Orapred ODT: Package Insert / Prescribing Info

1.1 Allergic Conditions

Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment in adult 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 corticosteroids

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/temporal arteritis
• 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

2.1 Recommended Dosing

Dosage of Orapred ODT 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.

Do not break or use partial Orapred ODT tablets. Use an appropriate formulation of prednisolone if indicated dose cannot be obtained using Orapred ODT. This may become important in the treatment of conditions that require tapering doses that cannot be adequately accommodated by Orapred ODT, e.g., tapering the dose below 10 mg.

The initial dose of Orapred ODT may vary from 10 to 60 mg (prednisolone base) per day, depending on the specific disease entity being treated. 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 of time, there is a lack of satisfactory clinical response, Orapred should be discontinued and the patient placed on 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 that 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 Orapred ODT for a period of time consistent with the patient's condition. If after long term therapy the drug is to be stopped, it is recommended that it be withdrawn gradually rather than abruptly.

Orapred ODT are packaged in a blister. Patients should be instructed not to remove the tablet from the blister until just prior to dosing. The blister pack should then be peeled open, and the orally disintegrating tablet placed on the tongue, where tablets may be swallowed whole as any conventional tablet, or allowed to dissolve in the mouth, with or without the assistance of water. Orally disintegrating tablet dosage forms are friable and are not intended to be cut, split, or broken.

Multiple Sclerosis
In the treatment of acute exacerbations of multiple sclerosis, daily doses of 200 mg of prednisolone for a week followed by 80 mg every other day for one month have been shown to be effective.

Pediatric
In pediatric patients, the initial dose of Orapred may vary depending on the specific disease entity being treated. The range of initial doses is 0.14 to 2 mg/kg/day in three or four divided doses (4 to 60 mg/m2bsa/day).

Nephrotic Syndrome
The standard regimen used to treat nephrotic syndrome in pediatric patients is 60 mg/m2/day given in three divided doses for 4 weeks, followed by 4 weeks of single dose alternate-day therapy at 40 mg/m2/day.

Asthma
The National Heart, Lung, and Blood Institute (NHLBI) recommended dosing for systemic prednisone, prednisolone or methylprednisolone in children whose asthma is uncontrolled by inhaled corticosteroids and long-acting bronchodilators is 1-2 mg/kg/day in single or divided doses.

It is further recommended that short course, or "burst" therapy, be continued until a child achieves a peak expiratory flow rate of 80% of his or her personal best or symptoms resolve. This usually requires 3 to 10 days of treatment, although it can take longer. There is no evidence that tapering the dose after improvement will prevent a relapse.

2.2 Recommended Monitoring

Blood pressure, body weight, routine laboratory studies, including serum potassium and fasting blood glucose, should be obtained at regular intervals during prolonged therapy. Appropriate diagnostic studies should be performed in patients with known or suspected peptic ulcer disease and in patients at risk for reactivation of latent tuberculosis infections.

2.3 Corticosteroid Comparison Chart

For the purpose of comparison, one 10 mg Orapred ODT tablet (13.4 mg prednisolone sodium phosphate) is equivalent to the following milligram dosage of the various glucocorticoids:

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.

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 HPA axis suppression with the potential for glucocorticosteroid 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.

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 Orapred ODT, 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 Orapred ODT withdrawal or dosage reduction as needed.

Tuberculosis
If Orapred ODT is 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 Orapred ODT 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-immune patients taking corticosteroids, including Orapred ODT. In corticosteroid-treated patients who have not had these diseases or are non-immune, particular care should be taken to avoid exposure to varicella and measles:

• If an Orapred ODT-treated patient is exposed to varicella, prophylaxis with varicella zoster immune globulin may be indicated. If varicella develops, treatment with antiviral agents may be considered.
• If an Orapred ODT-treated patient is exposed to measles, prophylaxis with immunoglobulin may be indicated.

Hepatitis B Virus Reactivation
Hepatitis B virus reactivation can occur in patients who are hepatitis B carriers treated with immunosuppressive dosages of corticosteroids, including Orapred ODT. Reactivation can also occur infrequently in corticosteroid-treated patients who appear to have resolved hepatitis B infection.

Screen patients for hepatitis B infection before initiating immunosuppressive (e.g., prolonged) treatment with Orapred ODT. For patients who show evidence of hepatitis B infection, recommend consultation with physicians with expertise in managing hepatitis B regarding monitoring and consideration for hepatitis B antiviral therapy.

Fungal Infections
Corticosteroids, including Orapred ODT, may exacerbate systemic fungal infections; therefore, avoid Orapred ODT use in the presence of such infections unless Orapred ODT is needed to control drug reactions. For patients on chronic Orapred ODT therapy who develop systemic fungal infections, Orapred ODT withdrawal or dosage reduction is recommended.

Amebiasis
Corticosteroids, including Orapred ODT, may activate latent amebiasis. Therefore, it is recommended that latent amebiasis or active amebiasis be ruled out before initiating Orapred ODT in patients who have spent time in the tropics or patients with unexplained diarrhea.

Strongyloides Infestation
Corticosteroids, including Orapred ODT, 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.

Cerebral Malaria
Avoid corticosteroids, including Orapred ODT, in patients with cerebral malaria.

5.3 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 hypertension, congestive heart failure, or renal insufficiency.

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

5.4 Use in Patients with Gastrointestinal Disorders

There is an increased risk of gastrointestinal (GI) 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.

5.5 Behavioral and Mood Disturbances

Corticosteroid 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.

5.6 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 (e.g., postmenopausal women) before initiating corticosteroid therapy and bone density should be monitored in patients on long term corticosteroid therapy.

