Established efficacy and safety based on clinical evidence1,2
Supported by 6 clinical studies (adults and pediatric patients), ALKINDI SPRINKLE1,3:
- Achieved desired clinical outcomes with increases in serum cortisol in pediatric patients
- Bioequivalent to hydrocortisone tablet and similar bioavailability to IV hydrocortisone
- No large declines or accelerations in growth were reported for the patients who continued in the ~2.5-year study period, and no adrenal crisis or trends were seen that might indicate over- or undertreatment
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Six clinical studies have been conducted using ALKINDI SPRINKLE, including the first and only phase 3, open-label study for primary adrenal insufficiency (AI) in neonates to children <6 years of age.1,2
Overall, ALKINDI SPRINKLE was well tolerated, with a safety profile similar to that seen for hydrocortisone tablet when used as a replacement therapy for AI. There were no serious adverse reactions to ALKINDI SPRINKLE observed in any of the 6 clinical studies conducted and no episodes of adrenal crisis observed in long-term follow-up over ~2.5 years.1
Phase 3 Study
ALKINDI SPRINKLE achieved clinically relevant increases in serum cortisol3
All pediatric age groups studied experienced clinically relevant serum cortisol increases in an open-label phase 3 study (overall P<0.0001).3
Cortisol Levels Following ALKINDI SPRINKLE Administration in All Patients1,3a
Graphs based on Neumann et al, 2018.
aEach color is representative of a different child.3
Median hydrocortisone doses (mg/m2) in cohorts (single morning dose)1:
- Cohort 1: 3.97 mg/m2
- Cohort 2: 5.06 mg/m2
- Cohort 3: 8.76 mg/m2
Patients in cohorts 1 and 2 achieved a similar rise of cortisol. A higher peak cortisol level was seen with patients in cohort 3 due to higher dosing.3
ALKINDI SPRINKLE Achieved a Median Peak Cortisol Level of 19.40 µg/dL at 60 Minutes Post Dose1bc
bEach data point is representative of a different child.1
cGraph shading represents the normal peak cortisol ranges for healthy children.3-5
The median peak cortisol level across cohorts was comparable to the normal peak cortisol ranges for healthy children. The levels of cohort 3 may be variable due to the immaturity of gastrointestinal and metabolic processes in neonates3,6
ALKINDI SPRINKLE was studied as a hydrocortisone replacement dose in newborns and children <6 years old1
A phase 3, open-label study was conducted to evaluate safety and efficacy.1
Intervention1
ALKINDI SPRINKLE granules 0.5 mg, 1 mg, 2 mg, and 5 mg
Population1
3 cohorts of neonates, infants, and children <6 years of age with AI due to either congenital adrenal hyperplasia (CAH), primary adrenal failure, or hypopituitarism.
- Cohort 1: 12 patients between ≥2 years and <6 years
- Cohort 2: 6 patients between ≥28 days to <2 years
- Cohort 3: 6 neonates between birth to <28 days
Intermittent sampling1
Blood
Study Design1
Primary Endpoint1
- Maximum levels of serum cortisol concentration up to 240 minutes after intake of ALKINDI SPRINKLE, using study samples taken at 0, 60, and 240 minutes post dose
Secondary Endpoints1
- Serum cortisol concentration up to 6 hours after intake of ALKINDI SPRINKLE
- Palatability of ALKINDI SPRINKLE
- PK parameters estimated in the population PK analysis
Safety Endpoint1
- Serious or nonserious adverse events and vital signs
- Male and female children less than 6 years of age1
- Diagnosis of AI as confirmed by an inappropriately low cortisol level1
- Receiving appropriate adrenocortical replacement therapy (hydrocortisone ± fludrocortisone)1
- Adequately hydrated and nourished1
- Clinically evident acute AI (adrenal crisis)1
- Inability of child to take oral therapy1
- Concomitant therapy (other than that required to treat AI, vitamin D, fluoride, thyroxine, and growth hormone)1
- Patients with clinical signs of acute infection or fever on day 11
The cause of AI was CAH in 23 of the 24 patients (95.8%). One patient in cohort 2 had hypopituitarism.1
Summary of Patient Demographics3
| Cohort 1 (n=12) |
Cohort 2 (n=6) |
Cohort 3 (n=6) |
Overall (N=24) |
|
|---|---|---|---|---|
| CHARACTERISTIC | ||||
| Mean (SD) age, weeks | 171.7 (49.2) | 63.9 (30.8) | 3.2 (0.5) | 102.6 (82.6) |
| Median (range) age, weeks | 171.0 (106.3, 244.0) | 70.9 (17.7, 94.9) | 3.3 (2.3, 3.7) | 100.6 (2.3, 244.0) |
| Male, % | 7 (58.3) | 4 (66.7) | 2 (33.3) | 13 (54.2) |
| ETHNIC ORIGIN | ||||
| White, n (%) | 12 (100) | 6 (100) | 6 (100) | 24 (100) |
| Mean (SD) body mass index (kg/m2) | 17.4 (1.7) | 17.7 (1.5) | 12.7 (1.8) | 16.3 (2.6) |
| Median (ranges) body mass index (kg/m2) | 17.4 (14.6, 20.6) | 17.3 (16.4, 20.5) | 12.3 (11.0, 15.1) | 16.6 (11.0, 20.6) |
| Mean body mass index SDS (SD) | 1.02 (1.0) | 0.71 (0.9) | a | |
| Median (ranges) body mass index SDS | 0.96 (-0.7, 2.1) | -0.31 (-1.3, 2.0) | a | 0.06 (-1.3, 2.1) |
| Mean (SD) body surface area (m2) | 0.64 (0.08) | 0.44 (0.08) | 0.22 (0.03) | 0.49 (0.19) |
| Median (ranges) body surface area (m2) | 0.64 (0.5, 0.8) | 0.49 (0.3, 0.5) | 0.22 (0.2, 0.3) | 0.51 (0.2, 0.8) |
| CONCOMITANT MEDICATIONS | ||||
| n (%) | 12 (100) | 6 (100) | 6 (100) | 24 (100) |
| Vitamins | 0 | 1 (16.7) | 4 (66.7) | 5 (20.8) |
| Fludrocortisone | 12 (100) | 5 (83.3) | 6 (100) | 23 (95.8) |
| Thyroxine | 0 | 1 (16.7) | 0 | 1 (4.2) |
| CONCURRENT CONDITIONS | ||||
| n (%) | ||||
| Virilizationb | 1 (8.3) | 0 | 4 (66.7) | 5 (20.8) |
| Hypothyroidism | 0 | 1 (1.67) | 0 | 1 (4.2) |
| Rhinitis | 0 | 1 (16.7) | 0 | 1 (4.2) |
| Skin infection | 1 (8.3) | 0 | 0 | 1 (4.2) |
| Renal hypoplasia | 0 | 0 | 1 (16.7) | 1 (4.2) |
| Atopic dermatitis | 1 (8.3) | 0 | 0 | 1 (4.2) |
aBMI-SDS not calculable due to missing reference data in newborns.
