Tramadol

(tra' ma dole)

PCaution when used during lactation : Caution when used during pregnancy

LCI  : Contraindicated in lactation

Molecule Info

 | See TERMINOLOGY & ABBREVIATIONS |
Indication(s)
Tramadol Hydrochloride is indicated for the management of moderate to moderately severe chronic pain in adults; Extended-Release formulations provide round-the-clock effect for an extended period of time.
Dosage & Administration
Tramadol Hydrochloride Immediate-Release Tablet

Adults (17 years of age and over)

For patients with moderate to moderately severe chronic pain not requiring rapid onset of analgesic effect, the tolerability of tramadol hydrochloride tablets can be improved by initiating therapy with a titration regimen. The total daily dose may be increased by 50 mg as tolerated every 3 days to reach 200 mg/day (50 mg q.i.d.). After titration, Tramadol Hydrochloride 50 to 100 mg can be administered as needed for pain relief every 4 to 6 hours not to exceed 400 mg/day.


For the subset of patients for whom rapid onset of analgesic effect is required and for whom the benefits outweigh the risk of discontinuation due to adverse events associated with higher initial doses, Tramadol Hydrochloride 50 mg to 100 mg can be administered as needed for pain relief every 4 to 6 hours, not to exceed 400 mg per day.

Place Tramadol Hydrochloride tablet on the tongue until it completely disintegrates and then swallow it. It may take approximately one minute for the tablet to disintegrate on the tongue. Tablet may be taken with or without water.

Individualization of Dose
Good pain management practice dictates that the dose be individualized according to patient need using the lowest beneficial dose. Studies with tramadol in adults have shown that starting at the lowest possible dose and titrating upward will result in fewer discontinuations and increased tolerability.

In all patients with creatinine clearance less than 30 mL/min, it is recommended that the dosing interval of Tramadol Hydrochloride be increased to 12 hours, with a maximum daily dose of 200 mg. Since only 7% of an administered dose is removed by hemodialysis, dialysis patients can receive their regular dose on the day of dialysis.

The recommended dose for adult patients with cirrhosis is 50 mg every 12 hours.

In general, dose selection for an elderly patient over 65 years old should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy. For elderly patients over 75 years old, total dose should not exceed 300 mg/day.

Tramadol Hydrochloride Extended-Release Tablet

Tramadol Hydrochloride Extended-Release is an extended-release formulation intended for once a day dosing in adults aged 18 years and older. Tramadol Hydrochloride Extended-Release may be available in 150mg strength. The tablets must be swallowed whole with liquid and must not be split, chewed, dissolved or crushed. Chewing, crushing or splitting the tablet could result in the uncontrolled delivery of tramadol, in overdose and death.

Do not administer Tramadol Hydrochloride Extended-Release at a dose exceeding 300 mg per day. Do not use Tramadol Hydrochloride Extended-Release more than once daily or concomitantly with other tramadol products.

Patients Not Currently on Tramadol Immediate-Release Products

Initiate treatment with Tramadol Hydrochloride Extended-Release at a dose of 100 mg once daily and titrated up as necessary to 150 mg, 200 mg and 300 mg every five days to achieve a balance between relief of pain and tolerability.

Patients Currently on Tramadol Immediate-Release Products

Calculate the 24-hour tramadol IR dose and initiate a total daily dose of Tramadol Hydrochloride Extended-Release rounded down to the next lowest 100 mg increment. The dose may subsequently be individualized according to patient need. Due to limitations in flexibility of dose selection with Tramadol Hydrochloride Extended-Release, some patients maintained on tramadol IR products may not be able to convert to Tramadol Hydrochloride Extended-Release.

Patients 65 Years of Age and Older

Initiate dosing of an elderly patient (over 65 years of age) should be initiated cautiously, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy. Tramadol Hydrochloride Extended-Release should be administered with even greater caution in patients over 75 years, due to the greater frequency of adverse events seen in this population.

Patients with Renal Impairment

The limited availability of dose strengths and once daily dosing of Tramadol Hydrochloride Extended-Release do not permit the dosing flexibility required for safe use in patients with severe renal impairment. Do not use Tramadol Hydrochloride Extended-Release in patients with creatinine clearance less than 30 mL/min.

Patients with Hepatic Impairment

The limited availability of dose strengths and once daily dosing of tramadol hydrochloride extended-release capsules do not permit the dosing flexibility required for safe use in patients with severe hepatic impairment. Do not use Tramadol Hydrochloride Extended-Release in patients with severe hepatic impairment (Child-Pugh Class C).

