TRAMADOL HYDROCHLORIDE (tramadol hydrochloride 100 mg) Dailymed

• Tramadol hydrochloride extended-release tablets should be prescribed only by healthcare providers knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks. (2.1)
• Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of tramadol hydrochloride extended-release tablets for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. (2.1, 5).
• Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse. (5.1)
• Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with tramadol hydrochloride extended-release tablets. Consider this risk when selecting an initial dose and when making dose adjustments. (2.1, 5.2)
• Do not exceed a daily dose of 300 mg tramadol. Do not use with other tramadol products. (2.1)
• For opioid-naïve and opioid non-tolerant patients, initiate tramadol hydrochloride extended-release tablets at a dose of 100 mg once daily, then titrate up by 100 mg increments every 5 days according to need and tolerance. (2.3)
• For patients currently on tramadol IR, calculate total 24-hr IR dose, and initiate tramadol hydrochloride extended-release tablets at a dose rounded down to next lower 100 mg increment; then adjust dose according to need and tolerance. See full prescribing information for instructions on conversion, titration, and maintenance of therapy. (2.3, 2.4)
• Do not abruptly discontinue tramadol hydrochloride extended-release tablets in a physically-dependent patient. (2.5)
• Discuss availability of naloxone with the patient and caregiver and assess each patient's need for access to naloxone, both when initiating and renewing treatment with tramadol hydrochloride extended-release tablets. Consider prescribing naloxone based on the patient's risk factors for overdose [2.2, 5.1, 5.3, 5.7].

2.1 Important Dosage and Administration Instructions

Tramadol hydrochloride extended-release tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.

• Do not use tramadol hydrochloride extended-release tablets concomitantly with other tramadol products [see Warnings and Precautions (5.3), (5.15)].
• Do not administer tramadol hydrochloride extended-release tablets at a dose exceeding 300 mg per day.
• Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see Warnings and Precautions (5.5)]. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of tramadol hydrochloride extended-release tablets for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
• Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)]
• Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with tramadol hydrochloride extended-release tablets. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions (5.5)].
• Instruct patients to swallow tramadol hydrochloride extended-release tablets whole [see Patient Counseling Information (17)], and to take it with liquid. Crushing, chewing, splitting, or dissolving tramadol hydrochloride extended-release tablets will result in uncontrolled delivery of tramadol and can lead to overdose or death [see Warnings and Precautions (5.1)].
• Tramadol hydrochloride extended-release tablets may be taken without regard to food, It is recommended that tramadol hydrochloride extended-release tablets be taken in a consistent manner [see Clinical Pharmacology (12.3)].

2.2 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 tramadol hydrochloride extended release tablets [see Warnings and Precautions (5.3), Patient Counseling Information (17)].

Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program).

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 [see Warnings and Precautions (5.1, 5.3, 5.7)].

Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose.

2.3 Initial Dosage

Patients Not Currently on a Tramadol Product

The initial dose of tramadol hydrochloride extended-release tablets is 100 mg once daily.

Patients Currently on Tramadol Immediate-Release (IR) Products

Calculate the 24-hour tramadol IR dose and initiate a total daily dose of tramadol hydrochloride extended-release tablets rounded down to the next lower 100 mg increment. The dose may subsequently be individualized according to patient need.

Due to limitations in flexibility of dose selection with tramadol hydrochloride extended-release tablets, some patients maintained on tramadol IR products may not be able to convert to tramadol hydrochloride extended-release tablets.

Conversion from Other Opioids to Tramadol Hydrochloride Extended-Release Tablets

When tramadol hydrochloride extended-release tablets therapy is initiated, discontinue all other opioid analgesics other than those used on an as needed basis for breakthrough pain when appropriate drugs.

2.4 Titration and Maintenance of Therapy

Individually titrate tramadol hydrochloride extended-release tablets by 100 mg every five days to a dose that provides adequate analgesia and minimizes adverse reactions. The maximum daily dose of tramadol hydrochloride extended-release tablets is 300 mg per day.

Continually reevaluate patients receiving tramadol hydrochloride extended-release tablets to assess the maintenance of pain control, signs and symptoms of opioids withdrawal and other adverse reactions, as well as to reassess for the development of addiction, abuse, or misuse [see Warnings and Withdrawal (5.1, 5.18)]. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During use of opioid therapy for an extended period of time, periodically reassess the continued need for the use of opioid analgesics.

