Can Hydrocortisone cause pain?

ADVERSE REACTIONS The following serious adverse reactions are described here and elsewhere in the label: Adrenal Crisis [see Warnings and Precautions (5.1) ] Systemic Adverse Reactions Due to Inactive Ingredients [see Warnings and Precautions (5.2) ] Immunosuppression and Increased Risk of Infection with Use of a Dosage Greater Than Replacement [see Warnings and Precautions (5.3) ] Growth Retardation [see Warnings and Precautions (5.4) ] Cushing's Syndrome Due to Use of Excessive Doses of Corticosteroids [see Warnings and Precautions (5.5) ] Decrease in Bone Mineral Density [see Warnings and Precautions (5.6) ] Psychiatric Adverse Reactions [see Warnings and Precautions (5.7) ] Ophthalmic Adverse Reactions [see Warnings and Precautions (5.8) ] Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.9) ] Risk of Kaposi's Sarcoma with Use of Dosage Greater than Replacement [see Warnings and Precautions (5.10) ] Vaccinations [see Warnings and Precautions (5.11) ] 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 Eton Pharmaceuticals, Inc. at 1-855-224-0233 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical studies 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 oral hydrocortisone was evaluated in an uncontrolled, open-label, single-arm clinical study in 18 pediatric patients with adrenocortical insufficiency treated with oral hydrocortisone granules. Adrenocortical insufficiency was due to congenital adrenal hyperplasia in 17 patients and to hypopituitarism in one patient. All patients received at least one dose of hydrocortisone granules. The age ranged from 36 days to 5.7 years at start of treatment; 8 patients were female and 10 were male; 100% were White. Adverse reactions that were reported in two or more patients (≥ 11%) are shown in Table 1. Table 1: Adverse Reactions Occurring in ≥11% of Pediatric Patients with Adrenocortical Insufficiency Treated with Hydrocortisone Granules for up to 29 Months Adverse Reactions N=18 n (%) Pyrexia 10 (56) Gastroenteritis 9 (50) Viral upper respiratory tract infection 8 (44) Vomiting 7 (39) Viral infection 6 (33) Conjunctivitis 5 (28) Otitis media viral 3 (17) Tonsillitis 3 (17) Body temperature increased 2 (11) Bronchitis 2 (11) Dental caries 2 (11) Diarrhea 2 (11) Genitourinary operation 2 (11) Pharyngitis 2 (11) Respiratory tract infection 2 (11) Rhinitis 2 (11) 6.2 Postmarketing Experience The following adverse reactions seen in pediatric and adult patients associated with the use of corticosteroids were identified in the literature and from postmarketing reports. Because some of these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. 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 hypo-pigmentation, 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 faces, secondary adrenocortical and pituitary unresponsiveness (particularly in times of stress, as in trauma, surgery or illness), suppression of growth in pediatric patients 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

WARNINGS AND PRECAUTIONS Adrenal Crisis : Undertreatment, sudden discontinuation of therapy, or switching from another oral hydrocortisone formulation may lead to adrenocortical insufficiency, adrenal crisis and death. Adrenal crisis may also be induced by stress events such as infections or surgery. During periods of stress switch to another oral hydrocortisone product and increase the dose. Switch patients who are vomiting, severely ill or unable to take oral medications to parenteral corticosteroid formulations. ( 5.1 ) Systemic Adverse Reactions Due to Inactive Ingredients : KHINDIVI contains the inactive ingredients polyethylene glycol 400, propylene and glycol, and glycerin, which may cause hyperosmolarity, metabolic acidosis, hypoglycemia, hepato-renal injury, central nervous toxicity, gastrointestinal adverse reactions. Discontinue KHINDIVI and switch to another hydrocortisone product if these adverse reactions occur. ( 5.2 ) Immunosuppression and Increased Risk of Infection with Use of a Dosage Greater Than Replacement : Use of a greater than replacement dosage can suppress the immune system and increase the risks of new infections or exacerbation of latent infections with any pathogen, including viral, bacterial, fungal, protozoan, or helminthic infections. Monitor patients for signs and symptoms of infections. ( 5.3 ) Growth Retardation : Long-term use in excessive doses may cause growth retardation. Use the minimum dosage of KHINDIVI to achieve desired clinical response and monitor the patient's growth. ( 5.4 ) Cushing's Syndrome Due to Use of Excessive Doses of Corticosteroids : Prolonged use with supraphysiologic doses may cause Cushing's syndrome. Monitor patients for signs and symptoms of Cushing's syndrome every 6 months. ( 5.5 ) Decrease in Bone Mineral Density : Corticosteroids decrease bone formation and increase bone resorption which may lead to inhibition of bone growth and development of osteoporosis. Use the minimum dosage of KHINDIVI to achieve desired clinical response.