Hydrocortisone

Introduction Overview

Generic Name

hydrocortisone

Brand Name

Khindivi

Dosage Form

oral solution

Drug Class

Glucocorticoids

Pharmacokinetics

Absorption:
Hydrocortisone in KHINDIVI oral solution is rapidly absorbed following oral administration. Pharmacokinetic studies in dexamethasone-suppressed healthy adult volunteers reported a mean maximum plasma concentration (Cmax) of 152 ng/mL (range 98-210 ng/mL) after a 5 mg dose. Peak plasma levels are reached swiftly with a mean time to maximum concentration (Tmax) of approximately 0.5 hours (range 0.25-0.75 hours). The absorption of KHINDIVI is not significantly affected by food, as administration following a high-fat meal does not produce clinically meaningful changes in the drug’s pharmacokinetic profile. This rapid and reliable absorption profile ensures predictable systemic exposure important for replacement therapy in pediatric patients.

Distribution:
Circulating hydrocortisone is extensively bound to plasma proteins, with more than 90% reversibly bound primarily to corticosteroid-binding globulin (CBG) and to a lesser extent albumin. The dual binding components play a fundamental role in the drug’s pharmacodynamics and pharmacokinetics, influencing free (active) cortisol concentrations. Following oral administration of 5 mg hydrocortisone, the apparent volume of distribution (Vd/F) is approximately 23 L (range 5-59 L) in healthy adults, reflecting distribution into extracellular fluid and tissues. The affinity to CBG is crucial for maintaining physiologic hormone activity and modulating cortisol availability under various physiological and pathological conditions.

Metabolism:
Hydrocortisone undergoes extensive hepatic metabolism via reduction, oxidation, and conjugation pathways. The primary metabolic routes produce tetrahydrocortisone and tetrahydrocortisol metabolites, which are subsequently conjugated, mainly as glucuronides, enhancing renal excretion. Metabolism also occurs in extrahepatic tissues, including the kidneys and adipose tissue, contributing to clearance. The pharmacologically active drug is largely converted to inactive metabolites, modulating systemic exposure and minimizing accumulation. The metabolic pathways are subject to alterations in liver function, drug interactions (notably with CYP3A4 modulators), and patient-specific factors influencing clearance rates.

Elimination:
Hydrocortisone and its metabolites are predominantly eliminated via renal excretion. The terminal half-life of hydrocortisone following a 5 mg dose of KHINDIVI in healthy volunteers is approximately 0.95 hours (range 0.3-2.3 hours), indicating a relatively short systemic persistence necessitating multiple daily dosing for replacement therapy. Less than 1% of the administered dose is excreted unchanged in the urine. The rapid elimination supports the need for dosing schedules that mimic natural circadian rhythms of cortisol secretion, typically dividing total daily doses into two to three administrations, particularly important in pediatric patients to maintain appropriate hormone levels and avoid peaks and troughs leading to adverse effects or inadequate treatment. Renal impairment may affect elimination, necessitating clinical monitoring.

Dosage Forms

Available Dosage Forms:
KHINDIVI is formulated as an oral solution with a concentration of 1 mg/mL hydrocortisone. This formulation is a clear, colorless to slightly yellow viscous liquid, flavored with berry for palatability in pediatric patients. The product is supplied in a 473 mL amber bottle designed for oral administration, accompanied by an oral dosing syringe to ensure precise measurement. The solution may be administered directly or via gastric tube with appropriate flushing to guarantee full delivery of the prescribed dose.

Dosages for Adults and Adolescents:
KHINDIVI is approved for use in pediatric patients aged 5 years and older for replacement therapy in adrenocortical insufficiency. The recommended starting dose is 8 to 10 mg/m2 of body surface area daily, administered orally. This dose is individualized based on patient age, residual endogenous cortisol production, and clinical response. The total daily dose is typically divided into three administrations (three times daily) to mimic physiological cortisol secretion, with older pediatric patients potentially receiving the dose divided twice daily. Dose rounding to the nearest 0.5 or 1 mg facilitates accurate dispensing.