Discontinuation of Treatment

Withdrawal symptoms may occur if Tramadol Hydrochloride Extended-Release is discontinued abruptly. Clinical experience with tramadol suggests that withdrawal symptoms may be reduced by tapering Tramadol Hydrochloride Extended-Release.

Tramadol Hydrochloride Parenteral
Moderate to severe pain
Adult: IM/IV inj over 2-3 min/IV infusion: 50-100 mg given every 4-6 hr.
Elderly: Lower initial dose. Max: 300 mg daily (>75 yr).

Hepatic impairment: Severe: Increase dosage interval to 12 hr.

Postoperative pain
Adult: IM/IV inj over 2-3 min/IV infusion: Initially, 100 mg followed by 50 mg every 10-20 min if necessary up to 250 mg for the 1st hr. Maintenance: 50-100 mg every 4-6 hr. Max: 600 mg daily.
Elderly: Lower initial dose. Max: 300 mg daily (>75 yr).

Hepatic impairment: Severe: increase dosage interval to 12 hr. 

Tramadol Hydrochloride Rectal
Moderate to severe pain
Adult: 100 mg suppository up to 4 times daily.
Elderly: Lower initial dose. Max: 300 mg daily (>75 yr).

Hepatic impairment: Severe: Increase dosage interval to 12 hr.

Special Populations: A dosage interval of 12 hrs is recommended in severe hepatic/renal impairment.

Incompatibility: Incompatible with injections of diazepam, diclofenac sodium, indometacin, midazolam, piroxicam, phenylbutazone, aciclovir, clindamycin and lysine aspirin if mixed in the same syringe.

Overdosage
Serious potential consequences of overdosage are respiratory depression, lethargy, coma, seizure, cardiac arrest and death. Fatalities have been reported in post marketing in association with both intentional and unintentional overdose with tramadol. In treating an overdose, primary attention should be given to maintaining adequate ventilation along with general supportive treatment. While naloxone will reverse some, but not all, symptoms caused by overdosage with tramadol, the risk of seizures is also increased with naloxone administration. In animals convulsions following the administration of toxic doses of tramadol could be suppressed with barbiturates or benzodiazepines but were increased with naloxone. Naloxone administration did not change the lethality of an overdose in mice. 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.
Contraindications
Tramadol Hydrochloride should not be administered to patients who have previously demonstrated hypersensitivity to tramadol, any other component of this product or other opioids. Tramadol Hydrochloride is contraindicated in any situation where other opioids are contraindicated, including acute intoxication with any of the following: alcohol, hypnotics, narcotics, centrally acting analgesics, opioids or psychotropic drugs. Tramadol Hydrochloride may worsen central nervous system and respiratory depression in these patients.
Warnings & Precautions

Seizure Risk

Seizures have been reported in patients receiving tramadol within the recommended dosage range. Spontaneous post-marketing reports indicate that seizure risk is increased with doses of tramadol above the recommended range. Concomitant use of tramadol increases the seizure risk in patients taking:

  • Selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors (SNRIs) antidepressants or anorectics,
  • Tricyclic antidepressants (TCAs), and other tricyclic compounds (e.g., cyclobenzaprine, promethazine, etc.),
  • Other opioids,
  • MAO inhibitors,
  • Neuroleptics, or
  • Other drugs that reduce the seizure threshold.

Risk of seizures may also increase in patients with epilepsy, those with a history of seizures, or in patients with a recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections).

In tramadol overdose, naloxone administration may increase the risk of seizure.

Anaphylactoid Reactions

Serious and rarely fatal anaphylactoid reactions have been reported in patients receiving therapy with tramadol. When these events do occur it is often following the first dose. Other reported allergic reactions include pruritus, hives, bronchospasm, angioedema, toxic epidermal necrolysis and Stevens-Johnson syndrome. Patients with a history of anaphylactoid reactions to codeine and other opioids may be at increased risk and therefore should not receive Tramadol Hydrochloride Extended-Release.

Respiratory Depression

Administer Tramadol Hydrochloride cautiously in patients at risk for respiratory depression. In these patients alternative non-opioid analgesics should be considered. If 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.

Interaction With Central Nervous System (CNS) Depressants, Including Alcohol and Drugs of Abuse

Tramadol may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression. Use Tramadol Hydrochloride Extended-Release with caution and in reduced dosages when administered to patients receiving CNS depressants such as alcohol, opioids, anesthetic agents, narcotics, phenothiazines, tranquilizers or sedative hypnotics. Tramadol Hydrochloride Extended-Release increases the risk of CNS and respiratory depression in these patients. Alcohol-containing beverages should not be consumed by patients using Tramadol Hydrochloride Extended-Release

Suicide Risk

  • Do not prescribe Tramadol Hydrochloride Extended-Release for patients who are suicidal or addiction-prone. Consideration should be given to the use of non-narcotic analgesics in patients who are suicidal or depressed.
  • Prescribe Tramadol Hydrochloride Extended-Release with caution for patients with a history of misuse and/or are taking CNS-active drugs including tranquilizers or antidepressant drugs, or alcohol in excess, and patients who suffer from emotional disturbance or depression.
  • Tell your patients not to exceed the recommended dose and to limit their intake of alcohol.

