Ultracet

Tramadol HCl, paracetamol.

ULTRACET tablets combine two centrally acting analgesics, tramadol and paracetamol.
Each tablet contains 37.5 mg tramadol hydrochloride and 325 mg paracetamol as the active ingredients.
Excipients/Inactive Ingredients: Inactive ingredients are powdered cellulose, pregelatinized starch, sodium starch glycolate, starch, magnesium stearate, OPADRY Light Yellow YS-1-6382-G (hypromellose, titanium dioxide, polyethylene glycol, yellow iron oxide, polysorbate 80) and carnauba wax.

Pharmacology: Mechanism of Action: Tramadol: Tramadol is a centrally acting synthetic opioid analgesic. Although its mode of action is not completely understood, from animal tests, at least two complementary mechanisms appear applicable: binding of parent and M1 metabolite to μ-opioid receptors and weak inhibition of reuptake of norepinephrine and serotonin.
Opioid activity is due to both low affinity binding of the parent compound and higher affinity binding of the O-demethylated 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 opiate 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 (see Pharmacokinetics as follows).
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 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.
Paracetamol: Paracetamol is a non-opiate, non-salicylate analgesic.
Tramadol/Paracetamol Combination: When evaluated in a standard animal model, the combination of tramadol and paracetamol exhibited a synergistic effect. That is, when tramadol and paracetamol were administered together, significantly less of each drug was needed to produce a given analgesic effect than would be expected if their effects were merely additive. Tramadol reaches peak activity in 2 to 3 hours with a prolonged analgesic effect, so that its combination with paracetamol, a rapid-onset, short-acting analgesic agent, provides substantial benefit to patients over either component alone.
Pharmacodynamics: Central Nervous System: Tramadol produces respiratory depression by direct action on brain stem respiratory centres. The respiratory depression involves both a reduction in the responsiveness of the brain stem centres to increases in CO₂ tension and to electrical stimulation.
Tramadol depresses the cough reflex by direct effect on the cough centre in the medulla. Antitussive effects may occur with doses lower than those usually required for analgesia.
Tramadol causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in the setting of oxycodone overdose.
Gastrointestinal Tract and Other Smooth Muscle: Tramadol causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in gastric, biliary and pancreatic secretions, spasm of the sphincter of Oddi, and transient elevations in serum amylase.
Endocrine System: Opioids may influence the hypothalamic-pituitary-adrenal or -gonadal axes. Some changes that can be seen include an increase in serum prolactin, and decreases in plasma cortisol and testosterone. Clinical signs and symptoms may be manifest from these hormonal changes.
Immune System: In vitro and animal studies indicate that opioids have a variety of effects on immune functions, depending on the context in which they are used. The clinical significance of these findings is unknown.
Cardiac Electrophysiology: In a randomized, double-blind, 4-way crossover, placebo- and positive-controlled, multiple dose ECG assessment study in healthy subjects (N=62), the following tramadol treatments were tested: A) 100 mg every 6 h on days 1-3 (400 mg/day), with a single 100 mg dose on day 4 and B) 150 mg every 6 h (600 mg/day) on days 1-3, with a single 150 mg dose on day 4. The maximum dose for ULTRACET is 8 tablets per day or 300 mg of tramadol/day. In both treatment arms, the maximum difference from placebo in the mean change from baseline QTcF interval occurred at the 8 h time point: 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 treatment groups were within the 10 ms threshold for QT prolongation (see Cardiovascular under Precautions; 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; Recommended Dose and Dosage Adjustment under Dosage & Administration; Overdosage). (See figure.)

Click on icon to see table/diagram/image

Concentration - Efficacy Relationships: The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent opioid agonists. The minimum effective analgesic concentration of tramadol for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance.
Concentration - Adverse Reaction Relationship: There is a relationship between increasing tramadol plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions (see Dosage & Administration).
Pharmacokinetics: Tramadol: Tramadol is administered as a racemate and both the (-) and (+) forms of both tramadol and M1 are detected in the circulation. The pharmacokinetics of plasma tramadol and paracetamol following oral administration of one tablet are shown in Table 1. Tramadol has a slower absorption and longer half-life when compared to paracetamol. (See Table 1.)

