Prednisolon Apotex

Allergy and anaphylaxis: bronchial asthma, drug hypersensitivity reactions, serum sickness, angioneurotic oedema, anaphylaxis, incapacitating allergies unresponsive to conventional treatment.

Arteritis/collagenosis: giant cell arteritis/polymyalgia rheumatica, mixed connective tissue disease, polyarteritis nodosa, polymyositis.

Blood disorders: haemolytic anaemia (auto-immune), leukaemia (acute and chronic lymphocytic), lymphoma, multiple myeloma, idiopathic thrombocytopenic purpura.

Cardiovascular disorders: post-myocardial infarction syndrome, rheumatic fever with severe carditis.

Endocrine disorders: primary and secondary adrenal insufficiency, congenital adrenal hyperplasia.

Gastro-intestinal disorders: regional ileitis (Crohn's disease), ulcerative colitis, persistent coeliac syndrome (coeliac disease unresponsive to gluten withdrawal), auto-immune chronic active hepatitis, multisystem disease affecting liver, biliary peritonitis.

Hypercalcaemia: sarcoidosis, vitamin D excess.

Infections (with appropriate chemotherapy): helminthic infestations, Herxheimer reaction, infectious mononucleosis, miliary tuberculosis, mumps orchitis (adult), tuberculous meningitis, rickettsial disease.

Muscular disorders: polymyositis, dermatomyositis.

Neurological disorders: infantile spasms, Shy-Drager syndrome, sub-acute demyelinating polyneuropathy.

Ocular disease: scleritis, posterior uveitis, retinal vasculitis, pseudo-tumours of the orbit, giant cell arteritis, malignant ophthalmic Graves disease.

Renal disorders: lupus nephritis, acute interstitial nephritis, minimal change glomerulonephritis, nephrotic syndrome.

Respiratory disease: allergic pneumonitis, asthma, occupational asthma, pulmonary aspergillosis, pulmonary fibrosis, pulmonary alveolitis, aspiration of foreign body, aspiration of stomach contents, pulmonary sarcoid, drug induced lung disease, adult respiratory distress syndrome, spasmodic croup, fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculosis chemotherapy.

Rheumatic disorders: rheumatoid arthritis, polymyalgia rheumatica, juvenile chronic arthritis, psoriatic arthritis, systemic lupus erythematosus, dermatomyositis, mixed connective tissue disease.

Skin disorders: pemphigus vulgaris, exfoliative dermatitis, bullous pemphigoid, systemic lupus erythematosus, pyoderma gangrenosum.

Miscellaneous: sarcoidosis, hyperpyrexia, Behçets disease, immunosuppression in organ transplantation.

RAYOS is indicated in the treatment of the following diseases or conditions:

Allergic Conditions

Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment in adults and pediatric populations with:

• Atopic dermatitis
• Drug hypersensitivity reactions
• Seasonal or perennial allergic rhinitis
• Serum sickness

Dermatologic Diseases

• Bullous dermatitis herpetiformis
• Contact dermatitis
• Exfoliative erythroderma
• Mycosis fungoides
• Pemphigus
• Severe erythema multiforme (Stevens-Johnson syndrome)

Endocrine Conditions

• Congenital adrenal hyperplasia
• Hypercalcemia of malignancy
• Nonsuppurative thyroiditis
• Primary or secondary adrenocortical insufficiency: hydrocortisone or cortisone is the first choice: synthetic analogs may be used in conjunction with mineralocorticoids where applicable

Gastrointestinal Diseases

During acute episodes in:

• Crohn's Disease
• Ulcerative colitis

Hematologic Diseases

• Acquired (autoimmune) hemolytic anemia
• Diamond-Blackfan anemia
• Idiopathic thrombocytopenic purpura in adults
• Pure red cell aplasia
• Secondary thrombocytopenia in adults

Neoplastic Conditions

For the treatment of:

• Acute leukemia
• Aggressive lymphomas

Nervous System Conditions

• Acute exacerbations of multiple sclerosis
• Cerebral edema associated with primary or metastatic brain tumor, craniotomy or head injury

Ophthalmic Conditions

• Sympathetic ophthalmia
• Uveitis and ocular inflammatory conditions unresponsive to topical steroids

Conditions Related to Organ Transplantation

• Acute or chronic solid organ rejection

Pulmonary Diseases

• Acute exacerbations of chronic obstructive pulmonary disease (COPD)
• Allergic bronchopulmonary aspergillosis
• Aspiration pneumonitis
• Asthma
• Fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate chemotherapy
• Hypersensitivity pneumonitis
• Idiopathic bronchiolitis obliterans with organizing pneumonia
• Idiopathic eosinophilic pneumonias
• Idiopathic pulmonary fibrosis
• Pneumocystis carinii pneumonia (PCP) associated with hypoxemia occurring in an HIV(+) individual who is also under treatment with appropriate anti-PCP antibiotics.
• Symptomatic sarcoidosis

Renal Conditions

• To induce a diuresis or remission of proteinuria in nephrotic syndrome, without uremia, of the idiopathic type or that due to lupus erythematosus

Rheumatologic Conditions

As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in:

• Acute gouty arthritis

During an exacerbation or as maintenance therapy in selected cases of:

• Ankylosing spondylitis
• Dermatomyositis/polymyositis
• Polymyalgia rheumatica
• Psoriatic arthritis
• Relapsing polychondritis
• Rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low dose maintenance therapy)
• Sjogren's syndrome
• Systemic lupus erythematosus
• Vasculitis

Specific Infectious Diseases

• Trichinosis with neurologic or myocardial involvement.
• Tuberculous meningitis with subarachnoid block or impending block used concurrently with appropriate antituberculous chemotherapy.

Non-infected inflammatory conditions of the eye.

Prednisolon Apotex is indicated in the treatment of the following diseases or conditions:

Allergic Conditions

Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment in adults and pediatric populations with:

• Atopic dermatitis
• Drug hypersensitivity reactions
• Seasonal or perennial allergic rhinitis
• Serum sickness

Dermatologic Diseases

• Bullous dermatitis herpetiformis
• Contact dermatitis
• Exfoliative erythroderma
• Mycosis fungoides
• Pemphigus
• Severe erythema multiforme (Stevens-Johnson syndrome)

Endocrine Conditions

• Congenital adrenal hyperplasia
• Hypercalcemia of malignancy
• Nonsuppurative thyroiditis
• Primary or secondary adrenocortical insufficiency: hydrocortisone or cortisone is the first choice: synthetic analogs may be used in conjunction with mineralocorticoids where applicable

Gastrointestinal Diseases

During acute episodes in:

• Crohn's Disease
• Ulcerative colitis

Hematologic Diseases

• Acquired (autoimmune) hemolytic anemia
• Diamond-Blackfan anemia
• Idiopathic thrombocytopenic purpura in adults
• Pure red cell aplasia
• Secondary thrombocytopenia in adults

Neoplastic Conditions

For the treatment of:

• Acute leukemia
• Aggressive lymphomas

Nervous System Conditions

• Acute exacerbations of multiple sclerosis
• Cerebral edema associated with primary or metastatic brain tumor, craniotomy or head injury

Ophthalmic Conditions

• Sympathetic ophthalmia
• Uveitis and ocular inflammatory conditions unresponsive to topical steroids

Conditions Related to Organ Transplantation

• Acute or chronic solid organ rejection

Pulmonary Diseases

• Acute exacerbations of chronic obstructive pulmonary disease (COPD)
• Allergic bronchopulmonary aspergillosis
• Aspiration pneumonitis
• Asthma
• Fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate chemotherapy
• Hypersensitivity pneumonitis
• Idiopathic bronchiolitis obliterans with organizing pneumonia
• Idiopathic eosinophilic pneumonias
• Idiopathic pulmonary fibrosis
• Pneumocystis carinii pneumonia (PCP) associated with hypoxemia occurring in an HIV(+) individual who is also under treatment with appropriate anti-PCP antibiotics.
• Symptomatic sarcoidosis

Renal Conditions

• To induce a diuresis or remission of proteinuria in nephrotic syndrome, without uremia, of the idiopathic type or that due to lupus erythematosus

Rheumatologic Conditions

As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in:

• Acute gouty arthritis

During an exacerbation or as maintenance therapy in selected cases of:

• Ankylosing spondylitis
• Dermatomyositis/polymyositis
• Polymyalgia rheumatica
• Psoriatic arthritis
• Relapsing polychondritis
• Rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low dose maintenance therapy)
• Sjogren's syndrome
• Systemic lupus erythematosus
• Vasculitis

Specific Infectious Diseases

• Trichinosis with neurologic or myocardial involvement.
• Tuberculous meningitis with subarachnoid block or impending block used concurrently with appropriate antituberculous chemotherapy.

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

Prednisolon Apotex^® is indicated for the treatment of steroid-responsive inflammation of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the globe.

Posology

Adults and the elderly

The lowest effective dose should be used for the minimum period.

Children

If there is lack of a satisfactory clinical response to Prednisolon Apotexe Tablets, the drug should be gradually discontinued and the patient transferred to alternative therapy.

Intermittent dosage regimen A single dose of Prednisolon Apotexe Tablets in the morning on alternate days or at longer intervals is acceptable therapy for some patients. When this regimen is practical, the degree of pituitary-adrenal suppression can be minimised.

Specific dosage guidelines The following recommendations for some corticosteroid-responsive disorders are for guidance only. Acute or severe disease may require initial high dose therapy with reduction to the lowest effective maintenance dose as soon as possible. Dosage reductions should not exceed 5-7.5mg daily during chronic treatment.

Allergic and skin disorders Initial doses of 5-15mg daily are commonly adequate.

Collagenosis Initial doses of 20-30mg daily are frequently effective. Those with more severe symptoms may require higher doses.

Rheumatoid arthritis The usual initial dose is 10-15mg daily. The lowest daily maintenance dose compatible with tolerable symptomatic relief is recommended.

