NDA 20-553/S-022
`Page 4
`
`OXYCONTIN®
`
`CII
`
`(OXYCODONE HCl CONTROLLED-RELEASE) TABLETS
`
`PACKAGE INSERT
`
`10 mg 20 mg 40 mg 80 mg* 160 mg*
`*80 mg and 160 mg for use in opioid-tolerant patients only
`
`WARNING:
`OxyContin® is an opioid agonist and a Schedule II controlled substance with
`an abuse liability similar to morphine.
`Oxycodone can be abused in a manner similar to other opioid agonists, legal or
`illicit. This should be considered when prescribing or dispensing OxyContin in
`situations where the physician or pharmacist is concerned about an increased risk
`of misuse, abuse, or diversion.
`
`OxyContin® tablets are a controlled-release oral formulation of oxycodone
`hydrochloride indicated for the management of moderate to severe pain when
`a continuous, around-the-clock analgesic is needed for an extended period of
`time.
`OxyContin® tablets are NOT intended for use as a prn analgesic.
`
`OxyContin® 80 mg and 160 mg Tablets ARE FOR USE IN OPIOID TOLERANT
`PATIENTS ONLY. These tablet strengths may cause fatal respiratory depression
`when administered to patients not previously exposed to opioids.
`
`OxyContin® (oxycodone hydrochloride controlled-release) TABLETS ARE TO
`BE SWALLOWED WHOLE AND ARE NOT TO BE BROKEN, CHEWED, OR
`CRUSHED. TAKING BROKEN, CHEWED, OR CRUSHED OxyContin® TABLETS
`LEADS TO RAPID RELEASE AND ABSORPTION OF A POTENTIALLY FATAL
`DOSE OF OXYCODONE.
`
`DESCRIPTION
`
`Collegium Exhibit 1031 - Page 1
`
`

`

`NDA 20-553/S-022
`Page 5
`
`PACKAGE INSERT
`
`OxyContin® (oxycodone hydrochloride controlled-release) tablets are an opioid
`analgesic supplied in 10 mg, 20 mg, 40 mg, 80 mg, and 160 mg tablet strengths for
`oral administration. The tablet strengths describe the amount of oxycodone per
`tablet as the hydrochloride salt. The structural formula for oxycodone hydrochloride
`is as follows:
`
`C H 3O
`
`O
`
`O
`
`C l
`
`C H 3
`
`N
`H
`
`O H
`
`C18 H21 NO4 • HCl
`
`MW 351.83
`
`The chemical formula is 4, 5-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-
`one hydrochloride.
`Oxycodone is a white, odorless crystalline powder derived from the opium alkaloid,
`thebaine. Oxycodone hydrochloride dissolves in water (1 g in 6 to 7 mL). It is
`slightly soluble in alcohol (octanol water partition coefficient 0.7). The tablets
`contain the following inactive ingredients: ammonio methacrylate copolymer,
`hydroxypropyl methylcellulose, lactose, magnesium stearate, povidone, red iron
`oxide (20 mg strength tablet only), stearyl alcohol, talc, titanium dioxide, triacetin,
`yellow iron oxide (40 mg strength tablet only), yellow iron oxide with FD&C blue No.
`2 (80 mg strength tablet only), FD&C blue No. 2 (160 mg strength tablet only) and
`other ingredients.
`
`Collegium Exhibit 1031 - Page 2
`
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`

`NDA 20-553/S-022
`Page 6
`
`CLINICAL PHARMACOLOGY
`Central Nervous System
`Oxycodone is a pure agonist opioid whose principal therapeutic action is analgesia.
`Other members of the class known as opioid agonists include substances such as
`morphine, hydromorphone, fentanyl, codeine, and hydrocodone. Pharmacological
`effects of opioid agonists include anxiolysis, euphoria, feelings of relaxation,
`respiratory depression, constipation, miosis, and cough suppression, as well as
`analgesia. Like all pure opioid agonist analgesics, with increasing doses there is
`increasing analgesia, unlike with mixed agonist/antagonists or non-opioid
`analgesics, where there is a limit to the analgesic affect with increasing doses.