Serotonin Syndrome Risk

The development of a potentially life-threatening serotonin syndrome may occur with use of tramadol products, including Tramadol Hydrochloride Extended-Release , particularly with concomitant use of serotonergic drugs such as SSRIs, SNRIs, TCAs, MAOIs and triptans, with drugs which impair metabolism of serotonin (including MAOIs) and with drugs which impair metabolism of tramadol (CYP2D6 and CYP3A4 inhibitors). This may occur within the recommended dose.

Serotonin syndrome 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, diarrhea).

Patients with Increased Intracranial Pressure or Head Trauma

Use Tramadol Hydrochloride Extended-Release with caution in patients with increased intracranial pressure or head injury. The respiratory depressant effects of opioids include carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure, and may be markedly exaggerated in these patients. Additionally, 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 Hydrochloride Extended-Release.

Use in Ambulatory Patients

Tramadol Hydrochloride Extended-Release may impair the mental and or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. Caution patients initiating therapy with Tramadol Hydrochloride Extended-Release or those whose dose has been increased to refrain from potentially hazardous activities until it is established that their mental and physical abilities are not significantly impaired.

Use With MAO Inhibitors and SSRIs

Use Tramadol Hydrochloride Extended-Release with great caution in patients taking monoamine oxidase inhibitors. Animal studies have shown increased deaths with combined administration. Concomitant use of Tramadol Hydrochloride Extended-Release with MAO inhibitors or SSRI's increases the risk of adverse reactions, including seizure and serotonin syndrome.

Withdrawal Symptoms

Withdrawal symptoms may occur if Tramadol Hydrochloride Extended-Release is discontinued abruptly. These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely hallucinations. Clinical experience with other formulations of tramadol suggests that withdrawal symptoms may be reduced by tapering Tramadol Hydrochloride Extended-Release when discontinuing tramadol therapy.

Misuse, Abuse and Diversion of Opioids

Tramadol Hydrochloride Extended-Release contains tramadol, an opioid agonist of the morphine-type. Such drugs are sought by drug abusers and people with addiction disorders and are subject to criminal diversion.

Tramadol can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing Tramadol Hydrochloride Extended-Release in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion.

Tramadol Hydrochloride Extended-Release could be abused by crushing, chewing, snorting, or injecting the dissolved product. These practices will result in the uncontrolled delivery of the opioid and pose a significant risk to the abuser that could result in overdose and death.

Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. The development of addiction to opioid analgesics in properly managed patients with pain has been reported to be rare. However, data are not available to establish the true incidence of addiction in chronic pain patients.

Healthcare professionals should contact their State Professional Licensing Board, or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.

Risk of Overdosage

Serious potential consequences of overdosage with Tramadol Hydrochloride Extended-Release are central nervous system depression, respiratory depression and death. In treating an overdose, primary attention should be given to maintaining adequate ventilation along with general supportive treatment.

Acute Abdominal Conditions

The administration of Tramadol Hydrochloride Extended-Release may complicate the clinical assessment of patients with acute abdominal conditions.

Adverse Drug Reactions
An orally swallowed immediate release tablet of tramadol was administered to 550 patients during the double-blind or open-label extension periods in U.S. studies of chronic nonmalignant pain. Of these patients, 375 were 65 years old or older. Table 2 reports the cumulative incidence rate of adverse reactions by 7, 30 and 90 days for the most frequent reactions (5% or more by 7 days). The most frequently reported events were in the central nervous system and gastrointestinal system. Although the reactions listed in the table are felt to be probably related to tramadol administration, the reported rates also include some events that may have been due to underlying disease or concomitant medication. The overall incidence rates of adverse experiences in these trials were similar for tramadol and the active control groups, acetaminophen 300 mg with codeine phosphate 30 mg, and aspirin 325 mg with codeine phosphate 30 mg, however, the rates of withdrawals due to adverse events appeared to be higher in the tramadol groups.

Incidence 1% to less than 5%, possibly causally related:
the following lists adverse reactions that occurred with an incidence of 1% to less than 5% in clinical trials, and for which the possibility of a causal relationship with tramadol exists.

Body as a Whole: Malaise.

