Ultracet Special Precautions

General: Patients should be instructed not to give ULTRACET (tramadol hydrochloride and paracetamol) tablets to anyone other than the patient for whom it was prescribed, as such inappropriate use may have severe medical consequences, including death. ULTRACET should be stored securely to avoid theft or misuse.
ULTRACET should only be prescribed by persons knowledgeable in the administration of potent opioids, in the management of patients receiving potent opioids for the treatment of pain, and in the detection and management of respiratory depression, including the use of opioid antagonists.
Patients should be cautioned not to consume alcohol while taking ULTRACET as it may increase the chance of experiencing serious adverse events, including death.
Hyperalgesia that will not respond to a further dose increase of opioids can occur at particularly high doses. A tramadol and paracetamol dose reduction or change in opioid may be required.
Seizure Risk: 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 (see Neurologic as follows and Interactions). Concomitant use of tramadol increases the seizure risk in patients taking: serotonergic drugs including selective serotonin reuptake inhibitors (SSRI antidepressants or anorectics) or serotonin-norepinephrine reuptake inhibitors (SNRIs); tricyclic antidepressants (TCAs) (e.g., imipramine and amitriptyline) and other tricyclic compounds (e.g., cyclobenzaprine, promethazine, etc.); or opioids.
Administration of tramadol may enhance the seizure risk in patients taking: monoamine oxidase inhibitors (MAOIs) (see Contraindications); neuroleptics; or other drugs that reduce the seizure threshold.
Risk of convulsions 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 (see Treatment under Overdosage).
Anaphylactic Reactions: Serious and rarely fatal anaphylactic reactions have been reported in patients receiving therapy with tramadol. When these rare reactions do occur, it is often following the first dose. Other reported allergic reactions include pruritus, hives, bronchospasm, angioedema, toxic epidermal necrolysis and Stevens-Johnson syndrome. Patients with a history of anaphylactic reactions to codeine and other opioids may be at increased risk and therefore should not receive ULTRACET (see Contraindications).
There have been post-marketing reports of hypersensitivity and anaphylaxis associated with the use of paracetamol. Clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, pruritus, and vomiting. There were infrequent reports of life-threatening anaphylaxis requiring emergency medical attention. Instruct patients to discontinue ULTRACET immediately and seek medical care if they experience these symptoms. Do not prescribe ULTRACET to patients with paracetamol allergy.
Abuse and Misuse: Like all opioids, ULTRACET is a potential drug of abuse and misuse, which can lead to overdose and death. Therefore, ULTRACET should be prescribed and handled with caution.
Patients should be assessed for their clinical risks for opioid abuse or addiction prior to being prescribed opioids. All patients receiving opioids should be routinely monitored for signs of misuse and abuse.
Opioids, such as ULTRACET, should be used with particular care in patients with a history of alcohol and illicit/prescription drug abuse. However, concerns about abuse, addiction, and diversion should not prevent the proper management of pain.
ULTRACET is intended for oral use only. The tablets should be swallowed whole, and not chewed or crushed. Abuse of oral dosage forms can be expected to result in serious adverse events, including death.
Dependence/Tolerance: As with other opioids, tolerance and physical dependence may develop upon repeated administration of ULTRACET and there is a potential for development of psychological dependence.
Physical dependence and tolerance reflect the neuroadaptation of the opioid receptors to chronic exposure to an opioid, and are separate and distinct from abuse and addiction. Tolerance, as well as physical dependence, may develop upon repeated administration of opioids, and are not by themselves evidence of an addictive disorder or abuse.
Patients on prolonged therapy should be tapered gradually from the drug if it is no longer required for pain control. Withdrawal symptoms may occur following abrupt discontinuation of therapy or upon administration of an opioid antagonist. Some of the symptoms that may be associated with abrupt withdrawal of an opioid analgesic include body aches, diarrhea, gooseflesh, loss of appetite, nausea, nervousness or restlessness, anxiety, runny nose, sneezing, tremors or shivering, stomach cramps, tachycardia, trouble with sleeping, unusual increase in sweating, palpitations, unexplained fever, weakness and yawning (see Adverse Reactions; Recommended Dose and Dosage Adjustment: Adjustment or Reduction of Dosage under Dosage & Administration).
