Deflazacort

Deflazacort is an Anti-inflammatory and Immunosuppressive agent, belonging to the pharmacological class of Corticosteroids.

Deflazacort has been approved to relieve symptoms and also for the treatment and maintenance of Duchenne muscular dystrophy.

Deflazacort is rapidly absorbed following oral intake, with its peak concentration occurring within 1-2 hours. A pharmacokinetic investigation established an area under the curve (AUC) of approximately 280 ng/ml · h. The oral suspension and tablet variants of Deflazacort exhibit similar bioavailability, and coadministration with food or crushed with applesauce has been demonstrated in clinical studies to have no effect on absorption or bioavailability. The volume of distribution was determined as around 204 ± 84 L in a particular study. Notably, the active metabolite of Deflazacort binds to proteins to the extent of approximately 40%. Once ingested orally, Deflazacort is metabolized through deacetylation at position 21, catalyzed by plasma esterases, resulting in the creation of the active metabolite 21-deflazacort. This metabolite undergoes further modification by the enzyme CYP3A4, leading to the generation of inactive products. This metabolic pathway also involves the production of the metabolite deflazacort 6-beta-OH. Elimination of Deflazacort predominantly occurs through urinary excretion, accounting for roughly 70% of the excreted dose, with the remaining 30% being expelled through feces. The elimination process is largely completed within 24 hours post-dosage, and the presence of 21-deflazacort constitutes approximately 18% of the eliminated compounds in the urine.

The common side effects of Deflazacort include Cushing-like appearance, Enhanced body weight, Heightened craving for food, Infection of the upper respiratory tract, Persistent cough, Frequent urination.

Deflazacort is available in the form of Tablets , Oral suspension.

Deflazacort is approved in Germany, Japan, Malaysia, India, the U.K.,and China.

Deflazacort, belonging to the pharmacological class of Corticosteroids. , acts as an Anti-inflammatory and Immunosuppressive agents.

Deflazacort functions as a corticosteroid prodrug, transforming into an active metabolite known as 21-deflazacort. This active compound binds to the glucocorticoid receptor, leading to anti-inflammatory and immunosuppressive actions within the body. Although the precise manner in which Deflazacort brings about its therapeutic effects in individuals with DMD remains uncertain, it is probable that its anti-inflammatory properties play a significant role.

Deflazacort has been approved to relieve symptoms and also for the treatment and maintenance of Duchenne muscular dystrophy.

After being taken orally on an empty stomach, deflazacort tablets or suspension typically reach a median Tmax of around 1 hour (with a range of 0.25 to 2 hours).

When deflazacort tablets were co-administered with a high-fat meal, the peak concentration (Cmax) decreased by approximately 30%, and the time to reach the peak concentration (Tmax) was delayed by one hour compared to administration on an empty stomach. Despite these changes, the overall systemic absorption, as measured by the area under the curve (AUC), remained unaffected.

Deflazacort is found to be available in the form of Tablets , Oral suspension.

Deflazacort can be used in the following treatment:

• Duchenne muscular dystrophy

Deflazacort can help to relieve symptoms and also for the treatment and maintenance of Duchenne muscular dystrophy.

Deflazacort is approved for use in the following clinical indications:

• Duchenne muscular dystrophy

• Duchenne muscular dystrophy: When administered orally, the typical dosage is 0.9 mg/kg taken once daily. In cases where patients encounter adverse effects that are difficult to tolerate, the dose may be reduced by 25% to 33% according to references. It's important to round the dose to the nearest possible amount when using tablets and to the nearest tenth of a mL when using the suspension.

Deflazacort is available in the following dosage forms and strengths:

• Tablets : 6mg, 18mg, 30mg, 36mg
• Oral suspension : 22.75mg/ml

Tablets , Oral suspension

• Dosage Adjustments in Kidney Patients:

There are found to be no dosage adjustments in the manufacturer's labeling .It is advised to use Deflazacort with caution.

• Dosage Adjustments in Hepatic Impairment Patients:

There are found to be no dosage adjustments in the manufacturer's labeling for mild to moderate impairments.