Cardiovascular: Vasodilation.

Central Nervous System: Anxiety, Confusion, Coordination disturbance, Euphoria, Miosis, Nervousness, Sleep disorder.

Gastrointestinal: Abdominal pain, Anorexia, Flatulence.

Musculoskeletal: Hypertonia.

Skin: Rash.

Special Senses: Visual disturbance.

Urogenital: Menopausal symptoms, Urinary frequency, Urinary retention.

Incidence less than 1%, possibly causally related: the following lists adverse reactions that occurred with an incidence of less than 1% in clinical trials and/or reported in post-marketing experience.

Body as a Whole: Accidental injury, Allergic reaction, Anaphylaxis, Death, Suicidal tendency, Weight loss, Serotonin syndrome (mental status change, hyperreflexia, fever, shivering, tremor, agitation, diaphoresis, seizures and coma).

Cardiovascular: Orthostatic hypotension, Syncope, Tachycardia.

Central Nervous System: Abnormal gait, Amnesia, Cognitive dysfunction, Depression, Difficulty in concentration, Hallucinations, Paresthesia, Seizure, Tremor.

Respiratory: Dyspnea.

Skin: Stevens-Johnson syndrome/Toxic epidermal necrolysis, Urticaria, Vesicles.

Special Senses: Dysgeusia.

Urogenital: Dysuria, Menstrual disorder.

Other adverse experiences, causal relationship unknown: A variety of other adverse events were reported infrequently in patients taking tramadol during clinical trials and/or reported in post-marketing experience. A causal relationship between tramadol and these events has not been determined. However, the most significant events are listed below as alerting information to the physician.

Cardiovascular: Abnormal ECG, Hypertension, Hypotension, Myocardial ischemia, Palpitations, Pulmonary edema, Pulmonary embolism.

Central Nervous System: Migraine, Speech disorders.

Gastrointestinal: Gastrointestinal bleeding, Hepatitis, Stomatitis, Liver failure.

Laboratory Abnormalities: Creatinine increase, Elevated liver enzymes, Hemoglobin decrease, Proteinuria.

Sensory: Cataracts, Deafness, Tinnitus.
Drug Interactions
In vitro studies indicate that tramadol is unlikely to inhibit the CYP3A4-mediated metabolism of other drugs when tramadol is administered concomitantly at therapeutic doses. 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.

Use With Carbamazepine
Patients taking carbamazepine may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of Tramadol Hydrochloride and carbamazepine is not recommended.

Use With Quinidine
Tramadol is metabolized to M1 by CYP2D6. Quinidine is a selective inhibitor of the isoenzyme, so that concomitant administration of quinidine and tramadol results in increased concentrations of tramadol and reduced concentrations of M1. The clinical consequences of these findings are unknown. In vitro drug interaction studies in human liver microsomes indicate that tramadol has no effect on quinidine metabolism.

Use With Inhibitors of CYP2D6
In vitro drug interaction studies in human liver microsomes indicate that concomitant administration with inhibitors of CYP2D6 such as fluoxetine, paroxetine, and amitriptyline could result in some inhibition of the metabolism of tramadol.

Use With Cimetidine
Concomitant administration with cimetidine does not result in clinically significant changes in tramadol pharmacokinetics. Therefore, no alteration of the Tramadol Hydrochloride dosage regimen is recommended.

Use With MAO Inhibitors
Interactions with MAO Inhibitors, due to interference with detoxification mechanisms, have been reported for some centrally acting drugs.

Use With Digoxin and Warfarin
Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity and alteration of warfarin effect, including elevation of prothrombin times.
Food Interaction
Tramadol Hydrochloride Extended-Release may be taken without regard to food.
Use in Special population & Pregnancy Category (FDA)
Pregnancy, Teratogenic Effects: Pregnancy Category C.

Tramadol has been shown to be embryotoxic and fetotoxic in mice, (120 mg/kg or 360 mg/m2), rats (≥25 mg/kg or 150 mg/m2) and rabbits (≥75 mg/kg or 900 mg/m2) at maternally toxic dosages, but was not teratogenic at these dose levels. These dosages on a mg/m2 basis are 1.4, ≥0.6, and ≥3.6 times the maximum daily human dosage (246 mg/m2) for mouse, rat and rabbit, respectively.

