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Tramadol Hydrochloride 50mg capsules are olive green/yellow capsule shell imprinted TRM on the cap and 50 on the body, containing a white to off-white powder.
Tramadol is a centrally acting synthetic analgesic of the aminocyclohexanol group with opioid-like effects. It is not derived from natural sources, nor is it chemically related to opiates. Although its mode of action is not completely understood, from animal tests, at least two complementary mechanisms appear applicable: binding to μ-opioid receptors and inhibition of re-uptake of noradrenaline and serotonin. The opioid-like activity of tramadol derives from low affinity binding of the parent compound to μ-opioid receptors and higher affinity binding of the principal active metabolite, mono O-desmethyltramadol (denoted M1) to μ-opioid receptors. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in μ-opioid binding. The contribution to human analgesia of tramadol relative to M1 is unknown.
Several animal tests have shown that anti-nociception induced by tramadol is only partially antagonised by naloxone. In addition, tramadol has been shown to inhibit reuptake of noradrenaline and serotonin in vitro, as have some other opioid analgesics. These latter mechanisms may contribute independently to the overall analgesic profile of tramadol.
The analgesic effect is dose-dependant but the relationship between serum concentrations and analgesic effect varies considerably between individuals. In one study, the median serum concentration of tramadol required for effective post-operative analgesia was 300 ng/mL, with individual values ranging from 20 to 990 ng/mL.
Apart from analgesia, tramadol may produce other symptoms similar to that of opioids including; dizziness, somnolence, nausea, constipation, sweating and pruritus. However, tramadol causes significantly less respiratory depression than morphine. In contrast to morphine, tramadol has not been shown to cause histamine release. At therapeutic doses, tramadol has no clinically significant effect on heart rate, left ventricular function or cardiac index. Orthostatic changes in blood pressure have been observed.
Tramadol is rapidly and almost completely absorbed after oral administration of 50mg capsules following a mean absorption delay (t0) of approximately 30 minutes. The absorption half life (t½) is 23 ± 10 minutes. After oral administration of two 50mg capsules, the mean absolute bioavailability (fabs) is 68-72%, and the peak serum level (Cmax) is reached approximately two hours after administration. Oral administration of tramadol with food does not significantly affect its rate or extent of absorption. Therefore tramadol can be administered without regard to food.
After repeated oral administration of 50mg and 100mg tramadol capsules at six hourly intervals, steady state is reached 30 to 36 hours after the first administration and the bioavailability is greater than 90%. The plasma concentrations at steady state exceeded by 52% and 36% those extrapolated from the single dose administration studies with 50mg and 100mg capsules respectively. This can be explained by first pass metabolic saturation.
The volume of distribution of tramadol is 2-3 L/kg following a 100mg intravenous dose. The binding of tramadol to human plasma proteins is approximately 20% and binding also appears to be independent of concentration up to 10 g/mL. Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range. Although not confirmed in humans, tramadol has been shown in rats to cross the blood-brain barrier.
Tramadol crosses the placenta. Very small amounts of tramadol and M1 are found in breast milk (0.1% and 0.02% respectively, of the administered dose).
Tramadol is extensively metabolised after oral administration. Approximately 10% of the dose is excreted in the urine as unchanged drug, whereas 60% or more 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. Only M1 is pharmacologically active. Production of M1 is dependent on the CYP2D6 isoenzyme of cytochrome P450.
Tramadol and its metabolites are excreted mainly via the renal route, with a cumulative renal excretion (tramadol and metabolites) of approximately 95%. The proportion of unchanged tramadol excreted by this route is greater in elderly subjects (34.9% and 23% respectively of the dose administered by the intravenous and oral route in the preceding study) than in young subjects (13.6% and 10.1% of the dose); mean doses obtained for all of the studies including those using other formulations.
Biliary excretion was shown to be of little importance. In a study of cholecystectomised patients, the cumulative biliary excretion of unchanged tramadol proved to be 240 times lower than its renal excretion and this relationship was 1/390 and 1/70 for the M1 and M1 conjugated metabolites respectively.
