring.

Conventional studies on local tolerability reveal no special hazards for humans.

DicloPLAST® is a Diclofenac Diethylamine Transdermal Patch (50 cm2) is comprised of an adhesive material containing Diclofenac Diethylamine with a unique backing layer & polymer matrix. The release liner is removed prior to topical application to the skin. Each adhesive patch contains 100 mg of Diclofenac Diethylamine in an aqueous base.

Diclofenac Diethylamine is a non-opioid analgesic chemically designated as 2-[2-(2,6-dichloroanilino)phenyl]acetic acid;N-ethylethanamine, with a molecular formula of C18H22Cl2N2O2 (molecular weight 369.3 g/mol), and the following structure:

8.1 Incompatibilities

Not applicable

8.2 Shelf life

Refer on pack

8.3 Packaging information

3 Patches per Pouch (58 x 87 mm)

8.4 Storage and handling instructions

Store in a cool place below 30°C. Protect from light & moisture. Store in the original package in order to protect from desiccation and light. Keep the sachet tightly closed in order to protect from desiccation and light. Keep out of reach of children. Used patches should be folded in half, with the adhesive side inwards. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Advise the patient to read the patient information label, as well as the Directions for Use on the product packaging. Inform patients, families, or their caregivers of the following information before initiating therapy with DicloPLAST® and periodically during the course of ongoing therapy.

Cardiovascular Thrombotic Events

Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately. Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding.

Hepatotoxicity

Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, instruct patients to stop DicloPLAST® and seek immediate medical therapy.

Heart Failure and Edema

Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur.

Anaphylactic Reactions

Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur.

Serious Skin Reactions

Advise patients to stop DicloPLAST® immediately if they develop any type of rash and to contact their healthcare provider as soon as possible.

Female Fertility

Advise females of reproductive potential who desire pregnancy that NSAIDs, including DicloPLAST®, may be associated with a reversible delay in ovulation. Fetal Toxicity Inform pregnant women to avoid use of DicloPLAST® and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus.

Avoid Concomitant Use of NSAIDs

Inform patients that the concomitant use of DicloPLAST® with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy. Alert patients that NSAIDs may be present in "over the counter" medications for treatment of colds, fever, or insomnia.

Use of NSAIDS and Low-Dose Aspirin

Inform patients not to use low-dose aspirin concomitantly with DicloPLAST® until they talk to their healthcare provider.

Eye Exposure

Instruct patients to avoid contact of DicloPLAST® with the eyes and mucosa. Advise patients that if eye contact occurs, immediately wash out the eye with water or saline and consult a physician if irritation persists for more than an hour.

Special Application Instructions

• Instruct patients that, if DicloPLAST® begins to peel-off, the edges of the patch may be taped down. If problems with adhesion persist, patients may overlay the patch with a mesh netting sleeve, where appropriate (e.g. to secure patches applied to ankles, knees, or elbows). The mesh netting sleeve must allow air to pass through and not be occlusive (non-breathable).
• Instruct patients not to apply DicloPLAST® to non-intact or damaged skin resulting from any etiology e.g. exudative dermatitis, eczema, infected lesion, burns or wounds.
• Instruct patients not to wear a DicloPLAST® when bathing or showering.
• Instruct patients to wash hands after applying, handling or removing the patch.

Deflazacort Suspension 6 mg/ 5 ml

Each 5 ml of suspension contains:

Deflazacort 6 mg

Excipients q.s.

Colour: quinolone yellow

Oral Suspension, 6 mg/ 5 ml

Cortimax Suspension: a bottle of 30 ml

Cortimax-XL Suspension: a bottle of 60 ml

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 life-threatening 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.

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:  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.

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.

Deflazacort withdrawal

In patients who have received more than physiological doses of systemic corticosteroids (approximately 9 mg/day or equivalent) for > 3 weeks, 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 9 mg 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 > 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.

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.
• 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-pituitary-adrenal 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 (≥1/10 000 to <1/1000); very rare (<1/10 000), 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 anti-diabetic 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 co-administered with quinolones, myopathy (acute myopathy may be precipitated by non-depolarising 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

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

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

4.9. Overdose

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 anti-inflammatory 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

Refer on pack

3.Packaging information

Cortimax Suspension: a bottle of 30 ml

Cortimax-XL Suspension: a bottle of 60 ml

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.

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.

Behavioural 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.

Aluminium Hydroxide, Magnesium Hydroxide, Simethicone & Oxetacaine Suspension

Each 5 ml contains:

Dried Aluminium Hydroxide Gel IP 300 mg

(added as Aluminium Hydroxide Paste)

Magnesium Hydroxide IP 150 mg

(added as Magnesium Hydroxide Paste USP)

Simethicone IP 125 mg

Oxetacaine IP 10 mg

Excipients q.s.

In a flavoured syrup base

Oral Suspension

200 ml bottle

4.1 Therapeutic Indications

Ancool® is indicated for the treatment of symptoms of functional gastrointestinal disorders like irritable bowel syndrome, functional dyspepsia, peptic ulcer, gasteroesophagal reflux disease which include smooth muscle spasms, flatulence, abdominal distension, hyperacidity, gastric distress, bloating etc.

4.2 Posology and method of administration

For oral administration:

Adults

5-10 ml taken 20 minutes to 1 hour after meals and at bedtime or as required.

Children (>5yrs): As an appropriate proportion of the adult dose.

Children under 5 years: Maximum of 5ml three times a day.

Elderly: The normal adult dose is appropriate.

It is preferable to take it undiluted. However, a sip of water may be taken if desired.

4.3 Contraindications

Should not be used in patients who are hypersensitive to any of the active substances or excipients.

Patients are severely debilitated or suffering from kidney failure, or hypophosphataemia.

4.4 Special warnings and precautions for use

Aluminium hydroxide may cause constipation and magnesium salts overdose may cause hypomotility of the bowel; large doses of this product may trigger or aggravate intestinal obstruction and ileus in patients at higher risk such as those with renal impairment, or the elderly.

Aluminium hydroxide is not well absorbed from the gastrointestinal tract, and systemic effects are therefore rare in patients with normal renal function. However, excessive doses or long-term use, or even normal doses in patients with low-phosphorous diets, may lead to phosphate depletion (due to aluminium-phosphate binding) accompanied by increased bone resorption and hypercalciuria with the risk of osteomalacia. Medical advice is recommended in case of long-term use or in patients at risk of phosphate depletion.

In patients with renal impairment, plasma levels of both aluminium and magnesium increase. In these patients, a long-term exposure to high doses of aluminium and magnesium salts may lead to encephalopathy, dementia, microcytic anemia or worsen dialysis-induced osteomalacia.

