Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/269
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ULTRAM ER (Tablet, Extended Release)
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ULTRAM ER should not be used in patients with: . ULTRAM ER must be swallowed whole and must not be chewed, crushed, or split . Adults (18 years of age and over) Patients Not Currently on Tramadol Immediate-Release Products For patients not currently treated with tramadol immediate-release (IR) products, ULTRAM ER should be initiated at a dose of 100 mg once daily and titrated up as necessary by 100-mg increments every five days to relief of pain and depending upon tolerability. ULTRAM ER should not be administered at a dose exceeding 300 mg per day. Patients Currently on Tramadol Immediate-Release Products For patients maintained on tramadol IR products, calculate the 24-hour tramadol IR dose and initiate a total daily dose of ULTRAM ER rounded down to the next lowest 100 mg increment. The dose may subsequently be individualized according to patient need. Due to limitations in flexibility of dose selection with ULTRAM ER, some patients maintained on tramadol IR products may not be able to convert to ULTRAM ER.
ULTRAM ER should not be administered at a dose exceeding 300 mg per day. The concomitant use of ULTRAM ER with other tramadol products is not recommended . Individualization of Dose Good pain management practice dictates that the dose be individualized according to patient need using the lowest beneficial dose. Start at the lowest possible dose and titrate upward as tolerated to achieve an adequate effect. Clinical studies of ULTRAM ER have not demonstrated a clinical benefit at a total daily dose exceeding 300 mg. In general, dosing of an elderly patient (over 65 years of age) should be initiated cautiously, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy. ULTRAM ER should be administered with even greater caution in patients over 75 years, due to the greater frequency of adverse events seen in this population.
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ULTRAM ER (tramadol hydrochloride) is a centrally acting synthetic analgesic in an extended-release formulation. The chemical name is (��) cis-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochloride. Its structural formula is: Figure 1 The molecular weight of tramadol HCl is 299.8. It is a white, bitter, crystalline and odorless powder that 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 ER tablets contain 100, 200 or 300 mg of tramadol HCl in an extended-release formulation. The tablets are white to off-white in color and contain the inactive ingredients ethylcellulose, dibutyl sebacate, polyvinyl pyrrolidone, sodium stearyl fumarate, colloidal silicon dioxide, and polyvinyl alcohol.
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Mechanism of Action ULTRAM ER 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��-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��-opioid receptors. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in��-opioid binding. Tramadol-induced analgesia is only partially antagonized by the opiate antagonist naloxone in several animal tests. The relative contribution of both tramadol and M1 to human analgesia is dependent upon the plasma concentrations of each compound. Tramadol has been shown to inhibit reuptake of norepinephrine and serotonin in vitro, as have some other opioid analgesics. These mechanisms may contribute independently to the overall analgesic profile of tramadol. The relationship between exposure of tramadol and M1 and efficacy has not been evaluated in the ULTRAM ER clinical studies. Apart from analgesia, tramadol administration may produce a constellation of symptoms (including dizziness, somnolence, nausea, constipation, sweating and pruritus) similar to that of other opioids. In contrast to morphine, tramadol has not been shown to cause histamine release. At therapeutic doses, tramadol has no effect on heart rate, left-ventricular function or cardiac index. Orthostatic hypotension has been observed.<br/>Pharmacokinetics: The analgesic activity of tramadol is due to both parent drug and the M1 metabolite. ULTRAM ER is administered as a racemate and both the [-] and [+] forms of both tramadol and M1 are detected in the circulation. The pharmacokinetics of ULTRAM ER are approximately dose-proportional over a 100-400 mg dose range in healthy subjects. The observed tramadol AUC values for the 400-mg dose were 26% higher than predicted based on the AUC values for the 200-mg dose. The clinical significance of this finding has not been studied and is not known. Absorption In healthy subjects, the bioavailability of a ULTRAM ER 200 mg tablet relative to a 50 mg every six hours dosing regimen of the immediate-release dosage form (ULTRAM) was approximately 85-90%. Consistent with the extended-release nature of the formulation, there is a lag time in drug absorption following ULTRAM ER administration. The mean peak plasma concentrations of tramadol and M1 after administration of ULTRAM ER tablets to healthy volunteers are attained at about 12 h and 15 h, respectively, after dosing (see Table 1 and Figure 2). Following administration of the ULTRAM ER, steady-state plasma concentrations of both tramadol and M1 are achieved within four days with once daily dosing. The mean (%CV) pharmacokinetic parameter values for ULTRAM ER 200 mg administered once daily and tramadol HCl immediate-release (ULTRAM) 50 mg administered every six hours are provided in Table 1. Figure 2: Mean Steady-State Tramadol (a) and M1 (b) Plasma Concentrations on Day 8 Post Dose after Administration of 200 mg ULTRAM ER Once-Daily and 50 mg ULTRAM Every 6 Hours. Food Effects After a single dose administration of 200 mg ULTRAM ER tablet with a high fat meal, the Cand AUCof tramadol decreased 28% and 16%, respectively, compared to fasting conditions. Mean Twas increased by 3 hr (from 14 hr under fasting conditions to 17 hr under fed conditions). While ULTRAM ER may be taken without regard to food, it is recommended that it be taken in a consistent manner. 