Blood disorders and lymphoma An initial daily dose of 15-60mg is often necessary with reduction after an adequate clinical or haematological response. Higher doses may be necessary to induce remission in acute leukaemia.

Special populations

Method of administration

Prednisolon Apotexe tablets should be taken following a meal to reduce the risk of gastric irritation.

Recommended Dosing

Dosage of RAYOS should be individualized according to the severity of the disease and the response of the patient. For pediatric patients, the recommended dosage should be governed by the same considerations rather than strict adherence to the ratio indicated by age or body weight.

The maximal activity of the adrenal cortex is between 2 am and 8 am and is minimal between 4 pm and midnight. Exogenous corticosteroids suppress adrenocorticoid activity the least when given at the time of maximal activity. RAYOS is a delayed-release formulation of prednisone which releases the active substance beginning approximately 4 hours after intake. The timing of RAYOS administration should take into account the delayed-release pharmacokinetics and the disease or condition being treated.

The initial dosage of RAYOS may vary from 5 to 60 mg per day depending on the specific disease entity being treated. Patients currently on immediate release prednisone, prednisolone, or methylprednisolone should be switched to RAYOS at an equivalent dose based on relative potency (2.4).

In situations of less severity, lower doses will generally suffice while in selected patients higher initial doses may be required. The initial dosage should be maintained or adjusted until a satisfactory response is noted. If after a reasonable period there is a lack of satisfactory clinical response, RAYOS should be discontinued and the patient transferred to other appropriate therapy. It should be emphasized that dosage requirements are variable and must be individualized on the basis of the disease under treatment and the response of the patient.

After a favorable response is noted, the proper maintenance dosage should be determined by decreasing the initial drug dosage in small decrements at appropriate time intervals until the lowest dosage which will maintain an adequate clinical response is reached. It should be kept in mind that constant monitoring is needed in regard to drug dosage. Included in the situations which may make dosage adjustments necessary are changes in clinical status secondary to remissions or exacerbations in the disease process, the patient's individual drug responsiveness, and the effect of patient exposure to stressful situations not directly related to the disease entity under treatment. In this latter situation it may be necessary to increase the dosage of RAYOS for a period of time consistent with the patient's condition. If a period of spontaneous remission occurs in a chronic condition, treatment should be discontinued. If after long-term therapy the drug is to be stopped, it is recommended that it be withdrawn gradually rather than abruptly.

Recommended Monitoring

Blood pressure, body weight, routine laboratory studies (including 2-hour postprandial blood glucose and serum potassium), and chest X-ray should be obtained at regular intervals during prolonged therapy with RAYOS. Upper GI X-rays are desirable in patients with known or suspected peptic ulcer disease.

Method of Administration

RAYOS is for oral administration.

RAYOS should be taken daily with food.

RAYOS tablets should not be broken, divided, or chewed because the delayed release of prednisone is dependent on an intact coating. Â

Corticosteroid Comparison Chart

For the purpose of comparison, one 5 mg RAYOS tablet is the equivalent milligram dosage of the following various corticosteroids:

These dose relationships apply only to oral or intravenous administration of these compounds. When these substances or their derivatives are injected intramuscularly or into joint spaces, their relative properties may be greatly altered.

Posology

Adults and the elderly

One or two drops applied topically to the eye as required.

Paediatric population

At the discretion of the physician.

Recommended Dosing

Dosage of Prednisolon Apotex should be individualized according to the severity of the disease and the response of the patient. For pediatric patients, the recommended dosage should be governed by the same considerations rather than strict adherence to the ratio indicated by age or body weight.

The maximal activity of the adrenal cortex is between 2 am and 8 am and is minimal between 4 pm and midnight. Exogenous corticosteroids suppress adrenocorticoid activity the least when given at the time of maximal activity. Prednisolon Apotex is a delayed-release formulation of prednisone which releases the active substance beginning approximately 4 hours after intake. The timing of Prednisolon Apotex administration should take into account the delayed-release pharmacokinetics and the disease or condition being treated.

The initial dosage of Prednisolon Apotex may vary from 5 to 60 mg per day depending on the specific disease entity being treated. Patients currently on immediate release prednisone, prednisolone, or methylprednisolone should be switched to Prednisolon Apotex at an equivalent dose based on relative potency (2.4).

In situations of less severity, lower doses will generally suffice while in selected patients higher initial doses may be required. The initial dosage should be maintained or adjusted until a satisfactory response is noted. If after a reasonable period there is a lack of satisfactory clinical response, Prednisolon Apotex should be discontinued and the patient transferred to other appropriate therapy. It should be emphasized that dosage requirements are variable and must be individualized on the basis of the disease under treatment and the response of the patient.

After a favorable response is noted, the proper maintenance dosage should be determined by decreasing the initial drug dosage in small decrements at appropriate time intervals until the lowest dosage which will maintain an adequate clinical response is reached. It should be kept in mind that constant monitoring is needed in regard to drug dosage. Included in the situations which may make dosage adjustments necessary are changes in clinical status secondary to remissions or exacerbations in the disease process, the patient's individual drug responsiveness, and the effect of patient exposure to stressful situations not directly related to the disease entity under treatment. In this latter situation it may be necessary to increase the dosage of Prednisolon Apotex for a period of time consistent with the patient's condition. If a period of spontaneous remission occurs in a chronic condition, treatment should be discontinued. If after long-term therapy the drug is to be stopped, it is recommended that it be withdrawn gradually rather than abruptly.

Recommended Monitoring

Blood pressure, body weight, routine laboratory studies (including 2-hour postprandial blood glucose and serum potassium), and chest X-ray should be obtained at regular intervals during prolonged therapy with Prednisolon Apotex. Upper GI X-rays are desirable in patients with known or suspected peptic ulcer disease.

Method of Administration

Prednisolon Apotex is for oral administration.

Prednisolon Apotex should be taken daily with food.

Prednisolon Apotex tablets should not be broken, divided, or chewed because the delayed release of prednisone is dependent on an intact coating. Â

Corticosteroid Comparison Chart

For the purpose of comparison, one 5 mg Prednisolon Apotex tablet is the equivalent milligram dosage of the following various corticosteroids:

These dose relationships apply only to oral or intravenous administration of these compounds. When these substances or their derivatives are injected intramuscularly or into joint spaces, their relative properties may be greatly altered.

Posology

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 - 4weeks, with monitoring of pituitary-adrenal axis parameters if necessary.

Paediatric population

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

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.

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

Shake well before using. Instill one to two drops into the conjunctival sac two to four times daily. During the initial 24 to 48 hours, the dosing frequency may be increased if necessary. Care should be taken not to discontinue therapy prematurely.

If signs and symptoms fail to improve after 2 days, the patient should be re-evaluated (see PRECAUTIONS).

- Systemic infections unless specific anti-infective therapy is employed.

- Ocular herpes simplex because of possible perforation.

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

RAYOS is contraindicated in patients who have known hypersensitivity to prednisone or to any of the excipients. Rare instances of anaphylaxis have occurred in patients receiving corticosteroid therapy.

Use is contraindicated in viral, fungal, tuberculous and other bacterial infections.

Prolonged application to the eye of preparations containing corticosteroids has caused increased intraocular pressure and therefore the drops should not be used in patients with glaucoma.

In children, long-term, continuous topical corticosteroid therapy should be avoided due to possible adrenal suppression.

Prednisolon Apotex is contraindicated in patients who have known hypersensitivity to prednisone or to any of the excipients. Rare instances of anaphylaxis have occurred in patients receiving corticosteroid therapy.

Prednisolon Apotex^® suspension is contraindicated in acute untreated purulent ocular infections, in most viral diseases of the cornea and conjunctiva including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, and varicella, and also in mycobacterial infection of the eye and fungal diseases of ocular structures.

Prednisolon Apotex^® suspension is also contraindicated in individuals with known or suspected hypersensitivity to any of the ingredients of this preparation and to other corticosteroids.

Raised intracranial pressure Raised intracranial pressure with papilloedema (pseudotumour cerebri) associated with corticosteroid treatment has been reported in both children and adults.'Undesirable effects').

Visual disturbance

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

Use in the elderly

Treatment of elderly patients, particularly if long term, should be undertaken with caution bearing in mind the more serious consequences of the common side-effects of corticosteroids in old age, especially osteoporosis, diabetes, hypertension, hypokalaemia, susceptibility to infection and thinning of the skin. Close clinical supervision is required to avoid life threatening reactions.

Paediatric population

Corticosteroids cause growth retardation in infancy, childhood and adolescence, which may be irreversible, and therefore long-term administration of pharmacological doses should be avoided. If prolonged therapy is necessary, treatment should be limited to the minimum suppression of the hypothalamo-pituitary adrenal axis and growth retardation. The growth and development of infants and children should be closely monitored. Treatment should be administered where possible as a single dose on alternate days.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Alterations in Endocrine Function

Hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing's syndrome, and hyperglycemia. Monitor patients for these conditions with chronic use.

Corticosteroids can produce reversible hypothalamic-pituitary adrenal (HPA) axis suppression with the potential for corticosteroid insufficiency after withdrawal of treatment. Drug-induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted. If the patient is receiving corticosteroids already, dosage may have to be increased.

Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently. Mineralocorticoid supplementation is of particular importance in infancy.

Metabolic clearance of corticosteroids is decreased in hypothyroid patients and increased in hyperthyroid patients. Changes in thyroid status of the patient may necessitate adjustment in dosage.

Increased Risks Related to Infection

Corticosteroids may increase the risks related to infections with any pathogen, including viral, bacterial, fungal, protozoan, or helminthic infections. The degree to which the dose, route and duration of corticosteroid administration correlates with the specific risks of infection is not well characterized, however, with increasing doses of corticosteroids, the rate of occurrence of infectious complications increases.

Corticosteroids may mask some signs of infection and may reduce resistance to new infections.

Corticosteroids may exacerbate infections and increase risk of disseminated infections.