bVirilization of the female genitalia according to Prader stage II-IV.
Dose Characteristics by Cohort1,3
| Cohort 1 | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ≥2 years and <6 years (n=12) | ||||||||||||
| ALKINDI SPRINKLE Morning Dose Taken |
2.5 | 2.5 | 2 | 2 | 2.5 | 3 | 2.5 | 2 | 2.5 | 2.5 | 4 | 2.5 |
| Dose per BSA (mg/m2) |
4.167 | 3.676 | 3.030 | 2.632 | 4.717 | 4.839 | 4.098 | 3.509 | 3.846 | 4.808 | 5.128 | 3.731 |
| Cortisol @ 60 min (μg/dL) |
18.17 | 15.37 | 17.79 | 16.05 | 25.29 | 19.92 | 23.37 | 19.00 | 20.77 | 23.15 | 21.77 | 19.80 |
| Cohort 2 | ||||||
|---|---|---|---|---|---|---|
| ≥28 days to <2 years (n=6) | ||||||
| ALKINDI SPRINKLE Morning Dose Taken |
2 | 2.5 | 2 | 2 | 2 | 2.5 |
| Dose per BSA (mg/m2) |
4.082 | 5.208 | 5.405 | 6.250 | 4.000 | 4.902 |
| Cortisol @ 60 min (μg/dL) |
16.17 | 22.05 | 15.21 | 18.39 | 13.09 | 14.45 |
| Cohort 3 | ||||||
|---|---|---|---|---|---|---|
| 0 to <28 days (n=6) | ||||||
| ALKINDI SPRINKLE Morning Dose Taken |
2 | 2 | 2 | 2 | 2 | 1 |
| Dose per BSA (mg/m2) |
9.524 | 7.692 | 10.562 | 8.000 | 10.526 | 4.348 |
| Cortisol @ 60 min (μg/dL) |
32.85 | 12.55 | 49.39 | 42.35 | 52.38 | 14.78 |
No serious TEAEs or discontinuations were associated with ALKINDI SPRINKLE treatment1,3
No serious treatment-emergent adverse events (TEAEs) were reported, and there were no TEAEs with a suspected causal relationship to ALKINDI SPRINKLE.1,3
- None of the patients discontinued ALKINDI SPRINKLE for any reason
- 12 TEAEs were reported by 8 (33.3%) patients overall: 33.3% in each cohort
Summary of TEAEs by SOC and Preferred Term1
| Cohort 1 (n=12) |
Cohort 2 (n=6) |
Cohort 3 (n=6) |
Overall (N=24) |
|
|---|---|---|---|---|
| SOC: Preferred Term | Number of events/subjects(% of subjects in cohort) | |||
| GASTROINTESTINAL DISORDERS |
3/3 (25.0) | 1/1 (16.7) | 3/2 (33.3) | 7/6 (25.0) |
| Diarrhea | 2/2 (16.7) | 1/1 (16.7) | 0 | 3/3 (12.5) |
| Vomiting | 1/1 (8.3) | 0 | 1/1 (16.7) | 2/2 (8.3) |
| Infantile spitting up | 0 | 0 | 2/1 (16.7) | 2/1 (4.2) |
| SKIN AND SUBCUTANEOUS TISSUE DISORDERS |
3/2 (16.7) | 1/1 (16.7) | 0 | 4/3 (12.5) |
| Rash | 1/1 (8.3) | 1/1 (16.7) | 0 | 2/2 (8.3) |
| Hyperhidrosis | 2/1 (8.3) | 0 | 0 | 2/1 (4.2) |
| GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS |
1/1 (8.3) | 0 | 0 | 1/1 (4.2) |
| Fatigue | 1/1 (8.3) | 0 | 0 | 1/1 (4.2) |
Extension Study
Long-term ALKINDI SPRINKLE data demonstrated normal patient growth and development trends1*
Appropriate increases in growth were observed with no consistent trends suggesting growth acceleration or suppression in ~95% (17/18) of patients (the exception was 1 patient with hypopituitarism and growth deficiency).1
~95% (17/18) of patients experienced
growth rate patterns that were in the ranges of healthy children, with no
adverse progression of sexual development reported by patients with CAH.1
No large declines or accelerations in
growth were reported for the patients who continued in the ~2.5-year follow-up study, and
no trends were seen that might indicate over- or
undertreatment.1
100% (12/12) of patients who completed
the study achieved appropriate cortisol levels and did not experience an
adrenal crisis during the study period (~2.5 years).1ALKINDI SPRINKLE was evaluated for long-term safety in neonates and children over a period of 2.5 years1
A phase 3, open-label, long-term follow-up study of safety and biochemical disease control with ALKINDI SPRINKLE was conducted in patients who were previously enrolled in the Infacort 003 study.1
Intervention1
ALKINDI SPRINKLE granules 0.5 mg, 1 mg, 2 mg, and 5 mg
Population1
18 neonates, infants, and children with congenital adrenal hyperplasia (CAH) and AI
Intermittent sampling1
Blood
