PREDNISOLONE BIOGARAN 20 mg Effervescent tablet, scored, Bottle/20

Scored effervescent tablet.

Prednisolone.........................................................................................................................................................20 mg

As prednisolone sodium metasulfobenzoate.................................................................31,44 mg

For one scored effervescent tablet.

Excipients with known effect: lactose, glucose (maltodextrin), sodium, sodium benzoate and sorbitol.

For the complete list of excipients, see section Composition.

Excipients:

DISEASES OR CONDITIONS

• COLLAGEN DISEASES-CONNECTIVE TISSUE DISORDERS

• Evolving flares of systemic diseases, including: disseminated lupus erythematosus, vasculitis, polymyositis, visceral sarcoidosis.

• DERMATOLOGICAL

• Severe autoimmune bullous dermatoses, in particular pemphigus and bullous pemphigoid;
• severe forms of infantile haemangiomas;
• certain forms of lichen planus;
• certain acute urticarias;
• severe forms of neutrophilic dermatoses.

• DIGESTIVE

• Progressive phases of ulcerative colitis and Crohn's disease;
• chronic active autoimmune hepatitis (with or without cirrhosis);
• severe acute alcoholic hepatitis, histologically proven.

• ENDOCRINE

• Severe subacute De Quervain thyroiditis;
• certain hypercalcaemias.

• HEMATOLOGIC

• Severe immunological thrombocytopenic purpura;
• autoimmune haemolytic anaemias;
• in combination with various chemotherapies in the treatment of malignant lymphoid haemopathies;
• chronic acquired or congenital erythroblastopenias.

• INFECTIOUS

• Tuberculous pericarditis and severe forms of tuberculosis threatening vital prognosis;
• pneumopathy due to Pneumocystis carinii with severe hypoxia.

• NEOPLASTIC

• Antiemetic treatment during antineoplastic chemotherapy;
• oedematous and inflammatory flare associated with antineoplastic treatments (radiotherapy and chemotherapy).

• NEPHROLOGICAL

• Nephrotic syndrome with minimal glomerular lesions;
• nephrotic syndrome of primary focal and segmental hyalinosis;
• stage III and IV lupus nephropathy;
• intrarenal granulomatous sarcoidosis;
• vasculitis with renal involvement;
• primary extracapillary glomerulonephritis.

• NEUROLOGICAL

• Myasthenia;
• cerebral oedema of tumour cause;
• chronic, idiopathic, inflammatory polyradiculoneuritis;
• infantile spasms (West syndrome)/Lennox-Gastaut syndrome;
• relapsing multiple sclerosis, following intravenous corticosteroid therapy.

• OPHTHALMOLOGICAL

• Severe anterior and posterior uveitis;
• oedematous exophthalmos;
• certain optic neuropathies, following intravenous corticosteroid therapy (in this indication, oral route as first intention is not recommended).

• ENT

• Certain serous otitis media;
• nasal sinus polyposis;
• certain acute or chronic sinusitis;
• seasonal allergic rhinitis in short courses;
• acute stridulous laryngitis (subglottic laryngitis) in children.

• RESPIRATORY

• Persistent asthma, preferably as a short course in case of failure of treatment with high-dose inhaled therapy;
• exacerbations of asthma, in particular severe acute asthma;
• chronic obstructive pulmonary disease under evaluation of the reversibility of the obstructive syndrome;
• progressive sarcoidosis;
• diffuse interstitial pulmonary fibroses.

• RHEUMATOLOGICAL

• Rheumatoid arthritis and certain polyarthritis;
• polymyalgia rheumatica-like pseudo-polyarthritis and Horton's disease;
• acute rheumatic fever;
• severe and refractory cervicobrachial neuralgia.

• ORGAN AND ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION

• Prophylaxis or treatment of graft rejection;
• prophylaxis or treatment of graft-versus-host disease.

Dosage

RESERVED FOR ADULTS AND CHILDREN WEIGHING MORE THAN 10 KG.

