PEDIAPRED®
Rh´ne-Poulenc Rorer
Prednisolone Sodium Phosphate
Glucocorticoid – Anti-inflammatory
Action And Clinical Pharmacology: Prednisolone sodium phosphate is a synthetic adrenocortical steroid derivative with predominantly glucocorticoid properties possessing anti-inflammatory and immunosuppressive action.
Prednisolone sodium phosphate belongs to the pharmacologic class of glucocorticoid/anti-inflammatory drugs which, following systemic absorption, diffuse across cell membranes and complex with specific cytoplasmic receptors. These complexes may enter the cell nucleus, bind to DNA and stimulate transcription of mRNA. Subsequent cellular responses result in a variety of local and systemic effects. Anti-inflammatory processes such as edema, fibrin deposition, decreased prostaglandin/thromboxane synthesis, capillary dilatation, migration of leukocytes, the phagocytosis stage of wound healing and cicatrization are inhibited. Immune reactions are suppressed. Metabolically, protein catabolism and increased gluconeogenesis along with decreased peripheral utilization of glucose leads to glycogen storage in the liver, increased blood glucose concentration and insulin resistance (diabetogenic effect). During therapy lipolysis is enhanced and abnormal distribution of fat may result (Cushingoid effect). Skeletal calcium is mobilized and lost via renal excretion. Glucocorticoids in general augment renal glomerular filtration and promote urate excretion.
In respect of electrolyte and water balance, sodium tends to be reabsorbed and potassium and hydrogen excreted resulting in water retention and risk of hypokalemic alkalosis.
Pharmacokinetics: Prednisolone is rapidly and well absorbed from the gastrointestinal tract following oral administration. Prednisolone sodium phosphate oral liquid produces a 20% higher peak plasma level of prednisolone which occurs approximately 15 minutes earlier than that seen with tablet formulations. Prednisolone is 70 to 90% protein-bound in the plasma and it is eliminated from the plasma with a half-life of 2 to 4 hours. It is metabolized mainly in the liver and excreted in the urine as sulfate and glucuronide conjugates.
Indications And Clinical Uses: Management of conditions known to be responsive to prednisone or prednisolone where anti-inflammatory action or immunosuppression or adrenocortical supplementation and replacement is required.
For most indications, glucocorticoid administration provides symptomatic relief, but has no effect on the underlying disease processes. Use of these medications does not eliminate the need for other therapies that may be required.
Prednisolone sodium phosphate oral liquid is appropriate for pediatric usage and for those patients with difficulty swallowing solid oral dosage forms.
Contra-Indications: Untreated systemic fungal infections. Hypersensitivity to prednisolone sodium phosphate or other corticosteroids, or to any of its ingredients. tag_WarningWarnings
Manufacturers’ Warnings In Clinical States: Glucocorticoid-induced suppression of HPA (Hypothalamic-Pituitary-Adrenal) function is dependent on dose and duration of treatment. Recovery occurs gradually as the steroid dose is reduced and withdrawn. Suppression persists for a period of time after withdrawal depending on dose and length of treatment time.
In patients on corticosteroid therapy subjected to unusual stress, increased dosage of rapidly acting corticosteroids before, during and after the stressful situation is indicated.
Corticosteroids may mask some signs of infection, and new infections may appear during their use. There may be decreased resistance and inability to localize infection when corticosteroids are used.
If corticosteroids have to be used in the presence of fungal or bacterial infections, institute appropriate anti-infective therapy.
Prolonged use of corticosteroids may produce posterior subcapsular cataracts or glaucoma with possible damage to the optic nerves and may enhance the establishment of secondary ocular infections due to fungi or viruses.
Average and large doses of corticosteroids can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium. 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. All corticosteroids increase calcium excretion. While on corticosteroid therapy, patients should not be vaccinated against measles. Other immunization procedures should not be undertaken in patients who are on corticosteroids, especially on high doses, because of possible hazards of neurological complications and lack of antibody response.
The use of corticosteroids in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for the management of the disease in conjunction with an appropriate antituberculous regimen.
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.
Patients who are on drugs which suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles can have a more serious or even fatal course in non-immune children or adults who have not had these diseases and particular care should be taken to avoid exposure. It is not known whether the risk of developing serious cases of these infections is due to prior corticosteroid treatment or to the contribution of the underlying disease which is being treated. If exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled i.m. immunoglobulin (IG) may be indicated. If chickenpox develops, treatment with antiviral agents may be considered.
