Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: Laboratoires CTRS, 63, rue de l’Est, 92100 Boulogne-Billancourt, France, Email: ctrs@ctrs.fr
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Active viral disease (especially viral hepatitis, herpes, varicella, shingles).
Uncontrolled psychoses.
When Neofordex is given in combination with other medicinal products, refer to their Summaries of Product Characteristics for additional contraindications.
Neofordex is a high-dose glucocorticoid. This should be taken into consideration in the surveillance of the patient. The benefit from dexamethasone treatment should be carefully and continuously weighed against actual and potential risks.
Treatment with high-dose dexamethasone increases the risk of developing serious infections, in particular due to bacteria, yeasts and/or parasites. Such infections can also be caused by microorganisms that rarely cause disease under normal circumstances (opportunistic infections). Signs of a developing infection may be masked by dexamethasone therapy.
Before the start of treatment, any source of infection, especially tuberculosis, should be removed. During treatment, patients should be closely monitored for the appearance of infections. In particular, pneumonia occurs commonly. Patients should be informed of the signs and symptoms of pneumonia and be advised to seek medical attention in case of their appearance. In case of active infectious disease, appropriate anti- infective treatment must be added to the treatment with Neofordex.
In cases of prior tuberculosis with major radiological sequelae or if it is not certain that a full 6-month rifampicin treatment course has been followed, a prophylactic anti-tuberculosis treatment is required.
There is a risk of severe strongyloidiasis. Patients from endemic areas (tropical and sub-tropical regions, southern Europe) should have a stool examination and if required an eradication of the parasite before initiating dexamethasone treatment.
Certain viral diseases (varicella, measles) can be aggravated in patients receiving glucocorticoid treatment or who have received glucocorticoid treatment within the previous 3 months. Patients must avoid contact with subjects with chickenpox or measles. Immunocompromised patients who have not previously had chickenpox or measles are particularly at risk. If such patients have been in contact with people with chickenpox or measles, a preventive treatment with intravenous normal immunoglobulin or passive immunisation with varicella zoster immunoglobulin (VZIG) must be started as appropriate. Exposed patients should be advised to seek medical attention without delay.
Neofordex should not be used with live attenuated vaccines (see section 4.5). Vaccinations with inactivated vaccines are usually possible. However, the immune response and hence the effect of the vaccination can be diminished by high glucocorticoid doses.
Dexamethasone can suppress skin reaction to allergy testing. It can also affect the nitro blue tetrazolium (NBT) test for bacterial infections and cause false-negative results.
Patients and/or carers should be warned that potentially severe psychiatric adverse reactions may occur with systemic steroids (see section 4.8). Symptoms typically emerge within a few days or weeks of starting the treatment. Risks may be higher with high doses (see also section 4.5 for pharmacokinetic interactions that can increase the risk of adverse reactions), 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 psychoses.
Insomnia may be minimised by administering Neofordex in the morning.
Treatment for active gastric or duodenal ulceration should be commenced prior to initiation of corticosteroids. Appropriate prophylaxis should be considered for patients with a previous history of, or risk factors for, gastric or duodenal ulceration, haemorrhage or perforation. Patients should be monitored clinically, including by endoscopy.
Systemic treatment with glucocorticoids can induce chorioretinopathy which may result in impaired vision including loss of vision.
Prolonged use of corticosteroids may produce subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to fungi or viruses. Particular care is needed when treating patients with glaucoma (or family history of glaucoma) as well as when treating patients with ocular herpes simplex, because of possible corneal perforation.
Corticosteroids can favour the development of tendonitis and, in exceptional cases, rupture of the affected tendon. This risk is increased by concomitant use of fluoroquinolones and in patients undergoing dialysis with secondary hyperparathyroidism or after renal transplantation.
The common adverse reactions to systemic corticosteroids may be associated with more serious consequences in old age, especially osteoporosis, hypertension, hypokalaemia, diabetes, susceptibility to infection and thinning of the skin. Close clinical supervision is required to avoid life-threatening reactions.