Carcinogenesis, Mutagenesis, Impairment of Fertility: There are no animal or laboratory studies on the combination product (tramadol and paracetamol) to evaluate carcinogenesis, mutagenesis, or impairment of fertility.
A slight but statistically significant increase in two common murine tumours, pulmonary and hepatic, was observed in a mouse carcinogenicity study, particularly in aged mice. Mice were dosed orally up to 30 mg/kg (90 mg/m² or 0.5 times the maximum daily human tramadol dosage of 185 mg/m²) for approximately two years, although the study was not done with the Maximum Tolerated Dose. This finding is not believed to suggest risk in humans. No such finding occurred in a rat carcinogenicity study (dosing orally up to 30 mg/kg, 180 mg/m², or 1 times the maximum daily human tramadol dosage).
Tramadol was not mutagenic in the following assays: Ames Salmonella microsomal activation test, CHO/HPRT mammalian cell assay, mouse lymphoma assay (in the absence of metabolic activation), dominant lethal mutation tests in mice, chromosome aberration test in Chinese hamsters, and bone marrow micronucleus tests in mice and Chinese hamsters. Weakly mutagenic results occurred in the presence of metabolic activation in the mouse lymphoma assay and micronucleus test in rats. Overall, the weight of evidence from these tests indicates that tramadol does not pose a genotoxic risk to humans.
No effects on fertility were observed for tramadol at oral dose levels up to 50 mg/kg (350 mg/m²) in male rats and 75 mg/kg (450 mg/m²) in female rats. These dosages are 1.6 and 2.4 times the maximum daily human tramadol dosage of 185 mg/m².
No drug-related teratogenic effects were observed in the progeny of rats treated orally with tramadol and paracetamol. The tramadol/paracetamol combination product was shown to be embryotoxic and fetotoxic in rats at a maternally toxic dose, 50/434 mg/kg tramadol/paracetamol (300/2604 mg/m² or 1.6 times the maximum daily human tramadol/paracetamol dosage of 185/1591 mg/m²), but was not teratogenic at this dose level. Embryo and fetal toxicity consisted of decreased fetal weights and increased supernumerary ribs.
Tramadol alone was evaluated in peri- and post-natal studies in rats. Progeny of dams receiving oral (gavage) dose levels of 50 mg/kg (300 mg/m² or 1.6 times the maximum daily human tramadol dosage) or greater had decreased weights, and pup survival was decreased early in lactation at 80 mg/kg (480 mg/m² or 2.6 times the maximum daily human tramadol dosage).
Cardiovascular: Tramadol and paracetamol administration may result in severe hypotension in patients whose ability to maintain adequate blood pressure is compromised by reduced blood volume, or concurrent administration of drugs such as phenothiazines and other tranquilizers, sedative/hypnotics, tricyclic antidepressants or general anesthetics. These patients should be monitored for signs of hypotension after initiating or titrating the dose of ULTRACET.
The use of ULTRACET in patients with circulatory shock should be avoided as it may cause vasodilation that can further reduce cardiac output and blood pressure.
QTc Interval Prolongation: The effect of tramadol on the QT/QTc interval was evaluated in a dedicated randomized, double-blind, 4-way crossover, placebo- and positive-controlled, multiple dose ECG study in healthy subjects (N=62). The study involved administration of tramadol at a supra-therapeutic dose of 100 mg every 6 h on days 1-3 (400 mg/day), with a single 100 mg dose on day 4, or 150 mg every 6 h (600 mg/day) on days 1-3, with a single 150 mg dose on day 4. The maximum placebo-adjusted mean change from baseline in the QTcF interval was 5.5 ms (90% CI 3.2, 7.8) in the 400 mg/day treatment arm and 6.5 ms (90% CI 4.1, 8.8) in the 600 mg/day mg treatment arm, both occurring at the 8 h time point. Both treatment groups were within the 10 ms threshold for QT prolongation (see Pharmacology: Pharmacodynamics: Cardiac Electrophysiology under Actions). Post-marketing experience with the use of tramadol-containing products included rare reports of QT prolongation reported with an overdose (see Other Clinically Significant Adverse Experiences Previously Reported in Clinical Trials or Post-marketing Reports with Tramadol under Adverse Reactions; Overview: QTc Interval-Prolonging Drugs under Interactions; Overdosage).
