HYDROCORTISONE: 24,551 Adverse Event Reports & Safety Profile

DESCRIPTION SOLU-CORTEF Sterile Powder is an anti-inflammatory glucocorticoid that contains hydrocortisone sodium succinate as the active ingredient. SOLU-CORTEF Sterile Powder is available in several packages for intravenous or intramuscular administration. 100 mg Plain Vials containing hydrocortisone sodium succinate equivalent to 100 mg hydrocortisone, 0.8 mg monobasic sodium phosphate anhydrous, 8.73 mg dibasic sodium phosphate dried. SOLU-CORTEF 100 mg plain does not contain diluent (see DOSAGE AND ADMINISTRATION, Preparation of Solutions ). ACT-O-VIAL ® System (Single-Dose Vial) in four strengths: 100 mg ACT-O-VIAL 250 mg ACT-O-VIAL 500 mg ACT-O-VIAL 1,000 mg ACT-O-VIAL Each 2 mL contains (when mixed): Each 2 mL contains (when mixed): Each 4 mL contains (when mixed): Each 8 mL contains (when mixed): Hydrocortisone sodium succinate equiv. to 100 mg Hydrocortisone equiv. to 250 mg Hydrocortisone equiv. to 500 mg Hydrocortisone equiv. to 1,000 mg Hydrocortisone Monobasic sodium phosphate anhydrous 0.8 mg 2 mg 4 mg 8 mg Dibasic sodium phosphate dried 8.73 mg 21.8 mg 44 mg 87.32 mg The diluent, as part of the packaging presentation for the ACT-O-VIAL ® system, is comprised of Water for Injection only, and does not contain any preservative. When necessary, the pH of each formula was adjusted with sodium hydroxide so that the pH of the reconstituted solution is within the USP specified range of 7 to 8. The chemical name for hydrocortisone sodium succinate is pregn-4-ene-3,20-dione,21-(3-carboxy-1-oxopropoxy)-11,17-dihydroxy-, monosodium salt, (11β)- and its molecular weight is 484.52. The structural formula is represented below: Hydrocortisone sodium succinate is a white or nearly white, odorless, hygroscopic amorphous solid. It is very soluble in water and in alcohol, very slightly soluble in acetone, and insoluble in chloroform.

Chemical

Structure

INDICATIONS AND USAGE Hydrocortisone Tablets are indicated in the following conditions. 1.

Endocrine Disorders

Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the first choice; synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy mineralocorticoid supplementation is of particular importance) Congenital adrenal hyperplasia Non suppurative thyroiditis Hypercalcemia associated with cancer 2.

Rheumatic

Disorders As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in: Psoriatic arthritis Rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy) Ankylosing spondylitis Acute and subacute bursitis Acute nonspecific tenosynovitis Acute gouty arthritis Post-traumatic osteoarthritis Synovitis of osteoarthritis Epicondylitis 3.

Collagen Diseases

During an exacerbation or as maintenance therapy in selected cases of: Systemic lupus erythematosus Systemic dermatomyositis (polymyositis) Acute rheumatic carditis 4.

Dermatologic Diseases Pemphigus

Bullous dermatitis herpetiformis Severe erythema multiforme (Stevens-Johnson syndrome) Exfoliative dermatitis Mycosis fungoides Severe psoriasis Severe seborrheic dermatitis 5.

Allergic States

Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment: Seasonal or perennial allergic rhinitis Serum sickness Bronchial asthma Contact dermatitis Atopic dermatitis Drug hypersensitivity reactions 6.

Ophthalmic Diseases

Severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa such as: Allergic conjunctivitis Keratitis Allergic corneal marginal ulcers Herpes zoster ophthalmicus Iritis and iridocyclitis Chorioretinitis Anterior segment inflammation Diffuse posterior uveitis and choroiditis Optic neuritis Sympathetic ophthalmia 7.

Respiratory Diseases

Symptomatic sarcoidosis Loeffler's syndrome not manageable by other means Berylliosis Fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy Aspiration pneumonitis 8.

Hematologic Disorders

Idiopathic thrombocytopenic purpura in adults Secondary thrombocytopenia in adults Acquired (autoimmune) hemolytic anemia Erythroblastopenia (RBC anemia) Congenital (erythroid) hypoplastic anemia 9.