( 5.6 ) Psychiatric Adverse Reactions : Use may be associated with severe psychiatric adverse reactions such as euphoria, mania, psychosis with hallucinations and delirium or depression. Symptoms typically emerge within a few days or weeks of starting the treatment. Most reactions resolve after either dose reduction or withdrawal, although specific treatment may be necessary. Monitor patients for behavioral and mood disturbances during treatment. Instruct caregivers and/or patients to seek medical advice if psychiatric symptoms develop. ( 5.7 ) Ophthalmic Adverse Reactions : Cataracts, glaucoma and central serous chorioretinopathy have been reported with prolonged use of high doses. Monitor patients for blurred vision or other visual disturbances and if they occur, refer them to an ophthalmologist. ( 5.8 ) Gastrointestinal Adverse Reactions : Increased risk in patients with certain gastrointestinal disorders. Signs and symptoms may be masked. ( 5.9 ) 5.1 Adrenal Crisis Undertreatment with KHINDIVI or sudden discontinuation of therapy with KHINDIVI may lead to adrenocortical insufficiency, adrenal crisis, and death. Adrenal crisis may also be induced by stress events such as infections or surgery when patients require higher doses of corticosteroids. Symptoms of adrenocortical insufficiency include poor feeding, fatigue, low muscle tone, joint pain, nausea, vomiting, hypoglycemia, low blood pressure and electrolyte disturbances. During periods of stress (e.g., infections, surgery), switch to another oral hydrocortisone product and increase the dose, if oral medications are tolerated. Switch patients who are vomiting, severely ill, or unable to take oral medications to parenteral corticosteroid formulations without delay. Once the patient recovers, gradually reduce the steroid dosage used during the acute event and do not switch back to KHINDIVI until the maintenance dosage can be resumed. KHINDIVI is not approved for stress dosing. KHINDIVI contains inactive ingredients polyethylene glycol 400, propylene glycol, and glycerin at levels that individually or in combination may result in hyperosmolarity, metabolic acidosis, hypoglycemia, hepato-renal injury, central nervous system toxicity (e.g., seizure and coma) and/or gastrointestinal adverse reactions [see Warnings and Precautions (5.2) ] . Use of KHINDIVI for stress dosing will result in a greater exposure to inactive ingredients and may increase the risk of these adverse reactions. When switching patients to KHINDIVI from other oral hydrocortisone formulations, consider the potential for dosing inaccuracy if other oral hydrocortisone formulations have been manipulated (e.g., split or crushed tablets, compounded formulations). Manipulation of oral hydrocortisone formulations may result in a relative difference in hydrocortisone exposure when using the same dosage to initiate KHINDIVI treatment. Monitor patients after switching to KHINDIVI to ensure KHINDIVI is providing the same level of hydrocortisone exposure as the previously used oral hydrocortisone formulation. If symptoms of adrenal insufficiency occur, increase the total daily dosage of KHINDIVI. 5.2 Systemic Adverse Reactions Due to Inactive Ingredients Hyperosmolarity KHINDIVI is not approved in pediatric patients less than 5 years of age. KHINDIVI contains the inactive ingredients polyethylene glycol 400, propylene glycol, and glycerin, which undergo substantial systemic absorption. These inactive ingredients, individually or in combination may increase plasma osmolarity in all pediatric patients, especially in pediatric patients less than 5 years of age due to incomplete maturity of the alcohol dehydrogenase enzyme that metabolizes propylene glycol and polyethylene glycol 400. Monitor pediatric patients using KHINDIVI for signs and symptoms consistent with hyperosmolarity. Discontinue KHINDIVI and switch to another hydrocortisone formulation if this occurs. Metabolic Acidosis and Other Adverse Reactions KHINDIVI contains the inactive ingredient polyethylene glycol 400 and propylene glycol that may result in metabolic acidosis, hypoglycemia, hepato-renal injury, and central nervous system toxicity (e.g., seizure and coma). These adverse reactions may increase the risk of adrenal crisis [see Warnings and Precautions (5.1) ] . Monitor laboratory values and for physical signs and symptoms of these adverse reactions. Discontinue KHINDIVI and switch to another hydrocortisone formulation if these adverse reactions occur. Laxative Effects Due to Inactive Ingredients KHINDIVI contains the inactive ingredients polyethylene glycol 400 and glycerin, which alone or in combination, may cause gastrointestinal irritation resulting in vomiting and/or diarrhea. These gastrointestinal reactions may increase the risk of adrenal crisis in patients with adrenal insufficiency [see Warnings and Precautions (5.1) ] . Monitor for signs or symptoms of gastrointestinal irritation and associated fluid and electrolyte abnormalities. Discontinue KHINDIVI and switch to another hydrocortisone formulation if these adverse reactions occur. 5.3 Immunosuppression and Increased Risk of Infection with Use of a Dosage Greater Than Replacement Use of the recommended dosage of KHINDIVI [see Dosage and Administration (2.1 , 2.2) ] as a replacement therapy in pediatric patients with adrenocortical insufficiency is not expected to cause immunosuppression or increase the risk of infection. The use of a greater than replacement dosage can suppress the immune system and increase the risk of infection with any pathogen, including viral, bacterial, fungal, protozoan, or helminthic pathogens. The use of KHINDIVI at greater than replacement dosage 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 Infections associated with the use of