The use of prednisone in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for management of the disease in conjunction with an appropriate anti-tuberculous regimen.

Chickenpox and measles can have a more serious or even fatal course in non-immune children or adults on corticosteroids. In children or adults who have not had these diseases, particular care should be taken to avoid exposure. If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. If chickenpox develops, treatment with antiviral agents may be considered.

Corticosteroids should be used with great care in patients with known or suspected Strongyloides (threadworm) infestation. In such patients, corticosteroid-induced immunosuppression may lead to Strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia.

Corticosteroids may exacerbate systemic fungal infections and therefore should not be used in the presence of such infections unless they are needed to control drug reactions.

Corticosteroids may increase risk of reactivation or exacerbation of latent infection.

If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis.

Corticosteroids may activate latent amebiasis. Therefore, it is recommended that latent amebiasis or active amebiasis be ruled out before initiating corticosteroid therapy in any patient who has spent time in the tropics or any patient with unexplained diarrhea.

Corticosteroids should not be used in cerebral malaria.

Alterations in Cardiovascular/Renal Function

Corticosteroids can cause elevation of blood pressure, salt, and water retention, and increased excretion of potassium and calcium. These effects are less likely to occur with the synthetic derivatives except when used in large doses. Dietary salt restriction and potassium supplementation may be necessary. These agents should be used with caution in patients with congestive heart failure, hypertension, or renal insufficiency.

Literature reports suggest an apparent association between use of corticosteroids and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with corticosteroids should be used with great caution in these patients.

Use in Patients with Gastrointestinal Disorders

There is an increased risk of gastrointestinal perforation in patients with certain GI disorders. Signs of GI perforation, such as peritoneal irritation may be masked in patients receiving corticosteroids.

Corticosteroids should be used with caution if there is a probability of impending perforation, abscess, or other pyogenic infections; diverticulitis; fresh intestinal anastomoses; and active or latent peptic ulcer.

Behavioral and Mood Disturbances

Corticosteroids use may be associated with central nervous system effects ranging from euphoria, insomnia, mood swings, personality changes, and severe depression, to frank psychotic manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated by corticosteroids.

Decrease in Bone Density

Corticosteroids decrease bone formation and increase bone resorption both through their effect on calcium regulation (i.e., decreasing absorption and increasing excretion) and inhibition of osteoblast function. This, together with a decrease in the protein matrix of the bone secondary to an increase in protein catabolism, and reduced sex hormone production, may lead to inhibition of bone growth in children and adolescents and the development of osteoporosis at any age. Special consideration should be given to patients at increased risk of osteoporosis (i.e., postmenopausal women) before initiating corticosteroid therapy and bone density should be monitored in patients on long term corticosteroid therapy.

Ophthalmic Effects

Prolonged use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to fungi or viruses.

The use of oral corticosteroids is not recommended in the treatment of optic neuritis and may lead to an increase in the risk of new episodes.

Intraocular pressure may become elevated in some individuals. If corticosteroid therapy is continued for more than 6 weeks, intraocular pressure should be monitored.

Corticosteroids should be used cautiously in patients with ocular herpes simplex because of possible corneal perforation. Corticosteroids should not be used in active ocular herpes simplex.

Vaccination

Administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids. Killed or inactivated vaccines may be administered; however, the response to such vaccines cannot be predicted. Immunization procedures may be undertaken in patients who are receiving corticosteroids as replacement therapy, e.g., for Addison's disease.

While on corticosteroid therapy, patients should not be vaccinated against smallpox. Other immunization procedures should not be undertaken in patients who are on corticosteroids, especially on high dose, because of possible hazards of neurological complications and a lack of antibody response.

Effect on Growth and Development

Long-term use of corticosteroids can have negative effects on growth and development in children.

Growth and development of pediatric patients on prolonged corticosteroid therapy should be carefully monitored.

Use in Pregnancy

Prednisone can cause fetal harm when administered to a pregnant woman. Human and animal studies suggest that use of corticosteroids during the first trimester of pregnancy is associated with an increased risk of orofacial clefts, intrauterine growth restriction, and decreased birth weight. If this drug is used during pregnancy, or if the patient becomes pregnant while using this drug, the patient should be apprised of the potential hazard to the fetus.

Neuromuscular Effects

Although controlled clinical trials have shown corticosteroids to be effective in speeding the resolution of acute exacerbations of multiple sclerosis, they do not show that they affect the ultimate outcome or natural history of the disease. The studies do show that relatively high doses of corticosteroids are necessary to demonstrate a significant effect.

An acute myopathy has been observed with the use of high doses of corticosteroids, most often occurring in patients with disorders of neuromuscular transmission (e.g., myasthenia gravis), or in patients receiving concomitant therapy with neuromuscular blocking drugs (e.g., pancuronium). This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevation of creatine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years.

Kaposi's Sarcoma

Kaposi's sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. Discontinuation of corticosteroids may result in clinical improvement.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Prednisone was not formally evaluated in carcinogenicity studies. Review of the published literature identified carcinogenicity studies of prednisolone, the active metabolite of prednisone, at doses which were less than the typical clinical doses. In a 2-year study, male Sprague-Dawley rats administered prednisolone in drinking water at a dose of 368 mcg/kg/day (equivalent to 3.5 mg/day in a 60-kg individual based on a mg/m² body surface area comparison) developed increased incidences of hepatic adenomas. Lower doses were not studied, and therefore, a no effect level could not be identified. In an 18-month study, intermittent oral gavage administration of prednisolone did not induce tumors in female Sprague-Dawley rats when given 1, 2, 4.5, or 9 times per month at 3 mg/kg prednisone (equivalent to 29 mg in a 60-kg individual based on a mg/m² body surface area comparison).

Prednisone was not formally evaluated for genotoxicity. However, in published studies prednisolone was not mutagenic with or without metabolic activation in the Ames bacterial reverse mutation assay using Salmonella typhimurium and Escherichia coli, or in a mammalian cell gene mutation assay using mouse lymphoma L5178Y cells, according to current evaluation standards. In a published chromosomal aberration study in Chinese Hamster Lung (CHL) cells, a slight increase was seen in the incidence of structural chromosomal aberrations with metabolic activation at the highest concentration tested, however, the effect appears to be equivocal. Prednisolone was not genotoxic in an in vivo micronucleaus assay in the mouse, though the study design did not meet current criteria.

Prednisone was not formally evaluated in fertility studies. However, menstrual irregularities have been described with clinical use.

Use In Specific Populations

Pregnancy

Teratogenic Effects

Pregnancy Category D : Multiple cohort and case controlled studies in humans suggest that maternal corticosteroid use during the first trimester increases the rate of cleft lip with or without cleft palate from about 1/1000 infants to 3-5/1000 infants. Two prospective case control studies showed decreased birth weight in infants exposed to maternal corticosteroids in utero.

RAYOS was not formally evaluated for effects on reproduction. Published literature indicates prednisolone, the active metabolite of prednisone, has been shown to be teratogenic in rats, rabbits, hamsters, and mice with increased incidence of cleft palate in offspring. In teratogenicity studies, cleft palate along with elevation of fetal lethality (or increase in resorptions) and reductions in fetal body weight were seen in rats at maternal doses of 30 mg/kg (equivalent to 290 mg in a 60 kg individual based on mg/m² body surface comparison) and higher. Cleft palate was observed in mice at a maternal dose of 20 mg/kg (equivalent to 100 mg in a 60 kg individual based on mg/m² comparison). Additionally, constriction of the ductus arteriosus has been observed in fetuses of pregnant rats exposed to prednisolone.

In humans, the risk of decreased birth weight appears to be dose related and may be minimized by administering lower corticosteroid doses. It is likely that underlying maternal conditions contribute to intrauterine growth restriction and decreased birth weight, but it is unclear to what extent these maternal conditions contribute to the increased risk of orofacial clefts.

Prednisolone can cause fetal harm when used in pregnancy. RAYOS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while using this drug, the patient should be apprised of the potential hazard to the fetus. Infants born to mothers who have received substantial doses of corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism.

Nursing Mothers

Prednisolone, the active metabolite of prednisone, is secreted in human milk. Reports suggest that prednisolone concentrations in human milk are 5 to 25% of maternal serum levels, and that total infant daily doses are small, about 0.14% of the maternal daily dose. The risk of infant exposure to prednisolone through breast milk should be weighed against the known benefits of breastfeeding for both the mother and baby.

Caution should be exercised when RAYOS is administered to a nursing woman. If RAYOS must be prescribed to a breastfeeding mother, the lowest dose should be prescribed to achieve the desired clinical effect. High doses of corticosteroids for long periods could potentially produce problems in infant growth and development and interfere with endogenous corticosteroid production.

Pediatric Use

The efficacy and safety of prednisone in the pediatric population are based on the well-established course of effect of corticosteroids which is similar in pediatric and adult populations. Published studies provide evidence of efficacy and safety in pediatric patients for the treatment of nephrotic syndrome ( > 2 years of age), and aggressive lymphomas and leukemias ( > 1 month of age). However, some of these conclusions and other indications for pediatric use of corticosteroid, e.g., severe asthma and wheezing, are based on adequate and well-controlled trials conducted in adults, on the premises that the course of the diseases and their pathophysiology are considered to be substantially similar in both populations. The adverse effects of prednisone in pediatric patients are similar to those in adults. Like adults, pediatric patients should be carefully observed with frequent measurements of blood pressure, weight, height, intraocular pressure, and clinical evaluation for the presence of infection, psychosocial disturbances, thromboembolism, peptic ulcers, cataracts, and osteoporosis.

