Tramadol and acetaminophen: uses, appearance and warnings

Tramadol hydrochloride and acetaminophen tablets are indicated for the management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. Limitations of Use: Tramadol hydrochloride and acetaminophen tablets are indicated for short-term use of five days or less. Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy [see Warnings and Precautions (5.1) ] , reserve opioid analgesics, including tramadol hydrochloride and acetaminophen tablets, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Tramadol hydrochloride and acetaminophen tablets are a combination of tramadol hydrochloride, an opioid agonist, and acetaminophen, and is indicated for the management of acute pain, severe enough to require an opioid analgesic and for which alternative treatments are inadequate. ( 1 ) Limitations of Use: Tramadol hydrochloride and acetaminophen tablets are indicated for short-term use of five days or less. Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration, and persist over the course of therapy, reserve opioid analgesics, including tramadol hydrochloride and acetaminophen tablets for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. ( 1 , 5.1 )

Each tramadol hydrochloride and acetaminophen tablet, USP contains 37.5 mg of tramadol hydrochloride, USP and 325 mg of acetaminophen, USP. The tablets are beige colored, film-coated, biconvex capsule shaped tablets with “AN 617” debossed on one side and plain on the other side. Tablets: tramadol hydrochloride 37.5 mg and acetaminophen 325 mg. ( 3 )

Tramadol hydrochloride and acetaminophen tablets USP, 37.5 mg/325 mg, are supplied as beige colored, film-coated, biconvex capsule shaped tablets with “AN 617” debossed on one side and plain on the other side. They are available as: Bottles of 30: NDC 53746-617-30 Bottles of 100: NDC 53746-617-01 Bottles of 500: NDC 53746-617-05 Bottles of 1,000: NDC 53746-617-10 Dispense in a tight container. Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Dispense in a tight container as defined in the USP. Store tramadol hydrochloride and acetaminophen tablets securely and dispose of properly [see Patient Counseling Information (17) ].

Tramadol hydrochloride and acetaminophen tablets are contraindicated for: all children younger than 12 years of age [see Warnings and Precautions (5.6) ] post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Warnings and Precautions (5.6) ] . Tramadol hydrochloride and acetaminophen tablets are also contraindicated in patients with: Significant respiratory depression [see Warnings and Precautions (5.2) ] . Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.13) ] . Patients with known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.18) ] . Previous hypersensitivity to tramadol, acetaminophen, any other component of this product, or opioids [see Warnings and Precautions (5.19) ]. 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 ) Post-operative 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 ) Previous hypersensitivity to tramadol hydrochloride, acetaminophen, any other component of this product, or opioids. ( 4 ) Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days ( 4 )

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. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation. ( 5.8 ) Serotonin Syndrome: May be life-threatening. Can occur with use of tramadol alone, with concomitant use of serotonergic drugs, with drugs that impair metabolism of serotonin or tramadol. ( 5.10 ) Risk of Seizure: Can occur at the recommended dose of tramadol. Concomitant use with other drugs may increase seizure risk. Risk may increase in patients with epilepsy, a history of seizures, and in patients with a recognized risk for seizures. ( 5.11 ) Risk of Suicide: Do not prescribe for suicidal or addiction-prone patients. ( 5.12 ) 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. ( 5.13 ) Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.14 ) Severe Hypotension: Regularly evaluate during dosage initiation and titration. Avoid use of tramadol hydrochloride and acetaminophen in patients with circulatory shock. ( 5.15 ) 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 and acetaminophen in patients with impaired consciousness or coma. ( 5.16 ) 5.1 Addiction, Abuse and Misuse Tramadol hydrochloride and acetaminophen tablets contains tramadol, a Schedule IV controlled substance. As an opioid, tramadol hydrochloride and acetaminophen exposes users to the risks of addiction, abuse, and misuse [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 and acetaminophen. Addiction can occur at recommended doses and if the drug is misused or abused. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In post-marketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use [see Adverse Reactions (6.2) ] . Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing tramadol hydrochloride and acetaminophen, and reassess all patients receiving tramadol hydrochloride and acetaminophen 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 and acetaminophen, but use in such patients necessitates intensive counseling about the risks and proper use of tramadol hydrochloride and acetaminophen along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2) , Warnings and Precautions (5.2) ] . Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing tramadol hydrochloride and acetaminophen. 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 overdose reversal agents, depending on the patient’s clinical status [see Overdosage (10) ] . Carbon dioxide (CO 2 ) 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 and acetaminophen, 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 tramadol hydrochloride and acetaminophen are essential [see Dosage and Administration (2) ] . Overestimating the tramadol hydrochloride and acetaminophen 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 and acetaminophen, 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. …

The following serious adverse reactions are discussed, or described in greater detail, in other sections: Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.8) ] Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1) ] Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2) ] Interactions with Benzodiazepines or 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) ] Hepatotoxicity [see Warnings and Precautions (5.9) ] Serotonin Syndrome [see Warnings and Precautions (5.10) ] Seizures [see Warnings and Precautions (5.11) ] Suicide [see Warnings and Precautions (5.12) ] Adrenal Insufficiency [see Warnings and …

Table 2 includes clinically significant interactions with tramadol hydrochloride and acetaminophen. Table 2: Clinically Significant Drug Interactions with Tramadol Hydrochloride and Acetaminophen Inhibitors of CYP2D6 Clinical Impact: The concomitant use of tramadol hydrochloride and acetaminophen and CYP2D6 inhibitors may result in an increase in the plasma concentration of tramadol and a decrease in the plasma concentration of M1, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride and acetaminophen is achieved. Since M1 is a more potent μ-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol. …