Online Tramadol

Sells Tramadol,famous FDA approved brand name and, generic medications with or without prescription, high quality, low prices, secure ordering, free shipping. DRUG CLASS AND MECHANISM: Tramadol is an effective pain reliever (analgesic). Its mode of action resembles that of narcotics, but it has significantly less potential for abuse and addiction than the narcotics. Tramadol is as effective as narcotics in relieving pain but does not depress respiration, a side effect of most narcotics. Tramadol is not a nonsteroidal antiinflammatory drug (NSAID), and does not have the increased risk of stomach ulceration and internal bleeding that can occur with the use of NSAIDs. DRUG INTERACTIONS: Tramadol can impair thinking and the physical abilities required for driving or operating machinery. Tramadol should be avoided in patients intoxicated with alcohol, hypnotics, and narcotics. Large doses of tramadol administered with alcohol or anesthetic agents can impair breathing. Tramadol can increase the risk of seizure in epileptic patients, especially with simultaneous use of tricyclic antidepressants, such as Elavil. No dosage adjustment or reduction is necessary in healthy elderly patients 65-75 years of age. Patients over the age of 75 years, and those with liver and kidney dysfunction may need lower dosages. The safety of tramadol in children has not been established. Tramadol may rarely be habit forming. Tramadol should be avoided in patients with a history of opiate addiction or hypersensitivity to opiate medications. I was in a really hepeless state when I first was given Tramadol. Other medicaments were ineffective and I was in pain very often. One day I found Tramadol gives the best result in traumatic pain. I ask the doctor for this medicine and since then I take 200 mg dose daily. I must be carefull because it may staggers, so it's better for me to stay in bed for a while. I am really happy taking Tramadol which alleviates my pain a lot! Richard from U.K. I think that Tramadol is the best medicament for everyone who suffers and it always appeases a pain. I decided to buy Tramadol because I had a long-drawn-out pain, which made me crazy. I had tried many times different pills, I had ever known about, but none of them gave the result as I needed. PillsBargain offers Tramadol and other prescription drugs. Shop conveniently, privately and safely for FDA approved prescription medications. Free FedEx 3-day express on all orders. Cheap Tramadol 50mg 120 Ct. $78.99, Soma & More... Save 75%+. Order Online, Toll-Free, 1-888 LOOK-NICE, COD, Fedex Overnight, Lowest Prices! FDA approved! M.D. Consult, Membership Fees Waived. Fast delivery from USA Licensed Dr./Pharmacy. Courteous Staff, Discreet Shipping. Saturday deliveries, Order by 1 Tramadol (Generic Ultram) Directions Follow the directions for using this medicine provided by your doctor. STORE THIS MEDICINE at room temperature, away from heat and light. IF YOU MISS A DOSE OF THIS MEDICINE, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do NOT take 2 doses at once. Tramadol - Side Effects SIDE EFFECTS, that may go away during treatment, include dizziness, nausea, drowsiness, dry mouth, constipation, headache, or sweating. If they continue or are bothersome, check with your doctor. CHECK WITH YOUR DOCTOR AS SOON AS POSSIBLE if you experience skin rash, itching, seizures, or hallucinations. If you notice other effects not listed above, contact your doctor, nurse, or pharmacist. Tramadol - Precautions DO NOT EXCEED THE RECOMMENDED DOSE OR TAKE THIS MEDICINE for longer than prescribed. IF YOU EXPERIENCE difficulty breathing or tightness of chest; swelling of eyelids, face, or lips; or develop a rash or hives, tell your doctor immediately. Do not take any more of this medicine unless your doctor tells you to do so. AVOID ALCOHOL while you are using this medicine. This medicine will add to the effects of alcohol and other depressants. DO NOT DRIVE, OPERATE MACHINERY, OR DO ANYTHING ELSE THAT COULD BE DANGEROUS until you know how you react to this medicine. Using this medicine alone, with other medicines, or with alcohol may lessen your ability to drive or to perform other potentially dangerous tasks. BEFORE YOU BEGIN TAKING ANY NEW MEDICINE, either prescription or over-the-counter, check with your doctor or pharmacist. FOR WOMEN: IF YOU PLAN ON BECOMING PREGNANT, discuss with your doctor the benefits and risks of using this medicine during pregnancy. THIS MEDICINE IS EXCRETED IN BREAST MILK. DO NOT BREAST-FEED while taking this medicine. Tramadol - Notes Do not share this medicine with others for whom it was not prescribed. Do not use this medicine for other health conditions. Keep this product out of the reach of children. If using this medicine for an extended period of time, obtain refills before your supply runs out. Tramadol (INN) (IPA: [E?trA¦mE™dE’l]) is an atypical opioid which is a centrally acting analgesic, used for treating moderate to severe pain. It is a synthetic agent, unrelated to other opioids, and appears to have actions on the GABAergic, noradrenergic and serotonergic systems. Tramadol was developed by the German pharmaceutical company GrA?nenthal GmbH and marketed under the trade name Tramal. GrA?nenthal has also cross licensed the drug to many other pharmaceutical companies that market it under various names, some of which are listed below. Tramadol is available in both injectable (intravenous and/or intramuscular) and oral preparations. It is usually marketed as the hydrochloride salt (tramadol hydrochloride). Dosages vary depending on the degree of pain experienced by the patient. Tramadol is approximately 10% as potent as morphine, when given by the IV/IM route. Oral doses range from 50a€“400 mg daily, with up to 600 mg daily when given IV/IM. Tramadol is used to relieve moderate to moderately severe pain. It may be used to treat pain caused by surgery and chronic conditions such as cancer or joint pain. Tramadol is in a class of medications called opiate (narcotic) analgesics. It works by decreasing the body's sense of pain. Commonly reported side effects include nausea, constipation, dizziness, headache, drowsiness, and vomiting. Less commonly reported side effects include itching, sweating, dry mouth, diarrhea, rash, visual disturbances, and vertigo. IMPORTANT NOTE: The following information is intended to supplement, not substitute for, the expertise and judgment of your physician, pharmacist or other healthcare professional. It should not be construed to indicate that use of the drug is safe, appropriate, or effective for you. Consult your healthcare professional before using this drug. TRAMADOL - ORAL (TRAH-muh-dall) COMMON BRAND NAME(S): Ultram USES: Tramadol is used for pain relief. HOW TO USE: Take this medication by mouth as prescribed. It is usually taken every 4 to 6 hours as needed. Use this medication exactly as prescribed. Do not increase your dose, use it more frequently or use it for a longer period of time than prescribed because this drug can be habit-forming. Also, if used for an extended period of time, do not suddenly stop using this drug without your doctor's approval. When used for extended periods, this medication may not work as well and may require different dosing. Consult your doctor if the medication stops working well. SIDE EFFECTS: This medication may cause dizziness, weakness, incoordination, nausea or vomiting, stomach upset, constipation, headache, drowsiness, anxiety, irritability, dry mouth, or increased sweating. If any of these effects persist or worsen, inform your doctor. Notify your doctor if you develop any of these serious effects while taking this medication: chest pain, rapid heart rate, skin rash or itching, mental confusion, disorientation, seizures, tingling of the hands or feet, trouble breathing. In the unlikely event you have an allergic reaction to this drug, seek immediate medical attention. Symptoms of an allergic reaction include: rash, itching, swelling, dizziness, breathing trouble. If you notice other effects not listed above, contact your doctor or pharmacist. PRECAUTIONS: Tell your doctor your medical history, especially of: kidney disease, liver disease, seizure disorder, lung disease, history of drug or alcohol dependency, any allergies you may have. Limit alcohol as it may add to the dizziness or drowsiness effects caused by the medication. Because this drug may make you dizzy/drowsy, use caution performing tasks requiring alertness such as driving. This medication should be used only when clearly needed during pregnancy. Discuss the risks and benefits with your doctor. Tramadol is excreted into breast milk. Because the effects on a nursing infant are not known, consult your doctor before breast- feeding. DRUG INTERACTIONS: Tell your doctor of all prescription and nonprescription medications you may use, especially of: carbamazepine, narcotic pain relievers (e.g., codeine), drugs used to aid sleep, antidepressants (e.g., SSRI-types such as fluoxetine or fluvoxamine), MAO inhibitors (e.g., furazolidone, linezolid, phenelzine, procarbazine, selegiline, tranylcypromine), psychiatric medicine (e.g., nefazodone), "triptan"-type drugs, anti-anxiety drugs (e.g., diazepam), sibutramine. Also, report use of certain antihistamines (e.g., diphenhydramine) which are also present in many cough-and-cold products. Do not start or stop any medicine without doctor or pharmacist approval. OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. Symptoms of overdose may include cold and clammy skin, low body temperature, slowed breathing, slowed heartbeat, drowsiness, dizziness, lightheadedness, deep sleep, loss of consciousness, or seizures. NOTES: Do not share this medication with others. MISSED DOSE: If you miss a dose, take it as soon as remembered; do not take it if it is near the time for the next dose, instead, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up. STORAGE: Store this medication at room temperature between 59 and 86 degrees F (15 to 30 degrees C) away from heat and light. Do not store in the bathroom. Keep this and all medications out of the reach of children. Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed. • Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/ or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist. tramadol Drug information Generic Name: tramadol (TRAM a dol) Brand Names: Ultram, Ultram ER What is the most important information I should know about tramadol? • You should not take tramadol if you have ever been addicted to drugs or alcohol. • Take tramadol exactly as it was prescribed for you. Do not take it in larger doses or for longer than recommended by your doctor. Do not take more than 300 milligrams of tramadol in one day. • Do not stop using this medication suddenly without talking to your doctor. You may need to gradually reduce the dose. Withdrawal symptoms may occur when you stop using tramadol. Withdrawal symptoms include anxiety, sweating, nausea, diarrhea, tremors, chills, hallucinations, trouble sleeping, or breathing problems. Call your doctor at once if you have any of these withdrawal symptoms after you stop using tramadol. • Do not crush the tramadol tablet. This medicine is for oral (by mouth) use only. Powder from a crushed tablet should not be inhaled or diluted with liquid and injected into the body. Using this medicine by inhlation or injection can cause life-threatening side effects, overdose, or death. • Seizures (convulsions) have occurred in some people taking tramadol. You may be more likely to have a seizure while taking tramadol if you have a history of seizures or head injury, a metabolic disorder, or if you are taking certain medicines such as antidepressants, muscle relaxers, or medicine for nausea and vomiting. • Seek emergency medical attention if you think you have used too much of this medicine. A tramadol overdose can be fatal. Symptoms of a tramadol overdose may include drowsiness, shallow breathing, slow heartbeat, extreme weakness, cold or clammy skin, feeling light-headed, fainting, or coma. • While you are taking tramadol, do not drink alcohol or use drugs that make you sleepy (such as cold medicine, other pain medications, muscle relaxants, and medicine for seizures, depression or anxiety). These drugs may slow your breathing or increase drowsiness when used together with tramadol. • Tramadol can cause side effects that may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be awake and alert. What is tramadol? • Tramadol is a narcotic pain reliever. • Tramadol is used to treat moderate to severe pain. Tramadol extended-release is used to treat moderate to severe chronic pain when treatment is needed around the clock. • Tramadol may also be used for purposes other than those listed in this medication guide. What should I discuss with my healthcare provider before taking tramadol? • You should not take tramadol if you have ever been addicted to drugs or alcohol. • Do not take tramadol if you are intoxicated (drunk), or if you have recently used any of the following drugs: · alcohol; · narcotic pain medicine; · sedatives or tranquilizers (such as Valium); · medicine for depression or anxiety; · medicine for mental illness (such as bipolar disorder, schizophrenia); or · street drugs. • Seizures have occurred in some people taking tramadol. Your risk of a seizure may be higher if you have any of these conditions: · a history of drug or alcohol addiction; · a history of epilepsy or other seizure disorder; · a history of head injury; or · a metabolic disorder. • Talk with your doctor about your individual risk of having a seizure from this medicine. • Before taking tramadol, tell your doctor if you have: · kidney disease; · liver disease; · a stomach disorder; or · a history of depression, mental illness, or suicide attempt. • If you have any of these conditions, you may not be able to use tramadol, or you may need a dosage adjustment or special tests during treatment. • FDA pregnancy category C. This medication may be harmful to an unborn baby. Tramadol may also cause serious or fatal side effects in a newborn if the mother uses the medication during pregnancy or labor. Tell your doctor if you are pregnant or plan to become pregnant during treatment. • Tramadol can pass into breast milk and may harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby. • Older adults may be more sensitive to the effects of tramadol. If you are over 65, your doctor may recommend a lower dose. • Tramadol should not be given to a child younger than 16 years of age. How should I take tramadol? • Take tramadol exactly as it was prescribed for you. Do not take it in larger doses or for longer than recommended by your doctor. Do not take more than 300 milligrams of tramadol in one day. • Take each dose with a full glass of water. • Tramadol can be taken with or without food, but take it the same way each time. • Do not crush the tramadol tablet. This medicine is for oral (by mouth) use only. Powder from a crushed tablet should not be inhaled or diluted with liquid and injected into the body. Using this medicine by inhlation or injection can cause life-threatening side effects, overdose, or death. • Do not crush, chew, or break an extended-release tablet. Swallow the pill whole. It is specially made to release medicine slowly in the body. Breaking the pill would cause too much of the drug to be released at one time. • If you use the tramadol extended-release tablet, the tablet shell may pass into your stools (bowel movements). This is normal and does not mean that you are not receiving enough of the medicine. • Tramadol may be habit-forming. Tell your doctor if you feel the medicine is not working as well in relieving your pain. Do not change your dose without talking to your doctor. • Do not stop using this medication suddenly without talking to your doctor. You may need to gradually reduce the dose. Withdrawal symptoms may occur when you stop using tramadol. Withdrawal symptoms include anxiety, sweating, nausea, diarrhea, tremors, chills, hallucinations, trouble sleeping, or breathing problems. Call your doctor at once if you have any of these withdrawal symptoms after you stop using tramadol. • Store tramadol at room temperature away from moisture and heat. What happens if I miss a 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. What happens if I overdose? • Seek emergency medical attention if you think you have used too much of this medicine. A tramadol overdose can be fatal. • Symptoms of a tramadol overdose may include drowsiness, shallow breathing, slow heartbeat, extreme weakness, cold or clammy skin, feeling light-headed, fainting, or coma. What should I avoid while taking tramadol? • Do not drink alcohol while you are taking tramadol. Alcohol may cause a dangerous decrease in your breathing when used together with tramadol. • Avoid using drugs that make you sleepy (such as cold medicine, other pain medications, muscle relaxants, and medicine for seizures, depression or anxiety). These drugs may slow your breathing or increase drowsiness when used together with tramadol. • Tramadol can cause side effects that may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be awake and alert. What are the possible side effects of tramadol? • Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. • Stop using tramadol and call your doctor at once if you have any of these serious side effects: · seizure (convulsions); · a red, blistering, peeling skin rash; or · shallow breathing, weak pulse. • Continue taking tramadol and talk to your doctor if you have any of these less serious side effects: · dizziness, drowsiness, weakness; · nausea, vomiting, constipation, loss of appetite; · blurred vision; · flushing (redness, warmth, or tingly feeling); or · sleep problems (insomnia). • 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? • You may be more likely to have a seizure (convulsions) if you take tramadol while you are using certain other medicines. Do not take tramadol without telling your doctor if you also use any of the following: · an MAO inhibitor such as isocarboxazid (Marplan), tranylcypromine (Parnate), phenelzine (Nardil), or selegiline (Eldepryl, Emsam); or · an antidepressant such as amitriptyline (Elavil), citalopram (Celexa), clomipramine (Anafranil), desipramine (Norpramin), escitalopram (Lexapro), fluoxetine (Prozac, Sarafem), fluvoxamine (Luvox), imipramine (Tofranil), nortriptyline (Pamelor); paroxetine (Paxil), or sertraline (Zoloft). • Before taking tramadol, tell your doctor if you also use: · carbamazepine (Tegretol); · warfarin (Coumadin); · digoxin (Lanoxin, Lanoxicaps); · ketoconazole (Nizoral); · erythromycin (E-Mycin, E.E.S., Ery-Tab); · rifampin (Rifadin, Rimactane, Rifater); · St. John's wort; · quinidine (Quinaglute, Quinadex, Cardioquin, Quinora); or · drugs that make you sleepy (such as cold medicine, other pain medications, muscle relaxants, and medicine for seizures, depression or anxiety). • If you are using any of these drugs, you may not be able to use tramadol or you may need dosage adjustments or special tests during treatment. • There may be other drugs not listed that can affect tramadol. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor. Where can I get more information? • Your pharmacist has more information about tramadol written for health professionals that you may read. 