Children who are treated with corticosteroids by any route, including systemically administered corticosteroids, may experience a decrease in their growth velocity. This negative impact of corticosteroids on growth has been observed at low systemic doses and in the absence of laboratory evidence of HPA axis suppression (i.e., cosyntropin stimulation and basal cortisol levels). Growth velocity may therefore be a more sensitive indicator of systemic corticosteroid exposure in children than some commonly used tests of HPA axis function. The linear growth of children treated with corticosteroids by any route should be monitored, and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of other treatment alternatives. In order to minimize the potential growth effects of corticosteroids, children should be titrated to the lowest effective dose

Geriatric Use

No overall differences in safety or effectiveness were observed between elderly subjects and younger subjects, and other reported clinical experience with prednisone has not identified differences in responses between the elderly and younger patients. However, the incidence of corticosteroid-induced side effects may be increased in geriatric patients and are dose-related. Osteoporosis is the most frequently encountered complication, which occurs at a higher incidence rate in corticosteroid-treated geriatric patients as compared to younger populations and in age-matched controls. Losses of bone mineral density appear to be greatest early on in the course of treatment and may recover over time after steroid withdrawal or use of lower doses (i.e., ≥ 5 mg/day). Prednisone doses of 7.5 mg/day or higher have been associated with an increased relative risk of both vertebral and nonvertebral fractures, even in the presence of higher bone density compared to patients with involution osteoporosis. Routine screening of geriatric patients, including regular assessments of bone mineral density and institution of fracture prevention strategies, along with regular review of prednisone indication should be undertaken to minimize complications and keep the prednisolone dose at the lowest acceptable level. Co­administration of certain bisphosphonates have been shown to retard the rate of bone loss in corticosteroid-treated males and postmenopausal females, and these agents are recommended in the prevention and treatment of corticosteroid-induced osteoporosis.

It has been reported that equivalent weight-based doses yield higher total and unbound prednisolone plasma concentrations and reduced renal and non-renal clearance in elderly patients compared to younger populations. Dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Care should be taken to ensure that the eye is not infected before Minims Prednisolone is used.

Systemic absorption may be reduced by compressing the lacrimal sac at the medial canthus for a minute during and following the instillation of the drops. (This blocks the passage of drops via the naso-lacrimal duct to the wide absorptive area of the nasal and pharyngeal mucosa. It is especially advisable in children.).

Visual disturbance

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Alterations in Endocrine Function

Hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing's syndrome, and hyperglycemia. Monitor patients for these conditions with chronic use.

Corticosteroids can produce reversible hypothalamic-pituitary adrenal (HPA) axis suppression with the potential for corticosteroid insufficiency after withdrawal of treatment. Drug-induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted. If the patient is receiving corticosteroids already, dosage may have to be increased.

Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently. Mineralocorticoid supplementation is of particular importance in infancy.

Metabolic clearance of corticosteroids is decreased in hypothyroid patients and increased in hyperthyroid patients. Changes in thyroid status of the patient may necessitate adjustment in dosage.

Increased Risks Related to Infection

Corticosteroids may increase the risks related to infections with any pathogen, including viral, bacterial, fungal, protozoan, or helminthic infections. The degree to which the dose, route and duration of corticosteroid administration correlates with the specific risks of infection is not well characterized, however, with increasing doses of corticosteroids, the rate of occurrence of infectious complications increases.

Corticosteroids may mask some signs of infection and may reduce resistance to new infections.

Corticosteroids may exacerbate infections and increase risk of disseminated infections.

The use of prednisone in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for management of the disease in conjunction with an appropriate anti-tuberculous regimen.

Chickenpox and measles can have a more serious or even fatal course in non-immune children or adults on corticosteroids. In children or adults who have not had these diseases, particular care should be taken to avoid exposure. If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. If chickenpox develops, treatment with antiviral agents may be considered.

Corticosteroids should be used with great care in patients with known or suspected Strongyloides (threadworm) infestation. In such patients, corticosteroid-induced immunosuppression may lead to Strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia.

Corticosteroids may exacerbate systemic fungal infections and therefore should not be used in the presence of such infections unless they are needed to control drug reactions.

Corticosteroids may increase risk of reactivation or exacerbation of latent infection.

If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis.

Corticosteroids may activate latent amebiasis. Therefore, it is recommended that latent amebiasis or active amebiasis be ruled out before initiating corticosteroid therapy in any patient who has spent time in the tropics or any patient with unexplained diarrhea.

Corticosteroids should not be used in cerebral malaria.

Alterations in Cardiovascular/Renal Function

Corticosteroids can cause elevation of blood pressure, salt, and water retention, and increased excretion of potassium and calcium. These effects are less likely to occur with the synthetic derivatives except when used in large doses. Dietary salt restriction and potassium supplementation may be necessary. These agents should be used with caution in patients with congestive heart failure, hypertension, or renal insufficiency.

Literature reports suggest an apparent association between use of corticosteroids and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with corticosteroids should be used with great caution in these patients.

Use in Patients with Gastrointestinal Disorders

There is an increased risk of gastrointestinal perforation in patients with certain GI disorders. Signs of GI perforation, such as peritoneal irritation may be masked in patients receiving corticosteroids.

Corticosteroids should be used with caution if there is a probability of impending perforation, abscess, or other pyogenic infections; diverticulitis; fresh intestinal anastomoses; and active or latent peptic ulcer.

Behavioral and Mood Disturbances

Corticosteroids use may be associated with central nervous system effects ranging from euphoria, insomnia, mood swings, personality changes, and severe depression, to frank psychotic manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated by corticosteroids.

Decrease in Bone Density

Corticosteroids decrease bone formation and increase bone resorption both through their effect on calcium regulation (i.e., decreasing absorption and increasing excretion) and inhibition of osteoblast function. This, together with a decrease in the protein matrix of the bone secondary to an increase in protein catabolism, and reduced sex hormone production, may lead to inhibition of bone growth in children and adolescents and the development of osteoporosis at any age. Special consideration should be given to patients at increased risk of osteoporosis (i.e., postmenopausal women) before initiating corticosteroid therapy and bone density should be monitored in patients on long term corticosteroid therapy.

Ophthalmic Effects

Prolonged use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to fungi or viruses.

The use of oral corticosteroids is not recommended in the treatment of optic neuritis and may lead to an increase in the risk of new episodes.

Intraocular pressure may become elevated in some individuals. If corticosteroid therapy is continued for more than 6 weeks, intraocular pressure should be monitored.

Corticosteroids should be used cautiously in patients with ocular herpes simplex because of possible corneal perforation. Corticosteroids should not be used in active ocular herpes simplex.

Vaccination

Administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids. Killed or inactivated vaccines may be administered; however, the response to such vaccines cannot be predicted. Immunization procedures may be undertaken in patients who are receiving corticosteroids as replacement therapy, e.g., for Addison's disease.

While on corticosteroid therapy, patients should not be vaccinated against smallpox. Other immunization procedures should not be undertaken in patients who are on corticosteroids, especially on high dose, because of possible hazards of neurological complications and a lack of antibody response.

Effect on Growth and Development

Long-term use of corticosteroids can have negative effects on growth and development in children.

Growth and development of pediatric patients on prolonged corticosteroid therapy should be carefully monitored.

Use in Pregnancy

Prednisone can cause fetal harm when administered to a pregnant woman. Human and animal studies suggest that use of corticosteroids during the first trimester of pregnancy is associated with an increased risk of orofacial clefts, intrauterine growth restriction, and decreased birth weight. If this drug is used during pregnancy, or if the patient becomes pregnant while using this drug, the patient should be apprised of the potential hazard to the fetus.

Neuromuscular Effects

Although controlled clinical trials have shown corticosteroids to be effective in speeding the resolution of acute exacerbations of multiple sclerosis, they do not show that they affect the ultimate outcome or natural history of the disease. The studies do show that relatively high doses of corticosteroids are necessary to demonstrate a significant effect.

An acute myopathy has been observed with the use of high doses of corticosteroids, most often occurring in patients with disorders of neuromuscular transmission (e.g., myasthenia gravis), or in patients receiving concomitant therapy with neuromuscular blocking drugs (e.g., pancuronium). This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevation of creatine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years.

Kaposi's Sarcoma

Kaposi's sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. Discontinuation of corticosteroids may result in clinical improvement.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Prednisone was not formally evaluated in carcinogenicity studies. Review of the published literature identified carcinogenicity studies of prednisolone, the active metabolite of prednisone, at doses which were less than the typical clinical doses. In a 2-year study, male Sprague-Dawley rats administered prednisolone in drinking water at a dose of 368 mcg/kg/day (equivalent to 3.5 mg/day in a 60-kg individual based on a mg/m² body surface area comparison) developed increased incidences of hepatic adenomas. Lower doses were not studied, and therefore, a no effect level could not be identified. In an 18-month study, intermittent oral gavage administration of prednisolone did not induce tumors in female Sprague-Dawley rats when given 1, 2, 4.5, or 9 times per month at 3 mg/kg prednisone (equivalent to 29 mg in a 60-kg individual based on a mg/m² body surface area comparison).

Prednisone was not formally evaluated for genotoxicity. However, in published studies prednisolone was not mutagenic with or without metabolic activation in the Ames bacterial reverse mutation assay using Salmonella typhimurium and Escherichia coli, or in a mammalian cell gene mutation assay using mouse lymphoma L5178Y cells, according to current evaluation standards. In a published chromosomal aberration study in Chinese Hamster Lung (CHL) cells, a slight increase was seen in the incidence of structural chromosomal aberrations with metabolic activation at the highest concentration tested, however, the effect appears to be equivocal. Prednisolone was not genotoxic in an in vivo micronucleaus assay in the mouse, though the study design did not meet current criteria.

Prednisone was not formally evaluated in fertility studies. However, menstrual irregularities have been described with clinical use.

Use In Specific Populations

Pregnancy

Teratogenic Effects

Pregnancy Category D : Multiple cohort and case controlled studies in humans suggest that maternal corticosteroid use during the first trimester increases the rate of cleft lip with or without cleft palate from about 1/1000 infants to 3-5/1000 infants. Two prospective case control studies showed decreased birth weight in infants exposed to maternal corticosteroids in utero.