Specific Patient Populations:
KHINDIVI has not been approved for use in pediatric patients younger than 5 years due to risks associated with the inactive ingredients and metabolic immaturity. For stress dosing during illness or surgery, KHINDIVI is not appropriate; alternate hydrocortisone formulations without the same inactive ingredients should be used. During changes from other hydrocortisone products to KHINDIVI, the total daily hydrocortisone dose should initially remain unchanged, with careful monitoring and dosage adjustments as necessary to avoid adrenal insufficiency symptoms. Administration via gastric tube is viable, ensuring the tube is flushed with 20 mL of water post-dose to guarantee full delivery. Patients should be instructed to use the oral syringe supplied to avoid dosing inaccuracies.

Mechanism Of Action

Hydrocortisone, the active component of KHINDIVI, is a naturally occurring glucocorticoid hormone that binds to cytoplasmic glucocorticoid receptors (GR) in various tissues, eliciting profound effects on carbohydrate, protein, and lipid metabolism. Upon binding, the hydrocortisone-GR complex translocates to the nucleus where it modulates gene transcription by interacting with glucocorticoid response elements (GREs). This genomic action upregulates anti-inflammatory proteins while repressing pro-inflammatory genes, thereby exerting potent anti-inflammatory and immunosuppressive effects.

In addition to genomic effects, hydrocortisone influences non-genomic pathways involving membrane-bound receptors and secondary messenger systems which contribute to rapid cellular responses. These include modulation of vascular tone, inhibition of leukocyte migration, and stabilization of lysosomal membranes. Hydrocortisone’s salt-retaining activity also impacts electrolyte and water balance by acting on mineralocorticoid receptors, albeit to a lesser extent in replacement doses, important in maintaining homeostasis in adrenocortical insufficiency.

Clinically, hydrocortisone’s mechanistic role in KHINDIVI is to replace deficient endogenous cortisol in patients with adrenal insufficiency, restoring metabolic, immunologic, and homeostatic functions essential for survival and stress response. Compared to synthetic analogs, hydrocortisone’s short half-life and balanced glucocorticoid and mineralocorticoid activities make it particularly suitable for physiological replacement therapy.

Research corroborates hydrocortisone’s efficacy in normalizing biochemical parameters and clinical symptoms of cortisol deficiency when carefully titrated. KHINDIVI’s oral solution format allows precise dosing in pediatric patients, ensuring targeted physiological effects and minimizing risks associated with supraphysiologic dosing such as growth suppression and Cushingoid features.

Pharmacological Actions

Replacement therapy providing glucocorticoid activity to compensate for adrenocortical insufficiency.
Modulation of gene expression leading to anti-inflammatory and immunosuppressive effects.
Regulation of carbohydrate metabolism, promoting gluconeogenesis and maintaining blood glucose levels.
Maintenance of vascular tone through sensitization of vascular smooth muscle to vasoconstrictors.
Inhibition of immune cell activation and cytokine production reducing inflammatory responses.
Salt-retaining activity contributing to electrolyte and fluid balance.
Stabilization of lysosomal membranes preventing release of inflammatory enzymes.
Suppression of prostaglandin and leukotriene synthesis mitigating inflammatory mediator release.
Promotion of protein catabolism and redistribution affecting muscle and skin tissue metabolism.
Enhancement of lipolysis resulting in redistribution of body fat deposits.

