Generic Name: oxycodone hydrochloride
Dosage Form: tablet, film coated, extended release
FULL PRESCRIBING INFORMATION
OxyContin contains oxycodone which is an opioid agonist and a Schedule II controlled substance with an abuse liability similar to morphine. (9)
OxyContin 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. (9.2)
OxyContin is a controlled-release oral formulation of oxycodone hydrochloride indicated for the management of moderate to severe pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time. (1)
OxyContin is not intended for use on an as-needed basis. (1)
Patients considered opioid tolerant are those who are taking at least 60 mg oral morphine/day, 25 mcg transdermal fentanyl/hour, 30 mg oral oxycodone/day, 8 mg oral hydromorphone/day, 25 mg oral oxymorphone/day, or an equianalgesic dose of another opioid for one week or longer. (2.7)
OxyContin 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 opioid-tolerant patients, as they may cause fatal respiratory depression when administered to patients who are not tolerant to the respiratory-depressant or sedating effects of opioids. (2.7)
Persons at increased risk for opioid abuse include those with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). Patients should be assessed for their clinical risks for opioid abuse or addiction prior to being prescribed opioids. All patients receiving opioids should be routinely monitored for signs of misuse, abuse and addiction. (2.2)
OxyContin must be swallowed whole and must not be cut, broken, chewed, crushed, or dissolved. Taking cut, broken, chewed, crushed or dissolved OxyContin tablets leads to rapid release and absorption of a potentially fatal dose of oxycodone. (2.1)
The concomitant use of OxyContin with all cytochrome P450 3A4 inhibitors such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir) may result in an increase in oxycodone plasma concentrations, which could increase or prolong adverse effects and may cause potentially fatal respiratory depression. Patients receiving OxyContin and a CYP3A4 inhibitor should be carefully monitored for an extended period of time and dosage adjustments should be made if warranted. (7.2)
1 INDICATIONS AND USAGE
OxyContin is a controlled-release oral formulation of oxycodone hydrochloride indicated for the management of moderate to severe pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time.
Limitations of Usage
OxyContin is not intended for use on an as-needed basis.
OxyContin is not indicated for the management of pain in the immediate postoperative 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 indicated for postoperative use following the immediate post-operative period only 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).
OxyContin is not indicated for pre-emptive analgesia (preoperative administration for the management of postoperative pain).
OxyContin is not indicated for rectal administration.
2 DOSAGE AND ADMINISTRATION
Safe Administration Instructions
OxyContin tablets must be swallowed whole and must not be cut, broken, chewed, crushed or dissolved. Taking cut, broken, chewed, crushed or dissolved OxyContin tablets leads to rapid release and absorption of a potentially fatal dose of oxycodone.
OxyContin tablets should be taken one tablet at a time. Take each tablet with enough water to ensure complete swallowing immediately after placing in the mouth [see Patient Counseling Information (17.1)].
Selection of patients for treatment with OxyContin should be governed by the same principles that apply to the use of similar opioid analgesics. Physicians should individualize treatment using a progressive plan of pain management such as outlined by the World Health Organization, Federation of State Medical Boards Model Policy, and the American Pain Society. Healthcare professionals should follow appropriate pain management principles of careful assessment and ongoing monitoring.
Initiating Therapy with OxyContin
It is critical to initiate the dosing regimen for each patient individually. Attention should be given to:
- risk factors for abuse or addiction; including whether the patient has a previous or current substance abuse problem, a family history of substance abuse, or a history of mental illness or depression;
- the age, general condition and medical status of the patient;
- the patient's opioid exposure and opioid tolerance (if any);
- the daily dose, potency, and kind of the analgesic(s) the patient has been taking;
- the reliability of the conversion estimate used to calculate the dose of oxycodone;
- the special instructions for OxyContin 60 mg and 80 mg tablets, a single dose greater than 40 mg, or total daily doses greater than 80 mg [see Dosage and Administration (2.7)]; and
- the balance between pain control and adverse reactions.