Use of corticosteroids requires appropriate monitoring in patients with ulcerative colitis (due to perforation risk), recent intestinal anastomoses, diverticulitis, recent myocardial infarction (risk of left ventricular free wall rupture), diabetes mellitus (or family history), renal insufficiency, hepatic impairment, osteoporosis and myasthenia gravis.
During treatment, a diet low in simple sugars and high in protein should be followed due to the hyperglycaemic effect of corticosteroids and their stimulation of protein catabolism with a negative nitrogen balance.
Water and sodium retention is common and can lead to hypertension. Sodium intake should be reduced and blood pressure should be monitored. Particular care is needed when treating patients with renal impairment, hypertension or congestive heart failure.
Potassium levels should be monitored during treatment. Potassium supplementation should be given particularly if there is a risk of cardiac arrhythmia or concurrent hypokalaemic medicinal products.
Glucocorticoid therapy may reduce the effect of anti-diabetic and antihypertensive treatment. The dose of insulin, oral anti-diabetics and anti-hypertensive medicinal products may have to be increased.
Depending on the duration of treatment, calcium metabolism may be impaired. Calcium and vitamin D levels should be monitored. In patients not already prescribed bisphosphonates for multiple myeloma related bone disease, bisphosphonates should be considered, particularly if risk factors for osteoporosis are present.
Neofordex contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
When Neofordex is given in combination with other medicinal products, the Summary of Product Characteristics of these other medicinal products must be consulted prior to initiation of treatment with Neofordex.
When Neofordex is used in combination with known teratogens (e.g. thalidomide, lenalidomide, pomalidomide, plerixafor), particular attention to pregnancy testing and prevention requirements is needed (see section 4.6).
In patients with multiple myeloma, the combination of dexamethasone with thalidomide and its analogues is associated with an increased risk of venous thromboembolism (predominantly deep vein thrombosis and pulmonary embolism) and arterial thromboembolism (predominantly myocardial infarction and cerebrovascular event) (see sections 4.5 and 4.8).
Consequently, patients with known risk factors for thromboembolism (including prior thrombosis) should be closely monitored. Action should be taken to try to minimize all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia). Concomitant administration of erythropoietic medicinal products may also increase thrombotic risk in these patients. Therefore, erythropoietic medicinal products, or other medicinal products that may increase the risk of thrombosis, such as hormone replacement therapy, should be used with caution in multiple myeloma patients receiving dexamethasone with thalidomide and its analogues. A haemoglobin concentration above 12 g/dl should lead to discontinuation of erythropoietic medicinal products.
Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, arm or leg swelling. Prophylactic antithrombotic treatment should be recommended, especially in patients with additional thrombotic risk factors. The decision to take antithrombotic prophylactic measures should be made after careful assessment of an individual patient’s underlying risk factors.
If the patient experiences any thromboembolic events, treatment must be discontinued and standard anticoagulation therapy started. Once the patient has been stabilised on the anticoagulation treatment and any complications of the thromboembolic event have been managed, the treatment with dexamethasone and thalidomide or its analogues may be restarted at the original dose dependent upon a benefit risk assessment. The patient should continue anticoagulation therapy during the course of treatment with dexamethasone and thalidomide or its analogues.
The combination of dexamethasone with lenalidomide in multiple myeloma patients is associated with a higher incidence of grade 4 neutropenia (5.1% in lenalidomide/dexamethasone-treated patients compared with 0.6% in placebo/dexamethasone-treated patients; see section 4.8). Grade 4 febrile neutropenia episodes were observed infrequently (0.6% in lenalidomide/dexamethasone-treated patients compared to 0.0% in placebo/dexamethasone treated patients; see section 4.8). Neutropenia was the most frequently reported Grade 3 or 4 haematological adverse reaction in patients with relapsed/refractory multiple myeloma treated with the combination of dexamethasone with pomalidomide. Patients should be monitored for haematological adverse reactions, especially neutropenia. Patients should be advised to promptly report febrile episodes. A dose reduction of lenalidomide or pomalidomide may be required. In case of neutropenia, the physician should consider the use of growth factors in patient management.
