Glucocorticoids ATC code: H02AB07

Prednisone

Each modified-release tablet contains 1 mg, 2 mg or 5 mg prednisone. 1 mg tablet: Also contains 40.7 mg of lactose. 2 mg tablet: Also contains 39.7 mg of lactose. 5 mg tablet: Also contains 36.9 mg of lactose.

Modified-release tablet The 1 mg tablets are pale yellowish-white, cylindrical tablets with “NP1” embossed on one side. The 2 mg tablets are yellowish-white, cylindrical tablet with “NP2” embossed on one side. The 5 mg tablets are light yellow, cylindrical tablets with “NP5” embossed on one side.

Lodotra is indicated for the treatment of moderate to severe, active rheumatoid arthritis in adults particularly when accompanied by morning stiffness.

The appropriate dose depends on the severity of the condition and the individual response of the patient. In general, for the initiation of the therapy 10 mg prednisone is recommended. In certain cases, a higher initial dose might be required (e.g. 15 or 20 mg prednisone). Depending on the clinical symptoms and the patient's response, the initial dose can be reduced in steps to a lower maintenance dose.

When changing over from the standard regimen (glucocorticoid administration in the morning) to Lodotra administered at bedtime (at about 10 pm), the same dose (in mg prednisone equivalent) should be maintained. Following the change-over, the dose may be adjusted according to the clinical situation.

For doses not realisable/practicable with this strength other strengths of this medicinal product are available. For long-term therapy of rheumatoid arthritis, the individual dose of up to 10 mg prednisone daily should be adjusted according to the severity of the course of the disease.

Depending on the treatment result, the dose can be reduced in steps of 1 mg every 2 - 4 weeks to reach the appropriate maintenance dose.

In order to discontinue the therapy with Lodotra, the dose should be reduced in steps of 1 mg every 2 - 4 weeks, with monitoring of pituitary-adrenal axis parameters if necessary

The appropriate dose depends on the severity of the condition and the individual response of the patient. In general, for the initiation of the therapy 10 mg prednisone is recommended. In certain cases, a higher initial dose might be required (e.g. 15 or 20 mg prednisone). Depending on the clinical symptoms and the patient's response, the initial dose can be reduced in steps to a lower maintenance dose.

When changing over from the standard regimen (glucocorticoid administration in the morning) to Lodotra administered at bedtime (at about 10 pm), the same dose (in mg prednisone equivalent) should be maintained. Following the change-over, the dose may be adjusted according to the clinical situation.

For doses not realisable/practicable with this strength other strengths of this medicinal product are available. For long-term therapy of rheumatoid arthritis, the individual dose of up to 10 mg prednisone daily should be adjusted according to the severity of the course of the disease.

Depending on the treatment result, the dose can be reduced in steps of 1 mg every 2 - 4 weeks to reach the appropriate maintenance dose.

In order to discontinue the therapy with Lodotra, the dose should be reduced in steps of 1 mg every 2 - 4 weeks, with monitoring of pituitary-adrenal axis parameters if necessary.

Method of Administration:

Lodotra should be taken at bedtime (at about 10 pm), with or after the evening meal and be swallowed whole with sufficient liquid. If more than 2 - 3 hours have passed since the evening meal, it is recommended to take Lodotra with a light meal or snack (e.g. a slice of bread with ham or cheese). Lodotra should not be administered in the fasted state. This could result in a reduced bioavailability.

Lodotra is designed to release the active substance with a delay of approximately 4 - 6 hours after intake, the release of the active substance and the pharmacological effects will start during the night.

Lodotra modified-release tablets consist of a prednisone-containing core and an inert coating. Delayed release of prednisone is dependent on an intact coating. For this reason, the modified-release tablets are not to be broken, divided or chewed.

Because of insufficient data on tolerability and efficacy, the use in children and adolescents is not recommended.

In patients with hypothyroidism or hepatic cirrhosis, comparatively low doses may be sufficient or a dose reduction may be necessary.