Many drugs that cause QTc prolongation are suspected to increase the risk of torsade de pointes. Torsade de pointes is a polymorphic ventricular tachyarrhythmia. Generally, the risk of torsade de pointes increases with the magnitude of QTc prolongation produced by the drug. Torsade de pointes may be asymptomatic or experienced by the patient as dizziness, palpitations, syncope, or seizures. If sustained, torsade de pointes can progress to ventricular fibrillation and sudden cardiac death.
Particular care should be exercised when administering ULTRACET to patients who are suspected to be at an increased risk of experiencing torsade de pointes during treatment with a QTc-prolonging drug.
Risk factors for torsade de pointes in the general population include, but are not limited to, the following: female gender; age 65 years or older; baseline prolongation of the QT/QTc interval; presence of pathological genetic variants affecting cardiac ion channels or regulatory proteins, especially congenital long QT syndromes; family history of sudden cardiac death at <50 years; cardiac disease (e.g., myocardial ischemia or infarction, congestive heart failure, left ventricular hypertrophy, cardiomyopathy, conduction system disease); history of arrhythmias (especially ventricular arrhythmias, atrial fibrillation, or recent conversion from atrial fibrillation); electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypocalcemia); bradycardia (<50 beats per minute); acute neurological events (e.g., intracranial or subarachnoid hemorrhage, stroke, intracranial trauma); nutritional deficits (e.g., eating disorders, extreme diets); diabetes mellitus; autonomic neuropathy.
When drugs that prolong the QTc interval are prescribed, healthcare professionals should counsel their patients concerning the nature and implications of the ECG changes, underlying diseases and disorders that are considered to represent risk factors, demonstrated and predicted drug-drug interactions, symptoms suggestive of arrhythmia, risk management strategies, and other information relevant to the use of the drug.
Use in Drug and Alcohol Addiction: ULTRACET is an opioid with no approved use in the management of addictive disorders. Its proper usage in individuals with drug or alcohol dependence, either active or in remission is for the management of pain requiring opioid analgesia. Patients with a history of addiction to drugs or alcohol may be at higher risk of becoming addicted to ULTRACET unless used under extreme caution and awareness.
Endocrine and Metabolism: 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.
Hyponatremia: Hyponatremia has been reported very rarely with the use of tramadol, usually in patients with predisposing risk factors, such as elderly patients and/or patients using concomitant medications that may cause hyponatremia (e.g., antidepressants, benzodiazepines, diuretics). In some reports, hyponatremia appeared to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and resolved with discontinuation of ULTRACET and appropriate treatment (e.g., fluid restriction). During ULTRACET treatment, monitoring for signs and symptoms of hyponatremia is recommended for patients with predisposing risk factors.
Gastrointestinal Effects: Tramadol and other morphine-like opioids have been shown to decrease bowel motility. Tramadol and paracetamol may obscure the diagnosis or clinical course of patients with acute abdominal conditions (see Contraindications).
Neonatal Opioid Withdrawal Syndrome (NOWS): Prolonged maternal use of opioids during pregnancy can result in withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening.
Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn.
Use of ULTRACET is contraindicated in pregnant women (see Contraindications).
Neurologic: Serotonin toxicity / Serotonin syndrome: Serotonin toxicity, also known as serotonin syndrome, is a potentially life-threatening condition and has been reported with tramadol, including ULTRACET, particularly during combined use with other serotonergic drugs (see Interactions).
Serotonin toxicity is characterised by neuromuscular excitation, autonomic stimulation (e.g. tachycardia, flushing) and altered mental state (e.g., anxiety, agitation, hypomania). In accordance with the Hunter Criteria, serotonin toxicity diagnosis is likely when, in the presence of at least one serotonergic agent, one of the following is observed: Spontaneous clonus; Inducible clonus or ocular clonus with agitation or diaphoresis; Tremor and hyperreflexia; Hypertonia and body temperature >38°C and ocular clonus or inducible clonus.
If concomitant treatment with ULTRACET and other serotonergic agents is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see Interactions). If serotonin toxicity is suspected, discontinuation of the serotonergic agents should be considered.