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, hydroxypropyl methylcellulose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, titanium dioxide and wax. CLINICAL PHARMACOLOGY Pharmacodynamics ULTRAM is a centrally acting synthetic opioid analgesic. 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 (see CLINICAL PHARMACOLOGY , Pharmacokinetics ). 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 ULTRAM. Analgesia in humans begins approximately within one hour after administration and reaches a peak in approximately two to three hours. Apart from analgesia, ULTRAM 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, ULTRAM has no effect on heart rate, left-ventricular function or cardiac index. Orthostatic hypotension has been observed. Pharmacokinetics The analgesic activity of ULTRAM is due to both parent drug and the M1 metabolite (see CLINICAL PHARMACOLOGY , Pharmacodynamics ). 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 2.7L/kg and is only 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 (see PRECAUTIONS , Drug Interactions ). 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. 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. Steady-state plasma concentrations of both tramadol and M1 are achieved within two days with q.i.d. dosing. There is no evidence of self-induction (see Figure 1 and Food Effects: Oral administration of ULTRAM with food does not significantly affect its rate or extent of absorption, therefore, ULTRAM can be administered without regard to food. 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 (see PRECAUTIONS , Drug Interaction ). 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 (see WARNINGS ) 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 (see DOSAGE AND ADMINISTRATION ). 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 (see DOSAGE AND ADMINISTRATION ). 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 (see DOSAGE AND ADMINISTRATION ). 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. Clinical Studies ULTRAM 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 ULTRAM 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. ULTRAM has been studied in three long-term controlled trials involving a total of 820 patients, with 530 patients receiving ULTRAM. 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 ULTRAM in divided doses were generally comparable to five doses of acetaminophen 300 mg with codeine phosphate 30 mg (TYLENOL® with Codeine #3) 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 (TYLOX®) daily. Titration Trials In a randomized, blinded clinical study with 129 to 132 patients per group, a 10-day titration to a daily ULTRAM 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. In a second study with 54 to 59 patients per group, patients who had nausea or vomiting when titrated over 4 days were randomized to re-initiate ULTRAM therapy using slower titration rates. A 16-day titration schedule, starting with 25 mg qAM and using additional doses in 25 mg increments every third day to 100 mg/day (25 mg q.i.d.), followed by 50 mg increments in the total daily dose every third day to 200 mg/day (50 mg q.i.d.), resulted in fewer discontinuations due to nausea or vomiting and fewer discontinuations due to any cause than did a 10-day titration schedule. 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 (see PRECAUTIONS , Drug Interaction ). 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 (see WARNINGS ) and serotonin syndrome. ULTRAM 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 ULTRAM 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. ULTRAM has been studied in three long-term controlled trials involving a total of 820 patients, with 530 patients receiving ULTRAM. 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 ULTRAM in divided doses were generally comparable to five doses of acetaminophen 300 mg with codeine phosphate 30 mg (TYLENOL® with Codeine #3) 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 (TYLOX®) daily. 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/m 2 or 0.36 times the maximum daily human dosage of 246 mg/m 2 ) 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/m 2 , 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/m 2 ) in male rats and 75 mg/kg (450 mg/m 2 ) in female rats. These dosages are 1.2 and 1.8 times the maximum daily human dosage of 246 mg/m 2 , respectively. Pregnancy, Teratogenic Effects: Pregnancy Catogery C Tramadol has been shown to be embryotoxic and fetotoxic in mice, (120 mg/kg or 360 mg/m 2 ), rats (>/=25 mg/kg or 150 mg/m 2 ) and rabbits (>/=75 mg/kg or 900 mg/m 2 ) at maternally toxic dosages, but was not teratogenic at these dose levels. These dosages on a mg/m 2 basis are 1.4, >/=0.6, and >/=3.6 times the maximum daily human dosage (246 mg/m 2 ) 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/m 2 ), rats (up to 80 mg/kg or 480 mg/m 2 ) or rabbits (up to 300 mg/kg or 3600 mg/m 2 ) 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/m 2 ), 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/m 2 ), respectively The information contained in the Thomson Healthcare (Micromedex) products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you. The use of the Thomson Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Healthcare does not assume any responsibility or risk for your use of the Thomson Healthcare products. The information contained in the Thomson Healthcare (Micromedex) products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you. The use of the Thomson Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Healthcare does not assume any responsibility or risk for your use of the Thomson Healthcare products. Abnormal dreams; appetite decreased; back pain; bladder pain; blistering, crusting, irritation, itching, or reddening of skin; bloody or cloudy urine; body aches or pain; change in hearing; clamminess; cold flu-like symptoms; confusion; cough producing mucus; cracked, dry, scaly skin; decreased interest in sexual intercourse; difficult, burning, or painful urination; difficulty breathing; difficulty in moving; disturbance in attention; ear congestion; ear drainage; earache or pain in ear; excessive gas; fall; false or unusual sense of well-being; feeling hot; feeling jittery; flushing or redness of the skin; general feeling of bodily discomfort; goosebumps; headache, severe and throbbing; hoarseness; hot flashes; inability to have or keep an erection; itching, pain, redness, swelling, tenderness, warmth on skin; joint sprain; joint stiffness; joint swelling; loss in sexual ability, desire, drive, or performance; loss of voice; lower back or side pain; muscle aching or cramping; muscle injury; muscle pain or stiffness; muscle spasms or twitching; nasal congestion; neck pain; night sweats; pain; pain in limb; pain or tenderness around eyes and cheekbones; pain, swelling, or redness in joints; skin discoloration; swelling; swelling of hands, ankles, feet, or lower legs; tightness of chest; trouble in holding or releasing urine; troubled breathing; trouble in sleeping; weight increased or decreased Abdominal fullness; abnormal or decreased touch sensation; blisters under the skin; bloating; blood in urine; blood pressure increased; blurred vision; chest pain or discomfort; change in walking and balance; chills; convulsions (seizures); darkened urine; difficult urination; dizziness or lightheadedness when getting up from a lying or sitting position; fainting; fast heartbeat; frequent urge to urinate; gaseous abdominal pain; heart rate increased; indigestion; irregular heartbeat; loss of memory; numbness and tingling of face, fingers, or toes; numbness, tingling, pain, or weakness in hands or feet; pain in arms, legs, or lower back, especially pain in calves and/or heels upon exertion; pain or discomfort in arms, jaw, back or neck; pains in stomach, side, or abdomen, possibly radiating to the back; pale bluish-colored or cold hands or feet; recurrent fever; seeing, hearing, or feeling things that are not there; severe cramping; severe nausea; severe redness, swelling, and itching of the skin; shortness of breath; sweats; trembling and shaking of hands or feet; trouble performing routine tasks; weak or absent pulses in legs; yellow eyes or skin This medicine will add to the effects of alcohol and other CNS depressants (medicine that causes drowsiness). Some examples of CNS depressants are antihistamines or medicine for hay fever, other allergies, or colds; sedatives, tranquilizers, or sleeping medicine; prescription pain medicine or narcotics; barbiturates; medicine for seizures; muscle relaxants; or anesthetics, including some dental anesthetics. Do not drink alcoholic beverages, and check with your medical doctor or dentist before taking any of the medicines listed above while you are using this medicine . This medicine may cause some people to become drowsy, dizzy, or lightheaded. Make sure you know how you react to this medicine before you drive, use machines, or do anything else that could be dangerous if you are dizzy or are not alert . Dizziness, lightheadedness, or fainting may occur , especially when you get up suddenly from a lying or sitting position. Getting up slowly may help lessen this problem. Nausea or vomiting may occur, especially after the first couple of doses. This effect may go away if you lie down for awhile. However, if nausea or vomiting continues, check with your medical doctor or dentist. Lying down for a while may also help relieve some other side effects, such as dizziness or lightheadedness, that may occur. Before having any kind of surgery (including dental surgery) or emergency treatment, tell the medical doctor or dentist in charge that you are taking this medicine. Taking tramadol together with medicines that are used during surgery or dental or emergency treatments may cause increased side effects. If you think you or someone else may have taken an overdose of tramadol, get emergency help at once . Signs of an overdose include convulsions (seizures) and pinpoint pupils of the eyes.