The combination of dexamethasone with lenalidomide in multiple myeloma patients is associated with a higher incidence of grade 3 and grade 4 thrombocytopenia (9.9% and 1.4%, respectively, in lenalidomide/dexamethasone-treated patients compared to 2.3% and 0.0% in placebo/dexamethasone-treated patients) (see section 4.8). Thrombocytopenia was also reported very commonly by patients with relapsed/refractory multiple myeloma treated with the combination of dexamethasone with pomalidomide. Patients and physicians are advised to be observant for signs and symptoms of bleeding, including petechiae and epistaxes, especially in case of concomitant treatment susceptible to induce bleeding. A dose reduction of lenalidomide or pomalidomide may be required.
A complete blood cell count, including white blood cell count with differential count, platelet count, haemoglobin, and haematocrit should be performed at baseline, every week for the first 8 weeks of dexamethasone/lenalidomide treatment and monthly thereafter to monitor for cytopenias.
Prior to the use of Neofordex in combination with any other medicinal product, reference should be made to the Summary of Product Characteristics of that product.
The following combinations should be avoided due to safety concerns:
The following combinations require precautions due to safety concerns:
Dexamethasone is metabolized via cytochrome P450 3A4 (CYP3A4), and transported by the P-glycoprotein (P-gp, also known as MDR1). Concomitant administration of dexamethasone with inducers or inhibitors of CYP3A4 or P-gp may lead to decreased or increased plasma concentrations of dexamethasone, respectively.
The following combinations require precautions due to changes in dexamethasone pharmacokinetics:
Dexamethasone is a moderate inducer of CYP3A4 and of P-gp. Concomitant administration of dexamethasone with substances that are metabolised via CYP3A4 or transported by P-gp could lead to increased clearance and decreased plasma concentrations of these substances:
Repeated, daily administration of dexamethasone also leads to reduced dexamethasone plasma levels due to the induction of CYP3A4 and P-gp. No dose adjustment is needed in the treatment of multiple myeloma.
Dexamethasone has no clinically significant pharmacokinetic interaction with thalidomide, lenalidomide, pomalidomide, bortezomib, vincristine or doxorubicin.
Women should avoid pregnancy during Neofordex treatment. Dexamethasone may cause congenital malformations (see section 5.3). Dexamethasone may be used with known teratogens (e.g. thalidomide, lenalidomide, pomalidomide, plerixafor), or with cytotoxic substances which are contraindicated in pregnancy. Patients receiving Neofordex in combination with products containing thalidomide, lenalidomide or pomalidomide should adhere to the pregnancy prevention programmes of those products. Reference should be made to all the relevant Summary of Product Characteristics prior to the commencement of any combination treatment for additional information.
Women of childbearing potential and their male partners should take appropriate contraceptive measures. In particular, the requirements of the pregnancy prevention programme for combination treatment with thalidomide or its analogues must be followed. The efficacy of oral contraceptives may be reduced during dexamethasone treatment (see section 4.5).
Based on human experience, dexamethasone is suggested to cause congenital malformations, particularly intra-uterine growth retardation and rarely neonatal adrenal insufficiency, when administered during pregnancy.
Studies in animals have shown reproductive toxicity (see section 5.3).
Neofordex should not be used during pregnancy unless the clinical condition of the woman requires treatment with dexamethasone.
Glucocorticoids are excreted in human milk and effects have been shown in breastfed newborns/infants of treated women.
A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Neofordex therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.
Studies in animals have shown reductions in female fertility (see Section 5.3). No data on male fertility are available.
Neofordex has moderate influence on the ability to drive and use machines.
Dexamethasone may cause confusional state, hallucinations, dizziness, somnolence, fatigue, syncope and blurred vision (see section 4.8). If affected, patients should be instructed not to drive, use machines or perform hazardous tasks while being treated with dexamethasone.