Aluminium hydroxide may be unsafe in patients with porphyria undergoing hemodialysis. The prolonged use of antacids in patients with renal failure should be avoided.

Pediatric population: In young children the use of magnesium hydroxide can produce a hypermagnesemia, especially if they present renal impairment or dehydration.

If held in the mouth for a long time, Ancool® owing to its oxetacaine content may anesthetize the tongue and impair taste sensation.

4.5 Drug Interactions

Ancool® should not be taken simultaneously with other medicines as they may interfere with their absorption if taken within 1 hour.

Aluminium-containing antacids may prevent the proper absorption of drugs such as tetracyclines, vitamins, ciprofloxacin, ketoconazole, hydroxychloroquine, chloroquine, chlorpromazine, rifampicin, cefdinir, cefpodoxime, levothyroxine, rosuvastatin, H2 antagonists, atenolol, cyclines, diflunisal, digoxin, bisphosphonates, ethambutol, fluoroquinolones, sodium fluoride, glucocorticoids, indomethacin, isoniazid, lincosamides, metoprolol, phenothiazine neuroleptics, penicillamine,propranolol and iron salts.

Levothyroxine may also bind to simeticone which may delay or reduce the absorption of levothyroxine.

Polystyrene sulphonate

Caution is advised when used concomitantly with polystyrene sulphonate due to the potential risks of reduced effectiveness of the resin in binding potassium, of metabolic alkalosis in patients with renal failure (reported with aluminium hydroxide and magnesium hydroxide), and of intestinal obstruction (reported with aluminium hydroxide).

Quinidine:

Concomitant use of aluminium products with quinidines may increase the serum levels of quinidine and lead to quinidine overdosage.

Tetracycline:

Because of the aluminium content, Maalox Plus should not be concomitantly administered with tetracycline-containing antibiotics or any tetracycline salts.

Citrates:

Aluminium hydroxide and citrates may result in increased aluminium levels, especially in patients with renal impairment.

Urine alkalinisation secondary to administration of magnesium hydroxide may modify excretion of some drugs; thus, increased excretion of salicylates has been seen.

4.6 Use in Special Populations

The safety of Ancool® Suspension in pregnancy has not been established.

Pregnancy:

There are no available data on Ancool® use in pregnant women. No conclusions can be drawn regarding whether or not Maalox Plus is safe for use during pregnancy. Ancool® should be used during pregnancy only if the potential benefits to the mother outweigh the potential risks, including those to the fetus.

Lactation:

Because of the limited maternal absorption, when used as recommended, minimal amounts, if any, of aluminium hydroxide and magnesium salt combinations are expected to be excreted into breast milk.

Simeticone is not absorbed from the gastrointestinal tract.

No effect on the breastfed newborn/infant are anticipated since the systemic exposure of the breast-feeding woman to aluminium hydroxide, magnesium hydroxide and simeticone is negligible.

4.7 Effects on ability to drive and use machines

None stated.

4.8 Undesirable effects

The following CIOMS frequency rating is used, when applicable:

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 available data).

Immune system disorders

Frequency not known: hypersensitivity reactions, such as pruritus, urticaria, angioedema and anaphylactic reactions

Gastrointestinal disorders

Gastrointestinal side-effects are uncommon. Uncommon: diarrhoea or constipation Frequency not known: Abdominal pain

Injury, poisoning and procedural complications:

Frequency not known: Hyperaluminemia (related to Aluminium component).

Metabolism and nutrition disorders

Very rare: Hypermagnesemia, including observations after prolonged administration of magnesium hydroxide to patients with renal impairment

Frequency not known:

Hyperaluminemia

Hypophosphatemia, in prolonged use or at high doses or even normal doses of the product in patients with low-phosphorus diets which may result in increased bone resorption hypercalciuria, osteomalacia.

Oxetacaine

Glossitis of the hypersensitivity type, dizziness, faintness and drowsiness have occasionally occurred, especially when the recommended dose is exceeded.

Reporting of suspected adverse reactions

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

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

4.9 Overdose

Serious symptoms are unlikely following overdosage.

Reported symptoms of acute overdose with aluminium hydroxide and magnesium salts combination include diarrhoea, abdominal pain, vomiting.

Large doses of this product may trigger or aggravate intestinal obstruction and ileus in patients at risk.

Aluminium and magnesium are eliminated through urinary route; treatment of acute overdose consists of administration of IV Calcium Gluconate, rehydration and forced diuresis. In case of renal function deficiency, haemodialysis or peritoneal dialysis is necessary.

5.1 Mechanism of Action

Dried aluminium hydroxide gel - antacid Magnesium Hydroxide - antacid Simeticone - antifoaming agent/anti-flatulent Oxetacaine: potent gastric mucosal anaesthetic agent The antacids that act by neutralizing the acid in the stomach and by inhibiting pepsin,

which is a proteolytic enzyme.

5.2 Pharmacodynamic properties

Ancool® is a balanced mixture of two antacids, an anti-flatulent/antifoaming agent simeticone and a potent gastric mucosal anaesthetic agent oxetacaine. The two antacids are magnesium hydroxide which is fast acting and aluminium hydroxide which is a slow acting antacid. The combination produces a fast onset of action and an increase in total buffering time. Aluminium hydroxide on its own is an astringent and may cause constipation. This effect is balanced by the effect of the magnesium hydroxide which is in common with other magnesium salts may cause diarrhoea.

Oxetacaine is a potent local anaesthetic agent and provides prompt relief to the pain in acutely inflamed gastric mucosa.

Simethicone is a surfactant that may decrease foaming and hence esophageal reflux. It is included in many antacid preparations for the management of flatulence. Simethicone acts by decreasing the surface tension of gas bubbles, thus facilitating their coalescence and expulsion as flatus or belching. Simethicone facilitates the passage of gas through bowel lumen and allows patients to excrete a greater volume of gas at one time, thereby reducing the number of flatus events. Thus, less residual gas is present to cause uncomfortable or painful pressure in the stomach and intestines.

5.3 Pharmacokinetic Properties

Aluminium hydroxide, when given by mouth most of it remains in the gastrointestinal tract forming insoluble, poorly absorbable aluminium salts such as hydroxide, carbonates and phosphates which are excreted in the feces.

Magnesium hydroxide is a quick acting antacid and its action is for prolonged duration. In the stomach, magnesium hydroxide combines with gastric acid to form magnesium chloride. In the small intestine, magnesium hydroxide is regenerated and excreted in feces. In contrast to almost all other local anaesthetic, oxetacaine ionizes only to a very small extent at a low pH, such as that of gastric acid. Since the anesthetic effect is due to the non-ionized molecules, which are lipid soluble and can penetrate nerve membranes,

oxetacaine maintains its activity even at low pH. Normally oxetacaine when administered alone is absorbed into blood, metabolized in the liver and excreted in the urine. But when given with aluminium and magnesium hydroxide, its absorption is retarded and hence it remains in contact with gastric mucosa for longer time.

