Prednisone delayed release

1 INDICATIONS AND USAGE Prednisone delayed-release tablets are indicated in the treatment of the following diseases or conditions: Prednisone delayed-release tablets are a corticosteroid indicated as an anti-inflammatory or immunosuppressive agent for certain allergic, dermatologic, gastrointestinal, hematologic, ophthalmologic, nervous system, renal, respiratory, rheumatologic, specific infectious diseases or conditions and organ transplantation ( 1 ) for the treatment of certain endocrine conditions ( 1 ) for palliation of certain neoplastic conditions ( 1 ) 1.1 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 1.2 Dermatologic Diseases Bullous dermatitis herpetiformis Contact dermatitis Exfoliative erythroderma Mycosis fungoides Pemphigus Severe erythema multiforme (Stevens-Johnson syndrome) 1.3 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 1.4 Gastrointestinal Diseases During acute episodes in: Crohn's Disease Ulcerative colitis 1.5 Hematologic Diseases Acquired (autoimmune) hemolytic anemia Diamond-Blackfan anemia Idiopathic thrombocytopenic purpura in adults Pure red cell aplasia Secondary thrombocytopenia in adults 1.6 Neoplastic Conditions For the treatment of: Acute leukemia Aggressive lymphomas 1.7 Nervous System Conditions Acute exacerbations of multiple sclerosis Cerebral edema associated with primary or metastatic brain tumor, craniotomy or head injury 1.8 Ophthalmic Conditions Sympathetic ophthalmia Uveitis and ocular inflammatory conditions unresponsive to topical steroids 1.9 Conditions Related to Organ Transplantation Acute or chronic solid organ rejection 1.10 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 1.11 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 1.12 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 1.13 Specific Infectious Diseases Trichinosis with neurologic or myocardial involvement. Tuberculous meningitis with subarachnoid block or impending block used concurrently with appropriate antituberculous chemotherapy.

2 DOSAGE AND ADMINISTRATION Individualize dosing based on disease severity and patient response. The timing of administration should take into account the delayed-release pharmacokinetics and the disease or condition being treated ( 2 , 12.1 ): Initial dose: Prednisone delayed-release tablets 5 mg administered once per day. Patients currently on immediate-release prednisone, prednisolone, or methylprednisolone should be switched to prednisone delayed-release tablets at an equivalent dose based on relative potency. ( 2.1 , 2.4 ) Maintenance dose: Use lowest dosage that will maintain an adequate clinical response. ( 2.1 ) Discontinuation: Withdraw gradually if discontinuing long-term or high-dose therapy. ( 2.1 ) Prednisone delayed-release tablets should be taken daily with food. ( 2.3 , 12.3 ) Prednisone delayed-release tablets should be swallowed whole and not broken, divided, or chewed. ( 2.3 ) 2.1 Recommended Dosing Dosage of prednisone delayed-release tablets 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. Prednisone delayed-release tablet is a delayed-release formulation of prednisone which releases the active substance beginning approximately 4 hours after intake [ see Clinical Pharmacology (12.3) ]. The timing of prednisone delayed-release tablets administration should take into account the delayed-release pharmacokinetics and the disease or condition being treated. The initial dosage of prednisone delayed-release tablets 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 prednisone delayed-release tablets 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, prednisone delayed-release tablets 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 prednisone delayed-release tablets 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. 2.2 Recommended Monitoring Blood pressure, body weight, routine laboratory studies (including 2-hour postprandial blood glucose and serum potassium), and …