PREDNISOLONE BIOGARAN 20 mg is suitable for loading treatments or short-term treatments requiring medium or high doses in adults and children weighing more than 10 kg.

For maintenance treatment and for doses below 20 mg per day, more appropriate dosage strengths exist.

 

ADULT

The dosage varies depending on the diagnosis, the severity of the condition, the prognosis, the patient's response and tolerance to treatment.

Loading treatment : 0,35 to 1,2 mg/kg/day. For guidance : 1 to 4 tablets per day in an adult weighing 60 kg.

During severe inflammatory diseases, the dosage ranges from 0,75 to 1,2 mg/kg/day. For guidance : 2 to 4 tablets per day for an adult weighing 60 kg.

Very exceptional situations may require higher doses.

Paediatric population

CHILDREN WEIGHING MORE THAN 10 kg:

The dosage must be adapted to the condition and to the child's weight.

Loading treatment : of 0,5 to 2 mg/kg/day. For information only : ½ to 2 tablets for a child weighing 20 kg.

Alternate-day corticosteroid therapy (one day without corticosteroid and the second day with a dose double the daily dose that would otherwise have been required) is used in children to try to limit growth retardation. This alternate-day regimen can only be considered after control of the inflammatory disease with high corticosteroid doses, and when no rebound is observed during tapering.

IN GENERAL

Treatment "at the loading dose" must be continued until durable control of the disease.

In case of long-term treatment, the tapering must be slow. Obtaining a withdrawal is the goal sought. Maintaining a maintenance dose (minimum effective dose) is a compromise that is sometimes necessary.

For prolonged treatment and high doses, the initial doses may be divided into two daily intakes. Subsequently, the daily dose may be administered as a single intake, preferably in the morning during a meal.

TREATMENT DISCONTINUATION

The pace of withdrawal depends mainly on the duration of treatment, the starting dose and the disease.

Treatment results in suppression of ACTH and cortisol secretion, sometimes with prolonged adrenal insufficiency. On withdrawal, discontinuation must be carried out gradually, in steps, due to the risk of relapse: reduction of 10% every 8 to 15 days on average.

For short courses of less than 10 days, stopping treatment does not require tapering.

During dose tapering (prolonged course): at a dose of 5 to 7 mg prednisone equivalent, when the underlying disease no longer requires corticosteroid therapy, it is advisable to replace the synthetic corticosteroid with 20 mg/day of hydrocortisone until recovery of corticotropic function. If corticosteroid therapy must be maintained at a dose below 5 mg prednisone equivalent per day, a small dose of hydrocortisone may be added to reach a hydrocortisone equivalent of 20 to 30 mg per day. When the patient is only on hydrocortisone, the corticotropic axis can be tested by endocrine tests. These tests alone do not rule out the possibility of adrenal insufficiency occurring during stress.

On hydrocortisone or even after stopping, the patient must be warned of the need to increase the usual dose or resume replacement treatment (for example 100 mg of hydrocortisone intramuscularly every 6 to 8 hours) in case of stress: surgical intervention, trauma, infection.

Method of administration

Oral use.

Anti-inflammatory equivalence (equipotency) for 5 mg of prednisone: 5 mg of prednisolone.

The tablets should be dissolved in a glass of water, during the meal.

This medicine is generally contraindicated in the following situations (there is, however, no absolute contraindication to corticosteroid therapy for a vital indication):

• hypersensitivity to the active substance or to any of the excipients listed in section Composition ;

• any infectious state, excluding the specified indications (see section Indications) ;

• certain active viral infections (notably hepatitis, herpes, chickenpox, shingles);

• psychotic states not yet controlled by treatment;

• live vaccines.

Special warnings

In case of gastroduodenal ulcer, corticosteroid therapy is not contraindicated if antiulcer treatment is combined.

In case of a history of peptic ulcer, corticosteroid therapy may be prescribed, with clinical monitoring and, if necessary, after fibroscopy.

