Drug Name

Tramadol

Generic Name

Tramadol hydrochloride (TRA-ma-dole HYE-droe-KLOR-ide)

Manufacturer / Distributor

Teva Pharmaceuticals USA

Dosage Form

TABLET, FILM COATED

Route Of Administration

ORAL

Imprint Code

93;58

Size

12mm

Alternatives

Pain
Vicodin, Naprosyn (Naproxen), Oxycodone, Morphine, Percocet, OxyContin

Drug Uses

Tramadol is used to relieve pain, including pain after surgery. The long-acting tablets are used for chronic ongoing pain. The effects of tramadol are similar to those of narcotic analgesics. Although tramadol is not classified as a narcotic, it may become habit-forming, causing mental or physical dependence.

Contains

Tramadol hydrochloride tablets are a centrally acting analgesic. The chemical name for Tramadol hydrochloride is cis-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol hydrochloride.
Tramadol hydrochloride is a white, bitter, crystalline and odorless powder. It is readily soluble in water and ethanol and has a pKa of 9.41. The n-octanol/water log partition coefficient (logP) is 1.35 at pH 7. Tramadol hydrochloride tablets contain 50 mg of Tramadol hydrochloride and are white in color. In addition, each tablet contains the following inactive ingredients:
colloidal silicon dioxide, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, pregelatinized starch, sodium starch glycolate and titanium dioxide.

Chemical formula

How Taken

Take tramadol exactly as directed by your doctor. If you do not understand these directions, ask your pharmacist, nurse, or doctor to explain them to you.
Take each dose with a full glass of water.
Tramadol can be taken with or without food.
Side effects from treatment with tramadol may be decreased by a slow increase in dose, as directed by your doctor. The tablets can easily be broken in half at the score if needed. The maximum dose of tramadol for an average healthy adult is 100 mg per dose, every 4 to 6 hours, up to 400 mg per day. People over 75 years of age should not take more than 300 mg per day. People with liver or kidney disease may need lower daily doses. Follow your doctor's directions.
Do not take more of this medication than is prescribed for you. If the pain is not being controlled, talk to your doctor. Taking more than the prescribed amount of this medication could result in seizures or decreased breathing.

Dosage and Administration

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 the following 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 tablets 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 tablets 50 mg to 100 mg can be administered as needed for pain relief every four to six hours, not to exceed 400 mg per day.

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 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.

Missed Dose

Since tramadol is taken on an as-needed basis, missing a dose is usually not a problem. Take the dose as soon as you remember, and do not take another dose for the amount of time prescribed by your doctor.
Do not take a double dose of this medication.

Overdose

Seek emergency medical attention if you think you have used too much of this medicine. Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center ( http://www.aapcc.org/findyour.htm ), or emergency room immediately.
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.

Storage

Store Tramadol at 77 degrees F (25 degrees C). Brief storage between 59 and 86 degrees F (15 and 30 degrees C) is permitted. Store away from heat, moisture, and light.
Do not store in the bathroom. Keep Tramadol out of the reach of children and away from pets.

How Supplied

Tramadol hydrochloride tablets, 50 mg, are available as white, film-coated, unscored, oval-shaped tablets, debossed [93] on one side and debossed [58] on the other side. They are available in bottles of 100 and 500.
Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

What is the most important information I should know about Tramadol?

Seizures have been reported as a rare side effect of treatment with tramadol. The risk of seizures may be increased in patients who take more than the prescribed dose, have a history of seizures or epilepsy, have head trauma, have a metabolic disorder, have a central nervous system infection, are experiencing alcohol or drug withdrawal, or are taking certain medications. Talk to your doctor about factors that may increase the risk of seizures during treatment.
Do not drink alcohol while taking tramadol. Alcohol may cause a dangerous decrease in breathing and/or liver problems when used during treatment with tramadol.
Use caution when driving, operating machinery, or performing other hazardous activities. Tramadol may cause dizziness or drowsiness. If you experience dizziness or drowsiness, avoid these activities.
Do not take more of this medication than is prescribed for you. If the pain is not being controlled, talk to your doctor. Taking more than the prescribed amount of this medication could result in seizures or decreased breathing.

What should I discuss with my doctor before taking Tramadol?

Seizures have been reported as a rare side effect of treatment with tramadol. The risk of seizures may be increased in patients who have any of the conditions or are taking any of the medications listed below: Do not take tramadol without first talking to your doctor if you

