Tramapan

TRAMAPAN tablets are available as white to off-white, round, biconvex film-coated tablets plain on both the surfaces. Each film-coated tablet contains 37.5mg tramadol hydrochloride and 325mg paracetamol.
Excipients/Inactive Ingredients: Colloidal silicon dioxide, magnesium stearate, maize starch, pre-gelatinised starch, sodium starch glycolate and Opadry White as film coat. The film coat contains HPMC 2910/Hypromellose, titanium dioxide and macrogol/PEG.

Pharmacotherapeutic group: Analgesics, Opioids in combination with non-opioid analgesics, ATC code: N02AJ13.
Pharmacology: Pharmacodynamics: Tramadol is a centrally acting opioid analgesic. It is a non-selective pure agonist at opioid receptors with a higher affinity for the μ receptor. In addition, 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.
Tramadol has an antitussive effect. In contrast to morphine, analgesic doses of tramadol over a wide range have no respiratory depressant effect. Also gastrointestinal motility is not affected. Effects on the cardiovascular system tend to be slight. The potency of tramadol is reported to be 10%-17% that of morphine. Paracetamol is another centrally acting analgesic. Although the exact site and mechanism of its analgesic action is not clearly defined, paracetamol appears to produce analgesia by elevation of the pain threshold. The potential mechanism may involve inhibition of the nitric oxide pathway mediated by a variety of neurotransmitter receptor including N-methyl-D-aspartate and Substance P.
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.
Pharmacokinetics: General: Tramadol is administered as a racemate and both the [+] and [-] forms of both tramadol and its M1 metabolite are detected in the circulation. Although tramadol is rapidly absorbed after administration, it 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 1.8h [(+)-Tramadol/(-)-Tramadol] and 0.9h (Paracetamol), respectively. Mean elimination half lives t1/2 are 5.1/4.7 h [(+)-Tramadol/(-)-Tramadol] and 2.5 h (Paracetamol).
Single and multiple oral dose pharmacokinetic studies of TRAMAPAN in volunteers showed no significant drug interactions between tramadol and paracetamol.
Absorption: Racemic tramadol is rapidly and almost completely absorbed after oral administration. The mean absolute bioavailability of a single 100mg oral dose is approximately 75%. With multiple dosing, bioavailability increases to approximately 90%.
Oral absorption of paracetamol following administration of TRAMAPAN 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: When TRAMAPAN 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 or the extent of absorption of either tramadol or paracetamol were not affected. The clinical significance of this difference is unknown.
Metabolism: Plasma concentration profiles for tramadol and its M1 metabolite measured following dosing of TRAMAPAN in volunteers showed no significant change compared to dosing with tramadol alone. Tramadol is extensively metabolized after oral administration. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as 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 as principal separate pathways: conjugation with glucuronide; conjugation with sulfate; and oxidation via the cytochrome, P450-dependent, mixed-function oxidase enzyme pathway.
Elimination: Tramadol and its metabolites are eliminated primarily by the kidney. 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: Preclinical Safety Data: 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.
Carcinogenicity/Mutagenicity: A slight but statistically significant increase in two common murine tumors, pulmonary and hepatic, were observed in a mouse carcinogenicity study with tramadol, particularly in aged mice (dosing orally up to 30 mg/kg 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.
Various animal bioassays on a weight-of-evidence basis have demonstrated no evidence of carcinogenic potential for paracetamol.
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.
Paracetamol has been found to have no mutagenic potential using the Ames Salmonella - Microsomal Activation Test, the Basic test on Drosophila germ cells, and the Micronucleus test on mouse bone marrow.
Impairment of Fertility/Effect on Reproduction: No effects on fertility were observed for tramadol at oral dose levels up to 50mg/kg in male rats and 75mg/kg in female rats.
Tramadol was evaluated in peri- and post-natal studies in rats. Progeny of rats receiving oral (gavage) dose levels of 50 mg/kg or greater had decreased weights, and pup survival was decreased early in lactation at 80mg/kg (6 to 10 times the maximum human dose). No toxicity was observed for progeny of rats receiving 8, 10, 20, 25 and 40 mg/kg. Maternal toxicity was observed at all dose levels of tramadol in this duty, but the effects on progeny were evident only at higher dose levels where maternal toxicity was more severe.
There was no effect on pregnancy or offspring when paracetamol alone was given at dose levels of 600 mg/kg/day in the diet of male rats for 60 days prior to mating and to female rats from 14 days before mating to the end of pregnancy. An oral dose of 600mg/kg/day produced no teratogenicity or embryotoxicity when given from days 6 through 15 of pregnancy. When paracetamol was given from day 16 of pregnancy through a 3-week lactation period, no deleterious effect was noted on pregnancy rate or on percent of live births, but a decrease in body weight gain and survival rate was noted among offspring of drug-treated females. In another study, paracetamol 250mg/kg/day did not affect fetal length or weight, incidence of resorptions, or placental weight.