The standardized protocol for follow-up included an initial visit, monthly visits for the first 2 months of treatment, followed by visits every 3 months thereafter. Patients could continue to be treated in this study until they met the study withdrawal criteria, until ALKINDI SPRINKLE was commercially available locally, or until the study was discontinued.1
- Nature and occurrence of serious adverse events and adverse events observed throughout the study
- Standard deviation score for height and weight
- Cortisol (all participants) and adrenal androgen levels from dried blood spot samples (17-hydroxyprogesterone [17-OHP], androstenedione [A4], testosterone) in CAH participants only
- Male and female children less than 6 years of age1
- Diagnosis of AI as confirmed by an inappropriately low cortisol level1
- Receiving appropriate adrenocortical replacement therapy (hydrocortisone ± fludrocortisone)1
- Adequately hydrated and nourished1
- Clinically evident acute AI (adrenal crisis)1
- Inability of child to take oral therapy1
- Patients with clinical signs of acute infection or fever on inclusion1
The cause of AI was CAH in 17 (94.4%) of the 18 patients. One patient in cohort 2 had hypopituitarism.1
Summary of Patient Demographics1
| Cohort 1 (n=9) |
Cohort 2 (n=6) |
Cohort 3 (n=3) |
Overall (N=18) |
|
|---|---|---|---|---|
| VARIABLE | ||||
| AGE, (DAYS) | ||||
| Mean (SD) | 1546.4 (388.34) | 707.2 (214.72) | 75.7 (60.25) | 1021.6 (650.84) |
| Median | 1316.0 | 747.5 | 46.0 | 1000.0 |
| Range | 1077 to 2084 | 394 to 923 | 36 to 145 | 36 to 2084 |
| SEX, n (%) | ||||
| Female | 4 (44.4) | 2 (33.3) | 2 (66.7) | 8 (44.4) |
| Male | 5 (55.6) | 4 (66.7) | 1 (33.3) | 10 (55.6) |
| ETHNICITY, n (%) | ||||
| Not Hispanic or Latino | 9 (100.0) | 6 (100.0) | 3 (100.0) | 18 (100.0) |
| ETHNIC ORIGIN, n (%) | ||||
| White (Caucasian) | 9 (100.0) | 6 (100.0) | 3 (100.0) | 18 (100.0) |
| BMI (kg/m2) | ||||
| Mean (SD) | 17.01 (2.356) | 17.85 (1.384) | 15.35 (1.909) | 17.02 (2.083) |
| Median | 16.42 | 17.53 | 16.00 | 16.83 |
| Range | 13.7 to 22.1 | 16.4 to 20.1 | 13.2 to 16.8 | 13.2 to 22.1 |
| BSA (m2) | ||||
| Mean (SD) | 0.716 (0.0809) | 0.536 (0.0679) | 0.269 (0.0648) | 0.582 (0.1803) |
| Median | 0.708 | 0.563 | 0.271 | 0.594 |
| Range | 0.58 to 0.84 | 0.44 to 0.60 | 0.20 to 0.33 | 0.20 to 0.84 |
Average Dose and Dose Distribution of Hydrocortisone (Morning - Afternoon - Night) by Age Group7
| Children aged 0-3 months |
Children aged 4 months to <2 years |
Children aged 2 to <4 years |
Children aged 4 to 8.4 years |
|
|---|---|---|---|---|
| Mean Hydrocortisone Dose (mg) |
1.5 - 1.5 - 1.5 | 2.3 - 1.1 - 1.6 | 2.6 - 1.2 - 2.6 | 3.2 - 1.3 - 4.6 |
| Average Dose Distribution (%) |
33.3 - 33.3 - 33.3 | 46 - 22 - 32 | 40.6 - 18.7 - 40.6 | 36 - 14 - 50 |
ALKINDI SPRINKLE was well tolerated over a treatment period of approximately 2.5 years1
There were no treatment-emergent adverse events (TEAEs) leading to withdrawal from the study, and no TEAEs with a suspected causal relationship to ALKINDI SPRINKLE.1
- No cases of adrenal crisis were reported
- 193 TEAEs were reported by 14 (77.8%) patients overall
- 9 serious TEAEs were reported by 3 patients
Summary of TEAEs Reported in 2 or More Patients1
| Cohort 1 (n=9) |
Cohort 2 (n=6) |
Cohort 3 (n=3) |
Overall (N=18) |
|
|---|---|---|---|---|
| SOC: Preferred Term | Number of events/subjects(% of subjects in cohort) | |||
| INFECTIONS AND INFESTATIONS | 24/5 (55.6) | 42/5 (83.3) | 16/3 (100.0) | 82/13 (72.2) |
| Gastroenteritis | 7/4 (44.4) | 2/2 (33.3) | 6/3 (100.0) | 15/9 (50.0) |
| Viral upper respiratory tract infection | 3/2 (22.2) | 16/3 (50.0) | 2/2 (66.7) | 21/7 (38.9) |
| Viral infection | 4/4 (44.4) | 1/1 (16.7) | 1/1 (33.3) | 6/6 (33.3) |