• have a history of seizures or epilepsy;
• have a head injury;
• have a metabolic disorder;
• have a central nervous system infection;
• are experiencing alcohol or drug withdrawal;
• are taking a tricyclic antidepressant such as amitriptyline (Elavil), nortriptyline (Pamelor), doxepin (Sinequan), imipramine (Tofranil), clomipramine (Anafranil), and others;
• are taking a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), phenelzine (Nardil), or tranylcypromine (Parnate);
• are taking a psychiatric medication such as chlorpromazine (Thorazine), fluphenazine (Prolixin), haloperidol (Haldol), loxapine (Loxitane), mesoridazine (Serentil), perphenazine (Trilafon), thioridazine (Mellaril), thiothixene (Navane), and others;
• are taking a selective serotonin reuptake inhibitor (SSRI) such as fluoxetine (Prozac, Sarafem), fluvoxamine (Luvox), paroxetine (Paxil), sertraline (Zoloft), or citalopram (Celexa);
• are taking a narcotic pain reliever such as codeine, fentanyl (Duragesic), hydromorphone (Dilaudid), meperidine (Demerol), hydrocodone (Vicodin, Lorcet, Lortab, others), morphine (MS Contin, MSIR, RMS, Roxanol, others), oxycodone (Roxicodone, Percocet, Percodan, others), propoxyphene (Darvon, Darvocet, others), and others;
• are taking promethazine (Phenergan) or prochlorperazine (Compazine);
• are taking sibutramine (Meridia);
• are taking bupropion (Wellbutrin, Zyban); or
• are taking cyclobenzaprine (Flexeril).

Before taking tramadol, tell your doctor if you have

• kidney disease;
• liver disease; or
• a history of alcohol or drug dependence.

You may not be able to take tramadol, or you may require a dosage adjustment or special monitoring during treatment if you have any of the conditions listed above.
Tramadol is in the FDA pregnancy category C. This means that it is not known whether it will be harmful to an unborn baby. Do not take this medication without first talking to your doctor if you are pregnant.
It is also not known whether tramadol passes into breast milk. Do not take tramadol without first talking to your doctor if you are breast-feeding a baby.
If you are over 75 years of age, you may be more likely to experience side effects from tramadol. The maximum daily dose of tramadol for people over 75 years of age is 300 mg.
Tramadol is not approved by the FDA for use by children younger than 16 years of age.

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 mcg/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.

Excretion

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

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

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 IV dose of Tramadol. Following a single oral dose, and after adjusting for body weight, females had a 12% higher peak Tramadol concentration and a 35% higher area under the concentration-time curve compared to males. The clinical significance of this difference is unknown.

Renal Insufficiency

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 Impairment

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.

Possible side effects

If you experience any of the following serious side effects, stop taking tramadol and seek emergency medical attention or contact your doctor immediately:

• an allergic reaction (difficulty breathing; closing of your throat; swelling of your lips, tongue, or face; or hives); or
• seizures.

Other, less serious side effects may be more likely to occur. Continue to take tramadol and talk to your doctor if you experience

• dizziness, drowsiness, or headache;
• nervousness, tremor, or anxiety;
• nausea, vomiting, constipation, or diarrhea; or
• itching, dry mouth, or sweating.

Tramadol is habit forming. Physical and/or psychological dependence can occur, and withdrawal effects are possible if the medication is stopped suddenly after prolonged or high-dose treatment.
Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome.

What other drugs will affect Tramadol?

Tramadol may increase the risk of seizures especially in patients who have epilepsy or another seizure disorder. Also, tramadol may increase the risk of seizures if you are taking any of the following drugs:

• a tricyclic antidepressant such as amitriptyline (Elavil), nortriptyline (Pamelor), doxepin (Sinequan), imipramine (Tofranil), clomipramine (Anafranil), and others;
• a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), phenelzine (Nardil), or tranylcypromine (Parnate);
• an antipsychotic medication such as chlorpromazine (Thorazine), fluphenazine (Prolixin), haloperidol (Haldol), loxapine (Loxitane), mesoridazine (Serentil), perphenazine (Trilafon), thioridazine (Mellaril), thiothixene (Navane), and others;
• a selective serotonin reuptake inhibitor (SSRI) such as fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), sertraline (Zoloft), or citalopram (Celexa);
• a narcotic pain reliever such as codeine, fentanyl (Duragesic), hydromorphone (Dilaudid), meperidine (Demerol), hydrocodone (Vicodin, Lorcet, Lortab, others), morphine (MS Contin, MSIR, RMS, Roxanol, others), oxycodone (Roxicodone, Percocet, Percodan, others), propoxyphene (Darvon, Darvocet, others), and others;
• promethazine (Phenergan) or prochlorperazine (Compazine);
• bupropion (Wellbutrin, Zyban); or
• cyclobenzaprine (Flexeril).

Do not take tramadol without first talking to your doctor if you are taking any of the medicines listed above.
Before taking tramadol, tell your doctor if you are taking any of the following medicines:

• carbamazepine (Tegretol);
• quinidine (Quinaglute Dura-Tabs, Cardioquin, Quinora, others);
• warfarin (Coumadin); or
• digoxin (Lanoxin, Lanoxicaps).

You may not be able to take tramadol, or you may require a dosage adjustment or special monitoring during treatment if you are taking any of the medicines listed above.
Tramadol may increase the effects of other drugs that cause drowsiness, including antidepressants, alcohol, antihistamines, sedatives (used to treat insomnia), other pain relievers, anxiety medicines, and muscle relaxants. Tell your doctor about all medicines that you are taking, and do not take any other prescription or over-the-counter medicines, including herbal products, without first talking to your doctor during treatment with tramadol.
Drugs other than those listed here may also interact with tramadol. Talk to your doctor and pharmacist before taking any prescription or over-the-counter medicines, including herbal products.

What should I avoid while taking Tramadol?