tramadol Drug information Generic Name: tramadol (TRAM a dol) Brand Names: Ultram, Ultram ER What is the most important information I should know about tramadol? • You should not take tramadol if you have ever been addicted to drugs or alcohol. • Take tramadol exactly as it was prescribed for you. Do not take it in larger doses or for longer than recommended by your doctor. Do not take more than 300 milligrams of tramadol in one day. • Do not stop using this medication suddenly without talking to your doctor. You may need to gradually reduce the dose. Withdrawal symptoms may occur when you stop using tramadol. Withdrawal symptoms include anxiety, sweating, nausea, diarrhea, tremors, chills, hallucinations, trouble sleeping, or breathing problems. Call your doctor at once if you have any of these withdrawal symptoms after you stop using tramadol. • Do not crush the tramadol tablet. This medicine is for oral (by mouth) use only. Powder from a crushed tablet should not be inhaled or diluted with liquid and injected into the body. Using this medicine by inhlation or injection can cause life-threatening side effects, overdose, or death. • Seizures (convulsions) have occurred in some people taking tramadol. You may be more likely to have a seizure while taking tramadol if you have a history of seizures or head injury, a metabolic disorder, or if you are taking certain medicines such as antidepressants, muscle relaxers, or medicine for nausea and vomiting. • Seek emergency medical attention if you think you have used too much of this medicine. A tramadol overdose can be fatal. Symptoms of a tramadol overdose may include drowsiness, shallow breathing, slow heartbeat, extreme weakness, cold or clammy skin, feeling light-headed, fainting, or coma. • While you are taking tramadol, do not drink alcohol or use drugs that make you sleepy (such as cold medicine, other pain medications, muscle relaxants, and medicine for seizures, depression or anxiety). These drugs may slow your breathing or increase drowsiness when used together with tramadol. • Tramadol can cause side effects that may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be awake and alert. What is tramadol? • Tramadol is a narcotic pain reliever. • Tramadol is used to treat moderate to severe pain. Tramadol extended-release is used to treat moderate to severe chronic pain when treatment is needed around the clock. • Tramadol may also be used for purposes other than those listed in this medication guide. What should I discuss with my healthcare provider before taking tramadol? • You should not take tramadol if you have ever been addicted to drugs or alcohol. • Do not take tramadol if you are intoxicated (drunk), or if you have recently used any of the following drugs: · alcohol; · narcotic pain medicine; · sedatives or tranquilizers (such as Valium); · medicine for depression or anxiety; · medicine for mental illness (such as bipolar disorder, schizophrenia); or · street drugs. • Seizures have occurred in some people taking tramadol. Your risk of a seizure may be higher if you have any of these conditions: · a history of drug or alcohol addiction; · a history of epilepsy or other seizure disorder; · a history of head injury; or · a metabolic disorder. • Talk with your doctor about your individual risk of having a seizure from this medicine. • Before taking tramadol, tell your doctor if you have: · kidney disease; · liver disease; · a stomach disorder; or · a history of depression, mental illness, or suicide attempt. • If you have any of these conditions, you may not be able to use tramadol, or you may need a dosage adjustment or special tests during treatment. • FDA pregnancy category C. This medication may be harmful to an unborn baby. Tramadol may also cause serious or fatal side effects in a newborn if the mother uses the medication during pregnancy or labor. Tell your doctor if you are pregnant or plan to become pregnant during treatment. • Tramadol can pass into breast milk and may harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby. • Older adults may be more sensitive to the effects of tramadol. If you are over 65, your doctor may recommend a lower dose. • Tramadol should not be given to a child younger than 16 years of age. How should I take tramadol? • Take tramadol exactly as it was prescribed for you. Do not take it in larger doses or for longer than recommended by your doctor. Do not take more than 300 milligrams of tramadol in one day. • Take each dose with a full glass of water. • Tramadol can be taken with or without food, but take it the same way each time. • Do not crush the tramadol tablet. This medicine is for oral (by mouth) use only. Powder from a crushed tablet should not be inhaled or diluted with liquid and injected into the body. Using this medicine by inhlation or injection can cause life-threatening side effects, overdose, or death. • Do not crush, chew, or break an extended-release tablet. Swallow the pill whole. It is specially made to release medicine slowly in the body. Breaking the pill would cause too much of the drug to be released at one time. • If you use the tramadol extended-release tablet, the tablet shell may pass into your stools (bowel movements). This is normal and does not mean that you are not receiving enough of the medicine. • Tramadol may be habit-forming. Tell your doctor if you feel the medicine is not working as well in relieving your pain. Do not change your dose without talking to your doctor. • Do not stop using this medication suddenly without talking to your doctor. You may need to gradually reduce the dose. Withdrawal symptoms may occur when you stop using tramadol. Withdrawal symptoms include anxiety, sweating, nausea, diarrhea, tremors, chills, hallucinations, trouble sleeping, or breathing problems. Call your doctor at once if you have any of these withdrawal symptoms after you stop using tramadol. • Store tramadol at room temperature away from moisture and heat. What happens if I miss a 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. What happens if I overdose? • Seek emergency medical attention if you think you have used too much of this medicine. A tramadol overdose can be fatal. • Symptoms of a tramadol overdose may include drowsiness, shallow breathing, slow heartbeat, extreme weakness, cold or clammy skin, feeling light-headed, fainting, or coma. What should I avoid while taking tramadol? • Do not drink alcohol while you are taking tramadol. Alcohol may cause a dangerous decrease in your breathing when used together with tramadol. • Avoid using drugs that make you sleepy (such as cold medicine, other pain medications, muscle relaxants, and medicine for seizures, depression or anxiety). These drugs may slow your breathing or increase drowsiness when used together with tramadol. • Tramadol can cause side effects that may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be awake and alert. What are the possible side effects of tramadol? • Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. • Stop using tramadol and call your doctor at once if you have any of these serious side effects: · seizure (convulsions); · a red, blistering, peeling skin rash; or · shallow breathing, weak pulse. • Continue taking tramadol and talk to your doctor if you have any of these less serious side effects: · dizziness, drowsiness, weakness; · nausea, vomiting, constipation, loss of appetite; · blurred vision; · flushing (redness, warmth, or tingly feeling); or · sleep problems (insomnia). • 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? • You may be more likely to have a seizure (convulsions) if you take tramadol while you are using certain other medicines. Do not take tramadol without telling your doctor if you also use any of the following: · an MAO inhibitor such as isocarboxazid (Marplan), tranylcypromine (Parnate), phenelzine (Nardil), or selegiline (Eldepryl, Emsam); or · an antidepressant such as amitriptyline (Elavil), citalopram (Celexa), clomipramine (Anafranil), desipramine (Norpramin), escitalopram (Lexapro), fluoxetine (Prozac, Sarafem), fluvoxamine (Luvox), imipramine (Tofranil), nortriptyline (Pamelor); paroxetine (Paxil), or sertraline (Zoloft). • Before taking tramadol, tell your doctor if you also use: · carbamazepine (Tegretol); · warfarin (Coumadin); · digoxin (Lanoxin, Lanoxicaps); · ketoconazole (Nizoral); · erythromycin (E-Mycin, E.E.S., Ery-Tab); · rifampin (Rifadin, Rimactane, Rifater); · St. John's wort; · quinidine (Quinaglute, Quinadex, Cardioquin, Quinora); or · drugs that make you sleepy (such as cold medicine, other pain medications, muscle relaxants, and medicine for seizures, depression or anxiety). • If you are using any of these drugs, you may not be able to use tramadol or you may need dosage adjustments or special tests during treatment. • There may be other drugs not listed that can affect tramadol. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor. Where can I get more information? • Your pharmacist has more information about tramadol written for health professionals that you may read. TRAMADOL HYDROCHLORIDE Manufacturer: Ortho-McNeil Prescribing Information DESCRIPTION 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. Its structural formula is: 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, hydroxypropyl methylcellulose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, titanium dioxide and wax. CLINICAL PHARMACOLOGY Pharmacodynamics ULTRAM is a centrally acting synthetic opioid analgesic. 