Patients who experience breakthrough pain may require a dosage adjustment of tramadol hydrochloride extended-release tablets, or may need rescue medication with an appropriate dose of an immediate-release analgesic. If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the tramadol hydrochloride extended-release tablets dosage.

If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after dosage increase), consider reducing the dosage [see Warnings and Precautions (5)]. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

2.5 Safe Reduction or Discontinuation Of Tramadol Hydrochloride Extended-Release Tablets

Do not abruptly discontinue tramadol hydrochloride extended-release tablets in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances.

When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking tramadol hydrochloride extended-release tablets, there are a variety of factors that should be considered, including the total daily dose of opioid (including tramadol hydrochloride extended-release tablets) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. 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 reaulic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with co-morbid pain and substance use disorders may benefit from referral to a speciaul.

There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on tramadol hydrochloride extended-release tablets who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper.

It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and 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. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances.

When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating 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 [see Warnings and Precautions (5.17), Drug Abuse and Dependence (9.3)].

3 Dosage Forms And Strengths

Extended-release tablets are available as:

100 mg tablets: White to off-white circular, biconvex, beveled edge coated tablets imprinted with 'L010' on one side and plain on the other side.

200 mg tablets: White to off-white circular, biconvex, beveled edge coated tablets imprinted with 'L011' on one side and plain on the other side.

300 mg tablets: White to off-white circular, biconvex, beveled edge coated tablets imprinted with 'L012' on one side and plain on the other side.

• Extended-release tablets 100 mg, 200 mg, and 300 mg (non-scored) (3)

4 Contraindications

Tramadol hydrochloride extended-release tablets are contraindicated for:

• all children younger than 12 years of age [see Warnings and Precautions (5.4)]
• post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Warnings and Precautions (5.4)] .

Tramadol hydrochloride extended-release tablets are also contraindicated in patients with:

• Significant respiratory depression [see Warnings and Precautions (5.3)]
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.12)]
• Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.15)]
• Hypersensitivity to tramadol (e.g., anaphylaxis) [see Warnings and Precautions (5.16), Adverse Reactions (6.2)]
• Concurrent use of monoamine oxidase inhibitors (MAOIs) or use within the last 14 days[see Drug Interactions (7)].

• Children younger than 12 years of age (4)
• Postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. (4)
• Significant respiratory depression (4)
• Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment (4)
• Known or suspected gastrointestinal obstruction, including paralytic ileus (4)
• Hypersensitivity to tramadol (4)
• Concurrent use of monoamine oxidase inhibitors (MAOIs) or use within the last 14 days (4)

5 Warnings And Precautions

• Opioid Induced Hyperalgesia (OIH) and Allodynia: Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation. (5.8)
• Serotonin Syndrome with Concomitant Use of Serotonergic Drugs: Potentially life-threatening condition could result from concomitant serotonergic drug administration. Discontinue tramadol hydrochloride extended-release tablets if serotonin syndrome is suspected. (5.9)
• Risk of Seizure: Present within recommended dosage range. Risk is increased with higher than recommended doses and concomitant use of SSRIs, SNRIs, anorectics, tricyclic antidepressants and other tricyclic compounds, other opioids, MAOIs, neuroleptics, other drugs that reduce seizure threshold, in patients with epilepsy or at risk for seizures. (5.10, 7)
• Risk of Suicide: Do not use tramadol hydrochloride extended-release tablets in suicidal or addiction-prone patients. Use with caution in those taking tranquilizers, antidepressants or abuse alcohol. (5.11)
• Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Regularly evaluate closely, particularly during initiation and titration. (5.12)
• Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. (5.13)
• Severe Hypotension: Regularly evaluate during dosage initiation and titration. Avoid use of tramadol hydrochloride extended-release tablets in patients with circulatory shock. (5.14)
• Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness: Regularly evaluate for sedation and respiratory depression. Avoid use of tramadol hydrochloride extended-release tablets in patients with impaired consciousness or coma. (5.15)

5.1 Addiction, Abuse, and Misuse

Tramadol hydrochloride extended-release tablet contains tramadol, a Schedule IV controlled substance. As an opioid, tramadol hydrochloride extended-release tablet exposes users to the risks of addiction, abuse, and misuse. Because extended-release products such as tramadol hydrochloride extended-release tablets deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of tramadol present [see Drug Abuse and Dependence(9)].