Click on icon to see table/diagram/image

A single-dose pharmacokinetic study of ULTRACET in volunteers showed no drug interactions between tramadol and paracetamol. Upon multiple oral dosing to steady state, however, the bioavailability of tramadol and metabolite M1 was lower for the combination tablets compared to tramadol administered alone. The decrease in AUC was 14% for (+)-tramadol, 10.4% for (-)-tramadol, 11.9% for (+)-M1 and 24.2% for (-)-M1. The cause of this reduced bioavailability is not clear. Following single or multiple dose administration of ULTRACET, no significant change in paracetamol pharmacokinetics was observed when compared to paracetamol given alone.
Absorption: The absolute bioavailability of tramadol from ULTRACET tablets has not been determined. Tramadol hydrochloride has a mean absolute bioavailability of approximately 75% following administration of a single 100 mg oral dose of tramadol HCl tablets. The mean peak plasma concentration of racemic tramadol and M1 after administration of two ULTRACET tablets occurs at approximately two and three hours, respectively, post-dose.
Peak plasma concentrations of paracetamol occur within one hour and are not affected by co-administration with tramadol. Oral absorption of paracetamol following administration of ULTRACET occurs primarily in the small intestine.
Food Effects: When ULTRACET was administered with food, the time to peak plasma concentration was delayed for approximately 35 minutes for tramadol and almost one hour for paracetamol. However, peak plasma concentration and the extent of absorption of either tramadol or paracetamol were not affected. The clinical significance of this difference is unknown.
Distribution: The volume of distribution of tramadol was 2.6 and 2.9 L/kg in male and female subjects, respectively, following a 100 mg intravenous dose. The binding of tramadol to human plasma proteins is approximately 20%, and binding also appears to be independent of concentration up to 10 μg/mL. Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range.
Paracetamol appears to be widely distributed throughout most body tissues except fat. Its apparent volume of distribution is about 0.9 L/kg. A relatively small portion (~ 20%) of paracetamol is bound to plasma protein.
Metabolism: Following oral administration, tramadol is extensively metabolized by a number of pathways, including CYP2D6 and CYP3A4, as well as by conjugation of parent and metabolites. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The major metabolic pathways appear to be N- and O-demethylation and glucuronidation or sulfation in the liver. Metabolite M1 (O-desmethyltramadol) is pharmacologically active in animal models.
Patients who are CYP2D6 ultra-rapid metabolizers convert tramadol to its active metabolite (M1) more rapidly and completely than other patients.
Conversely, some patients are CYP2D6 poor metabolizers of tramadol, or other drugs (e.g., debrisoquine, dextromethorphan, and tricyclic antidepressants) (see Special Populations and Conditions: Race as follows).
Based on a population PK analysis of Phase I studies in healthy subjects, concentrations of tramadol were approximately 20% higher in "CYP2D6 poor metabolizers" versus "extensive CYP2D6 metabolizers", while M1 concentrations were 40% lower. In vitro drug interaction studies in human liver microsomes indicate that inhibitors of CYP2D6 such as fluoxetine and its metabolite norfluoxetine, amitriptyline and quinidine inhibit the metabolism of tramadol to various degrees. The full pharmacological impact of these alterations in terms of either efficacy or safety is unknown. Concomitant use of serotonin reuptake inhibitors and MAO inhibitors may enhance the risk of adverse events, including seizure and serotonin syndrome (see Precautions).
Paracetamol: Paracetamol is primarily metabolized in the liver by first-order kinetics and involves three principal separate pathways: a. Conjugation with glucuronide.
