Deflazacort - Mechanism of Action, Indications, Dosage, and Adverse Drug Reactions

Overview

Deflazacort is a corticosteroid drug and is used to treat the uncommon hereditary disease known as Duchenne muscular dystrophy (DMD). A defective gene that leads to low amounts of the protein dystrophin causes DMD, a severe form of muscular dystrophy (skeletal muscle degeneration). Muscle atrophy (loss of skeletal muscle mass) and weakening are caused by a lack of dystrophin, an enzyme that helps maintain muscle cells intact. It reduces inflammation and suppresses the immune system by acting as an anti-inflammatory and immunosuppressive drug. On February 9, 2017, the Food and Drug Administration (FDA) initially authorized Deflazacort tablets and oral suspension for the treatment of Duchenne muscular dystrophy in patients five years of age and older, and later in 2019, it expanded to use in patients over two years of age.

Drug Group

As an oral steroid, Deflazacort belongs to the corticosteroids group and is used to treat a variety of illnesses, such as autoimmune (the body’s immune system attacks its own cells) and inflammatory disorders. Corticosteroids defend against infection and foreign substances by reducing inflammation and immune system activity.

What Is Deflazacort Used For?

Deflazacort is recommended in patients with Duchenne muscular dystrophy who are two years of age and older.

Contraindications

Deflazacort is not advised for patients who have a history of hypersensitivity (an exaggerated immune response) to Deflazacort or any of its inactive ingredients.

Dosage Forms and Available Strengths

The dosage forms and strengths of Deflazacort include round, white tablets with the following strengths:

• 6 mg (milligrams).

• 18 mg.

• 30 mg.

• 36 mg.

• An oral suspension is available in a whitish suspension at a dose of 22.75 mg/mL (milligrams per milliliter).

For Patients

What Is Duchenne Muscular Dystrophy?

Duchenne muscular dystrophy is a hereditary disorder that primarily affects the skeletal and cardiac muscles and is characterized by progressive muscle loss and destruction. Progressive muscle weakness, calf muscle enlargement, trouble walking, frequent falls, exhaustion, cardiomyopathy, respiratory issues, and cognitive impairment are the symptoms of Duchenne muscular dystrophy that usually manifest between the ages of two and four. A genetic mutation that stops the body from making the protein dystrophin, which serves as a shock absorber during muscle contractions, causes Duchenne muscular dystrophy.

How Does Deflazacort Work?

The corticosteroid prodrug (a medication given in an inactive form that the body converts into an active corticosteroid) Deflazacort has an active metabolite called 21-Deflazacort that attaches to the glucocorticoid receptor to produce immunosuppressive and anti-inflammatory actions. Its anti-inflammatory qualities contribute to its therapeutic benefit in Duchenne muscular dystrophy patients.

What Are the Benefits of Deflazacort?

Deflazacort provides Duchenne muscular dystrophy patients with several benefits:

• Improved Muscle Strength: Patients with Duchenne muscular dystrophy must take Deflazacort to maintain muscle function and strength. It might halt the development of muscular weakness.

• Decreased Inflammation: Deflazacort reduces muscle inflammation. This can reduce symptoms and enhance general health.

• Delay in Disease Course: Deflazacort can postpone the course of Duchenne muscular dystrophy, preserving patients' greater mobility and independence even though it is not a cure.

• Enhanced Quality of Life: Deflazacort helps Duchenne muscular dystrophy patients live better by maintaining muscle function.

How Is Deflazacort Administered?

• Deflazacort is available as a liquid suspension for oral use and as tablets.

• It is taken once a day, as directed on the prescription label, with or without food.

• Crush and combine the tablet with applesauce if patients cannot swallow it whole.

• Before using, shake the suspension well and stir it into milk or fruit juice. Grapefruit juice should not be combined with the dosage.

• The doctor might need to modify the dosage if the patient experiences unusual stress, such as surgery, illness, or infection.

