Endone

Uses

Endone is an opioid used in the management of moderate to severe pain.

Endone is indicated for the treatment of moderate to severe pain. There is also an extended release formulation indicated for chronic moderate to severe pain requiring continuous opioid analgesics for an extended period.

Endone is also used to associated treatment for these conditions: Severe Pain, Severe, Chronic Pain, Acute, moderate Pain, Acute, severe Pain, Chronic, moderate Pain

How Endone works

The full mechanism of oxycodone is not known. Under conditions of inflammation or hyperalgesia, opioid receptors in the heart, lungs, liver, gastrointestinal tract, and reproductive system are upregulated and transported to nerve terminals. Endone and its active metabolites, noroxycodone, oxymorphone, and noroxymorphone are opioid agonists. These compounds passively diffuse across the blood brain barrier or may be actively transported across by an unknown mechanism. Endone and its active metabolites can selectively bind to the mu opioid receptor, but also the kappa and delta opioid receptors in the central nervous system and periphery, and induce a G protein coupled receptor signalling pathway. Activation of mu opioid receptors inhibits N-type voltage operated calcium channels, inhibiting responses to pain.

Toxicity

Patients experiencing an overdose may present with respiratory depression, sleepiness, stupor, coma, skeletal muscle flaccidity, cold sweat, constricted pupils, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Overdose should be treated by maintaining airway, ventilation, and oxygenation. Oxygen and vasopressor treatment may be necessary to treat circulatory shock and pulmonary edema and defibrillation may be required for cardiac arrest of arrhythmia. Naloxone, nalmefene, or naltrexone may be used to counteract the effects of opioids but patients should be monitored in case further doses are required.

The intraperitoneal LD50 in mice is 320mg/kg, the oral LD50 is 426mg/kg. The oral lowest dose causing toxic effects in humans is 0.14mg/kg and subcutaneously in rats it is 1.53mg/kg.

Endone is pregnancy category B according to the FDA. There is a paucity of data regarding oxycodone use in pregnancy, though animal studies show no teratogenic effects. Rats given oxycodone during lactation showed smaller offspring, though after lactation, they recovered to normal size. Endone is excreted in breast milk and so patients should not breastfeed while taking oxycodone due to risk of sedation and respiratory depression in infants.

No studies on the carcinogenicity of oxycodone have been performed. Endone was genotoxic at 50mcg/mL with metabolic activation and at 400mcg/mL without. It was also clastogenic with metabolic activation at ≥1250mcg/mL. Endone was not found to be genotoxic in other tests. Endone does not affect reproduction and fertility in rats at doses of up to 8mg/kg/day.

Food Interaction

• Avoid alcohol.
• Take with or without food. Food does not significantly affect absorption.

[Major] GENERALLY AVOID: Alcohol may potentiate the central nervous system (CNS) depressant effects of opioid analgesics including oxycodone.

Concomitant use may result in additive CNS depression and impairment of judgment, thinking, and psychomotor skills.

In more severe cases, hypotension, respiratory depression, profound sedation, coma, or even death may occur.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of oxycodone.

The proposed mechanism is inhibition of CYP450 3A4-mediated metabolism of oxycodone by certain compounds present in grapefruit, resulting in decreased formation of metabolites noroxycodone and noroxymorphone and increased formation of oxymorphone due to a presumed shifting of oxycodone metabolism towards the CYP450 2D6-mediated route.

In 12 healthy, nonsmoking volunteers, administration of a single 10 mg oral dose of oxycodone hydrochloride on day 4 of a grapefruit juice treatment phase (200 mL three times a day for 5 days) increased mean oxycodone peak plasma concentration (Cmax), systemic exposure (AUC) and half-life by 48%, 67% and 17% (from 3.5 to 4.1 hours), respectively, compared to administration during an equivalent water treatment phase.

Grapefruit juice also decreased the metabolite-to-parent AUC ratio of noroxycodone by 44% and that of noroxymorphone by 45%.

In addition, oxymorphone Cmax and AUC increased by 32% and 56%, but the metabolite-to-parent AUC ratio remained unchanged.

Pharmacodynamic changes were modest and only self-reported performance was significantly impaired after grapefruit juice.

Analgesic effects were not affected.

MANAGEMENT: Patients should not consume alcoholic beverages or use drug products that contain alcohol during treatment with oxycodone.

Any history of alcohol or illicit drug use should be considered when prescribing oxycodone, and therapy initiated at a lower dosage if necessary.

Patients should be closely monitored for signs and symptoms of sedation, respiratory depression, and hypotension.

Due to a high degree of interpatient variability with respect to grapefruit juice interactions, patients treated with oxycodone may also want to avoid or limit the consumption of grapefruit and grapefruit juice.

Endone Drug Interaction

Major: zolpidem, fentanyl, cyclobenzaprine, pregabalin, morphine, alprazolamModerate: diphenhydramine, duloxetine, furosemide, ondansetronUnknown: amphetamine / dextroamphetamine, omega-3 polyunsaturated fatty acids, atorvastatin, polyethylene glycol 3350, esomeprazole, levothyroxine, acetaminophen, cyanocobalamin, ascorbic acid, cholecalciferol

Endone Disease Interaction

Major: impaired GI motility, infectious diarrhea, liver disease, prematurity, acute alcohol intoxication, drug dependence, gastrointestinal obstruction, hypotension, intracranial pressure, respiratory depressionModerate: adrenal insufficiency, biliary spasm, hypothyroidism, renal dysfunction, seizure disorders, urinary retention, arrhythmias

Volume of Distribution

2.6L/kg.

Elimination Route

Endone has an oral bioavailability of 60% to 87% that is unaffected by food.

The area under the curve is 135ng/mL*hr, maximum plasma concentration is 11.5ng/mL, and time to maximum concentration is 5.11hr in patients given a 10mg oral immediate release dose of oxycodone.

Half Life

The apparent elimination half life of oxycodone is 3.2 hours for immediate release formulations and 4.5 hours for extended release formulations. Noroxycodone has a half life of 5.8 hours, oxymorphone has a half life of 8.8 hours, noroxymorphone has a half life of 9 hours.

Clearance

Total plasma clearance is 1.4L/min in adults.

Elimination Route

Endone and its metabolites are eliminated in the urine. Unbound noroxycodone makes up 23% of the dose recovered in urine and oxymorphone makes up Label Conjugated oxymorphone makes up 10% of the recovered dose. Free and conjugated oxycodone makes up 8.9% of the recovered dose, noroxymorphone makes up 14%, and reduced metabolites make up 18%.

Innovators Monograph

You find simplified version here Endone