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed tramadol hydrochloride extended-release tablets. 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 tramadol hydrochloride extended-release tablets, and reassess all patients receiving tramadol hydrochloride extended-release tablets 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 tramadol hydrochloride extended-release tablets, but use in such patients necessitates intensive counseling about the risks and proper use of tramadol hydrochloride extended-release tablets along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.3)].

Abuse or misuse of tramadol hydrochloride extended-release tablets by cutting, breaking, chewing, crushing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of tramadol and can result in overdose and death [see Overdosage (10)].

Opioids are sought for non-medical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing tramadol hydrochloride extended-release tablets. 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. 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.

5.2 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 (10)]. 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 tramadol hydrochloride extended-release tablets, the risk is greatest during the initiation of therapy or following a dosage increase of tramadol hydrochloride extended-release tablets.

To reduce the risk of respiratory depression, proper dosing and titration of tramadol hydrochloride extended-release tablets are essential [see Dosage and Administration (2)]. Overestimating the tramadol hydrochloride extended-release tablets 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 tramadol hydrochloride extended-release tablets, especially by children, can result in respiratory depression and death due to an overdose of tramadol.

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Patient Counseling Information (17)].

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 (2.5)].

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 tramadol hydrochloride extended release tablets. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered [see Patient Counseling Information (17)].

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 (2.2), Warnings and Precautions (5.1, 5.3, Overdosage (10)].

5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of tramadol hydrochloride extended-release tablets 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 Drug Interactions (7)].

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 Dosage and Administration (2.2), Warnings and Precautions (5.3)].

5.4 Neonatal Opioid Withdrawal Syndrome

Use of tramadol hydrochloride extended-release tablets 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 of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1), Patient Counseling Information (17)].

5.5 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (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 healthcare providers. Healthcare providers are strongly encouraged to do all of the following:

• Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain.
• Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG .
• Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.
• Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities.

To obtain further information on the opioid analgesic REMS and for a ul of accredited REMS CME/CE, call 800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint.

5.6 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. Tramadol and codeine are subject to variability in metabolism based upon CYP2D6 genotype (described below), which can lead to increased exposure to an active metabolite. Based upon postmarketing reports with tramadol or with codeine, children younger than 12 years of age may be more susceptible to the respiratory depressant effects of tramadol. Furthermore, children with obstructive sleep apnea who are treated with opioids for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to their respiratory depressant effect. Because of the risk of life-threatening respiratory depression and death:

• Tramadol hydrochloride extended-release tablets are contraindicated for all children younger than 12 years of age [see Contraindications (4)].
• Tramadol hydrochloride extended-release tablets are contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications (4)] .
• Avoid the use of tramadol hydrochloride extended-release tablets 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 unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression.
• As with adults, when prescribing opioids for adolescents, healthcare providers should choose the lowest effective dose for the shortest period of time and inform patients and caregivers about these risks and the signs of opioid overdose [see Use in Specific Populations (8.4), Overdosage (10)].

Nursing Mothers

Tramadol is subject to the same polymorphic metabolism as codeine, with ultra-rapid metabolizers of CYP2D6 substrates being potentially exposed to life-threatening levels of O-desmethyltramadol (M1). At least one death was reported in a nursing infant who was exposed to high levels of morphine in breast milk because the mother was an ultra-rapid metabolizer of codeine. A baby nursing from an ultra-rapid metabolizer mother taking tramadol hydrochloride extended-release tablets could potentially be exposed to high levels of M1, and experience life-threatening respiratory depression. For this reason, breastfeeding is not recommended during treatment with tramadol hydrochloride extended-release tablets [see Use in Specific Populations (8.2)].

CYP2D6 Genetic Variability: Ultra-rapid metabolizer

Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (e.g., gene duplications denoted as *1/*1xN or *1/*2xN). The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 1 to 10% for Whites (European, North American), 3 to 4% for Blacks (African Americans), 1 to 2% for East Asians (Chinese, Japanese, Korean), and may be greater than 10% in certain racial/ethnic groups (i.e., Oceanian, Northern African, Middle Eastern, Ashkenazi Jews, Puerto Rican). These individuals convert tramadol into its active metabolite, O-desmethyltramadol (M1), more rapidly and completely than other people. This rapid conversion results in higher than expected serum M1 levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing) [see Overdosage (10)]. Therefore, individuals who are ultra-rapid metabolizers should not use tramadol hydrochloride extended-release tablets.