| Conjunctivitis | 1/1 (11.1) | 4/3 (50.0) | 1/1 (33.3) | 6/5 (27.8) |
| Otitis media viral | 1/1 (11.1) | 1/1 (16.7) | 1/1 (33.3) | 3/3 (16.7) |
| Tonsillitis | 1/1 (11.1) | 0 | 2/2 (66.7) | 3/3 (16.7) |
| Bronchitis | 0 | 6/2 (33.3) | 0 | 6/2 (11.1) |
| Respiratory tract infection | 1/1 (11.1) | 1/1 (16.7) | 0 | 2/2 (11.1) |
| Rhinitis | 0 | 2/2 (33.3) | 0 | 2/2 (11.1) |
| Pharyngitis | 2/2 (22.2) | 0 | 0 | 2/2 (11.1) |
| GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS |
11/4 (44.4) | 18/3 (50.0) | 16/3 (100.0) | 45/10 (55.6) |
| Pyrexia | 11/4 (44.4) | 18/3 (50.0) | 16/3 (100.0) | 45/10 (55.6) |
| GASTROINTESTINAL DISORDERS | 31/5 (55.6) | 0 | 5/3 (100.0) | 36/8 (44.4) |
| Vomiting | 10/5 (55.6) | 0 | 4/2 (66.7) | 14/7 (38.9) |
| Diarrhea | 5/1 (11.1) | 0 | 1/1 (33.3) | 6/2 (11.1) |
| INJURY, POISONING, AND PROCEDURAL COMPLICATIONS |
3/2 (22.2) | 2/2 (33.3) | 1/1 (33.3) | 6/5 (27.8) |
| SURGICAL AND MEDICAL PROCEDURES |
0 | 0 | 3/3 (100.0) | 3/3 (16.7) |
| Genitourinary operation | 0 | 0 | 2/2 (66.7) | 2/2 (11.1) |
| INVESTIGATIONS | 3/1 (11.1) | 3/1 (16.7) | 0 | 6/2 (11.1) |
| Body temperature increased | 3/1 (11.1) | 3/1 (16.7) | 0 | 6/2 (11.1) |
| MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS | 4/2 (22.2) | 0 | 0 | 4/2 (11.1) |
| SKIN AND SUBCUTANEOUS TISSUE DISORDERS |
2/1 (11.1) | 1/1 (16.7) | 0 | 3/2 (11.1) |
Bioequivalence Study to HC Tablet
ALKINDI SPRINKLE demonstrated bioequivalence to immediate-release hydrocortisone1
ALKINDI SPRINKLE 10 mg had a similar PK profile to hydrocortisone 10-mg tablet.1,8
Comparison of Mean Serum Cortisol Concentrations8
|
|
|---|---|
| TIME (h) |
-
Oral hydrocortisonetablet 10 mg
-
ALKINDISPRINKLE 10 mg
-
ALKINDISPRINKLE 5 mg
-
ALKINDISPRINKLE 2 mg
-
ALKINDISPRINKLE 0.5 mg
Summary of Bioequivalence1
| ALKINDI SPRINKLE 10 mg |
Hydrocortisone tablet 10 mg |
Ratio of ALKINDI
SPRINKLE: Hydrocortisone, % (90% Cl) |
|
|---|---|---|---|
| PARAMETER | Geometric Mean | Geometric Mean Ratio | |
| Cmax (μg/dL) | 20.51 | 21.66 | 3.43 (3.03-3.89) |
| AUC0-inf (h*μg/dL) | 58.06 | 57.47 | 3.66 (3.46-3.88) |
| Median | Median Difference (95% CI) | ||
| tmax (h) | 0.75 | 1.00 | 0.0 (−0.50 to 0.25) |
ALKINDI SPRINKLE was evaluated for bioequivalence to hydrocortisone 10-mg tablet1
A phase 1, single-center, open-label, randomized, 5-way crossover study was conducted to compare PK data and evaluate dose proportionality.1
Intervention1
- ALKINDI SPRINKLE granules 0.5 mg, 2 mg, 5 mg, and 10 mg (two 5-mg capsules)
- Hydrocortisone tablet 10 mg
Population1
16 dexamethasone-suppressed, healthy, adult male participants
Intermittent sampling1
Blood
Study Design1,8
- Maximum concentration (Cmax)
- Time at which Cmax occurs (tmax)
- Area under the concentration-time curve extrapolated to infinity (AUC0-inf)
The safety profile for ALKINDI SPRINKLE was shown to be equivalent to hydrocortisone tablet1
There were no serious treatment-emergent adverse events (TEAEs) or unexpected serious adverse reactions reported.1
- 7 mild TEAEs were reported by 5 (31.3%) participants following administration of ALKINDI SPRINKLE or hydrocortisone tablet during the study
There did not appear to be any dose-related changes in TEAE profiles between ALKINDI SPRINKLE and hydrocortisone.1
Summary of TEAEs by SOC and Preferred Term1
| Events/Subjects (%) | ||||||
|---|---|---|---|---|---|---|
| ALKINDI SPRINKLE | Hydrocortisone | Overall (N=16) |
||||
| 0.5 mg (N=16) |
2 mg (N=16) |
5 mg (N=16) |
10 mg (N=16) |
10 mg (N=16) |
||
| SOC: Preferred Term | ||||||
| GASTROINTESTINAL DISORDERS | ||||||
| Abdominal pain | 0 | 0 | 0 | 1/1 (6.3) | 0 | 1/1 (6.3) |
| Hypoesthesia oral | 0 | 0 | 0 | 2/2 (12.5) | 0 | 2/2 (12.5) |
| Nausea | 1/1 (6.3) | 0 | 0 | 0 | 0 | 1/1 (6.3) |