Neoplastic Diseases

For palliative management of: Leukemias and lymphomas in adults Acute leukemia of childhood 10.

Edematous

States To induce a diuresis or remission of proteinuria in the nephrotic syndrome, without uremia, of the idiopathic type or that due to lupus erythematosus. 11.

Gastrointestinal

Diseases To tide the patient over a critical period of the disease in: Ulcerative colitis Regional enteritis 12.

Miscellaneous

Tuberculous meningitis with subarachnoid block or impending block when used concurrently with appropriate antituberculous chemotherapy Trichinosis with neurologic or myocardial involvement

1.

Endocrine Disorders

Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the first choice; synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy mineralocorticoid supplementation is of particular importance) Congenital adrenal hyperplasia Non suppurative thyroiditis Hypercalcemia associated with cancer

2.

Rheumatic

Disorders As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in: Psoriatic arthritis Rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy) Ankylosing spondylitis Acute and subacute bursitis Acute nonspecific tenosynovitis Acute gouty arthritis Post-traumatic osteoarthritis Synovitis of osteoarthritis Epicondylitis

3.

Collagen Diseases

During an exacerbation or as maintenance therapy in selected cases of: Systemic lupus erythematosus Systemic dermatomyositis (polymyositis) Acute rheumatic carditis

4.

Dermatologic Diseases Pemphigus

Bullous dermatitis herpetiformis Severe erythema multiforme (Stevens-Johnson syndrome) Exfoliative dermatitis Mycosis fungoides Severe psoriasis Severe seborrheic dermatitis

5.

Allergic States

Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment: Seasonal or perennial allergic rhinitis Serum sickness Bronchial asthma Contact dermatitis Atopic dermatitis Drug hypersensitivity reactions

6.

Ophthalmic Diseases

Severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa such as: Allergic conjunctivitis Keratitis Allergic corneal marginal ulcers Herpes zoster ophthalmicus Iritis and iridocyclitis Chorioretinitis Anterior segment inflammation Diffuse posterior uveitis and choroiditis Optic neuritis Sympathetic ophthalmia

7.

Respiratory Diseases

Symptomatic sarcoidosis Loeffler's syndrome not manageable by other means Berylliosis Fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy Aspiration pneumonitis

8.

Hematologic Disorders

Idiopathic thrombocytopenic purpura in adults Secondary thrombocytopenia in adults Acquired (autoimmune) hemolytic anemia Erythroblastopenia (RBC anemia) Congenital (erythroid) hypoplastic anemia

9.

Neoplastic Diseases

For palliative management of: Leukemias and lymphomas in adults Acute leukemia of childhood

10.

Edematous

States To induce a diuresis or remission of proteinuria in the nephrotic syndrome, without uremia, of the idiopathic type or that due to lupus erythematosus.

11.

Gastrointestinal

Diseases To tide the patient over a critical period of the disease in: Ulcerative colitis Regional enteritis

12.

Miscellaneous

Tuberculous meningitis with subarachnoid block or impending block when used concurrently with appropriate antituberculous chemotherapy Trichinosis with neurologic or myocardial involvement

DOSAGE AND ADMINISTRATION Because of possible physical incompatibilities, SOLU-CORTEF should not be diluted or mixed with other solutions. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. This preparation may be administered by intravenous injection, by intravenous infusion, or by intramuscular injection, the preferred method for initial emergency use being intravenous injection. Following the initial emergency period, consideration should be given to employing a longer acting injectable preparation or an oral preparation. Therapy is initiated by administering SOLU-CORTEF Sterile Powder intravenously over a period of 30 seconds (e.g., 100 mg) to 10 minutes (e.g., 500 mg or more). In general, high dose corticosteroid therapy should be continued only until the patient's condition has stabilized, usually not beyond 48 hours to 72 hours. When high dose hydrocortisone therapy must be continued beyond 48 –72 hours, hypernatremia may occur. Under such circumstances, it may be desirable to replace SOLU-CORTEF with a corticoid such as methylprednisolone sodium succinate which causes little or no sodium retention. The initial dose of SOLU-CORTEF Sterile Powder is 100 mg to 500 mg, depending on the specific disease entity being treated. However, in certain overwhelming, acute, life-threatening situations, administration in dosages exceeding the usual dosages may be justified and may be in multiples of the oral dosages. This dose may be repeated at intervals of 2, 4, or 6 hours as indicated by the patient's response and clinical condition.

