OXYCODONE HYDROCHLORIDE

OXYCODONE HYDROCHLORIDE- oxycodone hydrochloride tablet, film coated, extended release
RedPharm Drug, Inc.

WARNING: ADDICTION, ABUSE AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; AND CYTOCHROME P450 3A4 INTERACTION

Addiction, Abuse, and Misuse

OXYCODONE HCl EXTENDED-RELEASE TABLETS expose patients and other users to the risks of opioid addiction, abuse and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing OXYCODONE HCl EXTENDED-RELEASE TABLETS and monitor all patients regularly for the development of these behaviors or conditions [see Warnings and Precautions (5.1)].

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression may occur with use of OXYCODONE HCl EXTENDED-RELEASE TABLETS. Monitor for respiratory depression, especially during initiation of OXYCODONE HCl EXTENDED-RELEASE TABLETS or following a dose increase. Instruct patients to swallow OXYCODONE HCl EXTENDED-RELEASE TABLETS whole; crushing, chewing, or dissolving OXYCODONE HCl EXTENDED-RELEASE TABLETS can cause rapid release and absorption of a potentially fatal dose of oxycodone [see Warnings and Precautions (5.2)].

Accidental Ingestion

Accidental ingestion of even one dose of OXYCODONE HCl EXTENDED-RELEASE TABLETS, especially by children, can result in a fatal overdose of oxycodone [see Warnings and Precautions (5.2)].

Neonatal Opioid Withdrawal Syndrome

Prolonged use of OXYCODONE HCl EXTENDED-RELEASE TABLETS during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.3)].

Cytochrome P450 3A4 Interaction

The concomitant use of OXYCODONE HCl EXTENDED-RELEASE TABLETS with all cytochrome P450 3A4 inhibitors may result in an increase in oxycodone plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in oxycodone plasma concentration. Monitor patients receiving OXYCODONE HCl EXTENDED-RELEASE TABLETS and any CYP3A4 inhibitor or inducer [see Warnings and Precautions (5.14) and Clinical Pharmacology (12.3)].

HIGHLIGHTS OF PRESCRIBING INFORMATION


These highlights do not include all the information needed to use OXYCODONE HCl EXTENDED-RELEASE TABLETS safely and effectively. See full prescribing information for OXYCODONE HCl EXTENDED-RELEASE TABLETS.
OXYCODONE HCL EXTENDED-RELEASE TABLETS, for oral use, CII
Initial U.S. Approval: 1950

WARNING: ADDICTION, ABUSE AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; AND CYTOCHROME P450 3A4 INTERACTION
SEE FULL PRESCRIBING INFORMATION FOR COMPLETE BOXED WARNING.

OXYCODONE HCl EXTENDED-RELEASE TABLETS expose users to risks of addictions, abuse and misuse, which can lead to overdose and death. Assess each patient’s risk before prescribing and monitor regularly for development of these behaviors and conditions. (5.1)
Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. Instruct patients to swallow OXYCODONE HCl EXTENDED-RELEASE TABLETS whole to avoid exposure to a potentially fatal dose of oxycodone. (5.2)
Accidental ingestion of OXYCODONE HCl EXTENDED-RELEASE TABLETS, especially in children, can result in a fatal overdose of oxycodone. (5.2)
Prolonged use of OXYCODONE HCl EXTENDED-RELEASE TABLETS during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. (5.3)
Initiation of CYP3A4 inhibitors (or discontinuation of CYP3A4 inducers) can result in a fatal overdose of oxycodone from OXYCODONE HCl EXTENDED-RELEASE TABLETS. (5.14, 12.3)