Do not drink alcohol while taking tramadol. Alcohol may cause a dangerous decrease in breathing and/or liver problems when used during treatment with tramadol.
Use caution when driving, operating machinery, or performing other hazardous activities. Tramadol may cause dizziness or drowsiness. If you experience dizziness or drowsiness, avoid these activities.
Avoid sleeping pills, tranquilizers, sedatives, and antihistamines except under the supervision of your doctor. These drugs may increase drowsiness caused by tramadol.
Tramadol may increase the effects of other drugs that cause drowsiness, including antidepressants, alcohol, other antihistamines, pain relievers, anxiety medicines, seizure medicines, and muscle relaxants. Dangerous sedation, dizziness, drowsiness, or decreased breathing may occur if tramadol is taken with any of these medications. Tell your doctor about all medicines that you are taking, and do not take any other prescription or over-the-counter medicines, including herbal products, without first talking to your doctor during treatment with tramadol.

Contraindications

Tramadol hydrochloride tablets should not be administered to patients who have previously demonstrated hypersensitivity to Tramadol, any other component of this product or opioids. Tramadol hydrochloride tablets are contraindicated in any situation where opioids are contraindicated, including acute intoxication with any of the following: alcohol, hypnotics, narcotics, centrally acting analgesics, opioids or psychotropic drugs. Tramadol may worsen central nervous system and respiratory depression in these patients.

Warnings

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 (SSRI antidepressants or anorectics),
• Tricyclic antidepressants (TCAs), and other tricyclic compounds (e.g., cyclobenzaprine, promethazine, etc.), or
• Other opioids.

Administration of Tramadol may enhance the seizure risk in patients taking:

• MAO inhibitors,
• 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, 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.

Respiratory Depression
Administer Tramadol cautiously in patients at risk for respiratory depression. In these patients alternative non-opioid analgesics should be considered. When large doses of Tramadol are administered with anesthetic medications or alcohol, respiratory depression may result. Respiratory depression should be treated as an overdose. If naloxone is to be administered, use cautiously because it may precipitate seizures.

Interaction with Central Nervous System (CNS) Depressants
Tramadol should be used 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 increases the risk of CNS and respiratory depression in these patients.

Increased Intracranial Pressure or Head Trauma
Tramadol should be used 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.

Use in Ambulatory Patients
Tramadol may impair the mental and or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. The patient using this drug should be cautioned accordingly.

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

Withdrawal
Withdrawal symptoms may occur if Tramadol is discontinued abruptly. These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely hallucinations. Other symptoms that have been seen less frequently with Tramadol discontinuation include: panic attacks, severe anxiety, and paresthesias. Clinical experience suggests that withdrawal symptoms may be avoided by tapering Tramadol at the time of discontinuation.

Physical Dependence and Abuse
Tramadol may induce psychic and physical dependence of the morphine-type (M-opioid). Tramadol 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. Dependence and abuse, including drug-seeking behavior and taking illicit actions to obtain the drug, are not limited to those patients with prior history of opioid dependence.

Risk of Overdosage
Serious potential consequences of overdosage with Tramadol hydrochloride tablets 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.

Precautions

Acute Abdominal Conditions

The administration of Tramadol may complicate the clinical assessment of patients with acute abdominal conditions.

Use in Renal and Hepatic Disease

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, dosing reduction is recommended. Metabolism of Tramadol and M1 is reduced in patients with advanced cirrhosis of the liver. In cirrhotic patients, dosing reduction is recommended.
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.

Information for Patients

• Tramadol hydrochloride tablets may impair mental or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery.
• Tramadol hydrochloride tablets should not be taken with alcohol containing beverages.
• Tramadol hydrochloride tablets should be used with caution when taking medications such as tranquilizers, hypnotics or other opiate containing analgesics.
• The patient should be instructed to inform the physician if they are pregnant, think they might become pregnant, or are trying to become pregnant.
• The patient should understand the single-dose and 24 hour dose limit and the time interval between doses, since exceeding these recommendations can result in respiratory depression, seizures and death.

Information For Patients

Carcinogenesis/ Mutagenesis/ Impairment of Fertility

A slight, but statistically significant, increase in two common murine tumors, pulmonary and hepatic, was observed in a mouse carcinogenicity study, particularly in aged mice. Mice were dosed orally up to 30 mg/kg (90 mg/m2 or 0.36 times the maximum daily human dosage of 246 mg/m2) 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 (dosing orally up to 30 mg/kg, 180 mg/m2, or 0.73 times the maximum daily human dosage).
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.
No effects on fertility were observed for Tramadol at oral dose levels up to 50 mg/kg (300 mg/m2) in male rats and 75 mg/kg (450 mg/m2) in female rats. These dosages are 1.2 and 1.8 times the maximum daily human dosage of 246 mg/m2, respectively.

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 (gavage) 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.

Nursing Mothers

Tramadol 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 mcg of Tramadol (0.1% of the maternal dose) and 27 mcg of M1.

Pediatric Use

The safety and efficacy of Tramadol in patients under 16 years of age have not been established. The use of Tramadol 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.

Adverse Reactions

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 m