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 maintains an adequate clinical response is reached. Situations that 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 the corticosteroid 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. In pediatric patients, the initial dose of hydrocortisone may vary depending on the specific disease entity being treated. The range of initial doses is 0.56 mg/kg/day to 8 mg/kg/day in three or four divided doses (20 mg/m 2 bsa/day to 240 mg/m 2 bsa/day). For the purpose of comparison, the following is the equivalent milligram dosage of the various glucocorticoids: Cortisone, 25 Triamcinolone, 4 Hydrocortisone, 20 Paramethasone, 2 Prednisolone, 5 Betamethasone,

0.75 Prednisone, 5 Dexamethasone,

0.75 Methylprednisolone, 4 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. Preparation of Solutions: 100 mg Plain For intravenous or intramuscular injection, prepare solution by aseptically adding not more than 2 mL of Bacteriostatic Water for Injection or Bacteriostatic Sodium Chloride Injection to the contents of one vial. For intravenous infusion , first prepare solution by adding not more than 2 mL of Bacteriostatic Water for Injection to the vial; this solution may then be added to 100 mL to 1,000 mL of the following: 5% dextrose in water (or isotonic saline solution or 5% dextrose in isotonic saline solution if patient is not on sodium restriction). From a microbiological point of view, unless the method of opening/reconstitution/dilution precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in use storage times and conditions are the responsibility of the user. This product, like many other steroid formulations, is sensitive to heat. Therefore, it should not be autoclaved when it is desirable to sterilize the exterior of the vial. DIRECTIONS FOR USING THE ACT-O-VIAL SYSTEM 1. Press down on plastic activator to force diluent into the lower compartment. 2. Gently agitate to effect solution. 3. Remove plastic tab covering center of stopper. 4. Sterilize top of stopper with a suitable germicide. 5. Insert needle squarely through center of stopper until tip is just visible. Invert vial and withdraw dose. Further dilution is not necessary for intravenous or intramuscular injection. For intravenous infusion, first prepare solution as just described.

The

100 mg solution may then be added to 100 mL to 1,000 mL of 5% dextrose in water (or isotonic saline solution or 5% dextrose in isotonic saline solution if patient is not on sodium restriction).

The

250 mg solution may be added to 250 mL to 1,000 mL, the 500 mg solution may be added to 500 mL to 1,000 mL, and the 1,000 mg solution to 1,000 mL of the same diluents. In cases where administration of a small volume of fluid is desirable, 100 mg to 3,000 mg of SOLU-CORTEF may be added to 50 mL of the above diluents. The resulting solutions are stable for at least 4 hours and may be administered either directly or by IV piggyback. When reconstituted as directed, pH's of the solutions range from 7 to 8. Image

CONTRAINDICATIONS: Product should not be used in patients with a history of sensitivity to any of its ingredients or adverse reactions to lidocaine or amide anesthetics, which usually do not cross-react with “caine” ester type anesthetics. If excessive irritation and significant worsening occur, discontinue use and seek the advice of your physician. Product and topical lidocaine should be used cautiously in those with impaired liver function, as well as the very ill or very elderly and those with significant liver disease. Product should be used with caution on patients receiving antiarrhythmic drugs of Class I since the adverse effects are additive and generally synergistic. This product is contraindicated for tuberculous or fungal lesions or skin vaccinia, varicella and acute herpes simplex. Topical corticosteroids are contraindicated in those patients with a history of hypersensitivity to any of the components of the preparation. structure structure2

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

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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span> . 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.1 , 2.2) ]</span> 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 corticosteroids at a greater than replacement dosage range from mild to severe or fatal, and the rate of infectious complications increases with increasing corticosteroid dosages. Monitor for the development of infection and consider KHINDIVI dosage reduction as needed <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span>.

5.4 Growth Retardation Long-term use of corticosteroids in excessive doses may cause growth retardation in pediatric patients. Historical cohorts of adults treated from childhood for congenital adrenal hyperplasia have been found to have growth retardation. Effects on linear growth are less likely when using corticosteroids as replacement therapy. Use the minimum dosage of KHINDIVI to achieve desired clinical response and monitor the patient&apos;s growth.

