ALKINDI SPRINKLE- hydrocortisone granule

Alkindi by

Drug Labeling and Warnings

Alkindi by is a Prescription medication manufactured, distributed, or labeled by Eton Pharmaceuticals, Inc.. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

  • 1 INDICATIONS AND USAGE

    ALKINDI SPRINKLE is indicated as replacement therapy in pediatric patients with adrenocortical insufficiency.

  • 2 DOSAGE AND ADMINISTRATION

    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/m2/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)].
    • When switching patients from oral hydrocortisone therapy to ALKINDI SPRINKLE, use the same total daily dose.

    2.2 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.
  • 3 DOSAGE FORMS AND STRENGTHS

    ALKINDI SPRINKLE oral granules are white to off-white granules contained within transparent capsules and are available as follows:

    StrengthImprint 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
  • 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)].

  • 5 WARNINGS AND PRECAUTIONS

    5.1 Adrenal Crisis

    Undertreatment with ALKINDI SPRINKLE or sudden discontinuation of therapy with ALKINDI SPRINKLE 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.

    Increase the dose of ALKINDI SPRINKLE during periods of stress (infections, surgery). 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 dose used during the acute event.

    5.2 Infections

    Excessive doses of corticosteroids may increase the risks of new infections or exacerbation of latent infections with any pathogen, including viral, bacterial, fungal, protozoan or helminthic infections.Appropriate replacement doses of corticosteroids for patients with adrenocortical insufficiency are not expected to cause immunosuppression and, therefore, should not increase risk of infection.Administration of live vaccine may be acceptable in pediatric patients with adrenocortical insufficiency receiving replacement doses of corticosteroids. Monitor patients for signs and symptoms of infections. Treat all infections seriously and initiate stress dosing of steroids early [see Warnings and Precautions (5.1)].

    5.3 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 ALKINDI SPRINKLE 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 of corticosteroids in supraphysiologic doses may cause Cushing’s syndrome. Symptoms and signs of Cushing’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’s syndrome every 6 months; pediatric patients under one year of age may require more frequent monitoring, e.g., every 3 to 4 months.

    5.5 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 ALKINDI SPRINKLE to achieve desired clinical response.

    5.6 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 [see Adverse Reactions (6)]. 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 ALKINDI SPRINKLE. Instruct caregivers and/or patients to seek medical advice if psychiatric symptoms develop.

    5.7 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.

    5.8 Gastrointestinal Adverse Reactions

    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.

    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)].

  • 6 ADVERSE REACTIONS

    The following serious adverse reactions are described here and elsewhere in the label:

    • Adrenal Crisis [see Warnings and Precautions (5.1)]
    • Infections [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)]

    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 ReactionsN=18
    (%)
    Pyrexia10 (56)
    Gastroenteritis9 (50)
    Viral upper respiratory tract infection8 (44)
    Vomiting7 (39)
    Viral infection6 (33)
    Conjunctivitis5 (28)
    Otitis media viral3 (17)
    Tonsillitis3 (17)
    Body temperature increased2 (11)
    Bronchitis2 (11)
    Dental caries2 (11)
    Diarrhea2 (11)
    Genitourinary operation2 (11)
    Pharyngitis2 (11)
    Respiratory tract infection2 (11)
    Rhinitis2 (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

  • 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.
  • 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)].

  • 10 OVERDOSAGE

    Treatment of acute overdosage is by supportive and symptomatic therapy.

  • 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 C21H30O5, 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:

    Structure

    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).

  • 12 CLINICAL PHARMACOLOGY

    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.

    12.2 Pharmacodynamics

    Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt-retaining properties, are used as replacement therapy in adrenocortical deficiency states.

    12.3 Pharmacokinetics

    Absorption

    Following oral administration, a dose of ALKINDI SPRINKLE 4x5 mg was approximately 87% bioavailable when compared to intravenous hydrocortisone in dexamethasone-suppressed healthy adult male volunteers. The median time to peak serum concentration (Tmax) was 0.75 hour post-dose following oral administration.

    In an open label, single dose study in 24 pediatric patients with adrenocortical insufficiency, ALKINDI SPRINKLE (1-4 mg based on body surface area) increased cortisol levels from baseline to median cortisol level 19.4 mcg/dL (range 12.5 – 52.4 mcg/dL) at Cmax (60 minutes post-dose).