Use low initial doses of OxyContin in patients who are not already opioid-tolerant [see Dosage and Administration (2.7)], especially those who are receiving concurrent treatment with muscle relaxants, sedatives, or other CNS active medications [see Warnings and Precautions (5.1, 5.3) and Drug Interactions (7.1, 7.3)].
Experience indicates a reasonable starting dose of OxyContin for patients who are taking non-opioid analgesics and require continuous around-the-clock therapy for an extended period of time is 10 mg every 12 hours. Individually titrate OxyContin to a dose that provides adequate analgesia and minimizes adverse reactions while maintaining an every-twelve-hour dosing regimen.
For initiation of OxyContin therapy for patients previously taking opioids, the conversion ratios found in Table 1 are a reasonable starting point, although not verified in well-controlled, multiple-dose trials. No fixed conversion ratio is likely to be satisfactory in all patients, especially patients receiving large opioid doses. A reasonable approach for converting from existing opioid therapy to OxyContin is as follows:
- Discontinue all other around-the-clock opioid drugs when OxyContin therapy is initiated.
- Using standard conversion ratio estimates (see Table 1), multiply the mg/day of each of the current opioids to be converted by their appropriate multiplication factor to obtain the equivalent total daily dose of oral oxycodone.
- Divide the calculated 24-hour oxycodone dose in half to approximate the every 12-hour dose of OxyContin.
- Round down, if necessary, to the appropriate OxyContin tablet strengths available.
- Close observation and frequent titration are indicated until patients are stable on the new therapy.
| Multiplication Factors for Converting the Daily Dose of Current Opioids to the Daily Dose of Oral Oxycodone1* | ||
|---|---|---|
| * To be used only for conversion to oral oxycodone. 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. | ||
| (mg/Day Opioid x Factor = mg/Day Oral Oxycodone) | ||
| Oral Opioid | Parenteral Opioid | |
| Oxycodone | 1 | -- |
| Codeine | 0.15 | -- |
| Hydrocodone | 0.9 | -- |
| Hydromorphone | 4 | 20 |
| Levorphanol | 7.5 | 15 |
| Meperidine | 0.1 | 0.4 |
| Methadone | 1.5 | 3 |
| Morphine | 0.5 | 3 |
Conversion from Transdermal Fentanyl to OxyContin
Eighteen hours following the removal of the transdermal fentanyl patch, OxyContin treatment can be initiated. Although there has been no systematic assessment of such conversion, a conservative oxycodone dose, approximately 10 mg every 12 hours of OxyContin, should be initially substituted for each 25 mcg/hr fentanyl transdermal patch. Follow the patient closely during conversion from transdermal fentanyl to OxyContin, as there is limited documented experience with this conversion.
Hepatic Impairment
For patients with hepatic impairment, start dosing patients at 1/3 to 1/2 the usual starting dose followed by careful dose titration [see Clinical Pharmacology (12.3)].
Managing Expected Opioid Adverse Reactions
Most patients receiving OxyContin, especially those who are opioid-naive, will experience adverse reactions. Patients do not usually become tolerant to the constipating effects of opioids, therefore, anticipate constipation and treat aggressively and prophylactically with a stimulant laxative with or without a stool softener. If nausea persists and is unacceptable to the patient, consider treatment with antiemetics or other modalities to relieve these symptoms.
Individualization of Dosage
Once therapy is initiated, assess pain relief and other opioid effects frequently. Titrate patients to adequate effect (generally mild or no pain with the regular use of no more than two doses of supplemental analgesia per 24 hours). Patients who experience breakthrough pain may require dosage adjustment or rescue medication. Because steady-state plasma concentrations are approximated within 24 to 36 hours, dosage adjustment may be carried out every 1 to 2 days.
There are no well-controlled clinical studies evaluating the safety and efficacy with dosing more frequently than every 12 hours. Increase the OxyContin dose by increasing the total daily dose, not by changing the 12-hour dosing interval. As a guideline, the total daily oxycodone dose usually can be increased by 25% to 50% of the current dose, each time an increase is clinically indicated.