5.5 Cushing&apos;s Syndrome Due to Use of Excessive Doses of Corticosteroids Prolonged use of corticosteroids in supraphysiologic doses may cause Cushing&apos;s syndrome. Symptoms and signs of Cushing&apos;s syndrome include weight gain, decreased height velocity, hyperglycemia, hypertension, edema, easy bruising, muscle weakness, red round face, depression, or mood swings. Monitor patients for signs and symptoms of Cushing&apos;s syndrome every 6 months.

5.6 Decrease in Bone Mineral Density Corticosteroids decrease bone formation and increase bone resorption which may lead to development of osteoporosis. Historical cohorts of adults treated from childhood for congenital adrenal hyperplasia have been found to have reduced bone mineral density and increased fracture rates. Use the minimum dosage of KHINDIVI to achieve desired clinical response.

5.7 Psychiatric Adverse Reactions Corticosteroid use may be associated with severe psychiatric adverse reactions. Euphoria, mania, psychosis with hallucinations and delirium or depression have been seen in patients at replacement doses of hydrocortisone <span class="opacity-50 text-xs">[see Adverse Reactions (6) ]</span>. Symptoms typically emerge within a few days or weeks of starting the treatment. Risks may be higher with high doses, although dose levels do not allow prediction of the onset, type, severity, or duration of reactions. Most reactions resolve after either dose reduction or withdrawal, although specific treatment may be necessary. Monitor patients for behavioral and mood disturbances during treatment with KHINDIVI. Instruct caregivers and/or patients to seek medical advice if psychiatric symptoms develop.

5.8 Ophthalmic Adverse Reactions Ophthalmic effects, such as cataract, glaucoma or central serous chorioretinopathy have been reported with prolonged use of corticosteroids in high doses. Monitor patients for blurred vision or other visual disturbances. If patients develop ophthalmic adverse reactions, refer them to an ophthalmologist for further evaluation.

5.9 Gastrointestinal Adverse Reactions Gastrointestinal Perforation There is an increased risk of gastrointestinal perforation in patients with certain gastrointestinal disorders. Signs of gastrointestinal 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.

Concomitant

Use with Non-Steroidal Anti-Inflammatory Drugs Concurrent administration of corticosteroids with non-steroidal anti-inflammatory drugs (NSAIDS) may increase the risk of gastrointestinal adverse reactions. Monitor patients receiving corticosteroids and concomitant NSAIDS for gastrointestinal adverse reactions [see Drug Interactions (7) ].

5.10 Risk of Kaposi&apos;s Sarcoma with Use of a Dosage Greater Than Replacement Kaposi&apos;s sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions at a dosage greater than replacement (supraphysiologic dosage). If patients take a supraphysiologic chronic dosage of KHINDIVI, they are at increased risk of developing Kaposi&apos;s sarcoma.

5.11 Vaccination Administration of live vaccines may be acceptable in KHINDIVI-treated pediatric patients with adrenocortical insufficiency who receive replacement corticosteroids.

PRECAUTIONS General: The lowest possible dose of corticosteroid should be used to control the condition under treatment. When reduction in dosage is possible, the reduction should be gradual. 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. Cardio-renal: As sodium retention with resultant edema and potassium loss may occur in patients receiving corticosteroids, these agents should be used with caution in patients with congestive heart failure, hypertension, or renal insufficiency. Endocrine: 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. 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. Gastrointestinal: Steroids should be used with caution in active or latent peptic ulcers, diverticulitis, fresh intestinal anastomoses, and non-specific ulcerative colitis, since they may increase the risk of a perforation. Signs of peritoneal irritation following gastrointestinal perforation in patients receiving corticosteroids may be minimal or absent. There is an enhanced effect due to decreased metabolism of corticosteroids in patients with cirrhosis. Musculoskeletal: Corticosteroids decrease bone formation and increase bone resorption both through their effect on calcium regulation (e.g., 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 (i.e., postmenopausal women) before initiating corticosteroid therapy. Local injection of a steroid into a previously infected site is not usually recommended. Neurologic-psychiatric: 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. 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. Ophthalmic: Intraocular pressure may become elevated in some individuals. If steroid therapy is continued for more than 6 weeks, intraocular pressure should be monitored. Other: Pheochromocytoma crisis, which can be fatal, has been reported after administration of systemic corticosteroids. In patients with suspected pheochromocytoma, consider the risk of pheochromocytoma crisis prior to administering corticosteroids.

