Khindivi

Description

KHINDIVI contains hydrocortisone, a corticosteroid also known as cortisol. The chemical name of hydrocortisone is 11β,17α,21-trihydroxy-pregn-4-ene-3,20-dione, with a chemical formula of C21H30O5 and a molecular weight of 362 g∙mol–1. Hydrocortisone appears as a white or almost white powder that is soluble in the pH range of 1-7. KHINDIVI is formulated as a clear, colorless to slightly yellow viscous solution for oral administration, with a concentration of 1 mg/mL. The inactive ingredients include berry flavor, butylated hydroxyanisole, ethyl maltol, glycerin (623 mg/mL), methylparaben, propylparaben, polyethylene glycol 400 (500 mg/mL), propylene glycol (50 mg/mL), and sucralose.

Uses and Indications

KHINDIVI is indicated as replacement therapy in pediatric patients 5 years of age and older with adrenocortical insufficiency.

Limitations of use include that KHINDIVI is not approved for increased dosing during periods of stress or acute events; a different hydrocortisone-containing drug product should be utilized for stress dosing.

No teratogenic or nonteratogenic effects have been reported.

Dosage and Administration

The dose of KHINDIVI should be individualized, utilizing the lowest effective dosage. In instances where stress dosing is required, a different hydrocortisone-containing drug product should be employed.

The recommended starting replacement dosage of KHINDIVI is 8 to 10 mg/m² daily. Adjustments to the dosage may be necessary based on the patient's age and the severity of disease symptoms. In patients with residual but decreased endogenous cortisol production, lower starting doses may be adequate.

The total daily dose should be divided into three separate doses, administered three times daily. For older patients, consideration may be given to dividing the daily dose into two doses, administered twice daily.

When transitioning from other oral hydrocortisone formulations, it is essential to maintain the same total daily hydrocortisone dosage. Should symptoms of adrenal insufficiency arise, an increase in the total daily dosage is warranted.

For comprehensive dosing and administration instructions, please refer to the Full Prescribing Information.

Contraindications

Use of KHINDIVI is contraindicated in patients with hypersensitivity to hydrocortisone or any component of the formulation. This contraindication is based on the potential for severe allergic reactions in susceptible individuals.

Warnings and Precautions

Undertreatment, abrupt discontinuation of therapy, or transitioning from another oral hydrocortisone formulation can precipitate adrenocortical insufficiency, leading to adrenal crisis and potentially fatal outcomes. Adrenal crisis may also be triggered by stress events, including infections or surgical procedures. In such circumstances, it is recommended to switch to an alternative oral hydrocortisone product and adjust the dosage accordingly. For patients who are vomiting, severely ill, or unable to take oral medications, a transition to parenteral corticosteroid formulations is advised.

KHINDIVI contains inactive ingredients such as polyethylene glycol 400, propylene glycol, and glycerin, which may result in hyperosmolarity, metabolic acidosis, hypoglycemia, hepato-renal injury, central nervous system toxicity, and gastrointestinal adverse reactions. Should any of these adverse effects manifest, discontinuation of KHINDIVI and a switch to another hydrocortisone product is warranted.

The use of KHINDIVI at dosages exceeding replacement levels can lead to immunosuppression, increasing the risk of new infections or exacerbating latent infections from various pathogens, including viral, bacterial, fungal, protozoan, or helminthic sources. Healthcare professionals should closely monitor patients for any signs and symptoms of infection.

Long-term administration of excessive doses may result in growth retardation. It is essential to utilize the minimum effective dosage of KHINDIVI to achieve the desired clinical response while monitoring the patient's growth.

Prolonged use of supraphysiologic doses of corticosteroids may induce Cushing's syndrome. Patients should be monitored for signs and symptoms of this condition at least every six months.

Corticosteroids are known to decrease bone mineral density by inhibiting bone formation and increasing bone resorption, which can lead to impaired bone growth and the development of osteoporosis. Therefore, it is crucial to administer the minimum dosage of KHINDIVI necessary to achieve the desired clinical outcome.