Prednisolon Apotex was not formally evaluated for effects on reproduction. Published literature indicates prednisolone, the active metabolite of prednisone, has been shown to be teratogenic in rats, rabbits, hamsters, and mice with increased incidence of cleft palate in offspring. In teratogenicity studies, cleft palate along with elevation of fetal lethality (or increase in resorptions) and reductions in fetal body weight were seen in rats at maternal doses of 30 mg/kg (equivalent to 290 mg in a 60 kg individual based on mg/m² body surface comparison) and higher. Cleft palate was observed in mice at a maternal dose of 20 mg/kg (equivalent to 100 mg in a 60 kg individual based on mg/m² comparison). Additionally, constriction of the ductus arteriosus has been observed in fetuses of pregnant rats exposed to prednisolone.

In humans, the risk of decreased birth weight appears to be dose related and may be minimized by administering lower corticosteroid doses. It is likely that underlying maternal conditions contribute to intrauterine growth restriction and decreased birth weight, but it is unclear to what extent these maternal conditions contribute to the increased risk of orofacial clefts.

Prednisolone can cause fetal harm when used in pregnancy. Prednisolon Apotex should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while using this drug, the patient should be apprised of the potential hazard to the fetus. Infants born to mothers who have received substantial doses of corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism.

Nursing Mothers

Prednisolone, the active metabolite of prednisone, is secreted in human milk. Reports suggest that prednisolone concentrations in human milk are 5 to 25% of maternal serum levels, and that total infant daily doses are small, about 0.14% of the maternal daily dose. The risk of infant exposure to prednisolone through breast milk should be weighed against the known benefits of breastfeeding for both the mother and baby.

Caution should be exercised when Prednisolon Apotex is administered to a nursing woman. If Prednisolon Apotex must be prescribed to a breastfeeding mother, the lowest dose should be prescribed to achieve the desired clinical effect. High doses of corticosteroids for long periods could potentially produce problems in infant growth and development and interfere with endogenous corticosteroid production.

Pediatric Use

The efficacy and safety of prednisone in the pediatric population are based on the well-established course of effect of corticosteroids which is similar in pediatric and adult populations. Published studies provide evidence of efficacy and safety in pediatric patients for the treatment of nephrotic syndrome ( > 2 years of age), and aggressive lymphomas and leukemias ( > 1 month of age). However, some of these conclusions and other indications for pediatric use of corticosteroid, e.g., severe asthma and wheezing, are based on adequate and well-controlled trials conducted in adults, on the premises that the course of the diseases and their pathophysiology are considered to be substantially similar in both populations. The adverse effects of prednisone in pediatric patients are similar to those in adults. Like adults, pediatric patients should be carefully observed with frequent measurements of blood pressure, weight, height, intraocular pressure, and clinical evaluation for the presence of infection, psychosocial disturbances, thromboembolism, peptic ulcers, cataracts, and osteoporosis.

Children who are treated with corticosteroids by any route, including systemically administered corticosteroids, may experience a decrease in their growth velocity. This negative impact of corticosteroids on growth has been observed at low systemic doses and in the absence of laboratory evidence of HPA axis suppression (i.e., cosyntropin stimulation and basal cortisol levels). Growth velocity may therefore be a more sensitive indicator of systemic corticosteroid exposure in children than some commonly used tests of HPA axis function. The linear growth of children treated with corticosteroids by any route should be monitored, and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of other treatment alternatives. In order to minimize the potential growth effects of corticosteroids, children should be titrated to the lowest effective dose

Geriatric Use

No overall differences in safety or effectiveness were observed between elderly subjects and younger subjects, and other reported clinical experience with prednisone has not identified differences in responses between the elderly and younger patients. However, the incidence of corticosteroid-induced side effects may be increased in geriatric patients and are dose-related. Osteoporosis is the most frequently encountered complication, which occurs at a higher incidence rate in corticosteroid-treated geriatric patients as compared to younger populations and in age-matched controls. Losses of bone mineral density appear to be greatest early on in the course of treatment and may recover over time after steroid withdrawal or use of lower doses (i.e., ≥ 5 mg/day). Prednisone doses of 7.5 mg/day or higher have been associated with an increased relative risk of both vertebral and nonvertebral fractures, even in the presence of higher bone density compared to patients with involution osteoporosis. Routine screening of geriatric patients, including regular assessments of bone mineral density and institution of fracture prevention strategies, along with regular review of prednisone indication should be undertaken to minimize complications and keep the prednisolone dose at the lowest acceptable level. Co­administration of certain bisphosphonates have been shown to retard the rate of bone loss in corticosteroid-treated males and postmenopausal females, and these agents are recommended in the prevention and treatment of corticosteroid-induced osteoporosis.

It has been reported that equivalent weight-based doses yield higher total and unbound prednisolone plasma concentrations and reduced renal and non-renal clearance in elderly patients compared to younger populations. Dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

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).

Visual disturbance

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

Scleroderma renal crisis

Caution is required in patients with systemic sclerosis because of an increased incidence of (possibly fatal) scleroderma renal crisis with hypertension and decreased urinary output observed with a daily dose of 15 mg or more prednisolone. Blood pressure and renal function (s-creatinine) should therefore be routinely checked. When renal crisis is suspected, blood pressure should be carefully controlled.

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.

Caution is necessary when corticosteroids, including prednisone, are prescribed to a patient with recent myocardial infarction due to a risk of myocardial rupture.

Caution is necessary when corticosteroids, including prednisone, are prescribed to patients with renal insufficiency.

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.

In patients with known or suspected Strongyloids (threadworm) infestation glucocorticoids may lead to Strongyloides hyperinfection and dissemination with widespread larval migration.

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.

WARNINGS

Prolonged use of corticosteroids may result in posterior subcapsular cataract formation and may increase intraocular pressure in susceptible individuals, resulting in glaucoma with damage to the optic nerve, defects in visual acuity and fields of vision. Prolonged use may also suppress the host immune response and thus increase the hazard of secondary ocular infections.

If this product is used for 10 days or longer, intraocular pressure should be routinely monitored even though it may be difficult in children and uncooperative patients. Steroids should be used with caution in the presence of glaucoma. Intraocular pressure should be checked frequently. Various ocular diseases and long-term use of topical corticosteroids have been known to cause corneal and scleral thinning. Use of topical corticosteroids in the presence of thin corneal or scleral tissue may lead to perforation.

Acute purulent infections of the eye may be masked or activity enhanced by the presence of corticosteroid medication.

The use of steroids after cataract surgery may delay healing and increase the incidence of bleb formation.

Use of ocular steroids may prolong the course and may exacerbate the severity of many viral infections of the eye (including herpes simplex). Employment of a corticosteroid medication in the treatment of patients with a history of herpes simplex requires great caution; frequent slit lamp microscopy is recommended.

Prednisolon Apotex^® suspension contains sodium bisulfite, a sulfite that may cause allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in non-asthmatic people.

PRECAUTIONS

General

The initial prescription and renewal of the medication order beyond 20 milliliters of PRED FORTE^® suspension should be made by a physician only after examination of the patient with the aid of magnification, such as slit lamp biomicroscopy, and, where appropriate, fluorescein staining. If signs and symptoms fail to improve after 2 days, the patient should be re-evaluated.

As fungal infections of the cornea are particularly prone to develop coincidentally with longterm local corticosteroid applications, fungal invasion should be suspected in any persistent corneal ulceration where a corticosteroid has been used or is in use. Fungal cultures should be taken when appropriate.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

No studies have been conducted in animals or in humans to evaluate the potential of these effects.

Pregnancy

Prednisolone has been shown to be teratogenic in mice when given in doses 1-10 times the human dose. Dexamethasone, hydrocortisone, and prednisolone were ocularly applied to both eyes of pregnant mice five times per day on days 10 through 13 of gestation. A significant increase in the incidence of cleft palate was observed in the fetuses of the treated mice. There are no adequate well-controlled studies in pregnant women. Prednisolone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

It is not known whether topical ophthalmic administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in breast milk. Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Because of the potential for serious adverse reactions in nursing infants from prednisolone, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and effectiveness in pediatric patients have been established. Use in pediatric patients is supported by evidence from adequate and well-controlled studies of prednisolone acetate ophthalmic suspension in adults with additional data in pediatric patients.

Geriatric Use

No overall differences in safety or effectiveness have been observed between elderly and younger patients.

The effect of Prednisolon Apotexe on the ability to drive or use machinery has not been evaluated. There is no evidence to suggest that Prednisolon Apotexe may affect these abilities.

Not relevant.

No studies on the effects on the ability to drive and use machines have been performed.

A wide range of psychiatric reactions including affective disorders (such as irritable, euphoric, depressed and labile mood, and suicidal thoughts), psychotic reactions (including mania, delusions, hallucinations, and aggravation of schizophrenia), behavioural disturbances, irritability, anxiety, sleep disturbances, and cognitive dysfunction including confusion and amnesia have been reported.'Special warnings and special precautions for use').

Undesirable effects are listed by MedDRA System Organ Classes.