• Dosage Adjustments in Pediatric Patients:

Duchenne muscular dystrophy (DMD): For children ≥2 years and adolescents, the recommended oral dose is approximately 0.9 mg/kg per day. The doses should be rounded according to the product formulation used. If using the oral suspension, round the dose up to the nearest 0.1 mL (tenth of a mL). If using tablets, round up to the nearest possible dose based on tablet strengths, using any combination of available tablet strengths. It's important to note that DMD predominantly affects males, with limited clinical trial experience in the female population. When discontinuing therapy after several days of administration, it's advised to gradually reduce the dose of Deflazacort.

There are no specific dietary restrictions associated with the use of Deflazacort. However, it's important to maintain a healthy and balanced diet while taking this medication to support overall well-being and help manage potential side effects.

Molecule Deflazacort may be contraindicated in the following conditions:

• Deflazacort should not be used by individuals with a known allergy to Deflazacort or any of its inactive components.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows :

Alterations in Endocrine Function:

Endocrine Effects: Serious hormone-related effects can occur with corticosteroid use, including Deflazacort. Monitoring for conditions like Cushing's syndrome, high blood sugar, and adrenal insufficiency is crucial, especially after stopping Deflazacort. Individuals with certain hormone-related conditions may be more vulnerable to these impacts.

Risk of Adrenal Insufficiency Following Corticosteroid Withdrawal:

Adrenal Insufficiency Risk: Stopping corticosteroids suddenly can lead to adrenal insufficiency, a potentially severe condition. It's recommended to gradually decrease the dose to minimize this risk. Adrenal insufficiency might persist for months after long-term use cessation. In situations of stress during this period, restarting corticosteroid treatment might be necessary.

Cushing’s Syndrome:

Corticosteroid Impact: Prolonged use of corticosteroids, like Deflazacort, can result in Cushing's syndrome, characterized by symptoms such as high blood pressure, obesity, muscle weakness, and mood changes.

Hyperglycemia:

Blood Sugar Concerns: Corticosteroids can elevate blood sugar levels, potentially worsening pre-existing diabetes or triggering new cases. Regular blood sugar monitoring and potential adjustments to diabetes treatment are important.

Considerations for Use in Individuals with Altered Thyroid Function:

Thyroid Function Impact: Individuals with thyroid conditions might require dose adjustments due to altered metabolism while using corticosteroids.

Pheochromocytoma Crisis:

Risk in Pheochromocytoma: People with suspected or diagnosed pheochromocytoma should exercise caution before initiating corticosteroid therapy due to the potential for triggering a pheochromocytoma crisis.

Immunosuppression and Increased Risk of Infection:

Immune System Impact: Corticosteroids, such as Deflazacort, can weaken the immune system, increasing the susceptibility to infections. The risk of infections may rise with higher corticosteroid doses.

Varicella Zoster and Measles Viral Infections:

Viral Infection Concerns: Chickenpox and measles can be severe for individuals on corticosteroids, particularly if they lack immunity to these diseases. Precautions to avoid exposure are essential.

Hepatitis B Virus Reactivation:

Hepatitis B Risk: Reactivation of the hepatitis B virus can occur in those taking corticosteroids, particularly if they have a history of hepatitis B infection.

Fungal Infections:

Fungal Infection Warning: Corticosteroid use can worsen systemic fungal infections and should be avoided in such cases.

Amebiasis and Strongyloides Infestation:

Parasitic Infection Concerns: Corticosteroid therapy might activate latent amebiasis and worsen Strongyloides infestations. Thorough evaluation is necessary before starting treatment.

These highlighted warnings provide essential information about potential risks and effects associated with using Deflazacort, and should be carefully considered by anyone using the medication.

There are no specific alcohol-related warnings associated with the use of Deflazacort mentioned in the provided information. However, it's important to note that combining alcohol with medications, including Deflazacort, can sometimes have unpredictable effects.

Corticosteroids administered systemically are detectable in human breast milk and might impede growth, disrupt natural corticosteroid production, or trigger other undesirable outcomes. While breastfeeding offers developmental and health advantages, it's crucial to weigh these benefits against the mother's requirement for Deflazacort and any potential negative repercussions on the breastfed baby due to Deflazacort exposure. Currently, there is no available information regarding the impact on milk production.

The utilization of corticosteroids during pregnancy should only be considered when the potential advantages outweigh the potential risks to the developing fetus. Newborns born to mothers who have received substantial corticosteroid doses during pregnancy should be closely monitored for signs of hypoadrenalism. Currently, there are no comprehensive and well-controlled investigations involving pregnant women that provide insight into the potential risks associated with Deflazacort use.

