This information is intended for use by health professionals

1. Name of the medicinal product

Neofordex 40 mg tablets

2. Qualitative and quantitative composition

Each tablet contains dexamethasone acetate, equivalent to 40 mg dexamethasone.

Excipient with known effect: Each tablet contains 98.1 mg lactose (as monohydrate). For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Tablet

White, oblong (11 mm × 5.5 mm) tablet with a score-line on one face.

The tablet can be divided for administration of a 20 mg dose (see section 4.2).

4. Clinical particulars
4.1 Therapeutic indications

Neofordex is indicated in adults for the treatment of symptomatic multiple myeloma in combination with other medicinal products.

4.2 Posology and method of administration

Treatment must be initiated and monitored under the supervision of physicians experienced in the management of multiple myeloma.

Posology

The dose and administration frequency varies with the therapeutic protocol and the associated treatment(s). Neofordex administration should follow instructions for dexamethasone administration when described in the Summary of Product Characteristics of the associated treatment(s). If this is not the case, local or international treatment protocols and guidelines should be followed. Prescribing physicians should carefully evaluate which dose of dexamethasone to use, taking into account the condition and disease status of the patient.

The usual posology of dexamethasone is 40 mg once per day of administration.

At the end of dexamethasone treatment, the dose should be tapered in a stepwise fashion until a complete stop.

Elderly

In elderly and/or frail patients, the daily dose may be reduced to 20 mg of dexamethasone, according to the appropriate treatment regimen.

Hepatic impairment or renal insufficiency

Patients with hepatic impairment or renal insufficiency require appropriate monitoring; patients with hepatic impairment should be dosed with caution as there are no data for this patient population (see sections 4.4 and 5.2).

Paediatric population

There is no relevant use of Neofordex in the paediatric population in the indication multiple myeloma.

Method of administration Oral use.

In order to minimise insomnia, the tablet should preferably be taken in the morning.

Tablets should be kept in the blister package until administration. Individual tablets in intact packaging should be separated from the blister using the perforation, e.g. for use in multi-compartment compliance aids.

Tablets may be broken in two equal halves using the score line to provide the 20 mg dose. Due to possible stability issues affecting half tablets stored after division, half-tablets that are not taken immediately should be discarded in agreement with local precautions for environmental protection (see also 6.4).

4.3 Contraindications

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.

4.4 Special warnings and precautions for use

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.

Risk of infection

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 antiinfective 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.

Psychiatric disorders

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.

Gastrointestinal disorders

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.

Eye disorders

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.

Tendonitis

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.

Elderly

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.

Monitoring

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.

Long-term treatment

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.

Lactose intolerance

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.

Use in combination with other multiple myeloma treatment(s)

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).

Venous and arterial thromboembolic events

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.

Neutropenia and thrombocytopenia

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.

4.5 Interaction with other medicinal products and other forms of interaction

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.

Pharmacodynamic interactions

The following combinations should be avoided due to safety concerns:

• With acetylsalicylic acid, at doses ≥ 1 g per dose or 3 g per day, due to an increased risk of bleeding. At doses ≥ 500 mg per dose or < 3 g per day, precautions are required due to increased risk of haemorrhage, ulcerations and gastro-intestinal perforation. However, antithrombotic prophylaxis with low-dose acetylsalicylic acid is possible.

• With live attenuated vaccines, due to risk of vaccine-related illness with risk of death.

The following combinations require precautions due to safety concerns:

• With hypokalaemic medicinal products: hypokalemic diuretics, single or in combination, laxatives, tetracosactide, intravenous amphotericin B, due to increased risk of hypokalaemia. Potassium levels should be monitored and corrected as necessary. In addition, amphotericin B carries a risk of cardiac enlargement and cardiac failure with concurrent use.

• With digitalis, as hypokalaemia enhances the toxic effects of digitalis. Any hypokalaemia should be corrected and patients should be monitored clinically, for electrolytes and by electrocardiograpy.

• With medicinal products that carry a risk of Torsades de Pointes, due to increased risk of ventricular arrhythmia. Any hypokalaemia should be corrected and patients should be monitored clinically, for electrolytes and by electrocardiography.

• With erythropoietic medicinal products or other medicinal products that may increase the risk of thrombosis, such as hormone replacement therapy, in patients receiving thalidomide or its analogues with Neofordex (see sections 4.4 and 4.8).

