Rindelt

Document: Rindelt tablet ENG SmPC change

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THEMEDICINAL PRODUCT

Rindelt, tablets, 2,5 mg

Rindelt, tablets, 5 mg

Rindelt, tablets, 10 mg

Rindelt, tablets, 20 mg

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One tablet contains 2,5 mg prednisolone

One tablet contains 5 mg prednisolone

One tablet contains 10 mg prednisolone

One tablet contains 20 mg prednisolone

Excipients:

2,5 mg tablet contains lactose monohydrate 39,5 mg

5 mg tablet contains lactose monohydrate 79 mg

10 mg tablet contains lactose monohydrate 158 mg

20 mg tablet contains lactose monohydrate 98,72 mg

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Tablet

Appearance:

2,5 mg: 6 mm, white, round, biplane tablet, scored on one side. The tablet can be divided in two equal parts.

5 mg: 8 mm, white, round, biplane tablet, scored on one side. The tablet can be divided in two equal parts.

10 mg: 10 mm, white, round, biconvex tablet, scored on one side. The tablet can be divided in two equal parts.

20 mg: 8mm, white, round, biconvex tablet, scored on one side. The tablet can be divided in two equal parts.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Prednisolone is indicated to treat conditions where the antiinflammatory and immunosuppressive effects of prednisolone is desired. Examples are rheumatoid arthritis, SLE, certain vasculites as temporal arteritis and polyarteritis nodosa, sarcoidodis, asthma bronchiale, colitis ulcerosa, hemolytic anemia and granulocytopenia and severe allergic conditions.

Rindelt is indicated in the treatment of tumors (certain cases of acute leukemia, lymphoma, mammary cancer and prostate cancer).

4.2 Posology and method of administration

The dose used will depend upon the disease, its severity, and the clinical response obtained. The lowest dosage that will produce an acceptable result should be used. The following regimens are for guidance only.

In general 10-30 mg daily for one to three weeks. In severe and acute conditions 50-60 mg or more can be administered for some days. Divided dosage is usually employed.

When the anticipated response is observed, the dose should be gradually reduced to the lowest possible dose maintaining an adequate clinical response. The daily dose should be reduced with 2,5 mg to 5 mg every second to every fifth day (at the highest doses quicker) and the daily maintenance dose should not be more than 10 mg daily.

If the daily maintenance dose is administered in the morning (8am), prednisolone will follow the natural daily cycle of the adrenal cortex and result in minimal suppression of the adrenal cortex. This strategy can be tested at first. In many cases a late evening dose or a split dose will be preferred (e.g. in case of rheumatic patients without morning joint stiffness and in asthmatic patients where corticosteroid protection during the night is necessary).

In certain cases of asthma, allergic conditions, dermatosis etc. the patient can benefit from double daily dose, with prednisolone onlyadministered every second day in the morning.

The therapy should be gradually reduced, especially after high doses, since the endogenous ACTH and cortisol secretion may be reduced after long term treatment.

Increased dose may be administered before or during situations of stress.

Increased dose may be administered in case of fever and stress.

For diabetic patients being treated with prednisolone, increased doses of insulin should be administered.

Rheumatoid arthritis: 7.5 to 10 mg daily. For maintenance therapy the lowest effective dosage is used.

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Systemic infection unless specific anti-infective therapy is employed.
Ventricular or duodenal ulcer.
Vaccines containing live, attenuated viruses or bacteria should not be given to patients receiving high‑dose corticosteroid therapy during treatment-induced immune deficiency.

In general no contraindications apply in conditions where the use of glucocorticoids may be life-saving.

4.4 Special warnings and precautions for use

Suppression of the HPA axis and other undesirable effects may be minimised by using the lowest effective dose for the minimum period, and by administering the daily requirement as a single morning dose or whenever possible as a single morning dose on alternate days. Frequent patient reviews are required to appropriately titrate the dose against disease activity (see section 4.2).

Anti-inflammatory/Immunosuppressive effects/Infection

Suppression of the inflammatory response and immune function increases the susceptibility to infections and their severity. The clinical presentation may often be atypical and serious infections such as septicaemia and tuberculosis may be masked and may reach an advanced stage before being recognised.

Appropriate anti-microbial therapy should accompany glucocorticoid therapy when necessary e.g. in tuberculosis and viral and fungal infections of the eye. There may be decreased resistance and inability to localise infection in patients on corticosteroids.

Chickenpox is of particular concern since this normally minor illness may be fatal in immunosuppressed patients. Patients without a definite history of chickenpox should be advised to avoid close personal contact with chickenpox or herpes zoster and if exposed they should seek urgent medical attention. If the patient is a child parents must be given the above advice. Passive immunisation with varicella zoster immunoglobulin (VZIG) is needed by exposed non-immune patients who are receiving systemic corticosteroids or who have used them within the previous 3 months; this should be given within 10 days of exposure to chickenpox. If a diagnosis of chickenpox is confirmed, the illness warrants specialist care and urgent treatment. Corticosteroids should not be stopped and the dose may need to be increased.