• Abruptly stopping Deflazacort might result in adverse effects such as weight loss, peeling skin, fever, joint and muscular discomfort, sleepiness, nausea, vomiting, and stomach distress. The doctor could gradually lower the Deflazacort dosage before quitting altogether to give the body time to adjust. If any of these problems arise, see a doctor immediately.

What Are the Side Effects of Deflazacort?

Deflazacort adverse effects are possible. If any of these symptoms of Deflazacort are severe or persistent, let the doctor know:

• Headache.

• Delicate, thin skin.

• Blotches or lines under the skin that are red or purple.

• Increased hair growth.

• Acne.

• Enlarged eyes.

• Missing or erratic menstrual cycles.

• Hindered the recovery of bruising and cuts.

• Alterations in the distribution of fat throughout the body.

• Weak muscles.

• Joint discomfort.

• Urinating a lot during the day.

• Lightheadedness.

• Trouble sleeping or remaining asleep.

• Increased appetite.

• Backache.

• Heartburn.

• Stomach upset.

Certain adverse effects of Deflazacort may be dangerous. Give the doctor a call right away if patients taking Deflazacort encounter any of the following symptoms:

• Fever, chills, cough, sore throat, or other infection-related symptoms.

• Seizures (uncontrolled electrical activity in the brain cells).

• Vision changes.

• Redness or pain in the eyes.

• Swelling in the arms, hands, feet, ankles, lower legs, lips, tongue, eyes, and throat.

• Breathing or swallowing difficulties.

• Breathlessness.

• Abrupt weight gain.

• Rash.

• Hives (skin rash).

• Itching.

• Blistering or peeling skin.

• Stomach ache.

• Disorientation.

• Abrupt mood swings.

• Personality changes.

• Inappropriate happiness.

• Depression.

• Persistent discomfort may start in the stomach and go to the back.

Deflazacort may slow children's growth and development. The physician will closely monitor the child's growth. Discuss the dangers of providing the child with Deflazacort with the physician.

Long-term users of Deflazacort may have cataracts (clouding of the eye lens) or glaucoma (eye conditions that damage the optic nerve). Discuss with the doctor the dangers of using Deflazacort and how frequently people should undergo visual examinations during the treatment.

Patients who take Deflazacort may be at increased risk for osteoporosis (a disease that weakens the bones). Discuss the potential risks of using Deflazacort with the physician.

If patients have any odd side effects while taking Deflazacort, contact the doctor who prescribed it.

What Are the Things to Inform the Doctor Before Taking Deflazacort?

1. If patients have an allergy to Deflazacort, they should avoid using it.

2. Children under the age of two should not use Deflazacort. One of the ingredients in Deflazacort oral suspension (liquid) has the potential to cause major adverse effects or even death in infants and premature babies.

3. Inform the doctor if patients have ever experienced:

• Any infection caused by bacteria, fungi, viruses, or parasites.

• Cardiac issues and elevated blood pressure.

• A blood clot or stroke (brain damage occurs from interrupted blood supply).

• Retention of fluids.

• Renal illness.

• Liver illness, particularly hepatitis B (liver infection).

• A digestive or stomach illness.

• Ileostomy or colostomy (surgical procedures to move waste out of the body).

• Cataracts (clouding of the eye lens), glaucoma (a disease that damages the optic nerves), or ocular herpes infection (viral eye infection).

• Diabetes (high blood sugar).

• A disease of the nerves and muscles, like myasthenia gravis (autoimmune disease).

• A low density of bone mineral.

• An issue with the pituitary, adrenal, or thyroid glands.

4. It is important to keep up with the vaccinations; let the physician know if patients just got vaccinated or have a booster shot coming up.

5. Osteoporosis (weak and brittle bones) can result from the use of steroids, mainly if patients smoke, are inactive, do not receive enough calcium or vitamin D, or have a family history of the condition.

6. Deflazacort used early in pregnancy may alter the baby's adrenal gland hormone levels and raise the baby's risk of cleft lip and palate (split in the lips and palate). Additionally, breastfeeding is not recommended while taking Deflazacort; speak with the doctor about potential risks.