The appropriate dose depends on the severity of the condition and the individual response of the patient. In general, for the initiation of the therapy 10 mg prednisone is recommended. In certain cases, a higher initial dose might be required (e.g. 15 or 20 mg prednisone). Depending on the clinical symptoms and the patient's response, the initial dose can be reduced in steps to a lower maintenance dose.

When changing over from the standard regimen (glucocorticoid administration in the morning) to Lodotra administered at bedtime (at about 10 pm), the same dose (in mg prednisone equivalent) should be maintained. Following the change-over, the dose may be adjusted according to the clinical situation.

For doses not realisable/practicable with this strength other strengths of this medicinal product are available. For long-term therapy of rheumatoid arthritis, the individual dose of up to 10 mg prednisone daily should be adjusted according to the severity of the course of the disease.

Depending on the treatment result, the dose can be reduced in steps of 1 mg every 2 - 4 weeks to reach the appropriate maintenance dose.

In order to discontinue the therapy with Lodotra, the dose should be reduced in steps of 1 mg every 2 - 4 weeks, with monitoring of pituitary-adrenal axis parameters if necessary.

Method of Administration:

Lodotra should be taken at bedtime (at about 10 pm), with or after the evening meal and be swallowed whole with sufficient liquid. If more than 2 - 3 hours have passed since the evening meal, it is recommended to take Lodotra with a light meal or snack (e.g. a slice of bread with ham or cheese). Lodotra should not be administered in the fasted state. This could result in a reduced bioavailability.

Lodotra is designed to release the active substance with a delay of approximately 4 - 6 hours after intake, the release of the active substance and the pharmacological effects will start during the night.

Lodotra modified-release tablets consist of a prednisone-containing core and an inert coating. Delayed release of prednisone is dependent on an intact coating. For this reason, the modified-release tablets are not to be broken, divided or chewed.

Because of insufficient data on tolerability and efficacy, the use in children and adolescents is not recommended.

In patients with hypothyroidism or hepatic cirrhosis, comparatively low doses may be sufficient or a dose reduction may be necessary.

Lodotra is contraindicated in patients with hypersensitivity to prednisone or to any of the excipients

A prednisone-based pharmacotherapy should only be given when absolutely necessary and should be accompanied by appropriate anti-infectious therapy in the presence of the following conditions:

- Acute viral infections (herpes zoster, herpes simplex, varicella, herpetic keratitis),

- HBsAg-positive chronic active hepatitis,

- Approximately 8 weeks before and 2 weeks after immunisation with live vaccines,

- Systemic mycoses and parasitoses (e.g. nematodes),

- Poliomyelitis,

- Lymphadenitis following BCG inoculation,

- Acute and chronic bacterial infections,

History of tuberculosis (caution: reactivation!) Due to their immunosuppressive properties glucocorticoids can induce or aggravate infections. Such patients should be monitored carefully e.g. by performing a tuberculin test. Patients at special risk should receive a tuberculostatic treatment.

In addition, a prednisone-based pharmacotherapy should only be given when necessary and should be accompanied if required by appropriate therapy in the presence of the following conditions:

- Gastrointestinal ulcers,

- Severe osteoporosis and osteomalacia

- Hypertension that is difficult to control,

- Severe diabetes mellitus,

- Psychiatric disorders (also if in patient's history),

- Narrow- and wide-angle glaucoma,

- Corneal ulcers and corneal injuries.

Because of the risk of intestinal perforation, prednisone may only be used if absolutely necessary and with adequate monitoring in cases of:

- Severe ulcerative colitis with imminent perforation,

- Diverticulitis,

- Entero-anastomoses (immediately postoperative).

Lodotra cannot achieve the desired blood concentration of prednisone if taken under fasting conditions. Therefore, Lodotra should always be taken with or after the evening meal in order to ensure sufficient efficacy. In addition, low plasma concentrations may occur in 6% -7% of Lodotra doses as observed across all pharmacokinetic studies and 11% in a single pharmacokinetic study when taken according to the recommendations. This should be considered if Lodotra is not sufficiently effective. In these situations a switch to a conventional immediate-release formulation may be considered.

