Ultracet

Addiction, Abuse and Misuse

• Prior to initiation, assess the risks for opioid addiction, abuse, and misuse. Monitor regularly for development of these behaviors and conditions.

• Increased risk in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (eg, major depression).

• To reduce these risks, prescribe the smallest appropriate quantity and advise the patient on the proper disposal of unused drug.

Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) 

• REMS is required for these products to ensure that the benefits outweigh the risks of addiction, abuse, and misuse. 

• 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,

• Emphasize 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 

• Monitor closely for respiratory depression especially within the first 24-72 hours of initiation or following a dose increase.

• Accidental ingestion of one dose of Ultracet, especially by children, can result in fatal overdose of tramadol.

• Educate patients and caregivers on how to recognize respiratory depression.

• Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Consider dose reduction if CSA develops. 

• Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose 

• Assess the potential need for access to naloxone when initiating and renewing therapy. 

• Consider prescribing naloxone based on risk factors for overdose (eg, history of opioid use disorder, prior opioid overdose, household members or other close contacts at risk for accidental ingestion or overdose).

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. 

• Tramadol and codeine are subject to variability in metabolism based upon CYP2D6 genotype, which can lead to increased exposure to an active metabolite. Children younger than 12 years of age may be more susceptible to the respiratory depressant effects of tramadol.

• Children with obstructive sleep apnea (OSA) 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:

• Ultracet is contraindicated for children <12 years of age.

• Ultracet is contraindicated for postoperative management in patients <18 years of age after tonsillectomy and/or adenoidectomy.

• Avoid use of Ultracet 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. Risk factors include conditions associated with hypoventilation (eg, postop status, OSA, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use with other drugs that cause respiratory depression).

• Health care providers should prescribe the lowest effective dose for the shortest period of time.

• 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). 

• For this reason, breastfeeding is not recommended during treatment with Ultracet.

• 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.

• CYP2D6 Genetic Variability: Ultra-rapid metabolizer

• Ultra-rapid metabolizers should not use Ultracet.

• Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (gene duplications denoted as *1/*1xN or *1/*2xN).

• Even at labeled dosage regimens, ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing).

Neonatal Opioid Withdrawal Syndrome

• Prolonged use during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening.

• Advise the patient of the risk of neonatal opioid withdrawal syndrome and treat appropriately if opioid use is required for a prolonged period during pregnancy.

• Monitor newborns for signs of neonatal opioid withdrawal syndrome.

Risks of Interactions with Drugs Affecting Cytochrome P450 Isoenzymes 

• Concomitant use or discontinuation of CYP450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with tramadol are complex.

• Carefully consider the use of these drugs with Ultracet and the effects on the parent drug, tramadol, and the active metabolite, M1.

• See Interactions.

Hepatotoxicity

• Cases of acute liver failure have been associated with acetaminophen, which at times resulted in liver transplant and death. Most of these cases have been associated with acetaminophen at doses >4000 mg/day.

• Increased risk of acute liver failure in individuals with underlying liver disease and those who ingest alcohol while taking acetaminophen.

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

• Risk of profound sedation, respiratory depression, coma and death with benzodiazepines or other CNS depressants including alcohol.

• Reserve concomitant use in those for whom alternative options are inadequate; limit dosages/durations to minimum required. Monitor for signs and symptoms of respiratory depression and sedation. 

• If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose.

Serotonin Syndrome Risk

• Discontinue Ultracet if serotonin syndrome is suspected.

• Risk for serotonin syndrome during concomitant use with serotonergic drugs including SSRIs, SNRIs, TCAs, triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (eg, mirtazapine, trazodone, tramadol), certain muscle relaxants (eg, cyclobenzaprine, metaxalone), and drugs that impair metabolism of serotonin (including MAO inhibitors).

Increased Risk of Seizures  

• Increased risk of seizures with doses of tramadol above the recommended range.

• Concomitant use of tramadol increases the seizure risk in patients taking:

• SSRIs and SNRIs antidepressants or anorectics,

• TCAs and other tricyclic compounds (eg, cyclobenzaprine, promethazine, etc)

• Other opioids,

• MAO inhibitors,

• Neuroleptics, or

• Other drugs that reduce the seizure threshold.

• Increased risk of seizures in patients with epilepsy, those with a history of seizures, or in those with a recognized risk for seizure (eg, head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections).

Suicide Risk 

• Do not prescribe Ultracet for patients who are suicidal or addiction-prone. Consider the use of non-narcotic analgesics in patients who are suicidal or depressed.

• Use caution in 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.

• Do not exceed the recommended dose and limit alcohol intake.

Adrenal Insufficiency

• Cases of adrenal insufficiency have been reported with opioid use, more often following greater than 1 month of use.

• If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. 

• If confirmed, 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.

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

• Contraindicated to use Ultracet in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment.

• Patients with Chronic Pulmonary Disease:

• Increased risk for decreased respiratory drive including apnea in patients with significant COPD or cor pulmonale, and those with substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression.

• Elderly, Cachectic, or Debilitated Patients: 

• Increased risk for life-threatening respiratory depression in these patients.

• Monitor these patients closely especially during initiation and titration of Ultracet, and when given concomitantly with other drugs that depress respiration. Consider using non-opioid analgesics in these patients.

Severe Hypotension 

• Ultracet may cause severe hypotension (eg, orthostatic hypotension, syncope) in ambulatory patients.

• 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 (eg, phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after initiating or titrating Ultracet.

• Avoid use of Ultracet in patients with circulatory shock because Ultracet may cause vasodilation in these patients that can further reduce cardiac output and blood pressure.

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

• The use of Ultracet in patients with evidence of increased intracranial pressure or brain tumors may result in further increased intracranial pressure. Monitor these patients for signs of sedation and respiratory depression especially during initiation.

• Avoid use of Ultracet in patients with impaired consciousness or coma.

Serious Skin Reactions

• Rarely, acetaminophen may cause serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal.

• Discontinue use at the first appearance of skin rash or any other sign of hypersensitivity.

Risk of Use in Patients with Gastrointestinal Conditions 

• Ultracet is contraindicated in patients with known or suspected GI obstruction, including paralytic ileus.

• Ultracet may cause spasm of the sphincter of Oddi and may cause increases in serum amylase. Monitor for worsening symptoms in patients with biliary tract disease, including acute pancreatitis.

Anaphylaxis and Other Hypersensitivity Reactions

• Discontinue use and seek medical care if anaphylaxis or other hypersensitivity reactions occur.

Increased Risk of Hepatotoxicity with Concomitant Use of Other Acetaminophen-containing Products 

• Do not use Ultracet with other acetaminophen containing products.

Withdrawal

• Avoid abrupt cessation in patients physically dependent on opioids. Gradually taper dosage when discontinuing Ultracet in a physically dependent patient. 

• Rapid tapering of tramadol and acetaminophen in a physically dependent on opioids may lead to a withdrawal syndrome and return of pain.

• Avoid using with mixed agonist/antagonist (eg, pentazocine, nalbuphine, and butorphanol) or partial agonist (eg, buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including Ultracet. 

Driving and Operating Machinery

• Ultracet may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. 

• Do not drive or operate dangerous machinery unless tolerant to Ultracet.

Hyponatremia

• Monitor for signs and symptoms of hyponatremia (eg, confusion, disorientation), during treatment with Ultracet, especially during initiation of therapy. 

• If signs and symptoms of hyponatremia are present, initiate appropriate treatment (eg, fluid restriction) and discontinue Ultracet.

Hypoglycemia

• Monitor blood glucose levels and consider discontinuing Ultracet if hypoglycemia is suspected.