In course of time, it mixes with the food and passes into intestine. However, the concentration obtained there is probably so low that no effect is produced on intestinal mucosa.

6.1 Animal toxicology or Pharmacology

Not available

Pharmacotherapeutic group: Drugs for acid related disorders; Antacids with antiflatulent.   Ancool is a combination of Oxetacaine, Aluminium Hydroxide, Magnesium Hydroxide and Simethicone. Oxetacaine is a local anaesthetic agent. Aluminium hydroxide and Magnesium hydroxide are antacids. Simethicone is liquid dimethicone activated with finely divided silicon dioxide to enhance the defoaming properties of the silicone.

8.1 List of excipients

Carboxymethylcellulose Sodium, Saccharin Sodium, Bronopol, Menthol, Liquid Sorbitol (Non Crystallising), Sodium Citrate, Propylene Glycol, Sorbitan Stearate, Citric Acid Monohydrate, Flavour Coolmints , Glycerol, Polysorbate 20.

8.2 Incompatibilities

Not available

8.3 Shelf life

24 Months

8.4 Packaging information

Bottle PET Transparent [200 ml] with silver cap & measuring cup 10 ml.

8.5 Storage and handling instructions

Store below 30°C, Protected from light. Keep out of reach of children. Shake Well Before Use. Store in tightly closed container and avoid freezing.

If held in the mouth for a long time, Ancool® owing to its oxetacaine content may anesthetize the tongue and impair taste sensation.

Do not take Ancool® Suspension at least 2 hours before or after taking other medicines as it may interact with other medications.

Avoid eating late at night or before bedtime.

Avoid taking Tea, Coffee, Spicy food, and Chocolate.

Avoid alcohol and smoking.

Ancool® Suspension may cause constipation. Drink plenty of water and eat more high-fiber foods. Inform your doctor if it becomes severe or does not go away.

It may take 4-6 weeks or more for the ulcers to heal completely. Do not stop taking the medicine without talking to your doctor first. 

It may take 4-6 weeks or more for the ulcers to heal completely. Do not stop taking the medicine without talking to your doctor first. 

S (+) Etodolac and Paracetamol Tablets (200mg + 325mg)

Each uncoated tablet contains:

S (+) Etodolac 200 mg

Paracetamol IP 325 mg

Excipients q.s

Tablet

200 mg of S (+) Etodolac and 325 mg of Paracetamol

4.1 Therapeutic indication

For the symptomatic treatment of acute pain and inflammation in patients with osteoarthritis, rheumatoid arthritis and ankylosing spondylitis.

4.2 Posology and method of administration

Adults: One tablet two times daily orally.

Paediatric population: Not recommended.

Method of administration: For oral administration.

To be taken preferably with or after food. Swallow the tablet whole with a glass of water.

4.3 Contraindications

• Patients with known hypersensitivity to S (+) Etodolac and/or Paracetamol.
• Patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs.
• Patients with severe hepatocellular insufficiency
• Setolac®-P Tablets should not be used in patients with active or history of recurrent peptic ulceration or a history of peptic ulcer disease (with two or more distinct episodes of proven ulceration or bleeding).
• During the last trimester of pregnancy.
• Patients with hepatic failure, active liver disease and renal failure.
• Setolac®-P tablet is not recommended for pediatric use.

4.4 Special warnings and precautions for use

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms.

The use of Setolac®-P Tablets with concomitant NSAIDs including cyclooxygenase-2-selective inhibitors should be avoided.

Cardiovascular and Cerebrovascular Effects

COX-2 selective and non-selective NSAIDs have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV events in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. NSAIDs, including Etodolac, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy. Fluid retention and edema have been observed in some patients taking NSAIDs. Setolac®-P tablets should be used with caution in patients with fluid retention or heart failure.

Pre-existing Asthma

Patients with asthma may have Aspirin-sensitive asthma. Since cross reactivity, including bronchospasm, between Aspirin and other NSAIDs has been reported in such Aspirin-sensitive patients, Setolac®-P tablets should not be administered to patients with this form of Aspirin sensitivity and should be used with caution in patients with pre-existing asthma.

Renal Effects

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. In these patients, administration of a NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. No information is available from controlled clinical studies regarding the use of S (+) Etodolac extended-release tablets in patients with advanced renal disease. Therefore, treatment with Setolac®-P tablets is not recommended in these patients with advanced renal disease.

Hepatic Effects

Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including S (+) Etodolac. Owing to the presence of Paracetamol, Setolac®-P tablets should be used with caution in patients with hepatocellular insufficiency or non-cirrhotic alcoholic liver disease. Impairment of renal or hepatic functions due to other causes may alter drug metabolism; patients receiving concomitant long term therapy, especially the elderly, should be observed for potential side effects and their drug doses adjusted as needed, or the drug discontinued.

Gastrointestinal Effects

NSAIDs, including Etodolac, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. Setolac®-P tablets should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. To minimize the potential risk for an adverse GI event in patients, the lowest effective dose should be used for the shortest possible duration. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population

Hematological Effects

Anemia is sometimes seen in patients receiving NSAIDs, including Etodolac, due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including Etodolac, should have their hemoglobin or haematocrit checked if they exhibit any signs or symptoms of anemia. NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Patients receiving Setolac®-P tablets who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.

SLE and mixed connective tissue disease:

In patients with systemic lupus erythematous (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 (see section 4.8). 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. Tablets should be discontinued at the first appearance of the skin rash, mucosal lesions, or any other sign of hypersensitivity

Anaphylactoid Reactions

As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to Etodolac. Setolac®-P tablets should not be given to patients with the Aspirin triad.

Other Precautions

• S (+) Etodolac cannot be expected to substitute corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation.
• The pharmacological activity of Setolac®-P in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.
• Setolac®-P tablets should be used with caution in patients with severe renal insufficiency (creatinine clearance 30 mL/min), Glucose-6-Phosphate Dehyrogenase (G6PD) deficiency, chronic alcoholism, excessive alcohol intake (3 or more alcoholic drinks every day), anorexia, bulimia or cachexia; chronic malnutrition (low reserves of hepatic glutathione), dehydration, and hypovolemia.

4.5 Drug interactions

ACE inhibitors: Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors.

Aspirin: When Etodolac is administered with Aspirin, its protein binding is reduced, although the clearance of free Etodolac is not altered.