TRAMAPAN is indicated for the treatment of moderate to severe pain.

The tablets should be taken orally, whole, not divided or chewed, with sufficient liquid, without regard to food. TRAMAPAN should under no circumstances be administered for longer than absolutely necessary. If long-term pain treatment with TRAMAPAN is necessary in view of the nature and severity of the illness, then careful and regular monitoring should be carried out (if necessary with breaks in treatment) to establish whether and to what extent further treatment is necessary.
Dosage - Adults and children 16 years of age and over: The maximum single dose of TRAMAPAN 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.
Treatment withdrawal: Do not stop use of TRAMAPAN abruptly. Withdrawal symptoms may be relieved by tapering the medication (see Treatment Withdrawal under Precautions).
Children below 16 years of age: The use of TRAMAPAN is contraindicated in children below 12 years of age (see Contraindications).
The safety and effectiveness of TRAMAPAN in children aged 12 to below 16 years of age has not been established (see Contraindications and Other risk factors for life-threatening respiratory depression in children under Precautions). Therefore, treatment is not recommended in this population.
Elderly (75 years of age and older): Elimination of the active components may be prolonged in elderly patients over 75 years of age. Therefore, if necessary the dosage interval may be extended according to the patients requirements.
Renal Insufficiency/Dialysis/Hepatic Insufficiency: The pharmacokinetics of the tramadol/paracetamol combination in patients with renal impairment has not been studied. Experience with tramadol suggests that impaired renal function results in a decreased rate and extent of excretion of tramadol. In patients with creatinine clearances of less than 30mL/min, it is recommended that the dosing interval of TRAMAPAN be increased not to exceed 2 tablets every 12 hours. The pharmacokinetics and tolerability of TRAMAPAN in patients with impaired hepatic function has not been studied. Tramadol and paracetamol are both extensively metabolized by the liver. The use of TRAMAPAN in patients with severe hepatic impairment is not recommended.

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: TRAMAPAN 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 overdose may include respiratory depression and/or seizures. The initial symptoms seen within the first 24 hours following a paracetamol overdose 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.
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 overdoses with TRAMAPAN may be a potentially lethal polydrug overdose, and immediate consultation with a regional poison control center or transfer to a hospital 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. Naloxone is not recommended in treating convulsions, since tramadol-induced convulsions were adversely affected by naloxone in animal experiments. In such cases diazepam should be given intravenously. Hemodialysis or hemofiltration is not expected to be helpful in an overdose because it removes less than 7% of the administered tramadol dose in a 4-hour dialysis period. In treating an overdosage of TRAMAPAN, primary attention should be given to maintaining adequate ventilation along with general supportive treatment. Keep open the respiratory tract (aspiration); maintain respiration and circulation depending on the symptoms. 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 adults and adolescents, hepatic toxicity may occur following ingestion of 7.5-10 grams in a period of eight hours or less. Regardless of the quantity of paracetamol reported to have been ingested, the paracetamol antidote n-acetylcysteine should be administered orally or intravenously as soon as possible, if possible within 10 hours after intoxication. Plasma samples to determine paracetamol plasma levels should be taken but results of assays should not be awaited before initiating treatment with n-acetylcysteine.