5.7 Risks of Interactions with Drugs Affecting Cytochrome P450 Isoenzymes

The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors on levels of tramadol and M1 from tramadol hydrochloride extended-release tablets are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with tramadol hydrochloride extended-release tablet requires careful consideration of the effects on the parent drug, tramadol which is a weak serotonin and norepinephrine reuptake inhibitor and µ-opioid agonist, and the active metabolite, M1, which is more potent than tramadol in µ-opioid receptor binding [see Drug Interactions (7)].

Risks of Concomitant Use or Discontinuation of Cytochrome P450 2D6 Inhibitors

The concomitant use of tramadol hydrochloride extended-release tablets with all cytochrome P450 2D6 inhibitors (e.g., amiodarone, quinidine) may result in an increase in tramadol plasma levels and a decrease in the levels of the active metabolite, M1. A decrease in M1 exposure in patients who have developed physical dependence to tramadol, may result in signs and symptoms of opioid withdrawal and reduced efficacy. The effect of increased tramadol levels may be an increased risk for serious adverse events including seizures and serotonin syndrome.

Discontinuation of a concomitantly used cytochrome P450 2D6 inhibitor may result in a decrease in tramadol plasma levels and an increase in active metabolite M1 levels, which could increase or prolong adverse reactions related to opioid toxicity and may cause potentially fatal respiratory depression.

Evaluate patients receiving tramadol hydrochloride extended-release tablets and any CYP2D6 inhibitor at frequent intervals for the risk of serious adverse events including seizures and serotonin syndrome, signs and symptoms that may reflect opioid toxicity, and opioid withdrawal when tramadol hydrochloride extended-release tablets are used in conjunction with inhibitors of CYP2D6 [see Drug Interactions (7)].

Cytochrome P450 3A4 Interaction

The concomitant use of tramadol hydrochloride extended-release tablets with cytochrome P450 3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir) or discontinuation of a cytochrome P450 3A4 inducer such as rifampin, carbamazepine, and phenytoin, may result in an increase in tramadol plasma concentrations, which could increase or prolong adverse reactions, increase the risk for serious adverse events including seizures and serotonin syndrome, and may cause potentially fatal respiratory depression.

The concomitant use of tramadol hydrochloride extended-release tablets with all cytochrome P450 3A4 inducers or discontinuation of a cytochrome P450 3A4 inhibitor may result in lower tramadol levels. This may be associated with a decrease in efficacy, and in some patients, may result in signs and symptoms of opioid withdrawal.

Evaluate patients receiving tramadol hydrochloride extended-release tablets and any CYP3A4 inhibitor at frequent intervals for the risk for serious adverse events including seizures and serotonin syndrome, signs and symptoms that may reflect opioid toxicity and opioid withdrawal when tramadol hydrochloride extended-release tablets are used in conjunction with inhibitors and inducers of CYP3A4 [see Drug Interactions (7)].

5.8 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 Dependence (9.3)]. 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 (2.2); Warnings and Precautions (5.7)].

5.9 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported with the use of tramadol, including tramadol hydrochloride extended-release tablets, particularly during concomitant use with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) [see Drug Interactions (7)]. This may occur within the recommended dosage range.

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue tramadol hydrochloride extended-release tablets if serotonin syndrome is suspected.

5.10 Increased Risk of Seizures

Seizures have been reported in patients receiving tramadol within the recommended dosage range. Spontaneous post-marketing reports indicate that seizure risk is increased with doses of tramadol above the recommended range.

Concomitant use of tramadol increases the seizure risk in patients taking: [see Drug Interactions (7)].

• Selective serotonin re-uptake inhibitors (SSRIs) and Serotonin-norepinephrine re-uptake inhibitors (SNRIs) antidepressants or anorectics,
• Tricyclic antidepressants (TCAs), and other tricyclic compounds (e.g., cyclobenzaprine, promethazine, etc.),
• Other opioids,
• MAO inhibitors [see Warnings and Precautions (5.8), Drug Interactions (7)]
• Neuroleptics, or
• Other drugs that reduce the seizure threshold.

