Ultracet

Tramadol hydrochloride, paracetamol.

Each tablet contains 37.5 mg tramadol hydrochloride and 325 mg paracetamol.
Tramadol hydrochloride: (±)cis-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochloride.
Paracetamol: N-acetyl-p-aminophenol (4-hydroxyacetanilide).
Excipients/Inactive Ingredients: Carnauba wax, Magnesium stearate, Corn starch, Powdered cellulose, Pregelatinized starch, Sodium starch glycolate.

Pharmacotherapeutic group: Analgesics, Opioids in combination with non-opioid analgesics. ATC code: N02AJ13.
Pharmacology: Pharmacodynamics: Pharmacodynamic effects: Tramadol is a centrally acting analgesic compound. 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.
Paracetamol is another centrally acting analgesic. The exact site and mechanism of its analgesic action is not clearly defined.
When evaluated in a standard animal model, the combination of tramadol and paracetamol exhibited a synergistic effect.
Pharmacokinetics: General: 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 ULTRACET tablet are shown in Table 1. Tramadol has a slower absorption and longer half-life when compared to paracetamol.
After a single oral dose of one Tramadol/Paracetamol combination tablet (37.5 mg/325 mg), peak plasma concentrations of 64.3/55.5 ng/mL [(+)-Tramadol/(-)-Tramadol] and 4.2 μg/ml (paracetamol) are reached after 1.8 h [(+)-Tramadol/(-)-Tramadol] and 0.9 h (Paracetamol), respectively. Mean elimination half-lives (t_½) are 5.1/4.7 h [(+)-Tramadol/(-)-Tramadol] and 2.5 h (Paracetamol).
Single and multiple dose pharmacokinetic studies of ULTRACET in volunteers showed no significant drug interactions between tramadol and paracetamol. (See Table 1.)

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Absorption: Tramadol hydrochloride has a mean absolute bioavailability of approximately 75% following administration of a single 100 mg oral dose of tramadol 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 in healthy adults.
Oral absorption of paracetamol following administration of ULTRACET is rapid and almost complete and occurs primarily in the small intestine. Peak plasma concentrations of paracetamol occur within 1 hour and are not affected by co-administration with tramadol.
Food effects: The oral administration of ULTRACET with food has no significant effect on the peak plasma concentration or extent of absorption of either tramadol or paracetamol, so that ULTRACET can be taken independently of meal times.
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%.
Paracetamol appears to be widely distributed throughout most body tissues except fat. Its apparent volume of distribution is about 0.9 L/kg.
A relative small portion (~20%) of paracetamol is bound to plasma protein.
Metabolism: Plasma concentration profiles for tramadol and its M1 metabolite measured following dosing of ULTRACET in volunteers showed no significant change compared to dosing with tramadol alone.
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. Tramadol is extensively metabolized by a number of pathways, including CYP2D6. Patients who are CYP2D6 ultra-rapid metabolizers may convert tramadol to its active metabolite (M1) more rapidly and completely than other patients (see CYP2D6 Ultra-Rapid Metabolism of Tramadol under Precautions). The prevalence of this CYP2D6 genotype varies by population and has been reported in literature to range from 1% to 10% in African Americans, Caucasian Americans, Asians and Europeans (including specific studies in Greeks, Hungarians and Northern Europeans) to as high as 29% in African/Ethiopians.
Paracetamol is primarily metabolized in the liver by first-order kinetics and involves three principle separate pathways: a) conjugation with glucuronide; b) conjugation with sulfate; and c) oxidation via cytochrome P-450 enzyme pathway.
Excretion: Tramadol and its metabolites are eliminated primarily by the kidney. The plasma elimination half-lives of racemic tramadol and M1 are approximately six and seven hours, respectively. The plasma elimination half-life of racemic tramadol increased from approximately six hours to seven 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.
Toxicology: Non-clinical Information: Tramadol/Paracetamol Combination: There are no animal or laboratory studies on the combination product (tramadol and paracetamol) to evaluate carcinogenesis, mutagenesis or impairment of fertility.
No drug-related teratogenic effects were observed in the progeny of rats treated orally with the combination of 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) 8.3 times the maximum human dose but was not teratogenic at this dose level. Embryo and fetal toxicity consisted of decreased fetal weights and increased supernumerary ribs. Lower and less severe maternally toxic dosages (10/87 and 25/217 mg/kg tramadol/paracetamol) did not produce embryo or fetal toxicity.
Tramadol Hydrochloride: Carcinogenicity/Mutagenicity: A slight but statistically significant increase in two common murine tumors, pulmonary and hepatic, was observed in a mouse carcinogenicity study, particularly in aged mice (dosing orally up to 30 mg/kg for approximately 2 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.
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.
Fertility: No effects on fertility were observed for tramadol at oral dose levels up to 50 mg/kg in male rats and 75 mg/kg in female rats.
Effect on reproduction: Tramadol was evaluated in peri- and post-natal studies in rats. Progeny of dams receiving oral (gavage) dose levels of 50 mg/kg or greater had decreased weights, and pup survival was decreased early in lactation at 80 mg/kg (6 to 10 times the maximum human dose). No toxicity was observed for progeny of dams receiving 8, 10, 20, 25 or 40 mg/kg. Maternal toxicity was observed at all dose levels of tramadol in this study, but effects on progeny were evident only at higher dose levels where maternal toxicity was more severe.

