Drug Name

Ultram (Tramadol)

Generic Name

Tramadol Tablets (TRA-ma-dole)

Manufacturer / Distributor

ORTHO-McNEIL PHARMACEUTICAL, INC.

Dosage Form

Tablets

Route Of Administration

ORAL

Imprint Code

Ultram;06;59

Size

13mm

Alternatives

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

Drug Uses

Ultram is a narcotic-like pain reliever.
Ultram is used to treat moderate to severe pain. Ultram extended-release is used to treat moderate to severe chronic pain when treatment is needed around the clock.
Ultram may also be used for other purposes not listed in this medication guide.

Drug class

Ultram is used to treat moderate to severe chronic pain when treatment is needed around the clock. Tramadol may also be used for other purposes not listed in this medication guide.

Contains

Ultram (tramadol hydrochloride tablets) is a centrally acting analgesic. The chemical name for tramadol hydrochloride is (±)cis-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochloride.
The molecular weight of tramadol hydrochloride is 299.8.
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. Ultram tablets contain 50 mg of tramadol hydrochloride and are white in color.
Inactive ingredients in the tablet are
corn starch, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, titanium dioxide and wax.

Chemical formula

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 Ultram can be improved by initiating therapy with the following titration regimen: Ultram should be started at 25 mg/day qAM and titrated in 25 mg increments as separate doses every 3 days to reach 100 mg/day (25 mg q.i.d.). Thereafter 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, Ultram 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, Ultram 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 Ultram 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

Take the missed dose as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at the next regularly scheduled time. Do not take extra medicine to make up the missed dose.

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.
Overdose symptoms may include:

• drowsiness,
• shallow breathing,
• slow heartbeat,
• extreme weakness,
• cold or clammy skin,
• feeling light-headed, fainting, or coma.

Storage

Store Ultram at 77 degrees F (25 degrees C).
Brief storage at temperatures 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 Ultram out of the reach of children and away from pets.

How Supplied

Ultram (tramadol hydrochloride tablets) Tablets - 50 mg are white, capsule-shaped, coated tablet imprinted "Ultram" on one side and "06 59" on the scored side.

100's NDC 0045-0659-60 bottles of 100 tablets
500's NDC 0045-0659-70 bottles of 500 tablets

Packages of 100 unit doses in blister packs - NDC 0045-0659-10 (10 cards of 10 tablets each).

What is the most important information I should know about Ultram (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 Ultram (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 mg/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. 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.

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 Ultram (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 Ultram (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

Ultram should not be administered to patients who have previously demonstrated hypersensitivity to tramadol, any other component of this product or opioids. Ultram is 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. Ultram may worsen central nervous system and respiratory depression in these patients.

Warnings

Seizure Risk

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

• Selective serotonin re-uptake inhibitors
• antidepressants (TCAs), and other tricyclic compounds (e.g., cyclobenzaprine, promethazine, etc.), or
• Other opioids.

Administration of Ultram 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 Ultram overdose, naloxone administration may increase the risk of seizure.

Reactions

Serious and rarely fatal anaphylactoid reactions have been reported in patients receiving therapy with Ultram. 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 Ultram.

Respiratory Depression

Administer Ultram cautiously in patients at risk for respiratory depression. In these patients alternative nonopioid analgesics should be considered. When large doses of Ultram 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

Ultram 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. Ultram increases the risk of CNS and respiratory depression in these patients.

Increased Intracranial Pressure or Head Trauma

Ultram 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 Ultram.

Use in Ambulatory Patients

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

Withdrawal

Withdrawal symptoms may occur if Ultram 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 Ultram discontinuation include panic attacks, severe anxiety, and paresthesias. Clinical experience suggests that withdrawal symptoms may be avoided by tapering Ultram at the time of discontinuation.

Physical Dependence and Abuse

Ultram may induce psychic and physical dependence of the morphine-type (µ-opioid). Ultram should not be used in opioid-dependent patients. Ultram 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 Ultram (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 Ultram 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

• Ultram may impair mental or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery.
• Ultram should not be taken with alcohol containing beverages.
• Ultram 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.

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. Ultram 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

Ultram 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 u of tramadol (0.1% of the maternal dose) and 27 u of M1.

Pediatric Use

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

Special warnings about Ultram

If you have stomach problems such as an ulcer, make sure your doctor is aware of them. Ultram may hide the symptoms, making them difficult to diagnose and treat.
Ultram can cause mental and physical addiction. If you've ever had a problem with narcotic painkillers such as Percocet, Demerol, or morphine, you should avoid Ultram. Withdrawal symptoms may occur if you stop taking Ultram abruptly. Such symptoms include anxiety, sweating, insomnia, pain, nausea, tremor, diarrhea, and respiratory problems. A gradual decrease in dosage will help prevent these symptoms.
Do not take more than the recommended dose of Ultram, since larger doses have been known to cause seizures, especially if you have epilepsy or are taking medications that also increase the risk of seizures. Among such medications are almost all antidepressant drugs, plus narcotics and major tranquilizers such as Loxitane and Stelazine.
If you have liver or kidney disease, be sure your doctor knows about it. Your dosage may have to be reduced.
Before you have any kind of surgery, make sure the doctor knows you are taking Ultram.
If you have any kind of breathing problem, use Ultram with caution or take a different kind of painkiller. Ultram can impair respiration, especially if taken with alcohol.
If you have experienced a head injury, consult your doctor before taking Ultram. The medication's effects may be stronger and could hide warning signs of serious trouble.

References

References and complaints