The half-life of tramadol is in the order of 5-7 hours in young adults, with relatively modest coefficients of variation. Following repeated administration, the increase in bioavailability is accompanied by an increase in renal excretion.
The half-life of M1 corresponds approximately to that of unchanged tramadol (6-8 hours).
Elimination of tramadol and M1 is impaired in patients with hepatic or renal impairment (see WARNINGS AND PRECAUTIONS). In patients with hepatic impairment, the mean half-life of tramadol was found to be 13 h (range up to 19 h ), and the mean half-life of M1 was 19 h (range up to 36 h). In patients with severe renal impairment (creatinine clearance < 5mL/min) the mean half-life of tramadol was 11 h (range up to 20 h), and the mean half life of M1 was 17 h (range up to 43 h).
In the elderly (age over 75 years), the volume of distribution of tramadol is decreased by 25% and clearance is decreased by 40%. As a result, tramadol Cmax and total exposure are increased by 30% and 50%, respectively, but the half-life of tramadol is only slightly prolonged (by 15%).
Relief of moderate to severe pain.
The dose of tramadol should be titrated to the severity of the pain and the clinical response of the individual patient.
The recommended dosage of tramadol in adults and adolescents over the age of 12 years is as follows:
For the treatment of moderate pain, tramadol 50 may be sufficient for the first dose, followed by tramadol 50 - 100mg two or three times daily as required.
For moderate to severe pain, tramadol 100mg is usually required for the first dose, followed by tramadol 50 - 100mg every four to six hours daily as required.
The maximum daily dose should not exceed 400mg per day.
Paediatric Use - the use of tramadol is not recommended, in children under 12 years of age.
Use in the Elderly - changes in renal and/or hepatic function in the elderly may require adjustment of dose. In subjects over the age of 75 years, serum concentrations are slightly elevated and the elimination half-life is slightly prolonged. Subjects in this age group are also expected to vary more widely in their ability to tolerate adverse drug effects. Daily doses of 300mg are not recommended in patients over 75 years.
Renal insufficiency - impaired renal function results in a decreased rate and extent of excretion of tramadol and M1. In patients with creatinine clearances of less than 30ml/min, adjustment of the dosage regimen is recommended. In these patients, the dosage interval of tramadol should be increased to twelve hours. Since only 7% of an administered dose is removed by haemodialysis, dialysis patients can receive their regular dose on the day of dialysis. Tramadol is not recommended in patients with severe renal impairment (creatinine clearance <10ml/min.).
Hepatic insufficiency - In hepatic impairment, the initial dose of Tramadol is 50mg. Depending on the severity of the impairment and individual clinical response, the recommended dosage interval (4-6 hours) may require to be extended, and/or the dose level titrated as required. The recommended dose interval for patients with cirrhosis is every 12 hours.
Tramadol is contraindicated in:
Tramadol must not be used for narcotic withdrawal treatment.
Respiratory Depression - tramadol should be administered cautiously in patients at risk of respiratory depression. When large doses of tramadol are administered with anaesthetic medications or alcohol, respiratory depression may result. Cases of intra-operative respiratory depression, usually with large intravenous doses of tramadol and with concurrent administration of respiratory depressants, have been reported.
Increased Intracranial Pressure or Head Trauma - tramadol should be used with caution in patients with increased intracranial pressure or head injury. Pupillary changes (miosis) from tramadol may obscure the existence, extent, or course of intracranial pathology. Clinicians should also maintain a high index of suspicion for adverse drug reaction when evaluating altered mental status in these patients if they are receiving tramadol.
Acute Abdominal Conditions - The administration of tramadol may complicate the clinical assessment of patients with acute abdominal conditions.
Renal and Hepatic Disease - Impaired renal function results in a decreased rate and extent of excretion of tramadol and M1. In patients with creatinine clearances of less than 30mL/min, dosage reduction is recommended (see Dosage and Administration). Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver. In cirrhotic patients, dosage reduction is recommended (see Dosage and Administration). With the prolonged half-life in these conditions, achievement of steady state is delayed, so that it may take several days for elevated plasma concentrations to develop.