If signs of excessive opioid-related adverse reactions are observed, the next dose may be reduced. If this adjustment leads to inadequate analgesia, a supplemental dose of immediate-release oxycodone may be given. Alternatively, non-opioid analgesic adjuvants may be employed. Adjust the dose to obtain an appropriate balance between pain relief and opioid-related adverse reactions.
During periods of changing analgesic requirements, including initial titration, maintain frequent contact between physician, other members of the healthcare team, the patient and, with proper consent, the caregiver/family.
Special Instructions for Patients who are not Opioid Tolerant
Do not begin treatment with OxyContin 60 mg and 80 mg Tablets, a single dose greater than 40 mg, or a total daily dose greater than 80 mg in patients who are not already tolerant to the respiratory-depressant and sedating effects of opioids. Use of these doses in patients who are not opioid tolerant may cause fatal respiratory depression. These doses are only for use in opioid-tolerant patients.
Patients considered opioid tolerant are those who are taking at least 60 mg oral morphine/day, 25 mcg transdermal fentanyl/hour, 30 mg oral oxycodone/day, 8 mg oral hydromorphone/day, 25 mg oral oxymorphone/day, or an equianalgesic dose of another opioid for one week or longer.
Instruct patients not to share or permit use by individuals other than the patient for whom OxyContin was prescribed, as such inappropriate use may have severe medical consequences, including death.
Continuation of Therapy
During chronic therapy, especially for non-cancer pain syndromes, reassess the continued need for around-the-clock opioid therapy regularly (e.g., every 6 to 12 months) as appropriate.
Cessation of Therapy
When the patient no longer requires therapy with OxyContin, taper the dose gradually to prevent signs and symptoms of withdrawal in the physically-dependent patient.
Conversion from OxyContin to Parenteral Opioids
To avoid overdose, follow conservative dose conversion ratios. When converting from OxyContin to parenteral opioids, it is advisable to calculate an equivalent parenteral dose and then initiate treatment at half of this calculated value.
3 DOSAGE FORMS AND STRENGTHS
- 10 mg film-coated tablets (round, white-colored, bi-convex tablets debossed with OP on one side and 10 on the other)
- 15 mg film-coated tablets (round, gray-colored, bi-convex tablets debossed with OP on one side and 15 on the other)
- 20 mg film-coated tablets (round, pink-colored, bi-convex tablets debossed with OP on one side and 20 on the other)
- 30 mg film-coated tablets (round, brown-colored, bi-convex tablets debossed with OP on one side and 30 on the other)
- 40 mg film-coated tablets (round, yellow-colored, bi-convex tablets debossed with OP on one side and 40 on the other)
- 60 mg film-coated tablets* (round, red-colored, bi-convex tablets debossed with OP on one side and 60 on the other)
- 80 mg film-coated tablets* (round, green-colored, bi-convex tablets debossed with OP on one side and 80 on the other)
* 60 mg and 80 mg tablets for use in opioid-tolerant patients only
4 CONTRAINDICATIONS
OxyContin is contraindicated in:
- patients who have significant respiratory depression
- patients who have or are suspected of having paralytic ileus
- patients who have acute or severe bronchial asthma
- patients who have known hypersensitivity to any of its components or the active ingredient, oxycodone.
5 WARNINGS AND PRECAUTIONS
Information Essential for Safe Administration
OxyContin tablets must be swallowed whole and must not be cut, broken, chewed, crushed, or dissolved. Taking cut, broken, chewed, crushed or dissolved OxyContin tablets leads to rapid release and absorption of a potentially fatal dose of oxycodone.
OxyContin 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 opioid-tolerant patients. Use of these doses in patients who are not opioid tolerant may cause fatal respiratory depression.
Instruct patients against use by individuals other than the patient for whom OxyContin was prescribed, as such inappropriate use may have severe medical consequences, including death.
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.