`With pure opioid agonist analgesics, there is no defined maximum dose; the ceiling
`to analgesic effectiveness is imposed only by side effects, the more serious of
`which may include somnolence and respiratory depression.
`Central Nervous System
`The precise mechanism of the analgesic action is unknown. However, specific
`CNS opioid receptors for endogenous compounds with opioid-like activity have
`been identified throughout the brain and spinal cord and play a role in the analgesic
`effects of this drug.
`Oxycodone produces respiratory depression by direct action on brain stem
`respiratory centers. The respiratory depression involves both a reduction in the
`responsiveness of the brain stem respiratory centers 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. Antitussive effects may occur with doses lower than those usually
`required for analgesia.
`Oxycodone causes miosis, even in total darkness. Pinpoint pupils are a sign of
`opioid overdose but are not pathognomonic (e.g. pontine lesions of hemorrhagic or
`ischemic origin may produce similar findings). Marked mydriasis rather than miosis
`may be seen with hypoxia in the setting of OxyContin® overdose (See
`OVERDOSAGE).
`
`Gastrointestinal Tract and Other Smooth Muscle
`Oxycodone causes a reduction in motility associated with an increase in smooth
`muscle tone in the antrum of the stomach and duodenum. Digestion of food in the
`small intestine is delayed and propulsive contractions are decreased. Propulsive
`peristaltic waves in the colon are decreased, while tone may be increased to the
`point of spasm resulting in constipation. Other opioid-induced effects may include a
`reduction in gastric, biliary and pancreatic secretions, spasm of sphincter of Oddi,
`and transient elevations in serum amylase.
`
`Cardiovascular System
`Oxycodone may produce release of histamine with or without associated peripheral
`vasodilation. Manifestations of histamine release and/or peripheral vasodilation
`may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.
`
`Concentration - Efficacy Relationships
`Studies in normal volunteers and patients reveal predictable relationships between
`oxycodone dosage and plasma oxycodone concentrations, as well as between
`concentration and certain expected opioid effects, such as pupillary constriction,
`
`Collegium Exhibit 1031 - Page 3
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`

`NDA 20-553/S-022
`Page 7
`
`sedation, overall “drug effect”, analgesia and feelings of “relaxation”.
`As with all opioids, the minimum effective plasma concentration for analgesia will
`vary widely among patients, especially among patients who have been previously
`treated with potent agonist opioids. As a result, patients must be treated with
`individualized titration of dosage to the desired effect. The minimum effective
`analgesic concentration of oxycodone for any individual patient may increase over
`time due to an increase in pain, the development of a new pain syndrome and/or
`the development of analgesic tolerance.
`
`Concentration - Adverse Experience Relationships
`OxyContin® tablets are associated with typical opioid-related adverse experiences.
` There is a general relationship between increasing oxycodone plasma
`concentration and increasing frequency of dose-related opioid adverse experiences
`such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-
`tolerant patients, the situation is altered by the development of tolerance to opioid-
`related side effects, and the relationship is not clinically relevant.
`
`As with all opioids, the dose must be individualized (see DOSAGE AND
`ADMINISTRATION), because the effective analgesic dose for some patients will be
`too high to be tolerated by other patients.
`
`PHARMACOKINETICS AND METABOLISM
`The activity of OxyContin® (oxycodone hydrochloride controlled-release) tablets is
`primarily due to the parent drug oxycodone. OxyContin® tablets are designed to
`provide controlled delivery of oxycodone over 12 hours.
`
`Breaking, chewing or crushing OxyContin® tablets eliminates the controlled delivery
`mechanism and results in the rapid release and absorption of a potentially fatal
`dose of oxycodone.