b. Conjugation with sulfate.
c. Oxidation via the cytochrome, P450-dependent, mixed-function oxidase enzyme pathway to form a reactive intermediate metabolite, which conjugates with glutathione and is then further metabolized to form cysteine and mercapturic acid conjugates. The principal cytochrome P450 isoenzyme involved appears to be CYP2E1, with CYP1A2 and CYP3A4 additional pathways.
In adults, the majority of paracetamol is conjugated with glucuronic acid and, to a lesser extent, with sulfate. These glucuronide-, sulfate- and glutathione-derived metabolites lack biologic activity. In premature infants, newborns and young infants, the sulfate conjugate predominates.
Excretion: Tramadol is eliminated primarily through metabolism by the liver and the metabolites are eliminated primarily by the kidneys. The plasma elimination half-lives of racemic tramadol and M1 are approximately 5-6 and 7 hours, respectively, after administration of ULTRACET. The apparent plasma elimination half-life of racemic tramadol increased to 7-9 hours upon multiple dosing of ULTRACET.
The half-life of paracetamol is about 2 to 3 hours in adults. It is somewhat shorter in children and somewhat longer in neonates and in cirrhotic patients. Paracetamol is eliminated from the body primarily by formation of glucuronide and sulfate conjugates in a dose-dependent manner. Less than 9% of paracetamol is excreted unchanged in the urine.
Special Populations and Conditions: Pediatrics: Individuals under 18 years of age should not take ULTRACET tablets.
The pharmacokinetics of ULTRACET tablets have not been studied in pediatric patients below 18 years of age.
Geriatrics: A population pharmacokinetic analysis of data obtained from a clinical trial in patients with chronic pain treated with ULTRACET which included 55 patients between 65 and 75 years of age and 19 patients over 75 years of age, showed no significant changes in pharmacokinetics of tramadol and paracetamol in elderly patients with normal renal and hepatic function.
Gender: Tramadol clearance was 20% higher in female subjects compared to males on four Phase I studies of ULTRACET in 50 male and 34 female healthy subjects. The clinical significance of this difference is unknown.
Race: Some patients are CYP2D6 ultra-rapid metabolizers of tramadol due to a specific genotype. These individuals convert tramadol into its active metabolite, M1, more rapidly and completely than other people leading to higher-than-expected serum M1 levels. 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 to 28% in North Africans, Ethiopians, and Arabs. Data are not available for other ethnic groups (see Respiratory under Precautions; Labour, Delivery and Nursing Women under Use in Pregnancy & Lactation).
In contrast, some patients exhibit the CYP2D6 poor metabolizer phenotype and do not convert tramadol to the active M1 metabolite sufficiently to benefit from the analgesic effect of the drug (see Overview under Interactions). The prevalence of this CYP2D6 phenotype is about 5-10 percent in Caucasians and 1 percent of Asians.
Hepatic Impairment: The pharmacokinetics and tolerability of ULTRACET in patients with impaired hepatic function has not been studied. Since tramadol and paracetamol are both extensively metabolized by the liver, the use of ULTRACET in patients with hepatic impairment is not recommended (see Contraindications; Hepatic under Precautions).
Renal Impairment: The pharmacokinetics of ULTRACET in patients with renal impairment have not been studied. Based on studies using tramadol alone, excretion of tramadol and metabolite M1 is reduced in patients with creatinine clearance of less than 30 mL/min. The total amount of tramadol and M1 removed during a 4-hour dialysis period is less than 7% of the administered dose based on studies using tramadol alone. ULTRACET is contraindicated in patients with severe renal impairment (see Contraindications; Renal under Precautions).