Severe psychiatric adverse reactions, including euphoria, mania, psychosis with hallucinations, delirium, or depression, may occur with the use of KHINDIVI. These symptoms typically arise within days to weeks of initiating treatment. Most psychiatric reactions resolve following dose reduction or discontinuation of the medication, although specific interventions may be required. Patients should be monitored for behavioral and mood disturbances, and caregivers should be instructed to seek medical advice if any psychiatric symptoms develop.

Prolonged use of high doses of KHINDIVI has been associated with ophthalmic adverse reactions, including cataracts, glaucoma, and central serous chorioretinopathy. Patients should be monitored for blurred vision or other visual disturbances, and referrals to an ophthalmologist should be made if such symptoms occur.

In patients with certain gastrointestinal disorders, there is an increased risk of gastrointestinal adverse reactions, which may be masked by the underlying condition. Careful monitoring is advised in these cases.

Side Effects

Common adverse reactions observed in patients include fluid retention, alteration in glucose tolerance, elevation in blood pressure, behavioral and mood changes, increased appetite, and weight gain.

In clinical trials, several adverse reactions were reported with varying frequencies. Pyrexia was noted in 56% of participants, while gastroenteritis occurred in 50%. Other common reactions included viral upper respiratory tract infections (44%), vomiting (39%), and viral infections (33%). Conjunctivitis was reported in 28% of subjects, with otitis media viral and tonsillitis each occurring in 17%. Additional reactions included increased body temperature (11%), bronchitis (11%), dental caries (11%), diarrhea (11%), genitourinary operations (11%), pharyngitis (11%), respiratory tract infections (11%), and rhinitis (11%).

Postmarketing experience has revealed a range of serious adverse reactions. Allergic reactions, including anaphylaxis and angioedema, have been reported. Cardiovascular events such as 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, and vasculitis have also been documented.

Dermatologic reactions include 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, and urticaria. Endocrine effects may manifest as abnormal fat deposits, decreased carbohydrate tolerance, development of a Cushingoid state, hirsutism, manifestations of latent diabetes mellitus, increased requirements for insulin or oral hypoglycemic agents in diabetics, menstrual irregularities, moon faces, secondary adrenocortical and pituitary unresponsiveness (particularly in times of stress), and suppression of growth in pediatric patients.

Fluid and electrolyte disturbances, including fluid retention, potassium loss, hypertension, hypokalemic alkalosis, and sodium retention, have been reported. Gastrointestinal adverse reactions may include abdominal distention, elevation in serum liver enzyme levels (usually reversible upon discontinuation), hepatomegaly, hiccups, malaise, nausea, pancreatitis, peptic ulcer with possible perforation and hemorrhage, and ulcerative esophagitis.

General adverse reactions encompass increased appetite and weight gain, while metabolic effects may lead to negative nitrogen balance due to protein catabolism. Musculoskeletal adverse reactions include osteonecrosis of femoral and humeral heads, Charcot-like arthropathy, loss of muscle mass, muscle weakness, osteoporosis, pathologic fractures of long bones, steroid myopathy, tendon rupture, and vertebral compression fractures.

Neurological adverse reactions may involve arachnoiditis, convulsions, depression, emotional instability, euphoria, headache, increased intracranial pressure with papilledema (pseudo-tumor cerebri), insomnia, meningitis, mood swings, neuritis, neuropathy, paraparesis/paraplegia, paresthesia, personality changes, sensory disturbances, and vertigo. Ophthalmic reactions include exophthalmos, glaucoma, increased intraocular pressure, posterior subcapsular cataracts, and central serous chorioretinopathy.

Reproductive adverse reactions may involve alterations in motility and number of spermatozoa. It is important to note that adrenal crisis may occur due to undertreatment, sudden discontinuation of therapy, or switching from another oral hydrocortisone formulation, potentially leading to adrenocortical insufficiency and death. Stress events such as infections or surgery may also induce adrenal crisis.