CNS Depression
OxyContin may cause somnolence, dizziness, alterations in judgment and alterations in levels of consciousness, including coma.
Interactions with Alcohol, CNS Depressants and Illicit Drugs
Hypotension, profound sedation, coma or respiratory depression may result if OxyContin is added to a regimen that includes other CNS depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). Therefore, use caution when deciding to initiate therapy with OxyContin in patients who are taking other CNS depressants. Take into account the types of other medications being taken, the duration of therapy with them, and the patient's response to those medicines, including the degree of tolerance that has developed to CNS depression. Consider the patient's use, if any, of alcohol and/or illicit drugs that cause CNS depression. If the decision to begin OxyContin is made, start with a lower OxyContin dose than usual [see Drug Interactions (7.3)].
Consider using a lower initial dose of a CNS depressant when given to a patient currently taking OxyContin due to the potential of additive CNS depressant effects.
Respiratory Depression
Decreased respiratory drive resulting in respiratory depression is the chief hazard from the use or abuse of opioid agonists, including OxyContin. The risk of opioid-induced respiratory depression is increased, for example, in elderly [see Use In Specific Populations (8.5)] or debilitated patients; following large initial doses in any patient who is not tolerant to the respiratory-depressant or sedating effects of opioids; or when opioids are given in conjunction with other agents that either depress respiratory drive or consciousness.
Use OxyContin with extreme caution in patients with any of the following:
- significant chronic obstructive pulmonary disease or cor pulmonale
- other risk of substantially decreased respiratory reserve
- hypoxia
- hypercapnia
- pre-existing respiratory depression
Respiratory depression induced by opioids typically follows a pattern entailing first a shift in CO2 responsiveness of the CNS respiratory drive center, which results in a decrease in the urge to breathe, despite the presence of hypercapnia. The increase in brain CO2 can result in sedation that can accentuate the sedation from the opioid itself. Profound sedation, unresponsiveness, infrequent deep ("sighing") breaths or atypical snoring frequently accompany opioid-induced respiratory depression. Eventually, hypoxia ensues. In addition to further decreasing consciousness, hypoxia, along with hypercapnia, can predispose to life-threatening cardiac arrhythmias.
Seizures
Oxycodone, as with other opioids, may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings. Use OxyContin with caution in patients with a history of seizure disorders.
Difficulty Swallowing and Gastrointestinal Effects
There have been post-marketing reports of difficulty in swallowing OxyContin tablets. These reports included choking, gagging, regurgitation and tablets stuck in the throat. Instruct patients not to pre-soak, lick or otherwise wet OxyContin tablets prior to placing in the mouth, and to take one tablet at a time with enough water to ensure complete swallowing immediately after placing in the mouth.
There have been rare post-marketing reports of cases of intestinal obstruction, and exacerbation of diverticulitis, some of which have required medical intervention to remove the tablet. Patients with underlying GI disorders such as esophageal cancer or colon cancer with a small gastrointestinal lumen are at greater risk of developing these complications.
Use caution when prescribing OxyContin for patients who have difficulty swallowing or have underlying GI disorders that may predispose them to obstruction.
The administration of OxyContin may obscure the diagnosis or clinical course in patients with acute abdominal conditions. Use OxyContin with caution in patients who are at risk of developing ileus.
Head Injury
The respiratory depressant effects of opioids include carbon dioxide retention, which can lead to an elevation of cerebrospinal fluid pressure. This effect may be exaggerated in the presence of head injury, intracranial lesions, or other sources of pre-existing increased intracranial pressure. Oxycodone may produce miosis that is independent of ambient light, and altered consciousness, either of which may obscure neurologic signs associated with increased intracranial pressure in persons with head injuries.
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. Administer OxyContin with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure.
Cytochrome P450 3A4 Inhibitors and Inducers
Since the CYP3A4 isoenzyme plays a major role in the metabolism of OxyContin, drugs that alter CYP3A4 activity may cause changes in clearance of oxycodone which could lead to changes in oxycodone plasma concentrations.