Tumor Lysis

Syndrome: In post marketing experience, tumor lysis syndrome (TLS) has been reported in patients with malignancies, including hematological malignancies and solid tumors, following the use of systemic corticosteroids alone or in combination with other chemotherapeutic agents. Patients at high risk of TLS, such as patients with tumors that have a high proliferative rate, high tumor burden and high sensitivity to cytotoxic agents, should be monitored closely and appropriate precautions should be taken. Information for Patients: Patients should be warned not to discontinue the use of corticosteroids abruptly or without medical supervision, to advise any medical attendants that they are taking corticosteroids, and to seek medical advice at once should they develop fever or other signs of infection. Persons who are on corticosteroids should be warned to avoid exposure to chicken pox or measles. Patients should also be advised that if they are exposed, medical advice should be sought without delay.

Drug

Interactions: Aminoglutethimide: Aminoglutethimide may lead to a loss of corticosteroid-induced adrenal suppression. Amphotericin B injection and potassium-depleting agents: When corticosteroids are administered concomitantly with potassium-depleting agents (e.g., amphotericin B, diuretics), patients should be observed closely for development of hypokalemia. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure. Antibiotics: Macrolide antibiotics have been reported to cause a significant decrease in corticosteroid clearance (see PRECAUTIONS : Drug Interactions , Hepatic Enzyme Inhibitors ). Anticholinesterases: Concomitant use of anticholinesterase agents and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy. Anticoagulants, oral: Coadministration of corticosteroids and warfarin usually results in inhibition of response to warfarin, although there have been some conflicting reports. Therefore, coagulation indices should be monitored frequently to maintain the desired anticoagulant effect. Antidiabetics: Because corticosteroids may increase blood glucose concentrations, dosage adjustments of antidiabetic agents may be required. Antitubercular drugs: Serum concentrations of isoniazid may be decreased. Cholestyramine: Cholestyramine may increase the clearance of corticosteroids. Cyclosporine: Increased activity of both cyclosporine and corticosteroids may occur when the two are used concurrently. Convulsions have been reported with this concurrent use. Digitalis glycosides: Patients on digitalis glycosides may be at increased risk of arrhythmias due to hypokalemia. Estrogens, including oral contraceptives: Estrogens may decrease the hepatic metabolism of certain corticosteroids, thereby increasing their effect.

Hepatic Enzyme

Inducers (e.g., barbiturates, phenytoin, carbamazepine, rifampin): Drugs that induce cytochrome P450 3A4 enzyme activity may enhance the metabolism of corticosteroids and require that the dosage of the corticosteroid be increased.

Hepatic Enzyme

Inhibitors (e.g., ketoconazole, macrolide antibiotics such as erythromycin and troleandomycin): Drugs that inhibit cytochrome P450 3A4 have the potential to result in increased plasma concentrations of corticosteroids. Ketoconazole: Ketoconazole has been reported to significantly decrease the metabolism of certain corticosteroids by up to 60%, leading to an increased risk of corticosteroid side effects. Nonsteroidal anti-inflammatory drugs (NSAIDs): Concomitant use of aspirin (or other nonsteroidal anti-inflammatory agents) and corticosteroids increases the risk of gastrointestinal side effects. Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia. The clearance of salicylates may be increased with concurrent use of corticosteroids. Skin tests: Corticosteroids may suppress reactions to skin tests. Vaccines: Patients on prolonged corticosteroid therapy may exhibit a diminished response to toxoids and live or inactivated vaccines due to inhibition of antibody response. Corticosteroids may also potentiate the replication of some organisms contained in live attenuated vaccines. Routine administration of vaccines or toxoids should be deferred until corticosteroid therapy is discontinued if possible (see WARNINGS : Immunosuppression and Increased Risk of Infection , Vaccination ). Carcinogenesis, Mutagenesis, Impairment of Fertility: No adequate studies have been conducted in animals to determine whether corticosteroids have a potential for carcinogenesis or mutagenesis. Steroids may increase or decrease motility and number of spermatozoa in some patients. Corticosteroids have been shown to impair fertility in male rats. Pregnancy: Teratogenic Effects Corticosteroids have been shown to be teratogenic in many species when given in doses equivalent to the human dose. Animal studies in which corticosteroids have been given to pregnant mice, rats, and rabbits have yielded an increased incidence of cleft palate in the offspring. There are no adequate and well-controlled studies in pregnant women. Corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Infants born to mothers who have received corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism.

