warnings and cautions
5 WARNINGS AND PRECAUTIONS Alterations in Endocrine Function: Hypothalamic-pituitary adrenal (HPA) axis suppression, Cushing’s syndrome, and hyperglycemia can occur. Monitor patients for these conditions with chronic use. (5.1) Immunosuppression and Increased Risk of Infections: Increased risk of new, exacerbation, dissemination, or reactivation of latent infections. (5.2) Alteration in Cardiovascular/Renal Function: Monitor for elevated blood pressure and sodium, and for decreased potassium levels. (5.3) Venous and Arterial Thromboembolism: Risk increased; consider anticoagulant prophylaxis and monitor for evidence of thromboembolism. (5.4) Vaccination: Avoid the administration of live or live attenuated vaccines in patients receiving immunosuppressive doses of corticosteroids. (5.5) Ophthalmic Effects: May include cataracts, infections, and glaucoma. (5.6) Gastrointestinal Perforation: Avoid use in active or latent peptic ulcers, diverticulitis, fresh intestinal anastomoses, and nonspecific ulcerative colitis, since they may increase the risk of a perforation. (5.7) Osteoporosis: Increased risk; monitor for changes in bone density with chronic use. (5.8) Behavioral and Mood Disturbances: May include euphoria, insomnia, mood swings, personality changes, severe depression, and psychosis. Monitor for signs and symptoms and manage promptly. (5.10) Kaposi’s Sarcoma: Kaposi’s sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. (5.11) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus. ( 5.13 , 8.1 ) 5.1 Alterations in Endocrine Function Corticosteroids, such as HEMADY, can cause serious and life-threatening alterations in endocrine function, especially with chronic use. Monitor patients receiving HEMADY for adrenal insufficiency after corticosteroid withdrawal and Cushing’s syndrome and hyperglycemia while receiving corticosteroids. In addition, patients with hypopituitarism, primary adrenal insufficiency, or congenital adrenal hyperplasia, altered thyroid function, or pheochromocytoma may be at risk for adverse endocrine events. Risk of Adrenal Insufficiency Following Corticosteroid Withdrawal Corticosteroids can produce reversible hypothalamic-pituitary adrenal (HPA) axis suppression, with the potential for the development of secondary adrenal insufficiency after withdrawal of corticosteroid treatment. Acute adrenal insufficiency can occur if glucocorticoids are withdrawn abruptly and can be fatal. The degree and duration of adrenocortical insufficiently produced is variable among patients and depends on the dose, frequency, and duration of glucocorticoid therapy. The risk may be reduced by gradually tapering the corticosteroid dose when withdrawing treatment. This insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, corticosteroid therapy should be reinstituted. For patients already taking corticosteroids during times of stress, the dosage may have to be increased. A steroid “withdrawal syndrome”, seemingly unrelated to adrenocortical insufficiency, may also occur following abrupt discontinuance of corticosteroids. This syndrome includes symptoms such as: anorexia, nausea, vomiting, lethargy, headache, fever, joint pain, desquamation, myalgia, and/or weight loss. These effects are thought to be due to the sudden change in glucocorticoid concentration rather than to low corticosteroid levels. Cushing’s Syndrome Cushing’s syndrome (hypercortisolism) may occur with prolonged exposure to exogenous corticosteroids, including HEMADY. Symptoms include hypertension, truncal obesity and thinning of the limbs, purple striae, facial rounding, facial plethora, muscle weakness, easy and frequent bruising with thin fragile skin, posterior neck fat deposition, osteopenia, acne, amenorrhea, hirsutism and psychiatric abnormalities. Using the lowest dose of corticosteroid for the shortest duration possible may reduce the risk. Hyperglycemia Corticosteroids can increase blood glucose, worsen pre-existing diabetes, and predispose those on long-term therapy to diabetes mellitus, and may reduce the effect of the antidiabetic drugs. Monitor blood glucose at regular intervals. For patients with hyperglycemia, anti-diabetic treatment should be initiated or adjusted accordingly. Considerations for Use in Patients with Altered Thyroid Function Metabolic clearance of corticosteroids is decreased in hypothyroid patients and increased in hyperthyroid patients. Changes in thyroid status of the patient may necessitate a dose adjustment of the corticosteroid. When concomitant administration of corticosteroids and levothyroxine is required, administration of corticosteroid should precede the initiation of levothyroxine therapy to avoid adrenal crisis. Pheochromocytoma Crisis There have been reports of pheochromocytoma crisis, which can be fatal, after administration of systemic corticosteroids. In patients with suspected or identified pheochromocytoma, consider the risk of pheochromocytoma crisis prior to administering HEMADY. 