No drug-related teratogenic effects were observed in progeny of mice (up to 140 mg/kg or 420 mg/m2), rats (up to 80 mg/kg or 480 mg/m2) or rabbits (up to 300 mg/kg or 3600 mg/m2) treated with tramadol by various routes. Embryo and fetal toxicity consisted primarily of decreased fetal weights, skeletal ossification and increased supernumerary ribs at maternally toxic dose levels. Transient delays in developmental or behavioral parameters were also seen in pups from rat dams allowed to deliver. Embryo and fetal lethality were reported only in one rabbit study at 300 mg/kg (3600 mg/m2), a dose that would cause extreme maternal toxicity in the rabbit. The dosages listed for mouse, rat and rabbit are 1.7, 1.9 and 14.6 times the maximum daily human dosage (246 mg/m2), respectively.

Non-teratogenic Effects
Tramadol was evaluated in peri- and post-natal studies in rats. Progeny of dams receiving oral dose levels of 50 mg/kg (300 mg/m2 or 1.2 times the maximum daily human tramadol dosage) or greater had decreased weights, and pup survival was decreased early in lactation at 80 mg/kg (480 mg/m2 or 1.9 and higher the maximum daily human dose).

There are no adequate and well-controlled studies in pregnant women. Tramadol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Neonatal seizures, neonatal withdrawal syndrome, fetal death and still birth have been reported during post-marketing.

Labor and Delivery
Tramadol Hydrochloride should not be used in pregnant women prior to or during labor unless the potential benefits outweigh the risks. Safe use in pregnancy has not been established. Chronic use during pregnancy may lead to physical dependence and post-partum withdrawal symptoms in the newborn. 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 labor.

The effect of tramadol if any, on the later growth, development, and functional maturation of the child is unknown.

Nursing Mothers
Tramadol Hydrochloride is not recommended for obstetrical preoperative medication or for post-delivery analgesia in nursing mothers because its safety in infants and newborns has not been studied. Following a single IV 100 mg dose of tramadol, the cumulative excretion in breast milk within 16 hours postdose was 100 µg of tramadol (0.1% of the maternal dose) and 27 µg of M1.

Pediatric Use
The safety and efficacy of Tramadol Hydrochloride in patients under 16 years of age have not been established. The use of Tramadol Hydrochloride in the pediatric population is not recommended.

Geriatric Use
In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy. In patients over 75 years of age, daily doses in excess of 300 mg are not recommended .

A total of 455 elderly (65 years of age or older) subjects were exposed to tramadol in controlled clinical trials. Of those, 145 subjects were 75 years of age and older.

In studies including geriatric patients, treatment-limiting adverse events were higher in subjects over 75 years of age compared to those under 65 years of age. Specifically, 30% of those over 75 years of age had gastrointestinal treatment-limiting adverse events compared to 17% of those under 65 years of age. Constipation resulted in discontinuation of treatment in 10% of those over 75.
Pharmacology

CLINICAL PHARMACOLOGY

Pharmacodynamics
Tramadol Hydrochloride is a centrally acting synthetic opioid analgesic in an orally disintegrating tablet form. Although its mode of action is not completely understood, from animal tests, at least two complementary mechanisms appear applicable: binding of parent and M1 metabolite to µ-opioid receptors and weak inhibition of reuptake of norepinephrine and serotonin.

Opioid activity is due to both low affinity binding of the parent compound and higher affinity binding of the O-demethylated metabolite M1 to µ-opioid receptors. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in µ-opioid binding. Tramadol-induced analgesia is only partially antagonized by the opiate antagonist naloxone in several animal tests. The relative contribution of both tramadol and M1 to human analgesia is dependent upon the plasma concentrations of each compound.

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. Analgesia in humans begins approximately within one hour after administration and reaches a peak in approximately two to three hours.

Apart from analgesia, tramadol administration may produce a constellation of symptoms (including dizziness, somnolence, nausea, constipation, sweating and pruritus) similar to that of other opioids. In contrast to morphine, tramadol has not been shown to cause histamine release. At therapeutic doses, tramadol has no effect on heart rate, left-ventricular function or cardiac index. Orthostatic hypotension has been observed.

Pharmacokinetics
The analgesic activity of tramadol is due to both parent drug and the M1 metabolite. Tramadol is administered as a racemate and both the [−] and [+] forms of both tramadol and M1 are detected in the circulation. Tramadol is well absorbed orally with an absolute bioavailability of 75%. Tramadol has a volume of distribution of approximately 2.7 L/kg and is 20% bound to plasma proteins. Tramadol is extensively metabolized by a number of pathways, including CYP2D6 and CYP3A4, as well as by conjugation of parent and metabolites. One metabolite, M1, is pharmacologically active in animal models. The formation of M1 is dependent upon CYP2D6 and as such is subject to inhibition, which may affect the therapeutic response. Tramadol and its metabolites are excreted primarily in the urine with observed plasma half-lives of 6.3 and 7.4 hours for tramadol and M1, respectively. Linear pharmacokinetics have been observed following multiple doses of 50 and 100 mg to steady-state.