The use of greater than replacement dosage can suppress the immune system, increasing the risks of new infections or exacerbation of latent infections. Long-term use in excessive doses may cause growth retardation and prolonged use with supraphysiologic doses may lead to Cushing's syndrome. Corticosteroids can decrease bone formation and increase bone resorption, potentially leading to osteoporosis. Severe psychiatric adverse reactions, including euphoria, mania, psychosis with hallucinations and delirium, or depression, have been associated with use. Additionally, increased risk of gastrointestinal adverse reactions may occur in patients with certain gastrointestinal disorders, where signs and symptoms may be masked.

Drug Interactions

Concomitant administration of KHINDIVI with CYP3A4 inhibitors may necessitate a reduction in the KHINDIVI dose due to the potential for increased plasma concentrations of the drug. Conversely, when administered alongside CYP3A4 inducers, an increase in the KHINDIVI dose may be required to achieve the desired therapeutic effect.

The use of estrogen and estrogen-containing products in conjunction with KHINDIVI may also warrant an increase in the KHINDIVI dose, as these agents can influence its pharmacokinetics.

When KHINDIVI is used with antidiabetic agents, caution is advised, as excessive doses of these agents may lead to elevated blood glucose levels. Therefore, monitoring and potential dose adjustments of the antidiabetic agents may be necessary to maintain glycemic control.

The concomitant use of KHINDIVI with nonsteroidal anti-inflammatory drugs (NSAIDs) raises the risk of gastrointestinal adverse reactions. Clinicians should be vigilant in monitoring for such effects when these medications are used together.

No specific drug interactions or laboratory test interactions have been identified beyond those mentioned.

Packaging & NDC

The table below lists all NDC Code configurations of Khindivi (hydrocortisone), the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

The safety and effectiveness of KHINDIVI have been established in pediatric patients aged 5 years and older for the replacement therapy of adrenocortical insufficiency. KHINDIVI is not approved for use in pediatric patients younger than 5 years of age.

Healthcare professionals should be aware that KHINDIVI contains inactive ingredients such as polyethylene glycol 400, propylene glycol, and glycerin, which can undergo substantial systemic absorption. This is particularly relevant for pediatric patients under 5 years of age, who may have incomplete alcohol dehydrogenase maturity, potentially leading to increased plasma osmolarity.

When prescribing KHINDIVI to pediatric patients aged 5 years and older, it is important to consider the total daily intake of polyethylene glycol 400, propylene glycol, and glycerin from all sources. Increased exposure to these ingredients may elevate the risk of systemic toxicity.

Geriatric Use

Elderly patients may require dose adjustments when receiving this medication. Specifically, for patients aged 65 years and older, it is recommended that the daily dose be divided by two and administered twice daily. This modification is advised to enhance safety and tolerability in the geriatric population, who may have altered pharmacokinetics and pharmacodynamics.

Healthcare providers should closely monitor elderly patients for any adverse effects and therapeutic efficacy, as age-related physiological changes can impact drug metabolism and response. Careful consideration of these factors is essential to optimize treatment outcomes in this demographic.

Pregnancy

Untreated adrenocortical insufficiency during pregnancy can lead to significant complications, including maternal mortality. The use of physiologic doses of hydrocortisone is not anticipated to result in major birth defects, miscarriage, or adverse maternal and fetal outcomes. Observational studies assessing hydrocortisone use in pregnant patients have not established a clear drug-associated risk for major birth defects or miscarriage.

The estimated background risk of major birth defects and miscarriage in the general U.S. population is reported to be 2–4% and 15–20%, respectively; however, the specific background risk for the indicated population remains unknown. Evidence from epidemiologic studies indicates a potential small increased risk of cleft lip, with or without cleft palate, associated with systemic corticosteroid use during the first trimester. It is important to note that the data regarding this risk are limited and present inconsistent findings. Methodological limitations in these studies include non-randomized designs, retrospective data collection, and a lack of dose-response data, as well as challenges in controlling for confounding factors such as underlying maternal disease and concomitant medication use.