| NERVOUS SYSTEM DISORDERS | ||||||
| Dysgeusia | 0 | 1/1 (6.3) | 0 | 0 | 0 | 1/1 (6.3) |
| Headache | 0 | 0 | 0 | 1/1 (6.3) | 0 | 1/1 (6.3) |
| VASCULAR DISORDERS | ||||||
| Flushing | 0 | 0 | 0 | 0 | 1/1 (6.3) | 1/1 (6.3) |
Bioequivalence Study to HC Tablet & Injection
ALKINDI SPRINKLE had a similar PK profile and bioavailability to tablet formulation of hydrocortisone1
ALKINDI SPRINKLE 20 mg was bioequivalent to hydrocortisone 20-mg tablet formulations.1
- The geometric least-squares mean 90% CI for the ratios of Cmax, AUC0-t, and AUC0-inf fell within 80% to 125%
ALKINDI SPRINKLE 20 mg was 87% bioavailable compared with hydrocortisone IV.1
- A median difference of <10 minutes was seen between the tmax for ALKINDI SPRINKLE vs hydrocortisone tablets
ALKINDI SPRINKLE was evaluated for bioequivalence to hydrocortisone 20-mg tablet and IV injection1
A phase 1, single-center, open-label, partially randomized, single-dose, 5-way crossover study was conducted to build a model of hydrocortisone metabolism and evaluate the pharmacokinetics, oral bioavailability, and relationship to metabolic parameters.1
Intervention1
- ALKINDI SPRINKLE granules 20 mg (four 5-mg capsules)
- Hydrocortisone tablet 20 mg
- Hydrocortisone 20 mg as 0.2 mL (100 mg/mL) bolus IV injection
Population1
14 dexamethasone-suppressed, healthy, adult male participants
Intermittent sampling1
Blood, saliva, and urine
Study Design1
- Total serum cortisol: concentration-time data
- Unadjusted data (noncompartmental pharmacokinetics)
- Maximum concentration (Cmax)
- Time at which Cmax occurs (tmax)
- Area under the serum concentration-time curve from time 0 to time t (AUC0-t)
- Baseline adjusted data (noncompartmental and compartmental pharmacokinetics)
- Maximum concentration (Cmax)
- Time at which Cmax occurs (tmax)
- Area under the serum concentration-time curve from time 0 to time t (AUC0-t)
- Area under the concentration-time curve extrapolated to infinity (AUC0-inf)
No TEAEs were associated with the administration of ALKINDI SPRINKLE1
There were no serious treatment-emergent adverse events (TEAEs) or unexpected serious adverse reactions reported.1
- 9 mild TEAEs were reported by 6 (42.9%) participants during the study with administered treatments other than ALKINDI SPRINKLE
No TEAEs were reported following ALKINDI SPRINKLE administration. There was little difference in the TEAE profiles observed, with 1 participant reporting a TEAE either when no treatment was administered or following treatment with dexamethasone, hydrocortisone tablet, or hydrocortisone IV.1
Summary of TEAEs by SOC and Preferred Term1
| Events/Subjects (%) | ||||||
|---|---|---|---|---|---|---|
| Study Perioda | ||||||
| 1 | 2 | 3-4 | 5 | Overall (N=14) | ||
| IMP: Hydrocortisone 20 mg | ||||||
| No Treatment (N=14) | Dexamethasone (N=14) | Oral ALKINDI SPRINKLE (N=14) | Oral Tablet (N=14) |
IV Solution (N=14) |
||
| SOC: Preferred Term | ||||||
| EYE DISORDERS | ||||||
| Vision blurred | 0 | 1/1 (7.1) | 0 | 0 | 0 | 1/1 (7.1) |
| GASTROINTESTINAL DISORDERS |
||||||
| Dyspepsia | 0 | 0 | 0 | 1/1 (7.1) | 0 | 1/1 (7.1) |
| GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS |
||||||
| Fatigue | 0 | 0 | 0 | 0 | 1/1 (7.1) | 1/1 (7.1) |
| Pyrexia | 1/1 (7.1) | 0 | 0 | 0 | 0 | 1/1 (7.1) |
| INFECTIONS AND INFESTATIONS |
||||||
| Nasopharyngitis | 1/1 (7.1) | 1/1 (7.1) | 0 | 0 | 0 | 2/2 (14.3) |
| NERVOUS SYSTEM DISORDERS |
||||||
| Headache | 1/1 (7.1) | 1/1 (7.1) | 0 | 0 | 0 | 2/2 (14.3) |
| PSYCHIATRIC DISORDERS | ||||||
| Mood swings | 0 | 0 | 0 | 0 | 1/1 (7.1) | 1/1 (7.1) |
aIn study periods 2-5, each patient received dexamethasone 1 mg (to suppress endogenous cortisol production) at approximately 10 pm on day 1 and 6 am and 12 pm on day 2.