Lodotra should not be substituted by prednisone immediate-release tablets in the same administration regime because of Lodotra's delayed release mechanism.

In case of substitution, termination, or discontinuing prolonged treatment, the following risks must be considered: Recurrence of the rheumatoid arthritis disease activity, acute adrenal failure (especially in stressful situations, e. g. during infections, after accidents, with increased physical strain), cortisone withdrawal syndrome.

Lodotra should not be given as for acute indications instead of prednisone immediate-release tablets due to its pharmacological properties.

During the use of Lodotra, a possibly increased need for insulin or oral anti-diabetics should be considered. Patients with diabetes mellitus should therefore be treated under close monitoring.

During the treatment with Lodotra, regular blood pressure checks are required in patients with hypertension that is difficult to control.

Patients with severe cardiac insufficiency have to be closely monitored because of the risk of deterioration of the condition.

Sleep disorder is documented to occur more frequently with Lodotra than with conventional immediate release formulations which are taken in the morning. If insomnia occurs and does not improve, a switch to a conventional immediate release formulation may be advisable.

The treatment with Lodotra can also mask signs and symptoms of an existing or developing infection and thus may render diagnostic efforts more difficult.

Even with low doses, long-term use of Lodotra results in an increased risk of infection. These possible infections may also be brought about by microorganisms that rarely cause infection under normal circumstances (so-called opportunistic infections).

Certain viral diseases (varicella, measles) may take a more severe course in patients treated with glucocorticoids. Immunosuppressed individuals without prior varicella or measles infection are at particular risk. If such individuals, while being treated with Lodotra, have contact with persons infected with varicella or measles, a preventive treatment should be initiated, if required.

Vaccinations with inactivated vaccines are generally possible. However, it has to be taken into account that the immune response and consequently the success of the vaccination may be impaired with higher doses of glucocorticoids.

In case of long-term therapy with Lodotra, regular medical follow-ups (including ophthalmologic examinations at three month intervals) are indicated; if comparatively high doses are given, sufficient supply of potassium supplements and restriction of sodium have to be ensured and serum potassium levels have to be monitored.

If during the treatment with Lodotra high levels of physical stress are caused by certain events (accidents, surgical procedure etc.), a temporary dose increase may become necessary.

Depending on the duration of the treatment and the dosage used, a negative impact on calcium metabolism must be expected. Osteoporosis prophylaxis is therefore recommended and is particularly important if other risk factors are present (including familial predisposition, advanced age, postmenopausal status, insufficient intake of protein and calcium, excessive smoking, excessive alcohol consumption, as well as reduced physical activity). The prophylaxis is based on a sufficient supply of calcium and vitamin D, as well as on physical activity. In case of pre-existing osteoporosis, an additional therapy should be considered.

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

When using high doses of prednisolone for an extended period of time (30 mg/day for a minimum of 4 weeks), reversible disturbances of spermatogenesis were observed that persisted for several months after discontinuation of the medicinal product

Cardiac glycosides: The effect of the glycosides can be enhanced by potassium deficiency.

Saluretics/laxatives: Potassium excretion is enhanced.

Antidiabetic agents: The blood sugar lowering effect is reduced.

Coumarin derivatives: The efficacy of coumarin anticoagulants may be reduced or enhanced.

Non-steroidal antiphlogistic/antirheumatic agents, salicylates and indomethacin: The risk of gastrointestinal haemorrhages is increased.

Non-depolarising muscle relaxants: Muscle relaxation may be prolonged.

Atropine and other anticholinergics: The concurrent use of Lodotra may result in additional increases in intraocular pressure.

Praziquantel: Glucocorticoids may lower the praziquantel concentrations in the blood.

Chloroquine, hydroxychloroquine, mefloquine: There is an increased risk of occurrence of myopathies, cardiomyopathies.

