Roxicodone 15, 30 mg (Oxycodone Hydrochloride ): Side Effects, Uses, Dosage, Interactions, Warnings (2024)

Description for Roxicodone 15, 30 mg

ROXICODONE^® (oxycodone hydrochloride tablets USP) is an opioid analgesic.

Each tablet for oral administration contains 5 mg, 15 mg or 30 mg of oxycodone hydrochloride USP.

Oxycodone hydrochloride is a white, odorless crystalline powder derived from the opium alkaloid, thebaine. Oxycodone hydrochloride dissolves in water (1 g in 6 to 7 mL) and is considered slightly soluble in alcohol (octanol water partition coefficient is 0.7).

Chemically, oxycodone hydrochloride is 4, 5α-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6- one hydrochloride and has the following structural formula:

The 5 mg ROXICODONE^® tablet contains inactive ingredients: microcrystalline cellulose and stearic acid. The 15 mg and 30 mg tablets contain the following inactive ingredients: microcrystalline cellulose; sodium starch glycolate; corn starch; lactose; stearic acid; D&C Yellow No. 10 (15 mg tablet); and FD&C Blue No. 2 (15 mg and 30 mg tablets).

The 5 mg, 15 mg and 30 mg tablets contain the equivalent of 4.5 mg, 13.5 mg and 27.0 mg, respectively, of oxycodone free base.

Uses for Roxicodone 15, 30 mg

ROXICODONE^® tablets are an immediate-release oral formulation of oxycodone hydrochlorideindicated for the management of moderate to severe pain where the use of an opioid analgesic isappropriate.

Dosage for Roxicodone 15, 30 mg

ROXICODONE^® is intended for the management of moderate to severe pain in patients who requiretreatment with an oral opioid analgesic. The dose should be individually adjusted according to severityof pain, patient response and patient size. If the pain increases in severity, if analgesia is not adequate, orif tolerance occurs, a gradual increase in dosage may be required.

Patients who have not been receiving opioid analgesics should be started on ROXICODONE^® in adosing range of 5 to 15 mg every 4 to 6 hours as needed for pain. The dose should be titrated basedupon the individual patient’s response to their initial dose of ROXICODONE^® . Patients with chronicpain should have their dosage given on an around-the-clock basis to prevent the reoccurrence of painrather than treating the pain after it has occurred. This dose can then be adjusted to an acceptable levelof analgesia taking into account side effects experienced by the patient.

For control of severe chronic pain, ROXICODONE^® should be administered on a regularly scheduledbasis, every 4 to 6 hours, at the lowest dosage level that will achieve adequate analgesia.

As with any potent opioid, it is critical to adjust the dosing regimen for each patient individually, takinginto account the patient’s prior analgesic treatment experience. Although it is not possible to list everycondition that is important to the selection of the initial dose of ROXICODONE^® , attention should begiven to: 1) the daily dose, potency, and characteristics of a pure agonist or mixed agonist/antagonist thepatient has been taking previously, 2) the reliability of the relative potency estimate to calculate the doseof oxycodone needed, 3) the degree of opioid tolerance, 4) the general condition and medical status ofthe patient, and 5) the balance between pain control and adverse experiences.

Conversion From Fixed-Ratio Opioid/Acetaminophen, Opioid/Aspirin, or Opioid/Nonsteroidal

Combination Drugs

When converting patients from fixed ratio opioid/non-opioid drug regimens a decision should be madewhether or not to continue the non-opioid analgesic. If a decision is made to discontinue the use of nonopioidanalgesic, it may be necessary to titrate the dose of ROXICODONE^® in response to the level ofanalgesia and adverse effects afforded by the dosing regimen. If the non-opioid regimen is continued asa separate single entity agent, the starting dose ROXICODONE^® should be based upon the most recentdose of opioid as a baseline for further titration of oxycodone. Incremental increases should be gaugedaccording to side effects to an acceptable level of analgesia.

Patients Currently On Opioid Therapy

If a patient has been receiving opioid-containing medications prior to taking ROXICODONE^® , thepotency of the prior opioid relative to oxycodone should be factored into the selection of the total dailydose (TDD) of oxycodone.

In converting patients from other opioids to ROXICODONE^® close observation and adjustment ofdosage based upon the patient’s response to ROXICODONE^® is imperative. Administration ofsupplemental analgesia for breakthrough or incident pain and titration of the total daily dose ofROXICODONE^® may be necessary, especially in patients who have disease states that are changingrapidly.