The expected clinical results with CYP3A4 inhibitors would be an increase in oxycodone plasma concentrations and possibly increased or prolonged opioid effects. The expected clinical results with CYP3A4 inducers would be a decrease in oxycodone plasma concentrations, lack of efficacy or, possibly, development of an abstinence syndrome in a patient who had developed physical dependence to oxycodone.
If co-administration is necessary, caution is advised when initiating OxyContin treatment in patients currently taking, or discontinuing, CYP3A4 inhibitors or inducers. Evaluate these patients at frequent intervals and consider dose adjustments until stable drug effects are achieved [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)].
Interactions with Mixed Agonist/Antagonist Opioid Analgesics
It is generally not advisable to administer mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) to a patient receiving OxyContin. In this situation, mixed agonist/antagonist analgesics may reduce the analgesic effect and may precipitate withdrawal symptoms in these patients.
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 may cause increases in the serum amylase.
Tolerance
Tolerance to opioids is demonstrated by the need for increasing doses to maintain adequate analgesic effect (in the absence of disease progression or other external factors). If tolerance develops, or if pain severity increases, a gradual increase in dose may be required. The first sign of tolerance is usually a reduced duration of effect. Tolerance to different effects of opioids may develop to varying degrees and at varying rates in a given individual. There is also inter-patient variability in the rate and extent of tolerance that develops to various opioid effects, whether the effect is desirable (e.g., analgesia) or undesirable (e.g., nausea).
Special Risk Groups
Use OxyContin with caution in the following conditions, due to increased risk of adverse reactions: alcoholism; delirium tremens; adrenocortical insufficiency; CNS depression; debilitation; kyphoscoliosis associated with respiratory compromise; myxedema or hypothyroidism; prostatic hypertrophy or urethral stricture; severe impairment of hepatic, pulmonary or renal function; and toxic psychosis.
Driving and Operating Machinery
OxyContin may impair the mental and physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Caution patients accordingly.
Use in Addiction Treatment
OxyContin has no approved use in the treatment of addiction. Its proper usage in individuals with drug or alcohol addiction (substance dependence), either active or in remission, is for the management of pain requiring opioid analgesia.
Laboratory Monitoring
Not every urine drug test for "opioids" or "opiates" detects oxycodone reliably, especially those designed for in-office use. Further, many laboratories will report urine drug concentrations below a specified "cut-off" value as "negative". Therefore, if urine testing for oxycodone is considered in the clinical management of an individual patient, ensure that the sensitivity and specificity of the assay is appropriate, and use caution in interpreting results.
6 ADVERSE REACTIONS
The following adverse reactions described elsewhere in the labeling include:
- Respiratory depression [see Boxed Warning, Warnings and Precautions (5.1, 5.4) and Overdosage (10)]
- CNS depression [see Warnings and Precautions (5.1, 5.2) and Overdosage (10)]
- Hypotensive effects [see Warning and Precautions (5.8) and Overdosage (10)]
- Drug abuse, addiction, and dependence [see Drug Abuse and Dependence (9.2, 9.3)]
- Paralytic ileus [see Warnings and Precautions (5.6)]
- Seizures [see Warnings and Precautions (5.5)]
Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety of OxyContin was evaluated in double-blind clinical trials involving 713 patients with moderate to severe pain of various etiologies. In open-label studies of cancer pain, 187 patients received OxyContin in total daily doses ranging from 20 mg to 640 mg per day. The average total daily dose was approximately 105 mg per day.
OxyContin may increase the risk of serious adverse reactions such as those observed with other opioid analgesics, including respiratory depression, apnea, respiratory arrest, circulatory depression, hypotension, or shock [see Overdosage (10)].