Dietary Considerations:

Deflazacort advises against consuming grapefruit or drinking grapefruit juice.

Missed Dose:

As soon as the patient remembers to take Deflazacort, they should do so; however, if the next dose is almost due, they should skip Deflazacort and stick to their regular dosing schedule instead of taking two doses of Deflazacort.

Overdose:

When Deflazacort is overdosed, it can cause severe symptoms like fainting out, breathing problems, or other dangerous reactions that call for emergency medical assistance.

Storage and Handling

Medication should be kept at room temperature, between 68°F (degrees Fahrenheit) and 77°F (20°C (degrees Celsius) and 25°C), in its original container, securely closed, and out of children's reach.

Disposal

After a month, discard any Deflazacort suspension that was not used. It is important to dispose of unnecessary prescriptions specifically to keep pets, kids, and other people from eating them. It is advised that Deflazacort be disposed of through the FDA's medicine take-back program.

For Doctors

Description:

Deflazacort, a corticosteroid with a molecular formula of C25H31NO6 and chemical name (11β,16β)-21-(acetyloxy)­11-hydroxy-2'-methyl-5'H-pregna-1,4-dieno[17,16-d]oxazole-3,20-dione. It is a white to off-white, odorless powder with a molecular weight of 441.517 grams per mole and is soluble in acetic acid, dichloromethane, methanol, and acetone.

What Are the Pharmacological Actions of Deflazacort?

Pharmacodynamics

Deflazacort is thought to help DMD patients with their symptoms by postponing the onset of symptoms, including muscle weakness and cardiorespiratory problems. This improves life quality and avoids operative procedures for conditions like scoliosis. Research indicates that patients receiving 0.9 mg/kg/day (milligrams per kilogram per day) of Deflazacort had a notable preservation of muscle mass.

Mechanism of Action

Through its active metabolite, 21-Deflazacort, Deflazacort possesses anti-inflammatory and immunosuppressive properties; however, the precise mechanism of action in patients with DMD is still unknown.

Pharmacokinetics

• Absorption: Following oral treatment, Deflazacort is quickly absorbed, reaching peak concentration in one to two hours. The area under the curve (AUC) for one pharmacokinetic study was 280 ng/ml · h (nanograms per milliliter per hour). Both the oral suspension and the tablet have comparable bioavailability. Deflazacort mixed with food or applesauce did not alter absorption or bioavailability in clinical trials.

• Distribution: A study found that the distribution's volume was 204 ± 84 L (liters). Deflazacort's active metabolite has a 40 percent protein binding affinity.

• Metabolism: Following oral consumption, plasma esterases deacetylate Deflazacort at position 21, resulting in the active metabolite 21-Deflazacort. CYP3A4 then continues to metabolize 21-Deflazacort to produce inactive metabolite products. Deflazacort 21-OH has a complex metabolism. Deflazacort 6-beta-OH is the metabolite of Deflazacort-21-OH.

• Excretion: Approximately 70 percent of the excreted dose of Deflazacort is eliminated through urine. This is the primary route of elimination. The remaining dosage, roughly 30 percent, is eliminated through the stool. After 24 hours, almost all of the elimination has occurred. Approximately 18 percent of the Deflazacort excreted in the urine comprises 21-Deflazacort. Deflazacort has a half-life of 1.1 to 1.9 hours.

What Are the Drug Interactions of Deflazacort?

• Moderate or Powerful CYP3A4 Inhibitors: As CYP3A4 is a substrate of Deflazacort's active metabolite, 21-desDFZ, co-administration of Clarithromycin increases overall exposure by approximately three times. Thus, when moderate or powerful CYP3A4 inhibitors are taken in conjunction with Deflazacort, administer one-third of the prescribed dosage of Deflazacort.

• Strong or Moderate CYP3A4 Inducers: Strong CYP3A4 inducers Deflazacort and Rifampin considerably decreased exposure to 21-desDFZ. Avoid combining Deflazacort with solid or moderate CYP3A4 inducers.