Fasted/Fed Bioequivalence Study
ALKINDI SPRINKLE demonstrated bioequivalence and bioavailability to Cortef®1
ALKINDI SPRINKLE 20-mg granules had comparable bioequivalence and bioavailability when administered vs Cortef tablets in fasted and fed states.1
Summary of Statistical Analysis of Relative Bioavailability1
| ALKINDI SPRINKLE/Cortef20 mg Ratio (90% CI) | ||
|---|---|---|
| PARAMETER | Part 1: Fasted (n=24) | Part 2: Fed (n=24) |
| Cmax (μg/dL) | 3.97 (3.70-4.26) | 3.28 (3.01-3.57) |
| AUC0-t (h*μg/dL) | 3.43 (3.19-3.69) | 3.84 (3.64-4.05) |
| AUC0-inf (h*μg/dL) | 3.42 (3.17-3.68) | 3.79 (3.61-3.98)a |
| Median Difference (95% CI) | ||
| tmax (h) | –0.38 (–0.50 to –0.25) | –0.25 (–0.75 to 0.25) |
an=23.
ALKINDI SPRINKLE 20 mg was bioequivalent to the Cortef 20-mg tablet.1
- The 90% CI for the ratios of Cmax, AUC0-t, and AUC0-inf fell within 80% to 125%
- A median difference of 15 minutes was seen between the tmax for ALKINDI SPRINKLE vs Cortef tablets
ALKINDI SPRINKLE was evaluated for bioequivalence to Cortef 20-mg tablet1
A phase 1, 2-part, single-center, open-label, randomized, single-dose, 2-period, crossover, bioequivalence study was conducted in the fasted and fed states.1
Intervention1
- ALKINDI SPRINKLE granules 20 mg (four 5-mg capsules)
- Cortef tablet 20 mg
Population1
51 dexamethasone-suppressed, healthy, adult male and female participants
Intermittent sampling1
Blood
Each part (1 and 2) comprised1:
- A prestudy screen (within 28 days before first administration)
- 2 treatment periods (where ALKINDI SPRINKLE and Cortef were administered in a randomized sequence)
- Poststudy follow-up
Study Design1
- The primary endpoint was the assessment of the following PK parameters:
- Area under the serum concentration-time curve from time 0 to time t (AUC0-t)
- Area under the serum concentration-time curve from time 0 to infinity (AUC0-inf)
- Maximum serum concentration (Cmax) for serum cortisol following ALKINDI SPRINKLE and Cortef administration
- Time to maximum concentration (tmax) for serum cortisol as specified by the study protocol
No serious TEAEs or discontinuations related to ALKINDI SPRINKLE treatment1
There were no serious adverse events, treatment-emergent adverse events (TEAEs) leading to withdrawal from the study, or TEAEs with a suspected causal relationship to any study medication.1
- 7 TEAEs were reported by 5 (9.8%) participants overall
Summary of TEAEs1
| Part 1: Fasted | Part 2: Fed | ||||||
|---|---|---|---|---|---|---|---|
| |
ALKINDI SPRINKLE (n=25) | Cortef (n=25) | Overall (N=26) | ALKINDI SPRINKLE (n=25) | Cortef (n=25) | Overall (N=25) | Total (N=51) |
| NUMBER OF TEAEs | 1 | 1 | 2 | 3 | 2 | 5 | 7 |
| PARTICIPANTS REPORTING, n (%) | |||||||
| TEAE | 1 (4.0) | 1 (4.0) | 1 (3.8) | 2 (8.0) | 2 (8.0) | 4 (16.0) | 5 (9.8) |
| Serious TEAE | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| TEAE leading to withdrawal | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| PARTICIPANTS WITH TEAE BY SEVERITY, n (%) | |||||||
| Mild | 1 (4.0) | 1 (4.0) | 1 (3.8) | 2 (8.0) | 2 (8.0) | 4 (16.0) | 5 (9.8) |
| Moderate | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Severe | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| PARTICIPANTS WITH TEAE BY RELATIONSHIP TO STUDY INTERVENTION, n (%) | |||||||
| Related to study intervention only | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Related to dexamethasone only | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Related to both, study intervention and dexamethasone | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Unrelated to study intervention or dexamethasone | 1 (4.0) | 1 (4.0) | 1 (3.8) | 2 (8.0) | 2 (8.0) | 4 (16.0) | 5 (9.8) |
Bioequivalence Study to Method of Administration
ALKINDI SPRINKLE 5 mg was found to be bioequivalent whether administered as dry granules directly on the back of the tongue or sprinkled onto soft food or yogurt.1
- The 90% CI for the ratios of Cmax, AUC0-t, and AUC0-inf fell within 80% to 125%
Summary of Statistical Analysis of Relative Bioavailability1
| ALKINDI SPRINKLE 5 mg Ratio (90% CI) | |||
|---|---|---|---|
| Soft Food/Back of the Tongue (N=18) |
Yogurt/Back of the Tongue (N=18) |
||
| PARAMETER | Geometric Mean Ratio | ||
| Cmax (μg/dL) | 3.61 (3.41-3.83) | 3.60 (3.42-3.80) | |
| AUC0-t (h*μg/dL) | 3.56 (3.42-3.70) | 3.75 (3.44-4.08) | |
| AUC0-inf (h*μg/dL) | 3.56 (3.42-3.71) | 3.74 (3.43-4.07) | |
| Median Difference (95% CI) | |||
| tmax (h) | 0.13 (0.00-0.25) | 0.13 (0.00-0.25) | |
Cmax and AUC results obtained using ANOVA with fixed effects for sequence, period, treatment, and patient (sequence).
tmax results obtained using the Wilcoxon signed-rank test and Hodges-Lehman test.