Maintenance Of Therapy

Continual re-evaluation of the patient receiving ROXICODONE^® is important, with special attention tothe maintenance of pain control and the relative incidence of side effects associated with therapy. If thelevel of pain increases, effort should be made to identify the source of increased pain, while adjustingthe dose as described above to decrease the level of pain.

During chronic therapy, especially for non-cancer-related pain (or pain associated with other terminalillnesses), the continued need for the use of opioid analgesics should be re-assessed as appropriate.

Cessation Of Therapy

When a patient no longer requires therapy with ROXICODONE^® or other opioid analgesics for thetreatment of their pain, it is important that therapy be gradually discontinued over time to prevent thedevelopment of an opioid abstinence syndrome (narcotic withdrawal). In general, therapy can bedecreased by 25% to 50% per day with careful monitoring for signs and symptoms of withdrawal(see Drug Abuse And Dependence section for description of the signs and symptoms ofwithdrawal). If the patient develops these signs or symptoms, the dose should be raised to the previouslevel and titrated down more slowly, either by increasing the interval between decreases, decreasing theamount of change in dose, or both. It is not known at what dose of ROXICODONE^® that treatment maybe discontinued without risk of the opioid abstinence syndrome.

HOW SUPPLIED

ROXICODONE^®® (oxycodone hydrochloride tablets USP) are available as follows:

5 mg white tablets scored (Identified 54 582)
[Embossed 54 582 on one side]

NDC 23635-580-25: Unit Dose, 25 tablets per card, 4 cards per shipper
NDC 23635-580-10: Bottles of 100 tablets

15 mg green tablets scored (Identified 54 710)
[Embossed 54 710 on one side]

NDC 23635-581-10: Bottles of 100 tablets

30 mg blue tablets scored (Identified 54 199)
[Embossed 54 199 on one side]

NDC 23635-582-10: Bottles of 100 tablets

DEA Order Form Required

Dispense in a tight, light-resistant container.
Protect from moisture.
Store at 25°C (77°F); excursions are permitted to 15° to 30°C (59° to 86°F) [see USP Controlled RoomTemperature].

Mallinckrodt, the “M” brand mark, the Mallinckrodt Pharmaceuticals logo and other brands aretrademarks of a Mallinckrodt company.

Distributed by: Mallinckrodt Brand Pharmaceuticals, Inc. Hazelwood, MO 63042 USA. Revised: Jan 2014

Side Effects for Roxicodone 15, 30 mg

ROXICODONE^® tablets have been evaluated in open label clinical trials in patients with cancer andnonmalignant pain. ROXICODONE^® tablets are associated with adverse experiences similar to thoseseen with other opioids.

Serious adverse reactions that may be associated with ROXICODONE^® therapy in clinical use arethose observed with other opioid analgesics and include: respiratory depression, respiratory arrest,circulatory depression, cardiac arrest, hypotension, and/or shock (see OVERDOSE, WARNINGS).

The less severe adverse events seen on initiation of therapy with ROXICODONE^® are also typicalopioid side effects. These events are dose dependent, and their frequency depends on the clinicalsetting, the patient’s level of opioid tolerance, and host factors specific to the individual. They shouldbe expected and managed as a part of opioid analgesia. The most frequent of these include nausea,constipation, vomiting, headache, and pruritus.

In many cases the frequency of adverse events during initiation of opioid therapy may be minimized bycareful individualization of starting dosage, slow titration and the avoidance of large rapid swings inplasma concentration of the opioid. Many of these adverse events will abate as therapy is continued andsome degree of tolerance is developed, but others may be expected to remain throughout therapy.

In all patients for whom dosing information was available (n=191) from the open-label and double-blindstudies involving ROXICODONE^® , the following adverse events were recorded in ROXICODONE^®treated patients with an incidence ≥ 3%. In descending order of frequency they were: nausea,constipation, vomiting, headache, pruritus, insomnia, dizziness, asthenia, and somnolence.

The following adverse experiences occurred in less than 3% of patients involved in clinical trials withoxycodone:

Body As A Whole

abdominal pain, accidental injury, allergic reaction, back pain, chills and fever, fever,flu syndrome, infection, neck pain, pain, photosensitivity reaction, and sepsis.