Nursing

Mothers: Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Because of the potential for serious adverse reactions in nursing infants from corticosteroids, a decision should be made whether to continue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric

Use: The efficacy and safety of corticosteroids 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). Other indications for pediatric use of corticosteroids (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 corticosteroids in pediatric patients are similar to those in adults (see ADVERSE REACTIONS ). 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. Pediatric patients 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 pediatric patients than some commonly used tests of HPA axis function. The linear growth of pediatric patients treated with corticosteroids should be monitored, and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of treatment alternatives. In order to minimize the potential growth effects of corticosteroids, pediatric patients should be titrated to the lowest effective dose. Hypertrophic cardiomyopathy was reported after administration of hydrocortisone to prematurely born infants, therefore appropriate diagnostic evaluation and monitoring of cardiac function and structure should be performed.

Geriatric

Use: Clinical studies did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, 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.

INTERACTIONS Table 2 Drug Interactions with ALKINDI SPRINKLE CYP3A4 Inhibitors Clinical Impact: Hydrocortisone is metabolized by cytochrome P450 3A4 (CYP3A4). Concomitant administration of inhibitors of CYP3A4 may lead to increases in serum concentrations of ALKINDI SPRINKLE and increase the risk of adverse reactions associated with the use of excessive doses. Intervention: Concomitant use of CYP3A4 inhibitors may require a decrease in the ALKINDI SPRINKLE dose. Examples: Anti-fungals: itraconazole, posaconazole, voriconazole Antibiotics: erythromycin and clarithromycin Antiretrovirals: ritonavir Grapefruit juice CYP3A4 Inducers Clinical Impact: Hydrocortisone is metabolized by cytochrome P450 3A4 (CYP3A4). Concomitant administration of inducers of CYP3A4 may lead to decreases in serum concentrations of ALKINDI SPRINKLE and increase the risk of adverse reactions, including adrenal crisis. Intervention: Concomitant use of CYP3A4 inducers may require an increase in the ALKINDI SPRINKLE dose. Examples: Anticonvulsants: phenytoin, carbamazepine and oxcarbazepine Antibiotics: rifampicin and rifabutin Barbiturates: phenobarbital and primidone Antiretrovirals: efavirenz and nevirapine Estrogen and Estrogen Containing Products Clinical Impact: Oral estrogen and estrogen-containing oral contraceptives may interact with hydrocortisone by increasing serum cortisol-binding globulin (CBG) concentration. Concomitant use may reduce the efficacy of ALKINDI SPRINKLE by binding and delaying or preventing absorption. Intervention: Concomitant use of estrogen/estrogen containing products may require an increase in the ALKINDI SPRINKLE dose.

Antidiabetic Agents Clinical

Impact: Corticosteroids in supraphysiologic doses may increase blood glucose concentrations. Intervention: Use of ALKINDI SPRINKLE in supraphysiologic doses may require a dose adjustment of antidiabetic agents.

Anticoagulant Agents Clinical

Impact: Concomitant use of warfarin and corticosteroids usually results in inhibition of response to warfarin, although there have been some conflicting reports. Intervention: Monitor coagulation indices in patients receiving ALKINDI SPRINKLE and concomitant warfarin to maintain the desired anticoagulant effect.

Cyclosporine Clinical

Impact: Increased activity of both cyclosporine and corticosteroids may occur when the two are used concurrently. Convulsions have been reported with concurrent use. Intervention: Monitor patients receiving ALKINDI SPRINKLE and concomitant cyclosporine.