`
`Oxycodone release from OxyContin® tablets is pH independent. Oxycodone is well
`absorbed from OxyContin® tablets with an oral bioavailability of 60% to 87%. The
`relative oral bioavailability of OxyContin® to immediate-release oral dosage forms is
`100%. Upon repeated dosing in normal volunteers in pharmacokinetic studies,
`steady-state levels were achieved within 24-36 hours. Dose proportionality and/or
`bioavailability has been established for the 10 mg, 20 mg, 40 mg, 80 mg, and 160
`mg tablet strengths for both peak plasma levels (Cmax) and extent of absorption
`(AUC). Oxycodone is extensively metabolized and eliminated primarily in the urine
`as both conjugated and unconjugated metabolites. The apparent elimination half-
`life of oxycodone following the administration of OxyContin® was 4.5 hours
`compared to 3.2 hours for immediate-release oxycodone.
`
`Collegium Exhibit 1031 - Page 4
`
`

`

`NDA 20-553/S-022
`Page 8
`
`Absorption
`
`About 60% to 87% of an oral dose of oxycodone reaches the central compartment in comparison to a
`parenteral dose. This high oral bioavailability is due to low pre-systemic and/or first-pass metabolism. In
`normal volunteers, the t½ of absorption is 0.4 hours for immediate-release oral oxycodone. In contrast,
`OxyContin® tablets exhibit a biphasic absorption pattern with two apparent absorption half-times of 0.6
`and 6.9 hours, which describes the initial release of oxycodone from the tablet followed by a prolonged
`release.
`Dose proportionality has been established for the 10 mg, 20 mg, 40 mg, and 80 mg tablet strengths for
`both peak plasma concentrations (Cmax) and extent of absorption (AUC) (see Table 1 below). Another
`study established that the 160 mg tablet is bioequivalent to 2 x 80 mg tablets as well as to 4 x 40 mg for
`both peak plasma concentrations (Cmax) and extent of absorption (AUC) (see Table 2 below). Given the
`short half-life of elimination of oxycodone from OxyContin®, steady-state plasma concentrations of
`oxycodone
`
`Plasma Oxycodone By Time
`
`100
`
`X X X X X X X
`
`10
`
`XXX
`
`XXX X X X X X X X
`
`X
`
`Oxycodone Concentration (ng/mL), Log Scale
`
`1
`
`0
`
`1
`
`2
`
`3
`
`4
`
`20 mg
`10 mg
`10 mg q12h Steady-State
`
`X
`
`5
`6
`7
`Hours From Dosing
`
`8
`
`9
`
`10
`
`11
`
`12
`
`40 mg
`
`80 mg
`
`160 mg Single Dose
`
`are achieved within 24-36 hours of initiation of dosing with OxyContin® tablets. In a study comparing 10
`mg of OxyContin® every 12 hours to 5 mg of immediate-release oxycodone every 6 hours, the two
`treatments were found to be equivalent for AUC and Cmax, and similar for Cmin (trough) concentrations.
`There was less fluctuation in plasma concentrations for the OxyContin® tablets than for the immediate-
`release formulation.
`
`Collegium Exhibit 1031 - Page 5
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`NDA 20-553/S-022
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`
`Table 1
`Mean [% coefficient variation]
`
`Regimen
`
`Dosage Form
`
`Single Dose
`
`Multiple
`Dose
`
`10 mg OxyContin
`20 mg OxyContin
`40 mg OxyContin
`80 mg OxyContin*
`
`10 mg OxyContin
`Tablets q12h
`5 mg immediate-
`release q6h
`
`AUC
`(ng•hr/mL)†
`
`100.7 [26.6]
`207.5 [35.9]
`423.1 [33.3]
`1085.5 [32.3]
`
`Cmax (ng/mL)
`
`10.6 [20.1]
`21.4 [36.6]
`39.3 [34.0]
`98.5 [32.1]
`
`Tmax
`(hrs)
`
`2.7 [44.1]
`3.2 [57.9]
`3.1 [77.4]
`2.1 [52.3]
`
`Trough
`Conc.
`(ng/mL)
`
`n.a.
`n.a.
`n.a.
`n.a.