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: ADDICTION, ABUSE AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; AND CYTOCHROME P450 3A4 INTERACTION
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Important Dosage and Administration Instructions
2.2 Initial Dosage in Adults who are not Opioid-Tolerant
2.3 Conversion from Opioids to OXYCODONE HCl EXTENDED-RELEASE TABLETS in Adults
2.4 Initial Dosage in Pediatric Patients 11 Years and Older
2.5 Titration and Maintenance of Therapy in Adults and Pediatric Patients 11 Years and Older
2.6 Dosage Modifications with Concomitant Use of Central Nervous System Depressants
2.7 Dosage Modifications in Geriatric Patients who are Debilitated and not Opioid-Tolerant
2.8 Dosage Modifications in Patients with Hepatic Impairment
2.9 Discontinuation of OXYCODONE HCl EXTENDED-RELEASE TABLETS
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Addiction, Abuse, and Misuse
5.2 Life-Threatening Respiratory Depression
5.3 Neonatal Opioid Withdrawal Syndrome
5.4 Interactions with Central Nervous System Depressants
5.5 Use in Elderly, Cachectic, and Debilitated Patients
5.6 Use in Patients with Chronic Pulmonary Disease
5.7 Hypotensive Effects
5.8 Use in Patients with Head Injury or Increased Intracranial Pressure
5.9 Difficulty in Swallowing and Risk for Obstruction in Patients at Risk for a Small Gastrointestinal Lumen
5.10 Use in Patients with Gastrointestinal Conditions
5.11 Use in Patients with Convulsive or Seizure Disorders
5.12 Avoidance of Withdrawal
5.13 Driving and Operating Machinery
5.14 Cytochrome P450 3A4 Inhibitors and Inducers
5.15 Laboratory Monitoring
6 ADVERSE REACTIONS
6.1 Clinical Trial Experience
6.2 Postmarketing Experience
7 DRUG INTERACTIONS
7.1 CNS Depressants
7.2 Drugs Affecting Cytochrome P450 Isoenzymes
7.3 Mixed Agonist/Antagonist and Partial Agonists Opioid Analgesics
7.4 Muscle Relaxants
7.5 Diuretics
7.6 Anticholinergics
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Labor and Delivery
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Hepatic Impairment
8.7 Renal Impairment
8.8 Gender Differences
9 DRUG ABUSE AND DEPENDENCE
9.1 Controlled Substance
9.2 Abuse
9.3 Dependence
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION

*
Sections or subsections omitted from the full prescribing information are not listed.

1 INDICATIONS AND USAGE

OXYCODONE HCl EXTENDED-RELEASE TABLETS are indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate in:

Adults; and
Opioid-tolerant pediatric patients 11 years of age and older who are already receiving and tolerate a minimum daily opioid dose of at least 20 mg oxycodone orally or its equivalent.

Limitations of Use

Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations [see Warnings and Precautions (5.1)], reserve OXYCODONE HCl EXTENDED-RELEASE TABLETS for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.
OXYCODONE HCl EXTENDED-RELEASE TABLETS are not indicated as an as-needed (prn) analgesic.

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosage and Administration Instructions

OXYCODONE HCl EXTENDED-RELEASE TABLETS should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.

Initiate the dosing regimen for each patient individually, taking into account the patient’s prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)].
Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating OXYCODONE HCl EXTENDED-RELEASE TABLETS therapy [see Warnings and Precautions (5.2)].
Must take OXYCODONE HCl EXTENDED-RELEASE TABLETS whole, with enough water to ensure complete swallowing immediately after placing in the mouth. Must take OXYCODONE HCl EXTENDED-RELEASE TABLETS one tablet at a time and must not pre-soak, lick or otherwise wet the tablet prior to placing in the mouth [see Warnings and Precautions (5.9)].Cutting, breaking, crushing, chewing, or dissolving OXYCODONE HCl EXTENDED-RELEASE TABLETS will result in uncontrolled delivery of oxycodone and can lead to overdose or death [see Warnings and Precautions (5.1)].

OXYCODONE HCl EXTENDED-RELEASE TABLETS 60 mg and 80 mg tablets, a single dose greater than 40 mg, or a total daily dose greater than 80 mg are only for use in patients in whom tolerance to an opioid of comparable potency has been established.

2.2 Initial Dosage in Adults who are not Opioid-Tolerant

The starting dosage for patients who are not opioid tolerant is OXYCODONE HCl EXTENDED-RELEASE TABLETS 10 mg orally every 12 hours. Adult patients who are opioid tolerant are those receiving, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, or an equianalgesic dose of another opioid.

Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression [see Warnings and Precautions (5.2)].

2.3 Conversion from Opioids to OXYCODONE HCl EXTENDED-RELEASE TABLETS in Adults

Conversion from Other Oral Oxycodone Formulations to OXYCODONE HCl EXTENDED-RELEASE TABLETS

If switching from other oral oxycodone formulations to OXYCODONE HCl EXTENDED-RELEASE TABLETS, administer one half of the patient’s total daily oral oxycodone dose as OXYCODONE HCl EXTENDED-RELEASE TABLETS every 12 hours.

Conversion from Other Opioids to OXYCODONE HCl EXTENDED-RELEASE TABLETS

There are no established conversion ratios for conversion from other opioids to OXYCODONE HCl EXTENDED-RELEASE TABLETS defined by clinical trials. Discontinue all other around-the-clock opioid drugs when OXYCODONE HCl EXTENDED-RELEASE TABLETS therapy is initiated and initiate dosing using OXYCODONE HCl EXTENDED-RELEASE TABLETS 10 mg orally every 12 hours.

It is safer to underestimate a patient’s 24-hour oral oxycodone requirements and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour oral oxycodone requirements which could result in adverse reactions. While useful tables of opioid equivalents are readily available, there is substantial inter-patient variability in the relative potency of different opioids.