Risk of seizures may also increase in patients with epilepsy, those with a history of seizures, or in patients with a recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections).

In tramadol overdose, naloxone administration may increase the risk of seizure.

5.11 Suicide Risk

• Do not prescribe tramadol hydrochloride extended-release tablets for patients who are suicidal or addiction-prone. Consideration should be given to the use of non-narcotic analgesics in patients who are suicidal or depressed. [see Drug Abuse and Dependence (9.2)]
• Prescribe tramadol hydrochloride extended-release tablets with caution for patients with a history of misuse and/or are currently taking CNS-active drugs including tranquilizers, or antidepressant drugs, or alcohol in excess, and patients who suffer from emotional disturbance or depression[see Drug Interactions (7)] .
• Inform patients not to exceed the recommended dose and to limit their intake of alcohol [see Dosage and Administration (2.1), Warnings and Precautions (5.7, 5.8, 5.14)] .

5.12 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

The use of tramadol hydrochloride extended-release tablets 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: Tramadol hydrochloride extended-release tablets-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 tramadol hydrochloride extended-release tablets [see Warnings and Precautions (5.3)].

Elderly, Cachectic, 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 and Precautions (5.3)].

Regularly evaluate patients, particularly when initiating and titrating tramadol hydrochloride extended-release tablets and when tramadol hydrochloride extended-release tablets are given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.3, 5.6)]. Alternatively, consider the use of non-opioid analgesics in these patients.

5.13 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.

5.14 Severe Hypotension

Tramadol hydrochloride extended-release tablets 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 Drug Interactions (7)]. Regularly evaluate these patients for signs of hypotension after initiating or titrating the dosage of tramadol hydrochloride extended-release tablets. In patients with circulatory shock, tramadol hydrochloride extended-release tablets may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of tramadol hydrochloride extended-release tablets in patients with circulatory shock.

5.15 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), tramadol hydrochloride extended-release tablets 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 tramadol hydrochloride extended-release tablets.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of tramadol hydrochloride extended-release tablets in patients with impaired consciousness or coma.

5.16 Risks of Use in Patients with Gastrointestinal Conditions

Tramadol hydrochloride extended-release tablets are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The tramadol in tramadol hydrochloride extended-release tablets 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.

5.17 Anaphylaxis and Other Hypersensitivity Reactions

Serious and rarely fatal hypersensitive reactions have been reported in patients receiving therapy with tramadol. When these events do occur it is often following the first dose. Other reported hypersensitivity reactions include pruritus, hives, bronchospasm, angioedema, toxic epidermal necrolysis and Stevens-Johnson syndrome. Patients with a history of hypersensitivity reactions to tramadol and other opioids may be at increased risk and therefore should not receive tramadol hydrochloride extended-release tablets. If anaphylaxis or other hypersensitivity occurs, stop administration of tramadol hydrochloride extended-release tablets immediately, discontinue tramadol hydrochloride extended-release tablets permanently, and do not rechallenge with any formulation of tramadol. Advise patients to seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction [see Patient Counseling Information (17)].

5.18 Withdrawal

Do not abruptly discontinue tramadol hydrochloride extended-release tablets in a patient physically dependent on opioids. When discontinuing tramadol hydrochloride extended-release tablets in a physically dependent patient, gradually taper the dosage. Rapid tapering of tramadol hydrochloride extended-release tablets in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see Dosage and Administration (2.5), Drug Abuse and Dependence (9)].

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 tramadol hydrochloride extended-release tablets. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [see Drug Interactions (7)].

5.19 Risks of Driving and Operating Machinery

Tramadol hydrochloride extended-release tablets 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 tramadol hydrochloride extended-release tablets and know how they will react to the medication [see Patient Counseling Information (17)].

5.20 Hyponatremia

Hyponatremia (serum sodium < 135 mmol/L) has been reported with the use of tramadol, and many cases are severe (sodium level < 120 mmol/L). Most cases of hyponatremia occurred in females over the age of 65 and within the first week of therapy. In some reports, hyponatremia resulted from the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Monitor for signs and symptoms of hyponatremia (e.g., confusion, disorientation), during treatment with tramadol hydrochloride extended-release tablets, especially during initiation of therapy. If signs and symptoms of hyponatremia are present, initiate appropriate treatment (e.g., fluid restriction) and discontinue tramadol hydrochloride extended-release tablets [see Dosage and Administration: Safe Reduction or Discontinuation of tramadol hydrochloride extended-release tablets (2.5)].

