Tramicet

Coated: A yellow color film coated elliptical tablet, one side impressed with 'YSP', and 'T/A' on the other side. "
Click on icon to see table/diagram/image
"
Ingredients: Each film coated tablet contains: Paracetamol 325 mg, Tramadol HCl 37.5 mg.

Pharmacotherapeutic group: Analgesics, Opioids in combination with non-opioid analgesics. ATC code: N02AJ13.
Pharmacology: Pharmacodynamics: 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: Tramadol has a slower absorption and longer half-life when compared to paracetamol. Single and multiple dose pharmacokinetics of Tramicet showed no significant drug interactions between tramadol and 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 t1/2 are 5.1/4.7 h [(+)Tramadol/(-)-Tramadol] and 2.5 h (paracetamol).
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 Tramicet tablets occur at approximately two and three hours, respectively, post-dose in healthy adults.
Oral absorptions of paracetamol following administration of Tramicet 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 Tramicet with food has no significant effect on the peak plasma concentration or extent of absorption of either tramadol or paracetamol, so Tramicet 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 protein is approximately 20%. Paracetamol appears to be widely distributed throughout most body tissue 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: Plasma concentration profiles for tramadol and its M1 metabolite measured following dosing of Tramicet 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 of 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.
Paracetamol is primarily metabolized in the liver by first-order kinetics and involves three principle separate pathways: a) Conjugation with glucuronide, b) Conjugation with sulphate, c) Oxidation via cytochrome P450 enzyme pathway.
Excretion: Tramadol and its metabolite are eliminated primarily by the kidneys. 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 Tramicet.
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 sulphate conjugates in a dose-dependent manner. Less than 9% of paracetamol is excreted unchanged in the urine.

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

Adults and children 16 years of age and over: The maximum single dose of Tramicet 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): Tramicet is not approved for use in patients below 12 years old.
Paediatric population: The safety and efficacy of Tramicet has not been studied in the paediatric population. Therefore, use of Tramicet is not recommended in patients under 12 years of age.
Treatment withdrawal: Do not stop use of Tramicet abruptly. Withdrawal symptoms may be relieved by tapering the medication.
Special populations: Children below 16 years of age: The use of Tramicet is contraindicated in children below 12 years of age. The safety and effectiveness of Tramicet in children aged 12 to below 16 years of age has not been established.
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 Tramicet be increased not to exceed 2 tablets every 12 hours.
Hepatic impairment: The use of Tramicet in patients with severe hepatic impairment is not recommended.
Mode of Administration: Tramicet tablets are for oral administration and can be administered without regard to food.

Overdose: 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: 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 seizure. The initial symptoms seen within the first 24 hours following a paracetamol overdose may include: gastrointestinal irritability, anorexia, nausea, vomiting, malaise, pallor and diaphoresis.
Tramadol: Serious potential consequence 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 or 72 hours post-ingestion.
Treatment: A single or multiple overdose with Tramicet 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.
In treating an overdosage of Tramicet, 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 of the management of an overdose. Hypotension is usually hypovolemic in aetiology and should respond to fluids. Vasopressors and other supportive measures should be employed as indicated. A cuffed endotracheal tube should be inserted when necessary to provide assisted respiration.
In adults and paediatric 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.

Tramicet 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.

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

Other risk factors for life-threatening respiratory depression in children: Life-threatening respiratory depression and death have occurred in children who received tramadol. Based upon post-marketing reports with tramadol, children younger than 12 years of age may be more susceptible to the respiratory depressant effects of tramadol. 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. Because of the risk of life-threatening respiratory depression and death, avoid the use of Tramicet 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.
Use with central nervous system (CNS) depressants including alcohol: The concomitant use of tramadol with CNS depressants, including alcohol, may cause additive CNS depressant effects, including profound sedation and respiratory depression. Tramicet should be used with caution and in reduced dosages when administered to patients receiving CNS depressants.
Drug dependence and potential for abuse: Upon repeated administration of opioids, tolerance, physical dependence, and psychological dependence may develop, even at recommended dosages. Tramicet 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.
Serotonin syndrome with concomitant use of serotonergic drugs: Use Tramicet with great caution in patients taking serotonergic drugs including SSRIs. Concomitant use of tramadol with serotonergic drugs including SSRIs increases the risk of adverse events, including seizure and serotonin syndrome.
Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concurrent use of Tramicet with serotonergic drugs (see Interactions). 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 Tramicet 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.
Respiratory depression: Administer Tramicet 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 Tramicet 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 anaesthetic 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.
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. 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.
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.
Seizure: 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: 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 convulsion may also increase in patients with epilepsy, those with a history of seizure, 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.
Anaphylactoid reactions: Patients with a history of anaphylactoid reactions to codeines and other opioids may be at increased risk and therefore, should not receive Tramicet.
Increased intracranial pressure or head trauma: Tramicet should be used with caution in patients with increased intracranial pressure or head injury.
Treatment withdrawal: Withdrawal symptoms may occur if Tramicet is discontinued abruptly. Panic attacks, severe anxiety, hallucinations, paraesthesia, 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.
Renal Impairment: In patients with creatinine clearance of less than 30 ml/min, it is recommended that the dosing interval of Tramicet be increased not to exceed 2 tablets every 12 hours. Tramicet is not recommended in patients with creatinine clearance of less than 10 ml/min.
Hepatic Impairment: The use of Tramicet in patients with severe hepatic impairment is not recommended.
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 Tramicet, 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 Tramicet and appropriate treatment (e.g. fluid restriction). During Tramicet treatment, monitoring for signs and symptoms of hyponatremia is recommended for patients with predisposing risk factors.
Risks from Concomitant Use with Benzodiazepines: Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Tramicet 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 Tramicet 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.
The recommended dose of Tramicet should not be exceeded.
Tramicet should not be co-administered with other tramadol or paracetamol-containing products.
Effects on Ability to Drive and Use Machine: Tramicet may impair mental or physical abilities require for the performance of potentially hazardous tasks such as driving a car or operating machinery.
Use in Children: The safety and efficacy of Tramicet has not been studied in the paediatric population. Therefore, use of Tramicet is not recommended in patients under 12 years of age.