ULTRACET is indicated for the management of moderate to severe pain.

Dosage: Adults and children 16 years of age and over: The maximum single dose of ULTRACET is 1 to 2 tablets every 4 to 6 hours as needed for pain relief up to a maximum of 8 tablets per day. The lowest effective dose should be used for the shortest period of time.
Adults and adolescents (12 years and older): ULTRACET is not approved for use in patients below 12 years old.
Paediatric population: 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.
Treatment withdrawal: Do not stop use of ULTRACET abruptly. Withdrawal symptoms may be relieved by tapering the medication (see Treatment withdrawal under Precautions).
Special populations: Children below 16 years of age: The use of ULTRACET is contraindicated in children below 12 years of age (see Contraindications).
The safety and effectiveness of ULTRACET in children aged 12 to below 16 years of age has not been established (see Contraindications and Use in Children: Other risk factors for life-threatening respiratory depression in children).
Elderly (65 years of age and older): No overall differences with regard to safety or pharmacokinetics were noted between subjects ≥65 years of age and younger subjects. However, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal or cardiac function, of concomitant disease and multiple drug therapy.
Renal impairment: 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.
Hepatic impairment: The use of ULTRACET in patients with severe hepatic impairment is not recommended.
Administration: ULTRACET tablets are for oral administration.
ULTRACET can be administered without regard to food.

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 and signs: ULTRACET is a combination product. The clinical presentation of overdose may include the signs and symptoms of tramadol toxicity, paracetamol toxicity or both. The initial symptoms of tramadol overdosage may include respiratory depression and/or seizures. The initial symptoms seen within the first 24 hours following an paracetamol overdose may include: gastrointestinal irritability, anorexia, nausea, vomiting, malaise, pallor and diaphoresis.
Tramadol: Serious potential consequences of overdosage of the tramadol component are respiratory depression, lethargy, coma, seizure, cardiac arrest and death. In addition, cases of QT prolongation have been reported during overdose.
Paracetamol: Paracetamol in massive overdosage may cause hepatic toxicity in some patients. Early symptoms following a potentially hepatotoxic overdosage may include: 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.
Treatment: A single or multiple overdose with ULTRACET may be a potentially lethal polydrug overdose, and appropriate expert consultation, if available, is recommended.
While naloxone will reverse some, but not all, symptoms caused by overdosage with tramadol, the risk of seizures is also increased with naloxone administration. 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 treating an overdosage of ULTRACET, primary attention should be given to maintaining adequate ventilation along with general supportive treatment. Because strategies for the management of overdose are continually evolving, it is advisable to contact a poison control center (where available) to determine the latest recommendations for the management of an overdose. Hypotension is usually hypovolemic in etiology and should respond to fluids. Vasopressors and other supportive measures should be employed as indicated. A cuffed endo-tracheal tube should be inserted when necessary, to provide assisted respiration.
In adult and pediatric patients, any individual presenting with an unknown amount of paracetamol ingested or with a questionable or unreliable history about the time of ingestion should have a plasma paracetamol level drawn and be treated with acetylcysteine. If an assay cannot be obtained and the estimated paracetamol ingestion exceeds 7.5 to 10 grams for adults and adolescents or 150 mg/kg for children, dosing with N-acetylcysteine should be initiated and continued for a full course of therapy.

ULTRACET is contraindicated: in all children younger than 12 years of age; children younger than 18 years to treat pain after surgery to remove the tonsils and/or adenoids; in patients who have previously demonstrated hypersensitivity to tramadol, paracetamol, any other component of this product or opioids; in cases of acute intoxication with alcohol, hypnotics, narcotics, centrally acting analgesics, opioids or psychotropic drugs; in patients using monoamine oxidase inhibitors (MAOIs) concurrently or within the last 14 days; adolescents between 12 and 18 years who are obese or have conditions such as obstructive sleep apnea or severe lung disease, which may increase the risk of serious breathing problems; in patients with significant respiratory depression (see Precautions).

This preparation contains PARACETAMOL.
Do not take any other paracetamol containing medicines at the same time.

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).

