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Warning: Allergy alert: Paracetamol may cause severe skin reactions. Symptoms may include skin reddening, blisters or rash.
These could be signs of a serious condition. If these reactions occur, stop use and seek medical assistance right away.
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 serotonergic drugs including: selective serotonin reuptake inhibitors (SSRI antidepressants or anorectics), tricyclic antidepressants (TCAs), 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), 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, central nervous system [CNS] infections). In tramadol overdose, naloxone administration may increase the risk of seizure.
Anaphylactic reactions: Patients with a history of anaphylactic reactions to codeine and other opioids may be at increased risk and therefore should not receive ULTRACET.
Serious and rarely fatal anaphylactic reactions have been reported in patients receiving therapy with tramadol.
Advise patients to seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction.
Respiratory depression: Patients with significant respiratory depression (see Contraindications) or acute, severe bronchial asthma are at increased risk of life-threatening respiratory depression when treated with opioids.
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.
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 Treatment withdrawal under Dosage & Administration; Treatment withdrawal as follows).
Cytochromes P450 (CYP) 2D6 ultra-rapid metabolism: Some individuals may be CYP2D6 ultra-rapid metabolisers. These individuals convert tramadol more rapidly than other people into its more potent opioid metabolites O-desmethyltramadol (M1). This rapid conversion could result in higher than expected opioid-like side effects including life-threatening respiratory depression (see Symptoms and signs: Tramadol under Overdosage).
The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5 to 1% in Chinese, Japanese and Hispanics, 1 to 10% in Caucasians, 3% in African Americans, and 16-28% in North Africans, Ethiopians, and Arabs. Data are not available for other ethnic groups.
Alternative medication, dose reduction and/or increased monitoring for signs of tramadol overdose, such as respiratory depression is recommended in patients known to be CYP2D6 ultra-rapid metabolizers (see Pharmacology: Pharmacokinetics under Actions). 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 Symptoms and signs: Tramadol under Overdosage).
Use with central nervous system (CNS) depressants, including alcohol: The concomitant use of tramadol (an active ingredient in ULTRACET) with CNS depressants, including alcohol, may cause additive CNS depressant effects, including profound sedation and respiratory depression. ULTRACET should be used with caution and in reduced dosages when administered to patients receiving CNS depressants (see Interactions).
Increased intracranial pressure or head trauma: ULTRACET should be used with caution in patients with increased intracranial pressure or head injury.
Drug dependence and potential for abuse: ULTRACET contains tramadol as an active ingredient. A portion of the analgesic effect of ULTRACET is attributable to the binding of the active ingredient, tramadol, to the mu-opioid receptor. Upon repeated administration of opioids, tolerance, physical dependence, and psychological dependence may develop, even at recommended dosages. Assess each patient's risk for opioid dependence and abuse prior to prescribing ULTRACET and monitor all patients receiving ULTRACET for development of these behaviors. 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).
ULTRACET should not be used in opioid-dependent patients. Tramadol has been shown to reinitiate physical dependence in some patients that have been previously dependent on other opioids.
Increased risk of hepatotoxicity with alcohol use: Chronic heavy alcohol abusers may be at increased risk of liver toxicity from excessive paracetamol use.
Treatment withdrawal: Withdrawal symptoms may occur if ULTRACET is discontinued abruptly. Panic attacks, severe anxiety, hallucinations, paresthesia, tinnitus, and unusual CNS symptoms have also been very rarely reported with abrupt discontinuation of tramadol hydrochloride. Clinical experience suggests that withdrawal symptoms may be relieved by tapering the medication.
Serotonin syndrome with concomitant use of serotonergic drugs: Use ULTRACET with great caution in patients taking serotonergic drugs including SSRIs. Concomitant use of tramadol with serotonergic drugs including SSRI's increases the risk of adverse events, including seizure and serotonin syndrome (see Interactions).
Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concurrent use of ULTRACET with serotonergic drugs (see Interactions with Other Medicaments). 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) and/or gastrointestinal symptoms (e.g. nausea, vomiting, diarrhoea) and can be fatal (see Interactions). The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue ULTRACET if serotonin syndrome is suspected.
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, decreased appetite, 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 dosing 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.
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 Postmarketing Experience under Adverse Reactions).
Serious Skin Reactions: Rarely, paracetamol 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. 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.
Hyponatremia: Hyponatremia has been reported very rarely with the use of ULTRACET usually in patients with predisposing risk factors, such as elderly patients and/or patients using concomitant medications that may cause hyponatremia. In some reports, this 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.
Precautions: General: The recommended dose of ULTRACET should not be exceeded.
ULTRACET should not be co-administered with other tramadol or paracetamol-containing products.
Risks from Concomitant Use with Benzodiazepines: Profound sedation, respiratory depression, coma, and death may result from the concomitant use of ULTRACET with benzodiazepines. Observational studies have demonstrated that concomitant use of opioids and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
If the decision is made to newly prescribe a benzodiazepine and an opioid together, prescribe the lowest effective dosages and minimum durations of concomitant use.
If the decision is made to prescribe a benzodiazepine in a patient already receiving an opioid, prescribe a lower initial dose of the benzodiazepine than indicated in the absence of an opioid, and titrate based on clinical response.
If the decision is made to prescribe an opioid in a patient already taking a benzodiazepine, prescribe a lower initial dose of the opioid, 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. Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine 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 benzodiazepines (see Interactions).
Effects on Ability to Drive and Use Machines: ULTRACET may impair mental or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery.
Renal impairment: ULTRACET has not been studied in patients with impaired renal function. In patients with creatinine clearances of less than 30 mL/min, it is recommended that the dosing interval of ULTRACET be increased not to exceed 2 tablets every 12 hours. ULTRACET is not recommended in patients with creatinine clearance of less than 10 mL/min.
Hepatic impairment: The use of ULTRACET in patients with severe hepatic impairment is not recommended.
Use in Children: The safety and efficacy of ULTRACET has not been studied in the paediatric population. Therefore, use of ULTRACET is not recommended in patients under 12 years of age.
Other risk factors for life-threatening respiratory depression in children: Life-threatening respiratory depression and death have occurred in children who received tramadol. Tramadol is subject to variability in metabolism based upon CYP2D6 genotype, which can lead to increased exposure to an active metabolite. Based upon postmarketing reports with tramadol, children younger than 12 years of age may be more susceptible to the respiratory depressant effects of tramadol (see Contraindications). 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 (see Contraindications). Because of the risk of life-threatening respiratory depression and death, avoid the use of ULTRACET in adolescents younger than 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 such as postoperative status, obstructive sleep apnea 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 Dosage & Administration and Symptoms and signs: Tramadol under Overdosage).
