Tramadol (Ultram)

Ultram brand of
TRAMADOL HYDROCHLORIDE

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).
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 Patients being treated with Ultram should receive the following information:
Ultram may impair mental or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery.
Carcinogenesis, Mutagenesis, Impairment of Fertility 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.
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 (dosing orally up to 30 mg/kg 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 rate carcinogenicity study.
No effects on fertility were observed for tramadol at oral dose levels up to 50 mg/kg in male rats and 75 mg/kg in female rats.
Teratogenic Effects: Usage in Pregnancy Pregnancy Category C 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.
Tramadol has been shown to be embryotoxic and fetotoxic in mice, rats and rabbits and maternally toxic doses 3 to 15 times the maximum human dose or higher (120 mg/kg in mice, 25 mg/kg or higher in rats and 75 mg/kg or higher in rabbits), but was not teratogenic at these dose levels. No harm to the fetus due to tramadol was seen at doses that were not maternally toxic.
No drug-related teratogenic effects were observed in progeny of mice, rats or rabbits treated with tramadol by various routes (up to 140 mg/kg for mice, 80 mg/kg for rats or 300 mg/kg for rabbits). Embryo and fetal toxicity consisted primarily of decreased fetal weights, skeletal ossification and increased supemumerary ribs at maternally toxic dose levels. Transient delays in developmental or behavioral parameters were also seen in pups in rat dams allowed to deliver. Embryo and fetal lethality were reported only in one rabbit study at 300 mg/kg, a dose that would cause extreme maternal toxicity in the rabbit.
In peri- and post-natal studies in rats, progeny of dams receiving oral (gavage) dose levels of 50 mg/kg or greater had decreased weights, and pup survival was decreased early in lactation at 80 mg/kg (6 to 10 times the maximum human dose). No toxicity was observed for progeny of dams receiving 8, 10, 20, 25 or 40 mg/kg. Maternal toxicity was observed at all dose levels, but effects on progeny were evident only at higher dose levels where maternal toxicity was more severe.
Labor and Delivery Ultram should not be used in pregnant women prior to or during labor unless the potential benefits outweigh the risks, because safe use in pregnancy has not been established. 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 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 pediatric use of Ultram (tramadol hydrochloride) is not recommended because safety and efficacy in patients under 16 years of age have not been established.
Use in the Elderly In subjects over the age of 75 years, serum concentrations are slightly elevated and the elimination half-life is slightly elevated and the elimination half-life is slightly prolonged. The aged also can be expected to vary more widely in their ability to tolerate adverse drug effects. Daily doses in excess of 300 mg are not recommended in patients over 75 (see DOSAGE AND ADMINISTRATION).
DRUG INTERACTION
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.
Concomitant administration of Ultram (tramadol hydrochloride) with carbamazepine causes a significant increase in tramadol metabolism, presumably through metabolic induction by carbamazepine. Patients receiving chronic carbamazepine doses of up to 800 mg daily may require up to twice the recommended dose of Ultram.
Tramadol is metabolized to M1 by the CYP2D6 P-450 isoenzyme. 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 this effect have not been fully investigated, and the effect on quinidine concentrations is unknown.
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.
Interactions with MAO Inhibitors due to interference with detoxification mechanisms, have been reported for some centrally acting drugs (see WARNINGS).
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 1 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. (TABLE 1)
Table 1 - Tramadol HCl, Adverse Reactions
Cumulative Incidence of Adverse Reactions for Ultram (tramadol HCl)
In Chronic Trials of Nonmalignant Pain
-----------------------------------------------------------------------
Up to 7 Days Up to 30 Days Up to 90 Days
-----------------------------------------------------------------------
Dizziness/Vertigo 26% 31% 33%
Nausea 24% 34% 40%
Constipation 24% 38% 46%
Headache 18% 26% 32%
Somnolence 16% 23% 25%
Vomiting 9% 13% 17%
Pruritus 8% 10% 11%
"CNS Stimulation" 7% 11% 14%
Asthenia 6% 11% 12%
Sweating 6% 7% 9%
Dyspepsia 5% 9% 13%
Dry Mouth 5% 9% 10%
Diarrhea 5% 6% 10%
-----------------------------------------------------------------------
1 "CNS Stimulation" is a composite of nervousness, anxiety, agitation,
tremor, spasticity, euphoria, emotional lability and hallucinations.