Cardiovascular

deep thrombophlebitis, heart failure, hemorrhage, hypotension, migraine, palpitation,and tachycardia.

Digestive

anorexia, diarrhea, dyspepsia, dysphagia, gingivitis, glossitis, and nausea and vomiting.

Hemic And Lymphatic

anemia and leukopenia.

Metabolic And Nutritional

edema, gout, hyperglycemia, iron deficiency anemia and peripheral edema.

Musculoskeletal

arthralgia, arthritis, bone pain, myalgia and pathological fracture.

Nervous

agitation, anxiety, confusion, dry mouth, hypertonia, hypesthesia, nervousness, neuralgia,personality disorder, tremor, and vasodilation.

Respiratory

bronchitis, cough increased, dyspnea, epistaxis, laryngismus, lung disorder, pharyngitis,rhinitis, and sinusitis.

Skin And Appendages

herpes simplex, rash, sweating, and urticaria.

Special Senses

amblyopia.

Urogenital

urinary tract infection.

Postmarketing Experience

Review of postmarketing reports showed the occurrence of the following adverse events:

Cardiac disorders: myocardial ischemia and ventricular fibrillation with overdose

General disorders and administrative site disorders: drug withdrawal syndrome neonatal

Immune system disorders: anaphylactic reactions

Respiratory, thoracic and mediastinal disorders: pharyngeal edema

Drug Interactions for Roxicodone 15, 30 mg

Oxycodone is metabolized in part to oxymorphone via the cytochrome p450 isoenzyme CYP2D6. Whilethis pathway may be blocked by a variety of drugs (e.g., certain cardiovascular drugs andantidepressants), such blockade has not yet been shown to be of clinical significance with this agent.However, clinicians should be aware of this possible interaction.

Neuromuscular Blocking Agents

Oxycodone, as well as other opioid analgesics, may enhance theneuromuscular blocking action of skeletal muscle relaxants and produce an increased degree ofrespiratory depression. Review of postmarketing reports has also shown that muscle relaxants, such ascyclobenzaprine, when used with oxycodone may potentially enhance serotonergic activity and result inthe development of serotonin syndrome.

CNS Depressants

Patients receiving narcotic analgesics, general anesthetics, phenothiazines, othertranquilizers, sedative-hypnotics or other CNS depressants (including alcohol) concomitantly withROXICODONE^® may exhibit an additive CNS depression. Interactive effects resulting in respiratorydepression, hypotension, profound sedation, or coma may result if these drugs are taken in combinationwith the usual dosage of ROXICODONE^® . When such combined therapy is contemplated, the dose ofone or both agents should be reduced.

Mixed Agonist/Antagonist Opioid Analgesics

Agonist/antagonist analgesics (i.e., pentazocine,nalbuphine, butorphanol and buprenorphine) should be administered with caution to patients who havereceived or are receiving a course of therapy with a pure opioid agonist analgesic such asROXICODONE^® . In this situation, mixed agonist/antagonist analgesics may reduce the analgesic effectof ROXICODONE^® and/or may precipitate withdrawal symptoms in these patients.

Monoamine Oxidase Inhibitors (MAOIs)

MAOIs have been reported to intensify the effects of at leastone opioid drug causing anxiety, confusion and significant depression of respiration or coma. The useof ROXICODONE^® is not recommended for patients taking MAOIs or within 14 days of stopping suchtreatment. Review of postmarketing reports has also shown that MAOIs, such as phenelzine, when usedwith oxycodone may potentially enhance serotonergic activity and result in the development ofserotonin syndrome.

Other Antidepressants (Tricyclic Antidepressant Or TCA, Serotonin-Norepinephrine Reuptake InhibitorOr SNRI And Selective Serotonin Reuptake Inhibitor Or SSRI

Review of postmarketing reports hasshown that other antidepressants, such as TCAs (e.g. doxepine), SSRIs (e.g. fluvoxamine) and SNRIs(e.g. duloxetine and venlafaxine), when used with oxycodone may potentially enhance serotonergicactivity and result in the development of serotonin syndrome.

Drug Abuse And Dependence

Controlled Substance

ROXICODONE^® contains oxycodone, a mu-agonist opioid of the morphine type and is aSchedule II controlled substance. ROXICODONE^®, like other opioids used in analgesia, can beabused and is subject to criminal diversion.