By determining bioequivalence, whether sprinkled on tongue or food, this study confirmed that patients could successfully take ALKINDI SPRINKLE even if they are not1:
- Eating solid foods
- Capable of swallowing a pill
ALKINDI SPRINKLE administered directly on the tongue vs in food was evaluated for bioavailability1
A phase 1, single-center, open-label, randomized, single-dose, 3-period crossover study was conducted to evaluate the bioavailability of administration as sprinkles on food compared with direct administration to the back of the tongue.1
Intervention1
ALKINDI SPRINKLE granules 5 mg
Population1
18 dexamethasone-suppressed, healthy, adult male participants
Intermittent sampling1
Blood
The study comprised a prestudy screen (within 28 days before first administration), followed by 3 treatment periods and a poststudy follow-up.1
- The PK parameters area under the serum concentration-time curve from time 0 to time t (AUC0-t), area under the concentration-time curve extrapolated to infinity (AUC0-inf), and maximum concentration (Cmax) of ALKINDI SPRINKLE administered as sprinkles with yogurt and soft food compared with ALKINDI SPRINKLE administered as dry granules to the back of the tongue
- Time at which Cmax occurs (tmax) of ALKINDI SPRINKLE administered as sprinkles with yogurt and soft food compared with ALKINDI SPRINKLE administered as dry granules to the back of the tongue
In this study no safety concerns were identified regardless of method of ALKINDI SPRINKLE administration1
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ANOVA=analysis of variance; AUC=area under the concentration-time curve; AUC0-inf=area under the concentration-time curve extrapolated to infinity; AUC0-t=area under the serum concentration-time curve from time 0 to time t; BMI=body mass index; BSA=body surface area; CI=confidence interval; Cmax=maximum concentration; DEX=dexamethasone; HC=hydrocortisone; IMP=investigational medicinal product; PK=pharmacokinetic; SD=standard deviation; SDS=standard deviation score; SOC=system organ class; tmax=time at which Cmax occurs.
*This study was designed as a safety study to evaluate the long-term use of ALKINDI SPRINKLE in routine clinical practice. Efficacy results were viewed as exploratory.1
References: 1. Data on file. Eton Pharmaceuticals, Inc. Deer Park, IL. 2. ALKINDI SPRINKLE. Package insert. Eton Pharmaceuticals, Inc; 2021. 3. Neumann U, Whitaker MJ, Wiegand S, et al. Absorption and tolerability of taste-masked hydrocortisone granules in neonates, infants and children under 6 years of age with adrenal insufficiency. Clin Endocrinol (Oxf). 2018;88(1):21-29. doi:10.1111/cen.13447. 4. Volovitz B, Kauschansky A, Nussinovitch M, Harel L, Varsano I. Normal diurnal variation in serum cortisol concentration in asthmatic children treated with inhaled budesonide. J Allergy Clin Immunol. 1995;96(6 pt 1):874-878. doi:10.1016/s0091-6749(95)70222-9. 5. Debono M, Ghobadi C, Rostami-Hodjegan A, et al. Modified-release hydrocortisone to provide circadian cortisol profiles. J Clin Endocrinol Metab. 2009;94(5):1548-1554. doi:10.1210/jc.2008-2380. 6. Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Developmental pharmacology—drug disposition, action, and therapy in infants and children. N Engl J Med. 2003;349(12):1157-1167. doi:10.1056/NEJMra035092. 7. Neumann U, Braune K, Whitaker MJ. A prospective study of children 0-7 years with CAH and adrenal insufficiency treated with hydrocortisone granules. J Clin Endocrinol Metab. 2020;dgaa626. doi:10.1210/clinem/dgaa626. 8. Whitaker MJ, Spielmann S, Digweed D, et al. Development and testing in healthy adults of oral hydrocortisone granules with taste masking for the treatment of neonates and infants with adrenal insufficiency. J Clin Endocrinol Metab. 2015;100(4):1681-1688. doi:10.1210/jc.2014-4060.
INDICATION AND IMPORTANT SAFETY INFORMATION
Contraindication
Hypersensitivity to hydrocortisone or any of the ingredients in ALKINDI SPRINKLE.
Warnings and Precautions
- Adrenal Crisis: Undertreatment or sudden discontinuation of therapy may lead to symptoms of adrenal insufficiency, adrenal crisis, and death. Adrenal crisis may also be induced by stressor events, such as infections or surgery. Monitor patients closely when switching from other forms of hydrocortisone to ALKINDI SPRINKLE. Instruct patients and/or caregivers to contact their healthcare provider if the full dose of ALKINDI SPRINKLE is not administered, as a repeat dose may be required. Increase the dose during periods of stress. Switch patients who are vomiting, severely ill, or unable to take oral medications to parenteral corticosteroid formulations.