No difference has been identified in systemic exposure (AUC), peak exposure (Cmax), time to peak exposure (Tmax), and apparent elimination half-life (t1/2) of tramadol and metabolites M1 and M5 between administration of Tramadol Hydrochloride with and without water and Ultram®.

Absorption:
Racemic tramadol is rapidly and almost completely absorbed after oral administration. The mean absolute bioavailability of a 100 mg oral dose is approximately 75%. The mean peak plasma concentration of racemic tramadol and M1 occurs at two and three hours, respectively, after administration in healthy adults. In general, both enantiomers of tramadol and M1 follow a parallel time course in the body following single and multiple doses although small differences (~ 10%) exist in the absolute amount of each enantiomer present.

Distribution:
The volume of distribution of tramadol was 2.6 and 2.9 liters/kg in male and female subjects, respectively, following a 100 mg intravenous dose. The binding of tramadol to human plasma proteins is approximately 20% and binding also appears to be independent of concentration up to 10 µg/mL. Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range.

Metabolism:
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 metabolites. The remainder is excreted either as unidentified or as unextractable metabolites. The major metabolic pathways appear to be N- and O- demethylation and glucuronidation or sulfation in the liver. One metabolite (O-desmethyltramadol, denoted M1) is pharmacologically active in animal models. Formation of M1 is dependent on CYP2D6 and as such is subject to inhibition, which may affect the therapeutic response.

Approximately 7% of the population has reduced activity of the CYP2D6 isoenzyme of cytochrome P-450. These individuals are "poor metabolizers" of debrisoquine, dextromethorphan, tricyclic antidepressants, among other drugs. Based on a population PK analysis of Phase I studies in healthy subjects, concentrations of tramadol were approximately 20% higher in "poor metabolizers" versus "extensive metabolizers," while M1 concentrations were 40% lower. Concomitant therapy with inhibitors of CYP2D6 such as fluoxetine, paroxetine and quinidine could result in significant drug interactions. In vitro drug interaction studies in human liver microsomes indicate that inhibitors of CYP2D6 such as fluoxetine and its metabolite norfluoxetine, amitriptyline and quinidine inhibit the metabolism of tramadol to various degrees, suggesting that concomitant administration of these compounds could result in increases in tramadol concentrations and decreased concentrations of M1. The full pharmacological impact of these alterations in terms of either efficacy or safety is unknown. Concomitant use of SEROTONIN re-uptake INHIBITORS and MAO INHIBITORS may enhance the risk of adverse events, including seizure and serotonin syndrome.

Elimination:
Tramadol is eliminated primarily through metabolism by the liver and the metabolites are eliminated primarily by the kidneys. The mean terminal plasma elimination half-lives of racemic tramadol and racemic M1 are 6.3 ± 1.4 and 7.4 ± 1.4 hours, respectively. The plasma elimination half-life of racemic tramadol increased from approximately six hours to seven hours upon multiple dosing.

Special Populations

Renal:
Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. In patients with creatinine clearances of less than 30 mL/min, adjustment of the dosing regimen is recommended. The total amount of tramadol and M1 removed during a 4-hour dialysis period is less than 7% of the administered dose.

Hepatic:
Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver, resulting in both a larger area under the concentration time curve for tramadol and longer tramadol and M1 elimination half-lives (13 hrs. for tramadol and 19 hrs. for M1). In cirrhotic patients, adjustment of the dosing regimen is recommended.

Geriatric:
Healthy elderly subjects aged 65 to 75 years have plasma tramadol concentrations and elimination half-lives comparable to those observed in healthy subjects less than 65 years of age. In subjects over 75 years, maximum serum concentrations are elevated (208 vs. 162 ng/mL) and the elimination half-life is prolonged (7 vs. 6 hours) compared to subjects 65 to 75 years of age. Adjustment of the daily dose is recommended for patients older than 75 years.

Gender:
Following a single oral dose of Tramadol Hydrochloride to healthy volunteers, no gender effect was observed. The AUC and Cmax values for Tramadol Hydrochloride were similar in males and females. Dosage adjustment based on gender is not recommended.

The absolute bioavailability of tramadol was 73% in males and 79% in females. The plasma clearance was 6.4 mL/min/kg in males and 5.7 mL/min/kg in females following a 100 mg dose of tramadol. 

CLINICAL STUDIES

Tramadol Hydrochloride is an orally disintegrating tablet, but there are no studies that indicate that its onset of action is faster than tramadol tablets.

An orally swallowed immediate release tablet of tramadol has been given in single oral doses of 50, 75 and 100 mg to patients with pain following surgical procedures and pain following oral surgery (extraction of impacted molars).