• Neuromuscular Blockers: Acute myopathy may be more common in patients receiving neuromuscular blocking medications like Pancuronium and corticosteroids like Deflazacort.

Clinical Studies

The trial aimed to assess how well Deflazacort treated DMD in children between the ages of five and 15. One hundred ninety-six male juvenile patients with a dystrophin gene mutation, weakness that began before the age of five, and blood creatinine kinase activity that was at least ten times greater than normal were included in the study. A placebo, an active comparator, or Deflazacort (0.9 or 1.2 mg/kg/day (milligrams per kilogram)) were randomly administered to patients. According to the findings, the average muscle strength score changed considerably more in the Deflazacort 0.9 mg/kg/day dosing group between baseline and week 12 of the research. By week 12, the Deflazacort 1.2 mg/kg/day group slightly outperformed the placebo but also experienced more significant adverse events. By week 52, the Deflazacort 0.9 mg/kg/day dose group showed that the treatment effect remained, while the marginal benefit of the 1.2 mg/kg/day dose had disappeared.

Warnings and Precautions

• Alterations in Endocrine Function: Serious endocrine alterations can result from long-term usage of Deflazacort. Following discontinuation, patients should be closely watched for pheochromocytoma, altered thyroid function, primary adrenal insufficiency, hypopituitarism, congenital adrenal hyperplasia, Cushing's syndrome, and hyperglycemia.

• Immunosuppression and Increased Risk of Infection: Deflazacort reduces immunity, increases infection risk, worsens pre-existing infections, and spreads diseases. It can intensify or reactivate latent infections, potentially leading to serious or deadly outcomes. It is advised to monitor the progression of the infection and modify the dosage accordingly.

• Alterations in Cardiovascular and Renal Function: Deflazacort can increase calcium and potassium excretion and raise blood pressure and sodium levels. Monitoring potassium and blood pressure is critical for detecting symptoms of volume overload. Patients with hypertension, renal insufficiency, or congestive heart failure should use Deflazacort with caution.

• Gastrointestinal Perforation: Patients with certain gastrointestinal illnesses, such as diverticulitis, ulcerative colitis, and peptic ulcers are more susceptible to gastrointestinal perforations when using corticosteroids. It is advisable to refrain from using Deflazacort if perforation, abscess, or other infections occur since peritoneal irritation may be overlooked.

• Behavioral and Mood Disturbances: Deflazacort can cause severe psychiatric adverse reactions, including hypomanic or manic symptoms during treatment and depressive episodes post-discontinuation. Patients should be informed that these reactions may improve with dose reduction or withdrawal.

• Effects on Bones: Bone mineral density can decline due to long-term Deflazacort usage.

• Ophthalmic Effects: Deflazacort may result in glaucoma, secondary eye infections, and posterior subcapsular cataracts. Patients with active ocular herpes simplex should avoid them since they may increase intraocular pressure. When using Deflazacort for an extended period, it is imperative to monitor intraocular pressure.

• Vaccinations: All vaccinations should be given to patients by recommended protocols, except for live-attenuated or live vaccines, which should be given four to six weeks before the initiation of Deflazacort.

• Serious Skin Rashes: Toxic epidermal necrolysis has been related to Deflazacort; symptoms usually appear within eight weeks. Stop using Deflazacort as soon as a rash appears, unless it is unrelated to the drug.

Specific Considerations

• Pregnancy: It is not advised to use Deflazacort while pregnant because of possible risks to the developing fetus, such as a greater chance of a cleft lip and palate.

• Breastfeeding: Deflazacort is not recommended, even though it can be used during breastfeeding. There is little evidence to show that it could enter breast milk and harm the unborn child.

• Pediatric Use: It is unknown whether there are any safety or efficacious effects in pediatric patients younger than two years old.

• Geriatric Use: Since DMD typically affects children and young adults, Deflazacort does not have geriatric experience.

• Renal and Hepatic Impairment: Dosage adjustments are unnecessary for patients with mild, moderate, or severe hepatic and renal impairment.