ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.Fluid and electrolyte disturbances: Sodium retention Fluid retention Congestive heart failure in susceptible patients Potassium loss Hypokalemic alkalosis HypertensionMusculoskeletal: Muscle weakness Steroid myopathy Loss of muscle mass Osteoporosis Vertebral compression fractures Aseptic necrosis of femoral and humeral heads Pathologic fracture of long bonesGastrointestinal: Peptic ulcer with possible subsequent perforation and hemorrhage Pancreatitis Abdominal distention Ulcerative esophagitisDermatological: Impaired wound healing Thin fragile skin Facial erythema Increased sweating May suppress reactions to skin tests Petechiae and ecchymosesNeurological: Convulsions Increased intracranial pressure with papilledema (pseudotumor cerebri) usually after treatment Vertigo HeadacheOphthalmic: Posterior subcapsular cataracts Increased intraocular pressure GlaucomaEndocrine: Menstrual irregularities Development of cushingoid state Suppression of growth in children Secondary adrenocortical and pituitary unresponsiveness, particularly in times of stress, as in trauma, surgery, or illness Decreased carbohydrate tolerance Manifestations of latent diabetes mellitus Increased requirements for insulin or oral hypoglycemic agents in diabeticsMetabolic: Negative nitrogen balance due to protein catabolismMiscellaneous: Hyperpigmentation or hypopigmentation Subcutaneous and cutaneous atrophy Sterile abscess Post-injection flare, following intra-articular use Charcot-like arthropathy Itching, burning, tingling in the ano-genital region. Sodium retention. Fluid retention. Congestive heart failure in susceptible patients. Potassium loss. Hypokalemic alkalosis. Hypertension. Muscle weakness. Steroid myopathy. Loss of muscle mass. Osteoporosis. Vertebral compression fractures. Aseptic necrosis of femoral and humeral heads. Pathologic fracture of long bones. Peptic ulcer with possible subsequent perforation and hemorrhage. Pancreatitis. Abdominal distention. Ulcerative esophagitis. Impaired wound healing. Thin fragile skin. Facial erythema. Increased sweating. May suppress reactions to skin tests. Petechiae and ecchymoses. Convulsions. Increased intracranial pressure with papilledema (pseudotumor cerebri) usually after treatment. Vertigo. Headache. Posterior subcapsular cataracts. Increased intraocular pressure. Glaucoma. Menstrual irregularities. Development of cushingoid state. Suppression of growth in children. Secondary adrenocortical and pituitary unresponsiveness, particularly in times of stress, as in trauma, surgery, or illness. Decreased carbohydrate tolerance. Manifestations of latent diabetes mellitus. Increased requirements for insulin or oral hypoglycemic agents in diabetics. Negative nitrogen balance due to protein catabolism. Hyperpigmentation or hypopigmentation. Subcutaneous and cutaneous atrophy. Sterile abscess. Post-injection flare, following intra-articular use. Charcot-like arthropathy. Itching, burning, tingling in the ano-genital region.

DESCRIPTION SECTION.

DESCRIPTION. Dexamethasone Sodium Phosphate Injection, USP, is water-soluble inorganic ester of dexamethasone which produces rapid response even when injected intramuscularly.Dexamethasone Sodium Phosphate, USP chemically is Pregna-1,4-diene-3,20-dione, 9-fluoro-11,17-dihydroxy-16-methyl-21-(phosphonooxy)-, disodium salt, (11ss, 16).It occurs as white to creamy white powder, is exceedingly hygroscopic, is soluble in water and its solutions have pH between 7.0 and 8.5. It has the following structural formula:Each mL of Dexamethasone Sodium Phosphate Injection, USP (Preservative Free) contains dexamethasone sodium phosphate, USP equivalent to 10 mg dexamethasone phosphate; 24.75 mg sodium citrate, dihydrate; and Water for Injection, q.s. pH adjusted with citric acid or sodium hydroxide, if necessary. pH: 7.0 to 8.5.Each mL Dexamethasone Sodium Phosphate Injection, USP (Preserved) contains dexamethasone sodium phosphate, USP equivalent to 10 mg dexamethasone phosphate; 13.5 mg sodium citrate, dihydrate; 10 mg benzyl alcohol; and Water for Injection, q.s. pH adjusted with citric acid or sodium hydroxide, if necessary. pH: 7.0 to 8.5.. Structural Formula.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. A. Intravenous or Intramuscular Administration. The initial dosage of dexamethasone sodium phosphate injection may vary from 0.50 mg/day to 9.0 mg/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. Usually the parenteral dosage ranges are one-third to one-half the oral dose given every 12 hours. However, in certain overwhelming, acute, life-threatening situations, administration of dosages exceeding the usual dosages may be justified and may be in multiples of the oral dosages.For the treatment of unresponsive shock high pharmacologic doses of this product are currently recommended. Reported regimens range from to mg/kg of body weight as single intravenous injection to 40 mg initially followed by repeat intravenous injection every to hours while shock persists.For the treatment of cerebral edema in adults an initial intravenous dose of 10 mg is recommended followed by mg intramuscularly every six hours until maximum response has been noted. This regimen may be continued for several days postoperatively in patients requiring brain surgery. Oral dexamethasone, to mg t.i.d., should be given as soon as possible and dosage tapered off over period of five to seven days. Nonoperative cases may require continuous therapy to remain free of symptoms of increased intracranial pressure. The smallest effective dose should be used in children, preferably orally. This may approximate 0.2 mg/kg/24 hours in divided doses.In treatment of acute exacerbations of multiple sclerosis daily doses of 200 mg of prednisolone for week followed by 80 mg every other day or 4-8 mg dexamethasone every other day for month have been shown to be effective.The initial dosage should be maintained or adjusted until satisfactory response is noted. If after reasonable period of time there is lack of satisfactory clinical response, dexamethasone sodium phosphate injection 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 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 patients individual drug responsiveness and the effect of patient exposure to stressful situations not directly related to the disease entity under treatment. In this later situation it may be necessary to increase the dosage of dexamethasone sodium phosphate injection for period of time consistent with the patients condition. If after long-term therapy the drug is to be stopped, it is recommended that it be withdrawn gradually rather than abruptly.. B. Intra-articular, soft tissue or intralesional administration.. The dose for intrasynovial administration is usually to mg for large joints and 0.8 to mg for small joints. For soft tissue and bursal injections dose of to mg is recommended. Ganglia require dose of to mg. dose of 0.4 to mg is used for injection into tendon sheaths. Injection into intervertebral joints should not be attempted at any time and hip joint injection cannot be recommended as an office procedure.Intrasynovial and soft tissue injections should be employed only when affected areas are limited to or sites. It should be remembered that corticoids provide palliation only and that other conventional or curative methods of therapy should be employed when indicated.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.Frequency of injection usually ranges from once every to days to once every to weeks. Frequent intra-articular injection may cause damage to joint tissue.