Therapeutic Or Clinical Uses

Replacement therapy for adrenal insufficiency in pediatric patients aged 5 years and older.
Management of congenital adrenal hyperplasia with impaired cortisol production.
Supportive treatment in patients with hypopituitarism leading to secondary adrenal insufficiency.
Utilized during stable maintenance therapy for chronic adrenocortical insufficiency.
Ensures physiological restoration of cortisol levels to prevent adrenal crisis in stable conditions.
Avoided in stress dosing situations; alternate hydrocortisone formulations are required then.
Facilitates replacement therapy in patients unable to take solid oral hydrocortisone forms.
Allows precise dose titration critical in pediatric populations to prevent under or overtreatment.
Useful in patients requiring hydrocortisone delivered via gastric tubes.
An option for patients exhibiting intolerance or adverse reactions to other hydrocortisone preparations.

Side Or Adverse Effects

Fluid retention leading to edema and weight gain.
Alterations in glucose tolerance potentially causing hyperglycemia.
Elevation in blood pressure secondary to mineralocorticoid effects.
Behavioral and mood changes including euphoria, mania, psychosis, and depression.
Increased appetite potentially contributing to obesity in chronic use.
Growth retardation in pediatric patients with excessive dosing.
Cushingoid features such as moon face, muscle weakness, and easy bruising.
Decrease in bone mineral density causing osteoporosis and increased fracture risk.
Ophthalmic effects including cataracts, glaucoma, and central serous chorioretinopathy.
Gastrointestinal adverse reactions such as irritation, ulcers, or masked symptoms of perforation.
Possible hypersensitivity reactions including anaphylaxis.
Systemic toxicity related to inactive ingredients such as hyperosmolarity and metabolic acidosis.
Laxative effects from excipients causing diarrhea or vomiting.
Increased susceptibility to infections due to immunosuppressive dosing.
Risk of Kaposi's sarcoma with prolonged supraphysiologic dosing.

Precautions

Use the lowest effective dose to avoid growth retardation in children.
Closely monitor for signs of adrenal insufficiency during dose adjustments or switching formulations.
Avoid use in pediatric patients under 5 years due to excipient-related toxicity risks.
Cautious use during periods of stress; do not use KHINDIVI for stress dosing.
Monitor for psychiatric symptoms and behavioral changes during treatment.
Evaluate bone mineral density regularly in long-term users.
Watch for signs of infection especially when doses exceed physiologic replacement.
Monitor blood pressure, blood glucose, and electrolyte levels routinely.
Discontinue KHINDIVI and switch therapy if systemic adverse reactions related to excipients occur.
Avoid abrupt withdrawal; taper doses to prevent adrenal crisis.
Avoid concomitant use with NSAIDs without appropriate monitoring due to GI risks.
Inspect for ocular adverse effects and refer to ophthalmology if visual symptoms arise.
Assess growth and development parameters regularly in pediatric patients.
Consider potential dosing inaccuracies when switching from compounded or manipulated hydrocortisone formulations.
Inform caregivers about necessity to contact healthcare providers if vomiting or inability to take oral meds develops.

Warnings

Risk of life-threatening adrenal crisis with undertreatment, sudden discontinuation, or inadequate dosing.
Not approved for increased dosing during stress or acute illness; use alternate hydrocortisone products then.
Potential systemic adverse reactions from inactive ingredients polyethylene glycol 400, propylene glycol, and glycerin.
Hyperosmolarity, metabolic acidosis, hypoglycemia, hepato-renal injury, and CNS toxicity possible due to excipients.
Immunosuppression and increased infection risk when doses exceed physiologic replacement.
Long-term excessive dosing associated with growth retardation, Cushing's syndrome, and decreased bone density.
Possible severe psychiatric adverse reactions including psychosis and mood disorders.
Ophthalmic complications like glaucoma and cataracts with prolonged high-dose use.
Increased risk of gastrointestinal perforation, especially with concurrent NSAID use.
Risk of Kaposi's sarcoma with chronic supraphysiologic corticosteroid therapy.
Masking of infection signs and symptoms may delay diagnosis of infections.
Risk of dosing inaccuracy when switching from manipulated oral hydrocortisone formulations.
In pediatric patients, immature metabolic pathways may increase toxicities from inactive ingredients.
Use in pregnancy requires careful risk-benefit assessment; hydrocortisone does not readily cross placenta.
Vaccination with live vaccines may be acceptable but should be monitored cautiously.