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 (see CLINICAL PHARMACOLOGY , Pharmacokinetics ). 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 ULTRAM. Analgesia in humans begins approximately within one hour after administration and reaches a peak in approximately two to three hours. Apart from analgesia, ULTRAM 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, ULTRAM has no effect on heart rate, left-ventricular function or cardiac index. Orthostatic hypotension has been observed. Pharmacokinetics The analgesic activity of ULTRAM is due to both parent drug and the M1 metabolite (see CLINICAL PHARMACOLOGY , Pharmacodynamics ). 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 2.7L/kg and is only 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 (see PRECAUTIONS , Drug Interactions ). 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. 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. Steady-state plasma concentrations of both tramadol and M1 are achieved within two days with q.i.d. dosing. There is no evidence of self-induction (see Figure 1 and Table 1 below). Figure 1: Mean Tramadol and M1 Plasma Concentration Profiles after a Single 100 mg Oral Dose and after Twenty-Nine 100 mg Oral Doses of Tramadol HCl given TRAMADOL HYDROCHLORIDE Manufacturer: Ortho-McNeil Prescribing Information DESCRIPTION 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. Its structural formula is: 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, hydroxypropyl methylcellulose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, titanium dioxide and wax. CLINICAL PHARMACOLOGY Pharmacodynamics ULTRAM is a centrally acting synthetic opioid analgesic. 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 (see CLINICAL PHARMACOLOGY , Pharmacokinetics ). 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 ULTRAM. Analgesia in humans begins approximately within one hour after administration and reaches a peak in approximately two to three hours. Apart from analgesia, ULTRAM 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, ULTRAM has no effect on heart rate, left-ventricular function or cardiac index. Orthostatic hypotension has been observed. Pharmacokinetics The analgesic activity of ULTRAM is due to both parent drug and the M1 metabolite (see CLINICAL PHARMACOLOGY , Pharmacodynamics ). 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 2.7L/kg and is only 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 (see PRECAUTIONS , Drug Interactions ). 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. 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. Steady-state plasma concentrations of both tramadol and M1 are achieved within two days with q.i.d. dosing. There is no evidence of self-induction (see Figure 1 and Table 1 below). Figure 1: Mean Tramadol and M1 Plasma Concentration Profiles after a Single 100 mg Oral Dose and after Twenty-Nine 100 mg Oral Doses of Tramadol HCl given INDICATIONS AND USAGE ULTRAM is indicated for the management of moderate to moderately severe pain in adults. 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 reuptake inhibitors (SSRI antidepressants or anorectics), Tricyclic 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 (see also WARNINGS - Use with 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. Anaphylactoid 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 (see CONTRAINDICATIONS ). Respiratory Depression Administer ULTRAM cautiously in patients at risk for respiratory depression. In these patients alternative non-opioid 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 (see WARNINGS , Seizure Risk and OVERDOSAGE ). 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. (See Respiratory Depression .) 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. (See DRUG ABUSE AND DEPENDENCE .) These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely hallucinations. Clinical experience suggests that withdrawal symptoms may be relieved by tapering the medication. Physical Dependence and Abuse ULTRAM may induce psychic and physical dependence of the morphine-type (µ-opioid) (see DRUG ABUSE AND DEPENDENCE ). 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 (see OVERDOSAGE ). 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 (see DOSAGE AND ADMINISTRATION ). Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver. In cirrhotic patients, dosing reduction is recommended (see DOSAGE AND ADMINISTRATION ). With the prolonged half-life in these conditions, achievement of steady-state is delayed, so that it may take several days for elevated plasma concentrations to develop. 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 (see PRECAUTIONS , Labor and Delivery ). 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. 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 ULTRAM. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of ULTRAM and carbamazepine is not recommended. Use With Quinidine Tramadol is metabolized to M1 by CYP2D6. Quinidine is a selective inhibitor of that isoenzyme, so that concomitant administration of quinidine and ULTRAM 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 of ULTRAM with cimetidine does not result in clinically significant changes in tramadol pharmacokinetics. Therefore, no alteration of the ULTRAM 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 (see WARNINGS , Use With MAO Inhibitors ). Use With Digoxin and Warfarin Post-marketing surveillance has revealed rare reports of digoxin toxicity and alteration of warfarin effect, including elevation of prothrombin times. 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/m 2 or 0.36 times the maximum daily human dosage of 246 mg/m 2 ) 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/m 2 , 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/m 2 ) in male rats and 75 mg/kg (450 mg/m 2 ) in female rats. These dosages are 1.2 and 1.8 times the maximum daily human dosage of 246 mg/m 2 , respectively. Pregnancy, Teratogenic Effects: Pregnancy Catogery C Tramadol has been shown to be embryotoxic and fetotoxic in mice, (120 mg/kg or 360 mg/m 2 ), rats (>/=25 mg/kg or 150 mg/m 2 ) and rabbits (>/=75 mg/kg or 900 mg/m 2 ) at maternally toxic dosages, but was not teratogenic at these dose levels. These dosages on a mg/m 2 basis are 1.4, >/=0.6, and >/=3.6 times the maximum daily human dosage (246 mg/m 2 ) 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/m 2 ), rats (up to 80 mg/kg or 480 mg/m 2 ) or rabbits (up to 300 mg/kg or 3600 mg/m 2 ) 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/m 2 ), 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/m 2 ), 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/m 2 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/m 2 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. Labor and Delivery ULTRAM 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 (see DRUG ABUSE AND DEPENDENCE ). 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 ULTRAM, if any, on the later growth, development, and functional maturation of the child is unknown. 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 µg of tramadol (0.1% of the maternal dose) and 27 µg 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 (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION ). 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. ADVERSE REACTIONS ULTRAM 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 ULTRAM 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 ULTRAM and the active control groups, TYLENOL® with Codeine #3 (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 ULTRAM groups. ULTRAM may induce psychic and physical dependence of the morphine-type (µ-opioid). (See WARNINGS .) 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. The risk in patients with substance abuse has been observed to be higher. ULTRAM is associated with craving and tolerance development. 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. Clinical experience suggests that withdrawal symptoms may be relieved by reinstitution of opioid therapy followed by a gradual, tapered dose reduction of the medication combined with symptomatic support. OVERDOSAGE Serious potential consequences of overdosage are respiratory depression, lethargy, coma, seizure, cardiac arrest and death. (See WARNINGS .) Fatalities have been reported in post marketing in association with both intentional and unintentional overdose with ULTRAM. 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 ULTRAM, 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. 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. CATEGORIES, BRAND NAMES, FORMULARIES & COST OF THERAPY CATEGORIES: Analgesics; Antipyretics; Central Nervous System Agents; FDA Approved 1995 Mar; FDA Class 1S ("Standard Review"); Opiate Agonists (Controlled); Pain BRAND NAMES: Ultram DESCRIPTION Ultram (tramadol hydrochloride) 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 water/n-octanol partition coefficient 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, hydroxypropyl methylcellulose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, titanium dioxide and wax. CLINICAL PHARMACOLOGY Pharmacodynamics Ultram is a centrally acting synthetic analgesic compound that is not derived from natural sources nor is it chemically related to opiates. Although its mode of action is not completely understood from animal tests, at least two complementary mechanisms appear applicable; binding to µ-opioid receptors and inhibition of reuptake of norepinephrine and serotonin. Ultram opioid activity derives from low affinity binding of the parent compound to µ-opioid receptors and higher affinity binding of the M1 metabolite. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in µ-opioid binding. The contribution to human analgesia of tramadol relative to M1 is unknown. Tramadol-induced antinociception is only partially antagonized by the opiate naloxone in several animal tests. In addition, tramadol has been shown to inhibit reuptake of norepinephrine and serotonin in vitro, as have some other opioid analgesics. These latter mechanisms may contribute independently to the overall analgesic profile of Ultram. Onset of analgesia in humans is evident within one hour after administration and reaches a peak in approximately two to three hours. peak plasma concentrations are reached about two hours after administration, which correlates closely with the time to peak pain relief. Apart from analgesia, Ultram administration may produce a constellation of symptoms (including dizziness, somnolence, nausea, constipation, sweating and pruritus) similar to that of an opioid. However, tramadol causes significantly less respiratory depression than morphine. In contrast to morphine, tramadol has not been shown to cause histamine release. At therapeutic doses, Ultram has no effect on heart rate, left-ventricular function or cardiac index. Orthostatic changes in blood pressure have been observed. Pharmacokinetics 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%. Oral administration of Ultram with food does not significantly affect its rate or extent of absorption. Therefore, Ultram can be administered without regard to food. The mean peak (± SD) plasma concentration of racemic tramadol is 308 ± 78 ng/ml and occurs at approximately two hours after a single 100 mg oral dose in healthy subjects. At this dose the mean peak plasma concentration of the active mono-O-desmethyl metabolite, racemic M1 is 55 ± 20 ng/ml and occurs approximately three hours post-dose. The separate [+]- and [-]-enantiomers of tramadol generally follow a parallel time course in plasma after a single 100 mg oral dose of Ultram. Following 100 mg oral administration of tramadol the maximum plasma concentrations of the [-]-enantiomer of tramadol are somewhat lower than those of the [+]-enantiomer (148 ± 33 vs. 168 ± 36 ng/ml respectively). The [-]-M1 enantiomer is present at slightly higher plasma concentrations than the [+]-M1 enantiomer (35 ± 10 vs. 26 ± 13 ng/ml respectively). At steady state following a 100 mg q.i.d. regimen of tramadol, 3 out of 18 subjects formed relatively low amounts of [+]-M1, while their [-]-M1 formation remained similar to that of other subjects. This is believed not to be clinically significant. Plasma concentrations of racemic tramadol are predictable over a 50 mg to 100 mg single-dose range. This is also true under multiple-dose conditions. Steady state is achieved after two days of dosing Ultram by a 100 mg q.i.d. regimen (maximum plasma concentration was 592 ± 177 ng/ml). The plasma half-life of tramadol following a single and multiple dosing was 6 and 7 hours, respectively. This increase in half-life upon multiple dosing is not considered to be clinically significant or to warrant dosage adjustment for chronic use. Mean plasma racemic tramadol and racemic M1 concentration-versus-time profiles following a single 100 mg oral dose of Ultram and following twenty-nine 100 mg doses four times daily. 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. Although not confirmed in humans, tramadol has been shown in rats to cross the blood-brain barrier. 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 an unextractable metabolites. The major metabolic pathways appear to be N- and O-demethylation and glucuronidation or sulfation in the liver. Only the one metabolite (mono-O-desmethyltramadol denoted M1) is pharmacologically active. Production of M1 is dependent on the CYP2D6 isoenzyme of cytochrome P-450. Elimination: 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 (see DOSAGE AND ADMINISTRATION). The total amount of tramadol and M1 removed during a dialysis period is less than 7% of the administrator dose. Hepatic: Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver resulting in a larger area under the serum-concentration-versus-time to curve 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 (see DOSAGE AND ADMINISTRATION). Age: 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 slightly elevated (208 vs. 162 ng/ml) and the elimination half-life is slightly 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 (see DOSAGE AND ADMINISTRATION). 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. This difference may not be of any clinical significance. Clinical Studies: Ultram (tramadol hydrochloride) has been given in single oral doses of 50, 75, 100, 150 and 200 mg to patients with pain following surgical procedures (orthopedic, gynecological, cesarean section) 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 Ultram tended to provide analgesia superior to codeine sulfate 60 mg, but it was not effective as the combination of aspirin 650 mg with codeine phosphate 60 mg. In single-dose models of pain following surgical procedures, 150 mg provided analgesia generally comparable to the combination of acetaminophen 650 mg with propoxyphene napsylate 100 mg, with a tendency toward later peak effect. Ultram (tramadol hydrochloride) has been studied in three long-term controlled trials involving a total of 820 patients with 530 patients receiving Ultram. Patients with chronic conditions such as low back pain, cancer, neuropathic pain and orthopedic and joint conditions entered a double-blind phase of one to three months. Average daily doses of approximately 250 mg of Ultram in divided doses produced analgesia comparable with five doses of acetaminophen 300 mg with codeine phosphate 30 mg (Tylenol® with Codeine #3) daily five doses of aspirin 325 mg with codeine phosphate 30 mg daily and with two to three doses of acetaminophen 500 mg with oxycodone hydrochloride 5 mg (Tylox®) daily. Following the double-blind period, some patients took Ultram in an open period for up to two years. INDICATIONS Ultram is indicated for the management of moderate to moderately severe pain. CONTRAINDICATION Ultram should not be administered to patients who have previously demonstrated hypersensitivity to tramadol or in cases of acute intoxication with alcohol, hypnotics, centrally acting analgesics, opioids or psychotropic drugs. WARNING Seizure Risk Tramadol causes seizures in animal models, and a few seizures have been reported in humans receiving excessive single oral doses (700 mg) or large intravenous doses (300 mg). Administration of Ultram may enhance the seizure risk in patients taking MAO inhibitors, neuroleptics, other drugs that reduce the seizure threshold patients with epilepsy, or patients otherwise at increased risk for seizure. In animal studies, naloxone administration increased the risk of convulsions. Use with 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, phenothiazines, tranquilizers or sedative hypnotics. Use with MAO Inhibitors Ultram should be used with great caution in patients taking monoamine oxidase inhibitors, since tramadol inhibits the uptake of norepinephrine and serotonin. PRECAUTIONS Respiratory Depression When large doses of Ultram are administered with anesthetic medications or alcohol, respiratory depression may result. Cases of intraoperative respiratory depression, usually with large intravenous doses of tramadol and with concurrent administration of respiratory depressants, have been reported in foreign experience. Such cases should be treated as overdoses (see OVERDOSAGE). Ultram should be administered cautiously in patients at risk for respiratory depression. Increased Intracranial Pressure or Head Trauma Ultram should be used with caution in patients with increased intracranial pressure or head injury. Pupillary changes (miosis) from tramadol may obscure the existence, extent or course of intracranial pathology. Clinicians should also maintain a high index of suspicion for adverse drug reaction when evaluating mental status in these patients if they are receiving Ultram. Acute Abdominal Conditions The administration of Ultram may complicate the clinical assessment of patients with acute abdominal conditions. Patients Physically Dependent on Opioids Ultram is not recommended for patients who are dependent on opioids. Patients who have recently taken substantial amounts of opioids may experience withdrawal symptoms. Because of the difficulty in assessing dependence in patients who have previously received substantial amounts of opioid medication, caution should be used in the administration of Ultram to such patients. 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 (see DOSAGE AND ADMINISTRATION). Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver. In cirrhotic patients, dosing reduction is recommended (see DOSAGE AND ADMINISTRATION).