Corticosteroids, including Deflazacort, have the ability to pass through the placental barrier. The use of corticosteroids, including Deflazacort, by expectant mothers has been associated with adverse developmental outcomes such as orofacial clefts (cleft lip, with or without cleft palate), intrauterine growth restriction, and reduced birth weight. While some epidemiological studies indicate an elevated risk of orofacial clefts, ranging from approximately 1 per 1000 infants to 3 to 5 per 1000 infants, it's worth noting that not all studies have reported a risk for orofacial clefts. In the context of intrauterine growth restriction and decreased birth weight, the magnitude of the risk appears to correlate with the dose; however, the underlying maternal condition could also contribute to these potential risks (see available data). The baseline risk of significant birth defects and miscarriage in the specified populations remains uncertain. In the general U.S. population, the estimated baseline risk of significant birth defects and miscarriage in pregnancies that are clinically recognized is around 2-4% and 15-20%, respectively.

There haven't been animal reproductive studies conducted specifically with Deflazacort. However, studies involving other corticosteroids administered to pregnant mice, rats, hamsters, and rabbits using clinically relevant doses have indicated an increased incidence of cleft palate. Some animal species also demonstrated increased embryofetal mortality, intrauterine growth retardation, and constriction of the ductus arteriosus.

Available Data:

Numerous cohort and case-controlled human studies propose that maternal corticosteroid usage during the first trimester is linked to a heightened occurrence of cleft lip, with or without cleft palate, elevating the incidence from approximately 1/1000 infants to 3-5/1000 infants. Two prospective case-controlled studies indicated reduced birth weight in infants exposed to maternal corticosteroid usage during pregnancy.

Deflazacort may be taken with or without food. However, it's advisable to take it consistently with regards to food intake to maintain a steady level in your body.

The adverse reactions related to Deflazacort can be categorized as follows:

Common

• Backache
• Blurred vision
• Body aches or discomfort
• Chills
• Cough
• Difficulty breathing
• Ear congestion
• Facial hair growth in females
• Fever
• Fractures
• Full or rounded face, neck, or trunk
• Headache
• Increased hair growth, particularly on the face
• Increased thirst or urination
• Irritability
• Reduced sexual desire or capability
• Loss of voice
• Irregular menstrual periods
• Muscle aches or deterioration
• Sneezing
• Sore throat
• Stuffy or runny nose
• Unusual tiredness or weakness
• Weight gain

Less Common

• Bladder pain
• Blood-stained or cloudy urine
• Diarrhea
• Painful, burning, or difficult urination
• Difficulty with movement
• Frequent urge to urinate
• Overall feeling of unease or illness
• Joint pain
• Decreased appetite
• Pain in the lower back or side
• Muscle pains or stiffness
• Nausea
• Shivering
• Sweating
• Swollen joints
• Sleep difficulties
• Vomiting

Rare

• Difficulty swallowing
• Dizziness
• Rapid heartbeat
• Itchy, rash, or hives
• Swelling or puffiness of eyelids, eyes, face, lips, or tongue

The clinically relevant drug interactions of Deflazacort is briefly summarized here:

CYP3A4 Inhibitors and Inducers

Effects of Moderate or Strong CYP3A4 Inhibitors:

Deflazacort's active metabolite, 21-desDFZ, is processed by CYP3A4 enzymes. Concurrent administration of Deflazacort and clarithromycin, a potent CYP3A4 inhibitor, amplified the total exposure to 21-desDFZ by approximately threefold. Therefore, when using moderate or strong CYP3A4 inhibitors (e.g., clarithromycin, fluconazole, diltiazem, verapamil, grapefruit juice) alongside Deflazacort, it is recommended to administer one-third of the prescribed Deflazacort dose.

Effects of Moderate or Strong CYP3A4 Inducers:

When Deflazacort was co-administered with rifampin, a robust CYP3A4 inducer, the exposure to 21-desDFZ significantly decreased. It is advised to avoid combining strong inducers (e.g., efavirenz) or moderate inducers (e.g., carbamazepine, phenytoin) of CYP3A4 with Deflazacort .

Neuromuscular Blockers

Patients taking corticosteroids, including Deflazacort, along with neuromuscular blocking drugs (e.g., pancuronium) could face an elevated risk of developing acute myopathy.