Adults: ULTRACET (tramadol hydrochloride and paracetamol) is indicated for the management of moderate to moderately severe pain.
ULTRACET has not been systematically evaluated beyond 12 weeks in controlled clinical trials. Therefore, the physician who elects to use ULTRACET for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
Geriatrics (> 65 years of age): In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, concomitant disease or other drug therapy.
Healthy elderly subjects aged 65 to 75 years administered tramadol have plasma concentrations and elimination half-lives comparable to those observed in healthy subjects less than 65 years of age. ULTRACET should be administered with greater caution in patients older than 75 years, due to the greater potential for adverse events in this population (see Precautions and Dosage & Administration).
Pediatrics (<18 years of age): 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.

ULTRACET should only be used in patients for whom alternative treatment options are ineffective or not tolerated (e.g., non-opioid analgesics).
ULTRACET must be swallowed whole. Cutting, breaking, crushing, chewing, or dissolving ULTRACET can lead to dangerous adverse events including death (see Precautions).
For acute pain, it is recommended that ULTRACET be used for a maximum of 7 days at the lowest dose that provides adequate pain relief.
All doses of opioids carry an inherent risk of fatal or non-fatal adverse events. This risk is increased with higher doses. For the management of chronic non-cancer, non-palliative pain, it is recommended that a maximum daily dosage of 300 mg (50 morphine milligram equivalent) of ULTRACET not be exceeded. Each patient should be assessed for their risk prior to prescribing ULTRACET, as the likelihood of experiencing serious adverse events can depend upon the type of opioid, duration of treatment, level of pain as well as the patient's own level of tolerance. In addition, the level of pain should be assessed routinely to confirm the most appropriate dose and the need for further use of ULTRACET (see Recommended Dose and Dosage Adjustment as follows).
Dosing Considerations: ULTRACET (tramadol hydrochloride and paracetamol) tablets should only be used during post-operative period in patients that can take oral medications (see Peri-Operative Considerations under Precautions).
ULTRACET is not indicated for rectal administration.
Do not co-administer ULTRACET tablets with other paracetamol- or tramadol-containing products.
ULTRACET may be taken with or without food.
The maximum recommended dose of ULTRACET should not be exceeded. The lowest effective dose should be used for the shortest period of time consistent with individual patient treatment goals.
Tramadol is converted to the active M1 metabolite by CYP2D6, hence its safety and efficacy is controlled by CYP2D6 activity, which has a high degree of variability in humans (see Pharmacology: Pharmacokinetics: Special Populations and Conditions: Race under Actions). Levels of CYP2D6 activity have been associated with outcomes from tramadol administration that range from an absence of effect to responses with the potential of serious medical consequences (see Respiratory under Precautions; Overview under Interactions).
Recommended Dose and Dosage Adjustment: Adults: For the management of pain, the recommended dose of ULTRACET is 1 or 2 tablets every 4 to 6 hours as needed for pain relief up to a maximum of 8 tablets per day.
Patients with Hepatic Impairment: ULTRACET is contraindicated in patients with severe hepatic impairment (see Contraindications).
Patients with Renal Impairment: ULTRACET is contraindicated in patients with severe renal impairment (see Contraindications).
Dose Titration: Dose titration is the key to success with opioid analgesic therapy. Proper optimization of doses scaled to the relief of the individual's pain should aim at administration of the lowest dose which will achieve the overall treatment goal of satisfactory pain relief with acceptable side effects.
Dosage adjustments should be based on the patient's clinical response.
Geriatrics: Respiratory depression has occurred in the elderly following administration of large initial doses of opioids to patients who were not opioid-tolerant or when opioids were co-administered with other agents that can depress respiration. ULTRACET should be initiated at a low dose and slowly titrated to effect (see Precautions; Pharmacology under Actions).
Pediatric Use: The safety and effectiveness of ULTRACET has not been studied in the pediatric population. Therefore, use of ULTRACET is not recommended in patients under 18 years of age.
Use with Non-Opioid Medications: If a non-opioid analgesic is being provided, it may be continued. If the non-opioid is discontinued, consideration should be given to increasing the opioid dose to compensate for the non-opioid analgesic. ULTRACET can be safely used concomitantly with usual doses of other non-opioid analgesics.
Management of Patients Requiring Rescue Medication: If ULTRACET is used as rescue medication in conjunction with extended-release tramadol tablets, the total daily dose of tramadol should not exceed 300 mg (8 tablets). Fentanyl products should not be used as rescue medication in patients taking ULTRACET.
Adjustment or Reduction of Dosage: Physical dependence with or without psychological dependence tends to occur with chronic administration of opioids, including ULTRACET. Withdrawal (abstinence) symptoms may occur following abrupt discontinuation of therapy. These symptoms may include body aches, diarrhea, gooseflesh, loss of appetite, nausea, nervousness or restlessness, runny nose, sneezing, tremors or shivering, stomach cramps, tachycardia, trouble with sleeping, unusual increase in sweating, palpitations, unexplained fever, weakness and yawning. Do not stop use of ULTRACET abruptly (see Dependence/Tolerance under Precautions).
Following successful relief of moderate to severe pain, periodic attempts to reduce the opioid dose should be made. Smaller doses or complete discontinuation may become feasible due to a change in the patient's condition or mental state. Patients on prolonged therapy should be withdrawn gradually from the drug if it is no longer required for pain control. In patients who are appropriately treated with opioid analgesics and who undergo gradual withdrawal for the drug, these symptoms are usually mild (see Precautions). Tapering should be carried out under medical supervision.
Patient should be informed that reducing and/or discontinuing opioids decreases their tolerance to these drugs. If treatment needs to be re-initiated, the patient must start at the lowest dose and titrate up to avoid overdose.
Missed Dose: If the patient forgets to take one or more doses, they should take their next dose at the next scheduled time and in the normal amount.