Interactions with Central Nervous System (CNS) Depressants (including benzodiazepines and alcohol): Tramadol should be used with caution and in a reduced dosage during concomitant administration of other opioid analgesics, general anesthetics, phenothiazines and other tranquilizers, sedative-hypnotics, tricyclic antidepressants, antipsychotics, antihistamines, benzodiazepines, centrally-active anti-emetics and other CNS depressants. Respiratory depression, hypotension and profound sedation, coma or death may result.
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 Interactions). 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. Follow patients closely for signs and symptoms of respiratory depression and sedation.
Advise both patients and caregivers about the risks of respiratory depression and sedation when ULTRACET is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs (see Interactions).
ULTRACET should not be consumed with alcohol as it may increase the chance of experiencing dangerous side effects, including death (see Contraindications; Incidence at least 1% - Causal Relationship at Least Possible or Greater: Sedation under Adverse Reactions; Interactions).
Severe pain antagonizes the subjective and respiratory depressant actions of opioid analgesics. Should pain suddenly subside, these effects may rapidly become manifest.
Head Injury: The respiratory depressant effects of tramadol, and the capacity to elevate cerebrospinal fluid pressure, may be greatly increased in the presence of an already elevated intracranial pressure produced by trauma. Also, tramadol may produce confusion, miosis, vomiting and other side effects which obscure the clinical course of patients with head injury. In such patients, tramadol must be used with extreme caution and only if it is judged essential (see Contraindications).
Peri-Operative Considerations: ULTRACET is not indicated for pre-emptive analgesia (administration pre-operatively for the management of post-operative pain). ULTRACET should only be used during post-operative period in patients that can take oral medications.
The administration of analgesics in the peri-operative period should be managed by healthcare providers with adequate training and experience (e.g., by an anesthesiologist).
Tramadol and other morphine-like opioids have been shown to decrease bowel motility. Ileus is a common post-operative complication, especially after intra-abdominal surgery with opioid analgesia. Caution should be taken to monitor for decreased bowel motility in post-operative patients receiving opioids. Standard supportive therapy should be implemented.
Psychomotor Impairment: ULTRACET may impair the mental and/or physical abilities needed for certain potentially hazardous activities such as driving a car or operating machinery. Patients should be cautioned accordingly. Patients should also be cautioned about the combined effects of tramadol with other CNS depressants, including other opioids, phenothiazine, sedative/hypnotics and alcohol.
Respiratory: Respiratory Depression: Administer ULTRACET cautiously in patients at risk for respiratory depression, including patients with substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression, as in these patients, even therapeutic doses of ULTRACET may decrease respiratory drive to the point of apnea. In these patients, alternative non-opioid analgesics should be considered.
When large doses of tramadol are administered with anesthetic medications or alcohol, respiratory depression may result. Respiratory depression should be treated as an overdose. If naloxone is to be administered, use cautiously because it may precipitate seizures (see Seizure Risk as previously mentioned; Symptoms: Tramadol under Overdosage).
Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression from opioid use, 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. Tramadol should be used with extreme caution in patients with substantially decreased respiratory reserve, pre-existing respiratory depression, hypoxia or hypercapnia (see Contraindications).
While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of ULTRACET, the risk is greatest during the initiation of therapy or following a dose increase. Patients should be closely monitored for respiratory depression when initiating therapy with ULTRACET and following dose increases. During treatment with ULTRACET, cases of severe respiratory depression have been reported in patients with risk factors of respiratory depression or in cases of overdose.
Life-threatening respiratory depression is more likely to occur in the elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients.
To reduce the risk of respiratory depression, proper dosing and titration of ULTRACET are essential. Overestimating the ULTRACET dose when converting patients from another opioid product can result in a fatal overdose with the first dose. In these patients, the use of non-opioid analgesics should be considered, if feasible (see Special Risk Groups as follows and Dosage & Administration).