`
`103.6 [38.6]
`
`15.1 [31.0]
`
`3.2 [69.5]
`
`7.2 [48.1]
`
`99.0 [36.2]
`
`15.5 [28.8]
`
`1.6 [49.7]
`
`7.4 [50.9]
`
`Table 2
`Mean [% coefficient variation]
`
`Regimen
`
`Dosage Form
`
`AUC∞
`(ng•hr/mL)†
`
`Cmax
`(ng/mL)
`
`Tmax
`(hrs)
`
`Trough
`Conc.
`(ng/mL)
`
`Single Dose
`
`4 x 40 mg OxyContin*
`2 x 80 mg OxyContin*
`1 x 160 mg OxyContin*
`
`1935.3 [34.7]
`1859.3 [30.1]
`1856.4 [30.5]
`
`152.0 [28.9]
`153.4 [25.1]
`156.4 [24.8]
`
`2.56 [42.3]
`2.78 [69.3]
`2.54 [36.4]
`
`n.a.
`n.a.
`n.a.
`
`† for single-dose AUC = AUC0-inf; for multiple-dose AUC = AUC0-T
` * data obtained while volunteers received naltrexone which can enhance absorption.
`
`OxyContin® IS NOT INDICATED FOR RECTAL ADMINISTRATION. Data from a
`study involving 21 normal volunteers show that OxyContin® tablets administered per
`rectum resulted in an AUC 39% greater and a Cmax 9% higher than tablets
`administered by mouth. Therefore, there is an increased risk of adverse events with
`rectal administration.
`
`Food Effects
`Food has no significant effect on the extent of absorption of oxycodone from
`OxyContin®. However, the peak plasma concentration of oxycodone increased by
`25% when OxyContin® 160 mg tablet was administered with a high fat meal.
`
`Distribution
`Following intravenous administration, the volume of distribution (Vss) for oxycodone
`was 2.6 L/kg. Oxycodone binding to plasma protein at 37°C and a pH of 7.4 was
`about 45%. Once absorbed, oxycodone is distributed to skeletal muscle, liver,
`intestinal tract, lungs, spleen, and brain. Oxycodone has been found in breast milk
`(see PRECAUTIONS).
`
`Metabolism
`Oxycodone hydrochloride is extensively metabolized to noroxycodone,
`oxymorphone, and their glucuronides. The major circulating metabolite is
`noroxycodone with an AUC ratio of 0.6 relative to that of oxycodone. Noroxycodone
`
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`

`NDA 20-553/S-022
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`
`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.
`The formation of oxymorphone, but not noroxycodone, is mediated by cytochrome
`P450 2D6 and, as such, its formation can, in theory, be affected by other drugs (see
`Drug-Drug Interactions).
`
`Excretion
`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.
`
`Special Populations
`Elderly
`The plasma concentrations of oxycodone are only nominally affected by age, being
`15% greater in elderly as compared to young subjects.
`
`Gender
`Female subjects have, on average, plasma oxycodone concentrations up to 25%
`higher than males on a body weight adjusted basis. The reason for this difference is
`unknown.
`
`Renal Impairment
`Data from a pharmacokinetic study involving 13 patients with mild to severe renal
`dysfunction (creatinine clearance <60 mL/min) show peak plasma oxycodone and
`noroxycodone concentrations 50% and 20% higher, respectively, and AUC values
`for oxycodone, noroxycodone, and oxymorphone 60%, 50%, and 40% higher than
`normal subjects, respectively. This is accompanied by an increase in sedation but
`not by differences in respiratory rate, pupillary constriction, or several other
`measures of drug effect. There was an increase in t½ of elimination for oxycodone
`of only 1 hour (see PRECAUTIONS).
`
`Hepatic Impairment
`Data from a study involving 24 patients with mild to moderate hepatic dysfunction
`show peak plasma oxycodone and noroxycodone concentrations 50% and 20%
`higher, respectively, than normal subjects. AUC values are 95% and 65% higher,
`respectively. Oxymorphone peak plasma concentrations and AUC values are lower
`by 30% and 40%. These differences are accompanied by increases in some, but not
`other, drug effects. The t½ elimination for oxycodone increased by 2.3 hours (see
`PRECAUTIONS).