Corticosteroid therapy may promote the occurrence of various infectious complications, notably due to bacteria, yeasts and parasites. The occurrence of malignant strongyloidiasis is a significant risk. All subjects coming from an endemic area (tropical, subtropical regions, southern Europe) must have a stool parasitological examination and systematic eradication treatment before corticosteroid therapy.

Evolving signs of infection may be masked by corticosteroid therapy.

After prolonged use of prednisolone, a corticosteroid withdrawal syndrome may occur.

Discontinuation of corticosteroids after prolonged treatment must be done gradually. The risks associated with abrupt discontinuation of treatment are exacerbation or recurrence of the underlying disease, acute adrenal insufficiency (particularly in stressful situations, for example during infections, after an accident, during intense physical exertion) or corticosteroid withdrawal syndrome. Corticosteroid withdrawal syndrome may present with a set of symptoms, the most typical of which are fever, anorexia, nausea, lethargy, malaise, arthralgia, skin desquamation, asthenia, hypotension and weight loss.

Before starting treatment, it is important to rule out any possibility of a visceral focus, particularly tuberculosis, and to monitor during treatment for the onset of infectious pathologies.

In case of past tuberculosis, prophylactic antituberculosis treatment is necessary if there are significant radiological sequelae and if it cannot be ensured that a well-conducted 6-month course of rifampicin has been given.

The use of corticosteroids requires particularly appropriate monitoring, notably in elderly subjects and in cases of ulcerative colitis (risk of perforation), recent intestinal anastomoses, renal insufficiency, hepatic insufficiency, osteoporosis, myasthenia gravis.

Due to the risk of growth retardation, prolonged use (and exposure to higher doses) of prednisolone should be avoided in children.

Oral or injectable corticosteroids may promote the onset of tendinopathy, or even tendon rupture (exceptional). This risk is increased when co-prescribed with fluoroquinolones and in dialysis patients with secondary hyperparathyroidism or who have undergone kidney transplantation.

This medicinal product is not recommended in combination with anti-inflammatory doses of acetylsalicylic acid (see section Interactions).

Visual disturbances: visual disturbances may occur during systemic or local corticosteroid therapy. In case of blurred vision or the appearance of any other visual symptom during corticosteroid therapy, an ophthalmological examination is required to look for, in particular, a cataract, glaucoma, or a rarer lesion such as central serous chorioretinopathy, described with the administration of systemic or local corticosteroids.

Crises related to the presence of a pheochromocytoma, which may be fatal, have been reported after administration of corticosteroids.

Corticosteroids should be administered to patients in whom a pheochromocytoma is suspected or identified only after appropriate assessment of the benefit/risk ratio (see section Adverse effects).

Scleroderma renal crisis: precautions are required for patients suffering from systemic sclerosis, as an increased incidence of scleroderma renal crisis (which may be fatal), accompanied by hypertension and a decrease in urinary output, has been reported with administration of a daily dose of 15 mg or more of prednisolone. Blood pressure and renal function (serum creatinine) should therefore be checked regularly. In case of suspected renal crisis, blood pressure must be carefully monitored.

Adrenal insufficiency

Secondary adrenocortical insufficiency may develop during treatment.

Glucocorticoid-induced suppression of the hypothalamic-pituitary-adrenal function depends on the dose and duration of treatment. Recovery occurs gradually as the steroid dose is reduced and stopped. However, relative insufficiency may persist for months after treatment is discontinued; therefore, in any stressful situation (for example during infections, after accidents, or in cases of increased physical exertion) treatment should be reinstated.

Since marketing, tumor lysis syndrome (TLS) has been reported in patients with malignant hemopathies following the use of prednisolone alone or in combination with other chemotherapy agents. Patients at high risk of TLS, such as patients with a high proliferation rate, a high tumor burden and high sensitivity to cytotoxic agents, must be closely monitored and appropriate precautions must be taken (see section Adverse effects Adverse effects

Special precautions for use

This medicine must not be used in children weighing less than 10 kg and therefore in premature infants and term newborns (see section Dosage and administration). However, hypertrophic cardiomyopathies have been reported after systemic administration of other glucocorticoids in premature infants. In infants treated with systemic glucocorticoids, cardiac echocardiography should be performed to monitor myocardial structure and function.