    Effect of Food

    The coadministration of ALKINDI SPRINKLE with soft food (yogurt and fruit puree) has been studied in healthy adult male volunteers, where it was shown to be bioequivalent to administration of dry granules directly to the back of the tongue.

    Distribution

    90% or more of circulating hydrocortisone is reversibly bound to protein.

    The binding is accounted for by two protein fractions. One, corticosteroid-binding globulin is a glycoprotein; the other is albumin.

    Elimination

    Hydrocortisone is metabolized in the liver and most body tissues to hydrogenated and degraded forms such as tetrahydrocortisone and tetrahydrocortisol which are excreted in the urine, mainly conjugated as glucuronides, together with a very small proportion of unchanged hydrocortisone.

    The terminal half-life of hydrocortisone is about 1.5 hours following intravenous and oral dosing of hydrocortisone tablets and ALKINDI SPRINKLE in dexamethasone-suppressed healthy adult male volunteers.

  • 13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    No adequate studies in animals have been conducted with hydrocortisone to evaluate carcinogenic or mutagenic potential. Corticosteroids have been shown to impair fertility in male rats.

  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    ALKINDI SPRINKLE oral granules are supplied as white to off-white granules in transparent capsules as follows:

    StrengthImprint on CapsulesAmount in BottleNDC
    0.5 mg“INF-0.5" in red ink50 capsules71863-109-50
    1 mg“INF-1.0" in blue ink50 capsules71863-110-50
    2 mg“INF-2.0" in green ink50 capsules71863-111-50
    5 mg“INF-5.0" in gray ink50 capsules71863-112-50

    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.

  • 17 PATIENT COUNSELING INFORMATION

    Advise the caregiver or patient to read the FDA-approved patient labeling (Medication Guide).

    Administration Information

    Advise the patient or caregiver that ALKINDI SPRINKLE is a granule formulation contained in a capsule. Do not swallow the capsule. Do not chew or crush the granules. Open the capsule and give the granules directly into the patient’s mouth. Alternatively, sprinkle the granules onto soft food and give immediately as the taste masking cover can dissolve in as little as 5 minutes. Avoid wetting the capsule as this may cause some granules to stick to the capsule. Immediately following administration, take a sip of fluids to ensure all granules have been swallowed. [see Dosage and Administration (2.2)].

    Adrenal Crisis

    Inform the patient or caregiver that undertreatment or sudden discontinuation of ALKINDI SPRINKLE may lead to adrenocortical insufficiency, adrenal crisis and death. Inform the patient or caregiver to contact their healthcare provider if they have prolonged vomiting, are severely ill or are unable to take oral medications. [see Warnings and Precautions (5.1)]

    Infections

    Advise the patient or caregiver that excessive doses of corticosteroids may increase the risk of infections. Inform the patient or caregiver that administration of live vaccine may be acceptable. Instruct the patient or caregiver to contact their healthcare provider if they develop any infections. [see Warnings and Precautions (5.2)]

    Growth Retardation

    Discuss with the caregiver that long-term use of corticosteroids in excessive doses may cause growth retardation in pediatric patients. [see Warnings and Precautions (5.3)]

    Cushing’s Syndrome

    Inform patients and caregivers that prolonged use of corticosteroids in supraphysiologic doses may cause Cushing’s syndrome and that symptoms and signs include weight gain, decreased height velocity, hyperglycemia, hypertension, edema, easy bruising, muscle weakness, red round face, depression or mood swings. [see Warnings and Precautions (5.4)]

    Decrease in Bone Mineral Density

    Inform the patient or caregiver that corticosteroids decrease bone formation and increase bone resorption that may lead to osteoporosis. [see Warnings and Precautions (5.5)]

    Psychiatric Adverse Reactions

    Advise the patient or caregiver that corticosteroid use may be associated with severe psychiatric adverse reactions such as euphoria, mania, psychosis with hallucinations or depression. Instruct caregivers and/or patients to seek medical advice if psychiatric symptoms develop. [see Warnings and Precautions (5.6)]

    Ophthalmic Adverse Reactions

    Inform patients or caregivers that ophthalmic effects such as cataract, glaucoma or central serous chorioretinopathy have been reported with prolonged use of high-dose corticosteroids. Instruct patients or caregivers to report any blurred vision or visual disturbances to their healthcare provider. [see Warnings and Precautions (5.7)]

    Gastrointestinal Adverse Reactions

    Discuss with patients or caregivers that use of corticosteroids may increase risk of gastrointestinal perforation in certain gastrointestinal disorders [see Warnings and Precautions (5.8)].

