Special Warning : אזהרת שימוש

WARNINGS

Addiction, Abuse, and Misuse
PERCOCET contains oxycodone, a schedule II controlled substance. As an opioid, PERCOCET exposes users to the risks of addiction, abuse, and misuse (see DRUG ABUSE AND DEPENDENCE).
Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed PERCOCET. Addiction can occur at recommended dosages and if the drug is misused or abused.
Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing PERCOCET, and reassess all patients receiving PERCOCET for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as PERCOCET, but use in such patients necessitates intensive counseling about the risks and proper use of PERCOCET along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose [see WARNINGS, Life-Threatening Respiratory Depression; DOSAGE AND ADMINISTRATION, Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose].
Opioids are sought for non-medical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing PERCOCET. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and proper disposal of unused drug [see PRECAUTIONS; Information for Patients/Caregivers].
Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status (see OVERDOSAGE). Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of PERCOCET, the risk is greatest during the initiation of therapy or following a dosage increase.
To reduce the risk of respiratory depression, proper dosing and titration of PERCOCET are essential (see DOSAGE AND ADMINISTRATION). Overestimating the PERCOCET dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.
Accidental ingestion of even one dose of PERCOCET, especially by children, can result in respiratory depression and death due to an overdose of oxycodone.
Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling emergency health services or getting emergency medical help right away in the event of a known or suspected overdose [see PRECAUTIONS, Information for Patients /Caregivers].
Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep related hypoxemia.
Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see DOSAGE AND ADMINISTRATION].
Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with PERCOCET.
Inform patients and caregivers that naloxone is dispensed with a doctor's prescription only.
Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling emergency health services or getting emergency medical help, even if naloxone is administered [see PRECAUTIONS, Information for Patients /Caregivers].
Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone [see DOSAGE AND ADMINISTRATION, Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose; WARNINGS, Addiction, Abuse, and Misuse, Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants; PRECAUTIONS, Information for Patients /Caregivers, OVERDOSAGE].
,
Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Profound sedation, respiratory depression, coma, and death may result from the concomitant use of PERCOCET with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics (see PRECAUTIONS; Drug Interactions).

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Inform patients and caregivers of this potential interaction, educate them on the signs and symptoms of respiratory depression (including sedation).
If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see WARNINGS, Life-Threatening Respiratory Depression; DOSAGE AND ADMINISTRATION, Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose].
Advise both patients and caregivers about the risks of respiratory depression and sedation when PERCOCET is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs.

Neonatal Opioid Withdrawal Syndrome

Use of PERCOCET for an extended period of time during pregnancy can result in withdrawal in the neonate.
Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for an extended period of time the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available (see PRECAUTIONS; Information for Patients/Caregivers, Pregnancy).

Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers Concomitant use of PERCOCET with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole- antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of oxycodone hydrochloride and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression (see WARNINGS), particularly when an inhibitor is added after a stable dose of PERCOCET is achieved.
Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in PERCOCET- treated patients may increase oxycodone plasma concentrations and prolong opioid adverse reactions. When using PERCOCET with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in PERCOCET-treated patients, evaluate patients at frequent intervals and consider dosage reduction of PERCOCET until stable drug effects are achieved (see PRECAUTIONS; Drug Interactions).
Concomitant use of PERCOCET with CYP3A4 inducers or discontinuation of an CYP3A4 inhibitor could decrease oxycodone hydrochloride plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to oxycodone hydrochloride. When using PERCOCET with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, evaluate patients at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur (see PRECAUTIONS; Drug Interactions).

Hepatotoxicity
Paracetamol has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of paracetamol at doses that exceed 4000 milligrams per day, and often involve more than one paracetamol-containing product. The excessive intake of paracetamol may be intentional to cause self-harm or unintentional as patients attempt to obtain more pain relief or unknowingly take other paracetamol-containing products.
The risk of acute liver failure is higher in individuals with underlying liver disease and in individuals who ingest alcohol while taking paracetamol.
Instruct patients to look for paracetamol on package labels and not to use more than one product that contains paracetamol. Instruct patients to seek medical attention immediately upon ingestion of more than 4000 milligrams of paracetamol per day, even if they feel well.


Opioid-Induced Hyperalgesia and Allodynia
Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [see DRUG ABUSE AND DEPENDENCE; Dependence]. Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non- painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior.
Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety) [see DOSAGE AND ADMINISTRATION, WARNINGS].

Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients
The use of PERCOCET in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.
Patients with Chronic Pulmonary Disease: PERCOCET-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of PERCOCET (see WARNINGS; Life Threatening Respiratory Depression).
Elderly, Cachetic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients (see WARNINGS; Life Threatening Respiratory Depression).
Regularly evaluate patients, particularly when initiating and titrating PERCOCET and when PERCOCET is given concomitantly with other drugs that depress respiration (see WARNINGS; Life Threatening Respiratory Depression). Alternatively, consider the use of non-opioid analgesics in these patients.

Adrenal Insufficiency
Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

Severe Hypotension
PERCOCET may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients.
There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g. phenothiazines or general anesthetics) [see PRECAUTIONS; Drug Interactions]. Regularly evaluate these patients for signs of hypotension after initiating or titrating the dosage of PERCOCET. In patients with circulatory shock PERCOCET may cause vasodilatation that can further reduce cardiac output and blood pressure. Avoid the use of PERCOCET with circulatory shock.

Serious Skin Reactions
Rarely, paracetamol may cause serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. Patients should be informed about the signs of serious skin reactions, and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.

Hypersensitivity/Anaphylaxis
There have been post-marketing reports of hypersensitivity and anaphylaxis associated with use of paracetamol.
Clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, pruritus, and vomiting. There were infrequent reports of life-threatening anaphylaxis requiring emergency medical attention.
Instruct patients to discontinue PERCOCET immediately and seek medical care if they experience these symptoms.
Do not prescribe PERCOCET for patients with paracetamol allergy [see PRECAUTIONS; Information for Patients /Caregivers].

Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness

In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), PERCOCET may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with PERCOCET.
Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of PERCOCET in patients with impaired consciousness or coma.

Risks of Use in Patients with Gastrointestinal Conditions

PERCOCET is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.
The administration of PERCOCET, or other opioids may obscure the diagnosis or clinical course in patients with acute abdominal conditions.
The oxycodone in PERCOCET may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Regularly evaluate patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

Increased Risk of Seizures in Patients with Seizure Disorders

The oxycodone in PERCOCET may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Regularly evaluate patients with a history of seizure disorders for worsened seizure control during PERCOCET therapy.

Withdrawal

Do not abruptly discontinue PERCOCET in a patient physically dependent on opioids. When discontinuing PERCOCET in a physically dependent patient, gradually taper the dosage. Rapid tapering of PERCOCET in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see DOSAGE AND ADMINISTRATION, DRUG ABUSE AND DEPENDENCE].

Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including PERCOCET. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [see PRECAUTIONS/Drug Interactions].

Risks of Driving and Operating Machinery

PERCOCET may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of PERCOCET and know how they will react to the medication [see PRECAUTIONS; Information for Patients /Caregivers].


PRECAUTIONS
Information for Patients/Caregivers
Advise the patient to read the patient labeling (Patient Information Leaflet).
Storage and Disposal
Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store PERCOCET securely, out of sight and reach of children and in a location not accessible by others, including visitors to the home.
Inform patients that leaving PERCOCET unsecured can pose a deadly risk to others in the home. [see WARNINGS, DRUG ABUSE AND DEPENDENCE].
Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly.
Expired, unwanted, or unused PERCOCET should be disposed of by flushing the unused medication down the toilet if a drug take-back option is not readily available.

Addiction, Abuse, and Misuse
Inform patients that the use of PERCOCET, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death (see WARNINGS). Instruct patients not to share PERCOCET with others and to take steps to protect PERCOCET from theft or misuse.

Life-Threatening Respiratory Depression
Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting PERCOCET or when the dosage is increased, and that it can occur even at recommended dosages.
Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of getting emergency medical help right away in the event of a known or suspected overdose [see WARNINGS, Life Threatening Respiratory Depression].

Accidental Ingestion
Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death (see WARNINGS).

Interactions with Benzodiazepines and Other CNS Depressants
Inform patients and caregivers that potentially fatal additive effects may occur if PERCOCET are used with benzodiazepines and other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a health care provider (see WARNINGS, PRECAUTIONS; Drug Interactions).

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose 
Discuss with the patient and caregiver the availability of naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with PERCOCET. Inform patients and caregivers about the various ways to obtain naloxone as permitted by the Ministry of Health [see WARNINGS, Life-Threatening Respiratory Depression; DOSAGE AND ADMINISTRATION].