TRAMAPAN is contraindicated: in all children younger than 12 years of age.
In post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy.
In patients who have previously demonstrated hypersensitivity to tramadol, paracetamol or any other components (see Description) of this product or opioids.
In cases of acute intoxication with alcohol, hypnotics, centrally acting analgesics, opioids or psychotropic drugs.
In patients using monoamine oxidase inhibitors (MAOI) concurrently or within the last 14 days (see Interactions).
In patients with significant respiratory depression (see Precautions).

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 anoretics), tricyclic antidepressants (TCAs) and other tricyclic compounds (e.g., cyclobenzaprine, promethazine, etc), or opioids. Patients with epilepsy or those susceptible to seizures should only be treated with TRAMAPAN if there are compelling circumstances.
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 TRAMAPAN.
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 TRAMAPAN cautiously in patients at risk of respiratory depression. When large doses of tramadol are administered with anesthetic medications or alcohol, respiratory depression may result. Treat such cases 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 and Precautions).
CYP2D6 Ultra-rapid metabolism of tramadol: Patients who are CYP2D6 ultra-rapid metabolizers may convert tramadol to its active metabolite (M1) more rapidly and completely than other patients. This rapid conversion may result in higher than expected serum M1 levels which could lead to an increased risk of respiratory depression (see Symptoms and signs: Tramadol under Overdosage). 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: Metabolism 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).
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 TRAMAPAN 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).
Use with Central Nervous System (CNS) depressants, including alcohol: The concomitant use of tramadol (an active ingredient in TRAMAPAN) with CNS depressants, including alcohol, may cause additive CNS depressant effects, including profound sedation and respiratory depression.
TRAMAPAN should be used with caution and in reduced dosages when administered to patients receiving CNS depressants (see Interactions).
Increased intracranial pressure or head trauma: TRAMAPAN should be used with caution patients with increased intracranial pressure or head injury.
Drug dependence and potential for abuse: TRAMAPAN contains tramadol as an active ingredient. A portion of the analgesic effect of TRAMAPAN 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 TRAMAPAN and monitor all patients receiving TRAMAPAN 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).
TRAMAPAN may reduce psychic and physical dependence of the morphine-type (mopioid): TRAMAPAN 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. Tramadol is not suitable as a substitute in opioid-dependent patient. Although it is an opioid agonist, it cannot suppress morphine withdrawal symptoms. Dependence and abuse, including drug-seeking behaviours and taking illicit actions to obtain this drug are not limited to those patients with poor history of opioid dependence. In severe respiratory insufficiency, TRAMAPAN is not recommended.
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 TRAMAPAN 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.
Use with serotonergic drugs: Use TRAMAPAN 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 (see Interactions).
Renal impairment: TRAMAPAN 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 TRAMAPAN be increased not exceed 2 tablets every 12 hours.
Hepatic impairment: The use of TRAMAPAN in patients with severe hepatic impairment is not recommended.
Serious skin reactions: Serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), have been reported very rarely in patients receiving paracetamol. 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 TRAMAPAN, 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 TRAMAPAN and appropriate treatment (e.g. fluid restriction). During TRAMAPAN treatment, monitoring for signs and symptoms of hyponatremia is recommended for patients with predisposing risk factors.
Gastrointestinal conditions: Patients with disorders of the biliary tract or a history of biliary surgery should be monitored for potential development of acute pancreatitis.
Opioid induced hyperalgesia: Opioid induced hyperalgesia (OIH) is a paradoxical response to an opioid in which there is an increase in pain perception despite stable or increased opioid exposure. It differs from tolerance, in which higher opioid doses are required to achieve the same analgesic effect or treat recurring pain. OIH may manifest as increased levels of pain, more generalized pain (i.e., less focal), or pain from ordinary (i.e. nonpainful) stimuli (allodynia) with no evidence of disease progression. When OIH is suspected, the dose of opioid should be reduced or tapered off, if possible, or a change in opioid may be required.
Hyperprolactinemia: Long term opioid use may be associated with increased prolactin levels and decreased sex hormone levels. Symptoms may include galactorrhea, gynecomastia, impotence, decreased libido, infertility, or amenorrhea. If hyperprolactinemia is suspected, appropriate laboratory testing is recommended and discontinuation of treatment with TRAMAPAN should be considered.
Adrenal insufficiency: Adrenal insufficiency has been reported with opioid use, more often following long-term use. Symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, or low blood pressure. If adrenal insufficiency is suspected, appropriate laboratory testing is recommended and discontinuation of treatment with TRAMAPAN should be considered.
Precautions general: The recommended dose of TRAMAPAN should not be exceeded.
TRAMAPAN should not be co-administered with other tramadol or paracetamol-containing compounds.
Effects of Ability to Drive and Use Machines: Even when used according to instructions, TRAMAPAN may impair mental or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery.