    Excretion of Granules

    ALKINDI SPRINKLE granules may sometimes be seen in stools since the center of the granule is not absorbed in the gut after the active substance has been released. Inform patients or caregivers that this does not mean the product is ineffective and they should not take another dose.

    ALKINDI SPRINKLE is manufactured for Eton Pharmaceuticals, Inc. by Glatt Pharmaceutical Services GmbH & Co. KG Werner-Glatt-Strasse 1, Binzen, Baden-Wuerttemberg, 79589, Germany,and is packaged by Delpharm Lille SAS, Parc d'Activités Roubaix-Est, 22 rue de Toufflers CS 50070, Lys Lez Lannoy, France.

    ALKINDI® is a registered trademark of Diurnal Limited.

    ALKINDI is covered by the following US patents: 9,649,280; 9,675,559; 9,717,740; and other patents in other countries internationally.

    ALKINDI SPRINKLE is distributed in the USA by Eton Pharmaceuticals, Inc. under license from Diurnal Limited.

  • MEDICATION GUIDE

    This Medication Guide has been approved by the U.S. Food and Drug AdministrationIssued:10/2020
    Medication Guide
    ALKINDI® SPRINKLE (ælˈkɪndi spr-en-kle)
    (hydrocortisone) oral granules

    Read this Medication Guide before you start giving ALKINDI SPRINKLE to your child, and each time your child gets a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your child’s medical condition or treatment.

    What is the most important information I should know about ALKINDI SPRINKLE?


    ALKINDI SPRINKLE may cause serious side effects, including:

    -     Adrenal gland problems. Not giving enough ALKINDI SPRINKLE or stopping ALKINDI SPRINKLE can cause serious and life-threating adrenal gland problems including death. Do not stop giving Alkindi Sprinkle without the advice of your healthcare provider. Tell your healthcare provider if your child has any of these symptoms:

         o loss of appetite                     o joint pain                         o low blood sugar
         o fatigue                                  o nausea                             o feeling lightheaded or dizzy
         o weakness                              o vomiting                         o dehydration

    Your healthcare provider will change the dose depending on your child’s size. During episodes of acute infections, surgery or major trauma, your healthcare provider may recommend increased doses of ALKINDI SPRINKLE or use of parenteral corticosteroid formulations instead.


    See “What are the possible side effects of ALKINDI SPRINKLE?” for more information about side effects.


    What is ALKINDI SPRINKLE?

    ALKINDI SPRINKLE contains a drug called hydrocortisone. Hydrocortisone belongs to a group of medicines known as corticosteroids. Hydrocortisone is a synthetic version of the hormone cortisol. Cortisol is made naturally by the adrenal glands in the body. ALKINDI SPRINKLE is a prescription medicine that contains hydrocortisone also called a corticosteroid. ALKINDI SPRINKLE (hydrocortisone) is a synthetic (man-made) corticosteroid used to replace the body’s cortisol when the adrenal glands do not make enough (adrenal insufficiency) in children from birth to 17 years ofage to treat adrenal insufficiency.

    Who should not take or be given ALKINDI SPRINKLE?


    Do not give your child ALKINDI SPRINKLE if they:

    • are allergic to hydrocortisone or any of the ingredients in ALKINDI SPRINKLE. See the end of this Medication Guide for a complete list of ingredients in ALKINDI SPRINKLE.
    • have any reaction like swelling or shortness of breath after being given ALKINDI SPRINKLE. Get medical help right away and tell your healthcare provider as soon as possible as these can be signs of an allergic reaction.

    What should I tell my healthcare provider before giving ALKINDI SPRINKLE?


