Usual Adult Dose for Pain

2 tablets orally every 12 hours as needed for pain

Comments:

• Patients should be monitored closely for respiratory depression, especially within the first 24 to 72 hours of starting therapy.

Renal Dose Adjustments

Severe renal dysfunction: Not recommended.

Comments:

• The pharmacokinetics and tolerability of this drug have not been studied in patients with renal dysfunction.

Liver Dose Adjustments

Moderate or severe liver dysfunction: Not recommended.

Comments:

• The pharmacokinetics and tolerability of this drug have not been studied in patients with liver dysfunction.

Dose Adjustments

Poor Metabolizers of CYP450 2C9 Substrates:

• Celecoxib is administered starting with half the lowest recommended dose in patients known/suspected to be poor CYP450 2C9 metabolizers (i.e., CYP450 2C9*3/*3), based on genotype or history/experience with other CYP450 2C9 substrates (e.g., warfarin, phenytoin).
• Because this combination drug is not available in lower strengths of celecoxib, it is not recommended in patients known/suspected to be poor CYP450 2C9 metabolizers.

• This drug should not be abruptly discontinued in patients who may be physically dependent on opioids.
• Rapid discontinuation of opioid analgesics in physically dependent patients has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide.
• Rapid discontinuation has been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse; patients may attempt to treat their pain or withdrawal symptoms with illicit opioids (e.g., heroin) and other substances.
• When deciding to decrease the dose or discontinue therapy in an opioid-dependent patient, various factors should be considered, including the total daily opioid dose (including this drug) the patient has been taking, the duration of therapy, the type of pain being treated, and the patient's physical and psychological attributes.
• It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic.
• When discontinuing opioid analgesics due to a suspected substance use disorder, the patient should be evaluated and treated, or referred for evaluation and treatment of the substance use disorder; treatment should include evidence-based approaches (e.g., medication assisted treatment of opioid use disorder); complex patients with comorbid pain and substance use disorders may benefit from referral to a specialist.
• While there are no standard opioid tapering schedules suitable for all patients, good clinical practice dictates a patient-specific plan to taper the opioid dose gradually.
• For patients taking this drug who are physically opioid-dependent, starting the taper in small increments (e.g., no greater than 10% to 25% of the total daily opioid dose) is recommended to avoid withdrawal symptoms, and dose-lowering should proceed at 2- to 4-week intervals.
• Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper.
• The patient may need to be given a reduced dosing schedule of this drug to accomplish a successful taper.
• The patient should be reassessed frequently to manage pain and withdrawal symptoms, should they emerge; common withdrawal symptoms (including restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, mydriasis) and other signs/symptoms (including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, increased blood pressure/respiratory rate/heart rate) may develop.
• If withdrawal symptoms occur, the taper may need to be paused for a period of time or the opioid analgesic dose may need to be increased to the prior dose, and then a slower taper should continue.
• Patients should be monitored for any changes in mood, emergence of suicidal thoughts, or use of other substances.
• When managing patients taking opioid analgesics (especially those treated for a long duration and/or with high doses for chronic pain), a multimodal approach to pain management (including mental health support, if needed) should be prepared before starting an opioid analgesic taper.
• A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic.

Precautions

The US FDA requires a Risk Evaluation and Mitigation Strategy (REMS) for all opioid analgesics used in the outpatient setting. It includes a medication guide and elements to assure safe use. For additional information: www.accessdata.fda.gov/scripts/cder/rems/index.cfm

US BOXED WARNINGS:

• ADDICTION, ABUSE, AND MISUSE: This drug exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death; each patient's risk should be assessed before prescribing this drug and all patients should be monitored regularly for the development of such behaviors and conditions.
• OPIOID ANALGESIC REMS: To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the US FDA has required a REMS for these products; under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to health care providers. Health care providers are strongly encouraged to: complete a REMS-compliant education program; counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products; emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist; and consider other tools to improve patient, household, and community safety.
• LIFE-THREATENING RESPIRATORY DEPRESSION: Serious, life-threatening, or fatal respiratory depression may occur with use of this drug; monitoring for respiratory depression, especially during initiation of this drug, is recommended.
• ACCIDENTAL INGESTION: Accidental ingestion of even 1 dose of this drug (especially by children) can be fatal.
• CARDIOVASCULAR THROMBOTIC EVENTS: NSAIDs cause an increased risk of serious cardiovascular thrombotic events (including myocardial infarction and stroke), which can be fatal; this risk may occur early in therapy and may increase with duration of use. This drug is contraindicated in the setting of coronary artery bypass graft (CABG) surgery.
• GASTROINTESTINAL (GI) BLEEDING, ULCERATION, AND PERFORATION: NSAIDs cause an increased risk of serious GI side effects (including bleeding, ulceration, and perforation of stomach or intestines), which can be fatal; such events can occur at any time during use and without symptoms. Elderly patients and patients with history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events.
• ULTRA-RAPID METABOLISM OF TRAMADOL AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN: Life-threatening respiratory depression and death have occurred in children who received tramadol; some of the reported cases followed tonsillectomy and/or adenoidectomy, and in at least 1 case, the child had evidence of being an ultra-rapid metabolizer of tramadol due to a CYP450 2D6 polymorphism. This drug is contraindicated in children younger than 12 years and in children younger than 18 years following tonsillectomy and/or adenoidectomy. Use of this drug should be avoided in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol.
• NEONATAL OPIOID WITHDRAWAL SYNDROME: Prolonged use of this drug during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated; it requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant patient, the patient should be apprised of the risk of neonatal opioid withdrawal syndrome and health care providers should ensure that appropriate treatment will be available.
• INTERACTIONS WITH DRUGS AFFECTING CYP450 ISOENZYMES: The effects of concomitant use or discontinuation of CYP450 3A4 inducers, CYP450 3A4 inhibitors, or CYP450 2D6 inhibitors with tramadol are complex; use of such agents requires careful consideration of the effects on the parent drug (tramadol) and the active metabolite (M1).
• RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS: Concomitant use of opioids with benzodiazepines or other CNS depressants (including alcohol) may result in profound sedation, respiratory depression, coma, and death. Concomitant prescribing of this drug and benzodiazepines/other CNS depressants should be reserved for use in patients for whom alternative treatment options are inadequate; treatment should be limited to the minimum duration; and patients should be followed for signs/symptoms of respiratory depression and sedation.

• All patients younger than 12 years
• Postoperative pain management in children younger than 18 years after tonsillectomy and/or adenoidectomy
• Significant respiratory depression
• In the setting of CABG surgery
• Acute or severe bronchial asthma in an unmonitored setting or without resuscitative equipment
• Known/suspected GI obstruction (including paralytic ileus)
• Previous hypersensitivity (e.g., anaphylaxis reactions, serious skin reactions) to either active component, opioids, sulfonamides, or to any of the ingredients
• Concomitant use of monoamine oxidase inhibitors or use within the last 14 days
• History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs (severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients)

Dialysis

Data not available

Other Comments

Administration advice:

• Do not exceed the recommended dose.
• Do not coadminister with other products containing celecoxib or tramadol.
• Use for the shortest duration consistent with individual patient treatment goals.
• When starting therapy, consider the patient's pain severity, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse.

• Store at 20C to 25C (68F to 77F); excursions permitted to 15C to 30C (59F to 86F).

• Each tablet contains celecoxib 56 mg and tramadol hydrochloride 44 mg.
• Limitations of Use: Due to the risks of addiction, abuse, and misuse with opioids (even at recommended doses), this drug should be reserved for use in patient for whom alternative treatment options (e.g., non-opioid analgesics):
• Have not been tolerated, or are not expected to be tolerated.
• Have not provided adequate analgesia, or are not expected to provide adequate analgesia.
• Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose:
• The availability of naloxone for the emergency treatment of opioid overdose should be discussed with the patient and caregiver, and the potential need for access to naloxone should be assessed, both when starting and renewing treatment with this drug.
• Patients and caregivers should be informed about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements/guidelines (e.g., by prescription, directly from pharmacist, as part of community-based program).
• Prescribing naloxone should be considered based on patient risk factors for overdose (e.g., concomitant use of CNS depressants, history of opioid use disorder, prior opioid overdose); however, presence of risk factors for overdose should not prevent proper pain management in any given patient.
• Prescribing naloxone should be considered if patient has household members (including children) or other close contacts at risk for accidental exposure/overdose.