`
`Drug-Drug Interactions (see PRECAUTIONS)
`Oxycodone is metabolized in part by cytochrome P450 2D6 to oxymorphone which
`represents less than 15% of the total administered dose. This route of elimination
`may be blocked by a variety of drugs (e.g., certain cardiovascular drugs including
`amiodarone and quinidine as well as polycyclic anti-depressants). However, in a
`study involving 10 subjects using quinidine, a known inhibitor of cytochrome P450
`2D6, the pharmacodynamic effects of oxycodone were unchanged.
`
`Collegium Exhibit 1031 - Page 7
`
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`

`NDA 20-553/S-022
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`
`Pharmacodynamics
`A single-dose, double-blind, placebo- and dose-controlled study was conducted
`using OxyContin® (10, 20, and 30 mg) in an analgesic pain model involving 182
`patients with moderate to severe pain. Twenty and 30 mg of OxyContin® were
`superior in reducing pain compared with placebo, and this difference was statistically
`significant. The onset of analgesic action with OxyContin® occurred within 1 hour in
`most patients following oral administration.
`
`CLINICAL TRIALS
`A double-blind placebo-controlled, fixed-dose, parallel group, two-week study was
`conducted in 133 patients with chronic, moderate to severe pain, who were judged
`as having inadequate pain control with their current therapy. In this study, 20 mg
`OxyContin® q12h but not 10 mg OxyContin® q12h decreased pain compared with
`placebo, and this difference was statistically significant.
`
`INDICATIONS AND USAGE
`OxyContin® tablets are a controlled-release oral formulation of oxycodone
`hydrochloride indicated for the management of moderate to severe pain when a
`continuous, around-the-clock analgesic is needed for an extended period of time.
`
`OxyContin® is NOT intended for use as a prn analgesic.
`
`Physicians should individualize treatment in every case, initiating therapy at the
`appropriate point along a progression from non-opioid analgesics, such as non-
`steroidal anti-inflammatory drugs and acetaminophen to opioids in a plan of pain
`management such as outlined by the World Health Organization, the Agency for
`Health Research and Quality (formerly known as the Agency for Health Care Policy
`and Research), the Federation of State Medical Boards Model Guidelines, or the
`American Pain Society.
`
`OxyContin® is not indicated for pain in the immediate post-operative period (the first
`12-24 hours following surgery), or if the pain is mild, or not expected to persist for an
`extended period of time. OxyContin is only indicated for post-operative use if the
`patient is already receiving the drug prior to surgery or if the postoperative pain is
`expected to be moderate to severe and persist for an extended period of time.
`Physicians should individualize treatment, moving from parenteral to oral analgesics
`as appropriate. (See American Pain Society guidelines.)
`
`CONTRAINDICATIONS
`OxyContin® is contraindicated in patients with known hypersensitivity to oxycodone,
`or in any situation where opioids are contraindicated. This includes patients with
`significant respiratory depression (in unmonitored settings or the absence of
`resuscitative equipment), and patients with acute or severe bronchial asthma or
`hypercarbia. OxyContin® is contraindicated in any patient who has or is suspected
`of having paralytic ileus.
`
`WARNINGS
`OxyContin (oxycodone hydrochloride controlled-release) TABLETS ARE TO
`BE SWALLOWED WHOLE, AND ARE NOT TO BE BROKEN, CHEWED OR
`CRUSHED. TAKING BROKEN, CHEWED OR CRUSHED OxyContin® TABLETS
`COULD LEAD TO THE RAPID RELEASE AND ABSORPTION OF A
`
`Collegium Exhibit 1031 - Page 8
`
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`

`NDA 20-553/S-022
`Page 12
`
`POTENTIALLY FATAL DOSE OF OXYCODONE.