PRECAUTIONS SECTION.

PRECAUTIONS. 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 mineralocorticoid should be administered concurrently.There is an enhanced effect of corticosteroids in patients with hypothyroidism and in those with cirrhosis.Corticosteroids should be used cautiously in patients with ocular herpes simplex for fear of 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 must 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.Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia.Steroids should be used with caution in nonspecific ulcerative colitis, if there is probability of impending perforation, abscess, or other pyogenic infection, also in diverticulitis, fresh intestinal anastomoses, active or latent peptic ulcer, renal insufficiency, hypertension, osteoporosis, and myasthenia gravis.Growth and development of infants and children on prolonged corticosteroid therapy should be carefully followed.Patients who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles and, if exposed, to obtain medical advice.Intra-articular injection of corticosteroid may produce systemic as well as local effects.Appropriate examination of any joint fluid present is necessary to exclude septic process.A marked increase in pain accompanied by local swelling, further restriction of joint motion, fever, and malaise are suggestive of septic arthritis. If this complication occurs and the diagnosis of sepsis is confirmed, appropriate antimicrobial therapy should be instituted.Local injection of steroid into previously infected joint is to be avoided. Corticosteroids should not be injected into unstable joints.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 significant effect. (See Dosage and Administration Section).Since complications of treatment with glucocorticoids are dependent on the size of the dose and the duration of treatment 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.

PREGNANCY SECTION.

Usage in Pregnancy. Since adequate human reproduction studies have not been done with corticosteroids, use of these drugs in pregnancy, nursing mothers or women of childbearing potential requires that the possible benefits of the drug be weighed against the potential hazards to the mother and embryo or fetus. Infants born of mothers who have received substantial doses of corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism.Average and large doses of cortisone or hydrocortisone 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. Patients with stressed myocardium should be observed carefully and the drug administered slowly since premature ventricular contractions may occur with rapid administration. Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion.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 in high doses, because of possible hazards of neurological complications and lack of antibody response.The use of dexamethasone sodium phosphate injection 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 anti-tuberculosis 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.Because rare instances of anaphylactoid reactions have occurred in patients receiving parenteral corticosteroid therapy, appropriate precautionary measures should be taken prior to administration, especially when the patient has history of allergy to any drug.

WARNINGS SECTION.

WARNINGS. Serious Neurologic Adverse Reactions with Epidural Administration. Serious neurologic events, some resulting in death, have been reported with epidural injection of corticosteroids. Specific events reported include, but are not limited to, spinal cord infarction, paraplegia, quadriplegia, cortical blindness, and stroke. These serious neurologic events have been reported with and without use of fluoroscopy. The safety and effectiveness of epidural administration of corticosteroids have not been established, and corticosteroids are not approved for this use.In patients on corticosteroid therapy subject to any 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.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.Children who are on immunosuppressant drugs are more susceptible to infections than healthy children. Chickenpox and measles, for example, can have more serious or even fatal course in children on immunosuppressant corticosteroids. In such children or in adults who have not had these diseases, particular care should be taken to avoid exposure. If exposed, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If chickenpox develops, treatment with antiviral agents may be considered.Similarly, 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.. Usage in Pregnancy. Since adequate human reproduction studies have not been done with corticosteroids, use of these drugs in pregnancy, nursing mothers or women of childbearing potential requires that the possible benefits of the drug be weighed against the potential hazards to the mother and embryo or fetus. Infants born of mothers who have received substantial doses of corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism.Average and large doses of cortisone or hydrocortisone 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. Patients with stressed myocardium should be observed carefully and the drug administered slowly since premature ventricular contractions may occur with rapid administration. Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion.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 in high doses, because of possible hazards of neurological complications and lack of antibody response.The use of dexamethasone sodium phosphate injection 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 anti-tuberculosis 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.Because rare instances of anaphylactoid reactions have occurred in patients receiving parenteral corticosteroid therapy, appropriate precautionary measures should be taken prior to administration, especially when the patient has history of allergy to any drug.