• Cardiovascular: For adverse cardiovascular events (during therapy); for signs of cardiac ischemia in patients with recent myocardial infarction; for signs of worsening heart failure in patients with severe heart failure; blood pressure (when starting and during therapy); for signs of hypotension (after starting therapy)
• Gastrointestinal: For signs/symptoms of GI ulceration and bleeding (during therapy); for worsening symptoms in patients with biliary tract disease, including acute pancreatitis
• Hematologic: For signs of bleeding in patients with increased risk
• Metabolic: For signs/symptoms of hyponatremia (during therapy, especially at start of therapy)
• Nervous System: For signs of sedation in susceptible patients (especially at start of therapy)
• Psychiatric: For development of opioid addiction, abuse, or misuse in all patients (during therapy)
• Renal: Renal function in patients with renal or liver dysfunction, heart failure, dehydration, or hypovolemia (during therapy)
• Respiratory: For signs of respiratory depression (especially at start of therapy [within the first 24 to 72 hours]); for changes in the signs and symptoms of asthma in patients with preexisting asthma

• Read the US FDA-approved patient labeling (Medication Guide).
• Due to risks associated with accidental ingestion, misuse, and abuse, store this drug securely, out of sight and reach of children, and in a location not accessible by others (including visitors to the home); leaving this drug unsecured can pose a deadly risk to others in the home.
• When medicines are no longer needed, dispose of them promptly (according to local state guidelines and/or regulations); if take-back programs are not available (preferred option), dispose of this drug by following these 4 steps: mix this drug (do not crush) with an unpalatable substance (e.g., dirt, cat litter, used coffee grounds), place the mixture in a container (e.g., sealed plastic bag), throw the container in the household trash, and delete all personal information on the prescription label of the empty bottle. You can visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines.
• Do not share this drug with others; take steps to protect this drug from theft or misuse.
• Watch for respiratory depression; it is very important to call 911 or otherwise get emergency medical help right away in case of known/suspected overdose, even if naloxone is administered.
• Report any symptoms of cardiovascular thrombotic events (including chest pain, shortness of breath, weakness, slurring of speech) to health care provider immediately.
• Report symptoms of GI ulcerations and bleeding (including pain in the upper part of the stomach, indigestion, bloody or dark stools, blood in vomit) to health care provider.
• Monitor adolescents (12 to 18 years of age) receiving this drug for signs of respiratory depression; do not give to children younger than 12 years or to children younger than 18 years after tonsillectomy and/or adenoidectomy.
• Potentially fatal additive effects may occur if this drug is used with benzodiazepines, CNS depressants (including alcohol), or some illicit drugs; do not use these concomitantly unless supervised by health care provider.
• Seek medical attention at once if symptoms of serotonin syndrome (e.g., agitation, confusion, hallucinations, fast heartbeat, high body temperature, incoordination, stiff muscles, nausea, vomiting, diarrhea) develop.
• Do not take this drug while using any drugs that inhibit monoamine oxidase; do not start monoamine oxidase inhibitors while taking this drug.
• Seek medical attention if a group of the nonspecific signs/symptoms of adrenal insufficiency (e.g., nausea, vomiting, anorexia, fatigue, weakness, dizziness, low blood pressure) occur.
• Take this drug properly; do not modify the dose without consulting with physician or other health care professional.
• If you have used this drug for more than a few weeks and discontinuation is indicated, it is important to safely taper the dose; follow the dose schedule provided for gradual discontinuation.
• Seek immediate medical attention if any symptoms of hypersensitivity reaction develop; seek immediate emergency help if signs of anaphylactic reaction (e.g., difficulty breathing, swelling of face or throat) occur.
• Inform health care provider if you have used opioids at any time during your pregnancy, especially near time of birth.
• Inform health care provider of known/suspected pregnancy.
• If pregnant, avoid using this drug and other NSAIDs starting at 30 weeks gestation; if this drug is needed between about 20 to 30 weeks gestation, you may need to be monitored for oligohydramnios if therapy continues beyond 48 hours.
• Do not breastfeed during treatment with this drug.
• This drug may affect ability to perform potentially hazardous activities (e.g., driving a car, operating heavy machinery); do not perform such tasks until you know how you will react to the medication.
• Do not exceed the single-dose or 24-hour dose limit or the time interval between doses; exceeding these recommendations can lead to respiratory depression, seizures, and death.
• If signs/symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, itching, diarrhea, yellow skin or eyes, right upper quadrant tenderness, influenza-like symptoms) occur, stop this drug and seek immediate medical therapy.
• Watch for symptoms of congestive heart failure (including shortness of breath, unexplained weight gain, edema) and contact health care provider if such symptoms occur.
• Stop this drug immediately if any type of rash or fever develops and contact health care provider as soon as possible.
• Concomitant use of this drug with other NSAIDs or salicylates is not recommended; do not use low-dose aspirin with this drug until you talk to health care provider.