Patients should be advised to take particular care to avoid exposure to measles and to seek immediate advice if exposure occurs. Prophylaxis with intramuscular normal immunoglobulin may be needed.

Corticosteroids in high doses may interfere with active immunisation.

Vaccination with a live vaccine should be administered under strict supervision.

Live vaccines should not be given to individuals with impaired immune responsiveness caused by high doses of corticosteroids. The antibody response to other vaccines may be diminished.

Eye disorders

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.

Fluid retention

Because of the possibility of fluid retention, care must be taken when corticosteroids are administered to patients with renal insufficiency or hypertension or congestive heart failure.

Adrenal Suppression

Adrenal cortical atrophy develops during prolonged therapy and may persist for years after stopping treatment. Withdrawal of corticosteroids after prolonged therapy must therefore always be gradual to avoid acute adrenal insufficiency, being tapered off over weeks or months according to the dose and duration of treatment.

In patients who have received more than physiological doses of systemic corticosteroids (approximately 7.5 mg prednisolone or equivalent) for greater than 3 weeks, withdrawal should not be abrupt. How dose reduction should be carried out depends largely on whether the disease is likely to relapse as the dose of systemic corticosteroids is reduced. Clinical assessment of disease activity may be needed during withdrawal. If the disease is unlikely to relapse on withdrawal of systemic corticosteroids but there is uncertainty about HPA suppression, the dose of systemic corticosteroid may be reduced rapidly to physiological doses. Once a daily dose equivalent to 7.5mg of prednisolone is reached, dose reduction should be slower to allow the HPA-axis to recover.

Abrupt withdrawal of systemic corticosteroid treatment, which has continued up to 3 weeks is appropriate if it is considered that the disease is unlikely to relapse.

Abrupt withdrawal of doses of up to 40mg daily of prednisolone, or equivalent for 3 weeks is unlikely to lead to clinically relevant HPA-axis suppression, in the majority of patients.

In the following patient groups, gradual withdrawal of systemic corticosteroid therapy should be considered even after courses lasting 3 weeks or less:

Patients who have had repeated courses of systemic corticosteroids, particularly if taken for greater than 3 weeks,
When a short course has been prescribed within one year of cessation of long-term therapy (months or years),
Patients who may have reasons for adrenocortical insufficiency other than exogenous corticosteroid therapy,
Patients receiving doses of systemic corticosteroid greater than 40mg daily of prednisolone,
Patients repeatedly taking doses in the evening.

Intercurrent illness and stress

During prolonged therapy any intercurrent illness, trauma or surgical procedure will require a temporary increase in dosage; if corticosteroids have been stopped following prolonged therapy they may need to be temporarily reintroduced.

General

In addition to the information given under the other headings, particular care is required when considering the use of systemic corticosteroids in patients with the following conditions and frequent patient monitoring is necessary:

diabetes mellitus
osteoporosis
hypertension
epilepsy
previous steroid myopathy
peptic ulceration
hypothyroidism
recent myocardial infarction
patients with a history of tuberculosis
newly established vascular and intestinal anastomosis
liver failure, blood levels of corticosteroid may be increased.

The risk of developing ulcers is increased by concomitant administration of NSAIDs and corticosteroids.

Psychiatric reactions

Patients/and or carers should be warned that potentially severe psychiatric adverse reactions may occur with systemic steroids (see Section 4.8 Undesirable effects). Symptoms typically emerge within a few days or weeks of starting the treatment. Risks may be higher with high doses/systemic exposure (see also Section 4.5 Interaction with other medicinal products and other forms of interaction), although dose levels do not allow prediction of the onset, type, severity or duration of reactions. Most adverse reactions resolve after either dose reduction or withdrawal of the medicine, 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 a 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 psychosis.

Pheochromocytoma crisis

Pheochromocytoma crisis, which can be fatal, has been reported after administration of systemic corticosteroids. Corticosteroids should only be administered to patients with suspected or identified pheochromocytoma after an appropriate risk/benefit evaluation.

Use in Children

Corticosteroids cause dose-related growth retardation in infancy, childhood and adolescence, which may be irreversible.

Use in the Elderly

The common adverse effects of 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.

Ingredients in the formulation

Rindelt contains lactose. Patients with rare hereditary problems of galactose-intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

The following combinations with Prednisolone may require dose adjustment:

Phenobarbital, phenytoin, carbamazepine: Phenobarbital (which is a metabolite of primidone), phenytoin and carbamazepine administered separately or in combination, induce the metabolism of hydrocortisone, prednisolone and methylprednisolone (demonstrated in children with asthma) resulting in the need of increased dose. It is likely that this interaction is applicable to the entire group of glucocorticoids.