Busulfan: Busulfan is eliminated from the body via conjugation with Glutathione. Concomitant use with Paracetamol may result in reduced Busulfan clearance.

Other analgesics including cyclooxygenase-2 selective inhibitor: Avoid concomitant use of two or more NSAIDs (including aspirin) as this may increase the risk of adverse effects (see section 4.4)

Anti-hypertensives: Reduced anti-hypertensive effect

Diuretics: Etodolac can reduce the natriuretic effect of furosemide and thiazides in some patients with possible loss of blood pressure control. Caution should be paid to the concomitant intake of enzyme-inducing agents. Induction of metabolism of Paracetamol from enzyme inducers may result in an increased level of hepatotoxic metabolites. 

Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.

Lithium: NSAIDs have produced an elevation of plasma Lithium levels and a reduction in renal Lithium clearance. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and Lithium are administered concurrently, subjects should be observed, carefully for signs of Lithium toxicity.

Cyclosporin, Digoxin, Methotrexate: Etodolac, like other NSAIDs, through effects on renal prostaglandins, may cause changes in the elimination of these drugs leading to elevated serum levels of Cyclosporine, Digoxin, Methotrexate, and increased toxicity. Nephrotoxicity associated with Cyclosporine may also be enhanced. Concomitant diflunisal increases Paracetamol plasma concentrations and this may increase hepatotoxicity.

Anti-coagulants: NSAIDs may enhance the effects of anti-coagulants, such as warfarin (see section 4.4)

Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs): Increased risk of gastrointestinal bleeding (see section 4.4)

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 an evidence of an increased risk of haemarthroses and haemtoma in HIV (+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.

Bilirubin tests can give a false positive result due to the presence of phenolic metabolites of Setolac®-P Tablets in the urine.

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 (see section 4.4)

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.

Phenylbutazone: Phenylbutazone causes increase (by about 80%) in the free fraction of Etodolac though the clinical implication of the same is not known.

Cholestyramine: The speed of absorption of paracetamol is reduced by cholestyramine. Therefore, the cholestyramine should not be taken within one hour if maximal analgesia is required.

Metoclopramide and Domperidone: The absorption of paracetamol is increased by metoclopramide and domperidone. However, concurrent use need not be avoided.

Warfarin: The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular use of paracetamol with increased risk of bleeding; occasional doses have no significant effect.

Chloramphenicol: Increased plasma concentration of chloramphenicol.

Phenytoin: Administered concomitantly may result in decreased Paracetamol effectiveness and an increased risk of hepatotoxicity.

Probenecid: Causes an almost 2-fold reduction in clearance of Paracetamol by inhibiting its conjugation with Glucuronic acid.

Salicylamide: May prolong the amount of time Paracetamol stays in the body.

4.6 Use in special populations

Fertility:

The use of Setolac®-P Tablets may impair female fertility and is not recommended in woman attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of Setolac®-P Tablets should be considered.

Pregnancy:

In teratology studies, isolated occurrences of alterations in limb development were found and included polydactyly, oligodactyly, syndactyly, and unossified phalanges in rats and oligodactyly and synostosis of metatarsals in rabbits. Drugs which inhibit prostaglandin biosynthesis may cause dystocia and delayed parturition as evidenced by studies in pregnant animals. 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, some inhibitors of prostaglandin biosynthesis have been shown to interfere with the risk of closure of the ductus arteriosus, use in the last trimester of pregnancy is contraindicated. The onset of labour may be delayed and the duration increased with an increased bleeding tendency in both mother and child.

From the 20th week of pregnancy onward, etodolac use may cause oligohydramnios resulting from foetal renal dysfunction. This may occur shortly after treatment initiation and is usually reversible upon discontinuation. In addition, there have been reports of ductus arteriosus constriction following treatment in the second trimester, most of which resolved after treatment cessation. Therefore, during the first and second trimester of pregnancy, etodolac should not be given unless clearly necessary. If etodolac is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible. Antenatal monitoring for oligohydramnios and ductus arteriosus constriction should be considered after exposure to etodolac for several days from gestational week 20 onward. Etodolac should be discontinued if oligohydramnios or ductus arteriosus constriction are found.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to:

- cardiopulmonary toxicity (premature constriction/closure of the ductus arteriosus and pulmonary hypertension);

- renal dysfunction (see above); the mother and the neonate, at the end of pregnancy, to:

- possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses.

- inhibition of uterine contractions resulting in delayed or prolonged labour.

Consequently, etodolac is contraindicated during the third trimester of pregnancy.

Lactation:

It is not known whether Setolac®-P is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from S (+) Etodolac, 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

Pediatric use:

Safety and effectiveness in pediatric patients below the age of 18 years have not been established.

Geriatric use:

As with any NSAID, caution should be exercised in treating the elderly (65 years and older) and when increasing the dose. Elderly patients may be more sensitive to the anti-prostaglandin effects of NSAIDs (on the gastrointestinal tract and kidneys) than younger patients. In particular, elderly or debilitated patients who receive NSAID therapy seem to have a lower tolerance for gastrointestinal ulceration or bleeding as compared to other individuals, and most spontaneous reports of fatal GI events are in this population. S (+) Etodolac is eliminated primarily by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

4.7 Effects on ability to drive and use machines

Setolac®-P may cause dizziness. So, you should not drive or operate heavy machinery if you feel dizzy or not fully alert.

4.8 Undesirable effects

Most frequently reported adverse reactions (approx. 1 - 10%):

Gastrointestinal experiences including: abdominal pain, constipation, diarrhea, dyspepsia, flatulence, gross bleeding / perforation, heartburn, nausea, GI ulcers (gastric / duodenal), vomiting.

Other events including: abnormal renal function, anemia, dizziness, edema, elevated liver enzymes, headaches, increased bleeding time, pruritis, rashes, tinnitus.

Additional NSAID Adverse Experiences Reported Occasionally with Body as a whole: Allergic reaction, anaphylactic / anaphylactoid reactions (including shock), chills, fever, sepsis.

Digestive system: Anorexia, cholestatic hepatitis / jaundice, dry mouth, duodenitis, esophagitis, gastritis, gastric peptic ulcers, glossitis, hepatic failure, hepatitis, hematemesis, intestinal ulceration, jaundice, liver necrosis, melena, pancreatitis, rectal bleeding, stomatitis. Less frequently, gastritis has been observed. Pancreatitis has been reported very rarely.

Hypersensitivity: Hypersensitivity reactions have been reported following treatment with NSAIDs. These may consist of (a)non-specific allergic reactions and anaphylaxis (b)respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea, or (c)assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura, angioedema and more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).