Patients physically dependent on opioids - tramadol is not recommended as a substitute in opioid dependent patients. Although tramadol is an opiate-agonist, it cannot suppress opioid withdrawal symptoms. Animal experiments have shown that under certain circumstances the administration of tramadol may provoke a withdrawal syndrome in opioid-dependent monkeys.
Because of the difficulty in assessing dependence in patients who have previously received substantial amounts of opioid medications, caution should therefore be used in the administration of tramadol to such patients. Cases of dependence and abuse of tramadol have been reported rarely.
Risk of seizure - Convulsions have been reported in patients receiving tramadol at the recommended dose levels. The risk may be increased when doses of tramadol exceed the recommended upper daily dose limit (400mg). In addition, tramadol may increase the seizure risk in patients taking other medication that lowers the seizure threshold (see Interactions). Patients with epilepsy or those susceptible to seizures should only be treated with tramadol if there are compelling circumstances.
Anaphylactoid reactions - Serious and rarely fatal anaphylactoid reactions have been reported in patients receiving tramadol. These reactions often occur following the first dose. Other reported reactions include pruritus, hives, bronchospasm and angioedema.
Intraoperative use - In one study using nitrous oxide/tramadol anaesthetic technique (with only intermittent administration of enflurane "as required"), tramadol was reported to enhance intraoperative recall. Hence its use during potentially very light levels of general anaesthesia should be avoided.
Two recent studies of tramadol administration during anaesthesia comprising continuous administration of isoflurane did not show clinical lightening of anaesthetic depth or intraoperative recall. Therefore, providing the current practice of administering continuous, potent (volatile or intravenous) anaesthetic agent is followed, tramadol may be used intraoperatively in the same way as other analgesic agents are routinely used.
Long-term use - Tramadol has been studied in controlled clinical trials for periods of up to three months. In one small-uncontrolled study, patients with cancer pain received a dose of 150 mg tramadol per day for up to six months. Beyond six months no clinical studies investigating the safety and efficacy of tramadol are available.
When tramadol treatment of pain is required long-term, careful and regular monitoring should be carried out to establish whether and to what extent ongoing treatment is necessary.
Carcinogenicity/Mutagenicity/Teratogenicity - 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.
A slight, but statistically significant increase in two common murine tumours, pulmonary and hepatic, was observed in a mouse carcinogenicity study, particularly in aged mice (dosing orally up to 30mg/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.
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 is Pregnancy Category C. There are no adequate and well-controlled studies with tramadol in pregnant women. Tramadol should be used during pregnancy only if the potential benefit outweighs the potential risk to the foetus because safe use in pregnancy has not been established.
Tramadol has been shown to be embryotoxic and foetotoxic in mice, rats and rabbits in maternally toxic doses 3 to 15 times the maximum human dose or higher (120mg/kg in mice, 25mg/kg or higher in rats and 75mg/kg or higher in rabbits), but was not teratogenic at these dose levels. No harm to the foetus due to tramadol was seen at doses that were not maternally toxic.
No drug-related teratogenic effects were observed in progeny of mice, rats or rabbits treated with tramadol by various routes (up to 140mg/kg for mice, 80mg/kg for rats or 300mg/kg for rabbits). Embryo and foetal toxicity consisted primarily of decreased foetal weights, skeletal ossification and increased supernumerary ribs at maternally toxic dose levels. Transient delays in development or behavioural parameters were also seen in pups from rat dams allowed to deliver. Embryo and foetal lethality were reported only in one rabbit study at 300mg/kg, a dose that would cause extreme maternal toxicity in the rabbit.
In peri- and post-natal studies in rats, progeny of dams receiving oral (gavage) dose levels of 50mg/kg or greater had decreased weights and pup survival was decreased early in lactation at 80mg/kg (6-10 times the maximum human dose). No toxicity was observed for progeny of dams receiving 8, 10, 20, 25 or 40mg/kg. Maternal toxicity was observed at all dose levels, but effects on progeny were evident only at higher dose levels where maternal toxicity was more severe.