Sleep Apnea: Opioids can cause sleep-related breathing disorders such as sleep apnea syndromes (including central sleep apnea [CSA]) and hypoxia (including sleep-related hypoxia) (see Adverse Reactions). Opioid use increases the risk of CSA in a dose-dependent fashion. Evaluate patients on an ongoing basis for the onset of a new sleep apnea, or a worsening of an existing sleep apnea. In these patients, consider reducing or stopping the opioid treatment if appropriate, using best practices for tapering of opioids (see Dependence/Tolerance as previously mentioned; Recommended Dose and Dosage Adjustment: Adjustment or Reduction of Dosage under Dosage & Administration).
Use with MAO Inhibitors (MAOIs): Concomitant use of ULTRACET with MAOIs is contraindicated (see Contraindications).
Animal studies have shown increased deaths with combined administration of MAOIs and tramadol. Concomitant use of tramadol with MAOIs increases the risk of adverse events, including seizure (see Seizure Risk as previously mentioned and Interactions) and serotonin syndrome (see Neurologic: Serotonin toxicity / Serotonin syndrome as previously mentioned).
Cytochromes P450 (CYP) 2D6 Ultra-Rapid Metabolism: Some individuals may be CYP2D6 ultra-rapid metabolizers. These individuals convert tramadol more rapidly than other people into its more potent opioid metabolite O-desmethyltramadol (M1). Even at labelled dosage regimens, this rapid conversion could result in higher than expected opioid-like side effects including life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing) (see Use in Pregnancy & Lactation: Labour, Delivery and Nursing Women as follows; Symptoms: Tramadol under Overdosage; Overview under Interactions). The prevalence of this CYP2D6 phenotype varies widely in the population (see Pharmacology: Pharmacokinetics: Special Populations and Conditions: Race under Actions).
Use in Patients with Chronic Pulmonary Disease: Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression for respiratory depression, particularly when initiating therapy and titrating with ULTRACET, as in these patients, even usual therapeutic doses of ULTRACET may decrease respiratory drive to the point of apnea. In these patients, use of alternative non-opioid analgesics should be considered, if possible. The use of ULTRACET is contraindicated in patients with acute or severe bronchial asthma, chronic obstructive airway, or status asthmaticus (see Contraindications).
Hepatic: Administration of paracetamol in doses higher than recommended may result in hepatic injury, including the risk of severe hepatotoxicity and death. The risk of acute liver failure is higher in individuals with underlying liver disease and in individuals who ingest alcohol while taking paracetamol.
The maximum daily dose of paracetamol includes all routes of administration (intravenous, oral and rectal) and all products containing paracetamol (oral solutions/drops, syrup, pills, capsules, suppositories, etc.). Instruct patients not to exceed the maximum recommended daily dose of paracetamol (see Dosing Considerations under Dosage & Administration). Advise patients to seek medical attention as soon as a paracetamol overdose is suspected. Advise them not to wait for symptoms to appear (see Symptoms: Paracetamol under Overdosage).
Use with Other Paracetamol-Containing Products: Due to the potential for paracetamol hepatotoxicity at doses higher than the recommended dose, ULTRACET should not be used concomitantly with other paracetamol-containing products. Patients with or without liver disease should not exceed the daily maximum dose of paracetamol. The maximum daily dose of paracetamol includes all routes of administration (intravenous, oral and rectal) and all products containing paracetamol (oral solutions/drops, syrup, pills, capsules, suppositories etc.).
Risk of Overdosage: Serious potential consequences of overdosage with ULTRACET are central nervous system depression, respiratory depression, seizures and death (see Seizure Risk and Respiratory as previously mentioned). A serious potential consequence of overdosage with paracetamol is hepatic (centrilobular) necrosis, leading to hepatic failure and death (see Hepatic as previously mentioned).
Emergency help should be sought immediately and treatment initiated without delay if overdose is suspected, even if symptoms are not apparent. In treating an overdose of tramadol, primary attention should be given to maintaining adequate ventilation along with general supportive treatment (see Treatment under Overdosage).
Do not prescribe ULTRACET for patients who are suicidal or addiction-prone.
ULTRACET should not be taken in doses higher than those recommended by the physician.
The judicious prescribing of tramadol is essential to the safe use of this drug. With patients who are depressed or suicidal, consideration should be given to the use of non-narcotic analgesics.