Abuse

Drug addiction is characterized by compulsive use, use for non-medical purposes, and continued usedespite harm or risk of harm. Drug addiction is a treatable disease, utilizing a multi-disciplinaryapproach, but relapse is common.

“Drug-seeking” behavior is very common in addicts and drug abusers. Drug-seeking tactics includeemergency calls or visits near the end of office hours, refusal to undergo appropriate examination,testing or referral, repeated “loss” of prescriptions, tampering with prescriptions and reluctance toprovide prior medical records or contact information for other treating physician(s). “Doctor shopping”to obtain additional prescriptions is common among drug abusers and people suffering from untreatedaddiction.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Physiciansshould be aware that addiction may not be accompanied by concurrent tolerance and symptoms ofphysical dependence. In addition, abuse of opioids can occur in the absence of true addiction and ischaracterized by misuse for nonmedical purposes, often in combination with other psychoactivesubstances. Careful record-keeping of prescribing information, including quantity, frequency, andrenewal requests is strongly advised.

ROXICODONE^® is intended for oral use only. Abuse of ROXICODONE^® poses a risk ofoverdose and death. The risk is increased with concurrent abuse of alcohol and othersubstances. Parenteral drug abuse is commonly associated with transmission of infectiousdiseases such as hepatitis and HIV.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, andproper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Infants born to mothers physically dependent on opioids will also be physically dependent andmay exhibit respiratory difficulties and withdrawal symptoms.

Dependence

Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (inthe absence of disease progression or other external factors). Physical dependence is manifested bywithdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist.Physical dependence and tolerance are not unusual during chronic opioid therapy.

The opioid abstinence or withdrawal syndrome is characterized by some or all of the following:restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Othersymptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominalcramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, orheart rate. In general, opioids should not be abruptly discontinued.

Warnings for Roxicodone 15, 30 mg

Respiratory Depression

Respiratory depression is the chief hazard from all opioid agonist preparations. Respiratory depressionoccurs most frequently in elderly or debilitated patients, usually following large initial doses in nontolerantpatients, or when opioids are given in conjunction with other agents that depress respiration.

ROXICODONE^® should be used with extreme caution in patients with significant chronic obstructivepulmonary disease or cor pulmonale, and in patients having substantially decreased respiratory reserve,hypoxia, hypercapnia, or pre-existing respiratory depression. In such patients, even usual therapeuticdoses of ROXICODONE^® may decrease respiratory drive to the point of apnea. In these patientsalternative non-opioid analgesics should be considered, and opioids should be employed only undercareful medical supervision at the lowest effective dose.

Hypotensive Effect

ROXICODONE^® , like all opioid analgesics, may cause severe hypotension in an individual whoseability to maintain blood pressure has been compromised by a depleted blood volume, or afterconcurrent administration with drugs such as phenothiazines or other agents which compromisevasomotor tone. ROXICODONE^® may produce orthostatic hypotension in ambulatory patients.ROXICODONE^® , like all opioid analgesics, should be administered with caution to patients incirculatory shock, since vasodilatation produced by the drug may further reduce cardiac output andblood pressure.

Head Injury And Increased Intracranial Pressure

The respiratory depressant effects of narcotics and their capacity to elevate cerebrospinal fluidpressure may be markedly exaggerated in the presence of head injury, other intracranial lesions or apre-existing increase in intracranial pressure. Furthermore, narcotics produce adverse reactions whichmay obscure the clinical course of patients with head injuries.

Precautions for Roxicodone 15, 30 mg

General

ROXICODONE^® tablets are intended for use in patients who require oral pain therapy with an opioidagonist. As with any opioid analgesic, it is critical to adjust the dosing regimen individually for eachpatient (see DOSAGE AND ADMINISTRATION).

Selection of patients for treatment with ROXICODONE^® should be governed by the same principlesthat apply to the use of other potent opioid analgesics. Opioid analgesics given on a fixed-dosageschedule have a narrow therapeutic index in certain patient populations, especially when combined withother drugs, and should be reserved for cases where the benefits of opioid analgesia outweigh theknown risks of respiratory depression, altered mental state, and postural hypotension. Physicians shouldindividualize treatment in every case, using nonopioid analgesics, prn opioids and/or combinationproducts, and chronic opioid therapy with drugs such as ROXICODONE^® (oxycodone hydrochloride)in a progressive plan of pain management such as outlined by the World Health Organization, theAgency for Health Care Policy and Research, and the American Pain Society.