In case of long-term treatment with corticosteroids

A diet low in rapidly absorbed sugars and high in protein should be combined, due to the hyperglycaemic effect and protein catabolism with negative nitrogen balance.

Fluid and sodium retention is common, partly responsible for a possible rise in blood pressure. This medicine contains sodium (see the paragraph "Excipients with known effect" below). Sodium intake will be reduced for daily dosages above 15 or 20 mg of prednisone equivalent and moderated in long-term treatments at low doses.

Potassium supplementation is only justified for high-dose treatments, prescribed for a long duration, or in case of risk of rhythm disorders or association with a hypokalaemic treatment.

The patient must systematically have an intake of calcium and vitamin D.

When corticosteroid therapy is essential, diabetes and arterial hypertension are not contraindications, but treatment may lead to their decompensation. Their management should be reassessed.

Certain viral diseases (chickenpox, herpes zoster and measles) can be very severe in patients treated with glucocorticoids. Unless they have previously had these viral diseases, patients must avoid any contact with individuals with chickenpox, herpes zoster or measles. If they are exposed to such infections while receiving prednisolone, they must contact a doctor immediately even if they have no symptoms.

Excipients with known effect

This medicine contains lactose and glucose. Patients with galactose intolerance, total lactase deficiency or glucose-galactose malabsorption syndrome (rare hereditary diseases) must not take this medicine.

This medicine contains less than 7 mg of sorbitol per tablet.

This medicine contains 10,50 mg of sodium benzoate per tablet. Sodium benzoate may increase the risk of jaundice (yellowing of the skin and eyes) in newborns (up to 4 weeks).

This medicine contains 1,2 mmol (27 mg) of sodium per tablet, which is equivalent to 1,4 % of the maximum recommended daily dietary intake of 2 g of sodium for an adult set by the WHO.

Hypokalaemia-inducing medicines

Hypokalaemia is a factor favouring the occurrence of heart rhythm disorders (torsades de pointes, in particular) and increasing the toxicity of certain medicines, for example digoxin. Therefore, medicines that may cause hypokalaemia are involved in a large number of interactions. These include potassium-depleting diuretics, alone or combined, stimulant laxatives, glucocorticoids, tetracosactide and amphotericin B (IV route).

Associations contraindicated

+ Live attenuated vaccines

Except for inhaled and topical routes, and for doses above 10 mg/day of prednisone equivalent (or > 2 mg/kg/day in children or > 20 mg/day in children over 10 kg) for more than two weeks, and for corticosteroid "pulses": risk of generalised vaccinia disease, possibly fatal.

Live attenuated vaccines are contraindicated even during the 3 months following discontinuation of corticosteroid therapy.

Contraindicated combinations (see section 4.4)

+ Acetylsalicylic acid

Increased bleeding risk.

Association not recommended with anti-inflammatory doses of acetylsalicylic acid (≥ 1 g per dose and/or ≥ 3 g per day).

Associations requiring precautions for use

+ Oral anticoagulants

Possible impact of corticotherapy on the metabolism of oral anticoagulants and on that of coagulation factors.

Bleeding risk specific to corticosteroid therapy (digestive mucosa, vascular fragility) at high doses or in prolonged treatment exceeding 10 days. When the association is justified, reinforce monitoring: where applicable, biological check at 8th day, then every 15 days during corticotherapy and after its discontinuation.

+ Other potassium-lowering agents

Increased risk of hypokalaemia. Monitor serum potassium and, if necessary, correct.

+ Enzyme-inducing anticonvulsants

Decrease in plasma concentrations and efficacy of corticosteroids due to increased hepatic metabolism by the inducer: the consequences are particularly significant in Addisonian patients treated with hydrocortisone and in cases of transplantation. Clinical and biological monitoring; adjust the corticosteroid dosage during treatment with the inducer and after its discontinuation.