Hypersensitivity Reactions: Serious Skin Reactions: Rarely, paracetamol can cause serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. It is important to recognize and react quickly to the initial symptoms of these reactions which may occur without warning but may be manifested by any serious skin reactions. Patients should be informed about the signs of serious skin reactions, and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.
Sexual Function/Reproduction: Long-term use of opioids may be associated with decreased sex hormone levels and symptoms such as low libido, erectile dysfunction, or infertility (see Other Clinically Significant Adverse Experiences Previously Reported in Clinical Trials or Post-marketing Reports with Tramadol: Androgen deficiency under Adverse Reactions).
Special Risk Groups: Tramadol should be administered with caution to patients with a history of alcohol and drug abuse and in a reduced dosage to debilitated patients, and in patients with severely impaired pulmonary function, Addison's disease, hypothyroidism, myxedema, toxic psychosis, prostatic hypertrophy or urethral stricture.
Patients with Hepatic Impairment: ULTRACET is contraindicated in patients with severe hepatic impairment (see Contraindications). In patients with compromised liver function, paracetamol could exacerbate liver insufficiency. Pain control may also be compromised because tramadol is not properly metabolized.
ULTRACET has not been studied in patients with impaired hepatic function. Theoretical risk factors for paracetamol hepatotoxicity in patients with chronic liver disease include slower metabolism of paracetamol, increased activity of the cytochrome P450 enzyme system, or depleted glutathione stores. Liver function should be monitored in patients with liver disease.
Patients with Renal Impairment: ULTRACET is contraindicated in patients with severe renal impairment (defined as glomerular filtration rate of less than 30 mL/min/1.73 m²). Paracetamol has been reported to cause toxicity in this population.
ULTRACET has not been studied in patients with impaired renal function. Experience with tramadol suggests that impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1 (see Contraindications; Pharmacology: Pharmacokinetics: Special Populations and Conditions: Renal Impairment under Actions).
Use in Pregnancy & Lactation: Pregnant Women: Animal reproduction studies have revealed no evidence of harm to the fetus due to tramadol and paracetamol. However, as studies in humans have not been conducted, and since tramadol and paracetamol crosses the placental barrier, ULTRACET is contraindicated in pregnant women (see Contraindications).
Prolonged maternal use of opioids during pregnancy can result in withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening (see Neonatal Opioid Withdrawal Syndrome (NOWS) as previously mentioned; Other Clinically Significant Adverse Experiences Previously Reported in Clinical Trials or Post-marketing Reports with Tramadol under Adverse Reactions).
Labour, Delivery and Nursing Women: ULTRACET is contraindicated in nursing women (see Contraindications). Following a single 100 mg i.v. dose of tramadol, the cumulative excretion in breast milk within 16 hours post-dose was 100 μg of tramadol (0.1% of the maternal dose) and 27 μg of M1.
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 breast-feeding infant who was exposed to high levels of morphine in breast milk because the mother was an ultra-rapid metabolizer of codeine. A baby breast-feeding from an ultra-rapid metabolizer mother taking ULTRACET could potentially be exposed to high levels of M1, and experience life-threatening respiratory depression. Therefore, maternal use of tramadol can lead to serious adverse reactions, including death in nursing infants (see Respiratory as previously mentioned).
Since opioids can cross the placental barrier and are excreted in breast milk, ULTRACET is also contraindicated during labour and delivery. Life-threatening respiratory depression can occur in the infant if opioids are administered to the mother. Naloxone, a drug that counters the effects of opioids, should be readily available if ULTRACET is used in this population.
Use in Children: The use of ULTRACET is contraindicated in children below 12 years of age (see Contraindications). The safety and efficacy of ULTRACET has not been studied in the pediatric population. Therefore, use of ULTRACET is not recommended in patients under 18 years of age. Further, adolescent patients (12 to 18 years old) who are obese or have conditions such as obstructive sleep apnea or severe lung disease may be at increased risk of serious breathing problems; the use of ULTRACET is not recommended in these pediatrics patients.
Avoid the 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 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.
Use in the Elderly: In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range and titrate slowly, reflecting the greater frequency of decreased hepatic, renal or cardiac function; concomitant disease and multiple drug therapy (see Dosage & Administration; Pharmacology: Pharmacokinetics: Special Populations and Conditions: Geriatrics under Actions).