Tramadol Hydrochloride (10 brand names, 5 dosage forms, 1 route)
Available dosage forms: TABLET, TABLET, EXTENDED RELEASE, CAPSULE, EXTENDED RELEASE, SOLUTION, TABLET, ORALLY DISINTEGRATING.
Routes of administration: ORAL.
Brand Names
- CONZIP
- QDOLO
- RYBIX ODT
- RYZOLT
- SEGLENTIS
- TRAMADOL HYDROCHLORIDE
- TRAMADOL HYDROCHLORIDE AND ACETAMINOPHEN
- ULTRACET
- ULTRAM
- ULTRAM ER
Boxed Warning
Addiction, Abuse, and Misuse Because the use of Tramadol hydrochloride extended-release tablet exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient’s risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions ( 5.1)] . Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of tramadol hydrochloride extended-release tablets, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of tramadol hydrochloride extended-release tablets are essential. Instruct patients to swallow tramadol hydrochloride extended-release tablets whole to avoid exposure to a potentially fatal dose of tramadol. [see Warnings and Precautions ( 5.2)] . Accidental Ingestion Accidental ingestion of even one dose of tramadol hydrochloride extended-release tablets, especially by children, can result in a fatal overdose of tramadol [see Warnings and Precautions ( 5.2)] . Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of tramadol hydrochloride extended-release tablets and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate [see Warnings and Precautions ( 5.3), Drug Interactions ( 7)] . Neonatal Opioid Withdrawal Syndrome (NOWS) Advise pregnant women using opioids for an extended period of time of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery [s
Indications and Usage
Tramadol hydrochloride extended-release tablet is indicated for the management of severe and persistent pain that requires an opioid analgesic and that cannot be adequately treated with alternative options, including immediate-release opioids. Limitations of Use Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosages or duration, and persist over the course of therapy [see Warnings and Precautions ( 5.1)] , reserve opioid analgesics, including tramadol hydrochloride extended-release 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 extended-release tablet is not indicated as an as-needed (prn) analgesic.
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)].
Adverse Reactions
The following serious or otherwise important 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)]
Drug Interactions
Table 2 includes clinically significant drug interactions with tramadol hydrochloride extended-release tablets. Inhibitors of CYP2D6 Clinical Impact: The concomitant use of tramadol hydrochloride extended-release tablets 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 extended-release tablets 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. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease and the M1 plasma concentration will increase which could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity and may cause potentially fatal respiratory depression [see Clinical Pharmacology ( 12.3)] . Intervention: If concomitant use of a CYP2D6 inhibitor is necessary, evaluate patients at frequent intervals for adverse reactions including opioid withdrawal, seizures, and serotonin syndrome. If a CYP2D6 inhibitor is discontinued, consider lowering tramadol hydrochloride extended-release tablets dosage until stable drug effects are achieved. Evaluate patients at frequent intervals for adverse events including respiratory depression and sedation. Examples Quinidine, fluoxetine, paroxetine and bupropion Inhibitors of CYP3A4 Clinical Impact: The concomitant use of tramadol hydrochloride extended-release tablets and CYP3A4 inhibitors can increase the plasma concentration of tramadol and may result in a greater amount of met
Mechanism of Action
Tramadol hydrochloride extended-release tablet contains tramadol, an opioid agonist and an inhibitor of reuptake of norepinephrine and serotonin. Although the mode of action of tramadol is not completely understood, the analgesic effect of tramadol is believed to be due to both binding to µ-opioid receptors and weak inhibition of reuptake of norepinephrine and serotonin. Opioid activity of tramadol is due to both low affinity binding of the parent compound and higher affinity binding of the O-desmethyl metabolite M1 to µ-opioid receptors. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in µ-opioid binding. Tramadol-induced analgesia is only partially antagonized by the opioid antagonist naloxone in several animal tests. The relative contribution of both tramadol and M1 to human analgesia is dependent upon the plasma concentrations of each compound. Tramadol has been shown to inhibit reuptake of norepinephrine and serotonin in vitro, as have some other opioid analgesics. These mechanisms may contribute independently to the overall analgesic profile of tramadol. Apart from analgesia, tramadol administration may produce a constellation of symptoms (including dizziness, somnolence, nausea, constipation, sweating and pruritus) similar to that of other opioids. In contrast to morphine, tramadol has not been shown to cause histamine release. At therapeutic doses, tramadol has no effect on heart rate, left-ventricular function, or cardiac index. Orthostatic hypotension has been observed.
Overdosage
Clinical Presentation Acute overdosage with tramadol hydrochloride extended-release tablets can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, QT prolongation, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology ( 12.2)] . Toxic leukoencephalopathy has been reported after opioid overdose and can present hours, days, or weeks after apparent recovery from the initial intoxication. Treatment of Overdose In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support measures. For clinically significant respiratory or circulatory depression secondary to opioid overdose, administer an opioid overdose reversal agent such as naloxone or nalmefene. While an opioid overdose reversal agent will reverse some, but not all, symptoms caused by overdosage with tramadol, the risk of seizures is also increased with reversal agent administration. In animals, convulsions following the administration of toxic doses of tramadol hydrochloride extended-release tablets could be suppressed with barbiturates or benzodiazepines but were increased with naloxone. Naloxone administration did not change the lethality of an overdose in mice. Hemodialysis is not expected to be helpful in an overdose because it removes less than 7% of the administered dose in a 4-hour dialysis period. Because the duration of opioid reversal is expected to be less than the duration of action of tramadol in tramadol hydrochloride exte