    Before you give your child ALKINDI SPRINKLE, tell your healthcare provider about all of your child’s medical conditions, including if they:

    • are feeling unwell, or their body is under stress because of surgery or trauma. Your healthcare provider may need to increase the dose of ALKINDI SPRINKLE for a short period of time.
    • have a fever or infection.
    • have nausea, vomiting, or diarrhea.
    • are due for vaccinations. Taking ALKINDI SPRINKLE should not stop your child from being vaccinated. Tell your healthcare provider when your child is due for vaccinations.
    • are scheduled for surgery.
    • cannot swallow medicines by mouth or are fed through a nasogastric or gastric tube.
    • are pregnant or plan to become pregnant. It is not known if ALKINDI SPRINKLE will harm your child’s unborn baby. Talk to your child’s healthcare provider if your child is pregnant or plans to become pregnant.
    • are breastfeeding or plans to breastfeed. It is not known if ALKINDI SPRINKLE passes into the breast milk. You and your child’s healthcare provider should decide if your child will receive ALKINDI SPRINKLE while your child breastfeeds.

    Tell your healthcare provider about all the medicines your child takes, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

    Some medicines, food and drink can affect the way that ALKINDI SPRINKLE works and may mean that your healthcare provider needs to change your child’s dose of ALKINDI SPRINKLE.

    Especially tell your healthcare provider if your child:

    • takes medicines used to treat fungal infections such as itraconazole, posaconazole, and voriconazole.
    • takes medicines used to treat bacterial infections such as rifampicin, rifabutin, erythromycin, and clarithromycin.
    • takes medicines used to treat human immunodeficiency virus (HIV) infection and AIDS such as ritonavir, efavirenz, and nevirapine.
    • takes seizure medicines such as phenytoin, carbamazepine, oxcarbazepine, phenobarbital, and primidone.
    • takes estrogen.
    • takes warfarin
    • takes nonsteroidal anti-inflammatory medicines such as aspirin, ibuprofen.
    • takes cyclosporine
    • takes diabetes medicines
    • drinks grapefruit juice.

    Know the medicines your child takes. Keep a list of them to show your healthcare provider and pharmacist when your child gets a new medicine.

    How should I give ALKINDI SPRINKLE?

    • See the detailed Instructions for Use that comes with your ALKINDI SPRINKLE for information on how to give a dose of ALKINDI SPRINKLE the right way.
    • Give ALKINDI SPRINKLE exactly as prescribed by your healthcare provider.
    • Do not stop giving ALKINDI SPRINKLE without talking to your healthcare provider. See “What is the most important information I should know about ALKINDI SPRINKLE?”
    • Do not let your child chew or crush the granules. Do not let your child swallow the capsule.
    • Do not let the capsules get wet as this may make some of the granules stick to the capsule.
    • Your child may sometimes pass the ALKINDI SPRINKLE granules in their stools (bowel movement). It does not mean that ALKINDI SPRINKLE is not working. Do not give your child another dose of ALKINDI SPRINKLE.
    • ALKINDI SPRINKLE granules should not be given through a nasogastric tube because the granules may block the tube.
    • If your child takes too much ALKINDI SPRINKLE, call your healthcare provider right away or go to the nearest emergency room.

    What are the possible side effects of ALKINDI SPRINKLE?

    ALKINDI SPRINKLE may cause serious side effects, including:

    • See “What is the most important information I should know about ALKINDI SPRINKLE?”
      - Infections. Taking too much ALKINDI SPRINKLE can increase risk of infections. Tell your healthcare provider if your child has any of these symptoms:

         o fever                                              o stomach area (abdominal) pain
         o cough                                            o diarrhea
         o flu-like symptoms

    • Slowed growth in children. Taking too much ALKINDI SPRINKLE and taking it for long periods of time can affect your child’s growth. Tell your healthcare provider if you are worried about your child’s growth. Your healthcare provider will change the dose depending on your child’s size.
    • Cushing’s syndrome. Taking too much ALKINDI SPRINKLE and taking it for long periods of time can cause Cushing’s syndrome. Tell your healthcare provider if your child has any of these symptoms:

          o weight gain                             o high blood                                o swelling                              o muscle                           o feeling
                                                                sugar                                                                                          weakness                          depressed
          o slowed                                     o high blood                                o bruising                              o red round,                      o mood swings
             growth in                                    pressure                                       easily                                     face
             height