`
`OxyContin 80 mg and 160 mg Tablets ARE FOR USE IN OPIOID-TOLERANT
`PATIENTS ONLY. These tablet strengths may cause fatal respiratory
`depression when administered to patients not previously exposed to opioids
`
`OxyContin® 80 mg and 160 mg Tablets are for use only in opioid tolerant
`patients requiring daily oxycodone equivalent dosages of 160 mg or more for
`the 80 mg tablet and 320 mg or more for the 160 mg tablet. Care should be
`taken in the prescribing of these tablet strengths. Patients should be
`instructed against use by individuals other than the patient for whom it was
`prescribed, as such inappropriate use may have severe medical
`consequences, including death.
`
`Misuse, Abuse and Diversion of Opioids
`
`Oxycodone is an opioid agonist of the morphine-type. Such drugs are sought by
`drug abusers and people with addiction disorders and are subject to criminal
`diversion.
`
`Oxycodone can be abused in a manner similar to other opioid agonists, legal or
`illicit. This should be considered when prescribing or dispensing OxyContin in
`situations where the physician or pharmacist is concerned about an increased risk
`of misuse, abuse, or diversion.
`
`OxyContin has been reported as being abused by crushing, chewing, snorting, or
`injecting the dissolved product. These practices will result in the uncontrolled
`delivery of the opioid and pose a significant risk to the abuser that could result in
`overdose and death (see WARNINGS and DRUG ABUSE AND ADDICTION).
`
`Concerns about abuse, addiction, and diversion should not prevent the proper
`management of pain. The development of addiction to opioid analgesics in properly
`managed patients with pain has been reported to be rare. However, data are not
`available to establish the true incidence of addiction in chronic pain patients.
`
`Healthcare professionals should contact their State Professional Licensing Board,
`or State Controlled Substances Authority for information on how to prevent and
`detect abuse or diversion of this product.
`
`Interactions with Alcohol and Drugs of Abuse
`Oxycodone may be expected to have additive effects when used in conjunction with
`alcohol, other opioids, or illicit drugs that cause central nervous system depression.
`
`DRUG ABUSE AND ADDICTION
`OxyContin® is a mu-agonist opioid with an abuse liability similar to morphine
`and is a Schedule II controlled substance. Oxycodone, like morphine and
`other opioids used in analgesia, can be abused and is subject to criminal
`diversion.
`
`Drug addiction is characterized by compulsive use, use for non-medical purposes,
`and continued use despite harm or risk of harm. Drug addiction is a treatable
`disease, utilizing a multi-disciplinary approach, but relapse is common.
`
`“Drug seeking” behavior is very common in addicts and drug abusers. Drug-
`seeking tactics include emergency calls or visits near the end of office hours,
`
`Collegium Exhibit 1031 - Page 9
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`

`NDA 20-553/S-022
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`
`refusal to undergo appropriate examination, testing or referral, repeated “loss” of
`prescriptions, tampering with prescriptions and reluctance to provide 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 untreated addiction.
`
`Abuse and addiction are separate and distinct from physical dependence and
`tolerance. Physicians should be aware that addiction may not be accompanied by
`concurrent tolerance and symptoms of physical dependence in all addicts. In
`addition, abuse of opioids can occur in the absence of true addiction and is
`characterized by misuse for non-medical purposes, often in combination with other
`psychoactive substances. OxyContin, like other opioids, has been diverted for
`non-medical use. Careful record-keeping of prescribing information, including
`quantity, frequency, and renewal requests is strongly advised.
`
`Proper assessment of the patient, proper prescribing practices, periodic re-
`evaluation of therapy, and proper dispensing and storage are appropriate measures
`that help to limit abuse of opioid drugs.
`
`OxyContin consists of a dual-polymer matrix, intended for oral use only.
`Abuse of the crushed tablet poses a hazard of overdose and death. This risk
`is increased with concurrent abuse of alcohol and other substances. With
`parenteral abuse, the tablet excipients, especially talc, can be expected to
`result in local tissue necrosis, infection, pulmonary granulomas, and
`increased risk of endocarditis and valvular heart injury. Parenteral drug
`abuse is commonly associated with transmission of infectious diseases such
`as hepatitis and HIV.