Adverse reactions to Neofordex correspond to the predictable safety profile of glucocorticoids. Hyperglycaemia, insomnia, muscle pain and weakness, asthenia, fatigue, oedema and weight increase occur very commonly. Less common but serious adverse reactions include: pneumonia and other infections and psychiatric disorders (see section 4.4). In combination with thalidomide or its analogues the most serious adverse reactions were venous thromboembolic events, predominantly deep vein thrombosis and pulmonary embolism, and myelosuppression, particularly neutropenia and thrombocytopenia (see section 4.4).
The incidence of predictable adverse reactions, including adrenal atrophy, correlates with dose, timing of administration and the duration of treatment (see section 4.4).
The adverse reactions observed in patients treated with dexamethasone are listed below by system organ class and frequency. Data are derived from historical experience and clinical studies in multiple myeloma patients in which dexamethasone was used as monotherapy or in combination with placebo. Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000 including isolated reports), not known (cannot be estimated from the available data).
Common: Pneumonia, herpes zoster, upper respiratory tract infection, lower respiratory tract infection, oral candidiasis, oral fungal infection, urinary tract infection, herpes simplex, candidal infection.
Not known: Infection, sepsis.
Common: Neutropenia, anaemia, thrombocytopenia, lymphopenia, leukopenia, leukocytosis.
Uncommon: Febrile neutropenia, pancytopenia, coagulopathy.
Common: Cushing’s syndrome.
Uncommon: Hypothyroidism.
Not known: Adrenal atrophy, steroid withdrawal syndrome, adrenal insufficiency, hirsutism, menstrual irregularity.
Very common: Hyperglycaemia.
Common: Hypokalaemia, diabetes mellitus, anorexia, increased or decreased appetite, hypoalbuminaemia, fluid retention, hyperuricaemia.
Uncommon: Dehydration, hypocalcaemia, hypomagnesemia.
Not known: Glucose tolerance impaired, sodium retention, metabolic alkalosis.
Very common: Insomnia.
Common: Depression, anxiety, aggression, confusional state, irritability, nervousness, mood alteration, agitation, euphoric mood.
Uncommon: Mood swings, hallucinations.
Not known: Mania, psychosis, behavioural disturbance.
Common: Peripheral neuropathy, dizziness, psychomotor hyperactivity, disturbance in attention, memory impairment, tremor, paraesthesia, headache, ageusia, dysgeusia, somnolence, lethargy, balance impaired, dysphonia.
Uncommon: Cerebrovascular accident, transient ischaemic attack, amnesia, coordination abnormal, ataxia, syncope.
Not known: Convulsions.
Common: Vision blurred, cataract.
Uncommon: Conjunctivitis, increased lacrimation.
Not known: Chorioretinopathy, glaucoma.
Common: Vertigo.
Common: Atrial fibrillation, supraventricular extrasystoles, tachycardia, palpitations.
Uncommon: Myocardial ischaemia, bradycardia.
Not known: Congestive heart failure.
Common: Venous thromboembolic reactions, predominantly deep vein thrombosis and pulmonary embolism, hypertension, hypotension, flushing, blood pressure increased, diastolic blood pressure decreased.
Not known: Purpura, bruising.
Common: Bronchitis, cough, dyspnoea, pharyngolaryngeal pain, hoarseness, hiccough.
Very Common: Constipation.
Common: Vomiting, diarrhoea, nausea, dyspepsia, stomatitis, gastritis, abdominal pain, dry mouth, abdominal distension, flatulence.
Not known: Pancreatitis, gastrointestinal perforation, gastrointestinal haemorrhage, gastrointestinal ulcer.
Common: Liver function tests abnormal, alanine aminotransferase increased.
Common: Rash, erythema, hyperhidrosis, pruritus, dry skin, alopecia.
Uncommon: Urticaria.
Not known: Skin atrophy, acne.
Very common: Muscular weakness, muscle cramps.