+ Digoxin

Hypokalaemia favouring toxic effects of cardiac glycosides. Correct any hypokalaemia beforehand and carry out clinical, electrolyte and electrocardiographic monitoring.

+ Isoniazid

Described for prednisolone: decrease in plasma concentrations of isoniazid. Proposed mechanism: increased hepatic metabolism of isoniazid and decreased metabolism of glucocorticoids. Clinical and biological monitoring.

 

+ Medicinal products liable to induce torsades de pointes

Increased risk of ventricular arrhythmias, particularly torsades de pointes. Correct any hypokalaemia before administering the product and carry out clinical, electrolyte and electrocardiographic monitoring.

+ Rifampicin

Decrease in plasma concentrations and efficacy of corticosteroids through increased hepatic metabolism caused by rifampicin; the consequences are particularly significant in Addisonian patients treated with hydrocortisone and in cases of transplantation. Clinical and biological monitoring; adjustment of the corticosteroid dosage during treatment with rifampicin and after its discontinuation.

+ CYP3A inhibitors

Concomitant administration of CYP3A inhibitors (for example itraconazole, clarithromycin, erythromycin) and products containing cobicistat or ritonavir could increase the risk of systemic side effects of corticosteroids. The association should be avoided, unless the benefits outweigh the increased risk of systemic corticosteroid side effects. Patients should be monitored for possible systemic corticosteroid side effects, and a reduction in the corticosteroid dose may be considered.

Associations to be taken into account

+ Fluoroquinolones

Possible increased risk of tendinopathy, or even tendon rupture (exceptional), particularly in patients receiving prolonged corticosteroid therapy.

+ Acetylsalicylic acid

Increased bleeding risk.

To be considered with analgesic or antipyretic doses (≥ 500 mg per dose and/or < 3 g per day).

+ Non-steroidal anti-inflammatory drugs

Increased risk of gastrointestinal ulceration and bleeding.

+ Ciclosporin

Increased effects of prednisolone: cushingoid appearance, reduced carbohydrate tolerance (decreased clearance of prednisolone).

+ Oestrogens

Caution is advised when a patient receiving glucocorticoids is treated concurrently with oestrogens or oestrogen-containing preparations, and clinical monitoring is recommended. A reduction in the prednisolone dose may be considered, if necessary.

Pregnancy

In animals, experimentation shows a teratogenic effect that varies according to species.

In humans, there is transplacental passage.

An increased incidence of cleft palate was observed in animal studies (see section Preclinical safety).

According to data from an epidemiological study, the use of glucocorticoids during the first trimester may increase the risk of cleft lip and/or cleft palate.

PREDNISOLONE BIOGARAN should only be used during pregnancy if the benefits for the mother outweigh the risks, including those for the foetus.

During chronic diseases requiring treatment throughout pregnancy, a slight intrauterine growth retardation is possible. Neonatal adrenal insufficiency has exceptionally been observed after corticosteroid therapy at high doses.

It is justified to observe a period of clinical (weight, diuresis) and biological monitoring of the newborn.

Breast-feeding

Prednisolone is excreted in breast milk. In case of treatment at high doses and on a chronic basis, breastfeeding is not recommended.

Adverse effects are listed by system organ class and may occur at the following frequencies: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10 000, < 1/1000), very rare (< 1/10 000) and not known (cannot be estimated from the available data).

Undesirable effects are mainly to be feared at high doses or with prolonged treatment over several months.