Rifampicin:Rifampicin induces the microsomal oxidation of gluocorticoids (hydrocortisone, prednisolone, methylprednisolone). This results in increased need for steroids during treatment with rifampicin and reduced need for steroids after such treatment.

Oral anticoagulants:Modified effect of anticoagulants administered with prednisolone has been reported. INR should therefore be monitored during prednisolone treatment. The efficacy of coumarin anticoagulants and warfarin may be enhanced by concurrent corticosteroid therapy and close monitoring of the INR or prothrombin time is required to avoid spontaneous bleeding.

Mifepristone may reduce the effect of corticosteroids for 3-4 days.

Erythromycin and ketoconazole may inhibit the metabolism of some corticosteroids.

Ciclosporin increases plasma concentration of prednisolone. The same effect is possible with ritonavir.

Oestrogens and other oral contraceptives may potentiate the effects of glucocorticoids and dosage adjustments may be required if oral contraceptives are added to or withdrawn from a stable dosage regimen.

The desired effects of hypoglycaemic agents (including insulin), anti-hypertensives and diuretics are antagonised by corticosteroids.

The growth promoting effect of somatotropin may be inhibited by the concomittant use of corticosteroids.

Steroids may reduce the effects of anticholinesterases in myasthenia gravis and cholecystographic x-ray media.

Concomitant use of aspirin and Non Steroidal Anti-Inflammatory Drugs (NSAIDs) with corticosteroids increases the risk of gastro-intestinal bleeding and ulceration.

The renal clearance of salicylates is increased by corticosteroids and steroid withdrawal may result in salicylate intoxication.

The hypokalaemic effects of acetazolamide, loop diuretics, thiazide diuretics, and carbenoxolone, are enhanced by corticosteroids. The risk of hypokalaemia is increased with theophylline and amphotericin. Corticosteroids should not be given concomitantly with amphotericin, unless required to control reactions.

The risk of hypokalaemia also increases if high doses of corticosteroids are given with high doses of bambuterol, fenoterol, formoterol, ritodrine, salbutamol, salmeterol and terbutaline. The toxicity of cardiac glycosides is increased if hypokalaemia occurs with corticosteroids.

Concomitant use with methotrexate may increase the risk of haematological toxicity.

High doses of corticosteroids impair the immune response and so live vaccines should be avoided (see also sections 4.3 and 4.4).

4.6 Fertility, pregnancy and lactation

Pregnancy

Administration of corticosteroids to pregnant animals can cause abnormalities of fetal development including cleft palate, intra-uterine growth retardation and effects on brain growth and development. There is no evidence that corticosteroids result in an increased incidence of congenital abnormalities, such as cleft palate / lip in man. However, when administered for prolonged periods or repeatedly during pregnancy, corticosteroids might increase the risk of intrauterine growth retardation. Hypoadrenalism might, in theory, occur in the neonate following prenatal exposure to corticosteroids but usually resolves spontaneously following birth and is rarely clinically important.

As with all drugs, corticosteroids should only be prescribed when the benefits to the mother and child outweigh the risks. When corticosteroids are essential however, patients with normal pregnancies may be treated as though they were in the non-pregnant state. Patients with pre-eclampsia or fluid retention require close monitoring.

Breastfeeding

Corticosteroids are excreted in small amounts in breast milk. Infants of mothers taking higher doses than this may have a degree of adrenal suppression but the benefits of breast feeding are likely to outweigh any theoretical risk.

4.7 Effects on ability to drive and use machines

Rindelt has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Apart from replacement therapy, treatment with corticosteroids always involves an overdose compared to the physiological state. Side effects occur mainly during long-term treatment, but these also depend on the size of the dose and individual sensitivity.

The below are side effects in accordance with MedDRA system organ classification and frequency conventions.

