Alkindi

1 INDICATIONS AND USAGE ALKINDI SPRINKLE is indicated as replacement therapy in pediatric patients with adrenocortical insufficiency. ALKINDI SPRINKLE is a corticosteroid indicated as replacement therapy in pediatric patients with adrenocortical insufficiency. (1)

2 DOSAGE AND ADMINISTRATION ' • Individualize the dose, using the lowest possible dosage. (2.1) • The recommended starting replacement dosage is 8 to 10 mg/m2 daily. Higher doses may be needed based on patient’s age and symptoms of the disease. Use of lower starting doses may be sufficient in patients with residual but decreased endogenous cortisol production. (2.1) • Round the dose to the nearest 0.5 mg or 1 mg. More than one capsule may be needed to supply the required dose. (2.1) • Divide the total daily dose in 3 doses and administer 3 times daily. Older patients may have their daily dose divided by 2 and administered twice daily. (2.1) • When switching from other oral hydrocortisone formulations, use the same total daily hydrocortisone dosage. If symptoms of adrenal insufficiency occur, increase total daily dosage. (2.2) • ALKINDI SPRINKLE are oral granules contained within capsules. Do not swallow the capsule. Do not chew or crush the granules. (2.3) • See the Full Prescribing Information for detailed administration instructions. (2.3) 2.1 Dosage Information Individualize the dose for each patient, using the lowest possible dosage. The recommended starting replacement dosage is 8 to 10 mg/m 2 /day daily. Higher doses may be needed based on patient’s age and symptoms of the disease. Use of lower starting doses may be sufficient in patients with residual but decreased endogenous cortisol production. Round the dose to the nearest 0.5 mg or 1 mg. The contents of more than one capsule may be needed to supply the required dose. Divide the total daily dose in 3 doses and administer 3 times daily. Older pediatric patients may have their daily dose divided by 2 and administered twice daily. Monitor patients for symptoms of under and/or overtreatment including signs and symptoms of adrenocortical insufficiency, linear growth and weight gain. Adjust doses accordingly. During episodes of acute febrile illness, gastroenteritis, surgery or major trauma, patients may need increased doses [see Warnings and Precautions ( 5.1 )] . 2.2 Switching to ALKINDI SPRINKLE from Other Oral Hydrocortisone Formulations When switching patients from other oral hydrocortisone formulations to ALKINDI SPRINKLE, use the same total daily hydrocortisone dosage. Closely monitor patients after switching to ALKINDI SPRINKLE for symptoms of adrenocortical insufficiency. If symptoms of adrenal insufficiency occur after switching, increase the total daily dosage of ALKINDI SPRINKLE [see Warnings and Precautions (5.1)]. 2.3 Administration Instructions ALKINDI SPRINKLE are oral granules contained within capsules. Do not swallow the capsules. Do not chew or crush the granules. Do not use ALKINDI SPRINKLE granules in nasogastric or gastric tubes as they may cause tube blockage. Open the capsule and administer the granules as follows: Hold the capsule so that the printed strength is at the top and tap to ensure all the granules are in the lower half of the capsule. Squeeze the bottom of the capsule gently and twist off the top of the capsule. The granules may be administered by pouring the granules directly onto the patient’s tongue, pouring the granules onto a spoon and placing in the patient’s mouth, or sprinkling onto a spoonful of cold or room temperature soft food (such as yogurt or fruit puree). The granules should be given and swallowed within 5 minutes to avoid a bitter taste as the outer taste masking cover can dissolve. Tap the capsule to ensure all the granules are removed. Avoid wetting the capsule on the tongue or soft food as this may result in granules remaining in the capsule. Immediately follow administration with ingestion of fluids such as water, milk, breast milk or formula to ensure all granules are swallowed. Do not add the granules to liquid as this can result in reductions in the dose administered and may result in a bitter taste. Instruct patients and/or caregivers to contact their healthcare provider if the full dose is not administered (e.g., …

3 DOSAGE FORMS AND STRENGTHS ALKINDI SPRINKLE oral granules are white to off-white granules contained within transparent capsules and are available as follows: Strength Imprint on Capsules 0.5 mg “INF-0.5” in red ink 1 mg “INF-1.0” in blue ink 2 mg “INF-2.0” in green ink 5 mg “INF-5.0” in gray ink Oral granules: 0.5 mg, 1 mg, 2 mg, 5 mg contained in capsules. ( 3 )

4 CONTRAINDICATIONS ALKINDI SPRINKLE is contraindicated in patients with hypersensitivity to hydrocortisone or to any of the ingredients in ALKINDI SPRINKLE. Anaphylactic reactions have occurred in patients receiving corticosteroids [see Adverse Reactions ( 6.2 )] . Hypersensitivity to hydrocortisone or to any of the ingredients in ALKINDI SPRINKLE. ( 4 )