The most common adverse reactions (>5%) reported by patients in clinical trials comparing OxyContin with placebo are shown in Table 2 below:
| Adverse Reaction | OxyContin (n=227) | Placebo (n=45) | |
|---|---|---|---|
| (%) | (%) | ||
| Constipation | (23) | (7) | |
| Nausea | (23) | (11) | |
| Somnolence | (23) | (4) | |
| Dizziness | (13) | (9) | |
| Pruritus | (13) | (2) | |
| Vomiting | (12) | (7) | |
| Headache | (7) | (7) | |
| Dry Mouth | (6) | (2) | |
| Asthenia | (6) | - | |
| Sweating | (5) | (2) |
In clinical trials, the following adverse reactions were reported in patients treated with OxyContin with an incidence between 1% and 5%:
Gastrointestinal disorders: abdominal pain, diarrhea, dyspepsia, gastritis, hiccups
General disorders and administration site conditions: chills, fever
Metabolism and nutrition disorders: anorexia
Musculoskeletal and connective tissue disorders: twitching
Psychiatric disorders: abnormal dreams, anxiety, confusion, dysphoria, euphoria, insomnia, nervousness, thought abnormalities
Respiratory, thoracic and mediastinal disorders: dyspnea, hiccups
Skin and subcutaneous tissue disorders: rash
Vascular disorders: postural hypotension
The following adverse reactions occurred in less than 1% of patients involved in clinical trials:
Blood and lymphatic system disorders: lymphadenopathy
Ear and labyrinth disorders: tinnitus
Eye disorders: abnormal vision
Gastrointestinal disorders: dysphagia, eructation, flatulence, gastrointestinal disorder, increased appetite, stomatitis
General disorders and administration site conditions: withdrawal syndrome (with and without seizures), edema, peripheral edema, thirst, malaise, chest pain, facial edema
Injury, poisoning and procedural complications: accidental injury
Investigations: ST depression
Metabolism and nutrition disorders: dehydration
Nervous system disorders: syncope, migraine, abnormal gait, amnesia, hyperkinesia, hypesthesia, hypotonia, paresthesia, speech disorder, stupor, tremor, vertigo, taste perversion
Psychiatric disorders: depression, agitation, depersonalization, emotional lability, hallucination
Renal and urinary disorders: dysuria, hematuria, polyuria, urinary retention
Reproductive system and breast disorders: impotence
Respiratory, thoracic and mediastinal disorders: cough increased, voice alteration
Skin and subcutaneous tissue disorders: dry skin, exfoliative dermatitis
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of controlled-release oxycodone. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: abuse, addiction, overdose, death, amenorrhea, symptoms associated with an anaphylactic or anaphylactoid reaction, cholestasis, dental caries, increased hepatic enzymes, muscular hypertonia, hyponatremia, ileus, palpitations (in the context of withdrawal), seizures, syndrome of inappropriate antidiuretic hormone secretion, and urticaria
In addition to the events listed above, the following have also been reported, potentially due to the swelling and hydrogelling property of the tablet: choking, gagging, regurgitation, tablets stuck in the throat and difficulty swallowing the tablet.
7 DRUG INTERACTIONS
Neuromuscular Junction Blocking Agents
OxyContin may enhance the neuromuscular blocking action of true skeletal muscle relaxants (such as pancuronium) and produce an increased degree and/or duration of respiratory depression.
Agents Affecting Cytochrome P450 Isoenzymes
Inhibitors of CYP3A4:
Since the CYP3A4 isoenzyme plays a major role in the metabolism of OxyContin, drugs that inhibit CYP3A4 activity, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may cause decreased clearance of oxycodone which could lead to an increase in oxycodone plasma concentrations. A published study showed that the co-administration of the antifungal drug, voriconazole, increased oxycodone AUC and Cmax by 3.6 and 1.7 fold, respectively. Although clinical studies have not been conducted with other CYP3A4 inhibitors, the expected clinical results would be increased or prolonged opioid effects. If co-administration with OxyContin is necessary, caution is advised when initiating therapy with, currently taking, or discontinuing CYP450 inhibitors. Evaluate these patients at frequent intervals and consider dose adjustments until stable drug effects are achieved [see Clinical Pharmacology (12.3)].