Tramadol is not recommended for obstetric preoperative medication or for post-delivery analgesia in nursing mothers because its safety in infants and newborns has not been studied. Low levels of tramadol have been detected in breast milk. Following a single intravenous 100mg dose of tramadol, the cumulative excretion in breast milk within 16 hours post-dose was 100 mcg of tramadol (0.1% of the maternal dose) and 27 mcg of M1.
Tramadol should not be used in pregnant women prior to or during labour unless the potential benefits outweigh the potential risks, because safe use in pregnancy has not been established. Tramadol has been shown to cross the placenta. The mean ratio of serum tramadol in the umbilical veins compared to maternal veins was 0.83 for 40 women given tramadol during labour.
The effect of tramadol, if any, on the later growth, development, and functional maturation of the child is unknown.
Tramadol may cause sedation. Use caution if intending to drive or operate machinery.
Adverse reactions that may occur after administration of tramadol resemble those known to occur with opioids. Adverse reactions were recorded in 13,802 patients from trials with different formulations of tramadol. The nature and incidence of reactions (in CIOMS format where common = 1/100 and <1/10; uncommon = 1/1000 and <1/100; rare = 1/10,000 and <1/1000; and very rare = < 1/10,000) were as follows:
| Cardiovascular | |
|---|---|
| Uncommon: | orthostatic dysregulation (tendency to collapse, and cardiovascular collapse) and tachycardia, increase in blood pressure, bradycardia |
Respiratory |
|
| Very rare: | worsening of asthma (causality not established), respiratory depression (when the recommended doses are considerably exceeded and other respiratory depressant substances are administered concomitantly) |
Gastrointestinal |
|
| Very common: | nausea |
| Common: | Constipation |
| Uncommon: | dyspepsia, diarrhoea, abdominal pain, flatulence, urge to vomit |
| Rare: | changes in appetite, |
| Very rare: | increase in liver enzyme values |
Neurological |
|
| Very common: | Dizziness |
| Common: | autonomic nervous effects (mainly dry mouth, perspiration), sedation, headache, asthenia, fatigue |
| Uncommon: | Trembling |
| Rare: | elevated mood, sensory effects, hallucinations, confusion, coordination disturbance, sleep disturbance, nightmares, motor system weakness, changes in appetite, tremor, respiratory depression, seizures |
Hypersensitivity and skin |
|
| Common: | sweating |
| Uncommon: | skin reactions, pruritus, rash |
| Rare: | shock reactions, anaphylaxis, allergic reactions |
Genitourinary |
|
| Rare: | micturition disorders (difficulty in passing urine and urinary retention) |
Special senses |
|
| Rare: | visual disturbance (blurred vision) |
The incidence of "non-specific CNS irritation" (dizziness), "autonomic nervous
effects" (perspiration), "orthostatic dysregulation (tendency to collapse and
cardiovascular collapse) and tachycardia" and "nausea/urge to vomit/vomiting"
was significantly increased with rapid intravenous administration and also
tended to be dose dependent.
Drug abuse and dependence - although tramadol can produce drug dependence of the μ-opioid type (like codeine or dextropropoxyphene) and potentially may be abused, there has been little evidence of abuse in clinical experience to date. In clinical trials, tramadol produced some effects similar to an opioid, and at supratherapeutic doses was recognised as an opioid in subjective/behavioural studies. Tolerance development has been reported to be relatively mild and withdrawal, when present, is not considered to be as severe as that produced by other opioids. Symptoms of withdrawal reactions, similar to those occurring during opiate withdrawal, may occur as follows: agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor, and gastrointestinal symptoms. Part of the activity of tramadol is thought to be derived from its active metabolite, which is responsible for some delay in onset of activity and some extension of the duration of μ-opioid activity. Delayed μ-opioid activity is believed to reduce a drug's abuse potential.