Organ Class	Common (≥1/100, <1/10)	Uncommon (≥1/1000 – <1/100 )	Rare (≥1/10 000, <1/1000)	Not known
Infections and infestations	Increased susceptibility to infections and increased severity of infections, recurrence of dormant infections (e.g. tuberculosis)
Blood and lymphatic system disorders				Leukocytosis.
Immune system disorders				Hypersensitivity, anaphylactic reaction.
Endocrine disorders	Growth inhibition (in children), inhibition of the endogenous ACTH- and cortisol secretion, Cushing-like symptoms.			Pheochromocytoma related crisis (see section 4.4). Diabetes mellitus exacerbated.
Metabolism and nutrition disorders	Hypokalaemia, sodium retention, increased gluconeogenesis, catabolic side effects, osteoporosis.			Hypokalaemic alkalosis, increased appetite, protein total abnormal.
Psychiatric disorders		Activation of previous psychiatric disorders (high doses)	Depression, mania in patients without known psychiatric history.	Dependence. Affective disorder: irritability, euphoric mood, depressed mood, affect lability, suicidal ideation. Psychotic disorder: mania, delusions, hallucinations, schizophrenia aggravated. Abnormal behavior, anxiety, sleep disorder. Cognitive disorder: confusion, amnesia.
Nervous system disorders			Benign intracranial hypertension.	Dizziness, headache. Papilloedema, epilepsy.
Eye disorders		Glaucoma, nuclear cataracts.		Papilloedema, chorioretinopathy, exophthalmos, corneal thinning, scleral thinning, eye infection viral, eye infection fungal.
Ear and labyrinth disorders				Vertigo.
Cardiac disorders				Myocardial rupture (post infarct), cardiac failure congestive.
Vascular disorders	Hypertonia.	Thrombosis.
Respiratory, thoracic and mediastinal disorders				Hiccups.
Gastrointestinal disorders				Dyspepsia, nausea, vomiting, abdominal distension, abdominal pain, diarrhoea, oesophageal ulcer, candidiasis, pancreatitis acute. Peptic ulcer haemorrhage, peptic ulcer perforation.
Skin and subcutaneous tissue disorders	Skin atrophy, impaired healing.			Skin striae, acne, telangiectasia, hyperhidrosis, rash, pruritus, urticaria, hirsutism.
Musculoskeletal and connective tissue disorders	Myoatrophy.		Avascular osteonecrosis, tendon rupture.	Multiple spinal fractures, myalgia, tendon rupture.
Reproductive system and breast disorders				Irregular menstruation, amenorrhoea.
General disorders and administration site conditions	Oedema.			Malaise.
Investigations				Weight increased.
Injury, poisoning and procedural complications				Contusion.

Withdrawal Symptoms

Too rapid a reduction of corticosteroid dosage following prolonged treatment can lead to acute adrenal insufficiency, hypotension and death (See Section 4.4)

A 'withdrawal syndrome' may also occur including fever, myalgia, arthralgia, rhinitis, conjunctivitis, painful itchy skin nodules and loss of weight.

In some instances, withdrawal symptoms may involve or resemble a clinical relapse of the disease for which the patient has been undergoing treatment.

Other effects that may occur during withdrawal or change of corticosteroid therapy include benign intracranial hypertension with headache and vomiting and papilloedema caused by cerebral oedema.

Latent rhinitis or eczema may be unmasked.

Pediatric population

The following side effects have been reported in the pediatric population.

Growth retardation in infancy, childhood and adolescence.

Intracranial pressure increased with papilloedema (pseudo tumour cerebri) after treatment withdrawal.

For psychiatric reactions in children, see section 4.4, “Psychiatric reactions”.

Reporting suspected adverse reactions after authorisation of the 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

[To be completed nationally]

4.9 Overdose

Toxicity and symptom:Acute toxicity even with massive doses of prednisolone does generally not result in any clinical problems.

Possible acute overdose can aggravate pre-existing medical conditions such as ulcers, electrolyte imbalance, infections and oedema.

Treatment: In general not required. If motivated gastric lavage, charcoal. Symptomatic treatment.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: glucocorticoids, ATC code: H02AB06

Syntetic glucocorticoid with antiinflammatoric, immunosuppressive and antiallergic effect.

Prednisolone has an antiinflammatoric effect 4-5 times more potent than cortison, but affects the metabolism of electrolytes to a lesser extent. The mechanism of action is not yet fully understood.

5.2 Pharmacokinetic properties

The absolute bioavailability of prednisolone is above 85% following oral administration of a single dose of 10 mg when compared to after intravenous administration. Maximum concentration in plasma is reached after approximately 1 hour and the half-life is 2-3 hours following a single dose of 10 mg. In normal doses, the duration of the therapeutic effect is 12-36 hours. Prednisolone is primarily metabolised in the liver. More than 90% of the administered dose is excreted in the urine. 7-15% is excreted in unchanged form.

5.3 Preclinical safety data

In animal trials corticosteroids have shown various types of malformation (cleft palate, skeletal malformations). After long-term treatment in animals, reduced placenta and birth weight was found.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose monohydrate

Potato starch

Gelatin

Talc

Magnesium stearate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

Containers: 3 years.

Blisters: 30 months.

6.4 Special precautions for storage

Containers: No special storage conditions.

Blisters: Do not store above 25ºC.

6.5 Nature and contents of container

Rindelt is packed in Al/PVC/PVDC blisters and HDPE containers with LDPE/HDPE cap in packages of 20 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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

7. MARKETING AUTHORISATION HOLDER

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<[To be completed nationally]>

8. MARKETING AUTHORISATION NUMBER(S)

<[To be completed nationally]>

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

<[To be completed nationally]>

10. DATE OF REVISION OF THE TEXT

2015-12-02