    • Weak, brittle, or soft bones. ALKINDI SPRINKLE can affect your child’s bones. Your healthcare provider will change the dose depending on your child’s size and will monitor your child’s growth and bones.
    • Changes in behavior. Your child’s behavior may change after starting or during treatment with ALKINDI SPRINKLE. Tell your healthcare provider right away if your child devlops any changes in behavior including:
      • strong feelings of happiness and excitement.
      • overexcited and overactivity.
      • loss of contact with reality, with feelings that are not real, and mental confusion.
      • depression.
    • Vision problems. Tell your healthcare provider if your child develops blurred vision or other vision problems during treatment with ALKINDI SPRINKLE. Your healthcare provider may have your child see an eye doctor.
    • Gastrointestinal problems. ALKINDI SPRINKLE can affect your child’s stomach or intestine. Tell your health care provider if your child has gastrointestinal illnesses such as stomach or intestinal ulcers, infections, gastrointestinal surgery.

    The most common side effects of ALKINDI SPRINKLE include:

         fluid retention                                        alteration in glucose tolerance              elevation in blood pressure
         behavioral and mood changes               increased appetite and weight
                                                                             gain


    These are not all the possible side effects of ALKINDI SPRINKLE. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

    How should I store ALKINDI SPRINKLE?

    • Store ALKINDI SPRINKLE at room temperature between 68°F to 77°F (20°C to 25°C).
    • Store in the original bottle to protect from light.
    • After the bottle has been opened, use the ALKINDI SPRINKLE capsules within 60 days.

    Keep ALKINDI and all medicines out of the reach of children.

    General information about the safe and effective use of ALKINDI SPRINKLE.

    Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ALKINDI SPRINKLE for a condition for which it was not prescribed. Do not give ALKINDI SPRINKLE to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about ALKINDI SPRINKLE that is written for health professionals.

    What are the ingredients in ALKINDI SPRINKLE?

    Active ingredient: hydrocortisone

    Inactive ingredients:

    granules: microcrystalline cellulose, hypromellose, magnesium stearate, ethyl cellulose.

    capsule: hypromellose

    printing ink: shellac, propylene glycol, concentrated ammonia solution.

    Manufactured by:

    Alkindi Sprinkle is manufactured for Eton Pharmaceuticals, Inc. by Glatt Pharmaceutical Services GmbH & Co. KG Werner-Glatt-Strasse 1, Binzen, Baden-Wuerttemberg,

    79589, Germany

    ALKINDI® is a registered trademark of Diurnal Limited.

    ALKINDI is covered by the following US patents: 9,649,280; 9,675,559; 9,717,740; and other patents in other countries internationally.

    For more information, go to www.alkindisprinkle.com or call 1-833-343-2500.

  • INSTRUCTIONS FOR USE

                                                                                                                                             Instructions for Use

                                                                                                                        ALKINDI® SPRINKLE(ælˈkɪndi spr-en-kle)
                                                                                                                                  (hydrocortisone) oral granules

    Read this Instructions for Use before you start using ALKINDI SPRINKLE, and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your child’s medical condition or treatment.

    Important information you need to know before giving ALKINDI SPRINKLE

    • ALKINDI SPRINKLE comes in a capsule that must be opened before use.
    • Do not let your child swallow the capsule. Small children may choke.
    • Do not let your child chew or crush the granules in the capsule.
    • Do not let the capsules get wet as this may make some of the granules stick to the capsule.
    • Your healthcare provider will decide the right dose of ALKINDI SPRINKLE for your child. Follow your healthcare provider’s instructions for the dose of ALKINDI SPRINKLE to give your child.
    • Ask your healthcare provider or pharmacist if you are not sure how to prepare or give the prescribed dose of ALKINDI SPRINKLE to your child.
    • Your child may sometimes pass the ALKINDI SPRINKLE granules in their stools (bowel movement). It does not mean that ALKINDI SPRINKLE is not working. Do not give your child another dose of ALKINDI SPRINKLE.

    Supplies needed to give ALKINDI SPRINKLE:

    • ALKINDI SPRINKLE capsule(s) for prescribed dose
    • 1 spoon
    • soft food such as yogurt or pureed fruit or sip of fluids such as water, milk, breastmilk or formula

    Preparing and giving ALKINDI SPRINKLE:

    Step 1: Check the expiration date on the ALKINDI SPRINKLE bottle. Do not use ALKINDI SPRINKLE after the expiration date on the bottle has passed.