Use with CNS depressants - tramadol should be used with caution and in reduced dosages when administered to patients receiving CNS depressants such as alcohol, opioids, anaesthetic agents, phenothiazines, tranquillisers or sedative hypnotics.
The combination of tramadol with mixed opiate agonists/antagonists (eg. buprenorphine, pentazocine) is not advisable because the analgesic effect of a pure agonist may theoretically be reduced in such circumstances.
Drugs which reduce the seizure threshold - Tramadol can induce convulsions and increase the potential for selective serotonin re-uptake inhibitors, tricyclic antidepressants, antipsychotics and other seizure threshold lowering agents to cause convulsions.
Use with other serotonergic agents - The presence of another drug that increases serotonin by any mechanism should alert the treating physician to the possibility of an interaction. In isolated cases there have been reports of serotonin syndrome in a temporal connection with the therapeutic use of tramadol in combination with other serotonergic medicines such as selective serotonin reuptake inhibitors (SSRIs). Signs of serotonin syndrome may be, for example, confusion, agitation, fever, sweating, ataxia, hyperreflexia, myoclonus and diarrhoea. Withdrawal of the serotonergic medicines usually brings about a rapid improvement. Drug treatment depends on the nature and severity of the symptoms.
Use with MAO Inhibitors - tramadol should not be used in patients who are taking MAO inhibitors or who have taken them within the last fourteen days since tramadol inhibits the uptake of noradrenaline and serotonin.
Drug-drug interactions - Caution should be exercised during concomitant treatment with tramadol and coumarin derivatives (eg. Warfarin) due to reports of increased international normalised ratio (INR) and ecchymoses in some patients
Tramadol does not appear to induce its own metabolism in humans, since observed maximal plasma concentrations after multiple oral doses are higher than expected based on single-dose data. Tramadol is a mild inducer of selected drug metabolism pathways measured in animals.
Concomitant administration of tramadol with carbamazepine causes a significant increased in tramadol metabolism, presumably through metabolic induction by carbamazepine. Patients receiving chronic carbamazepine doses of up to 800mg daily may require up to twice the recommended dose of tramadol.
Tramadol is metabolised to M1 by the CYP2D6 P450 isoenzyme. Quinidine is a selective inhibitor of that isoenzyme so that concomitant administration of quinidine and tramadol results in increased concentrations of tramadol and reduced concentrations of M1. The clinical consequences of this effect have not been fully investigated.
Concomitant administration of tramadol with cimetidine does not result in clinically significant changes in tramadol pharmacokinetics. Therefore no alteration of the tramadol dosage regimen is recommended.
Other drugs known to inhibit the CYP3A4 isoenzyme of cytochrome P450, such as ketoconazole and erythromycin, may inhibit the metabolism (via N-demethylation) of tramadol and probably the metabolism of M1. The clinical importance of such an interaction has not been studied.
Few cases of overdose with tramadol have been reported.
Serious potential consequences of overdosage are respiratory depression and seizure. Naloxone will reverse some, but not all symptoms caused by overdosage with tramadol, so that general supportive treatment is recommended. Adequate ventilation should be maintained. Haemodialysis is not expected to be helpful because it removes only a small percentage of the administered dose. Convulsions occurring in mice following the administration of toxic doses of tramadol could be suppressed with barbiturates or benzodiazepines, but were increased with naloxone. Naloxone did not change the lethality of an overdose in mice.
Tramadol Hydrochloride capsules 50mg should be stored below 25°C.
Prescription-only Medicine
Tramadol Hydrochloride 50mg capsules-packs of 100 capsules.
Excipients include croscarmellose sodium, microcrystalline cellulose, lactose monohydrate, magnesium sterate, ferric oxide, gelatin, indigo carmine, titanium dioxide, erythrosine, butyl alcohol, lecithin, methylated spirits, shellac, simeticone and water.
AFT Pharmaceuticals Ltd
P O Box 33-203
Takapuna
AUCKLAND
Telephone: 09 488 0232
Email: customer.service@aftpharm.com
20 November 2007