For management of a suspected drug overdose, contact the doctor immediately, even if there are no symptoms.
ULTRACET is a combination product. The clinical presentation of overdose may include the signs and symptoms of tramadol toxicity, paracetamol toxicity or both.
Accidental ingestion: Accidental ingestion of tramadol can result in respiratory depression and seizures due to an overdose of tramadol. Respiratory depression and seizures have been reported in a child following ingestion of a single tablet. Fatalities due to tramadol overdose have also been reported.
Symptoms: Tramadol: Serious potential consequences of overdosage are respiratory depression, serotonin syndrome, hyponatremia, lethargy, coma, seizure, cardiac arrest and death. In addition, cases of QT prolongation have been reported during overdose.
Fatalities have been reported in post-marketing in association with both intentional and unintentional overdose with tramadol. The initial symptoms of tramadol overdosage may include respiratory depression and/or seizures. In treating an overdose, primary attention should be given to maintaining adequate ventilation along with general supportive treatment.
Paracetamol: Serious potential consequences of overdosage with paracetamol are hepatic centrilobular necrosis, leading to hepatic failure and death. Renal tubular necrosis, hypoglycemia and coagulation defects also may occur. The initial symptoms seen within the first 24 hours following a paracetamol overdose are: gastrointestinal irritability, anorexia, nausea, vomiting, malaise, pallor and diaphoresis. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post-ingestion. Emergency help should be sought immediately and treatment initiated immediately if overdose is suspected, even if symptoms are not apparent.
Treatment: A single or multiple overdose with ULTRACET may be a potentially lethal polydrug overdose, and consultation with doctor is recommended. The stomach should be emptied promptly and vigorous supportive therapy is required in severe intoxication.
In treating an overdose of ULTRACET, primary attention should be given to maintaining adequate ventilation along with general supportive treatment. Hypotension is usually hypovolemic in etiology and should respond to fluids. Supportive measures (including oxygen and vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation. Intubation should be considered before gastric lavage of the unconscious patient and when necessary, to provide assisted respiration.
While naloxone will reverse some, but not all, symptoms caused by overdosage with tramadol, the risk of seizures is also increased with naloxone administration. In animals, convulsions following the administration of toxic doses of tramadol could be suppressed with barbiturates or benzodiazepines, but were increased with naloxone. Naloxone administration did not change the lethality of an overdose in mice. Based on experience with tramadol, 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.
In the treatment of paracetamol overdosage, gastric decontamination should be administered just prior to paracetamol antidote N-acetylcysteine (NAC) to decrease systemic absorption if paracetamol ingestion is known or suspected to have occurred within a few hours of presentation. Serum paracetamol levels should be obtained immediately if the patient presents 4 or more hours after ingestion to assess potential risk of hepatotoxicity; paracetamol levels drawn less than 4 hours post-ingestion may be misleading. The antidote NAC should be administered as soon as possible by intravenous or oral route of administration.

ULTRACET (tramadol hydrochloride and paracetamol) tablets is contraindicated in: Patients who are hypersensitive to the active substance tramadol and paracetamol or other opioid analgesics or to any ingredient in the formulation. For a complete listing, see Description.
Patients with known or suspected mechanical gastrointestinal obstruction (e.g., bowel obstruction or strictures) or any diseases/conditions that affect bowel transit (e.g., ileus of any type).
Patients with suspected surgical abdomen (e.g., acute appendicitis or pancreatitis).
Patients with severe hepatic or renal impairment (creatinine clearance of less than 30 mL/min and/or Child-Pugh Class C).
Patients with mild pain that can be managed with other pain medications.
Patients with acute or severe bronchial asthma, chronic obstructive airway, or status asthmaticus.
Patients with acute respiratory depression, elevated carbon dioxide levels in the blood, and cor pulmonale.
Patients with acute alcoholism, delirium tremens, and convulsive disorders.
Patients with severe CNS depression, increased cerebrospinal or intracranial pressure, and head injury.
Patients taking monoamine oxidase inhibitors (MAOIs) (or within 14 days following discontinuation of such therapy).
Women who are pregnant, nursing or during labour and delivery.
Any situation where opioids are contraindicated, including acute intoxication with any of the following: alcohol, hypnotics, centrally acting analgesics, opioids or psychotropic drugs. ULTRACET may worsen central nervous system and respiratory depression in these patients.
Post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy.
All children younger than 12 years of age.

Limitations of Use: Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the risks of overdose and death with immediate release opioid formulations, ULTRACET (tramadol hydrochloride and paracetamol tablets) should only be used in patients for whom alternative treatment options (e.g., non-opioid analgesics) are ineffective, not tolerated, or would be otherwise inadequate to provide appropriate management of pain (see Dosage & Administration).
Addiction, Abuse, and Misuse: ULTRACET poses risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Each patient's risk should be assessed prior to prescribing ULTRACET, and all patients should be monitored regularly for the development of these behaviours or conditions (see Precautions). ULTRACET should be stored securely to avoid theft or misuse.
Life-threatening Respiratory Depression - OVERDOSE: Serious, life-threatening, or fatal respiratory depression may occur with use of ULTRACET. Infants exposed in-utero or through breast milk are at risk of life-threatening respiratory depression upon delivery or when nursed. Patients should be monitored for respiratory depression, especially during initiation of ULTRACET or following a dose increase.
ULTRACET must be swallowed whole. Cutting, breaking, crushing, chewing or dissolving ULTRACET can lead to dangerous adverse events including death (see Precautions). Further, instruct patients of the hazards related to taking opioids including fatal overdose.
Accidental Exposure: Accidental ingestion of even one dose of ULTRACET, especially by children, can result in a fatal overdose of tramadol and paracetamol (see Disposal under Cautions for Usage, for instructions on proper disposal).
Neonatal Opioid Withdrawal Syndrome: Prolonged maternal use of ULTRACET during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening (see Precautions).
Interaction with Alcohol: The co-ingestion of alcohol with ULTRACET should be avoided as it may result in dangerous additive effects, causing serious injury or death (see Precautions and Interactions).
Hepatotoxicity: ULTRACET contains paracetamol. Paracetamol has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of paracetamol at doses that exceed the maximum daily limits, and often involve more than one paracetamol-containing product.
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 (see Neurologic under Precautions; Interactions).
Reserve concomitant prescribing of ULTRACET and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
Limit dosages and durations to the minimum required.
Follow patients for signs and symptoms of respiratory depression and sedation.