• With non-steroidal anti-inflammatory drugs (NSAIDs), due to an increased risk of gastrointestinal ulceration.

• With hypoglycaemic medicinal products, as dexamethasone can raise glycaemic levels and diminish glucose tolerance, with a possibility of ketoacidosis. Patients should be made aware of this risk and self-monitoring of blood and urine should be reinforced, especially during the initiation of treatment. The posology of anti-diabetic medicinal products may have to be adjusted during and after the treatment with dexamethasone.

• With anti-hypertensive medicinal products, due to a reduction of their effect (water and sodium retention). The dose of the anti-hypertensive treatment may have to be adjusted during the treatment with dexamethasone.

• With fluoroquinolones, due to possibly increased risk of tendonitis and, in exceptional cases, rupture of the affected tendon, particularly after long-term treatment.

• With methotrexate, due to an increased risk of haematological toxicity.

Pharmacokinetic interactions Effects of other medicinal products on dexamethasone

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:

− Medicinal products that may reduce dexamethasone plasma concentration:

• Aminogluthetimide, due to a reduction of the efficacy of dexamethasone through an increase of its hepatic metabolism.

• Anticonvulsants that are hepatic enzyme inducers: carbamazepine, fosphenytoin, phenobarbital, phenytoin, primidone, due to the reduction of dexamethasone plasma levels and hence its efficacy.

• With rifampicin, due to reduction of dexamethasone plasma concentrations and efficacy by an increase of its hepatic metabolism.

• Topical gastro-intestinal medicinal products, antacids and activated carbon, as well as colestyramine, due to reduction of the intestinal absorption of dexamethasone. The administration of such medicinal products and Neofordex should be separated by at least two hours.

• Ephedrine, due to a reduction in dexamethasone plasma levels by increased metabolic clearance. − Medicinal products that may increase dexamethasone plasma concentration:

• Aprepitant and fosaprepitant, due to an increase of dexamethasone plasma concentrations by a reduction of its hepatic metabolism.

• Clarithromycin, erythromycin, telithromycin, itraconazole, ketoconazole, posaconazole, voriconazole, nelfinavir, ritonavir: Increased dexamethasone plasma concentration due to reduction of its hepatic metabolism by these enzyme inhibitors.

Effects of dexamethasone on other medicinal products

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:

• Oral contraceptives, as it cannot be excluded that the efficacy of oral contraceptives may be reduced during treatment. No interaction study has been performed with oral contraceptives. Effective measures to avoid pregnancy must be taken (see section 4.6). Efficacy of hormone replacement therapy may also be reduced.

• Oral anticoagulants, due to a possible impact of corticosteroids on the metabolism of the oral anticoagulant and on coagulation factors, as well as the haemorrhagic risk (mucosa of the digestive tract, vascular fragility) of dexamethasone therapy itself at high doses or treatment periods above 10 days. It the combination is required, monitoring should be reinforced and coagulation parameters controlled after one week and then every other week of treatment as well as after the end of treatment.

• Docetaxel and cyclophosphamide, due to reduction of their plasma levels by induction of CYP3A and P-gp.

• Lapatinib, due to increased hepatotoxicity of lapatinib likely due to induction of CYP3A4 metabolism.

• Ciclosporin, due to a reduction of ciclosporin bioavailability and plasma levels. Ciclosporin may also increase the intracellular uptake of dexamethasone. In addition, convulsions have been reported with concurrent use of dexamethasone and ciclosporin. Concomitant use of dexamethasone and ciclosporine should be avoided.

• Midazolam, due a reduction in midazolam plasma levels by CYP3A4 induction. The efficacy of midazolam may be reduced.

• Ivermectin, due to a reduction of ivermectin plasma levels. Parasite eradication must be successfully terminated before dexamethasone use (see section 4.4).

• Rifabutin, due to reduced rifabutin plasma levels by induction of intestinal and hepatic CYP3A4.

• Indinavir, due to a strong reduction of indinavir plasma levels by intestinal CYP3A4 induction.

• Erythromycin, due to increased metabolism of erythromycin in non-carriers of the CYP3A5*1 allele after dexamethasone treatment.

• Isoniazid, as glucocorticoids may decrease isoniazid plasma concentrations, probably due to a stimulation of hepatic metabolism of isoniazid and a reduction of glucocorticoid metabolism.

• Praziquantel, due to the reduction of praziquantel plasma concentrations due to an increase of its hepatic metabolism by dexamethasone, with a risk of failure of treatment. The treatments with the two medicinal products should be separated by at least one week.