Pregnancy and Breast-feeding: Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition or post-natal development (see Pharmacology: Toxicology: Non-clinical Information: Preclinical Safety Data under Actions). Tramadol has been shown to cross the placenta. There is inadequate evidence available on the safety of tramadol in human pregnancy. Therefore TRAMAPAN should not be used in pregnant women. The effect of TRAMAPAN if any, on the later growth, development, and functional maturation of the child is unknown.
The use of opioids during childbirth might result in respiratory depression in the newborn infant.
Prolonged use of TRAMAPAN, or other opioids, during pregnancy may lead to neonatal opioid withdrawal syndrome. This risk is particularly increased during the last trimester of pregnancy.
TRAMAPAN 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 TRAMAPAN 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 TRAMAPAN.
Fertility: The effect of tramadol or tramadol/paracetamol combination on human fertility has not been evaluated.

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 TRAMAPAN 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 TRAMAPAN and provided safety data.
Placebo-controlled double-blind data - adverse reactions reported at ³1% 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 TRAMAPAN-treated patients (N=1,669) and with an incidence greater than the rate in placebo-treated patients (N=1,531), are shown in Table 1. The most commonly occurring adverse reactions from the 16 placebo-controlled trials (>5% of patients) were nausea, dizziness, vomiting, headache, somnolence, and constipation. (See Tables 1 and 2.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

Placebo-controlled, comparator-controlled, and open-label study data - adverse reactions reported at <1% incidence of TRAMAPAN-treated Patients: Adverse reactions not previously reported, which were reported by <1% of TRAMAPAN-treated patients (N=3,175) in the previously mentioned clinical trial dataset are shown in Table 3.
Placebo-controlled, comparator-controlled, and open-label clinical trial data - adverse reactions reported by ≥1% of TRAMAPAN-treated patients: Adverse reactions not reported in Table 1 that were reported by ≥1% of TRAMAPAN-treated patients (N=3,175) in the 21 clinical trials of TRAMAPAN are shown in Table 2. All patients received at least one dose of TRAMAPAN and provided safety data. (See Tables 3a and 3b.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

Adverse reactions reported with tramadol only: Table 4 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 TRAMAPAN-treated patients in the TRAMAPAN clinical trials. (See Table 4.)

Click on icon to see table/diagram/image

Postmarketing data: In addition to the adverse reactions reported during clinical trials and previously listed, the following adverse reactions have been reported during postmarketing experience (Table 5). 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 5, adverse reactions are presented by frequency category based on spontaneous reporting rates. (See Table 5.)

Click on icon to see table/diagram/image

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 Tables 6a and 6b.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

Incompatibilities: Not applicable.

Store in a cool (below 30°C), dry place. Protect from light.

Analgesics (Opioid)

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

POM