Conversion from Methadone to OXYCODONE HCl EXTENDED-RELEASE TABLETS

Close monitoring is of particular importance when converting from methadone to other opioid agonists. The ratio between methadone and other opioid agonists may vary widely as a function of previous dose exposure. Methadone has a long half-life and can accumulate in the plasma.

Conversion from Transdermal Fentanyl to OXYCODONE HCl EXTENDED-RELEASE TABLETS

If switching from transdermal fentanyl patch to OXYCODONE HCl EXTENDED-RELEASE TABLETS, ensure that the patch has been removed for at least 18 hours prior to starting OXYCODONE HCI EXTENDED-RELEASE TABLETS. Although there has been no systematic assessment of such conversion, start with a conservative conversion: substitute 10 mg of OXYCODONE HCI EXTENDED-RELEASE TABLETS every 12 hours for each 25 mcg per hour fentanyl transdermal patch. Follow the patient closely during conversion from transdermal fentanyl to OXYCODONE HCl EXTENDED-RELEASE TABLETS, as there is limited documented experience with this conversion.

2.4 Initial Dosage in Pediatric Patients 11 Years and Older

The following dosing information is for use only in pediatric patients 11 years and older already receiving and tolerating opioids for at least five consecutive days. For the two days immediately preceding dosing with OXYCODONE HCl EXTENDED-RELEASE TABLETS, patients must be taking a minimum of 20 mg per day of oxycodone or its equivalent. OXYCODONE HCl EXTENDED-RELEASE TABLETS is not appropriate for use in pediatric patients requiring less than a 20 mg total daily dose. Table 1, based on clinical trial experience, displays the conversion factor when switching pediatric patients 11 years and older (under the conditions described above) from opioids to OXYCODONE HCl EXTENDED-RELEASE TABLETS.

Discontinue all other around-the-clock opioid drugs when OXYCODONE HCl EXTENDED-RELEASE TABLETS therapy is initiated.

Although tables of oral and parenteral equivalents are readily available, there is substantial inter-patient variability in the relative potency of different opioid drugs and formulations. As such, it is preferable to underestimate a patient’s 24-hour oral oxycodone requirements and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour oral oxycodone requirements and manage an adverse reaction.

Consider the following when using the information in Table 1.

This is not a table of equianalgesic doses.

The conversion factors in this table are only for the conversion from one of the listed oral opioid analgesics to OXYCODONE HCl EXTENDED-RELEASE TABLETS.

The table cannot be used to convert from OXYCODONE HCl EXTENDED-RELEASE TABLETS to another opioid. Doing so will result in an over-estimation of the dose of the new opioid and may result in fatal overdose.

The formula for conversion from prior opioids, including oral oxycodone, to the daily dose of OXYCODONE HCl EXTENDED-RELEASE TABLETS is mg per day of prior opioid x factor = mg per day of OXYCODONE HCl EXTENDED-RELEASE TABLETS. Divide the calculated total daily dose by 2 to get the every-12-hour OXYCODONE HCl EXTENDED-RELEASE TABLETS dose. If rounding is necessary, always round the dose down to the nearest OXYCODONE HCl EXTENDED-RELEASE TABLET strength available.

Table 1: Conversion Factors When Switching Pediatric Patients 11 Years and Older to OXYCODONE HCl EXTENDED-RELEASE TABLETS

*
For patients receiving high-dose parenteral opioids, a more conservative conversion is warranted. For example, for high-dose parenteral morphine, use 1.5 instead of 3 as a multiplication factor.

Prior Opioid Conversion Factor
Oral Parenteral*
Oxycodone 1 —
Hydrocodone 0.9 —
Hydromorphone 4 20
Morphine 0.5 3
Tramadol 0.17 0.2

Step #1: To calculate the estimated total OXYCODONE HCl EXTENDED-RELEASE TABLETS daily dosage using Table 1:

For pediatric patients taking a single opioid, sum the current total daily dosage of the opioid and then multiply the total daily dosage by the approximate conversion factor to calculate the approximate OXYCODONE HCl EXTENDED-RELEASE TABLETS daily dosage.

For pediatric patients on a regimen of more than one opioid, calculate the approximate oxycodone dose for each opioid and sum the totals to obtain the approximate OXYCODONE HCl EXTENDED-RELEASE TABLETS daily dosage.

For pediatric patients on a regimen of fixed-ratio opioid/non-opioid analgesic products, use only the opioid component of these products in the conversion.

Step #2: If rounding is necessary, always round the dosage down to the nearest OXYCODONE HCl EXTENDED-RELEASE TABLET strength available and initiate OXYCODONE HCl EXTENDED-RELEASE TABLETS therapy with that dose. If the calculated OXYCODONE HCl EXTENDED-RELEASE TABLETS total daily dosage is less than 20 mg, there is no safe strength for conversion and do not initiate OXYCODONE HCl EXTENDED-RELEASE TABLETS.