`
`Respiratory Depression
`Respiratory depression is the chief hazard from oxycodone, the active ingredient in
`OxyContin®, as with all opioid agonists. Respiratory depression is a particular
`problem in elderly or debilitated patients, usually following large initial doses in non-
`tolerant patients, or when opioids are given in conjunction with other agents that
`depress respiration.
`Oxycodone should be used with extreme caution in patients with significant chronic
`obstructive pulmonary disease or cor pulmonale, and in patients having a
`substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing
`respiratory depression. In such patients, even usual therapeutic doses of
`oxycodone may decrease respiratory drive to the point of apnea. In these patients
`alternative non-opioid analgesics should be considered, and opioids should be
`employed only under careful medical supervision at the lowest effective dose.
`
`Head Injury
`OxyContin® may cause severe hypotension. There is an added risk to individuals
`whose ability to maintain blood pressure has been compromised by a depleted
`blood volume, or after concurrent administration with drugs such as phenothiazines
`or other agents which compromise vasomotor tone. Oxycodone may produce
`orthostatic hypotension in ambulatory patients. Oxycodone, like all opioid
`analgesics of the morphine-type, should be administered with caution to patients in
`circulatory shock, since vasodilation produced by the drug may further reduce
`cardiac output and blood pressure.
`
`Collegium Exhibit 1031 - Page 10
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`

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`
`Hypotensive Effect
`
`OxyContin® may cause severe hypotension. There is an added risk to individuals
`whose ability to maintain blood pressure has been compromised by a depleted
`blood volume, or after concurrent administration with drugs such as phenothiazines
`or other agents which compromise vasomotor tone. Oxycodone may produce
`orthostatic hypotension in ambulatory patients. Oxycodone, like all opioid
`analgesics of the morphine-type, should be administered with caution to patients in
`circulatory shock, since vasodilation produced by the drug may further reduce
`cardiac output and blood pressure.
`
`PRECAUTIONS
`
`General
`Opioid analgesics have a narrow therapeutic index in certain patient populations,
`especially when combined with CNS depressant drugs, and should be reserved for
`cases where the benefits of opioid analgesia outweigh the known risks of
`respiratory depression, altered mental state, and postural hypotension.
`Use of OxyContin® is associated with increased potential risks and should be used
`only with caution in the following conditions: acute alcoholism; adrenocortical
`insufficiency (e.g., Addison's disease); CNS depression or coma; delirium tremens;
`debilitated patients; kyphoscoliosis associated with respiratory depression;
`myxedema or hypothyroidism; prostatic hypertrophy or urethral stricture; severe
`impairment of hepatic, pulmonary or renal function; and toxic psychosis.
`The administration of oxycodone may obscure the diagnosis or clinical course in
`patients with acute abdominal conditions. Oxycodone may aggravate convulsions
`in patients with convulsive disorders, and all opioids may induce or aggravate
`seizures in some clinical settings.
`
`Interactions with other CNS Depressants
`OxyContin® should be used with caution and started in a reduced dosage (1/3 to
`1/2 of the usual dosage) in patients who are concurrently receiving other central
`nervous system depressants including sedatives or hypnotics, general anesthetics,
`phenothiazines, other tranquilizers, and alcohol. Interactive effects resulting in
`respiratory depression, hypotension, profound sedation, or coma may result if these
`drugs are taken in combination with the usual doses of OxyContin®.
`
`Interactions with Mixed Agonist/Antagonist Opioid Analgesics
`Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, and
`buprenorphine) should be administered with caution to a patient who has received
`or is receiving a course of therapy with a pure opioid agonist analgesic such as
`oxycodone. In this situation, mixed agonist/antagonist analgesics may reduce the
`analgesic effect of oxycodone and/or may precipitate withdrawal symptoms in these
`patients.