The following are the side effects involving Deflazacort:

• Cushing-like appearance
• Enhanced body weight
• Heightened craving for food
• Infection of the upper respiratory tract
• Persistent cough
• Frequent urination

The use of Deflazacort should be prudent in the following group of special populations:

Pregnancy:

The utilization of corticosteroids during pregnancy should only be considered when the potential advantages outweigh the potential risks to the developing fetus. Newborns born to mothers who have received substantial corticosteroid doses during pregnancy should be closely monitored for signs of hypoadrenalism. Currently, there are no comprehensive and well-controlled investigations involving pregnant women that provide insight into the potential risks associated with Deflazacort use.

Corticosteroids, including Deflazacort, have the ability to pass through the placental barrier. The use of corticosteroids, including Deflazacort, by expectant mothers has been associated with adverse developmental outcomes such as orofacial clefts (cleft lip, with or without cleft palate), intrauterine growth restriction, and reduced birth weight. While some epidemiological studies indicate an elevated risk of orofacial clefts, ranging from approximately 1 per 1000 infants to 3 to 5 per 1000 infants, it's worth noting that not all studies have reported a risk for orofacial clefts. In the context of intrauterine growth restriction and decreased birth weight, the magnitude of the risk appears to correlate with the dose; however, the underlying maternal condition could also contribute to these potential risks (see available data). The baseline risk of significant birth defects and miscarriage in the specified populations remains uncertain. In the general U.S. population, the estimated baseline risk of significant birth defects and miscarriage in pregnancies that are clinically recognized is around 2-4% and 15-20%, respectively.

There haven't been animal reproductive studies conducted specifically with Deflazacort. However, studies involving other corticosteroids administered to pregnant mice, rats, hamsters, and rabbits using clinically relevant doses have indicated an increased incidence of cleft palate. Some animal species also demonstrated increased embryofetal mortality, intrauterine growth retardation, and constriction of the ductus arteriosus.

Available Data:

Numerous cohort and case-controlled human studies propose that maternal corticosteroid usage during the first trimester is linked to a heightened occurrence of cleft lip, with or without cleft palate, elevating the incidence from approximately 1/1000 infants to 3-5/1000 infants. Two prospective case-controlled studies indicated reduced birth weight in infants exposed to maternal corticosteroid usage during pregnancy.

Lactation:

Corticosteroids administered systemically are detectable in human breast milk and might impede growth, disrupt natural corticosteroid production, or trigger other undesirable outcomes. While breastfeeding offers developmental and health advantages, it's crucial to weigh these benefits against the mother's requirement for Deflazacort and any potential negative repercussions on the breastfed baby due to Deflazacort exposure. Currently, there is no available information regarding the impact on milk production.

Pediatric:

The safety and efficacy of Deflazacort for treating DMD have been established in patients aged 5 years and above. The use of Deflazacort in pediatric patients is backed by a comprehensive study involving 196 males that was randomized, double-blind, and placebo- as well as active-controlled [see Clinical Studies (14)].

However, the safety and effectiveness of Deflazacort have not been verified in pediatric patients under the age of 5.

Deflazacort Oral Suspension contains benzyl alcohol and is not sanctioned for use in pediatric patients below 5 years of age. Serious adverse events, including fatal outcomes and instances of "gasping syndrome," have been reported in premature neonates and low birth weight infants in neonatal intensive care units who were administered drugs containing benzyl alcohol as a preservative. In such cases, benzyl alcohol doses ranging from 99 to 234 mg/kg/day led to elevated levels of benzyl alcohol and its metabolites in the blood and urine (blood benzyl alcohol levels ranged from 0.61 to 1.378 mmol/L). These cases also exhibited adverse reactions like progressive neurological deterioration, seizures, intracranial bleeding, abnormalities in blood composition, skin breakdown, liver and kidney dysfunction, low blood pressure, slow heart rate, and cardiovascular collapse. Preterm, low-birth weight infants might be more susceptible to these reactions due to potential challenges in metabolizing benzyl alcohol. The exact threshold at which severe adverse reactions could occur due to benzyl alcohol exposure is not determined (Deflazacort Oral Suspension contains 10.45 mg of benzyl alcohol per mL; Deflazacort Tablets , Oral suspension do not contain benzyl alcohol).