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).

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) under Precautions; 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 under Precautions).
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.

Adverse Drug Reaction Overview: Adverse effects of ULTRACET (tramadol hydrochloride and paracetamol) tablets are similar to those of other opioid analgesics, and represent an extension of pharmacological effects of the drug class. The major hazards of opioids include respiratory and central nervous system depression and to a lesser degree, circulatory depression, respiratory arrest, shock and cardiac arrest.
The most frequently observed adverse effects of ULTRACET are headache, dizziness, nausea, constipation and somnolence as presented in Table 2.
Clinical Trial Adverse Drug Reactions: Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
ULTRACET (tramadol hydrochloride and paracetamol) tablets were administered to 1,597 patients during the double-blind or open-label extension periods in studies of chronic non-malignant pain. Of these patients, 539 were 65 years old or older. The most frequently reported events were in the central nervous and gastrointestinal systems. These are common effects associated with other drugs with opioid agonist activity. (See Table 2.)

Click on icon to see table/diagram/image

Incidence at least 1% - Causal Relationship at Least Possible or Greater: The following lists treatment-emergent adverse reactions that occurred with an incidence of at least 1% in clinical trials with a population of 2,836 tramadol/paracetamol-exposed subjects in the 18 acute and chronic pain studies combined.
Body as a Whole: asthenia, fatigue, hot flushes.
Central and Peripheral Nervous System: dizziness, headache, tremor.
Gastrointestinal System: abdominal pain, constipation, diarrhea, dyspepsia, flatulence, dry mouth, nausea, vomiting.
Psychiatric Disorders: anorexia, anxiety, confusion, euphoria, insomnia, nervousness, somnolence.
Skin and Appendages: pruritus, rash, increased sweating.
Among these, the most common (≥ 5% of subjects) treatment-emergent adverse events were nausea (14%), dizziness (10%), somnolence (9%), constipation (8%), vomiting (5%), and headache (5%). These data are consistent with data presented in Table 2.
Sedation: Sedation is a common side effect of opioid analgesics, especially in opioid naïve individuals. Sedation may also occur partly because patients often recuperate from prolonged fatigue after the relief of persistent pain. Most patients develop tolerance to the sedative effects of opioids within three to five days and, if the sedation is not severe, will not require any treatment except reassurance. If excessive sedation persists beyond a few days, the dose of the opioid should be reduced and alternate causes investigated. Some of these are: concurrent CNS depressant medication, hepatic or renal dysfunction, brain metastases, hypercalcemia and respiratory failure. If it is necessary to reduce the dose, it can be carefully increased again after three or four days if it is obvious that the pain is not being well controlled. Dizziness and unsteadiness may be caused by postural hypotension, particularly in elderly or debilitated patients, and may be alleviated if the patient lies down.
Nausea and Vomiting: Nausea is a common side effect on initiation of therapy with opioid analgesics and is thought to occur by activation of the chemoreceptor trigger zone, stimulation of the vestibular apparatus and through delayed gastric emptying. The prevalence of nausea declines following continued treatment with opioid analgesics. When instituting therapy with an opioid for chronic pain, the routine prescription of an antiemetic should be considered. In the cancer patient, investigation of nausea should include such causes as constipation, bowel obstruction, uremia, hypercalcemia, hepatomegaly, tumor invasion of celiac plexus and concurrent use of drugs with emetogenic properties. Persistent nausea which does not respond to dosage reduction may be caused by opioid-induced gastric stasis and may be accompanied by other symptoms including anorexia, early satiety, vomiting and abdominal fullness. These symptoms respond to chronic treatment with gastrointestinal prokinetic agents.
Constipation: Practically all patients become constipated while taking opioids on a persistent basis. In some patients, particularly the elderly or bedridden, fecal impaction may result. It is essential to caution the patients in this regard and to institute an appropriate regimen of bowel management at the start of prolonged opioid therapy. Stimulant laxatives, stool softeners, and other appropriate measures should be used as required. As fecal impaction may present as overflow diarrhea, the presence of constipation should be excluded in patients on opioid therapy prior to initiating treatment for diarrhea.