Precautions: During prolonged corticosteroid therapy, routine laboratory studies such as urinalysis, 2-hour postprandial blood sugar determinations, blood pressure monitoring, body weight and chest x-ray should be performed at regular intervals. If doses of prednisolone sodium phosphate are high, serum potassium should be monitored regularly. Serious consideration of upper gastrointestinal studies should be contemplated when patients complain of gastric symptoms while on this medication. In general, prolonged therapy above 8 mg/day is associated with increased incidence of adverse effects; mental disorders are associated with doses exceeding 40 mg/day.
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 reinstated. Since mineralocorticoid secretion may be impaired, salt and/or mineralocorticoid should be administered concurrently.
Children: Growth and development of infants and children on prolonged corticosteroid therapy should be carefully observed. Administration of corticosteroids to children should be limited to the least amount compatible with an effective therapeutic regimen.
Pediatric patients demonstrate greater susceptibility to corticosteroid induced HPA axis suppression and Cushing’s syndrome than mature patients. HPA axis suppression, Cushing’s syndrome and intracranial hypertension have been reported in children taking oral corticosteroids. Manifestations of adrenal suppression in children include linear growth retardation, delayed weight gain, low plasma cortisol levels and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches and bilateral papilloedema.
General Use: There is an enhanced effect of corticosteroids in patients with hypothyroidism and in those with cirrhosis of the liver.
Corticosteroids should be used cautiously in patients with ocular herpes simplex because of possible corneal perforation.
The lowest possible dose of corticosteroid should be used to control the condition under treatment, and when reduction in dosage is possible, the reduction should be gradual.
Psychic derangements may appear when corticosteroids are used, 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.
Following prolonged therapy, psychological and/or physiological dependence may develop. Withdrawal of glucocorticoids may result in symptoms of the glucocorticoid withdrawal syndrome including: fever, myalgia, arthralgia and malaise. This may occur in patients even without evidence of adrenal insufficiency.
ASA and other NSAIDs should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia.
Corticosteroids should be used with caution in the following clinical conditions: nonspecific ulcerative colitis (if there is a probability of impending perforation), abscess or other pyogenic infection, diverticulitis, fresh intestinal anastomoses, active or latent peptic ulcer, renal insufficiency, hypertension, osteoporosis, cardiac disease, thromboembolic disorders and diabetes mellitus.
In myasthenia gravis, hospitalization with careful observation is recommended because transient worsening of symptoms, possibly leading to respiratory distress may precede clinical improvement.
Since complications of treatment with glucocorticoids are dependent on the size of the dose and the duration of treatment, a risk/benefit decision must be made in each individual case as to dose and duration of treatment and as to whether daily or intermittent therapy should be used.
Patients should be warned not to discontinue the use of prednisolone sodium phosphate abruptly or without medical supervision, to advise any medical attendants that they are taking prednisolone sodium phosphate and to seek medical advice at once should they develop fever or other signs of infection (see Information for the Patient).
Persons who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles. Patients should also be advised that if they are exposed, medical advice should be sought without delay (see Warnings).
Steroids may increase or decrease motility and number of spermatozoa in some male patients. However, it is not known whether reproductive capacity in humans is adversely affected.
Carcinogenicity and Mutagenicity: Limited information is available. Glucocorticoids produce cleft palate in the offspring when administered to pregnant mice, rats and hamsters. There are few studies on the carcinogenicity or mutagenicity of prednisolone in animals.
Drug Interactions: Although no unusual drug interactions have been detected during clinical trials, the same precautions should be exercised as for other glucocorticoids. It is recommended to increase the maintenance dose of glucocorticoids if the following drugs are administered at the same time: anticonvulsants (phenobarbital, phenytoin), certain antibiotics (rifampin), anticoagulants (coumadin) and bronchodilators (ephedrine). If the patient receiving glucocorticoids is treated at the same time with some other antibiotics (erythromycin), ketoconazole, estrogens or preparations containing estrogens, a reduction in the dose of prednisolone sodium phosphate is recommended. Since prednisolone sodium phosphate is metabolized in the liver, the possibility remains that concomitant administration of other hepatically metabolized drugs may lead to interactions (e.g., barbiturates).
Anticholinesterase effects may be antagonized in myasthenia gravis. Toxicity may be enhanced when cyclosporin and glucocorticoids are combined in organ transplant patients. Coadministration with digitalis glycosides may enhance the possibility of digitalis toxicity associated with hypocalcemia. Isoniazid and salicylate serum concentrations may be decreased upon coadministration with glucocorticoids.
Potassium-depleting agents (e.g., thiazide diuretics) may enhance hypocalcemia and hypokalemia secondary to glucocorticoid use. Coadministration with nonsteroidal anti-inflammatories may increase the risk of gastrointestinal ulceration. Immunologic response to vaccines and toxoids is reduced by glucocorticoids which may also potentiate the replication of organisms in attenuated vaccines (e.g., measles). Glucocorticoids may alter laboratory or radiological tests for serum T3 or serum protein-bound iodine, may decrease T4 minimally or decrease the uptake of 31odine.