Use of ROXICODONE^® is associated with increased potential risks and should be used only withcaution in the following conditions: acute alcoholism; adrenocortical insufficiency (e.g., Addison’sdisease); convulsive disorders; CNS depression or coma; delirium tremens; debilitated patients;kyphoscoliosis associated with respiratory depression; myxedema or hypothyroidism; prostatichypertrophy or urethral stricture; severe impairment of hepatic, pulmonary or renal function; and toxicpsychosis.

The administration of ROXICODONE^® , like all opioid analgesics, may obscure the diagnosis orclinical course in patients with acute abdominal conditions. Oxycodone may aggravate convulsions inpatients with convulsive disorders, and all opioids may induce or aggravate seizures in some clinicalsettings.

Tolerance And Physical Dependence

Physical dependence and tolerance are not unusual during chronic opioid therapy. Significant toleranceshould not occur in most patients treated with the lowest doses of oxycodone. It should be expected,however, that a fraction of patients will develop some degree of tolerance and require progressivelyhigher dosages of ROXICODONE^® to maintain pain control during chronic treatment. The dosageshould be selected according to the patient’s individual analgesic response and ability to tolerate sideeffects. Tolerance to the analgesic effects of opioids is usually paralleled by tolerance to side effectsexcept for constipation.

Physical dependence results in withdrawal symptoms in patients who abruptly discontinue the drug ormay be precipitated through the administration of drugs with opioid antagonist activity. IfROXICODONE^® is abruptly discontinued in a physically dependent patient, an abstinence syndromemay occur (see Drug Abuse And Dependence). If signs and symptoms of withdrawal occur,patients should be treated by reinstitution of opioid therapy followed by gradual tapered dose reductionof ROXICODONE^® combined with symptomatic support (see DOSAGE AND ADMINISTRATION:Cessation of Therapy).

Use In Pancreatic/Biliary Tract Disease

ROXICODONE^® may cause spasm of the sphincter of Oddi and should be used with caution in patientswith biliary tract disease, including acute pancreatitis. Opioids like ROXICODONE^® may causeincreases in the serum amylase level.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Long-term studies have not been performed in animals to evaluate the carcinogenic potential ofROXICODONE^®® or oxycodone. The possible effects on male or female fertility have not been studiedin animals.

Oxycodone hydrochloride was genotoxic in an in vitro mouse lymphoma assay in the presence ofmetabolic activation. There was no evidence of genotoxic potential in an in vitro bacterial reversemutation assay (Salmonella typhimurium and Escherichia coli) or in an assay for chromosomal aberrations(in vivo mouse bone marrow micronucleus assay).

Pregnancy

Teratogenic Effects

Category B

Reproduction studies in Sprague-Dawley rats and New Zealandrabbits revealed that when oxycodone was administered orally at doses up to 16 mg/kg (approximately 2times the daily oral dose of 90 mg for adults on a mg/m² basis) and 25 mg/kg (approximately 5 times thedaily oral dose of 90 mg on a mg/m² basis), respectively was not teratogenic or embryo-fetal toxic.There are no adequate and well controlled studies of oxycodone in pregnant women. Because animalreproductive studies are not always predictive of human responses, ROXICODONE^® should be usedduring pregnancy only if potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects

Neonates whose mothers have taken oxycodone chronically may exhibitrespiratory depression and/or withdrawal symptoms, either at birth and/or in the nursery.

Labor And Delivery

ROXICODONE^® is not recommended for use in women during or immediately prior to labor.Occasionally, opioid analgesics may prolong labor through actions which temporarily reduce thestrength, duration and frequency of uterine contractions. Neonates, whose mothers received opioidanalgesics during labor, should be observed closely for signs of respiratory depression. A specificnarcotic antagonist, naloxone, should be available for reversal of narcotic-induced respiratorydepression in the neonate.

Nursing Mothers

Oxycodone has been detected in breast milk. Withdrawal symptoms can occur in breast-feeding infantswhen maternal administration of an opioid analgesic is stopped. Ordinarily, nursing should not beundertaken while a patient is receiving ROXICODONE^® since oxycodone may be excreted in milk.