Somatropin: The efficacy of somatropin may be reduced.

Oestrogens (e.g. oral contraceptives): May enhance the efficacy of glucocorticoids.

Liquorice: Inhibition of the metabolism of glucocorticoids is possible.

Rifampicin, phenytoin, barbiturates, bupropion and primidone: The efficacy of glucocorticoids is reduced.

Cyclosporine: The blood levels of cyclosporine are increased. There is an increased risk of seizures.

Amphotericine B: The risk of hypokalaemia may be increased.

Cyclophosphamide: The effects of cyclophosphamide may be enhanced.

ACE inhibitors: Increased risk of occurrence of blood count changes.

Aluminium and magnesium antacids: The absorption of glucocorticoids is reduced. However, due to the delayed release mechanism of Lodotra an interaction between prednisone and aluminium/magnesium antacids is unlikely.

Impact on diagnostic methods: Skin reactions caused by allergy testing may be suppressed. The TSH increase following the administration of protirelin may be reduced

The frequency and severity of the undesirable effects listed below depend on dosage and duration of treatment. In the recommended dose range for Lodotra (low-dose corticoid therapy with daily doses ranging from 1 to 10 mg), the listed undesirable effects occur less frequently with lower severity compared to doses above 10 mg.

The following undesirable effects may occur depending on the duration of treatment and the dosage:

very common ( 1/10); common ( 1/100 to < 1/10); uncommon ( 1/1000 to < 1/100); rare ( 1/10000 to < 1/1000); very rare (< 1/10000), not known (cannot be estimated from the available data)

Blood and lymphatic system disorders:

Common: Moderate leucocytosis, lymphopoenia, eosinopoenia, polycythaemia

Immune system disorders:

Common: Reduced immune defence, masking of infections, exacerbation of latent infections

Rare: Allergic reactions

Endocrine disorders:

Common: Adrenal suppression and induction of Cushing's syndrome (typical symptoms: moon-shaped face, upper body obesity and plethora)

Rare: Disturbed sexual hormone secretion (amenorrhoea, impotence), disturbance of the thyroid function

Metabolism and nutritional disorders:

Common: Sodium retention with oedema, increased potassium excretion (caution: arrhythmias), increased appetite and weight gain, reduced glucose tolerance, diabetes mellitus, hypercholesterolaemia and hypertriglyceridaemia

Psychiatric disorders:

Common: Insomnia

Rare: Depression, irritability, euphoria, increased impulse, psychosis

Nervous system disorders:

Common: Headache

Rare: Pseudotumor cerebri, manifestation of a latent epilepsy and increased predisposition to develop seizures in cases of manifest epilepsy

Eye disorders:

Common: Cataract, especially with posterior subcapsular opacity, glaucoma

Rare: Aggravation of symptoms associated with corneal ulcer, promotion of viral, fungal and bacterial eye inflammations

Vascular disorders:

Uncommon: Hypertension, increased risk of arteriosclerosis and thrombosis, vasculitis (also as withdrawal syndrome following long-term therapy)

Disorders of the gastrointestinal tract:

Uncommon (no concomitant NSAIDs): Gastrointestinal ulcerations, gastrointestinal haemorrhages

Rare: Pancreatitis

Skin and subcutaneous tissue disorders:

Common: Striae rubrae, atrophy, telangiectasia, increased capillary fragility, petechiae, ecchymoses

Uncommon: Hypertrichosis, steroid acne, delayed healing of wounds, rosacea-like (perioral) dermatitis, changes in skin pigmentation

Rare: Hypersensitivity reactions, e.g. drug exanthema

Musculoskeletal and connective tissue disorders:

Common: Muscular atrophy and weakness, osteoporosis (dose-related, may occur even with short-term use)

Rare: Aseptic osteonecrosis (humeral and femoral head)

Napp Pharmaceuticals Limited

POM-Prescription Only Medicine

23 January 2012