Cardiovascular and cerebrovascular:

Congestive heart failure, flushing, palpitations, tachycardia, syncope, vasculitis (including necrotizing and allergic). Oedema, hypertension and cardiac failure have been reported in association with NSAID treatment Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with an increased risk of arterial thrombotic events (for example myocardial infarction or stroke).

Hepatic: 

Abnormal liver function, hepatitis and jaundice Metabolic and nutritional:

Hyperglycemia in previously controlled diabetic patients.

Neurological and special senses: Visual disturbances, photophobia, blurred vision, optic neuritis, headaches, paraethesia, reports of aseptic meningitis (especially in patients with existing auto-immune disorders, such as systemic lupus erythematous, mixed connective tissue disease), with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation (See section 4.4), depression, confusion, hallucinations, tinnitus, vertigo, dizziness, malaise, fatigue and drowsiness. Anxiety, confusion, depression, dream abnormalities, insomnia, nervousness, paresthesia, somnolence, tremors, vertigo.

Blood and lymphatic system:

Agranulocytosis, ecchymosis, eosinophilia, hemolytic anemia, leukopenia, neutropenia, pancytopenia, purpura, thrombocytopenia and aplastic anaemia. There have been reports of blood dyscrasias including methaemoglobenaemia and agranulocytosis, but these were not necessarily causality related to paracetamol.

Respiratory system:

Asthma, dyspnea, pulmonary infiltration with eosinophilia.

Dermatological: 

Bullous reactions including Stevens Johnson Syndrome and Toxic Epidermal Necrolysis (very rare). Photosensitivity. Angioedema, cutaneous vasculitis with purpura, erythema multiforme, hyperpigmentation, sweating, urticaria, vesiculobullous rash. Fixed drug eruption (FDE) is associated with Paracetamol use.

Urogenital system:

Dysuria, elevated BUN, oliguria / polyuria, proteinuria, renal failure, renal insufficiency, renal papillary necrosis, serum creatinine increase, urinary frequency, Nephrotoxicity in various forms, including interstitial nephritis, nephrotic syndrome.

Reporting of side effects

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: http://www.zuventus.co.in/safety.aspx By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

Etodolac

Symptoms include headache, nausea, vomiting, epigastric pain, gastro-intestinal bleeding, rarely diarrhoea, disorientation, excitation, coma, drowsiness, dizziness, tinnitus, fainting, occasionally convulsions. In cases of significant poisoning acute renal failure and liver damage are possible.

Management: 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 indigestion of a potentially life-threatening overdose. 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. Frequent or prolonged convulsions should be treated with intravenous diazepam. Other measures may be indicated by the patient's clinical condition. The standard practices of gastric lavage, activated charcoal administration and general supportive therapy should be undertaken.

Paracetamol

Symptoms of paracetamol over dosage in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose. In severe poisoning, hepatic failure may progress to encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema, and death. Acute renal failure with acute tubular necrosis, strongly suggested by loin pain, haematuria and proteinuria, may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported.

Management: Immediate treatment is essential in the management of paracetamol overdose. Despite a lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention. Symptoms may be limited to nausea or vomiting and may not reflect the severity of overdose or the risk of organ damage.

Treatment with activated charcoal should be considered if the overdose has been taken within 1 hour. Plasma paracetamol concentration should be measured at 4 hours or later after ingestion (earlier concentrations are unreliable). Treatment with N-acetylcysteine may be used up to 24 hours after ingestion of paracetamol however, the maximum protective effect is obtained up to 8 hours post ingestion. If required the patient should be given intravenous-N-acetylcysteine, in line with the established dosage schedule. If vomiting is not a problem, oral methionine may be a suitable alternative for remote areas, outside hospital.

Management of patients who present with serious hepatic dysfunction beyond 24 hours from ingestion should be discussed with the NPIS or a liver unit

5.1 Mechanism of Action

S (+) Etodolac is the pharmacologically active component of racemate Etodolac. The anti-inflammatory, analgesic, and antipyretic activities of S (+) Etodolac have been observed to be due to inhibition of cyclooxygenase-2 (COX-2) resulting in inhibition of prostaglandin synthesis.

The precise mechanism of the analgesic and antipyretic properties of Paracetamol has yet to be established. It acts both centrally as well as peripherally. Paracetamol is an antipyretic with good analgesic property.

5.2 Pharmacodynamic properties

Etodolac

Inhibition of prostaglandin synthesis and COX-2 selectivity: All non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to inhibit the formation of prostaglandins. It is this action which is responsible both for their therapeutic effects and some of their side-effects. The inhibition of prostaglandin synthesis observed with etodolac differs from that of other NSAIDs. In an animal model at an established anti-inflammatory dose, cytoprotective PGE concentration in the gastric mucosa have been shown to be reduced to a lesser degree and for a shorter period than other NSAIDs. This finding is consistent with subsequent in-vitro studies which have found etodolac to be selective for induced cyclo-oxygenase 2 (COX-2, associated with inflammation) over COX-1 (cytoprotective).

Furthermore, studies in human cell models have confirmed that etodolac is selective for the inhibition of COX-2.

The clinical benefit of preferential COX-2 inhibition over COX-1 has yet to be proven.

Anti-inflammatory effects: Experiments have shown etodolac to have marked anti-inflammatory activity, being more potent than several clinically established NSAIDs.

Paracetamol

Analgesic – The mechanism of analgesic action has not been fully determined. Paracetamol may act predominantly by inhibiting prostaglandin synthesis in the central nervous system (CNS) and to a lesser extent, through a peripheral action by blocking pain-impulse generation. The peripheral action may also be due to inhibition of prostaglandin synthesis or to inhibition of the synthesis or actions of other substances that sensitise pain receptors to mechanical or chemical stimulation.

Antipyretic – Paracetamol probably produces anti-pyresis by acting centrally on the hypothalamic heat-regulation centre to produce peripheral vasodilation resulting in increased blood flow through the skin, sweating and heat loss. The central action probably involves inhibition of prostaglandin synthesis in the hypothalamus.

5.3 Pharmacokinetic properties

S (+) Etodolac is well absorbed and does not undergo significant first-pass metabolism following oral administration. The extent of absorption of S (+) Etodolac is not affected after a meal. Food intake, however, reduces the peak concentration reached by approximately one-half and increases the time to peak concentration.

Paracetamol is well absorbed from the gastrointestinal tract in humans. The ingestion of food along with Paracetamol does not seem to affect its absorption.

