Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: Laboratoires CTRS, 63, rue de l’Est, 92100 Boulogne-Billancourt, France, Email: ctrs@ctrs.fr
Pharmacotherapeutic group: Corticosteroids for systemic use, glucocorticoids
ATC code: H02AB02
Dexamethasone is a synthetic glucocorticoid; it combines high anti-inflammatory effects with low mineralocorticoid activity. At high doses (e.g. 40 mg), it reduces the immune response.
Dexamethasone has been shown to induce multiple myeloma cell death (apoptosis) via a down-regulation of Nuclear Factor-κB activity and an activation of caspase-9 through second mitochondria-derived activator of caspase (Smac; an apoptosis promoting factor) release. Prolonged exposure was required to achieve maximum levels of apoptotic markers along with increased caspase-3 activation and DNA fragmentation. Dexamethasone also down-regulated anti apoptotic genes and increased IκB-α protein levels.
Dexamethasone apoptotic activity is enhanced by the combination with thalidomide or its analogues and with proteasome inhibitor (e.g. bortezomib).
Multiple myeloma is a progressive rare haematologic disease. It is characterized by excessive numbers of abnormal plasma cells in the bone marrow and overproduction of intact monoclonal immunoglobulin (IgG, IgA, IgD, or IgE) or Bence-Jones protein only (free immunoglobulin monoclonal κ and λ light chains).
No clinical efficacy and safety studies have been conducted using Neofordex in the treatment of multiple myeloma.
The efficacy and safety of dexamethasone combination treatment in multiple myeloma has been confirmed in numerous clinical studies in newly diagnosed patients and in patients with relapsed or refractory disease. The patient populations studied included a wide range of ages, as well as patients considered eligible or ineligible for autologous stem cell transplantation. High-dose (40 mg or 20 mg) oral dexamethasone has been studied in the therapy of multiple myeloma in combination with chemotherapy in the VAD regimen (vincristine, adriamycin/doxorubicin and dexamethasone) or in association with novel agents, including thalidomide and its analogues as well as proteasome inhibitors. In controlled studies, combination treatment with dexamethasone consistently showed better outcomes in terms of survival and response than single-agent dexamethasone.
The European Medicines Agency has waived the obligation to submit the results of studies with Neofordex in all subsets of the paediatric population in multiple myeloma (see section 4.2 for information on paediatric use).
After oral administration of Neofordex, dexamethasone peak plasma levels are reached at a median of three hours. Bioavailability of dexamethasone is approximately 80%. There is a linear relationship between administered and bioavailable doses.
Dexamethasone is transported by the P-glycoprotein (also known as MDR1). Other MDR transporters may also have a role in dexamethasone transport.
Dexamethasone is bound by plasma proteins, principally albumin, up to about 80%, depending on the administered dose. At very high doses the majority of dexamethasone circulates unbound in the blood. The volume of distribution is approximately 1 l/kg. Dexamethasone crosses the blood-brain barrier and the placental barrier and passes into breast milk.
A minor part of administered dexamethasone is excreted unchanged by the kidney. The major part is hydrogenated or hydroxylated in humans, the major metabolites being hydroxy-6-dexamethasone and dihydro-20-dexamethasone. 30 to 40% are conjugated to glucuronic acid or sulphated in the human liver and excreted in this form in the urine. Dexamethasone is metabolized via cytochrome P450 3A4 (CYP3A4).
Other cytochrome P450 isoenzymes may also play a role in dexamethasone biotransformation.
The plasma half-life of dexamethasone is approximately 250 minutes.
No data are available on the biotransformation of dexamethasone in hepatically impaired patients.
Smoking has no influence on dexamethasone pharmacokinetics. No differences were found in dexamethasone pharmacokinetics between subjects of European and Asian (Indonesian and Japanese) descent.
Glucocorticoids have only weak acute toxicity. No chronic toxicity and carcinogenicity data are available. Genotoxicity findings have been shown to be artefactual. In reproductive toxicity studies in mice, rats, hamsters, rabbits and dogs, dexamethasone has led to embryo-fetal malformations such as increase in cleft palate and skeletal defects; decreases in thymus, spleen and adrenal weight; lung, liver, and kidney abnormalities; and inhibition of growth. Post-natal development assessment of animals treated prenatally presented decreased glucose tolerance and insulin sensitivity, behavioural alterations and decrease in brain and body weight. In males, fertility may be decreased through germ cell apoptosis and spermatogenic defects. Data on female fertility are contradictory.
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