5.21 Hypoglycemia

Cases of tramadol- associated hypoglycemia have been reported, some resulting in hospitalization. In most cases, patients had predisposing risk factors (e.g. diabetes). If hypoglycemia is suspected, monitor blood glucose levels and consider drug discontinuation as appropriate [see Dosage and Administration: Safe Reduction or Discontinuation of tramadol hydrochloride extended-release tablets (2.5)].

6 Adverse Reactions

The following serious adverse reactions are described in greater detail, in other sections:

• Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)]
• Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2)]
• Interactions with Benzodiazepines and Other CNS Depressants [see Warnings and Precautions (5.3)]
• Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.4)]
• Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-Threatening Respiratory Depression in Children [see Warnings and Precautions (5.6)]
• Opioid-Induced Hyperalgesia and Allodynia [See Warnings and Precautions (5.8)]
• Serotonin Syndrome [see Warnings and Precautions (5.9)]
• Seizures [see Warnings and Precautions (5.10)]
• Suicide [see Warnings and Precautions (5.11)]
• Adrenal Insufficiency [see Warnings and Precautions (5.13)]
• Severe Hypotension [see Warnings and Precautions (5.14)]
• Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.16)]
• Hypersensitivity Reactions [see Warnings and Precautions (5.17)]
• Withdrawal [see Warnings and Precautions (5.18)]

Most common adverse reactions (≥10% and ≥2 x placebo rate): Dizziness, constipation, nausea, headache, somnolence, flushing, pruritus, vomiting, insomnia, dry mouth. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials 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.

Tramadol hydrochloride extended-release tablet was administered to a total of 3108 patients during studies conducted in the U.S. These included four double-blind studies in patients with osteoarthritis and/or chronic low back pain and one open-label study in patients with chronic non-malignant pain. A total of 901 patients were 65 years or older. The frequency of adverse reactions generally increased with doses from 100 mg to 400 mg in the two pooled, twelve-week, randomized, double-blind, placebo-controlled studies in patients with chronic non-malignant pain (see Table 1). The most common adverse reactions from Table 1 occurring in ≥10% and ≥2 x placebo rate of the patients treated with tramadol hydrochloride extended-release tablets are dizziness (not vertigo), nausea, constipation, headache, somnolence, flushing, pruritus, vomiting, insomnia, and dry mouth.

Table 1: Incidence (%) of patients with adverse reaction rates ≥ 5% from two 12-week placebo-controlled studies in patients with moderate to moderately severe chronic pain by dose (N=1811).

MedDRA Preferred Term	Tramadol Hydrochloride Extended-Release Tablets				Placebo
	100 mg (N=403) n (%)	200 mg (N=400)  n (%)	300 mg (N=400) n (%)	400 mg (N=202) n (%)	(N=406) n (%)
Dizziness (not vertigo)	64 (16)	81 (20)	90 (23)	57 (28)	28 (7)
Nausea	61 (15)	90 (23)	102 (26)	53 (26)	32 (8)
Constipation	49 (12)	68 (17)	85 (21)	60 (30)	17 (4)
Headache	49 (12)	62 (16)	46 (12)	32 (16)	43 (11)
Somnolence	33 (8)	45 (11)	29 (7)	41 (20)	7 (2)
Flushing	31 (8)	40 (10)	35 (9)	32 (16)	18 (4)
Pruritus	25 (6)	34 (9)	30 (8)	24 (12)	4 (1)
Vomiting	20 (5)	29 (7)	34 (9)	19 (9)	11 ( 3)
Insomnia	26 (7)	32 (8)	36 (9)	22 (11)	13 (3)
Dry Mouth	20 (5)	29 (7)	39 (10)	18 (9)	6 (2)
Diarrhea	15 (4)	27 (7)	37 (9)	10 (5)	17 (4)
Asthenia	14 (4)	24 (6)	26 (7)	13 (6)	7 (2)
Postural hypotension	7 (2)	17 (4)	8 (2)	11 (5)	9 (2)
Sweating increased	6 (2)	8 (2)	15 (4)	13 (6)	1 (0)
Anorexia	3 (1)	7 (2)	21 (5)	12 (6)	1 (0)

Adverse reactions With Incidence Rates of 1.0% to <5.0% During Clinical Trials

The following adverse reactions were reported from all the chronic pain studies (N=3108).