tell your doctor and pharmacist if you are allergic to tramadol or other narcotic pain medications such as meperidine (Demerol), morphine, codeine (or medications that contain codeine such as Tylenol with Codeine), hydrocodone (e.g., Vicodin), hydromorphone (e.g., Dilaudid), oxycodone (e.g., Percocet), propoxyphene (e.g., Darvon, Darvon N), any other medications, or corn. tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking. Be sure to mention any of the following: amiodarone (Cordarone, Pacerone); antihistamines; bupropion (Wellbutrin);celecoxib (Celebrex); cimetidine (Tagamet);cyclobenzaprine (Flexeril); digoxin (lanoxin); doxorubincin (Adriamycin);haloperidol (Haldol); imipenem and cilastatin (Primaxin); methadone (Dolophine, Methadose); monoamine oxidase (MAO) inhibitors, including isocarboxazid (Marplan), phenelzine (Nardil), selegiline (Eldepryl), and tranylcypromine (Parnate); medications for anxiety, mental illness, nausea, pain; medications for seizures, such as carbamazepine (Tegretol); metoclopramide (Reglan); nefazodone; promethazine (Phenergan); quinidine (Quinaglute; Quinidex); ranitidine (Zantac); ritonavir (Norvir, in Kaletra); sedatives; sleeping pills; selective serotonin reuptake inhibitors (SSRIs) such as citalopram (Celexa), fluoxetine (Prozac, Sarafem), fluvoxamine (Luvox), paroxetine (Paxil), and sertraline (Zoloft); ticlopidine (Ticlid); tranquilizers; tricylic antidepressants such as amitriptyline (Elavil), amoxapine (Asendin), clomipramine (Anafranil), desipramine (Norpramin), doxepin (Adapin, Sinequan), imipramine (Tofranil), nortriptyline (Aventyl, Pamelor), protriptyline (Vivactil), and trimipramine (Surmontil);venlafaxine (Effexor);warfarin (Coumadin). Many other medications may also interact with tramadol, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list. Your doctor may need to change the doses of your medications or monitor you carefully for side effects. tell your doctor if you have or have ever had seizures, head injury, infection in your brain or nervous system, increased intracranial pressure (increased pressure within the skull), diabetes, breathing problems or lung disease, or kidney or liver disease. Also tell your doctor if you drink or have ever drunk large amounts of alcohol, use or have ever used street drugs, or have overused prescription medications. tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking tramadol, call your doctor. if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking tramadol. you should know that this drug may make you drowsy and may affect your coordination. Do not drive a car or operate machinery until you know how this drug affects you. remember that alcohol can add to the drowsiness caused by this drug. The manufacturer states that tramadol should not be taken with alcohol containing beverages. you should know that tramadol may cause dizziness, lightheadedness, and fainting when you get up from a lying position. To avoid this, get out of bed slowly, resting your feet on the floor for a few minutes before standing up. Tramadol (INN) (IPA: [?tr?m?d?l]) is an atypical opioid which is a centrally acting analgesic, used for treating moderate to severe pain. It is a synthetic agent, unrelated to other opioids, and appears to have actions on the GABAergic, noradrenergic and serotonergic systems. Tramadol was developed by the German pharmaceutical company Grunenthal GmbH and marketed under the trade name Tramal. Grunenthal has also cross licensed the drug to many other pharmaceutical companies that market it under various names, some of which are listed below. Tramadol is available in both injectable (intravenous and/or intramuscular) and oral preparations. It is usually marketed as the hydrochloride salt (tramadol hydrochloride), which is associated with the brand name Ultram in the United States. It is also available in conjunction with acetaminophen as Ultracet. Dosages vary depending on the degree of pain experienced by the patient. Tramadol is approximately 10% as potent as morphine, when given by the IV/IM route. Oral doses range from 50–400 mg daily, with up to 600 mg daily when given IV/IM. Contents [hide] 1 Mechanism of action 2 Metabolism 3 Adverse effects 4 Dependence 5 Proprietary preparations 6 Often used to treat 7 Trivia 8 References 9 External links [edit] Mechanism of action The mechanism of action of tramadol has yet to be fully elucidated, but it is believed to work through modulation of the GABAergic, noradrenergic and serotonergic systems. The contribution of non-opioid activity is demonstrated by the analgesic effects of tramadol not being fully antagonised by the ?-opioid receptor antagonist naloxone. Tramadol is marketed as a racemic mixture with a weak affinity for the ?-opioid receptor (approximately 1/6000th that of morphine). The (+)-enantiomer is approximately four times more potent than the (-)-enantiomer in terms of ?-opioid receptor affinity and 5-HT reuptake, whereas the (-)-enantiomer is responsible for noradrenaline reuptake effects (Shipton, 2000). These actions appear to produce a synergistic analgesic effect, with (+)-tramadol exhibiting 10-fold higher analgesic activity than (-)-tramadol (Goeringer et al., 1997). The serotonergic modulating properties of tramadol mean that it has the potential to interact with other serotonergic agents. There is an increased risk of serotonin syndrome when tramadol is taken in combination with serotonin reuptake inhibitors (e.g. SSRIs), since these agents not only potentiate the effect of 5-HT but also inhibit tramadol's metabolism. It is suggested that tramadol could be effective for alleviating symptoms of depression and anxiety because of its action on GABAergic, noradrenergic and serotonergic systems. However, use of the drug for treatment of such disorders by a health professional is unlikely. [edit] Metabolism Tramadol undergoes hepatic metabolism via the cytochrome P450 isozyme CYP2D6, being O- and N-demethylated to 5 different metabolites. Of these, M1 is the most significant since it has 200 times the ?-affinity of (+)-tramadol, and furthermore has an elimination half-life of 9 hours compared to 6 hours for tramadol itself. In the 6% of the population who have slow CYP2D6 activity, there is therefore a slightly reduced analgesic effect. Phase II hepatic metabolism renders the metabolites water-soluble and they are renally excreted. Thus reduced doses may be used in renal and hepatic impairment. [edit] Adverse effects The most commonly reported adverse drug reactions are nausea, vomiting and sweating. Drowsiness is reported, although it is less of an issue compared to other opioids. Respiratory depression, a common side effect of most opioids, is not clinically significant in normal doses. By itself, it does not increase the seizure threshold, though it may do if used in combination with SSRIs, tricyclic antidepressants, or in patients with epilepsy. [edit] Dependence Some controversy exists regarding the dependence liability of tramadol. Grunenthal has promoted it as an opioid with a low risk of dependence compared to traditional opioids, claiming little evidence of such dependence in clinical trials. They offer the theory that since the M1 metabolite is the principal agonist at ?-opioid receptors, the delayed agonist activity reduces dependence liability. The noradrenaline reuptake effects may also play a role in reducing dependence. Despite these claims it is apparent, in community practice, that dependence to this agent does occur. This would be expected since analgesic and dependence effects mediated by the same ?-opioid receptor. However, this dependence liability is considered relatively low by health authorities, such that tramadol is classified as a Schedule 4 Prescription Only Medicine in Australia, rather than as a Schedule 8 Controlled Drug like other opioids (Rossi, 2004). Similarly, tramadol is not currently scheduled by the U.S. DEA, unlike other opioid analgesics. Nevertheless, the Prescribing Information for Ultram warns that tramadol "may induce psychological and physical dependence of the morphine-type." [edit] Proprietary preparations Grunenthal, which still owns the patent to tramadol, has cross-licensed the agent to various pharmaceutical companies internationally. Thus tramadol is marketed under many trade names including: Adolonta, Contramal, Crispin, Lumidol, Nobligan, Siverol, Tiparol, Toplagic, Tradol, Tradolan, Tralgit, Tramacet, Tramacip, Tramadin, Tramal, Tramahexal, Tramazac, Tramedo, Ultracet, Ultram, Zamadol and Zydol. [edit] Often used to treat Severe pain Most types of Neuralgia, including Trigeminal Neuralgia Multiple other conditions that result in severe pain to the victim. [edit] Trivia Rapper Russell Jones (a.k.a. Ol' Dirty Bastard) died from a combination of cocaine and a Tramadol overdose on November 13, 2004. [edit] References Goeringer K, Logan B, Christian G. "Identification of tramadol and its metabolites in blood from drug-related deaths and drug-impaired drivers.". J Anal Toxicol 21 (7): 529-37. PMID 9399121. (2004) Ed. Rossi S Australian Medicines Handbook. Adelaide: Australian Medicines Handbook. ISBN 0-9578521-4-2. Shipton E (2000). "Tramadol--present and future.". Anaesth Intensive Care 28 (4): 363-74. PMID 10969362. Ultram (PDF). Ortho-McNeil. – U.S. Prescribing Information McDiarmid T, Mackler L, Schneider D (January 2005). "Clinical inquiries. What is the addiction risk associated with tramadol?". J Fam Pract 54 (1): 72-3. PMID 15623411. tramadol Drug information Generic Name: tramadol (TRAM a dol) Brand Names: Ultram, Ultram ER What is the most important information I should know about tramadol? • You should not take tramadol if you have ever been addicted to drugs or alcohol. • Take tramadol exactly as it was prescribed for you. Do not take it in larger doses or for longer than recommended by your doctor. Do not take more than 300 milligrams of tramadol in one day. • Do not stop using this medication suddenly without talking to your doctor. You may need to gradually reduce the dose. Withdrawal symptoms may occur when you stop using tramadol. Withdrawal symptoms include anxiety, sweating, nausea, diarrhea, tremors, chills, hallucinations, trouble sleeping, or breathing problems. Call your doctor at once if you have any of these withdrawal symptoms after you stop using tramadol. • Do not crush the tramadol tablet. This