6.1 Animal Toxicology or Pharmacology

Etodolac: Not Available

Paracetamol: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development. Conventional studies using the currently accepted standards for the evaluation of toxicity to reproduction and development are not available

(S)-etodolac is the S-enantiomer of etodolac. It is a preferential inhibitor of cyclo-oxygenase 2 and a non-steroidal anti-inflammatory, whereas the enantiomer, (R)-etodolac, is inactive. The racemate is commonly used for the treatment of rheumatoid arthritis and osteoarthritis, and for the alleviation of postoperative pain. Chemical Name: 2-[(1S)-1,8-diethyl-4,9-dihydro-3H-pyrano[3,4-b]indol-1-yl]acetic acid Molecular Formula: C17H21NO3 Molecular Weight: 287.35 g/mol

Structure:

Paracetamol is a well-established analgesic.

Chemical Name: N-(4-hydroxyphenyl)acetamide

Molecular Formula: C₈H₉NO₂

Molecular Weight: 151.2 g/mol

Structure:

8.1 Incompatibilities

None

8.2 Shelf life

Refer on the pack.

8.3 Packaging Information

PVC-Alu blister strip of 10 tablets

8.4 Storage and handling instructions

Store below 30ºC. Protect from light and moisture. Keep out of reach of children. Tablet should be swallowed whole & not to be broken, chewed or crushed.

Any unused product or waste material should be disposed of in accordance with local requirements.

• Take it with food to avoid getting an upset stomach.
• The drug should be taken precisely as it has been prescribed. Meant for oral consumption, Setolac®-P Tablet should be taken whole. Do not chew or crush it as it may reduce its effect on the body.
• It is best that you do not stop the medication mid-course as the pain may reoccur. Complete the entire treatment course for the best results.
• Avoid consuming alcohol when taking Setola®-P Tablet as it may cause excessive drowsiness and increase the risk of liver damage.
• Do not take it with any other medicine containing acetaminophen (drugs for pain / fever or cough-and-cold) without asking your doctor first.

Chlorpheniramine Maleate & Dextromethorphan Hydrobromide syrup

Each 5 ml Contains:

Dextromethorphan Hydrobromide IP 10 mg

Chlorpheniramine maleate IP 2 mg

Excipients q. s.

Colour: Sunset Yellow FCF

In a mentholated flavoured syrup base

Syrup

100 ml bottle

4.1 Therapeutic Indication

For the temporary relief of cough due to throat irritation, sneezing & running nose.

4.2 Posology and method of administration

2 to 5 years of age: 2.5 ml (1/2 teaspoonful) 3 to 4 times a day.

6 to 12 years of age: 5 ml (1 teaspoonful) 3 to 4 times a day.

Adult (> 12 years of age): 10 ml (2 teaspoonful) 3 to 4 times a day.

4.3 Contraindications

• Hypersensitivity to Chlorpheniramine, Dextromethorphan or to any component of the formulation.
• Receiving monoamine oxidase inhibitors [MAOIs] (drugs for depression, psychiatric or emotional conditions, or Parkinson's disease) with or within 2 weeks.
• Patients with risk of developing respiratory failure
• Acute Asthma
• Patient with liver disease
• Persistent or chronic productive cough

4.4 Special warnings and precautions for use

Chlorpheniramine maleate

This medicine should be given with caution to patients with epilepsy, severe cardiovascular disorders, liver disorders, renal impairment, glaucoma, urinary retention, prostatic enlargement, pyloroduodenal obstruction, asthma, bronchitis, bronchiectasis, thyrotoxicosis and severe hypertension.

Special care should be taken when using chlorpheniramine maleate in children and the elderly as they are more likely to experience the neurological anticholinergic effects and paradoxical excitation (e.g. Increased energy, restlessness, nervousness). Avoid use in elderly patients with confusion.

The anticholinergic properties of chlorphenamine may cause drowsiness, dizziness, blurred vision and psychomotor impairment in some patients which may seriously affect ability to drive and use machinery. The effects of alcohol may be increased and therefore concurrent use should be avoided.

Should not be used with other antihistamine containing products, including antihistamine containing cough and cold medicines.

Concurrent use with drugs which cause sedation such as anxiolytics and hypnotics may cause an increase in sedative effects, therefore medical advice should be sought before taking chlorphenamine concurrently with these medicines.

Dextromethorphan Hydrobromide

Dextromethorphan should not be given to patients at risk of developing respiratory failure. Caution is needed in patients with a history of asthma and it should not be given during an acute attack. Care is also advisable in patients with bronchitis, emphysema, or in other conditions where chronic or persistent cough occurs.

4.5 Drugs interactions

Chlorpheniramine maleate

This medicine may enhance the sedative effects of alcohol, hypnotics, anxiolytics, sedatives, opioid analgesics and neuroleptics.

The anti-muscarinic effects of chlorpheniramine are enhanced by other anti-muscarinic drugs and both anti-muscarinic and sedative effects are enhanced by monoamine oxidase inhibitors and tricyclic antidepressants.

Metabolism of phenytoin may be inhibited by chlorpheniramine with the possible development of phenytoin toxicity.

Dextromethorphan Hydrobromide

Monoamine Oxidase Inhibitors (MAOIs): Dextromethorphan should not be used concurrently in patients taking monoamine oxidase inhibitors (MAOIs) or within 14 days of stopping treatment with MAOIs as there is a risk of serotonin syndrome (pyrexia, hallucinations, gross excitation or coma, hypertension, arrhythmias).

CYP2D6 inhibitors: Dextromethorphan is metabolized by CYP2D6 and has an extensive first-pass metabolism. Concomitant use of potent CYP2D6 enzyme inhibitors can increase the dextromethorphan concentrations in the body to levels multi-fold higher than normal. This increases the patient's risk for toxic effects of dextromethorphan (agitation, confusion, tremor, insomnia, diarrhoea and respiratory depression) and development of serotonin syndrome. Potent CYP2D6 enzyme inhibitors include SSRIs such as fluoxetine and paroxetine, quinidine and terbinafine. In concomitant use with quinidine, plasma concentrations of dextromethorphan have increased up to 20-fold, which has increased the CNS adverse effects of the agent. Amiodarone, flecainide and propafenone, sertraline, bupropion, methadone, cinacalcet, haloperidol, perphenazine and thioridazine also have similar effects on the metabolism of dextromethorphan. If concomitant use of CYP2D6 inhibitors and dextromethorphan is necessary, the patient should be monitored and the dextromethorphan dose may need to be reduced.

CNS depressants: Dextromethorphan might exhibit additive CNS depressant effects when co-administered with alcohol, antihistamines, psychotropics, and other CNS depressant drugs.