Nonsteroidal

Anti-inflammatory Drugs (NSAIDs)

Clinical

Impact: Concomitant use of NSAIDs and corticosteroids increases the risk of gastrointestinal adverse reactions. Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia. The clearance of salicylates may be increased with concurrent use of corticosteroids; this could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when corticosteroid is withdrawn. Intervention: Monitor patients receiving ALKINDI SPRINKLE and concomitant NSAIDs. CYP3A4 Inhibitors : concomitant administration may require a decrease in the ALKINDI SPRINKLE dose. ( 7 ) CYP3A4 Inducers : concomitant administration may require an increase in the ALKINDI SPRINKLE dose. ( 7 ) Estrogen and Estrogen Containing Products : concomitant administration may require an increase in the ALKINDI SPRINKLE dose. ( 7 ) Antidiabetic agents: excessive doses may increase blood glucose concentrations. Dose adjustment of antidiabetic agents may be required. ( 7 ) NSAIDs: concomitant administration increases risk of gastrointestinal adverse reactions. ( 7 )

See

17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling (Medication Guide).

Revised

12/2024

Active ingredient........................................................................Purpose Hydrocortisone 1%........................................................................Anti-itch

Inactive I ngredients aloe barbadensis leaf juice, avena sativa (oat) kernel extract, cyclopentasiloxane, dimethicone, dimethicone/vinyl dimethicone crosspolymer, disodium EDTA, glycerin, hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer, isohexadecane, maltodextrin, menthyl lactate, methyl gluceth-20, methylparaben, polysorbate 60, propylparaben, SD Alcohol 40-2 (15%), sodium citrate, water CHATTEM® *Refers to the ingredient hydrocortisone Distributed by CHATTEM, INC. P.O.

Box

2219, Chattanooga, TN 37409-0219 USA ©2008 www.ditchtheitch.com 0042740-02 Cortizone-10 ® Crem e

Inactive Ingredients aloe barbadensis leaf juice, aluminum sulfate, beeswax, calcium acetate, cetearyl alcohol, dextrin, glycerin, maltodextrin, methylparaben, mineral oil, petrolatum, propylparaben, sodium cetearyl sulfate, sodium lauryl sulfate, water *Refers to the ingredient hydrocortisone CHATTEM® Distributed by CHATTEM, INC. P.O.

Box

2219, Chattanooga,TN 37409-0219 USA ©2008 www.chattem.com 0040433-02 Minor change Cortizone-10 ® Cre me Intensive Healing Formula

Inactive Ingredients water, glycerin, dimethicone, petrolatum, jojoba esters, cetyl alcohol, aloe barbadensis leaf juice, stearyl alcohol, distearyldimonium chloride, cetearyl alcohol, steareth-21, steareth-2, polysorbate 60, stearamidopropyl PG-dimonium chloride phosphate, methyl gluceth-20, chamomilla recutita (matricaria) flower extract, tocopheryl acetate, magnesium ascorbyl phosphate, hydrolyzed collagen, hydrolyzed elastin, retinyl palmitate, hydrolyzed jojoba esters, glyceryl stearate, EDTA, PPG-12/SMDI copolymer, potassium hydroxide, avena sativa (oat) kernel extract, menthyl lactate, diazolidinyl urea, benzyl alcohol, methylparaben, BHT, propylparaben *Refers to the ingredient hydrocortisone †Contains 7 healing moisturizers and vitamins A, C & E CHATTEM® Distributed by CHATTEM, INC. P.O.

Box

2219, Chattanooga, TN 37409-0219 USA ©2008 0040439-02 Cortizone-10 ® Ointment

Inactive Ingredients petrolatum *Refers to the ingredient hydrocortisone CHATTEM® Distributed by CHATTEM, INC. P.O.

Box

2219, Chattanooga, TN 37409-0219 USA ©2008 www.chattem.com 0040437-02 Cortizone-10 ® Plus Cre me

Inactive Ingredients aloe barbadensis leaf juice, aluminum sulfate, beeswax, calcium acetate, cetearyl alcohol, cetyl alcohol, cholecalciferol, dextrin, glycerin, isopropyl palmitate, maltodextrin, methylparaben, mineral oil, petrolatum, propylene glycol, propylparaben, retinyl palmitate, sodium cetearyl sulfate, sodium lauryl sulfate, tocopheryl acetate, water, zea mays (corn) oil *Refers to the ingredient hydrocortisone CHATTEM® Distributed by CHATTEM, INC. P.O.

Box

2219, Chattanooga,TN 37409-0219 USA ©2008 www.chattem.com 0040435-02