The following adverse effects occur less frequently with opioid analgesics and include those reported in ULTRACET clinical trials, whether related or not to tramadol and paracetamol.
Less Common Clinical Trial Adverse Drug Reactions (<1%): The following lists clinically relevant treatment-emergent adverse reactions that occurred with an incidence of less than 1% in tramadol/paracetamol clinical trials.
Body as a Whole: chest pain, rigors, syncope, withdrawal syndrome, allergic reaction.
Cardiovascular Disorders: hypertension, aggravated hypertension, hypotension, dependent edema.
Central and Peripheral Nervous System: ataxia, convulsions, hypertonia, migraine, aggravated migraine, involuntary muscle contractions, paresthesia, stupor, vertigo.
Gastrointestinal System: dysphagia, melena, tongue edema.
Hearing and Vestibular Disorders: tinnitus.
Heart Rate and Rhythm Disorders: arrhythmia, palpitation, tachycardia.
Liver and Biliary System: abnormal hepatic function, SGPT (ALAT) increased, SGOT (ASAT) increased.
Metabolic and Nutritional Disorders: weight decrease, hypoglycemia, increased alkaline phosphatase, weight increase.
Musculoskeletal System Disorders: arthralgia.
Platelets, Bleeding and Clotting Disorders: increased coagulation time, purpura.
Psychiatric Disorders: amnesia, depersonalisation, depression, drug abuse, emotional lability, hallucination, impotence, bad dreams, abnormal thinking.
Red Blood Cell Disorders: anemia.
Respiratory System: dyspnea, bronchospasm.
Skin and Appendages Disorders: dermatitis, erythematous rash.
Urinary System: albuminuria, micturition disorder, oliguria, urinary retention.
Vision Disorders: abnormal vision.
White Cell and RES Disorders: granulocytopenia and leukocytosis.
Other Clinically Significant Adverse Experiences Previously Reported in Clinical Trials or Post-marketing Reports with Tramadol: Other events which have been reported with the use of tramadol products and for which a causal association has not been determined include: vasodilation, orthostatic hypotension, myocardial ischemia, pulmonary edema, allergic reactions (including anaphylaxis and urticaria, Stevens- Johnson syndrome/TENS), cognitive dysfunction, difficulty concentrating, suicidal tendency, hepatitis, liver failure, worsening of asthma, and gastrointestinal bleeding. Reported laboratory abnormalities included elevated creatinine and liver function tests.
Additional events which have been reported with the use of tramadol products and for which a causal association has not been determined include: abdominal discomfort, agitation, chest discomfort, cold sweat, disorientation, dry throat, ear discomfort, feeling abnormal, feeling jittery, gait disturbance, irritability, lethargy, malaise, memory impairment, prothrombin time prolonged, psychomotor hyperactivity, sleep disorder, thirst, vision blurred.
Serotonin syndrome (whose symptoms may include mental status change, hyperreflexia, fever, shivering, tremor, agitation, diaphoresis, seizures and coma) has been reported with tramadol when used concomitantly with other serotonergic agents such as SSRIs and MAOIs.
Post-marketing experience with the use of tramadol containing products included rare reports of delirium, miosis, mydriasis, and speech disorder, and very rare reports of movement disorder including dyskinesia and dystonia. Electrocardiogram QT prolonged, ventricular fibrillation, and ventricular tachycardia have been reported during post-market use.
Cases of hypoglycemia have been reported in patients taking tramadol, mostly in patients with pre-disposing risk factors, including diabetes, elderly and renal insufficiency. Caution should be exercised when prescribing tramadol to diabetic patients. More frequent monitoring of blood glucose levels may be appropriate, including at initiation or dose increase.
Cases of hyponatremia and/or SIADH have been reported very rarely in patients taking tramadol, usually in patients with predisposing risk factors, such as the elderly or those using concomitant medications that may cause hyponatremia.
Androgen deficiency: Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date. Patients presenting with symptoms of androgen deficiency should undergo laboratory evaluation.
Other Clinically Significant Adverse Experiences Previously Reported in Clinical Trials or Post-marketing Reports with Paracetamol: Allergic reactions (primarily skin rash) or reports of hypersensitivity secondary to paracetamol are rare and generally controlled by discontinuation of the drug and, when necessary, symptomatic treatment. There have been several reports that suggest that paracetamol may produce hypoprothrombinemia when administered with warfarin-like compounds. In other studies, prothrombin time did not change.
Additional events which have been reported with the use of paracetamol products and for which a causal association has not been determined include: feeling hot, fixed eruption, pruritus generalized.