5.2 Immunosuppression and Increased Risk of Infections Corticosteroids, including HEMADY, suppress the immune system and increase the risk of infection with any pathogen, including viral, bacterial, fungal, protozoan, or helminthic. Corticosteroids reduce resistance to new infections, exacerbate existing infections, increase the risk of disseminated infections, increase the risk of reactivation or exacerbation of latent infections, and mask some signs of infection. These infections can be severe, and at times fatal. The degree to which the dose, route, and duration of corticosteroid administration correlates with the specific risks of infection is not well characterized; however, the rate of occurrence of infectious complications increases with increasing doses of corticosteroids. Monitor for the development of infection and consider withdrawal of HEMADY or reduction of the dose of corticosteroids as needed. Varicella Zoster and Measles Viral Infections Chickenpox caused by Varicella Zoster virus and measles can have a serious or even fatal course in non-immune children or adult on corticosteroids, including HEMADY. In patients who have not had these diseases, particular care should be taken to avoid exposure. If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If a patient is exposed to measles, prophylaxis with immune globulin (IG) may be indicated. If chickenpox develops, treatment with antiviral agents may be considered. Hepatitis B Virus Reactivation Hepatitis B virus reactivation can occur in patients who are hepatitis B carriers undergoing treatment with immunosuppressive drugs including corticosteroids. Reactivation can also occur in patients who appear to have resolved hepatitis B infection. Fungal Infections HEMADY is contraindicated in patients with systemic fungal infections. Corticosteroids may exacerbate systemic fungal infections. For patients on chronic corticosteroids who have developed systemic fungal infections, withdrawal of corticosteroids or reduction of the dose of corticosteroids is recommended. The following infections have been reported during the use of corticosteroids to treat other conditions that HEMADY is not indicated for: Amebiasis Corticosteroids may activate latent amebiasis. Rule out latent amebiasis or active amebiasis before initiating corticosteroid therapy in any patient who has spent time in the tropics or any patient with unexplained diarrhea. Strongyloides Infestation In patients with known or suspected Strongyloides (threadworm) infestation, 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. For patients on HEMADY who develop known or suspected Strongyloides (threadworm) infection, withdrawal of corticosteroids or reduction of the dose of corticosteroids is recommended. Tuberculosis The use of corticosteroids in active tuberculosis should generally be limited to cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for the management of the disease in conjunction with an appropriate anti-tuberculous 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. Cerebral Malaria Corticosteroids should not be used in cerebral malaria. 5.3 Alterations in Cardiovascular/Renal Function Corticosteroids, including HEMADY, can cause elevation of blood pressure, salt, and water retention, and increased excretion of potassium and calcium. Monitor blood pressure and assess for signs and symptoms of volume overload. Monitor serum potassium levels. Dietary salt restriction and potassium supplementation may be necessary. HEMADY should be used with caution in patients with congestive heart failure. Literature reports suggest an association between use of corticosteroids and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with HEMADY should be used with great caution in these patients. 