Assessment of undesirable effects is based on the following frequency groupings:

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

Not known: cannot be estimated from the available data

System Organ Class	Frequency	Undesirable Effect
Infections and Infestations	Not known	Increases susceptibility to, and severity of infections1, opportunistic infections, recurrence of dormant tuberculosis2, oesophageal candidiasis.
Blood and lymphatic system disorders	Not known	Leucocytosis.
Immune system disorders	Not known	Hypersensitivity including anaphylaxis.
Endocrine disorders	Not known	Suppression of the hypothalamo-pituitary adrenal axis3, cushingoid facies, impaired carbohydrate tolerance with increased requirement for antidiabetic therapy, manifestation of latent diabetes mellitus.
Metabolism and nutrition disorders	Not known	Sodium and water retention, hypokalaemic alkalosis, potassium loss, negative nitrogen and calcium balance, glucose intolerance and protein catabolism. Increase both high and low density lipoprotein cholesterol concentration in the blood. Increased appetite4. Weight gain, obesity, hyperglycaemia, dyslipidaemia.
	Very rare	Calciphylaxis5
Psychiatric disorders	Common	Irritability, depressed and labile mood, suicidal thoughts, psychotic reactions, mania, delusions, hallucinations, and aggravation of schizophrenia. behavioural disturbances, irritability, anxiety, sleep disturbances, and cognitive dysfunction including confusion and amnesia.
	Not known	Euphoria, psychological dependence, depression.
Nervous system disorders	Not known	Depression, insomnia, dizziness, headache, vertigo. Raised intracranial pressure with papilloedema (pseudotumor cerebri)6. Aggravation of epilepsy, epidural lipomatosis. vertebrobasilar stroke7
Eye disorders	Not known Severe exacerbation of bullous exudative retinal detachment; central serous chorioretinopathy or lasting visual loss in some patients with idiopathic central serous chorioretinopathy.8
Ear and labyrinth disorders	Not known	Vertigo.
Cardiac disorders	Not known	Congestive heart failure in susceptible patients, hypertension, increased risk of heart failure. Increased risk of cardiovascular disease, including myocardial infarction.9
Vascular disorders	Not known	Thromboembolism.
Gastrointestinal disorders	Not known	Dyspepsia, nausea, peptic ulceration with perforation and haemorrhage, abdominal distension, abdominal pain, diarrhoea, oesophageal ulceration, acute pancreatitis.
Skin and subcutaneous tissue disorders	Not known	Hirsutism, skin atrophy, bruising, striae, telangiectasia, acne, increased sweating, pruritis, rash, urticaria.
Musculoskeletal and connective tissue disorders	Not known	Proximal myopathy, osteoporosis, vertebral and long bone fractures, avascular osteonecrosis, tendon rupture, tendinopathies (particularly of the Achilles and patellar tendons), myalgia, growth suppression in infancy, childhood and adolescence.
Renal and urinary disorders	Not known	Scleroderma renal crisis10
Reproductive system and breast disorders	Not known	Menstrual irregularity, amenorrhoea.
General disorders and administration site conditions	Not known	Fatigue, malaise, impaired healing
Investigations	Not known	Increased intra-ocular pressure, may suppress reactions to skin tests. 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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard Common adverse reactions for corticosteroids include fluid retention, alteration in glucose tolerance, elevation in blood pressure, behavioral and mood changes, increased appetite and weight gain. Allergic Reactions: Anaphylaxis, angioedema Cardiovascular: Bradycardia, cardiac arrest, cardiac arrhythmias, cardiac enlargement, circulatory collapse, congestive heart failure, fat embolism, hypertension, hypertrophic cardiomyopathy in premature infants, myocardial rupture following recent myocardial infarction, pulmonary edema, syncope, tachycardia, thromboembolism, thrombophlebitis, vasculitis Dermatologic: Acne, allergic dermatitis, cutaneous and subcutaneous atrophy, dry scalp, edema, facial erythema, hyper or hypo-pigmentation, impaired wound healing, increased sweating, petechiae and ecchymoses, rash, sterile abscess, striae, suppressed reactions to skin tests, thin fragile skin, thinning scalp hair, urticaria Endocrine: Abnormal fat deposits, decreased carbohydrate tolerance, development of Cushingoid state, hirsutism, manifestations of latent diabetes mellitus and increased requirements for insulin or oral hypoglycemic agents in diabetics, menstrual irregularities, moon facies, secondary adrenocortical and pituitary unresponsiveness (particularly in times of stress, as in trauma, surgery or illness), suppression of growth in children Fluid and Electrolyte Disturbances: Fluid retention, potassium loss, hypertension, hypokalemic alkalosis, sodium retention Gastrointestinal: Abdominal distention, elevation in serum liver enzymes levels (usually reversible upon discontinuation), hepatomegaly, hiccups, malaise, nausea, pancreatitis, peptic ulcer with possible perforation and hemorrhage, ulcerative esophagitis General: Increased appetite and weight gain Metabolic: Negative nitrogen balance due to protein catabolism Musculoskeletal: Osteonecrosis of femoral and humeral heads, charcot-like arthropathy, loss of muscle mass, muscle weakness, osteoporosis, pathologic fracture of long bones, steroid myopathy, tendon rupture, vertebral compression fractures Neurological: Arachnoiditis, convulsions, depression, emotional instability, euphoria, headache, increased intracranial pressure with papilledema (pseudo-tumor cerebri) usually following discontinuation of treatment, insomnia, meningitis, mood swings, neuritis, neuropathy, paraparesis/paraplegia, paresthesia, personality changes, sensory disturbances, vertigo Ophthalmic: Exophthalmos, glaucoma, increased intraocular pressure, posterior subcapsular cataracts, and central serous chorioretinopathy Reproductive: Alteration in motility and number of spermatozoa Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of RAYOS was evaluated in 375 rheumatoid arthritis patients in two controlled trials. Patients treated with RAYOS ranged in age from 20 to 80 years (median age 56 years), with 85% female, 99% Caucasian, 1% African-American, and < 1% Asian. Patients received RAYOS 3 mg to 10 mg once daily at 10 pm; the majority (84%) received ≥ 5 mg. The clinical trial experience did not raise new safety concerns beyond those already established for immediate-release prednisone. Postmarketing Experience Adverse reactions have been identified during post approval use of RAYOS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The postmarketing experience has not raised new safety concerns beyond those already established for immediate-release prednisone. Eye disorders <) Prolonged treatment with corticosteroids in high dosage is occasionally associated with cataract. The systemic effects of steroids are possible following the use of Minims Prednisolone, but are, however, unlikely due to the reduced absorption of topical eye drops. Cases of corneal calcification have been reported very rarely in association with the use of phosphate containing eye drops in some patients with significantly damaged corneas. 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: United Kingdom Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard Common adverse reactions for corticosteroids include fluid retention, alteration in glucose tolerance, elevation in blood pressure, behavioral and mood changes, increased appetite and weight gain. Allergic Reactions: Anaphylaxis, angioedema Cardiovascular: Bradycardia, cardiac arrest, cardiac arrhythmias, cardiac enlargement, circulatory collapse, congestive heart failure, fat embolism, hypertension, hypertrophic cardiomyopathy in premature infants, myocardial rupture following recent myocardial infarction, pulmonary edema, syncope, tachycardia, thromboembolism, thrombophlebitis, vasculitis Dermatologic: Acne, allergic dermatitis, cutaneous and subcutaneous atrophy, dry scalp, edema, facial erythema, hyper or hypo-pigmentation, impaired wound healing, increased sweating, petechiae and ecchymoses, rash, sterile abscess, striae, suppressed reactions to skin tests, thin fragile skin, thinning scalp hair, urticaria Endocrine: Abnormal fat deposits, decreased carbohydrate tolerance, development of Cushingoid state, hirsutism, manifestations of latent diabetes mellitus and increased requirements for insulin or oral hypoglycemic agents in diabetics, menstrual irregularities, moon facies, secondary adrenocortical and pituitary unresponsiveness (particularly in times of stress, as in trauma, surgery or illness), suppression of growth in children Fluid and Electrolyte Disturbances: Fluid retention, potassium loss, hypertension, hypokalemic alkalosis, sodium retention Gastrointestinal: Abdominal distention, elevation in serum liver enzymes levels (usually reversible upon discontinuation), hepatomegaly, hiccups, malaise, nausea, pancreatitis, peptic ulcer with possible perforation and hemorrhage, ulcerative esophagitis General: Increased appetite and weight gain Metabolic: Negative nitrogen balance due to protein catabolism Musculoskeletal: Osteonecrosis of femoral and humeral heads, charcot-like arthropathy, loss of muscle mass, muscle weakness, osteoporosis, pathologic fracture of long bones, steroid myopathy, tendon rupture, vertebral compression fractures Neurological: Arachnoiditis, convulsions, depression, emotional instability, euphoria, headache, increased intracranial pressure with papilledema (pseudo-tumor cerebri) usually following discontinuation of treatment, insomnia, meningitis, mood swings, neuritis, neuropathy, paraparesis/paraplegia, paresthesia, personality changes, sensory disturbances, vertigo Ophthalmic: Exophthalmos, glaucoma, increased intraocular pressure, posterior subcapsular cataracts, and central serous chorioretinopathy Reproductive: Alteration in motility and number of spermatozoa Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of Prednisolon Apotex was evaluated in 375 rheumatoid arthritis patients in two controlled trials. Patients treated with Prednisolon Apotex ranged in age from 20 to 80 years (median age 56 years), with 85% female, 99% Caucasian, 1% African-American, and < 1% Asian. Patients received Prednisolon Apotex 3 mg to 10 mg once daily at 10 pm; the majority (84%) received ≥ 5 mg. The clinical trial experience did not raise new safety concerns beyond those already established for immediate-release prednisone. Postmarketing Experience Adverse reactions have been identified during post approval use of Prednisolon Apotex. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The postmarketing experience has not raised new safety concerns beyond those already established for immediate-release prednisone. 