Data from juvenile animal toxicity studies reveal that oral administration of Deflazacort (at doses of 0, 0.1, 0.3, and 1.0 mg/kg/day) to juvenile rats from postnatal day 21 to 80 resulted in decreased body weight gain and negative effects on skeletal and lymphoid tissue development (including reduced cellularity of the growth plate and altered bone distribution). Neurological and neurobehavioral anomalies were also observed at mid and/or high doses. The plasma exposure (AUC) to 21-desDFZ at the lowest tested dose (0.1 mg/kg/day) was lower than that in humans receiving the recommended human dose of Deflazacort (0.9 mg/kg/day).

Geriatric Use:

Since DMD primarily affects children and young adults, there is a lack of geriatric data available for Deflazacort.

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Deflazacort.

In instances of acute overdose, the approach to treatment involves prompt gastric lavage or the induction of vomiting, followed by the administration of supportive and symptomatic care. In cases of chronic overdose occurring during the presence of serious conditions necessitating ongoing steroid treatment, a temporary reduction in the Deflazacort dosage may be implemented, or the consideration of alternate day therapy may be warranted.

Pharmacodynamics:

Deflazacort exhibits anti-inflammatory effects in individuals with Duchenne muscular dystrophy (DMD), potentially leading to improvements in various symptoms, including muscle weakness and cardiorespiratory issues, while also delaying their onset. This contributes to an enhanced quality of life and reduces the requirement for surgical interventions like scoliosis procedures, which are commonly associated with DMD. Clinical studies have demonstrated significant preservation of muscle mass in patients receiving a general deflazacort dosage of 0.9 mg/kg/day in comparison to control groups. The following observations are based on extended-duration clinical trials involving Deflazacort:

• Muscle Strength Effects:

Among individuals who underwent prolonged deflazacort treatment, muscle strength was notably higher, with a mean score of 63 ± 4% at age 16, in contrast to a mean muscle strength score of 31 ± 3% for control patients. Additionally, patients taking Deflazacort showed marked improvements in activities such as climbing stairs and transitioning from a supine position.

• Effects on Ambulation:

Patients administered deflazacort demonstrated significantly prolonged ambulation ability, with notable differences observed at 12 years and 18 years of age compared to the control group. The control group experienced a mean ambulation loss two years earlier than those treated with Deflazacort.

• Effects on Cardiac Function:

Long-term deflazacort treatment led to higher mean left ventricular ejection fractions, indicative of improved cardiac function. The preservation of cardiac performance was evident through a mean difference of approximately 7% in ejection fraction between study groups receiving deflazacort and control groups.

• Effects on Spinal Alignment:

Children subjected to deflazacort treatment displayed a considerable reduction in the occurrence and severity of scoliosis. Furthermore, long-term deflazacort therapy eliminated the necessity for scoliosis surgery in these patients.

In summary, Deflazacort's anti-inflammatory properties appear to offer benefits for individuals with DMD, encompassing enhancements in muscle strength, ambulation, cardiac function, and spinal alignment, leading to an improved overall quality of life and a decreased need for surgical interventions associated with DMD-related complications. These findings are drawn from extensive clinical investigations involving the extended use of Deflazacort.

Pharmacokinetics:

• Absorption:

Upon oral intake in a fasted state, the time required to reach the median Tmax for deflazacort Tablets , Oral suspension or suspension is approximately 1 hour, with a range of 0.25 to 2 hours.

• Effect of Food:

When deflazacort Tablets , Oral suspension are co-administered with a high-fat meal, the maximum plasma concentration (Cmax) is reduced by approximately 30%, and the time to reach maximum concentration (Tmax) is delayed by one hour compared to fasting conditions. However, this alteration in food intake does not impact the overall systemic absorption, as indicated by the area under the curve (AUC). The bioavailability of deflazacort Tablets , Oral suspension remains consistent with that of the oral suspension. Administering Deflazacort with food or mixing it with applesauce does not alter its absorption or bioavailability.

• Distribution:

Approximately 40% of the active metabolite of Deflazacort is bound to proteins.

• Elimination and Metabolism:

Following oral ingestion, Deflazacort rapidly undergoes conversion into the active metabolite known as 21-desDFZ through the action of esterases. The enzyme CYP3A4 further metabolizes 21-desDFZ into multiple inactive metabolites.

• Excretion:

Urinary excretion is the primary mode of eliminating Deflazacort, accounting for around 68% of the administered dose. Almost all elimination is completed within 24 hours after dosing. The metabolite 21-desDFZ contributes to 18% of the eliminated drug in the urine.

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