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��g/mL. Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range. Metabolism Tramadol is extensively metabolized after oral administration. The major metabolic pathways appear to be N���(mediated by CYP3A4 and CYP2B6) and O���(mediated by CYP2D6) demethylation and glucuronidation or sulfation in the liver. One metabolite (O-desmethyl tramadol, 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 . Elimination Tramadol is eliminated primarily through metabolism by the liver and the metabolites are eliminated primarily by the kidneys. 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 mean terminal plasma elimination half-lives of racemic tramadol and racemic M1 after administration of ULTRAM ER are approximately 7.9 and 8.8 hours, respectively.<br/>Special Populations: Renal Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. The pharmacokinetics of tramadol were studied in patients with mild or moderate renal impairment after receiving multiple doses of ULTRAM ER 100 mg. There is no consistent trend observed for tramadol exposure related to renal function in patients with mild (CLcr: 50-80 mL/min) or moderate (CLcr: 30-50 mL/min) renal impairment in comparison to patients with normal renal function. However, exposure of M1 increased 20-40% with increased severity of the renal impairment (from normal to mild and moderate). ULTRAM ER has not been studied in patients with severe renal impairment (CLcr<30 mL/min). The limited availability of dose strengths of ULTRAM ER does not permit the dosing flexibility required for safe use in patients with severe renal impairment. Therefore, ULTRAM ER should not be used in patients with severe renal impairment . The total amount of tramadol and M1 removed during a 4-hour dialysis period is less than 7% of the administered dose. Hepatic Pharmacokinetics of tramadol was studied in patients with mild or moderate hepatic impairment after receiving multiple doses of ULTRAM ER 100 mg. The exposure of (+)- and (-)-tramadol was similar in mild and moderate hepatic impairment patients in comparison to patients with normal hepatic function. However, exposure of (+)- and (-)-M1 decreased ~50% with increased severity of the hepatic impairment (from normalto mild and moderate). The pharmacokinetics of tramadol after the administration of ULTRAM ER has not been studied in patients with severe hepatic impairment. After the administration of tramadol immediate-release tablets to patients with advanced cirrhosis of the liver, tramadol area under the plasma concentration time curve was larger and the tramadol and M1 half-lives were longer than subjects with normal hepatic function. The limited availability of dose strengths of ULTRAM ER does not permit the dosingflexibility required for safe use in patients with severe hepatic impairment. Therefore, ULTRAM ER should not be used in patients with severe hepatic impairment . Geriatric The effect of age on the absorption of tramadol from ULTRAM ER in patients over the age of 65 years has not been studied and is unknown . Gender Based on pooled multiple-dose pharmacokinetics studies for ULTRAM ER in 166 healthy subjects (111 males and 55 females), the dose-normalized AUC values for tramadol were somewhat higher in females than in males. There was a considerable degree of overlap in values between male and female groups. Dosage adjustment based on gender is not recommended.<br/>Drug Interactions: The formation of the active metabolite, M1, is mediated by CYP2D6. Approximately 7% of the population has reduced activity of the CYP2D6 isoenzyme of cytochrome P-450. Based on a population PK analysis of Phase I studies with immediate-release tablets in healthy subjects, concentrations of tramadol were approximately 20% higher in "poor metabolizers" versus "extensive metabolizers," while M1 concentrations were40% lower. In vitro drug interaction studies in human liver microsomes indicate that inhibitors of CYP2D6 (fluoxetine, 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. Tramadol is also metabolized by CYP3A4. Administration of CYP3A4 inhibitors, such as ketoconazole and erythromycin, or inducers, such as rifampin and St. John's Wort, with ULTRAM ER may affect the metabolism of tramadol leading to altered tramadol exposure . Quinidine Tramadol is metabolized to M1 by CYP2D6. A study was conducted to examine the effect of quinidine, a selective inhibitor of CYP2D6, on the pharmacokinetics of tramadol by administering 200 mg quinidine two hours before the administration of ULTRAM ER 100 mg. The results demonstrated that the exposure of tramadol increased 50-60% and the exposure of M1 decreased 50-60% . In vitro drug interaction studies in human liver microsomes indicate that tramadol has no effect on quinidine metabolism. Carbamazepine Carbamazepine, a CYP3A4 inducer, increases tramadol metabolism. Patients taking carbamazepine may have a significantly reduced analgesic effect of tramadol. Because of the seizure risk associated with tramadol, concomitant administration of ULTRAM ER and carbamazepine is not recommended . Cimetidine Concomitant administration of tramadol immediate-release tablets with cimetidine does not result in clinically significant changes in tramadol pharmacokinetics. No alteration of the ULTRAM ER dosage regimen with cimetidine is recommended.