Pediatric Use

The safety and efficacy of oxycodone in pediatric patients have not been evaluated.

Geriatric Use

Of the total number of subjects in clinical studies of ROXICODONE^® , 20.8% (112/538) were 65 andover, while 7.2% (39/538) were 75 and over. No overall differences in safety or effectiveness wereobserved between these subjects and younger subjects, and other reported clinical experience has notidentified differences in responses between the elderly and younger patients, but greater sensitivity ofsome older individuals cannot be ruled out.

Hepatic Impairment

Since oxycodone is extensively metabolized, its clearance may decrease in hepatic failure patients.Dose initiation in patients with hepatic impairment should follow a conservative approach. Dosagesshould be adjusted according to the clinical situation.

Renal Impairment

Published data reported that elimination of oxycodone was impaired in end-stage renal failure. Meanelimination half-life was prolonged in uremic patients due to increased volume of distribution andreduced clearance. Dose initiation should follow a conservative approach. Dosages should be adjustedaccording to the clinical situation.

Ambulatory Patients

ROXICODONE^® may impair the mental and/or physical abilities required for the performance ofpotentially hazardous tasks such as driving a car or operating machinery. The patient using this drugshould be cautioned accordingly.

Overdose Information for Roxicodone 15, 30 mg

Signs And Symptoms

Acute overdose with ROXICODONE^® can be manifested by respiratory depression, somnolenceprogressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils,bradycardia, hypotension, and death.

Treatment

To treat ROXICODONE^® overdose, primary attention should be given to the re-establishment of apatent airway and institution of assisted or controlled ventilation. Supportive measures (includingoxygen and vasopressors) should be employed in the management of circulatory shock and pulmonaryedema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massageor defibrillation.

The narcotic antagonists, naloxone or nalmefene, are specific antidotes for opioid overdose. Opioidantagonists should not be administered in the absence of clinically significant respiratory orcirculatory depression secondary to ROXICODONE^® overdose. If needed the appropriate dose ofnaloxone hydrochloride or nalmefene should be administered simultaneously with efforts at respiratoryresuscitation (see package insert for each drug for the details). Since the duration of action ofoxycodone may exceed that of the antagonist, the patient should be kept under continued surveillanceand repeated doses of the antagonist should be administered as needed to maintain adequate respiration.Gastric emptying may be useful in removing unabsorbed drug.

Opioid antagonists should be administered cautiously to persons who are suspected to be physicallydependent on any opioid agonist, including oxycodone (see Opioid-Tolerant Individuals).

Opioid-Tolerant Individuals

In an individual physically dependent on opioids, administration of a usual dose of antagonist willprecipitate an acute withdrawal. The severity of the withdrawal syndrome produced will depend on thedegree of physical dependence and the dose of the antagonist administered. Use of an opioid antagonistshould be reserved for cases where such treatment is clearly needed. If it is necessary to treat seriousrespiratory depression in the physically dependent patient, administration of the antagonist should bebegun with care and by titration with smaller than usual doses.

Contraindications for Roxicodone 15, 30 mg

ROXICODONE^® is contraindicated in patients with known hypersensitivity to oxycodone, or in anysituation where opioids are contraindicated. This includes patients with significant respiratorydepression (in unmonitored settings or the absence of resuscitative equipment) and patients with acute orsevere bronchial asthma or hypercarbia. ROXICODONE^® is contraindicated in any patient who has oris suspected of having paralytic ileus.

Clinical Pharmacology for Roxicodone 15, 30 mg

Pharmacology

The analgesic ingredient, oxycodone, is a semi-synthetic narcotic with multiple actions qualitativelysimilar to those of morphine; the most prominent of these involves the central nervous system andorgans composed of smooth muscle.

Oxycodone, as the hydrochloride salt, is a pure agonist opioid whose principal therapeutic action isanalgesia and has been in clinical use since 1917. Like all pure opioid agonists, there is no ceilingeffect to analgesia, such as is seen with partial agonists or non-opioid analgesics. Based upon a singledose,relative-potency study conducted in humans with cancer pain, 10 to 15 mg of oxycodone givenintramuscularly produced an analgesic effect similar to 10 mg of morphine given intramuscularly. Bothdrugs have a 3 to 4 hour duration of action. Oxycodone retains approximately one half of its analgesicactivity when administered orally.