Overview: Based on its pharmacodynamic and pharmacokinetic properties, tramadol and paracetamol exhibits a potential for pharmacodynamic and pharmacokinetic interactions. The various types of interactions, associated general recommendations and lists of examples are described in Tables 3a and 3b as follows. These lists of examples are not comprehensive and therefore it is recommended that the label of each drug that is co-administered with tramadol and paracetamol be consulted for information related to interaction pathways, potential risks, and specific actions to be taken with regards to co-administration (see Pharmacology: Pharmacokinetics: Metabolism under Actions). (See Tables 3a and 3b.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

QTc Interval-Prolonging Drugs: The concomitant use of ULTRACET with QTc interval-prolonging drugs should be avoided. Drugs that have been associated with QTc interval prolongation and/or torsade de pointes include, but are not limited to, the examples in the following list. Chemical/pharmacological classes are listed if some, although not necessarily all, class members have been implicated in QTc interval prolongation and/or torsade de pointes: Class IA antiarrhythmics (e.g., quinidine, procainamide, disopyramide); Class III antiarrhythmics (e.g., amiodarone, sotalol, ibutilide, dronedarone); Class 1C antiarrhythmics (e.g., flecainide, propafenone); antipsychotics (e.g., chlorpromazine, pimozide, haloperidol, droperidol, ziprasidone, risperidone); antidepressants (e.g., fluoxetine, citalopram, venlafaxine, tricyclic/tetracyclic antidepressants [e.g., amitriptyline, imipramine, maprotiline]); opioids (e.g., methadone); macrolide antibiotics and analogues (e.g., erythromycin, clarithromycin, azithromycin, tacrolimus); quinolone antibiotics (e.g., moxifloxacin, levofloxacin, ciprofloxacin); pentamidine; antimalarials (e.g., quinine, chloroquine); azole antifungals (e.g., ketoconazole, fluconazole, voriconazole); domperidone; 5-hydroxytryptamine (5-HT)3 receptor antagonists (e.g., ondansetron); tyrosine kinase inhibitors (e.g., sunitinib, nilotinib, ceritinib, vandetanib); arsenic trioxide; histone deacetylase inhibitors (e.g., vorinostat); beta-2 adrenoceptor agonists (e.g., salmeterol, formoterol).
Drugs that Affect Electrolytes: The use of ULTRACET with drugs that can decrease electrolyte levels should be avoided to the extent possible. Drugs that can decrease electrolyte levels include, but are not limited to, the following: loop, thiazide, and related diuretics; laxatives and enemas; amphotericin B; high-dose corticosteroids; proton pump inhibitors.
The previous list of potentially interacting drugs is not comprehensive. Current information sources should be consulted for newly approved drugs that prolong the QTc interval or decrease electrolytes, as well as for older drugs for which these effects have recently been established. (See Cardiovascular under Precautions; Other Clinically Significant Adverse Experiences Previously Reported in Clinical Trials or Post-marketing Reports with Tramadol under Adverse Reactions; Pharmacology: Pharmacodynamics: Cardiac Electrophysiology under Actions.)
Drug-Food Interactions: When ULTRACET was administered with food, the time to peak plasma concentration was delayed for approximately 35 minutes for tramadol and almost one hour for paracetamol. However, peak plasma concentration and the extent of absorption of either tramadol or paracetamol were not affected. The clinical significance of this difference is unknown.
Drug-Lifestyle Interactions: The concomitant use of alcohol should be avoided (see Warnings).

Special Handling Instructions: ULTRACET should never be thrown into household trash, where children and pets may find it. It should be returned to a pharmacy for proper disposal.
Disposal: ULTRACET should be kept in a safe place, out of the sight and reach of children before, during and after use. ULTRACET should not be used in front of children, since they may copy these actions.
ULTRACET should never be disposed of in household trash. Disposal via a pharmacy take-back program is recommended. Unused or expired ULTRACET should be properly disposed of as soon as it is no longer needed to prevent accidental exposure to others, including children or pets. If temporary storage is required before disposal, a sealed child-proof container, such as a biohazard waste container or a lockable medication box could be obtained from a pharmacy.

Dispense in a tight container. Store at or below 25°C.
Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store ULTRACET securely.

Analgesics (Opioid)

N02AJ13 - tramadol and paracetamol ; Belongs to the class of opioids in combination with other non-opioid analgesics. Used to relieve pain.

P₁S₁S₃