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.