medicine is for oral (by mouth) use only. Powder from a crushed tablet should not be inhaled or diluted with liquid and injected into the body. Using this medicine by inhlation or injection can cause life-threatening side effects, overdose, or death. • Seizures (convulsions) have occurred in some people taking tramadol. You may be more likely to have a seizure while taking tramadol if you have a history of seizures or head injury, a metabolic disorder, or if you are taking certain medicines such as antidepressants, muscle relaxers, or medicine for nausea and vomiting. • Seek emergency medical attention if you think you have used too much of this medicine. A tramadol overdose can be fatal. Symptoms of a tramadol overdose may include drowsiness, shallow breathing, slow heartbeat, extreme weakness, cold or clammy skin, feeling light-headed, fainting, or coma. • While you are taking tramadol, do not drink alcohol or use drugs that make you sleepy (such as cold medicine, other pain medications, muscle relaxants, and medicine for seizures, depression or anxiety). These drugs may slow your breathing or increase drowsiness when used together with tramadol. • Tramadol can cause side effects that may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be awake and alert. What is tramadol? • Tramadol is a narcotic pain reliever. • Tramadol is used to treat moderate to severe pain. Tramadol extended-release is used to treat moderate to severe chronic pain when treatment is needed around the clock. • Tramadol may also be used for purposes other than those listed in this medication guide. What should I discuss with my healthcare provider before taking tramadol? • You should not take tramadol if you have ever been addicted to drugs or alcohol. • Do not take tramadol if you are intoxicated (drunk), or if you have recently used any of the following drugs: · alcohol; · narcotic pain medicine; · sedatives or tranquilizers (such as Valium); · medicine for depression or anxiety; · medicine for mental illness (such as bipolar disorder, schizophrenia); or · street drugs. • Seizures have occurred in some people taking tramadol. Your risk of a seizure may be higher if you have any of these conditions: · a history of drug or alcohol addiction; · a history of epilepsy or other seizure disorder; · a history of head injury; or · a metabolic disorder. • Talk with your doctor about your individual risk of having a seizure from this medicine. • Before taking tramadol, tell your doctor if you have: · kidney disease; · liver disease; · a stomach disorder; or · a history of depression, mental illness, or suicide attempt. • If you have any of these conditions, you may not be able to use tramadol, or you may need a dosage adjustment or special tests during treatment. • FDA pregnancy category C. This medication may be harmful to an unborn baby. Tramadol may also cause serious or fatal side effects in a newborn if the mother uses the medication during pregnancy or labor. Tell your doctor if you are pregnant or plan to become pregnant during treatment. • Tramadol can pass into breast milk and may harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby. • Older adults may be more sensitive to the effects of tramadol. If you are over 65, your doctor may recommend a lower dose. • Tramadol should not be given to a child younger than 16 years of age. How should I take tramadol? • Take tramadol exactly as it was prescribed for you. Do not take it in larger doses or for longer than recommended by your doctor. Do not take more than 300 milligrams of tramadol in one day. • Take each dose with a full glass of water. • Tramadol can be taken with or without food, but take it the same way each time. • Do not crush the tramadol tablet. This medicine is for oral (by mouth) use only. Powder from a crushed tablet should not be inhaled or diluted with liquid and injected into the body. Using this medicine by inhlation or injection can cause life-threatening side effects, overdose, or death. • Do not crush, chew, or break an extended-release tablet. Swallow the pill whole. It is specially made to release medicine slowly in the body. Breaking the pill would cause too much of the drug to be released at one time. • If you use the tramadol extended-release tablet, the tablet shell may pass into your stools (bowel movements). This is normal and does not mean that you are not receiving enough of the medicine. • Tramadol may be habit-forming. Tell your doctor if you feel the medicine is not working as well in relieving your pain. Do not change your dose without talking to your doctor. • Do not stop using this medication suddenly without talking to your doctor. You may need to gradually reduce the dose. Withdrawal symptoms may occur when you stop using tramadol. Withdrawal symptoms include anxiety, sweating, nausea, diarrhea, tremors, chills, hallucinations, trouble sleeping, or breathing problems. Call your doctor at once if you have any of these withdrawal symptoms after you stop using tramadol. • Store tramadol at room temperature away from moisture and heat. What happens if I miss a 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. What happens if I overdose? • Seek emergency medical attention if you think you have used too much of this medicine. A tramadol overdose can be fatal. • Symptoms of a tramadol overdose may include drowsiness, shallow breathing, slow heartbeat, extreme weakness, cold or clammy skin, feeling light-headed, fainting, or coma. What should I avoid while taking tramadol? • Do not drink alcohol while you are taking tramadol. Alcohol may cause a dangerous decrease in your breathing when used together with tramadol. • Avoid using drugs that make you sleepy (such as cold medicine, other pain medications, muscle relaxants, and medicine for seizures, depression or anxiety). These drugs may slow your breathing or increase drowsiness when used together with tramadol. • Tramadol can cause side effects that may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be awake and alert. What are the possible side effects of tramadol? • Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. • Stop using tramadol and call your doctor at once if you have any of these serious side effects: · seizure (convulsions); · a red, blistering, peeling skin rash; or · shallow breathing, weak pulse. • Continue taking tramadol and talk to your doctor if you have any of these less serious side effects: · dizziness, drowsiness, weakness; · nausea, vomiting, constipation, loss of appetite; · blurred vision; · flushing (redness, warmth, or tingly feeling); or · sleep problems (insomnia). • 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? • You may be more likely to have a seizure (convulsions) if you take tramadol while you are using certain other medicines. Do not take tramadol without telling your doctor if you also use any of the following: · an MAO inhibitor such as isocarboxazid (Marplan), tranylcypromine (Parnate), phenelzine (Nardil), or selegiline (Eldepryl, Emsam); or · an antidepressant such as amitriptyline (Elavil), citalopram (Celexa), clomipramine (Anafranil), desipramine (Norpramin), escitalopram (Lexapro), fluoxetine (Prozac, Sarafem), fluvoxamine (Luvox), imipramine (Tofranil), nortriptyline (Pamelor); paroxetine (Paxil), or sertraline (Zoloft). • Before taking tramadol, tell your doctor if you also use: · carbamazepine (Tegretol); · warfarin (Coumadin); · digoxin (Lanoxin, Lanoxicaps); · ketoconazole (Nizoral); · erythromycin (E-Mycin, E.E.S., Ery-Tab); · rifampin (Rifadin, Rimactane, Rifater); · St. John's wort; · quinidine (Quinaglute, Quinadex, Cardioquin, Quinora); or · drugs that make you sleepy (such as cold medicine, other pain medications, muscle relaxants, and medicine for seizures, depression or anxiety). • If you are using any of these drugs, you may not be able to use tramadol or you may need dosage adjustments or special tests during treatment. • There may be other drugs not listed that can affect tramadol. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor. Where can I get more information? • Your pharmacist has more information about tramadol written for health professionals that you may read. -------------------------------------------------------------------------------- • Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed. • Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/ or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist. Copyright 1996-2006 Cerner Multum, Inc. Version: 9.02. Revision date: 6/ 12/ 06. 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, hydroxypropyl methylcellulose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, titanium dioxide and wax. CLINICAL PHARMACOLOGY Pharmacodynamics ULTRAM is a centrally acting synthetic opioid analgesic. 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 (see CLINICAL PHARMACOLOGY , Pharmacokinetics ). 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 ULTRAM. Analgesia in humans begins approximately within one hour after administration and reaches a peak in approximately two to three hours. Apart from analgesia, ULTRAM 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, ULTRAM has no effect on heart rate, left-ventricular function or cardiac index. Orthostatic hypotension has been observed. Pharmacokinetics The analgesic activity of ULTRAM is due to both parent drug and the M1 metabolite (see CLINICAL PHARMACOLOGY , Pharmacodynamics ). 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 2.7L/kg and is only 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 (see PRECAUTIONS , Drug Interactions ). 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. 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 en