Immunization procedures may be undertaken in patients who are receiving corticosteroids as replacement therapy (e.g., Addison’s disease).
Pregnancy: Prednisolone sodium phosphate (corticosteroids) have been shown to be teratogenic in various animal species when given in doses equivalent to the human dose. There are no adequate and well-controlled studies in pregnant women. Prednisolone sodium phosphate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal studies in which prednisolone sodium phosphate has been given to pregnant rodents and rabbits have yielded an increased incidence of cleft palate in the offspring.
Infants born to mothers who have received substantial doses of corticosteroids during pregnancy, should be carefully observed for signs of hypoadrenalism.
Lactation: Prednisolone sodium phosphate is excreted in breast milk. Caution should be exercised when this drug is administered to a nursing woman.
Adverse Reactions: Corticosteroids have a potential for multiple adverse effects. There are essentially 2 types of toxicity observed when administered in therapeutic dosages: withdrawal effects, which could produce life-threatening adrenal insufficiency, and high dosage over long periods, which could produce fluid/electrolyte disturbances, hyperglycemia, increased susceptibility to infections, peptic ulceration, osteoporosis, myopathy, behavioral disturbances, cataracts, or Cushing’s habitus. Single doses, or short courses of therapy (over several days) are usually with less harmful effects. The approach to therapy should follow logical and rational sequence of: (i) attempting to control the condition with more conventional mode(s) of management, (ii) weighing the benefits of steroid therapy against the risks, (iii) commencing therapy with high loading dose, reducing to the minimum effective dosage as soon as possible.
Fluid and Electrolyte Disturbances: sodium retention, fluid retention, congestive heart failure in susceptible patients, potassium loss, hypokalemic alkalosis, hypertension.
Musculoskeletal: Muscle weakness, steroid myopathy, loss of muscle mass, osteoporosis, vertebral compression fractures, aseptic necrosis of femoral and humeral heads, pathologic fracture of long bones.
Gastrointestinal: peptic ulcer with possible perforation and hemorrhage, pancreatitis, abdominal distention, ulcerative esophagitis.
Dermatologic: impaired wound healing, thin fragile skin, petechiae and ecchymoses, facial erythema, increased sweating, may suppress reactions to skin tests.
Metabolic: negative nitrogen balance due to protein catabolism.
Neurological: convulsions, increased intracranial pressure with papilledema (pseudotumor cerebri) usually after treatment, vertigo, headache.
Endocrine: menstrual irregularities, development of cushingoid state, secondary adrenocortical and pituitary unresponsiveness, particularly in times of stress, as in trauma, surgery or illness, suppression of growth in children, decreased carbohydrate tolerance, manifestations of latent diabetes mellitus, increased requirements for insulin or oral hypoglycemic agents in diabetics.
Ophthalmic: posterior subcapsular cataracts, increased intraocular pressure, glaucoma, exophthalmos.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: The effects of accidental ingestion of large quantities of prednisolone over a very short period of time have not been reported.
Treatment of acute overdosage is by immediate gastric lavage or emesis. For chronic overdosage in the face of severe disease requiring continuous steroid therapy the dosage of prednisolone may be reduced only temporarily, or alternate day treatment may be introduced.
Dosage And Administration: The initial dosage of prednisolone sodium phosphate may vary from 5 to 60 mL (5 to 60 mg prednisolone base)/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 period of time there is a lack of satisfactory clinical response, prednisolone sodium phosphate should be discontinued and the patient transferred to other appropriate therapy (see Table I). 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. Standardized dosing is not available for oral corticosteroids. Therefore, any adjustments in consideration of age or renal function of the patient should be taken into account, along with the patient’s weight and severity of the disease when the initial dosage is established. 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 prednisolone sodium phosphate 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 to avoid glucocorticoid withdrawal syndrome.
If on a once daily therapy, prednisolone sodium phosphate should be administered in the morning to simulate the natural circadian rhythm of corticosteroid secretion.
Availability And Storage: Each 5 mL of dye-free, colorless to light straw-colored, raspberry-flavored solution contains: prednisolone 5 mg as prednisolone sodium phosphate USP in a palatable, aqueous vehicle. Nonmedicinal ingredients: disodium edetate, flavor raspberry, methylparaben, purified water, sodium phosphate and sorbitol. Bottles of 120 mL. Store at 15 to 30°C. Do not refrigerate. Keep cap tightly closed.
PEDIAPRED® Rh´ne-Poulenc Rorer Prednisolone Sodium Phosphate Glucocorticoid – Anti-inflammatory
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