In single-dose models of pain following oral surgery, pain relief was demonstrated in some patients at doses of 50 mg and 75 mg. A dose of 100 mg of orally swallowed immediate release tablet of tramadol tended to provide analgesia superior to codeine sulfate 60 mg, but it was not as effective as the combination of aspirin 650 mg with codeine phosphate 60 mg.

An orally swallowed immediate release tablet of tramadol has been studied in three long-term controlled trials involving a total of 820 patients, with 530 patients receiving an orally swallowed immediate release tablet of tramadol. Patients with a variety of chronic painful conditions were studied in double-blind trials of one to three months duration. Average daily doses of approximately 250 mg of an orally swallowed immediate release tablet of tramadol in divided doses were generally comparable to five doses of acetaminophen 300 mg with codeine phosphate 30 mg daily, five doses of aspirin 325 mg with codeine phosphate 30 mg daily, or two to three doses of acetaminophen 500 mg with oxycodone hydrochloride 5 mg daily.

Titration Trials
In a randomized, blinded clinical study with 129 to 132 patients per group, a 10-day titration to a daily orally swallowed immediate release tablet of tramadol dose of 200 mg (50 mg q.i.d.), attained in 50 mg increments every 3 days, was found to result in fewer discontinuations due to dizziness or vertigo than titration over only 4 days or no titration.

ATC Classification
N02AX02 - tramadol; Belongs to the class of other opioids. Used to relieve pain.