- Infections: Excessive doses may increase the risks of new infections or exacerbation of latent infections with any pathogen, including viral, bacterial, fungal, protozoan, or helminthic infections. Monitor patients for signs and symptoms of infections. Treat all infections seriously, and initiate stress dosing of steroids early.
- Growth Retardation: Long-term use in excessive doses may cause growth retardation. Use the minimum dosage of ALKINDI SPRINKLE to achieve desired clinical response and monitor the patient’s growth.
- Cushing’s Syndrome Due to Use of Excessive Doses of Corticosteroids: Prolonged use with supraphysiologic doses may cause Cushing’s syndrome. Monitor patients for signs and symptoms of Cushing’s syndrome every 6 months; pediatric patients under one year of age may require more frequent monitoring.
- Decrease in Bone Mineral Density: Corticosteroids decrease bone formation and increase bone resorption, which may lead to inhibition of bone growth and development of osteoporosis. Use the minimum dosage of ALKINDI SPRINKLE to achieve desired clinical response.
- Psychiatric Adverse Reactions: Use may be associated with severe psychiatric adverse reactions, such as euphoria, mania, psychosis with hallucinations and delirium, or depression. Symptoms typically emerge within a few days or weeks of starting the treatment. Most reactions resolve after either dose reduction or withdrawal, although specific treatment may be necessary. Monitor patients for behavioral and mood disturbances during treatment. Instruct caregivers and/or patients to seek medical advice if psychiatric symptoms develop.
- Ophthalmic Adverse Reactions: Cataracts, glaucoma, and central serous chorioretinopathy have been reported with prolonged use of high doses. Monitor patients for blurred vision or other visual disturbances, and if they occur, refer them to an ophthalmologist.
- 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 nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of gastrointestinal adverse reactions. Monitor patients receiving corticosteroids and concomitant NSAIDs for gastrointestinal adverse reactions.
Adverse Reactions
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.
To report a suspected adverse event related to ALKINDI SPRINKLE, contact Eton Pharmaceuticals, Inc. at 1-855-224-0233 or the U.S. Food and Drug Administration (FDA) at http://www.fda.gov/MedWatch or call 1-800-FDA-1088.
INDICATION
ALKINDI SPRINKLE is a corticosteroid indicated for replacement therapy in pediatric patients with adrenocortical insufficiency.
Please see full Prescribing Information for more information.
USE INDICATION & IMPORTANT SAFETY INFORMATION
INDICATION AND IMPORTANT SAFETY INFORMATION
Contraindication
Hypersensitivity to hydrocortisone or any of the ingredients in ALKINDI SPRINKLE.
Warnings and Precautions
- Adrenal Crisis: Undertreatment or sudden discontinuation of therapy may lead to symptoms of adrenal insufficiency, adrenal crisis, and death. Adrenal crisis may also be induced by stressor events, such as infections or surgery. Monitor patients closely when switching from other forms of hydrocortisone to ALKINDI SPRINKLE. Instruct patients and/or caregivers to contact their healthcare provider if the full dose of ALKINDI SPRINKLE is not administered, as a repeat dose may be required. Increase the dose during periods of stress. Switch patients who are vomiting, severely ill, or unable to take oral medications to parenteral corticosteroid formulations.
- Infections: Excessive doses may increase the risks of new infections or exacerbation of latent infections with any pathogen, including viral, bacterial, fungal, protozoan, or helminthic infections. Monitor patients for signs and symptoms of infections. Treat all infections seriously, and initiate stress dosing of steroids early.
- Growth Retardation: Long-term use in excessive doses may cause growth retardation. Use the minimum dosage of ALKINDI SPRINKLE to achieve desired clinical response and monitor the patient’s growth.
- Cushing’s Syndrome Due to Use of Excessive Doses of Corticosteroids: Prolonged use with supraphysiologic doses may cause Cushing’s syndrome. Monitor patients for signs and symptoms of Cushing’s syndrome every 6 months; pediatric patients under one year of age may require more frequent monitoring.
- Decrease in Bone Mineral Density: Corticosteroids decrease bone formation and increase bone resorption, which may lead to inhibition of bone growth and development of osteoporosis. Use the minimum dosage of ALKINDI SPRINKLE to achieve desired clinical response.
- Psychiatric Adverse Reactions: Use may be associated with severe psychiatric adverse reactions, such as euphoria, mania, psychosis with hallucinations and delirium, or depression. Symptoms typically emerge within a few days or weeks of starting the treatment. Most reactions resolve after either dose reduction or withdrawal, although specific treatment may be necessary. Monitor patients for behavioral and mood disturbances during treatment. Instruct caregivers and/or patients to seek medical advice if psychiatric symptoms develop.
- Ophthalmic Adverse Reactions: Cataracts, glaucoma, and central serous chorioretinopathy have been reported with prolonged use of high doses. Monitor patients for blurred vision or other visual disturbances, and if they occur, refer them to an ophthalmologist.
- 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 nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of gastrointestinal adverse reactions. Monitor patients receiving corticosteroids and concomitant NSAIDs for gastrointestinal adverse reactions.
Adverse Reactions
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.
To report a suspected adverse event related to ALKINDI SPRINKLE, contact Eton Pharmaceuticals, Inc. at 1-855-224-0233 or the U.S. Food and Drug Administration (FDA) at http://www.fda.gov/MedWatch or call 1-800-FDA-1088.
INDICATION
ALKINDI SPRINKLE is a corticosteroid indicated for replacement therapy in pediatric patients with adrenocortical insufficiency.
Please see full Prescribing Information for more information.
