Oxycodone Hydrochloride (Page 8 of 9)
The activity of Oxycodone Hydrochloride Oral Solution is primarily due to the parent drug oxycodone.
The oral bioavailability of oxycodone is 60 — 87%. This high oral bioavailability (compared to other oral opioids) is due to lower pre-systemic and/or first-pass metabolism of oxycodone.
Presence of food may slightly delay the rate (Cmax and Tmax) and enhance the extent of absorption (AUC) of oxycodone from Oxycodone Hydrochloride Oral Solution. Overall, food is not expected to have a clinically significant impact on the absorption of Oxycodone Hydrochloride Oral Solution.
Following intravenous administration, the volume of distribution (Vss) for oxycodone was 2.6 L/kg. Plasma protein binding of oxycodone at 37°C and a pH of 7.4 was about 45%. Oxycodone has been found in breast milk [see Use in Specific Populations (8.2)].
Oxycodone hydrochloride is extensively metabolized to noroxycodone, oxymorphone, noroxymorphone, which are subsequently glucuronidated. CYP3A4 mediated N-demethylation to noroxycodone is the primary metabolic pathway of oxycodone with a less contribution from CYP2D6 mediated O-demethylation to oxymorphone. Therefore, the formation of these and related metabolites can, in theory, be affected by other drugs. The major circulating metabolite is noroxycodone with an AUC ratio of 0.6 relative to that of oxycodone. Noroxycodone is reported to be a considerably weaker analgesic than oxycodone. Oxymorphone, although possessing analgesic activity, is present in the plasma only in low concentrations. The correlation between oxymorphone concentrations and opioid effects was much less than that seen with oxycodone plasma concentrations. The analgesic activity profile of other metabolites is not known.
Oxycodone and its metabolites are excreted primarily via the kidney. The amounts measured in the urine have been reported as follows: free oxycodone up to 19%; conjugated oxycodone up to 50%; free oxymorphone 0%; conjugated oxymorphone ≤ 14%; both free and conjugated noroxycodone have been found in the urine but not quantified. The total plasma clearance was 0.8 L/min for adults. Apparent elimination half-life of oxycodone following the administration of Oxycodone Hydrochloride Oral Solution was approximately 3.5 hours.
Age: Geriatric Population
Information obtained from oxycodone tablets indicate that the plasma concentrations of oxycodone did not appear to be increased in patients over of the age of 65.
Because oxycodone is extensively metabolized in the liver, its clearance may decrease in hepatic-impaired patients. A dose adjustment is recommended in these patients [see Use in Special Populations (8.6)].
Because this drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function, a dose reduction is recommended for renal impaired patients [see Use in Special Populations (8.7)].
Drug Interactions Studies
CYP3A4 is the major enzyme involved in noroxycodone formation. A published study showed that the co-administration of voriconazole, a CYP3A4 inhibitor, increased oxycodone AUC and Cmax by 3.6 and 1.7 fold, respectively.
A published study showed that the co-administration of rifampin, a drug metabolizing enzyme inducer, decreased oxycodone AUC and Cmax values by 86% and 63%, respectively.
Oxycodone is metabolized in part to oxymorphone via the cytochrome p450 isoenzyme CYP2D6. While this pathway may be blocked by a variety of drugs (e.g., certain cardiovascular drugs and antidepressants), such blockade has not yet been shown to be of clinical significance with this agent.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals to evaluate the carcinogenic potential of oxycodone have not been conducted.
Oxycodone hydrochloride was genotoxic in an in vitro mouse lymphoma assay in the presence of metabolic activation. There was no evidence of genotoxic potential in an in vitro bacterial reverse mutation assay ( Salmonella typhimurium and Escherichia coli) or in an assay for chromosomal aberrations ( in vivo mouse bone marrow micronucleus assay).
Impairment of Fertility
Studies in animals to evaluate the potential impact of oxycodone on fertility have not been conducted.
16 HOW SUPPLIED/STORAGE AND HANDLING
Oxycodone Hydrochloride Oral Solution, USP, 5 mg per 5 mL (1 mg/mL) is available as follows:
NDC# 63629-1174-1: 16 fl. oz. (473 mL) bottle packaged with calibrated measuring cup
Dispense in a tight, light-resistant container as defined in the USP/NF.
Store at controlled room temperature 20°-25°C (68°- 77°F); excursions are permitted to 15° — 30°C (59° — 86°F). [See USP Controlled Room Temperature]
Store Oxycodone Hydrochloride Oral Solution securely and dispose of properly [see PATIENT COUNSELING INFORMATION (17)].
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Storage and Disposal:
Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store Oxycodone Hydrochloride Oral Solution securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home [see Warnings and Precautions (5.1, 5.2), Drug Abuse and Dependence (9.2)]. Inform patients that leaving Oxycodone Hydrochloride Oral Solution unsecured can pose a deadly risk to others in the home.
Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Expired, unwanted, or unused Oxycodone Hydrochloride Oral Solution should be disposed of by flushing the unused medication down the toilet if a drug take-back option is not readily available. Inform patients that they can visit www.fda.gov/drugdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines.
Advise patients that Oxycodone Hydrochloride Oral Solution, is available in multiple concentrations. Inform patients about which concentration they have been prescribed. Instruct patients how to measure and take the correct dose of Oxycodone Hydrochloride Oral Solution, and to always use the enclosed cup when administering Oxycodone Hydrochloride Oral Solution to ensure the dose is measured and administered accurately [see Warnings and Precautions (5.1)].
If the prescribed concentration is changed, instruct patients on how to correctly measure the new dose to avoid errors which could result in accidental overdose and death.
Addiction, Abuse, and Misuse
Inform patients that the use of Oxycodone Hydrochloride Oral Solution, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.2)]. Instruct patients not to share Oxycodone Hydrochloride Oral Solution with others and to take steps to protect Oxycodone Hydrochloride Oral Solution from theft or misuse.
Life-Threatening Respiratory Depression
Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting Oxycodone Hydrochloride Oral Solution or when the dosage is increased, and that it can occur even at recommended dosages. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Warnings and Precautions (5.4)].
Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose
Discuss with the patient and caregiver the availability of naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with Oxycodone Hydrochloride Oral Solution. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program) [see Dosage and Administration (2.2), Warnings and Precautions (5.4)].
Educate patients and caregivers on how to recognize the signs and symptoms of an overdose.
Explain to patients and caregivers that naloxone’s effects are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if naloxone is administered [see Overdosage (10)].
If naloxone is prescribed, also advise patients and caregivers:
• How to treat with naloxone in the event of an opioid overdose
• To tell family and friends about their naloxone and to keep it in a place where family and friends can access it in an emergency
• To read the Patient Information (or other educational material) that will come with their naloxone. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do.
Inform patients that accidental ingestion, especially by, children, may result in respiratory depression or death [see Warnings and Precautions (5.4)].
Interactions with Benzodiazepines and Other CNS Depressants
Inform patients and caregivers that potentially fatal additive effects may occur if Oxycodone Hydrochloride Oral Solution is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a health care provider [see Warnings and Precautions (5.7), Drug Interactions (7)].
Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications. [see Drug Interactions (7)].
Inform patients to avoid taking Oxycodone Hydrochloride Oral Solution while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking Oxycodone Hydrochloride Oral Solution [see Drug Interactions (7)]
Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions (5.9)].
Important Administration Instructions
Instruct patients how to properly take Oxycodone Hydrochloride Oral Solution. [see Dosage and Administration (2.1), Warnings and Precautions (5.1)]
• Advise patients to always use the enclosed calibrated dosing cup when administering Oxycodone Hydrochloride Oral Solution to ensure the dose is measured and administered accurately [see Warnings and Precautions (5.1)].
• Advise patients never to use household teaspoons or tablespoons to measure Oxycodone Hydrochloride Oral Solution.
• Advise patients not to adjust the dose of Oxycodone Hydrochloride Oral Solution without consulting with a physician or other healthcare provider.
Important Discontinuation Instructions
In order to avoid developing withdrawal symptoms, instruct patients not to discontinue Oxycodone Hydrochloride Oral Solution without first discussing a tapering plan with the prescriber [see Dosage and Administration (2.5)].
Inform patients that Oxycodone Hydrochloride Oral Solution may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see Warnings and Precautions (5.10)].
Inform patients that anaphylaxis has been reported with ingredients contained in Oxycodone Hydrochloride Oral Solution. Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications (4),Adverse Reactions (6)].
Neonatal Opioid Withdrawal Syndrome
Inform female patients of reproductive potential that prolonged use of Oxycodone Hydrochloride Oral Solution during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions (5.5), Use in Specific Populations (8.1)].
Inform female patients of reproductive potential that Oxycodone Hydrochloride Oral Solution can (or may) cause fetal harm and to inform the healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1)].
Advise nursing mothers to monitor infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct nursing mothers to seek immediate medical care if they notice these signs [see Use in Specific Populations (8.2)].
Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Populations (8.3)].
Driving or Operating Heavy Machinery
Inform patients that Oxycodone Hydrochloride Oral Solution may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see Warnings and Precautions (5.15)].
Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions (6), Clinical Pharmacology (12.2)].
WES Pharma Inc
Westminster, MD 21157
Eywa Pharma Inc.,
2 Research Way, Floor 3, Princeton, NJ 08540
To request medical information contact WES Pharma Inc at 1-888-212-6921.
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