Inducers of CYP3A4:
CYP450 inducers, such as rifampin, carbamazepine, and phenytoin, may induce the metabolism of oxycodone and, therefore, may cause increased clearance of the drug which could lead to a decrease in oxycodone plasma concentrations, lack of efficacy or, possibly, development of an abstinence syndrome in a patient who had developed physical dependence to oxycodone. A published study showed that the co-administration of rifampin, a drug metabolizing enzyme inducer, decreased oxycodone (oral) AUC and Cmax by 86% and 63%, respectively. If co-administration with OxyContin is necessary, caution is advised when initiating therapy with, currently taking, or discontinuing CYP3A4 inducers. Evaluate these patients at frequent intervals and consider dose adjustments until stable drug effects are achieved.
Inhibitors of CYP2D6:
Oxycodone is metabolized in part to oxymorphone via cytochrome CYP2D6. While this pathway may be blocked by a variety of drugs (e.g., certain cardiovascular drugs including amiodarone and quinidine as well as polycyclic antidepressants), such blockade has not been shown to be of clinical significance during oxycodone treatment.
CNS Depressants
Start OxyContin at 1/3 to 1/2 of the usual dosage in patients who are concurrently receiving other CNS depressants including sedatives or hypnotics, general anesthetics, phenothiazines, centrally acting anti-emetics, tranquilizers, and alcohol because respiratory depression, hypotension, and profound sedation or coma may result. No specific interaction between oxycodone and monoamine oxidase inhibitors has been observed, but caution in the use of any opioid in patients taking this class of drugs is appropriate [see Warnings and Precautions (5.2 )].
Interactions with Mixed Agonist/Antagonist Opioid Analgesics
Mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) should generally not be administered to a patient who has received or is receiving a course of therapy with a pure opioid agonist analgesic such as OxyContin. In this situation, mixed agonist/antagonist analgesics may reduce the analgesic effect of oxycodone and may precipitate withdrawal symptoms in these patients.
8 USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category B
There are no adequate and well-controlled studies of oxycodone use during pregnancy. Based on limited human data in the literature, oxycodone does not appear to increase the risk of congenital malformations. In animal reproduction and developmental toxicology studies, no evidence of fetal harm was observed. Because animal reproduction studies are not always predictive of human response, oxycodone should be used during pregnancy only if clearly needed.
Teratogenic Effects
The effect of oxycodone in human reproduction has not been adequately studied. Studies with oral doses of oxycodone hydrochloride in rats up to 8 mg/kg/day and rabbits up to 125 mg/kg/day, equivalent to 0.5 and 15 times an adult human dose of 160 mg/day, respectively on a mg/m2 basis, did not reveal evidence of harm to the fetus due to oxycodone. In a pre- and postnatal toxicity study, female rats received oxycodone during gestation and lactation. There were no long-term developmental or reproductive effects in the pups [see Nonclinical Toxicology (13.1)].
Non-Teratogenic Effects
Oxycodone hydrochloride was administered orally to female rats during gestation and lactation in a pre- and postnatal toxicity study. There were no drug-related effects on reproductive performance in these females or any long-term developmental or reproductive effects in pups born to these rats. Decreased body weight was found during lactation and the early post-weaning phase in pups nursed by mothers given the highest dose used (6 mg/kg/day, equivalent to approximately 0.4-times an adult human dose of 160 mg/day, on a mg/m2 basis). However, body weight of these pups recovered.
Labor and Delivery
Opioids cross the placenta and may produce respiratory depression and psychophysiologic effects in neonates. OxyContin is not recommended for use in women immediately prior to and during labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. Occasionally, opioid analgesics may prolong labor through actions which temporarily reduce the strength, duration and frequency of uterine contractions. However this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor.
Closely observe neonates whose mothers received opioid analgesics during labor for signs of respiratory depression. Have a specific opioid antagonist, such as naloxone or nalmefene, available for reversal of opioid-induced respiratory depression in the neonate.