5.4 Venous and Arterial Thromboembolism Thromboembolism is a known adverse reaction of dexamethasone, including HEMADY. The risk for venous and arterial thromboembolism increases significantly when dexamethasone is administered with anti-myeloma products (e.g., thalidomide, lenalidomide, pomalidomide, and carfilzomib). Refer to the Prescribing Information of these anti-myeloma products for information about the risk of venous and arterial thromboembolism. Consider thromboprophylaxis based on an assessment of individual patients’ underlying risk factors and the anti-myeloma drugs. Agents that also may increase the risk of thromboembolism should be used with caution in patients with multiple myeloma receiving combination regimens of HEMADY and anti-myeloma products. 5.5 Vaccination Avoid administration of live or live attenuated vaccines in patients receiving immunosuppressive doses of corticosteroids for the treatment of multiple myeloma. Killed or inactivated vaccines may be administered. However, the response to such vaccines cannot be predicted. 5.6 Ophthalmic Effects 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 bacteria, fungi, or viruses. Consider referral to an ophthalmologist for patients who develop ocular symptoms or use corticosteroid-containing products for more than 6 weeks. 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. Corticosteroids should not be used in patients with active ocular herpes simplex. Intraocular pressure may become elevated in some individuals. If steroid therapy is continued for more than 6 weeks, intraocular pressure should be monitored. 5.7 Gastrointestinal Perforation There is an increased risk of gastrointestinal perforation during corticosteroid use in patients with certain gastrointestinal disorders such as active or latent peptic ulcers, diverticulitis, fresh intestinal anastomoses, and nonspecific ulcerative colitis. Signs of gastrointestinal perforation, such as peritoneal irritation, may be masked in patients receiving corticosteroids. Avoid corticosteroids if there is a possibility of impending perforation, abscess, or other pyrogenic infections; diverticulitis; fresh intestinal anastomoses; or active or latent peptic ulcer. 5.8 Osteoporosis 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 pediatric patients 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 HEMADY therapy. 5.9 Myopathy An acute myopathy has been observed with the use of high doses of corticosteroids, most often occurring in patients with disorders of neuromuscular transmission (e.g., myasthenia gravis), or in patients receiving concomitant therapy with neuromuscular blocking drugs (e.g., pancuronium). This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevation of creatine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years. 5.10 Behavioral and Mood Disturbances Potentially severe psychiatric adverse reactions may occur with systemic corticosteroids, including HEMADY. Symptoms typically emerge within a few days or weeks of starting treatment and may be dose-related. These reactions may improve after either dose reduction or withdrawal, although pharmacologic treatment may be necessary. Psychiatric adverse reactions usually involve hypomanic or manic symptoms (e.g., euphoria, insomnia, mood swings) during treatment and depressive episodes after discontinuation of treatment. Inform patients and caregivers of the potential for behavioral and mood changes and encourage them to seek medical attention if psychiatric symptoms develop, especially if depressed mood or suicidal ideation is suspected. 5.11 Kaposi's Sarcoma Kaposi’s sarcoma has been reported to occur in patients receiving corticosteroid therapy to treat other chronic conditions for which HEMADY is not indicated. Discontinuation of corticosteroids may result in clinical improvement. 5.12 HEMADY in Combination with Anti-Myeloma Products HEMADY is administered in combination regimens with anti-myeloma products; please refer to the Prescribing Information of these products for additional information. 5.13 Embryo-Fetal Toxicity Based on findings from clinical and animal reproduction studies, corticosteroids, including HEMADY, can cause fetal harm when administered to a pregnant woman. Dexamethasone administration to pregnant women has resulted in adverse effects on fetal growth, skeletal development/osteogenesis and low birth weight with prolonged use. Dexamethasone administration to pregnant animals during organogenesis resulted in structural abnormalities, embryo-fetal mortality, functional impairment, and alterations to growth at doses equivalent to or below the recommended doses. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with HEMADY and for at least one month after the last dose [see Use in Specific Populations ( 8.1 , 8.3 )] .