    Step 2: Remove the prescribed dose of ALKINDI SPRINKLE capsules from the bottle.

    Step 3: Hold and Tap
    IMAGE-1
    Hold the capsule with the writing at the top. Tap the capsule to make sure the granules fall to the bottom.
    Step 4: Squeeze
    IMAGE-2
    Gently squeeze the bottom of the capsule to loosen the top of the capsule from the bottom.
    Step 5: Twist
    IMAGE-3 Carefully twist off the top of the capsule.

    Step 6: Giving ALKINDI SPRINKLE

    ALKINDI SPRINKLE can be given (a) with food onto a spoon, (b) without food onto a spoon, or (c) directly into the child’s mouth.

    Do not add the granules to a fluid before giving ALKINDI SPRINKLE because it can result in less than the full dose given and it may leave a bitter taste in the mouth.

    (a) With food onto a spoon
    IMAGE-4
    Pour all granules from each capsule directly onto a spoonful of cold or room temperature soft food (such as yogurt or fruit puree) and give right away.
    (b) Without food onto a spoon
    IMAGE-5

    Pour all granules directly onto a spoon and place them in the child’s mouth.
    (c) Directly onto the child’s tongue.
    IMAGE-6 Pour all granules that make up the prescribed dose directly onto the child’s tongue.

    Tap the capsule to make sure all granules are removed.

    The ALKINDI SPRINKLE granules should be given and swallowed within 5 minutes to avoid a bitter taste.

    Step 7: Give Fluids

    After giving ALKINDI SPRINKLE, give a sip of fluids such as water, milk, breastmilk or formula right away to make sure all granules are swallowed.

    Throwing Away (disposal of) ALKINDI SPRINKLE:

    Ask your pharmacist how to throw away medicines you no longer use.

    How should I store ALKINDI SPRINKLE?

    • Store ALKINDI SPRINKLE at room temperature between 68°F to 77°F (20°C to 25°C).
    • Store in the original bottle to protect from light.
    • After the bottle has been opened, use the ALKINDI SPRINKLE capsules within 60 days.

    Keep ALKINDI and all medicines out of the reach of children.

    Alkindi Sprinkle is manufactured for Eton Pharmaceuticals, Inc. by Glatt Pharmaceutical Services GmbH & Co. KG Werner-Glatt-Strasse 1, Binzen, Baden-Wuerttemberg, 79589, Germany

    ALKINDI® is a registered trademark of Diurnal Limited.

    ALKINDI is covered by the following US patents: 9,649,280; 9,675,559; 9,717,740; and other patents in other countries internationally.

    For more information, go to www.alkindisprinkle.com or call 1-833-343-2500.

    This Instructions for Use has been approved by the U.S. Food and Drug Administration.

    Issued: 10/2020

  • PRINCIPAL DISPLAY PANEL

    Alkindi Sprinkle (hydrocortisone) oral granules 0.5 mg - NDC: 71863-109-50 - 50 Tablets Carton Label

    Alkindi Sprinkle (hydrocortisone) oral granules 0.5 mg - NDC: <a href=/NDC/71863-109-50>71863-109-50</a> - 50 Tablets Carton Label

    Alkindi Sprinkle (hydrocortisone) oral granules 0.5 mg - NDC: 71863-109-50 - 50 Tablets Container Label

    Alkindi Sprinkle (hydrocortisone) oral granules 0.5 mg - NDC: <a href=/NDC/71863-109-50>71863-109-50</a> - 50 Tablets Container Label

    Alkindi Sprinkle (hydrocortisone) oral granules 1 mg - NDC: 71863-110-50 - 50 Tablets Carton Label

    Alkindi Sprinkle (hydrocortisone) oral granules 1 mg - NDC: <a href=/NDC/71863-110-50>71863-110-50</a> - 50 Tablets Carton Label

    Alkindi Sprinkle (hydrocortisone) oral granules 1 mg - NDC: 71863-110-50 - 50 Tablets Container Label