Neonates whose mothers have been taking opioids chronically may also exhibit withdrawal signs, either at birth and/or in the nursery, because they have developed physical dependence. This is not, however, synonymous with addiction [see Drug Abuse and Dependence (9.3)]. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening and should be treated according to protocols developed by neonatology experts.
Nursing Mothers
Oxycodone has been detected in breast milk. Instruct patients not to undertake nursing while receiving OxyContin. Do not initiate OxyContin therapy while nursing because of the possibility of sedation or respiratory depression in the infant.
Withdrawal symptoms can occur in breast-fed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.
Pediatric Use
Safety and effectiveness of OxyContin in pediatric patients below the age of 18 years have not been established.
Geriatric Use
In controlled pharmacokinetic studies in elderly subjects (greater than 65 years) the clearance of oxycodone was slightly reduced. Compared to young adults, the plasma concentrations of oxycodone were increased approximately 15% [see Clinical Pharmacology (12.3)]. Of the total number of subjects (445) in clinical studies of oxycodone hydrochloride controlled-release tablets, 148 (33.3%) were age 65 and older (including those age 75 and older) while 40 (9.0%) were age 75 and older. In clinical trials with appropriate initiation of therapy and dose titration, no untoward or unexpected adverse reactions were seen in the elderly patients who received oxycodone hydrochloride controlled-release tablets. Thus, the usual doses and dosing intervals may be appropriate for elderly patients. However, reduce the starting dose to 1/3 to 1/2 the usual dosage in debilitated, non-opioid-tolerant patients. Respiratory depression is the chief risk in elderly or debilitated patients, usually the result of large initial doses in patients who are not tolerant to opioids, or when opioids are given in conjunction with other agents that depress respiration. Titrate the dose of OxyContin cautiously in these patients.
Hepatic Impairment
A study of OxyContin in patients with hepatic impairment demonstrated greater plasma concentrations than those seen at equivalent doses in persons with normal hepatic function. Therefore, in the setting of hepatic impairment, start dosing patients at 1/3 to 1/2 the usual starting dose followed by careful dose titration [see Clinical Pharmacology (12.3)].
Renal Impairment
In patients with renal impairment, as evidenced by decreased creatinine clearance (<60 mL/min), the concentrations of oxycodone in the plasma are approximately 50% higher than in subjects with normal renal function. Follow a conservative approach to dose initiation and adjust according to the clinical situation [see Clinical Pharmacology (12.3)].
Gender Differences
In pharmacokinetic studies with OxyContin, opioid-naive females demonstrate up to 25% higher average plasma concentrations and greater frequency of typical opioid adverse events than males, even after adjustment for body weight. The clinical relevance of a difference of this magnitude is low for a drug intended for chronic usage at individualized dosages, and there was no male/female difference detected for efficacy or adverse events in clinical trials.
9 DRUG ABUSE AND DEPENDENCE
Controlled Substance
OxyContin contains oxycodone, which is a Schedule II controlled substance with an abuse liability similar to morphine. OxyContin, like morphine and other opioids used for analgesia, can be abused and is subject to criminal diversion.
Abuse
Abuse of OxyContin poses a hazard of overdose and death. This risk is increased with compromising the tablet and with concurrent abuse of alcohol or other substances.
With parenteral abuse, the tablet excipients can result in death, 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.
Opioid drugs are sought by people with substance use disorders (abuse or addiction, the latter of which is also called "substance dependence") and criminals who supply them by diverting medicines out of legitimate distribution channels. OxyContin is a target for theft and diversion.
"Drug-seeking" behavior is very common in persons with substance use disorders. Drug-seeking tactics include, but are not limited to, emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated "loss" of prescriptions, altering or forging of 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 people with untreated substance use disorders, and criminals who divert controlled substances.
The risks of misuse and abuse should be considered when prescribing or dispensing OxyContin. Concerns about abuse and addiction, should not prevent the proper management of pain, howeve
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