Effects On Central Nervous System

The precise mechanism of the analgesic action is unknown.However, specific CNS opioid receptors for endogenous compounds with opioid-like activity havebeen identified throughout the brain and spinal cord and play a role in the analgesic effects of this drug.A significant feature of opioid-induced analgesia is that it occurs without loss of consciousness. Therelief of pain by morphine-like opioids is relatively selective, in that other sensory modalities, (e.g.,touch, vibrations, vision, hearing, etc.) are not obtunded.

Oxycodone produces respiratory depression by direct action on brain stem respiratory centers. Therespiratory depression involves both a reduction in the responsiveness of the brain stem respiratorycenters to increases in carbon dioxide tension and to electrical stimulation.

Oxycodone depresses the cough reflex by direct effect on the cough center in the medulla. Antitussiveeffects may occur with doses lower than those usually required for analgesia. Oxycodone causesmiosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic(e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Markedmydriasis rather than miosis may be seen due to hypoxia in overdose situations.

Effects On Gastrointestinal Tract And Other Smooth Muscle

Oxycodone, like other opioid analgesics,produces some degree of nausea and vomiting which is caused by direct stimulation of thechemoreceptor trigger zone (CTZ) located in the medulla. The frequency and severity of emesisgradually diminishes with time.

Oxycodone may cause a decrease in the secretion of hydrochloric acid in the stomach that reducesmotility while increasing the tone of the antrum, stomach, and duodenum. Digestion of food in the smallintestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colonare decreased, while tone may be increased to the point of spasm resulting in constipation. Otheropioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincterof Oddi, and transient elevations in serum amylase.

Effects On Cardiovascular System

Oxycodone, in therapeutic doses, produces peripheral vasodilatation(arteriolar and venous), decreased peripheral resistance, and inhibits baroreceptor reflexes.Manifestations of histamine release and/or peripheral vasodilatation may include pruritus, flushing, redeyes, sweating, and/or orthostatic hypotension.

Caution should be used in hypovolemic patients, such as those suffering acute myocardial infarction,because oxycodone may cause or further aggravate their hypotension. Caution should also be used inpatients with cor pulmonale who received therapeutic doses of opioids.

Pharmacodynamics

The relationship between the plasma level of oxycodone and the analgesic response will depend on thepatient’s age, state of health, medical condition and extent of previous opioid treatment.

The minimum effective plasma concentration of oxycodone to achieve analgesia will vary widelyamong patients, especially among patients who have been previously treated with potent agonist opioids.Thus, patients need to be treated with individualized titration of dosage to the desired effect. Theminimum effective analgesic concentration of oxycodone for any individual patient may increase withrepeated dosing due to an increase in pain and/or development of tolerance.

Pharmaco*kinetics

The activity of ROXICODONE^® (oxycodone hydrochloride) tablets is primarily due to the parent drugoxycodone. ROXICODONE^® tablets are designed to provide immediate release of oxycodone.

Table 1 Pharmaco*kinetic Parameters (Mean ± SD)

Absorption

About 60% to 87% of an oral dose of oxycodone reaches the systemic circulation incomparison to a parenteral dose. This high oral bioavailability (compared to other oral opioids) is dueto lower presystemic and/or first-pass metabolism of oxycodone. The relative oral bioavailability ofROXICODONE^® 15 mg and 30 mg tablets, compared to the 5 mg ROXICODONE^® tablets, is 96% and101% respectively. ROXICODONE^® 15 mg tablets and 30 mg tablets are bioequivalent to the 5 mgROXICODONE^® tablet (see Table 1 for pharmaco*kinetic parameters). Dose proportionality ofoxycodone has been established using the ROXICODONE^® 5 mg tablets at doses of 5 mg, 15 mg (three5 mg tablets) and 30 mg (six 5 mg tablets) based on extent of absorption (AUC) (see Figure 1). It takesapproximately 18 to 24 hours to reach steady-state plasma concentrations of oxycodone withROXICODONE^® .

Food Effect

A single-dose food effect study was conducted in normal volunteers using the 5 mg/5 mLsolution. The concurrent intake of a high fat meal was shown to enhance the extent (27% increase inAUC), but not the rate of oxycodone absorption from the oral solution (see Table 1). In addition, foodcaused a delay in Tmax (1.25 to 2.54 hour). Similar effects of food are expected with the 15 mg and 30mg tablets.