Pregnancy: Tramadol has been shown to cross the placenta. There are no adequate and well-controlled studies in pregnant women. Safe use in pregnancy has not been established. ULTRACET is not recommended for pregnant women.
The use of opioids during childbirth might result in respiratory depression in the newborn infant.
Prolonged use of ULTRACET, or other opioids, during pregnancy may lead to neonatal opioid withdrawal syndrome. This risk is particularly increased during the last trimester of pregnancy.
Breast-feeding: ULTRACET is not recommended for breast-feeding mothers because its safety in infants and newborns has not been studied.
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. For this reason, breast-feeding is not recommended during treatment with ULTRACET.
Approximately 0.1% of the maternal dose of tramadol is excreted in breast milk. In the immediate post-partum period, for maternal oral daily dosage up to 400 mg, this corresponds to a mean amount of tramadol ingested by breast-fed infants of 3% of the maternal weight-adjusted dosage. For this reason tramadol should not be used during lactation or alternatively, breast-feeding should be discontinued during treatment with tramadol. Discontinuation of breast-feeding is generally not necessary following a single dose of tramadol.
Fertility: The effect of tramadol or tramadol/paracetamol combination on human fertility has not been evaluated.

Cutaneous hypersensitivity reactions including skin rashes, angioedema, Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis have been reported.
Throughout this section, adverse reactions are presented. Adverse reactions are adverse events that have been considered to be reasonably causally associated with the use of tramadol hydrochloride/paracetamol based on a comprehensive assessment of the available adverse event information. A causal relationship with tramadol hydrochloride/paracetamol cannot be reliably established in individual cases. Further, because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Clinical trial data: The safety of ULTRACET was evaluated in 3,175 patients, 16 to 90 years of age, who participated in a total of 21 clinical trials of which 20 were double-blind, controlled (i.e., placebo or active, or both) and 1 was open-label with no control group. These 20 double-blind, controlled trials comprised 11 multiple-dose and 9 single-dose. The duration of treatment ranged from one dose to up to 23 months. All patients received at least one dose of ULTRACET and provided safety data.
Placebo-controlled double-blind data - adverse reactions reported at ≥1% incidence: Sixteen of the 21 clinical trials were double-blind, placebo-controlled trials with a duration of treatment ranging from one dose to 91 days. Adverse reactions determined from all 21 clinical trials and reported in the 16 double-blind placebo-controlled clinical trials for ≥1% of ULTRACET-treated patients (N=1,669) and with an incidence greater than the rate in placebo-treated patients (N=1,531), are shown in Table 2. The most commonly occurring adverse reactions from the 16 placebo-controlled trials (>5% of patients) were nausea, dizziness, vomiting, headache, somnolence, and constipation. (See Table 2.)

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Placebo-controlled, comparator-controlled, and open-label clinical trial data - adverse reactions reported by ≥1% of ULTRACET-treated patients: Adverse reactions not reported in Table 2 that were reported by ≥1% of ULTRACET-treated patients (N=3,175) in the 21 clinical trials of ULTRACET are shown in Table 3. All patients received at least one dose of ULTRACET and provided safety data. (See Table 3.)

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Placebo-controlled, comparator-controlled, and open-label study data - adverse reactions reported at <1% incidence of ULTRACET-treated patients: Adverse reactions not reported previously, which were reported by <1% of ULTRACET-treated patients (N=3,175) in the previously mentioned clinical trial dataset are shown in Table 4. (See Table 4.)

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Adverse reactions reported with tramadol only: Table 5 lists the adverse reactions relating to the active moiety, tramadol, that were identified in clinical trials and/or postmarketing experience with tramadol but were not reported by any ULTRACET-treated patients in the ULTRACET clinical trials. (See Table 5.)

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Postmarketing data: In addition to the adverse reactions reported during clinical trials and listed previously, the following adverse reactions have been reported during postmarketing experience (Table 6). The frequencies are provided according to the following convention: Very common ≥1/10; Common ≥1/100 and <1/10; Uncommon ≥1/1000 and <1/100; Rare ≥1/10000 and <1/1000; Very rare <1/10000; Not known (cannot be estimated from the available data).
In Table 6, adverse reactions are presented by frequency category based on spontaneous reporting rates. (See Table 6.)

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Serotonin syndrome: (see Precautions).
Adrenal insufficiency: (see Precautions).
Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids. 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 casual 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.
Infertility: Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible.

Based on its pharmacodynamic and pharmacokinetic properties, tramadol and paracetamol exhibits a potential for pharmacodynamic and pharmacokinetic interactions. The various types of interaction, associated general recommendations and lists of examples are described 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 Table 7.)

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Incompatibilities: None known.
Instructions for Use and Handling and Disposal: Any unused ULTRACET should be disposed of in accordance with local requirements.

Store below 30°C in the original package.
Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store ULTRACET securely, in a location not accessible by others.
Shelf Life: 3 years.

Analgesics (Opioid)

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

B