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 Cardiac disorders: Not known: Tachycardia Immune system disorders: Common: Reduced immune defence, masking of infections, exacerbation of latent infections Rare: Allergic reactions Infections and infestations: Common: Increases susceptibility to and severity of infections 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 nutrition disorders: Common: Sodium retention with oedema, increased potassium excretion (caution: arrhythmias), increased appetite and weight gain, reduced glucose tolerance, diabetes mellitus, hypercholesterolaemia and hypertriglyceridaemia Not known: Reversible epidural, epicardial or mediastinal lipomatosis, hypokalaemic alkalosis 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) Gastrointestinal disorders: Uncommon (no concomitant NSAIDs): Gastrointestinal ulcerations, gastrointestinal haemorrhages Rare: Pancreatitis Not known: Nausea, diarrhoea, vomiting 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 Not known: Hirsutism 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) Not known: Steroid myopathy, tendon rupture, vertebral and long bone fractures Renal and urinary disorders Not known: Scleroderma renal crisis* *see section Description of selected adverse reactions Description of selected adverse reactions Scleroderma renal crisis Amongst the different subpopulations the occurrence of scleroderma renal crisis varies. The highest risk has been reported in patients with diffuse systemic sclerosis. The lowest risk has been reported in patients with limited systemic sclerosis (2%) and juvenile onset 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 are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard The following adverse reactions have been identified during use of Prednisolon Apotex®. Because reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions include elevation of intraocular pressure (IOP) with possible development of glaucoma and infrequent optic nerve damage, posterior subcapsular cataract formation, and delayed wound healing. The development of secondary ocular infection (bacterial, fungal, and viral) has occurred. Fungal and viral infections of the cornea are particularly prone to develop coincidentally with long-term applications of steroids. The possibility of fungal invasion should be considered in any persistent corneal ulceration where steroid treatment has been used (see PRECAUTIONS). Other adverse reactions reported with the use of prednisolone acetate ophthalmic suspension include: allergic reactions; dysgeusia; foreign body sensation; headache; pruritus; rash; transient burning and stinging upon instillation and other minor symptoms of ocular irritation; urticaria; and visual disturbance (blurry vision). Keratitis, conjunctivitis, corneal ulcers, mydriasis, conjunctival hyperemia, loss of accommodation and ptosis have occasionally been reported following local use of corticosteroids. Corticosteroid-containing preparations have also been reported to cause acute anterior uveitis and perforation of the globe. Overdose Modified-release tablet Suspension/Drops Acute intoxications with Lodotra are not known. In case of overdosing, an increase in undesirable effects, especially endocrine, metabolic and electrolyte-related effects, can be expected. There is no known antidote for prednisone. Overdosage will not ordinarily cause acute problems. If accidentally ingested, drink fluids to dilute. Pharmacodynamic properties Eye drops; Injection; Ointment for external use; Pills; Solution for intravenous and intramuscular injection; Substance-powder; Suspension for injection Substance Modified-release tablet Pharmacotherapeutic group: glucocorticoid steroid, ATC code: H02A B06 Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt- retaining properties, are used as replacement therapy in adrenocortical deficiency states. Their synthetic analogs are primarily used for their potent anti-inflammatory effects in disorders of many organ systems. Glucocorticoids cause profound and varied metabolic effects. In addition, they modify the body's immune responses to diverse stimuli. Pharmacotherapeutic group: Corticosteroids, plain, ATC code: S01BA04 Mechanism of action The actions of corticosteroids are mediated by the binding of the corticosteroid molecules to receptor molecules located within sensitive cells. Corticosteroid receptors are present in human trabecular meshwork cells and in rabbit iris ciliary body tissue. Prednisolone, in common with other corticosteroids, will inhibit phospholipase A2 and thus decrease prostaglandin formation. The activation and migration of leucocytes will be affected by prednisolone. A 1% solution of prednisolone has been demonstrated to cause a 5.1% reduction in polymorphonuclear leucocyte mobilisation to an inflamed cornea. Corticosteroids will also lyse and destroy lymphocytes. These actions of prednisolone all contribute to its anti-inflammatory effect. Pharmacotherapeutic group: Glucocorticoids, ATC code: H02AB07 Prednisone is a non-fluorinated glucocorticoid for systemic therapy. Prednisone shows a dose-dependent effect on the metabolism of almost all tissues. Under physiological conditions, these effects are vital to maintain homoeostasis of the organism at rest and under stress, as well as for the control of the activities of the immune system. In doses typically prescribed for Lodotra, prednisone has an immediate anti-inflammatory (antiexsudative and antiproliferative) effect and a delayed immunosuppressive effect. It inhibits chemotaxis and the activity of immune cells as well as the release and effect of mediators of inflammatory and immune reactions, e.g. of lysosomal enzymes, prostaglandins and leucotrienes. Prolonged therapy with high doses results in impaired response of the immune system and of the adrenal cortex. The mineralotropic effect that is pronounced in hydrocortisone is still detectable in prednisone and may require monitoring of serum electrolyte levels. In patients with rheumatoid arthritis, pro-inflammatory cytokines such as the interleukins IL-1 and IL-6 and tumor necrosis factor alpha (TNFα) reach peak plasma levels in the early morning hours (e.g. IL- 6 between 7 to 8 am). Cytokine concentrations were shown to decrease after administration of Lodotra and subsequent night-time release of prednisone (with start of absorption between 2 - 4 am and Cmax between 4 - 6 am). The efficacy and safety of Lodotra was assessed in two randomised, double-blind controlled studies in patients with active rheumatoid arthritis. In the first study, a multi-centre randomised double-blind phase III study of 12 week duration in a total of 288 patients pre-treated with prednisone or prednisolone, the group switching to Lodotra at the same dose showed a mean reduction of 23% in the duration of morning stiffness whereas the duration in the reference group did not change. Details are presented in the following table. Relative change in the duration of morning stiffness after 12 weeks of treatment: Relative change [%] Lodotra (n = 125) Prednisone IR (n = 129) Mean (SD) Median (min, max) -23 (89) -34 (-100, 500) 0 (89) -13 (-100, 610) In a subsequent open label extension phase (9 months treatment) the mean relative change in the duration of morning stiffness compared to baseline was about −50 %. Change in the duration of morning stiffness after 12 months treatment with Lodotra: Duration of Morning stiffness [min] Lodotra Mean (SD) N 0 months Start of the study 156 (97) 107 12 months End of open label phase 74 (92) 96 In the same study, after 12 weeks of treatment, a median decrease of the pro-inflammatory cytokine IL-6 of 29 % was observed in the group treated with Lodotra, whereas no change was observed in the comparator group who received standard prednisone. After 12 months of treatment with Lodotra the IL-6 level remains stable. Change in the IL-6 level after 12 months: IL-6 [IU/L] Lodotra median (min, max) N 0 months Start of the study 860 (200, 23000) 142 12 months End of open label phase 470 (200, 18300) 103 Values < 200 IU/L were set to 200 IU/L for statistical analyses The efficacy of Lodotra given on top of a DMARD was confirmed in a second randomised, placebo-controlled trial in patients insufficiently responding to DMARD therapy alone. At 12 weeks the Lodotra patients had a significantly higher ACR20 and ACR50 response rate (46.8% and 22.1%, respectively) compared to placebo patients (29.4% and 10.1%, respectively). There was also a greater mean change in DAS 28 scores from baseline (5.2 for the Lodotra group and 5.1 for the placebo group) to week 12 in the Lodotra group (−1.2 points) as compared with that seen in the placebo group (−0.7 point change). In addition, after 12 weeks of therapy the mean duration of morning stiffness was 86.0 minutes (-66 minutes change) in the Lodotra group and 114.1 minutes (-42.6 minutes change) in the placebo group. Lodotra could be safely used in combination with other DMARDs. Pharmacokinetic properties Eye drops; Injection; Ointment for external use; Pills; Solution for intravenous and intramuscular injection; Substance-powder; Suspension for injection Solution; Syrup; Tablet, Delayed Release Substance Delayed release Modified-release tablet Prednisolon Apotexe is rapidly and apparently almost completely absorbed after oral administration; it reaches peak plasma concentrations after 1-3 hours. There is however wide inter-subject variation suggesting impaired absorption in some individuals. Plasma half-life is about 3 hours in adults and somewhat less in children. Its initial absorption, but not its overall bioavailability, is affected by food. Prednisolon Apotexe has a biological half-life lasting several hours, making it suitable for alternate-day administration regimens. Although peak plasma Prednisolon Apotexe levels are somewhat lower after administration of Prednisolon Apotexe and absorption is delayed, total absorption and bioavailability are the same as after plain Prednisolon Apotexe. Prednisolon Apotexe shows dose dependent pharmacokinetics, with an increase in dose leading to an increase in volume of distribution and plasma clearance. The degree of plasma protein binding determines the distribution and clearance of free, pharmacologically active drug. Reduced doses are necessary in patients with hypoalbuminaemia. Prednisolon Apotexe is metabolised primarily in the liver to a biologically inactive compound. Liver disease prolongs the half-life of Prednisolon Apotexe and, if the patient has hypoalbuminaemia, also increases the proportion of unbound drug and may thereby increase adverse effects. Prednisolon Apotexe is excreted in the urine as free and conjugated metabolites, together with small amounts of unchanged Prednisolon Apotexe. Significant differences in the pharmacokinetics of Prednisolon Apotexe amongst menopausal women have been described. The postmenopausal women had reduced unbound clearance (30%), reduced total clearance and increased half-life of Prednisolon Apotexe. The pharmacokinetic profile of RAYOS has an approximately 4-hour lag time from that of immediate-release prednisone formulations. While the pharmacokinetic profile of RAYOS when given with food differs in terms of lag time from IR prednisone, its absorption, distribution, and elimination processes are comparable. Absorption Prednisone is released from RAYOS when taken with food approximately 4 hours after oral ingestion. This causes a delay in the