5 WARNINGS AND PRECAUTIONS Hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing's syndrome, and hyperglycemia: Monitor patients for these conditions with chronic use. Taper doses gradually for withdrawal after chronic use. ( 5.1 ) Immunosuppression and Increased Risk of Infection: Increased susceptibility to new infection and increased risk of exacerbation, dissemination, or reactivation of latent infection. Signs and symptoms of infection may be masked. ( 5.2 ) Elevated blood pressure, salt and water retention, and hypokalemia: Monitor blood pressure and sodium, potassium serum levels ( 5.3 ) GI perforation: increased risk in patients with certain GI disorders. Signs and symptoms may be masked. ( 5.4 ) Behavioral and mood disturbances: May include euphoria, insomnia, mood swings, personality changes, severe depression, and psychosis. Existing conditions may be aggravated. ( 5.5 ) Decreases in bone density: Monitor bone density in patients receiving long term corticosteroid therapy. ( 5.6 ) Ophthalmic effects: May include cataracts, infections, and glaucoma. Monitor intraocular pressure if corticosteroid therapy is continued for more than 6 weeks ( 5.7 ) Live or live attenuated vaccines: Do not administer to patients receiving immunosuppressive doses of corticosteroids. ( 5.8 ) Negative effects on growth and development: Monitor pediatric patients on long-term corticosteroid therapy. ( 5.9 ) Embryo-Fetal Toxicity: Can cause fetal harm with first trimester use. Advise patients of potential harm to the fetus. ( 5.10 ) 5.1 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. 5.2 Immunosuppression and Increased Risk of Infection Corticosteroids, including prednisone delayed-release tablets, suppress the immune system and increase the risk of infection with any pathogen, including viral, bacterial, fungal, protozoan, or helminthic pathogens. Corticosteroids can: Reduce resistance to new infections Exacerbate existing infections Increase the risk of disseminated infections Increase the risk of reactivation or exacerbation of latent infections Mask some signs of infection Corticosteroid-associated infections can be mild but can be severe and at times fatal. The rate of infectious complications increases with increasing corticosteroid dosages. Monitor for the development of infection and consider prednisone delayed-release tablets withdrawal or dosage reduction as needed. Tuberculosis If prednisone delayed-release tablets are used to treat a condition in patients with latent tuberculosis or tuberculin reactivity, reactivation of tuberculosis may occur. Closely monitor such patients for reactivation. During prolonged prednisone delayed-release tablets therapy, patients with latent tuberculosis or tuberculin reactivity should receive chemoprophylaxis. Varicella Zoster and Measles Viral Infections Varicella and measles can have a serious or even fatal course in non…

4 CONTRAINDICATIONS Prednisone delayed-release tablets are 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 [ see Adverse Reactions (6) ]. Known hypersensitivity to prednisone or any excipients in the formulation ( 4 , 6 )

7 DRUG INTERACTIONS Anticoagulant agents: May enhance or diminish anticoagulant effects. ( 7.4 ) Antidiabetic agents: May increase blood glucose concentrations. Dose adjustments of antidiabetic agents may be required. ( 7.5 ) CYP 3A4 inducers and inhibitors: May, respectively, increase or decrease clearance of corticosteroids, necessitating dose adjustment. ( 7.7 , 7.8 ) Cyclosporine: Increase in activity of both, cyclosporine and corticosteroid when administered concurrently. Convulsions have been reported with concurrent use. ( 7.10 ) NSAIDs including aspirin and salicylates: Increased risk of gastrointestinal side effects. ( 7.13 ) 7.1 Aminoglutethimide Aminoglutethimide may lead to loss of corticosteroid-induced adrenal suppression. 7.2 Amphotericin B Injection There have been cases reported in which concomitant use of Amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure [see Drug Interactions (7.14) ] . 7.3 Anticholinesterase Agents Concomitant use of anticholinesterase agents and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy. 7.4 Anticoagulant Agents Co-administration of corticosteroids and warfarin usually results in inhibition of response to warfarin, although there have been some conflicting reports. Therefore, coagulation indices should be monitored frequently to maintain the desired anticoagulant effect. 7.5 Antidiabetic Agents Because corticosteroids may increase blood glucose concentrations, dosage adjustments of antidiabetic agents may be required. 7.6 Antitubercular Drugs Serum concentrations of isoniazid may be decreased. 7.7 CYP 3A4 Inducers (e.g., Barbiturates, Phenytoin, Carbamazepine, and Rifampin) Drugs such as barbiturates, phenytoin, ephedrine, and rifampin, which induce hepatic microsomal drug metabolizing enzyme activity may enhance the metabolism of corticosteroids and require that the dosage of the corticosteroid be increased. 7.8 CYP 3A4 Inhibitors (e.g., Ketoconazole, Macrolide Antibiotics) Ketoconazole has been reported to decrease the metabolism of certain corticosteroids by up to 60% leading to increased risk of corticosteroid side effects. 7.9 Cholestyramine Cholestyramine may increase the clearance of corticosteroids. 7.10 Cyclosporine Increased activity of both cyclosporine and corticosteroids may occur when the two are used concurrently. Convulsions have been reported with this concurrent use. 7.11 Digitalis Patients on digitalis glycosides may be at increased risk of arrhythmias due to hypokalemia. 7.12 Estrogens, Including Oral Contraceptives Estrogens may decrease the hepatic metabolism of certain corticosteroids, thereby increasing their effect. 7.13 Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) Including Aspirin and Salicylates Concomitant use of aspirin or other nonsteroidal anti-inflammatory drugs and corticosteroids increases the risk of gastrointestinal side effects. Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia. The clearance of salicylates may be increased with concurrent use of corticosteroids; this could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when corticosteroid is withdrawn. 7.14 Potassium-Depleting Agents (e.g., Diuretics, Amphotericin B) When corticosteroids are administered concomitantly with potassium-depleting agents, patients should be observed closely for development of hypokalemia. 7.15 Skin Tests Corticosteroids may suppress reactions to skin tests. 7.16 Toxoids and Live or Attenuated Vaccines Patients on corticosteroid therapy may exhibit a diminished response to toxoids and live or inactivated vaccines due to inhibition of antibody response. Corticosteroids may also potentiate the replication of some organisms contained in live attenuated vaccines. Routine administration of vaccin…