Brand/Product Info


Total Products : 53                                                     
Brand Name Manufacturer/Marketer Composition Dosage Form Pack Size & Price
ANADOL Square Pharmaceuticals Ltd. Tramadol 50mg Capsule 4x10's: 322.80 MRP
ANADOL INJ Square Pharmaceuticals Ltd. Tramadol 100mg/2 ml IM/IV Injection 2x5's: 201.40 MRP
ANADOL SR Square Pharmaceuticals Ltd. Tramadol 100mg Capsule 3x10's: 362.70 MRP
ANADOL SUPP Square Pharmaceuticals Ltd. Tramadol 100mg Suppository 4x5's: 302.00 MRP
DOLAN Techno Drugs Tramadol hydrochloride 50mg Capsule 30's: 180.00 MRP
DOLAN Injection Techno Drugs Tramadol hydrochloride INN 100mg/2ml Injection 10 amps: 180.00 MRP
DOLONIL The Acme Laboratories Ltd. Tramadol hydrochloride 50mg Capsule 20's: 150.60 MRP
DOLONIL Injection The Acme Laboratories Ltd. Tramadol hydrochloride (I/V) 100mg/2ml Injection 5 amps:100.35 MRP
DOLONIL SR The Acme Laboratories Ltd. Tramadol hydrochloride 100mg Capsule (sustained release) 16's: 224.96 MRP
DOLORAN Sandoz/Novartis Tramadol Hydrochloride BP 50mg Capsule 30's: MRP 255.00
DOLORAN Injection Sandoz/Novartis Tramadol Hydrochloride 100mg/2ml Injection 5 amps: 200.00 MRP
DOLORAN PRT Sandoz/Novartis Tramadol Hydrochloride BP 100mg Tablet (per rectal) 30's: MRP 450.00
DOLORAN SUPPOSITORY Sandoz/Novartis Tramadol hydrochloride 100mg Suppository 10's: MRP 200.00
DOLOREX Biopharma Laboratories Ltd Tramadol hydrochloride 50mg & 100mg Capsule 50mg x30's, 100mg x10's: 225.90 & 130.50 MRP
DOLOREX Injection Biopharma Laboratories Ltd Tramadol hydrochloride 100mg/2ml Injection 5 amps: 100.40 MRP
DOLOTRAM Sun Pharmaceutical (Bangladesh) Ltd. Tramadol hydrochloride 50mg Capsule 30's: 195.00 MRP
FUDOL Pharmasia Limited Tramadol hydrochloride 50mg Capsule 30's: 225.90 MRP
IMADOL 50 Delta Pharma Limited Tramadol hydrochloride 50mg Capsule 30's: 225.00 MRP
KADOL Kemiko Pharmaceuticals Ltd Tramadol hydrochloride 50mg Capsule 30's: 210.00 MRP
LUCIDOL Beximco Pharmaceuticals Ltd Tramadol Hydrochloride 50mg Capsule 30's: 225.00 MRP
LUCIDOL INJECTION Beximco Pharmaceuticals Ltd Tramadol Hydrochloride 100mg/2ml Ampoule Injection 5's: 100.00 MRP
LUCIDOL SUPPOSITORY Beximco Pharmaceuticals Ltd Tramadol Hydrochloride 100mg Suppository 5's: 75.00 MRP
MURTRUM Monico Pharma Limited Tramadol hydrochloride 100mg/2ml Injection 5 amps: 100.00 MRP
OPIDOL Navana Pharmaceuticals Limited Tramadol hydrochloride 50mg & 100mg Capsule 50mg x30's, 100mg x20's: 180.60 & 200.80. MRP
PENDOL Alco Pharma Ltd Tramadol hydrochloride 50mg Capsule 30's: 180.00 MRP
RAPIDOL Renata Limited Tramadol hydrochloride 100mg/2ml Injection 5 amps: 125.00 MRP
SYNDOL Healthcare Pharmacuticals Ltd. Tramadol Hydrochloride 100mg/2ml Injection 30's MRP 255 Tk
SYNDOL Injection Healthcare Pharmacuticals Ltd. Tramadol Hydrochloride BP 50 mg Injection 5's: 125.00 MRP
TAMADOL Mystic Pharmaceuticals Limited Tramadol hydrochloride 50mg Capsule 30's: 217.50 MRP
TENDIA ACI Ltd. Tramadol hydrochloride 50mg Capsule 30's: 225.90 IP
TENDIA ER ACI Ltd. Tramadol hydrochloride 100mg Capsule 30's: 421.50 MRP
TENDIA Injection ACI Ltd. Tramadol hydrochloride 100mg/2ml Injection 5 amps: 100.35 IP
TRAMAL Grunenthal/UniMed Tramadol hydrochloride 100mg Suppository 5's: 204.02 MRP
TRAMAL Rtd Grunenthal/UniMed Tramadol hydrochloride 100mg Capsule 30's: 791.50 MRP
TRAMANIL Ziska Pharmaceuticals Ltd. Tramadol hydrochloride 100mg/2ml Injection 5 amps: 100.00 MRP
TRANAL Opsonin Pharma Limited Tramadol hydrochloride 50mg Capsule 20's: 150.00 MRP
TRANAL Injection Opsonin Pharma Limited Tramadol hydrochloride 100mg/2ml Injection 5 amps: 100.00 MRP
TRANAL Suppository Opsonin Pharma Limited Tramadol hydrochloride 100mg Suppository 10's: 150.00 MRP
TROL Apex Pharmaceuticals Ltd. Tramadol hydrochloride 50mg Capsule 30's: 135.00 MRP
TRUMEN General Pharmaceuticals Ltd Tramadol hydrochloride 50mg Capsule 40's: 301.20 MRP
ULTRADOL Ad-din pharmaceuticals Ltd. Tramadol hydrochloride 50mg Capsule 30's: 225.00 MRP
UTRAMAL Unimed & Unihealth Manufacturers Ltd. Tramadol hydrochloride 50mg Capsule 30's: 300.00 MRP
UTRAMAL Injection Unimed & Unihealth Manufacturers Ltd. Tramadol hydrochloride 100mg/2ml Injection 5 amps: 225.00 MRP
UTRAMAL Rtd. Unimed & Unihealth Manufacturers Ltd. Tramadol hydrochloride 100mg Capsule (extended release) 30's: 600.00 MRP
Winpain 1 Incepta Pharmaceuticals Limited Tramadol Hydrochloride 50 mg/ml Injection 1x5's:MRP 75 Tk
Winpain 2 Incepta Pharmaceuticals Limited Tramadol Hydrochloride 100mg/2ml Injection 1x5's:MRP 100 Tk
Winpain 50 Incepta Pharmaceuticals Limited Tramadol Hydrochloride BP 50 mg Capsule 40's:MRP 300 Tk
Winpain ER Incepta Pharmaceuticals Limited Tramadol Hydrochloride BP 100mg Capsule 20's:MRP 280 Tk
XTRAPEL Beacon Pharmaceuticals Limited Tramadol hydrochloride 50mg & 100mg Capsule 50ml: 90.00 MRP
XTRAPEL-100 Beacon Pharmaceuticals Limited Tramadol hydrochloride 100mg/2ml Injection 5 amps: 100.35 MRP
ZYDOL Novo Healthcare and Pharma Ltd. Tramadol hydrochloride 100mg/2ml Injection 5 amps: 90.00 MRP
ZYDOL 50 Novo Healthcare and Pharma Ltd. Tramadol hydrochloride 50mg Capsule 30's: 225.00 MRP
ZYDOL SR Novo Healthcare and Pharma Ltd. Tramadol hydrochloride 100mg Capsule (sustained release) 30's: 360.00 MRP

 

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