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ULTRAM ER (tramadol hydrochloride) Extended-release tablets are supplied in the following package and dose strength forms: 100 mg: Round, convex, white to off-white tablets imprinted with "100" over "ER" on one side in black ink Bottle of 30 tablets���NDC 0062-0653-30 200 mg: Round, convex, white to off-white tablets imprinted with "200" over "ER" on one side in black ink Bottle of 30 tablets���NDC 0062-0655-30 300 mg: Round, convex, white to off-white tablets imprinted with "300" over "ER" on one side in black ink Bottle of 30 tablets���NDC 0062-0657-30 Store at 25��C (77��F); excursions permitted to 15-30��C (59 - 86��F).
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tramadol hydrochloride
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ULTRAM ER (Tablet, Extended Release)
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ULTRAM ER was administered to a total of 3108 patients during studies conducted in the U.S. These included four double-blind studies in patients with osteoarthritis and/or chronic low back pain and one open-label study in patients with chronic non-malignant pain. A total of 901 patients were 65 years or older. The frequency of adverse events generallyincreased with doses from 100 mg to 400 mg in the two pooled, twelve-week, randomized, double-blind, placebo-controlled studies in patients with chronic non-malignant pain (see Table 2). The following adverse events were reported from all the chronic pain studies (N=3108). The lists below include adverse events not otherwise noted in Table 2. Adverse events with incidence rates of 1.0% to<5.0% Eye disorders: vision blurred Gastrointestinal disorders: abdominal pain upper, dyspepsia, abdominal pain, sore throat General disorders: weakness, pain, feeling hot, influenza like illness, fall, rigors, lethargy, pyrexia, chest pain Infections and infestations: nasopharyngitis, upper respiratory tract infection, sinusitis, influenza, gastroenteritis viral, urinary tract infection, bronchitis Investigations: blood creatine phosphokinase increased, weight decreased Metabolism and nutrition disorders: appetite decreased Musculoskeletal, connective tissue and bone disorders: arthralgia, back pain, pain in limb, neck pain Nervous system disorders: tremor, paresthesia, hypoesthesia Psychiatric disorders: nervousness, anxiety, depression, restlessness Respiratory, thoracic and mediastinal disorders: sneezing, cough, rhinorrhea, nasal congestion, dyspnea, sinus congestion Skin and subcutaneous tissue disorders: sweating increased, dermatitis Vascular disorders: hot flushes, vasodilatation Adverse events with incidence rates of 0.5% to<1.0% and serious adverse events reported in at least 2 patients. Cardiac disorders: palpitations, myocardial infarction Ear and labyrinth disorders: tinnitus, vertigo Gastrointestinal disorders: flatulence, toothache, constipation aggravated, appendicitis, pancreatitis General disorders: feeling jittery, edema lower limb, shivering, joint swelling, malaise, drug withdrawal syndrome, peripheral swelling Hepato-biliary disorders: cholelithiasis, cholecystitis Infections and infestations: cellulitis, ear infection, gastroenteritis, pneumonia, viral infection Injury and poisoning: joint sprain, muscle injury Investigations: alanine aminotransferase increased, blood pressure increased, aspartate aminotransferase increased, heart rate increased, blood glucose increased, liver function tests abnormal , Musculoskeletal, connective tissue and bone disorders: muscle cramps, muscle spasms, joint stiffness, muscle twitching, myalgia, osteoarthritis aggravated Nervous system disorders: migraine, sedation, syncope, disturbance in attention, dizziness aggravated Psychiatric disorders: euphoric mood, irritability, libido decreased, sleep disorder, agitation, disorientation, abnormal dreams Renal and urinary disorders: difficulty in micturition, urinary frequency, hematuria, dysuria, urinary retention Respiratory, thoracic and mediastinal disorders: yawning Skin and subcutaneous tissue disorders: contusion, piloerection, clamminess, night sweats, urticaria Vascular disorders: hypertension aggravated, hypertension, peripheral ischemia
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ULTRAM ER is indicated for the management of moderate to moderately severe chronic pain in adults who require around-the-clock treatment of their pain for an extended period of time.
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ULTRAM ER
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