4.6 Use in special populations

Pregnant Women

There are no adequate and well-controlled studies of this combination in pregnant women. There are no adequate controlled studies of chlorpheniramine in pregnant women and therefore should not be used during pregnancy. There are no adequate and well-controlled studies of Dextromethorphan in pregnant women. Dextromethorphan should not be used during pregnancy or lactation unless the potential benefit of treatment to the mother outweighs the possible risk to the developing foetus or nursing infant.

Caution is advised when Soventus®-DX Syrup is used during pregnancy.

Lactating Women

Chlorpheniramine may be secreted in breast milk. Hence, it is not recommended in nursing mothers because of the risk of adverse effects, such as unusual excitement or irritability in infants. Chlorpheniramine may also inhibit lactation. It is not known whether dextromethorphan or its metabolites are excreted in breast milk. 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.

Paediatric Patients

Safety and efficacy of this formulation in neonates and children below 2 years of age has not been established. Thus, Soventus®-DX Syrup is not recommended for use in paediatric patients below 2 years of age.

Geriatric Patients

The elderly patients taking Chlorpheniramine are more likely to experience neurological anticholinergic effects. Elderly patients with normal renal and hepatic function may be given the same dose as recommended for adults. Elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Renal Impairment Patients

Caution should be exercised while using Soventus®-DX syrup in patients with significant renal dysfunction. Dose should be reduced or the dosing interval must be extended in patients with severe renal impairment.

Hepatic Impairment Patients

In hepatic impairment, Soventus®-DX syrup should be used with caution.

4.7 Effects on ability to drive and use machines

Soventus®-DX Syrup may cause side effects which could affect your ability to drive. Chlorpheniramine may cause blurred vision, dizziness, drowsiness and interfere with human performance and therefore may seriously influence the ability to drive and operate machinery. Dextromethorphan can impair cognitive function and can affect a patient's ability to drive safely.

4.8 Undesirable Effects

Chlorpheniramine maleate

Adverse reactions identified during post-marketing use with chlorphenamine are listed below. As these reactions are reported voluntarily from a population of uncertain size, the frequency of some reactions is unknown but likely to be rare or very rare:

Children and the elderly are more susceptible to neurological anticholinergic effects and paradoxical excitation (e.g. increased energy, restlessness, nervousness)

Dextromethorphan Hydrobromide

ADRs are presented by frequency category based on 1) incidence in adequately designed clinical trials or epidemiology studies, if available, or 2) when incidence cannot be estimated, frequency category is listed as 'Not known’.

frequency category is listed as 'Not known’.

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 : http://www.zuventus.co.in/safety.aspx

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

4.9 Overdose

The estimated lethal dose of chlorphenamine is 25 to 50mg/kg body weight. Symptoms and signs include sedation, paradoxical excitation of the CNS, toxic psychosis, convulsions, apnoea, anticholinergic effects, dystonic reactions and cardiovascular collapse including arrhythmias. Symptomatic and supportive measures should be provided with special attention to cardiac, respiratory, renal and hepatic functions and fluid and electrolyte balance. If overdosage is by the oral route, treatment with activated charcoal should be considered provided there are no contraindications for use and the overdose has been taken recently (treatment is most effective if given within an hour of ingestion.) Treat hypotension and arrhythmias vigorously. CNS convulsions may be treated with i.v. diazepam. Haemoperfusion may be used in severe cases.

Dextromethorphan is thought to be of low toxicity, but the effects in overdosage will be potentiated by simultaneous ingestion of alcohol and psychotropic drugs. Symptoms of overdose may include mydriasis, nausea and vomiting, CNS depression, excitation, lethargy, nystagmus, psychomotor hyperactivity, serotonin syndrome, somnolence (drowsiness), dizziness, dysarthria (slurred speech), mental confusion, psychotic disorder (psychosis), and respiratory depression. Treatment should be symptomatic and supportive. Gastric lavage may be of use. Naloxone has Patients should be kept under observation and symptomatic and supportive treatment is advised. been used successfully to reverse central or peripheral opioid effects of dextromethorphan in children (0.01mg/kg body weight).

5.1 Mechanism of Action

Chlorpheniramine maleate

Chlorpheniramine is a first-generation alkylamine antihistamine. It is a less sedating H1 blocker with autonomic effects (anti-cholinergic action), used in the prevention of the symptoms of allergic conditions such as rhinitis.

Dextromethorphan Hydrobromide

Dextromethorphan (D-3-methoxy-N-methylmorphinan) is the D-isomer of the codeine analog methorphan. It is an antitussive drug and one of the active ingredients used to prevent coughs.

5.2 Pharmacodynamic properties

Chlorpheniramine maleate

Chlorphenamine is a potent antihistamine (H1-antagonist). Antihistamines diminish or abolish the actions of histamine in the body by competitive reversible blockade of histamine H1-receptor sites on tissues. Chlorphenamine also has anticholinergic activity. Antihistamines act to prevent the release of histamine, prostaglandins and leukotrienes and have been shown to prevent the migration of inflammatory mediators. The actions of chlorphenamine include inhibition of histamine on smooth muscle, capillary permeability and hence reduction of oedema and wheal in hypersensitivity reactions such as allergy and anaphylaxis.

Dextromethorphan Hydrobromide

Dextromethorphan is the dextrorotatory isomer of 3-methoxy-N-methyl-morphinan. It is a synthetic morphine derivative that, in contrast to its levo-rotatory isomer, has no significant analgesic, respiratory depressant or physical dependency properties at recommended doses.

Dextromethorphan is a non-opioid antitussive drug. It exerts its antitussive activity by acting on the cough centre in the medulla oblongata, raising the threshold for the cough reflex. The onset of antitussive effects are realised within 15 to 30 minutes of oral administration, lasting for approximately 3 to 6 hours.

The major metabolite of dextromethorphan, dextrorphan, binds with high affinity to σ-receptors to produce its antitussive activity without exhibiting the classic opiate effects that occur from binding into μ- and δ-receptors. Dextrorphan also exhibits binding activity at serotonergic receptors and was shown to enhance serotonin activity by inhibiting the reuptake of serotonin. In larger than therapeutic doses, dextrorphan is also an antagonist of N-methyl-D-aspartate (NMDA) receptors.

5.3 Pharmacokinetic properties

Chlorpheniramine maleate

Chlorpheniramine maleate is almost completely absorbed after administration by mouth, peak plasma concentrations occurring at about 2.5 to 6 hours. The drug is widely distributed including passage into the CNS, with a volume of distribution of between 1 and 10L/KG. About 70% of chlorpheniramine in the circulation is protein-bound. Chlorpheniramine undergoes some first pass metabolism and enterohepatic recycling. Chlorpheniramine is extensively metabolised, principally to inactive desmethylated metabolites which are excreted primarily in the urine, together with about 35% unchanged drug. Only trace amounts are excreted in the faeces. The mean elimination half-life has been reported to be about 30 hours, with mean values ranging from 2 to 43 hours.