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.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

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.

Contraception in males and females

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).

Pregnancy

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.

Breast-feeding

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.

Fertility

Studies in animals have shown reductions in female fertility (see Section 5.3). No data on male fertility are available.

4.7 Effects on ability to drive and use machines

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.

4.8 Undesirable effects

Summary of the safety profile

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).

Tabulated list of adverse reactions

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).

System organ class

Adverse reactions

Infections and Infestations

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.

Blood and the lymphatic system disorders

Common: Neutropenia, anaemia, thrombocytopenia, lymphopenia, leukopenia, leukocytosis;

Uncommon: Febrile neutropenia, pancytopenia, coagulopathy.

Endocrine disorders

Common: Cushing's syndrome;

Uncommon: Hypothyroidism;

Not known: Adrenal atrophy, steroid withdrawal syndrome, adrenal insufficiency, hirsutism, menstrual irregularity.

Metabolism and nutrition disorders

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.

Psychiatric disorders

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.

Nervous system disorders

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.

Eye disorders

Common: Vision blurred, cataract;

Uncommon: Conjunctivitis, increased lacrimation; Not known: Chorioretinopathy, glaucoma.

Ear and labyrinth disorders

Common: Vertigo.

Cardiac disorders

Common: Atrial fibrillation, supraventricular extrasystoles, tachycardia, palpitations;

Uncommon: Myocardial ischaemia, bradycardia; Not known: Congestive heart failure.

Vascular disorders

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.

Respiratory, thoracic, or mediastinal disorders

Common: Bronchitis, cough, dyspnoea, pharyngolaryngeal pain, hoarseness, hiccough.

Gastrointestinal disorders

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.

Hepatobiliary disorders

Common: Liver function tests abnormal, alanine aminotransferase increased.

Skin and subcutaneous tissue disorders

Common: Rash, erythema, hyperhidrosis, pruritus, dry skin, alopecia;

Uncommon: Urticaria;

Not known: Skin atrophy, acne.

Musculoskeletal and connective tissue disorders

Very common: Muscular weakness, muscle cramps;

Common: Myopathy, musculoskeletal pain, arthralgia, pain in extremity;

Not known: Pathological fracture, osteonecrosis, osteoporosis, tendon rupture.

Renal and urinary disorders

Common: Pollakiuria;

Uncommon: Renal failure.

General disorders and administration site conditions

Very common: Fatigue, asthenia, oedema (including peripheral and facial oedema);

Common: Pain, mucosal inflammation, pyrexia, chills, malaise; Not known: Impaired healing.

Investigations

Common: Weight decreased, weight increased.

Description of selected adverse reactions

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 3/4 neuropathic reactions, compared to 0.9% of patients treated with dexamethasone alone.

Reporting of suspected adverse reactions

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.

4.9 Overdose

Acute toxicity of dexamethasone is weak and toxic effects have rarely been observed after an acute overdose. No antidote exists and treatment is symptomatic.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Corticosteroids for systemic use, glucocorticoids, ATC code: H02AB02

Mechanism of action

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).

Clinical efficacy and safety

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.

Paediatric population

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).

5.2 Pharmacokinetic properties

Absorption

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.

Distribution

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.

Biotransformation

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.

Elimination

The plasma half-life of dexamethasone is approximately 250 minutes.

Specific groups of patients

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.

5.3 Preclinical safety data

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.

6. Pharmaceutical particulars
6.1 List of excipients

Lactose monohydrate

Microcrystalline cellulose

Magnesium stearate

Colloidal anhydrous silica

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

Tablets should be kept in the blister package until administration. Individual tablets in intact packaging should be separated from the blister using the perforation, e.g. for use in multi-compartment compliance aids. Halved tablets that are not taken immediately should be disposed of (see section 6.6).

6.5 Nature and contents of container

10 x 1 tablets in OPA/Aluminium /PVC-Aluminium perforated unit dose blister. Pack size of 10 tablets.

6.6 Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local requirements. Advise patients to not dispose of unused tablets through household waste or wastewater.

7. Marketing authorisation holder

Laboratoires CTRS

63, rue de l'Est

92100 Boulogne-Billancourt

France

Email: ctrs@ctrs.fr

8. Marketing authorisation number(s)

EU/1/15/1053/001

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 16 March 2016

10. Date of revision of the text

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.