time until peak plasma concentrations (Tmax) are achieved. Median Tmax of RAYOS in 27 healthy male subjects was 6.0 - 6.5 hours compared to 2.0 hours for an immediate-release (IR) formulation. Subsequently, prednisone was absorbed at the same rate as the IR formulation. Peak plasma concentrations (Cmax) and exposure, as indicated by AUC0-last and AUC0-∞, were comparable for both prednisone IR and RAYOS administered 2.5 hours after a light meal or with normal meal (Figure 1). Figure 1: Mean Plasma Levels of Prednisone After a Single Dose of 5 mg Prednisone Administered as a 5 mg RAYOS Tablet or a 5 mg Immediate-Release (IR) Tablet A: 5 mg IR tablet under fasting conditions, administered at 2 am, B: 5 mg RAYOS, administered 2.5 hours after a light evening meal, and C: 5 mg RAYOS administered immediately after dinner In a study with 24 healthy subjects, oral absorption of prednisone from RAYOS was significantly affected by the intake of food. Under standard fasting conditions, both the maximum plasma concentration (Cmax) and the bioavailability of RAYOS were significantly lower than under fed conditions, shortly after intake of a high fat meal. RAYOS at dose levels of 1 mg, 2 mg, and 5 mg showed dose-proportionality in terms of peak and systemic exposure (Cmax, AUC0-∞, and AUC0-last) for the parent drug prednisone as well as for the active metabolite prednisolone. Metabolism Prednisone is completely converted to the active metabolite prednisolone, which is further metabolized mainly in the liver and excreted in the urine as sulfate and glucuronide conjugates. The exposure of prednisolone is 4-6 fold higher than that of prednisone. Excretion The terminal half-life of both prednisone and prednisolone from the administration of RAYOS was 2-3 hours, which is comparable to that from the IR formulation. The oral availability, distribution and excretion of prednisolone is well documented. A figure of 82 ± 13% has been quoted as the oral availability and 1.4 ± 0.3ml/min/kg as the clearance rate. A half life of 2.1 - 4.0 hours has been calculated. With regard to ocular pharmacokinetics, Prednisolon Apotex is a highly water soluble compound and is almost lipid insoluble. Therefore, theoretically it should not penetrate the intact corneal epithelium. Nevertheless, 30 minutes after instillation of a drop of 1% drug, corneal concentrations of 10µg/g and aqueous levels of 0.5µg/g have been attained. When a 0.5% solution was instilled in rabbit eyes every 15 minutes for an hour, an aqueous concentration of 2.5µg/ml was measured. Considerable variance exists in the intraocular penetration of prednisolone depending on whether the cornea is normal or abraded. Absorption It can be seen that only low levels of prednisolone will be absorbed systemically, particularly where the cornea is intact. Any prednisolone which is absorbed will be highly protein-bound in common with other corticosteroids. The pharmacokinetic profile of Prednisolon Apotex has an approximately 4-hour lag time from that of immediate-release prednisone formulations. While the pharmacokinetic profile of Prednisolon Apotex when given with food differs in terms of lag time from IR prednisone, its absorption, distribution, and elimination processes are comparable. Absorption Prednisone is released from Prednisolon Apotex when taken with food approximately 4 hours after oral ingestion. This causes a delay in the time until peak plasma concentrations (Tmax) are achieved. Median Tmax of Prednisolon Apotex in 27 healthy male subjects was 6.0 - 6.5 hours compared to 2.0 hours for an immediate-release (IR) formulation. Subsequently, prednisone was absorbed at the same rate as the IR formulation. Peak plasma concentrations (Cmax) and exposure, as indicated by AUC0-last and AUC0-∞, were comparable for both prednisone IR and Prednisolon Apotex administered 2.5 hours after a light meal or with normal meal (Figure 1). Figure 1: Mean Plasma Levels of Prednisone After a Single Dose of 5 mg Prednisone Administered as a 5 mg Prednisolon Apotex Tablet or a 5 mg Immediate-Release (IR) Tablet A: 5 mg IR tablet under fasting conditions, administered at 2 am, B: 5 mg Prednisolon Apotex, administered 2.5 hours after a light evening meal, and C: 5 mg Prednisolon Apotex administered immediately after dinner In a study with 24 healthy subjects, oral absorption of prednisone from Prednisolon Apotex was significantly affected by the intake of food. Under standard fasting conditions, both the maximum plasma concentration (Cmax) and the bioavailability of Prednisolon Apotex were significantly lower than under fed conditions, shortly after intake of a high fat meal. Prednisolon Apotex at dose levels of 1 mg, 2 mg, and 5 mg showed dose-proportionality in terms of peak and systemic exposure (Cmax, AUC0-∞, and AUC0-last) for the parent drug prednisone as well as for the active metabolite prednisolone. Metabolism Prednisone is completely converted to the active metabolite prednisolone, which is further metabolized mainly in the liver and excreted in the urine as sulfate and glucuronide conjugates. The exposure of prednisolone is 4-6 fold higher than that of prednisone. Excretion The terminal half-life of both prednisone and prednisolone from the administration of Prednisolon Apotex was 2-3 hours, which is comparable to that from the IR formulation. Absorption Lodotra are prednisone-containing modified-release tablets. Prednisone is released between 4 - 6 hours following intake of Lodotra. Subsequently, prednisone is rapidly and almost completely absorbed. Distribution Peak serum levels are reached approximately 6 - 9 hours after intake. Biotransformation More than 80 % of the prednisone is converted to prednisolone by first-pass hepatic metabolism. The ratio of prednisone to prednisolone is approximately 1:6 to 1:10. Prednisone itself exerts negligible pharmacologic effects. Prednisolone is the active metabolite. The compounds are reversibly bound to plasma proteins with high affinity for transcortin (corticosteroid binding globulin, CBG) and low affinity for plasma albumin. In the low dose range (up to 5 mg), approximately 6% of free prednisolone is present. Metabolic elimination is dose linear in this range. In the dose range above 10 mg, the binding capacity of transcortin is increasingly exhausted and more free prednisolone is present. This may result in a faster metabolic elimination. Elimination Prednisolone is primarily eliminated by hepatic metabolism, to approximately 70 % by glucoronidation and to approximately 30 % by sulphatation. There is also conversion to 11ß,17ß-dihydroxyandrosta-1,4-dien-3-one and to 1,4-pregnadien-20-ol. The metabolites exhibit no hormonal activity and undergo primarily renal elimination. Negligible amounts of prednisone and prednisolone are found unchanged in the urine. The plasma elimination half-life of prednis(ol)one is approximately 3 hours. In patients with severe hepatic dysfunction the half-life may be prolonged and a dose reduction should be considered. The duration of the biological effects of prednis(ol)one exceeds the duration of the presence in the serum. Bioavailability A bioavailability study in 27 healthy subjects conducted in 2003 revealed the following results in comparison with a prednisone immediate-release tablet: Parameter Lodotra 5 mg: 2.5 hours after a light meal Lodotra 5 mg: Immediately after a meal Reference preparation 5 mg fasted Maximum plasma concentration (Cmax): ng/ml 20.2 (18.5; 21.9) 21.8 (20.0; 23.7) 20.7 (19.0; 22.5) Time of maximum plasma concentration (tmax): h 6.0 (4.5; 10.0) 6.5 (4.5; 9.0) 2.0 (1.0; 4.0) Duration of the delay of drug release (tlag): h 4.0 (3.5; 5.0) 3.5 (2.0; 5.5) 0.0 (0.0; 0.5) Area under the concentration-time curve (AUC 0-∞): ng x h/ml 110 (101; 119) 123 (114; 133) 109 (101; 118) Values are least-square geometric means and range Figure: Mean plasma levels of prednisone after a single dose of 5 mg prednisone administered as Lodotra 5 mg or an immediate-release tablet. 5 mg immediate-release tablet (A: fasted, intake at 2 am), Lodotra 5 mg (B: 2.5 hours after a light evening meal) and Lodotra 5 mg (C: immediately after a full evening meal). The plasma concentration profiles of Lodotra are very similar to an immediate-release tablet, with the important difference that the Lodotra profile is delayed with 4 - 6 hours after drug intake. Lower plasma concentrations have been observed in 6-7% of doses. Dose proportionality was demonstrated for Lodotra 1 mg, 2 mg and 5 mg based on AUC and Cmax. Pharmacotherapeutic group Eye drops; Injection; Ointment for external use; Pills; Solution for intravenous and intramuscular injection; Substance-powder; Suspension for injection Substance Modified-release tablet glucocorticoid steroid, ATC code: H02A B06 Corticosteroids, plain, ATC code: S01BA04 Glucocorticoids, ATC code: H02AB07 Preclinical safety data Eye drops; Injection; Ointment for external use; Pills; Solution for intravenous and intramuscular injection; Substance-powder; Suspension for injection Substance Modified-release tablet There are no non-clinical data of relevance to the prescriber that are not already covered in other sections of the SmPC. The use of prednisolone in ophthalmology is well-established. Little specific toxicology work has been reported, however, the breadth of clinical experience confirms its suitability as a topical ophthalmic agent. Subchronic/chronic toxicity Light and electron microscopic changes in the Langerhans' islet cells of rats were observed following daily intraperitoneal administration of 33 mg/kg bw over 7 to 14 days in rats. In rabbits, experimental liver damage could be produced by administering 2 to 3 mg/kg bw/day for 2 to 4 weeks. Histotoxic effects (myonecroses) were reported following several weeks of administration of 0.5 to 5 mg/kg bw in guinea pigs and 4 mg/kg bw in dogs. Mutagenic and tumour-forming potential The toxicity observed in animal studies with prednisone was associated with exaggerated pharmacological activity. No genotoxic effects of prednisone have been observed in conventional genotoxicity tests. Reproductive toxicity In animal reproduction studies, glucocorticoids such as prednisone have been shown to induce malformations (cleft palate, skeletal malformations). With parenteral administration, minor anomalies of skull, jaw and tongue were found in rats. Intrauterine growth retardation was observed. Similar effects are considered unlikely to occur in patients at therapeutic doses. Incompatibilities Eye drops; Injection; Ointment for external use; Pills; Solution for intravenous and intramuscular injection; Substance-powder; Suspension for injection Substance Modified-release tablet None known Not applicable. Not applicable Special precautions for disposal and other handling Eye drops; Injection; Ointment for external use; Pills; Solution for intravenous and intramuscular injection; Substance-powder; Suspension for injection Substance Modified-release tablet Not available Each Minims unit should be discarded after a single use. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. Not applicable. Available in countries Netherlands A-Z index: ABCDEFGHIJKLMNOPQRSTUVYZ