Example conversion from a single opioid (e.g., hydrocodone) to OXYCODONE HCl EXTENDED-RELEASE TABLETS: Using theconversion factor of 0.9 for oral hydrocodone in Table 1, a total daily hydrocodone dosage of 50 mg is converted to 45 mg of oxycodone per day or 22.5 mg of OXYCODONE HCl EXTENDED-RELEASE TABLETS every 12 hours. After rounding down to the nearest strength available, the recommended OXYCODONE HCl EXTENDED-RELEASE TABLETS starting dosage is 20 mg every 12 hours.

Step #3: Close observation and titration are warranted until pain management is stable on the new opioid. Monitor patients for signs and symptoms of opioid withdrawal or for signs of over-sedation/toxicity after converting patients to OXYCODONE HCl EXTENDED-RELEASE TABLETS. [seeDosage and Administration (2.5)] for important instructions on titration and maintenance of therapy.

There is limited experience with conversion from transdermal fentanyl to OXYCODONE HCl EXTENDED-RELEASE TABLETS in pediatric patients 11 years and older. If switching from transdermal fentanyl patch to OXYCODONE HCl EXTENDED-RELEASE TABLETS, ensure that the patch has been removed for at least 18 hours prior to starting OXYCODONE HCl EXTENDED-RELEASE TABLETS. Although there has been no systematic assessment of such conversion, start with a conservative conversion: substitute 10 mg of OXYCODONE HCl EXTENDED-RELEASE TABLETS every 12 hours for each 25 mcg per hour fentanyl transdermal patch. Follow the patient closely during conversion from transdermal fentanyl to OXYCODONE HCl EXTENDED-RELEASE TABLETS.

If using asymmetric dosing, instruct patients to take the higher dose in the morning and the lower dose in the evening.

2.5 Titration and Maintenance of Therapy in Adults and Pediatric Patients 11 Years and Older

Individually titrate OXYCODONE HCl EXTENDED-RELEASE TABLETS to a dosage that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving OXYCODONE HCl EXTENDED-RELEASE TABLETS to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and adverse reactions, as well as monitoring for the development of addiction, abuse and misuse. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During chronic therapy, periodically reassess the continued need for the use of opioid analgesics.

Patients who experience breakthrough pain may require a dosage increase of OXYCODONE HCl EXTENDED-RELEASE TABLETS or may need rescue medication with an appropriate dose of an immediate-release analgesic. If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the OXYCODONE HCl EXTENDED-RELEASE TABLETS dosage. Because steady-state plasma concentrations are approximated in 1 day, OXYCODONE HCl EXTENDED-RELEASE TABLETS dosage may be adjusted every 1 to 2 days. If unacceptable opioid-related adverse reactions are observed, the subsequent dose may be reduced. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

There are no well-controlled clinical studies evaluating the safety and efficacy with dosing more frequently than every 12 hours. As a guideline for pediatric patients 11 years and older, the total daily oxycodone dosage usually can be increased by 25% of the current total daily dosage. As a guideline for adults, the total daily oxycodone dosage usually can be increased by 25% to 50% of the current total daily dosage, each time an increase is clinically indicated.

2.6 Dosage Modifications with Concomitant Use of Central Nervous System Depressants

If the patient is currently taking a central nervous system (CNS) depressant and the decision is made to begin OXYCODONE HCl EXTENDED-RELEASE TABLETS, start with 1/3 to 1/2 the recommended starting dosage of OXYCODONE HCl EXTENDED-RELEASE TABLETS and monitor patients for signs of respiratory depression, sedation, and hypotension [see Warnings and Precautions (5.4), Drug Interactions (7.1)].

2.7 Dosage Modifications in Geriatric Patients who are Debilitated and not Opioid-Tolerant

For geriatric patients who are debilitated and not opioid tolerant, start dosing patients at 1/3 to 1/2 the recommended starting dosage and titrate the dosage cautiously [see Use in Specific Populations (8.5)].

2.8 Dosage Modifications in Patients with Hepatic Impairment

For patients with hepatic impairment, start dosing patients at 1/3 to 1/2 the recommended starting dosage followed by careful dosage titration [see Clinical Pharmacology (12.3)].

2.9 Discontinuation of OXYCODONE HCl EXTENDED-RELEASE TABLETS

When the patient no longer requires therapy with OXYCODONE HCl EXTENDED-RELEASE TABLETS, gradually titrate the dosage downward to prevent signs and symptoms of withdrawal in the physically dependent patient. Do not abruptly discontinue OXYCODONE HCl EXTENDED-RELEASE TABLETS.

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