Dextromethorphan Hydrobromide

Absorption: Dextromethorphan is rapidly absorbed from the gastrointestinal tract with peak plasma concentrations reached in approximately 2 to 2.5 hours. The low plasma levels of dextromethorphan suggest low oral bioavailability secondary to extensive first-pass (pre-systemic metabolism) in the liver. The maximum clinical effects occur 5 to 6 hours after ingestion of dextromethorphan.

Distribution: Dextromethorphan is widely distributed in the human body. Dextromethorphan and its active metabolite, dextrorphan, are actively taken up and concentrated in brain tissue. It is not known if dextromethorphan or dextrorphan are excreted in breast milk or cross the placenta.

Metabolism: Dextromethorphan undergoes rapid and extensive first-pass metabolism in the liver after oral administration. Genetically controlled O-demethylation (CYD2D6) is the main determinant of dextromethorphan pharmacokinetics in human volunteers. It appears that there are distinct phenotypes for this oxidation process resulting in highly variable pharmacokinetics between subjects. Unmetabolised dextromethorphan, together with the three demethylated morphinan metabolites dextrorphan (also known as 3-hydroxy-N-methylmorphinan), 3- hydroxymorphinan and 3-methoxymorphinan have been identified as conjugated products in the urine. Dextrorphan, which also has antitussive action, is the main metabolite. In some individuals metabolism proceeds more slowly and unchanged dextromethorphan predominates in the blood and urine.

Excretion: Dextromethorphan is primarily excreted via the kidney as unchanged parent drug and its active metabolite, dextrorphan. Dextrorphan and 3-hydroxy-morphinan are further metabolised by glucuronidation and are eliminated via the kidneys. The elimination half-life of the parent compound is between 1.4 to 3.9 hours; dextrorphan is between 3.4 to 5.6 hours. The half-life of dextromethorphan in poor metabolisers is extremely prolonged, in the range of 45 hours.

6.1 Animal Toxicology or Pharmacology

Chlorpheniramine maleate

The antihistaminic potency of chlorpheniramine is confined mainly to its (+)-isomer. The racemate is similarly or slightly more toxic because of the contribution of (-)-isomer. The toxicity may therefore be non-specific, perhaps attributable to local anaesthetic action and the toxic effects (excitation/sedation, coma, convulsions and death) resemble those of other classic H1antihistamines. Toxic doses may cause hypotension attributable to myocardial depression, an effect which is clearer with the (-)-isomer. The experimental data on the carcinogenicity and mutagenicity of chlorpheniramine indicate lack of these adverse effects, but the racemate and the (+)-isomer have shown some embryotoxicity in fertility tests. Effective antihistaminic concentrations of chlorpheniramine in vitro are about 1-10µg/L and oral doses of 0.2-1 mg/kg antagonise histamine-induced bronchospasm in guinea pigs.

Dextromethorphan Hydrobromide

General toxicology: Acute oral toxicity studies conducted with Dextromethorphan report the following LD50 values (mg/kg): mouse, 210 and rat, 116. Acute subcutaneous toxicity with Dextromethorphan reports the LD50 value (mg/kg): mouse, 112. Acute intravenous toxicity with Dextromethorphan reports the LD50 value (mg/kg): rat, 16.3.

Repeat dose toxicity studies conducted in rats for 13-week duration at doses up to 100 mg/kg and 27 weeks at 10 mg/kg, and of 14 weeks in dogs by oral gavage at doses up to 4 mg/kg on five days per week. The only effect recorded was of reduced body weight gain in the rat 13-week study at the highest dose.

Genetic Toxicology: Dextromethorphan hydrobromide was negative in the bacterial reverse mutation assay (Ames test). Dextromethorphan 39 mg/kg is reported to be negative in in-vivo mouse micronucleus test and comet assay. Dextromethorphan was reported to be negative in in vitro chromosome aberration assay tested up to 200 μg/ml.

Carcinogenicity: There are no known reports of animal carcinogenicity studies for Dextromethorphan. The overall weight of evidence for Dextromethorphan and its structural analogues, support the conclusion that this class of phenanthrene-based chemicals, and Dextromethorphan, in particular, are not genotoxic in vitro or in vivo

Teratogenicity: There was no association between dextromethorphan and malformations.

Fertility: Mating, gestation, fertility, littering and lactation were studied in rats at doses up to 50 mg/kg and no adverse effects were found.

Each 5 ml of Soventus®-DX syrup contains 10 mg of Dextromethorphan hydrobromide and 2 mg of chlorpheniramine maleate for oral administration.

Chlorpheniramine maleate

Chlorphenamine is a potent antihistamine (H1-antagonist). Antihistamines diminish or abolish the actions of histamine in the body by competative reversible blockade of histamine H1-receptor sites on tissues. Chlorphenamine also has anticholinergic activity. Molecular Weight: 390.9 g/mol Molecular Formula: C₁₆H₁₉ClN₂.C₄H₄O₄ Chemical Name: (Z)-but-2-enedioic acid;3-(4-chlorophenyl)-N,N-dimethyl-3-pyridin-2-ylpropan-1-amine

Dextromethorphan Hydrobromide

Dextromethorphan is the dextrorotatory isomer of 3-methoxy-N-methyl-morphinan. It is a synthetic morphine derivative. Dextromethorphan is a non-opioid antitussive drug. It exerts its antitussive activity by acting on the cough centre in the medulla oblongata, raising the threshold for the cough reflex.

Molecular Weight: 352.3 g/mol

Molecular Formula: C₁₈H₂₆BrNO

Chemical Name:

(1S,9S,10S)-4-methoxy-17-methyl-17-azatetracyclo[7.5.3.01,10.02,7]heptadeca-2(7),3,5-triene;hydrobromide

8.1 Incompatibilities

Not applicable

8.2 Shelf life

Refer on Pack

8.3 Packaging information

100 ml bottle

8.4 Storage and handling information

Store in a cool & dark place. Keep out of reach of children

• Take exactly as directed by your doctor or on the label. Do not increase the dosage or take for longer than is recommended. Use a proper measuring cup or spoon to measure the dosage.
• If you are drowsy after taking Soventus®-DX Syrup, you should not drive or operate any machinery.
• Inform your doctor if you have a history of stomach ulcers or asthma.
• Inform your doctor if you are taking any other medications, e.g., anti-depressants.
• Consult your doctor if you do not see any improvement and have a cough for > 7 days.
• Avoid consuming alcohol while taking Soventus DX Syrup as it can cause excessive drowsiness.