System organ class	Adverse Effect
Infections and infestations	Frequency not known: increased susceptibility to infections
Benign, malignant and unspecified tumours (including cysts and polyps)	Frequency not known: pheochromocytoma crises, cases of tumour lysis syndrome have been reported in patients with haematological malignancies (see section Warnings and precautions)
Immune system disorders	Frequency not known: hypersensitivity
Endocrine disorders	Frequency not known: Cushing's syndrome, adrenocorticotropic hormone deficiency, adrenal deficiency or insufficiency, adrenal atrophy4, manifestation of latent diabetes, growth retardation in children, corticosteroid withdrawal syndrome1
Metabolism and nutrition disorders	Frequency undetermined: hypokalemia, metabolic alkalosis, fluid and sodium retention
Psychiatric disorders	Common: euphoric mood, insomnia, agitation (nervousness) Rare: manic-type episodes, confusional or confusional-oneiric states Frequency undetermined: depressive state upon treatment discontinuation
Nervous system disorders	Frequency undetermined: increased intracranial pressure with papilledema (idiopathic intracranial hypertension), generally after treatment discontinuation, convulsions (systemic or intrathecal route)
Eye disorders	Frequency undetermined: blurred vision, glaucoma and cataracts (including subcapsular), chorioretinopathies1
Cardiac disorders	Frequency undetermined: congestive heart failure, hypertrophic cardiomyopathies in premature infants1
Vascular disorders	Frequency undetermined: hypertension
Gastrointestinal disorders	Frequency undetermined: gastroduodenal ulcers, small intestine ulcer, perforations and gastrointestinal hemorrhages; acute pancreatitis has been reported, especially in children
Skin and subcutaneous tissue disorders	Frequency undetermined: skin atrophy, acne, purpura, ecchymosis, hypertrichosis
Musculoskeletal and connective tissue disorders	Frequency undetermined: osteonecrosis of the femoral and humeral heads, and of the knee, muscle atrophy preceded by muscle weakness (increased protein catabolism), osteoporosis, vertebral compression fractures, pathological fractures of long bones, tendon ruptures2
Renal and urinary disorders	Frequency undetermined: scleroderma renal crisis3
Disorders of the reproductive system and breast	Frequency undetermined: irregular menstruation
General disorders and administration site conditions	Frequency undetermined: delayed wound healing
Investigations	Frequency undetermined: decreased glucose tolerance, increased intraocular pressure
Injury, poisoning and procedural complications	Frequency undetermined: contusion

1 class effect of corticosteroids – See section Warnings and precautions "Special warnings and precautions for use"

2 in a few exceptional cases, tendon ruptures have been described, particularly with concomitant administration of fluoroquinolones.

3 scleroderma renal crisis

4 which is sometimes permanent.

Description of selected adverse reactions:

Scleroderma renal crisis

The frequency of scleroderma renal crisis varies among the different subpopulations. The highest risk was observed in patients with diffuse systemic sclerosis. The lowest risk was observed in patients with limited systemic sclerosis (2 %) and juvenile systemic sclerosis (1 %).

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 should report any suspected adverse reactions via the national reporting system: Agence nationale de sécurité du médicament et des produits de santé (ANSM) and the network of Regional Centres of Pharmacovigilance - Website: https://signalement.social-sante.gouv.fr/.

Pharmacotherapeutic class: Glucocorticoids, ATC code: H02AB06 (H: Systemic hormonal preparations, excluding sex hormones and insulins).

Physiological glucocorticoids (cortisone and hydrocortisone) are essential metabolic hormones.

Synthetic corticosteroids, including this specialty, are used mainly for their anti-inflammatory effect. At high doses, they reduce the immune response. Their metabolic and sodium-retaining effect is less than that of hydrocortisone.

Absorption

The peak plasma concentration is reached orally in 4 hours.

Distribution

The plasma half-life is between 2,5 and 3,5 hours.

Biotransformation

Metabolism is hepatic.

Elimination

Elimination is renal and biliary.

Animal studies in which glucocorticoids were administered to pregnant mice, rats and rabbits showed an increased incidence of cleft palate in litters.

3 years.

This medicine does not require any particular storage precautions.

No special requirements.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

List I

Marketing authorisation (AMM)

CIP 3400935740557 (Fl/20).

Price:

3,18 euros (Fl/20).

Social Security reimbursement at 65%.
Collection.