Unlike other corticosteroids, hydrocortisone is enzymatically deactivated by the placenta, which may limit fetal exposure. While corticosteroids have demonstrated teratogenic effects in various animal species at doses comparable to human doses, animal studies involving pregnant mice, rats, and rabbits without adrenocortical insufficiency have shown an increased incidence of cleft palate in the offspring. Given these considerations, healthcare professionals should carefully evaluate the risks and benefits of hydrocortisone use in pregnant patients, particularly in those with adrenocortical insufficiency.

Lactation

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. However, there are no data on the presence of hydrocortisone in breast milk, its effect on the breastfed infant, or its impact on milk production.

When considering the use of hydrocortisone in lactating mothers, the developmental and health benefits of breastfeeding should be weighed against the mother's clinical need for hydrocortisone and any potential adverse effects on the breastfed infant from hydrocortisone or from the underlying maternal condition.

Renal Impairment

There is no specific information available regarding dosage adjustments, special monitoring, or safety considerations for patients with renal impairment. Healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the absence of detailed guidance necessitates careful clinical judgment. Regular monitoring of renal function may be advisable in this patient population.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions outlined for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

In cases of acute overdosage, the primary approach involves supportive and symptomatic therapy. Healthcare professionals should closely monitor the patient for any adverse effects and provide appropriate interventions based on the clinical presentation.

Symptoms of overdosage may vary depending on the specific substance involved, and it is crucial for healthcare providers to assess the patient thoroughly. Management should focus on stabilizing the patient's condition and addressing any life-threatening symptoms that may arise.

In the event of an overdosage, it is recommended that healthcare professionals initiate immediate supportive care, which may include airway management, oxygen supplementation, intravenous fluids, and other necessary measures to ensure patient safety and comfort. Continuous monitoring of vital signs and laboratory parameters is essential to guide further treatment decisions.

Prompt recognition and management of overdosage can significantly improve patient outcomes, underscoring the importance of vigilance in clinical practice.

Nonclinical Toxicology

No adequate studies in animals have been conducted with hydrocortisone to evaluate its carcinogenic or mutagenic potential.

Corticosteroids have been shown to impair fertility in male rats.

Postmarketing Experience

The following adverse reactions associated with the use of corticosteroids have been identified in pediatric and adult patients through literature and postmarketing reports. Due to the voluntary nature of these reports from a population of uncertain size, it is not always feasible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Common adverse reactions include fluid retention, alterations 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, and 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, and urticaria.

Endocrine: Abnormal fat deposits, decreased carbohydrate tolerance, development of Cushingoid state, hirsutism, manifestations of latent diabetes mellitus, increased requirements for insulin or oral hypoglycemic agents in diabetics, menstrual irregularities, moon faces, secondary adrenocortical and pituitary unresponsiveness (particularly in times of stress), and suppression of growth in pediatric patients.

Fluid and Electrolyte Disturbances: Fluid retention, potassium loss, hypertension, hypokalemic alkalosis, and sodium retention.

Gastrointestinal: Abdominal distention, elevation in serum liver enzyme levels (usually reversible upon discontinuation), hepatomegaly, hiccups, malaise, nausea, pancreatitis, peptic ulcer with possible perforation and hemorrhage, and 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, and 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, and vertigo.

Ophthalmic: Exophthalmos, glaucoma, increased intraocular pressure, posterior subcapsular cataracts, and central serous chorioretinopathy.

Reproductive: Alteration in motility and number of spermatozoa.

Patient Counseling

Healthcare providers should advise patients and/or caregivers to read the FDA-approved patient labeling (Medication Guide) to ensure they are well-informed about the medication. It is important to instruct them to use an oral dosing syringe to accurately measure the prescribed amount of medication, and to inform them that these syringes can be obtained from their pharmacy.

Patients and/or caregivers should be advised to take a sip of water immediately after administration to ensure that the entire solution has been swallowed. For those administering the medication through a gastric tube, it is essential to flush with 20 mL of water to guarantee that the entire dose is delivered.

Healthcare providers must inform patients and/or caregivers that undertreatment, sudden discontinuation of KHINDIVI, or switching from another oral hydrocortisone formulation may lead to serious complications such as adrenocortical insufficiency, adrenal crisis, and even death. They should be instructed to switch to another oral hydrocortisone product and increase the dose during periods of stress, while avoiding the use of KHINDIVI for increased dosing during such times due to the heightened risk of systemic and gastrointestinal adverse reactions.