Contraindication

Known hypersensitivity to hydrocortisone or any component of KHINDIVI.
History of anaphylactic or severe allergic reactions to hydrocortisone or corticosteroids.
Patients younger than 5 years due to risk of toxicity from inactive ingredients.
Use in treatment of systemic fungal infections without appropriate concomitant antifungal therapy.
Patients with untreated systemic infections where corticosteroids are contraindicated due to immunosuppression risk.
Known hypersensitivity reactions to excipients such as polyethylene glycol 400, propylene glycol or glycerin if evidence of intolerance is present.
Use in patients with active gastrointestinal perforation or ulcers unless benefits outweigh risks.
Use is not indicated for stress dosing or acute adrenal crisis conditions.
Concurrent use in patients with systemic viral diseases without physician oversight.
Contraindicated in patients with hypersensitivity to preservatives such as methylparaben or propylparaben.

Drug Interactions

CYP3A4 inhibitors (e.g., itraconazole, posaconazole, voriconazole, erythromycin, clarithromycin, ritonavir) may increase hydrocortisone levels, requiring dose reduction.
CYP3A4 inducers (e.g., phenytoin, carbamazepine, oxcarbazepine, rifampicin, rifabutin, phenobarbital, primidone, efavirenz, nevirapine) may decrease hydrocortisone concentrations, necessitating dose increase.
Estrogen and estrogen-containing products increase cortisol-binding globulin levels, potentially reducing free hydrocortisone and necessitating dose adjustment.
Antidiabetic agents may require dose adjustments as corticosteroids can induce hyperglycemia.
Nonsteroidal anti-inflammatory drugs (NSAIDs) concomitant use increases risk of gastrointestinal adverse events; use cautiously with monitoring.
Warfarin interaction may reduce anticoagulant effects; coagulation parameters should be closely monitored.
Cyclosporine interaction may enhance toxicity of both drugs, including risk of convulsions; monitor patients closely.
Grapefruit juice can inhibit CYP3A4, potentially increasing hydrocortisone exposure.
Potential additive immunosuppression with other immunomodulatory agents.
Concomitant use with vaccines may require caution, especially with live vaccines.
Use with diuretics can exacerbate potassium loss and fluid retention; monitor electrolyte levels.
Drugs affecting gastric pH or motility might alter hydrocortisone absorption marginally.
Interactions with other metabolic enzyme modulators may alter clearance and effect profiles.
Inhibitors of alcohol dehydrogenase might affect toxicity profile related to inactive ingredients.

Preparations Of The Drug

KHINDIVI: hydrocortisone oral solution, 1 mg/mL concentration formulated as a clear, colorless to slightly yellow viscous liquid with berry flavoring.
Contains inactive ingredients polyethylene glycol 400 (500 mg/mL), propylene glycol (50 mg/mL), glycerin (623 mg/mL), methylparaben, propylparaben, butylated hydroxyanisole, ethyl maltol, and sucralose.
Supplied in a 473 mL amber glass bottle with accompanying oral dosing syringe for precise measurement.
Formulated for oral administration; suitable for use via gastric tube with appropriate flushing.
Must be stored between 2°C to 25°C (36°F to 77°F), protected from light and heat.
Once opened, the product must be used within 120 days; discard remaining medication thereafter.
Manufactured in compliance with USP standards for oral liquids and quality control.
Patented formulation providing consistent hydrocortisone dosing and improved palatability for pediatric use.
Not approved for use in pediatric patients under 5 years due to systemic absorption of excipients.
Marketed by Eton Pharmaceuticals, Inc., manufactured by Tulex Pharmaceuticals, Inc.
Packaged with detailed Medication Guide and patient counseling information to ensure safe use.