Educate patients and caregivers on how to recognize the signs and symptoms of an overdose.
Explain to patients and caregivers that naloxone’s effects are temporary, and that they must get emergency medical help right away in all cases of known or suspected opioid overdose, even if naloxone is administered [see OVERDOSAGE].

If naloxone is prescribed, also advise patients and caregivers:
• How to treat with naloxone in the event of an opioid overdose
• To tell family and friends about their naloxone and to keep it in a place where family and friends can access it in an emergency
• To read the Patient Information (or other educational material) that will come with their naloxone. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do.
Hyperalgesia and Allodynia
Inform patients and caregivers not to increase opioid dosage without first consulting a clinician. Advise patients to seek medical attention if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see WARNINGS; ADVERSE REACTIONS].

Serotonin Syndrome
Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications (see PRECAUTIONS; Drug Interactions).

Monoamine Oxidase Inhibitor (MAOI) Interaction
Inform patients to avoid taking PERCOCET while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking PERCOCET tablets [see PRECAUTIONS; Drug Interactions].

Important Administration Instructions

Instruct patients how to properly take PERCOCET [see DOSAGE AND ADMINISTRATION, WARNINGS].
Advise patients not to adjust the medication dose themselves and to consult with their healthcare provider prior to any dosage adjustment. Advise patients who are treated with PERCOCET for more than a few weeks not to abruptly discontinue the medication. Advise patients to consult with their physician for a gradual discontinuation dose schedule to taper off the medication.

Important Discontinuation Instructions

In order to avoid developing withdrawal symptoms, instruct patients not to discontinue PERCOCET without first discussing a tapering plan with the prescriber [see DOSAGE AND ADMINISTRATION].

Maximum Daily Dose of Paracetamol

Inform patients to not take more than 4000 milligrams of paracetamol per day. Advise patients to call their prescriber if they take more than the recommended dose.

Inform patients not to take high doses (in the recommended dose range) of paracetamol while fasting.

Driving or Operating Heavy Machinery
Inform patients that PERCOCET may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see PRECAUTIONS].

Constipation

Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see ADVERSE REACTIONS, CLINICAL PHARMACOLOGY].

Adrenal Insufficiency
Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms (see WARNINGS).

Hypotension

Inform patients that PERCOCET may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see WARNINGS].

Anaphylaxis

Inform patients that anaphylaxis have been reported with ingredients contained in PERCOCET. Advise patients how to recognize such a reaction and when to seek medical attention [see CONTRAINDICATIONS, ADVERSE REACTIONS].

Pregnancy

Neonatal Opioid Withdrawal Syndrome
Inform female patients of reproductive potential that use of PERCOCET for an extended period of time during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated (see WARNINGS, PRECAUTIONS; Pregnancy).
Embryo-Fetal Toxicity
Inform female patients of reproductive potential that PERCOCET can cause fetal harm and to inform the healthcare provider of a known or suspected pregnancy (see PRECAUTIONS; Pregnancy).

Lactation
Advise breastfeeding women using PERCOCET to carefully observe infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct breastfeeding women to seek immediate medical care if they notice these signs (see PRECAUTIONS; Nursing Mothers).

Infertility

Inform patients that use of opioids for an extended period of time may cause reduced fertility. It is not known whether these effects on fertility are reversible [see ADVERSE REACTIONS].


Laboratory Tests
Although oxycodone may cross-react with some drug urine tests, no available studies were found which determined the duration of detectability of oxycodone in urine drug screens. However, based on pharmacokinetic data, the approximate duration of detectability for a single dose of oxycodone is roughly estimated to be one to two days following drug exposure.
Urine testing for opiates may be performed to determine illicit drug use and for medical reasons such as evaluation of patients with altered states of consciousness or monitoring efficacy of drug rehabilitation efforts. The preliminary identification of opiates in urine involves the use of an immunoassay screening and thin-layer chromatography (TLC).
Gas chromatography/mass spectrometry (GC/MS) may be utilized as a third-stage identification step in the medical investigational sequence for opiate testing after immunoassay and TLC. The identities of 6-keto opiates (e.g., oxycodone) can further be differentiated by the analysis of their methoximetrimethylsilyl (MO-TMS) derivative.

Effects on Driving