Distribution

Following intravenous administration, the volume of distribution (Vss) for oxycodone was2.6 L/kg. Plasma protein binding of oxycodone at 37°C and a pH of 7.4 was about 45%. Oxycodone hasbeen found in breast milk (see PRECAUTIONS-Nursing Mothers).

Metabolism

Oxycodone hydrochloride is extensively metabolized to noroxycodone, oxymorphone, andtheir glucuronides. The major circulating metabolite is noroxycodone with an AUC ratio of 0.6 relativeto that of oxycodone. Oxymorphone is present in the plasma only in low concentrations. The analgesicactivity profile of other metabolites is not known at present.

The formation of oxymorphone, but not noroxycodone, is mediated by CYP2D6 and as such itsformation can, in theory, be affected by other drugs (see DRUG INTERACTIONS).

Elimination

Oxycodone and its metabolites are excreted primarily via the kidney. The amountsmeasured in the urine have been reported as follows: free oxycodone up to 19%; conjugated oxycodoneup to 50%; free oxymorphone 0%; conjugated oxymorphone ≤ 14%; both free and conjugatednoroxycodone have been found in the urine but not quantified. The total plasma clearance was 0.8 L/minfor adults. Apparent elimination half-life of oxycodone following the administration ofROXICODONE^® was 3.5 to 4 hours.

Special Populations

Geriatric

Population pharmaco*kinetic studies conducted with ROXICODONE^® , indicated that theplasma concentrations of oxycodone did not appear to be increased in patients over the age of 65.

Gender

Population pharmaco*kinetic analyses performed in the clinical study support the lack of gendereffect on the pharmaco*kinetics of oxycodone from ROXICODONE^® .

Race

Population pharmaco*kinetic analyses support the lack of race effect on oxycodonepharmaco*kinetics after administration of ROXICODONE^® , but these data should be interpretedconservatively, since the majority of patients enrolled into the studies were Caucasians (94%).

Renal Insufficiency

In a clinical trial supporting the development of ROXICODONE^® , too few patientswith decreased renal function were evaluated to study these potential differences. In previous studies,patients with renal impairment (defined as a creatinine clearance < 60 mL/min) had concentrations ofoxycodone in the plasma that were higher than in subjects with normal renal function. Based oninformation available on the metabolism and excretion of oxycodone, dose initiation in patients withrenal impairment should follow a conservative approach. Dosages should be adjusted according to theclinical situation.

Hepatic Failure

In a clinical trial supporting the development of ROXICODONE^® , too few patientswith decreased hepatic function were evaluated to study these potential differences. However, sinceoxycodone is extensively metabolized, its clearance may decrease in hepatic failure patients. Doseinitiation in patients with hepatic impairment should follow a conservative approach. Dosages should beadjusted according to the clinical situation.

Patient Information for Roxicodone 15, 30 mg

If clinically advisable, patients (or their caregivers) receiving ROXICODONE^® (oxycodonehydrochloride) tablets should be given the following information by the physician, nurse, pharmacist orcaregiver:

1. Patients should be advised to report episodes of breakthrough pain and adverse experiencesoccurring during therapy. Individualization of dosage is essential to make optimal use of thismedication.
2. Patients should be advised not to adjust the dose of ROXICODONE^® without consulting theprescribing professional.
3. Patients should be advised that ROXICODONE^® may impair mental and/or physical ability requiredfor the performance of potentially hazardous tasks (e.g., driving, operating heavy machinery).
4. Patients should not combine ROXICODONE^® with alcohol or other central nervous systemdepressants (sleep aids, tranquilizers) except by the orders of the prescribing physician, becauseadditive effects may occur.
5. Women of childbearing potential who become, or are planning to become pregnant, should beadvised to consult their physician regarding the effects of analgesics and other drug use duringpregnancy on themselves and their unborn child.
6. Patients should be advised that ROXICODONE^® is a potential drug of abuse. They should protect itfrom theft, and it should never be given to anyone other than the individual for whom it wasprescribed.
7. Patients should be advised that if they have been receiving treatment with ROXICODONE^® formore than a few weeks and cessation of therapy is indicated, it may be appropriate to taper theROXICODONE^® dose, rather than abruptly discontinue it, due to the risk of precipitatingwithdrawal symptoms. Their physician can provide a dose schedule to accomplish a gradualdiscontinuation of the medication.