6 ADVERSE REACTIONS The following serious adverse reactions are described here and elsewhere in the label: Adrenal Crisis [see Warnings and Precautions ( 5.1 )] Immunosuppression and Increased Risk of Infection with Use of a Dosage Greater Than Replacement [see Warnings and Precautions ( 5.2 )] Growth Retardation [see Warnings and Precautions ( 5.3 )] Cushing’s Syndrome Due to Use of Excessive Doses of Corticosteroids [see Warnings and Precautions ( 5.4 )] Decrease in Bone Mineral Density [see Warnings and Precautions ( 5.5 )] Psychiatric Adverse Reactions [see Warnings and Precautions ( 5.6 )] Ophthalmic Adverse Reactions [see Warnings and Precautions ( 5.7 )] Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.8 )] Risk of Kaposi's Sarcoma with Use of Dosage Greater Than Replacement [see Warnings and Precautions (5.9)] Vaccinations [see Warnings and Precautions (5.10)] 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. ALKINDI SPRINKLE was evaluated in an uncontrolled, open-label, single-arm clinical study in 18 pediatric patients with adrenocortical insufficiency. 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 ALKINDI SPRINKLE. 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 ALKINDI SPRINKLE for up to 29 Months Adverse Reactions N=18 (%) 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 Endocrin …

7 DRUG 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 04/2026

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Untreated adrenocortical insufficiency in pregnancy can result in a high rate of complications, including maternal mortality. The use of physiologic doses of hydrocortisone is not expected to cause major birth defects, miscarriage and adverse maternal and fetal outcomes. Available data from observational studies with hydrocortisone use in pregnancy have not identified a clear drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes (see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Data Human Data Available data from observational studies with hydrocortisone use in pregnant women have not identified a clear drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Evidence from published epidemiologic studies suggest that there may be a small increased risk of cleft lip with or without cleft palate associated with first trimester systemic corticosteroid use in pregnant patients. However, the data are limited and report inconsistent findings, and studies have important methodological limitations, including non-randomized design, retrospective data collection, lack of dose-response data and the inability to control for confounders,such as underlying maternal disease and use of concomitant medications. In addition, unlike other corticosteroids, hydrocortisone is enzymatically deactivated by the placenta and therefore, limits fetal exposure. Animal Data 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 without adrenocortical insufficiency have yielded an increased incidence of cleft palate in the offspring. 8.2 Lactation Risk Summary Cortisol is present in human milk. The use of hydrocortisone at a physiologic dose for adrenocortical insufficiency is not expected to adversely affect the breastfed infant or milk production. There are no data on the presence of hydrocortisone in breast milk, the effect on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ALKINDI SPRINKLE and any potential adverse effects on the breastfed infant from ALKINDI SPRINKLE or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of ALKINDI SPRINKLE have been established in pediatric patients for replacement therapy of adrenocortical insufficiency and the information on this use is discussed throughout the labeling. Use of ALKINDI SPRINKLE in pediatric patients is supported by use in pediatric patients for adrenocortical insufficiency with another hydrocortisone product, along with supportive pharmacokinetic and safety data in 24 pediatric patients with adrenocortical insufficiency. No new adverse reactions were identified [see Adverse Reactions (6) and Clinical Pharmacology (12.3)]. ALKINDI SPRINKLE are oral granules contained within capsules that must be opened and not swallowed whole to administer the granules. Additionally, ALKINDI SPRINKLE granules should not be administered via nasogastric or gastric tubes as they may cause tube blockage [see Dosage and Administration (2.2)].

12.1 Mechanism of Action Hydrocortisone is a glucocorticoid. Glucocorticoids, adrenocortical steroids, cause varied metabolic effects. In addition, they modify the body's immune responses to diverse stimuli..

11 DESCRIPTION ALKINDI SPRINKLE contains hydrocortisone, a corticosteroid, also known as cortisol. The chemical name of hydrocortisone is 11β,17α,21-trihydroxy-pregn-4-ene-3,20-dione and it has the chemical formula of C 21 H 30 O 5 , and molecular weight of 362 g·mol −1 . Hydrocortisone is a white or almost white powder soluble in the pH range of 1-7. Structural formula of hydrocortisone: ALKINDI SPRINKLE are oral granules contained within hard capsules. The inactive ingredients in the granules are microcrystalline cellulose, hypromellose, magnesium stearate and ethyl cellulose and the capsule shell contains hypromellose. The printing ink contains shellac, propylene glycol and concentrated ammonia solution. The printing ink also contains red iron oxide, potassium hydroxide for 0.5 mg (red), indigotine for 1 mg (blue), indigotine, yellow iron oxide, titanium dioxide for 2 mg (green) and titanium dioxide, black iron oxide, potassium hydroxide for 5 mg (gray). Structure

10 OVERDOSAGE Treatment of acute overdosage is by supportive and symptomatic therapy.

16 HOW SUPPLIED/STORAGE AND HANDLING ALKINDI SPRINKLE oral granules are supplied as white to off-white granules in transparent capsules as follows: Strength Imprint on Capsules Amount in Bottle NDC 0.5 mg “INF-0.5” in red ink 50 capsules 71863-109-50 1 mg “INF-1.0” in blue ink 50 capsules 71863-110-50 2 mg “INF-2.0” in green ink 50 capsules 71863-111-50 5 mg “INF-5.0” in gray ink 50 capsules 71863-112-50 Store at controlled room temperature (USP) 20°C to 25°C (68°F to 77°F). Excursions permitted to 15°C to 30 °C (59°F to 86°F). Store in the original bottle in order to protect from light. Once the bottle has been opened, use the capsules within 60 days.