Defacortil

Uses

• Anaphylaxis, asthma, severe hypersensitivity reactions
• Rheumatoid arthritis, juvenile chronic arthritis, polymyalgia rheumatica
• Systemic lupus erythematosus, dermatomyositis, mixed connective tissue disease (other than systemic sclerosis), polyarteritis nodosa, sarcoidosis
• Pemphigus, bullous pemphigoid, pyoderma gangrenosum
• Minimal change nephrotic syndrome, acute interstitial nephritis
• Rheumatic carditis
• Ulcerative colitis, Crohn's disease
• Uveitis, optic neuritis
• Autoimmune haemolytic anaemia, idiopathic thrombocytopenic purpura
• Acute and lymphatic leukaemia, malignant lymphoma, multiple myeloma
• Immune suppression in transplantation

Defacortil is also used to associated treatment for these conditions: Duchenne's Muscular Dystrophy (DMD)

How Defacortil works

Defacortil is a corticosteroid prodrug with an active metabolite, 21-deflazacort, which binds to the glucocorticoid receptor to exert anti-inflammatory and immunosuppressive effects on the body. The exact mechanism by which deflazacort exerts its therapeutic effects in patients with DMD is unknown but likely occurs via its anti-inflammatory activities.

Dosage

Defacortil dosage

Adults:

• For acute disorders:up to 120 mg/day Defacortil may need to be given initially. Maintenance doses in most conditions are within the range 3-18 mg/day.
• Rheumatoid arthritis: The maintenance dose is usually within the range 3-18 mg/day. The smallest effective dose should be used and increased if necessary.
• Bronchial asthma: In the treatment of an acute attack, high doses of 48-72 mg/day may be needed depending on severity and gradually reduced once the attack has been controlled. For maintenance in chronic asthma, doses should be titrated to the lowest dose that controls symptoms.
• Other conditions: The dose of Defacortil depends on clinical need titrated to the lowest effective dose for maintenance. Starting doses may be estimated on the basis of ratio of 5 mg prednisone or prednisolone to 6 mg Defacortil.

Children:

Alternate day administration may be appropriate. Doses of Defacortil usually lie in the range 0.25-1.5 mg/kg/day. The following ranges provide general guidance:

• Juvenile chronic arthritis: The usual maintenance dose is between 0.25 to 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: The initial dose should be between 0.25 - 1.0 mg/kg on alternate days.
• Defacortil withdrawal:In patients who have received more than physiological doses of systemic corticosteroids (approximately 9 mg per day or equivalent) for greater than 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.

Side Effects

After administration occasionally GI disturbances like dyspepsia, nausea; musculoskeletal disorders like myopathy; depressed mood, skin atrophy, acne etc. may occur.

Toxicity

The LD50 for the oral dose is 5200 mg/kg (mouse); Oral TDLO (woman): 0.12 mg/kg

A note on altered endocrine function and immunosuppression

Defacortil, as a steroid prodrug used over a long-term period, can cause hormone imbalance leading to diseases such as Cushing's Syndrome and hypothalamic-pituitary-adrenal axis suppression. It can also predispose to infection, as it promotes immunosuppression. It is important to monitor for hormonal imbalance and infection and provide necessary treatment if they occur.

Mutagenicity/carcinogenicity

Mutagenicity assays were negative in various laboratory and in vivo assays performed on rats. Chronic use in mice for 2 years in one study resulted in a higher rate of osteoma and osteosarcomas in mice receiving 0.06, 0.12, 0.25, 0.50, or 1.0 mg/kg of deflazacort daily.

Use in pregnancy

There are no sufficient data to support the administration of deflazacort during pregnancy. Corticosteroid drugs such as deflazacort should only be used during pregnancy only if the benefits of therapy outweigh the potential risks.

Use in lactation

Corticosteroids, when administered systemically, are excreted in the breastmilk. Exposure may lead to disturbances in bone development and growth and endocrine disturbances in the exposed infant.

Precaution

The following clinical conditions require special caution and frequent patient monitoring is necessary: Adrenal suppression and infection, child, adolescents, elderly, history of TB and steroid myopathy, hypertension, recent myocardial infarction, congestive heart failure, liver failure, renal impairment, diabetes mellitus and glaucoma (including family history), osteoporosis, corneal perforation, epilepsy, peptic ulcer, hypothyroidism, pregnancy and lactation.

Interaction

Defacortil is metabolized in the liver. It is recommended to increase the maintenance dose of Defacortil 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 Defacortil.

Food Interaction

• Avoid grapefruit products. Grapefruit inhibits CYP3A metabolism, which may increase the serum concentration of deflazacort.
• Avoid St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of deflazacort.
• Take with or without food. The tablets may be crushed and mixed with applesauce and consumed immediately.

[Moderate] GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of 21-desdeflazacort, the active metabolite of deflazacort that is formed by esterases after oral administration and further metabolized by CYP450 3A4 to several inactive metabolites.

The proposed mechanism is inhibition of CYP450 3A4-mediated metabolism in the gut wall by certain compounds present in grapefruit.