Common: Myopathy, musculoskeletal pain, arthralgia, pain in extremity.
Not known: Pathological fracture, osteonecrosis, osteoporosis, tendon rupture.
Common: Pollakiuria.
Uncommon: Renal failure.
Very common: Fatigue, asthenia, oedema (including peripheral and facial oedema).
Common: Pain, mucosal inflammation, pyrexia, chills, malaise.
Not known: Impaired healing.
Common: Weight decreased, weight increased.
Prior to the use of Neofordex in combination with any other medicinal product, reference should be made to the Summary of Product Characteristics of that product.
The incidence rate of certain adverse reactions varies depending on the combination treatment used.
The combination of lenalidomide with dexamethasone in relapsed or refractory multiple myeloma patients is associated with a higher incidence of grade 4 neutropenia (5.1% in lenalidomide/dexamethasone-treated patients compared with 0.6% in placebo/dexamethasone-treated patients). Grade 4 febrile neutropenia episodes were observed infrequently (0.6% in lenalidomide/dexamethasone-treated patients compared to 0.0% in placebo/dexamethasone treated patients). A similar incidence of high-grade neutropenia was reported in newly diagnosed patients treated with the combination of lenalidomide and dexamethasone.
Neutropenia occurred in 45.3% of relapsed and refractory multiple myeloma patients who received low dose dexamethasone plus pomalidomide (Pom + LD-Dex), and in 19.5% of patients who received high dose dexamethasone (HD-Dex). Neutropenia was Grade 3 or 4 in 41.7% of patients who received Pom + LD-Dex, compared with 14.8% who received HD-Dex. In Pom + LD-Dex treated patients neutropenia was infrequently serious (2.0% of patients), did not lead to treatment discontinuation, and was associated with treatment interruption in 21.0% of patients, and with dose reduction in 7.7% of patients. Febrile neutropenia (FN) was experienced in 6.7% of patients who received Pom + LD-Dex, and in no patients who received HD-Dex. All were reported to be Grade 3 or 4. FN was reported to be serious in 4.0% of patients. FN was associated with dose interruption in 3.7% of patients, and with dose reduction in 1.3% of patients, and with no treatment discontinuations.
The combination of lenalidomide with dexamethasone in relapsed or refractory multiple myeloma patients is associated with a higher incidence of grade 3 and grade 4 thrombocytopenia (9.9% and 1.4%, respectively, in lenalidomide/dexamethasone-treated patients compared to 2.3% and 0.0% in placebo/dexamethasone-treated patients). A similar incidence of high-grade thrombocytopenia was reported in newly diagnosed patients treated with the combination of lenalidomide and dexamethasone. Thrombocytopenia occurred in 27.0% of relapsed and refractory multiple myeloma patients who received Pom + LD-Dex, and 26.8% of patients who received HD-Dex. Thrombocytopenia was Grade 3 or 4 in 20.7% of patients who received Pom + LD-Dex and in 24.2% who received HD-Dex. In Pom + LD-Dex treated patients, thrombocytopenia was serious in 1.7% of patients, led to dose reduction in 6.3% of patients, to dose interruption in 8% of patients and to treatment discontinuation in 0.7% of patients.
The combination of lenalidomide, thalidomide or pomalidomide with dexamethasone is associated with an increased risk of deep vein thrombosis and pulmonary embolism in patients with multiple myeloma (see section 4.5). Concomitant administration of erythropoietic medicinal products or previous history of deep vein thrombosis may also increase thrombotic risk in these patients.
Low-grade peripheral neuropathic reactions, predominantly grade 1 paraesthesia, may be observed with dexamethasone alone in up to 34% of newly diagnosed multiple myeloma patients. However, both incidence and severity of peripheral neuropathy increase with concomitant bortezomib or thalidomide administration. In one study, 10.7% of patients treated with thalidomide and dexamethasone experienced grade ¾ neuropathic reactions, compared to 0.9% of patients treated with dexamethasone alone.
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 the national reporting system listed in Appendix V.
Not applicable.
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