5.7 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 steroid therapy is continued for more than 6 weeks, intraocular pressure should be monitored.

Patients with Ocular Herpes Simplex
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.

5.8 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.

5.9 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.

5.10 Embryo-Fetal Toxicity

Prednisolone can cause fetal harm when administered to a pregnant woman. Human studies suggest a small but inconsistent increased risk of orofacial clefts with use of corticosteroids during the first trimester of pregnancy. Published animal studies show prednisolone to be teratogenic in rats, rabbits, hamsters, and mice with increased incidence of cleft palate in offspring. Intrauterine growth restriction and decreased birth weight have also been reported with corticosteroid use during pregnancy, however, the underlying maternal condition may also contribute to these risks. If this drug is used during pregnancy, or if the patient becomes pregnant while using this drug, advise the patient about the potential harm to the fetus. [see Use in Specific Populations (8.1)].

5.11 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. [see Dosage and Administration (2)].

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 creatinine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years.

5.12 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 of Kaposi’s sarcoma.

8.1 Pregnancy

Risk Summary
Based on findings from human and animal studies, corticosteroids including Orapred, 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 population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically 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 report 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 reported 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
Published literature indicates prednisolone has been shown to be teratogenic in rats, rabbits, hamsters, and mice with increased incidence of cleft palate in offspring, supportive of the clinical data. In teratogenicity studies, cleft palate along with an elevation of fetal lethality (or increase in resorptions) and reductions in fetal body weight occurred 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 was observed in fetuses of pregnant rats exposed to prednisolone.

8.2 Lactation

Risk Summary
Prednisolone is present in human milk. Published reports suggest infant daily doses are estimated to be less than 1% of the maternal daily dose. No adverse effects in the breastfed infant have been reported following maternal administration of prednisolone during breastfeeding. There are no available data on the effects of prednisolone on milk production. High doses of corticosteroids administered to lactating women for long periods could potentially produce problems in the breastfed infant including growth and development and interfere with endogenous corticosteroid production (see Clinical Considerations) [see Use in Specific Populations ( 8.4 )].The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Orapred and any potential adverse effects on the breastfed child from Orapred or from the mother's underlying condition.

Clinical Considerations
In order to minimize exposure, the lowest dose should be prescribed to a lactating women to achieve the desired clinical effect.

8.4 Pediatric Use

The efficacy and safety of prednisolone 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 prednisolone in pediatric patients are similar to those in adults [see Adverse Reactions (6)]. 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 plasma 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.

8.5 Geriatric Use

No overall differences in safety or effectiveness were observed between elderly subjects and younger subjects, and other reported clinical experience with prednisolone 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 appear to be 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). Prednisolone 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 involutional osteoporosis.

Routine screening of geriatric patients, including regular assessments of bone mineral density and institution of fracture prevention strategies, along with regular review of Orapred indication should be undertaken to minimize complications and keep the Orapred dose at the lowest acceptable level. Co-administration of bisphosphonates has 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. However, it is not clear whether dosing reductions would be necessary in elderly patients, since these pharmacokinetic alterations may be offset by age-related differences in responsiveness of target organs and/or less pronounced suppression of adrenal release of cortisol. 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.

12.1 Mechanism of Action

Prednisolone is a synthetic adrenocortical steroid drug with predominantly glucocorticoid properties. Some of these properties reproduce the physiological actions of endogenous glucocorticosteroids, but others do not necessarily reflect any of the adrenal hormones' normal functions; they are seen only after administration of large therapeutic doses of the drug. The pharmacological effects of prednisolone which are due to its glucocorticoid properties include: promotion of gluconeogenesis; increased deposition of glycogen in the liver; inhibition of the utilization of glucose; anti-insulin activity; increased catabolism of protein; increased lipolysis; stimulation of fat synthesis and storage; increased glomerular filtration rate and resulting increase in urinary excretion of urate (creatinine excretion remains unchanged); and increased calcium excretion. Depressed production of eosinophils and lymphocytes occurs, but erythropoiesis and production of polymorphonuclear leukocytes are stimulated. Inflammatory processes (edema, fibrin deposition, capillary dilatation, migration of leukocytes and phagocytosis) and the later stages of wound healing (capillary proliferation, deposition of collagen, cicatrization) are inhibited. Prednisolone can stimulate secretion of various components of gastric juice. Suppression of the production of corticotropin may lead to suppression of endogenous corticosteroids. Prednisolone has slight mineralocorticoid activity, whereby entry of sodium into cells and loss of intracellular potassium is stimulated. This is particularly evident in the kidney, where rapid ion exchange leads to sodium retention and hypertension.

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Orapred was not formally evaluated in carcinogenicity studies. Review of the published literature identified the potential for malignancy at doses within the therapeutic range. In a 2-year study, male Sprague-Dawley rats administered prednisolone in drinking water at an estimated continuous daily prednisolone consumption of 368 mcg/kg/day (equivalent to 3.5 mg/day in a 60 kg individual based on an mg/m2 body surface area comparison) developed increased incidences of hepatic adenomas. However infrequent administration of prednisolone did not result in malignancy. In an 18-month study, intermittent (1, 2, 4.5 or 9 times per month) oral gavage of 3 mg/kg prednisolone did not induce tumors in female Sprague-Dawley rats (equivalent to 29 mg in a 60 kg individual based on a mg/m2 body surface area comparison).

Orapred 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.

Orapred was not formally evaluated in fertility studies. However, alterations in motility and numbers of spermatozoa, and menstrual irregularities have been described with clinical use [see Adverse Reactions (6)].

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). [See USP controlled Room Temperature]. Protect from moisture.

Do not break or use partial Orapred ODT tablets. Keep out of the reach of children.