8.1 Pregnancy Risk Summary Based on findings from human and animal studies, corticosteroids, including prednisone delayed-release tablets, can cause fetal harm when administered to a pregnant woman (see Data ) [see Warnings and Precautions (5.10) ]. Published epidemiological studies suggest a small but inconsistent increased risk of orofacial clefts with use of corticosteroids during the first trimester. Intrauterine growth restriction and decreased birth weight have also been reported with maternal use of corticosteroids during pregnancy; however, the underlying maternal condition may also contribute to these risks (see Clinical Considerations ). Published animal studies show prednisolone to be teratogenic in rats, rabbits, hamsters, and mice with increased incidence of cleft palate in offspring (see Data ). Advise a pregnant woman about the potential harm to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinical recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Infants born to pregnant women who have received corticosteroids should be carefully monitored for signs and symptoms of hypoadrenalism [see Warnings and Precautions (5.1) ] Data Human Data Published epidemiological studies on the association between prednisolone and fetal outcomes have reported inconsistent findings and have important methodological limitations. Multiple cohort and case-controlled studies in humans suggest that maternal corticosteroid use during the first trimester increases the incidence of cleft lip with or without cleft palate from about 1/1000 infants to 3-5/1000 infants; however, a risk for orofacial clefts has not been observed in all studies. Methodological limitations of these studies include non-randomized design, retrospective data collection, and the inability to control for confounders such as underlying maternal disease and use of concomitant medications. Two prospective case control studies showed decreased birth weight in infants exposed to maternal corticosteroids in utero. 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. Animal Data Prednisolone, the active metabolite of prednisone, administered during the period of organogenesis, 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/m 2 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/m 2 comparison). Additionally, constriction of the ductus arteriosus has been observed in fetuses of pregnant rats exposed to prednisolone. Prednisone delayed-release tablets was not formally evaluated in animal reproduction studies.

6 ADVERSE REACTIONS 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 hypopigmentation, 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 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. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact INA Pharmaceutics Inc at 1-866-835-0469 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 prednisone delayed-release tablets was evaluated in 375 rheumatoid arthritis patients in two controlled trials. Patients treated with prednisone delayed-release tablets 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 prednisone delayed-release tablets 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. 6.2 Postmarketing Experience Adverse reactions have been identified during post approval use of prednisone delayed-release tablets. Bec…