In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands.

Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition.

Increased systemic exposure to 21-desdeflazacort may increase the risk of corticosteroid adverse effects such as hypercorticism, hyperglycemia, adrenal suppression, immunosuppression, hypertension, salt and water retention, electrolyte abnormalities, behavioral and mood disturbances, posterior subcapsular cataracts, glaucoma, bone loss, and growth retardation in children and adolescents.
br> MANAGEMENT: Defacortil should not be administered with grapefruit juice.

Defacortil Cholesterol interaction

[Moderate] Corticosteroids may elevate serum triglyceride and LDL cholesterol levels if used for longer than brief periods.

Patients with preexisting hyperlipidemia may require closer monitoring during prolonged corticosteroid therapy, and adjustments made accordingly in their lipid-lowering regimen.

Defacortil Hypertension interaction

[Moderate] Corticosteroids may cause hypernatremia, hypokalemia, fluid retention, and elevation in blood pressure.

These mineralocorticoid effects are most significant with fludrocortisone, followed by hydrocortisone and cortisone, then by prednisone and prednisolone.

The remaining corticosteroids, betamethasone, dexamethasone, methylprednisolone, and triamcinolone, have little mineralocorticoid activities.

However, large doses of any corticosteroid can demonstrate these effects, particularly if given for longer than brief periods.

Therapy with corticosteroids should be administered cautiously in patients with preexisting fluid retention, hypertension, congestive heart failure, and

Dietary sodium restriction and potassium supplementation may be advisable.

Defacortil Drug Interaction

Major: diltiazemModerate: metoprolol, metoprololUnknown: aripiprazole, zoledronic acid, alpha-lipoic acid, hydroxyzine, multivitamin, mycophenolate mofetil, sulfamethoxazole / trimethoprim, ubiquinone, albuterol / ipratropium, glucose, levothyroxine, levocarnitine, lithium, omega-3 polyunsaturated fatty acids, acetaminophen, thiamine, cholecalciferol

Defacortil Disease Interaction

Major: GI perforation, infections, prematurity, PUD, vaccination, Deflazacort hepatic impairmentModerate: (+) tuberculin test, cirrhosis, depression/psychoses, diabetes, electrolyte imbalance, fluid retention, hyperadrenocorticalism, hyperlipidemia, hypothyroidism, MI, myasthenia gravis, myopathy, ocular herpes simplex, ocular toxicities, osteoporosis, scleroderma, strongyloidiasis, thromboembolism

Volume of Distribution

One study determined the volume of distribution to be 204 ± 84 L.

Elimination Route

Defacortil is rapidly absorbed after oral administration with peak concentration occurring within 1-2 hours. One pharmacokinetic study determined an AUC (area under the curve) of 280 ng/ml · h.

The bioavailability of both the oral suspension and tablet are similar. In clinical studies, coadministration of deflazacort crushed with food or applesauce did not affect absorption or bioavailability.

Half Life

The half-life of deflazacort ranges from 1.1 to 1.9 h

Clearance

114 ±27 L/h, according to one noncompartmental pharmacokinetic study.

The clearance of corticosteroids is enhanced in hypothyroid patients and increased in patients with hyperthyroidism. Dosing adjustments may be considered according to thyroid status. A study of corticosteroid clearance was performed in patients with a creatinine clearance of 15 mL/min or less, and determined that the active metabolite of deflazacort, 21-deflazacort was similar to that in patients with normal renal clearance.

Elimination Route

Urinary excretion is the major route of deflazacort elimination, accounting for about about 70% of the excreted dose. The remainder of the dose (about 30%) is excreted in the feces. Elimination is almost completed by 24 hours post-dose. 21-deflazacort makes up about 18% of the eliminated drug in the urine.

Pregnancy & Breastfeeding use

Use in pregnancy: Defacortil does cross the placenta. When administered for prolonged periods or repeatedly during pregnancy, corticosteroids may increase the risk of intra-uterine growth retardation. As with all drugs, corticosteroids should only be prescribed when the benefits to the mother and child outweigh the risks.

Use in lactation: Corticosteroids are excreted in breast milk. Doses up to 50 mg daily of Defacortil are unlikely to cause systemic effects in the infant.

Contraindication

Hypersensitivity to or any of the ingredients. Patients receiving live virus immunisation.

Special Warning

Elderly: In elderly patients, no special precautions other than those usually adopted in patients receiving glucocorticoid therapy are necessary.

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

Renal impairment: In renal impaired patients, no special precautions other than those usually adopted in patients receiving glucocorticoid therapy are necessary.

Acute Overdose

In patients who have received more than physiological doses of systemic corticosteroids (approximately 9mg per day or equivalent) for greater than 3 weeks, withdrawal should not be abrupt. How dose reduction should becarried out depends largely on whether the disease is likely to relapse as the dose of systemic corticosteroids is reduced.

Storage Condition

Store in a cool (below 25° C.) and dry place , protected from light & moisture. Keep out of the reach of children.

Innovators Monograph

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