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. Tramicet is not recommended for pregnant women.
The use of opioids during childbirth might result in respiratory depression in the newborn infant. Prolonged use of Tramicet or other opioids during pregnancy may lead to neonatal opioid withdrawal syndrome. This risk is particularly increased during the last trimester of pregnancy.
Lactation: Tramicet is not recommended for breast-feeding mothers because its safety in infants and newborns has not been studied. 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.

The most commonly reported undesirable effects during the clinical trials performed with the paracetamol/tramadol combination were nausea, dizziness and somnolence, observed in more than 10% of the patients.
Cardiovascular system disorders: Uncommon: hypertension, palpitations, tachycardia, arrhythmia.
Central and peripheral nervous system disorders: Very common: dizziness, somnolence. Common: headache, trembling. Uncommon: involuntary muscular contractions, paraesthesia, tinnitus. Rare: ataxia, convulsions, syncope.
Psychiatric disorders: Common: confusion, mood changes (anxiety, nervousness, euphoria), sleep disorders. Uncommon: depression, hallucinations, nightmares, amnesia. Rare: drug dependence.
Vision disorders: Rare: blurred vision.
Respiratory system disorders: Uncommon: dyspnoea. Rare: Respiratory depression.
Gastrointestinal disorders: Very common: nausea. Common: vomiting, constipation, dry mouth, diarrhoea, abdominal pain, dyspepsia, flatulence. Uncommon: dysphagia, melaena.
Liver and biliary system disorders: Uncommon: hepatic transaminases increase.
Skin and appendages disorders: Common: sweating, pruritus. Uncommon: dermal reactions (e.g. rash, urticaria).
Body as a whole: Uncommon: shivers, hot flushes, thoracic pain.
Metabolism and nutrition disorders: Unknown: hypoglycaemia.
Post marketing surveillance: Very rare: abuse; Cutaneous hypersensitivity reactions including skin rashes, angioedema, Stevens-Johnson syndrome/Toxic Epidermal Necrolysis have been reported; Serotonin syndrome; Adrenal insufficiency; Androgen deficiency; Infertility.

Use with inhibitors of CYP3A4: The concomitant use of Tramicet and an inhibitor of CYP3A4 can increase the plasma concentration of tramadol and may result in a greater amount of metabolism via CYP2D6 and greater levels of M1.
Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir).
Use with CYP3A4 Inducers: The concomitant use of Tramicet and an inducer of CYP3A4 can decrease the plasma concentration of tramadol, resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to tramadol. Examples: Rifampin, carbamazepine, phenytoin.
Use with Benzodiazepines and Other Central Nervous System (CNS) Depressants including alcohol: The concomitant use of tramadol with central nervous system depressants, such as benzodiazepines and other sedatives/hypnotics, anesthetic agents, phenothiazines, tranquilizers, opioids or alcohol, may produce additive CNS depressant effects, such as profound sedation and respiratory depression. If concomitant use of Tramicet with a CNS depressant is clinically necessary, prescribe the lowest effective dosages and minimum duration for both drugs, and follow patients closely for signs of respiratory depression.
Use with Serotonergic Drugs: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Examples: Examples of serotonergic drugs are selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g. mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Use with Monoamine Oxidase Inhibitors (MAOIs): The concomitant use of Tramicet with MAOIs, or use within 14 days of their discontinuation, is contraindicated due to the increased risk of seizures and serotonin syndrome. MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity. Examples: Phenelzine, tranylcypromine, linezolid.
Use with Flucloxacillin: High anion gap metabolic acidosis (HAGMA) from pyroglutamic acid (5-oxoprolinemia) has been reported with concomitant use of therapeutic doses of acetaminophen and flucloxacillin.
Use with Warfarin: As medically appropriate, periodic evaluation of prothrombin time should be performed when Tramicet and these agents are administered concurrently due to reports of increased International Normalized Ratio (INR) in some patients.
Use with Inhibitors of CYP2D6: Concomitant administration with inhibitors of CYP2D6 could result in some inhibition of the metabolism of tramadol. Examples: Quinidine, fluoxetine, paroxetine, amitriptyline and bupropion.
Use with Cimetidine: Concomitant administration of tramadol and cimetidine does not result in clinically significant changes in tramadol pharmacokinetics.

Instructions for Use and Handling and Disposal: Any unused Tramicet 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 Tramicet 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