The uls below include adverse reactions not otherwise noted in Table 1.

Eye disorders: vision blurred

Gastrointestinal disorders: abdominal pain upper, dyspepsia, abdominal pain, sore throat

General disorders: weakness, pain, feeling hot, influenza like illness, fall, rigors, lethargy, pyrexia, chest pain

Infections and infestations: nasopharyngitis, upper respiratory tract infection, sinusitis, influenza, gastroenteritis viral, urinary tract infection, bronchitis

Investigations: blood creatine phosphokinase increased, weight decreased

Metabolism and nutrition disorders: appetite decreased

Musculoskeletal, connective tissue and bone disorders: arthralgia, back pain, pain in limb, neck pain

Nervous system disorders: tremor, paresthesia, hypoesthesia

Psychiatric disorders: nervousness, anxiety, depression, restlessness

Respiratory, thoracic and mediastinal disorders: sneezing, cough, rhinorrhea, nasal congestion, dyspnea, sinus congestion

Skin and subcutaneous tissue disorders: sweating increased, dermatitis

Vascular disorders: hot flushes, vasodilatation

Adverse Reactions With Incidence Rates of 0.5% to <1.0% and Serious Adverse Reactions Reported in at Least 2 patients During Clinical Trials

Cardiac disorders: palpitations, myocardial infarction

Ear and labyrinth disorders: tinnitus, vertigo

Gastrointestinal disorders: flatulence, toothache, constipation aggravated, appendicitis, pancreatitis

General disorders: feeling jittery, edema lower limb, shivering, joint swelling, malaise, drug withdrawal syndrome, peripheral swelling

Hepato-biliary disorders: cholelithiasis, cholecystitis

Infections and infestations: cellulitis, ear infection, gastroenteritis, pneumonia, viral infection

Injury and poisoning: joint sprain, muscle injury

Investigations: alanine aminotransferase increased, blood pressure increased, aspartate aminotransferase increased, heart rate increased, blood glucose increased, liver function tests abnormal

Musculoskeletal, connective tissue and bone disorders: muscle cramps, muscle spasms, joint stiffness, muscle twitching, myalgia, osteoarthritis aggravated

Nervous system disorders: migraine, sedation, syncope, disturbance in attention, dizziness aggravated

Psychiatric disorders: euphoric mood, irritability, libido decreased, sleep disorder, agitation, disorientation, abnormal dreams

Renal and urinary disorders: difficulty in micturition, urinary frequency, hematuria, dysuria, urinary retention

Respiratory, thoracic and mediastinal disorders: yawning

Skin and subcutaneous tissue disorders: contusion, piloerection, clamminess, night sweats, urticaria

Vascular disorders: hypertension aggravated, hypertension, peripheral ischemia

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of tramadol. Because these reactions 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.

Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

Anaphylaxis: Anaphylaxis has been reported with ingredients contained in tramadol hydrochloride extended-release tablets.

Androgen deficiency: Cases of androgen deficiency have occurred with use of opioids for an extended period of time. [see Clinical Pharmacology (12.2)].

QT prolongation/torsade de pointes: Cases of QT prolongation and/or torsade de pointes have been reported with tramadol use. Many of these cases were reported in patients taking another drug labeled for QT prolongation, in patients with a risk factor for QT prolongation (e.g., hypokalemia), or in overdose setting.

Metabolism and nutrition disorders:

Hyponatremia: cases of severe hyponatremia and/or SIADH have been reported in patients taking tramadol, most often in females over the age of 65, and within the first week of therapy [see Warnings and Precautions (5.20)].

Hypoglycemia: Cases of hypoglycemia have been reported in patients taking tramadol. Most reports were in patients with predisposing risk factors, including diabetes or renal insufficiency, or in elderly patients [see Warnings and Precautions (5.21)].

Hyperalgesia and Allodynia: cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration. [see Warnings and Precautions (5.8)]