Caregivers should be made aware that potential dosing inaccuracies from manipulated oral hydrocortisone formulations (e.g., split or crushed tablets, compounded formulations) may result in dosing differences when transitioning to KHINDIVI, which may necessitate dose adjustments. They should monitor the patient for symptoms of adrenocortical insufficiency in the days following the switch and contact their healthcare provider if symptoms arise, including prolonged vomiting, severe illness, or an inability to take oral medications.

Patients and/or caregivers should be informed that some inactive ingredients in KHINDIVI may increase the risk of hyperosmolarity, metabolic acidosis, loose stools, diarrhea, and other systemic adverse reactions, which could elevate the risk of adrenal crisis. They should contact their healthcare provider if the patient experiences altered mental status, abnormal urine output, or severe illness.

It is crucial to advise patients and/or caregivers that dosages greater than replacement levels of corticosteroids can suppress the immune system, increasing the risk of infections. They should be instructed to reach out to their healthcare provider if any infections develop.

Healthcare providers should discuss with caregivers the potential for long-term use of corticosteroids in excessive doses to cause growth retardation in pediatric patients. Additionally, they should inform patients and/or caregivers that prolonged use of corticosteroids in supraphysiologic doses may lead to Cushing's syndrome, with symptoms including weight gain, decreased height velocity, hyperglycemia, hypertension, edema, easy bruising, muscle weakness, a red round face, depression, or mood swings.

Patients and/or caregivers should also be informed that corticosteroids can decrease bone formation and increase bone resorption, potentially leading to osteoporosis. Furthermore, they should be made aware that corticosteroid use may be associated with severe psychiatric adverse reactions, such as euphoria, mania, psychosis with hallucinations, or depression, and should seek medical advice if any psychiatric symptoms develop.

Ophthalmic effects, including cataracts, glaucoma, or central serous chorioretinopathy, have been reported with prolonged use of high-dose corticosteroids. Patients or caregivers should be instructed to report any blurred vision or visual disturbances to their healthcare provider.

Healthcare providers should discuss the increased risk of gastrointestinal perforation associated with corticosteroid use in certain gastrointestinal disorders. Patients should also be informed of their risk of developing Kaposi's sarcoma. Lastly, it should be noted that the administration of live vaccines may be acceptable.

Storage and Handling

The product is supplied in configurations that adhere to the National Drug Code (NDC) standards. It should be stored at temperatures ranging from 2°C to 25°C (36°F to 77°F), with permissible excursions up to 30°C (86°F) as outlined by USP guidelines for refrigerated and controlled room temperature. It is essential to protect the product from light and heat to maintain its integrity.

Once opened, the product must be utilized within 120 days. Any unused portion after this period should be discarded to ensure safety and efficacy.

Additional Clinical Information

Postmarketing experience has revealed a range of common adverse reactions associated with corticosteroids. Patients may experience fluid retention, alterations in glucose tolerance, elevated blood pressure, behavioral and mood changes, increased appetite, and weight gain. Allergic reactions such as anaphylaxis and angioedema have also been reported.

Cardiovascular effects can include bradycardia, cardiac arrest, arrhythmias, circulatory collapse, and hypertension, among others. Dermatologic reactions may manifest as acne, allergic dermatitis, impaired wound healing, and thinning of the skin. Endocrine disturbances can lead to abnormal fat deposits, menstrual irregularities, and suppression of growth in pediatric patients. Fluid and electrolyte disturbances, gastrointestinal issues such as abdominal distention and pancreatitis, and metabolic changes like negative nitrogen balance are also noted. Musculoskeletal complications may include osteonecrosis and osteoporosis, while neurological effects can range from convulsions to increased intracranial pressure. Ophthalmic concerns include glaucoma and cataracts, and reproductive effects may involve alterations in sperm motility and count.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Khindivi as submitted by Eton Pharmaceuticals, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)