    Alkindi Sprinkle (hydrocortisone) oral granules 1 mg - NDC: <a href=/NDC/71863-110-50>71863-110-50</a> - 50 Tablets Container Label

    Alkindi Sprinkle (hydrocortisone) oral granules 2 mg - NDC: 71863-111-50 - 50 Tablets Carton Label

    Alkindi Sprinkle (hydrocortisone) oral granules 2 mg - NDC: <a href=/NDC/71863-111-50>71863-111-50</a> - 50 Tablets Carton Label

    Alkindi Sprinkle (hydrocortisone) oral granules 2 mg - NDC: 71863-111-50 - 50 Tablets Container Label

    Alkindi Sprinkle (hydrocortisone) oral granules 2 mg - NDC: <a href=/NDC/71863-111-50>71863-111-50</a> - 50 Tablets Container Label

    Alkindi Sprinkle (hydrocortisone) oral granules 5 mg - NDC: 71863-112-50 - 50 Tablets Carton Label

    Alkindi Sprinkle (hydrocortisone) oral granules 5 mg - NDC: <a href=/NDC/71863-112-50>71863-112-50</a> - 50 Tablets Carton Label

    Alkindi Sprinkle (hydrocortisone) oral granules 5 mg - NDC: 71863-112-50 - 50 Tablets Container Label

    Alkindi Sprinkle (hydrocortisone) oral granules 5 mg - NDC: <a href=/NDC/71863-112-50>71863-112-50</a> - 50 Tablets Container Label
  • INGREDIENTS AND APPEARANCE
    ALKINDI   SPRINKLE
    hydrocortisone granule
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 71863-109
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    Hydrocortisone (UNII: WI4X0X7BPJ) (Hydrocortisone - UNII:WI4X0X7BPJ) Hydrocortisone0.5 mg
    Inactive Ingredients
    Ingredient NameStrength
    MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)  
    HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    ETHYLCELLULOSE, UNSPECIFIED (UNII: 7Z8S9VYZ4B)  
    Product Characteristics
    Color    Score    
    ShapeCAPSULESize
    FlavorImprint Code INF;0;5
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 71863-109-501 in 1 CARTON09/29/2020
    150 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDANDA21387609/29/2020
    ALKINDI   SPRINKLE
    hydrocortisone granule
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 71863-110
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    Hydrocortisone (UNII: WI4X0X7BPJ) (Hydrocortisone - UNII:WI4X0X7BPJ) Hydrocortisone1 mg
    Inactive Ingredients
    Ingredient NameStrength
    MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)  
    HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    ETHYLCELLULOSE, UNSPECIFIED (UNII: 7Z8S9VYZ4B)  
    Product Characteristics
    Color    Score    
    ShapeCAPSULESize
    FlavorImprint Code INF;1;0
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 71863-110-501 in 1 CARTON09/29/2020
    150 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDANDA21387609/29/2020
    ALKINDI   SPRINKLE
    hydrocortisone granule
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 71863-111
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    Hydrocortisone (UNII: WI4X0X7BPJ) (Hydrocortisone - UNII:WI4X0X7BPJ) Hydrocortisone2 mg
    Inactive Ingredients
    Ingredient NameStrength
    MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)  
    HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    ETHYLCELLULOSE, UNSPECIFIED (UNII: 7Z8S9VYZ4B)  
    Product Characteristics
    Color    Score    
    ShapeCAPSULESize
    FlavorImprint Code INF;2;0
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 71863-111-501 in 1 CARTON09/29/2020
    150 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDANDA21387609/29/2020
    ALKINDI   SPRINKLE
    hydrocortisone granule
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 71863-112
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    Hydrocortisone (UNII: WI4X0X7BPJ) (Hydrocortisone - UNII:WI4X0X7BPJ) Hydrocortisone5 mg
    Inactive Ingredients
    Ingredient NameStrength
    MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)  
    HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    ETHYLCELLULOSE, UNSPECIFIED (UNII: 7Z8S9VYZ4B)  
    Product Characteristics
    Color    Score    
    ShapeCAPSULESize
    FlavorImprint Code INF;5;0
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 71863-112-501 in 1 CARTON09/29/2020
    150 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDANDA21387609/29/2020
    Labeler - Eton Pharmaceuticals, Inc. (080870465)

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