`
`Ambulatory Surgery and Post Operative Use
`OxyContin® is not indicated for pre-emptive analgesia (administration pre-
`operatively for the management of post-operative pain).
`OxyContin® is not indicated for pain in the immediate post-operative period
`
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`(the first 12 to 24 hours following surgery) for patients not previously taking
`the drug, because its safety in this setting has not been established.
`
`OxyContin® is not indicated for pain in the post-operative period if the pain is
`mild or not expected to persist for an extended period of time.
`
`OxyContin is only indicated for post-operative use if the patient is already
`receiving the drug prior to surgery or if the postoperative pain is expected to
`be moderate to severe and persist for an extended period of time. Physicians
`should individualize treatment, moving from parenteral to oral analgesics as
`appropriate (See American Pain Society guidelines).
`
`Patients who are already receiving OxyContin® tablets as part of ongoing analgesic
`therapy may be safely continued on the drug if appropriate dosage adjustments are
`made considering the procedure, other drugs given, and the temporary changes in
`physiology caused by the surgical intervention (see DOSAGE AND
`ADMINISTRATION ).
`
`OxyContin® and other morphine-like opioids have been shown to decrease bowel
`motility. Ileus is a common post-operative complication, especially after intra-
`abdominal surgery with opioid analgesia. Caution should be taken to monitor for
`decreased bowel motility in post-operative patients receiving opioids. Standard
`supportive therapy should be implemented.
`
`Use in Pancreatic/Biliary Tract Disease
`Oxycodone may cause spasm of the sphincter of Oddi and should be used with
`caution in patients with biliary tract disease, including acute pancreatitis. Opioids
`like oxycodone may cause increases in the serum amylase level.
`
`Tolerance and Physical Dependence
`Tolerance is the need for increasing doses of opioids to maintain a defined effect
`such as analgesia (in the absence of disease progression or other external factors).
`Physical dependence is manifested by withdrawal 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. Other symptoms also may develop, including: irritability,
`anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea,
`anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart
`rate.
`In general, opioids should not be abruptly discontinued (see DOSAGE AND
`ADMINISTRATION: Cessation of Therapy).
`
`Information for Patients/Caregivers
`If clinically advisable, patients receiving OxyContin® (oxycodone hydrochloride
`controlled-release) tablets or their caregivers should be given the following
`information by the physician, nurse, pharmacist, or caregiver:
`1. Patients should be aware that OxyContin® tablets contain oxycodone, which is
`a morphine-like substance.
`
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`2. Patients should be advised that OxyContin® tablets were designed to work
`properly only if swallowed whole. OxyContin® tablets will release all their contents
`at once if broken, chewed, or crushed, resulting in a risk of fatal overdose.
`3. Patients should be advised to report episodes of breakthrough pain and adverse
`experiences occurring during therapy. Individualization of dosage is essential to
`make optimal use of this medication.
`4. Patients should be advised not to adjust the dose of OxyContin® without
`consulting the prescribing professional.
`5. Patients should be advised that OxyContin® may impair mental and/or physical
`ability required for the performance of potentially hazardous tasks (e.g., driving,
`operating heavy machinery).
`6. Patients should not combine OxyContin® with alcohol or other central nervous
`system depressants (sleep aids, tranquilizers) except by the orders of the
`prescribing physician, because dangerous additive effects may occur, resulting in
`serious injury or death.
`7. Women of childbearing potential who become, or are planning to become,
`pregnant should be advised to consult their physician regarding the effects of
`analgesics and other drug use during pregnancy on themselves and their unborn
`child.
`8. Patients should be advised that OxyContin® is a potential drug of abuse. They
`should protect it from theft, and it should never be given to anyone other than the
`individual for whom it was prescribed.
`9. Patients should be advised that they may pass empty matrix "ghosts" (tablets)
`via colostomy or in the stool, and that this is of no concern since the active
`medication has already been absorbed.
`10. Patients should be advised that if they have been receiving treatment with
`OxyContin® for more than a few weeks and cessation of therapy is