FDA Label for Alkindi Sprinkle

1 Indications And Usage

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

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:

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)].

5.1 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)]

7 Drug Interactions

Other

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.

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.

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 (T_max) 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 C_max (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.

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.

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 - 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).

12.1 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.

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:

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).

Spl Medguide

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 - 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 Gently squeeze the bottom of the capsule to loosen the top of the capsule from the bottom.

Step 5: Twist 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 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 Pour all granules directly onto a spoon and place them in the child’s mouth.

(c) Directly onto the child’s tongue. 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

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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 71863-109-50 - 50 Tablets Carton Label - alkindi 0pt5mg 50s carton label

Alkindi Sprinkle (hydrocortisone) oral granules 0.5 mg - NDC 71863-109-50 - 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 71863-110-50 - 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 71863-111-50 - 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 71863-112-50 - 50 Tablets Container Label