Incidence less than 5% possibly casually related: TABLE 2 lists adverse reactions that occurred with an incidence of less than 5% in clinical trials, and for which the possibility of a casual relationship with Ultram exists. Reactions are separated according to whether the incidence was greater than 1%. (TABLE 2)
Table 2 - Tramadol HCl, Adverse Reactions
Possibly Ultram Related Adverse Reactions
with an Incidence of Less Than 5%
-----------------------------------------------------------------------
Incidence of Adverse Reaction
------------------------------------------------
Body System From 1% to <5% Less Than 1%
-----------------------------------------------------------------------
Body as a Whole Malaise Allergic reaction;
Accidental injury;
Weight loss
Cardiovascular Vasodilation Syncope; Orthostatic
hypotension; Tachycardia
Central Nervous System Anxiety; Confusion; Seizure (see WARNINGS);
Coordination Paresthesia; Cognitive
disturbance; dysfunction;
Euphoria; Nervous- Hallucinations; Tremor;
ness; Sleep dis- Amnesia; Difficulty in
order concentration; Abnormal
gait
Gastrointestinal Abdominal pain;
Anorexia; Flatulence
Musculoskeletal Hypertonia
Respiratory Dyspnea
Skin Rash Urticaria, Vesicles
Special Senses Visual disturbance Dysgeusia
Urogenital Urinary retention; Dysuria; Menstrual dis-
Urinary frequency; order
Menopausal symptoms
Other adverse experiences, casual relationship undetermined: A variety of other adverse events were reported infrequently in patients taking Ultram during clinical trials. A casual relationship between Ultram and these events has not been determined. However, the most significant events are listed below as alerting information to the physician.
Body as a whole: Suicidal tendency.
Cardiovascular: Abnormal ECG, hypertension, myocardial ischemia, palpitations.
Central Nervous System: Migraine
Gastrointestinal: Gastrointestinal bleeding, hepatitis, stomatitis.
Laboratory abnormalities: Creatinine increase, elevated liver enzymes, hemoglobin decrease, proteinuria.
Sensory: Cataracts, deafness, tinnitus.
DRUG ABUSE AND DEPENDENCE
Although tramadol can produce drug dependence of the µ-opioid type (like codeine or dextropropoxyphene) and potentially may be abused, there has been little evidence of abuse in foreign clinical experience. In clinical trials, tramadol produced effects similar to an opioid, and at supratherapeutic doses was recognized as an opioid in subjective/behavioral studies. Tolerance development has been reported to be relatively mild and withdrawal when present, is not considered to be as severe as that produced by other opioids. Part of tramadol's activity and some extension of the duration of µ-opioid activity. Delayed µ-opioid activity is believed to reduce a drug's abuse liability.
An assay for tramadol is not included in routine urine screens for drugs of abuse.
OVERDOSAGE:
Few cases of overdoses with tramadol have been reported. Estimates of ingested dose in foreign fatalities have been in the range of 3 to 5 g. A 3 g intentional overdose in a patient in the clinical studies produced emesis and no sequelae. The lowest dose reported to be associated with a fatality was possibly between 500 and 1000 mg in a 40 kg woman, but details of the case are not completely known.
Serious potential consequences of overdosage are respiratory depression and seizure. Naloxone will reverse some, but not all symptoms caused by overdosage with Ultram so that general supportive treatment is recommended. Primary attention should be given to the assurance of adequate respiratory exchange. Hemodialysis is not expected to be helpful because it removes only a small percentage of the administered dose. Convulsions occurring in mice following the administration of toxic doses of tramadol could be suppressed with barbiturates or benzodiazepines, but were increased with naloxone. Naloxone did not change the lethality of an overdose in mice.
DOSAGE AND ADMINISTRATION
For the treatment of painful conditions Ultram (tramadol hydrochloride) 50 mg to 100 mg can be administered as needed for relief every four to six hours, not to exceed 400 mg per day. For moderate pain Ultram 50 mg may be adequate as the initial dose, and for more severe pain Ultram 100 mg is usually more effective as the initial dose.
Individualization of Dose Available data do not suggest that a dosage adjustment is necessary in elderly patients 65 to 75 years of age unless they also have renal or hepatic impairment. For elderly patients over 75 years old not more than 300 mg/day in divided doses as above is recommended. In all patients with creatine 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 patients with cirrhosis is 50 mg every 12 hours. Patients receiving chronic carbamazepine doses up to 800 mg daily require up to twice the recommended dose of Ultram.
HOW SUPPLIED
Ultram (tramadol hydrochloride) 50 mg tablet (white, film-coated capsule-shaped tablet) engraved "McNeil" on one side and "659" on the other side.
Ultram (tramadol hydrochloride) 50 mg tablet - NDC 0045-0659 bottles of 100 tablets, and packages of 100 unit doses in blister packs (10 cards of 10 tablets each).
Dispense in a tight container. Store at controlled room temperature (15o to 30oC, (59o to 86oF).
(Ortho-McNeil Pharmaceutical, 3/95, 633-19-227-1)
(95/3/3)
HOW SUPPLIED - EQUIVALENTS NOT AVAILABLE:
Tablet, Uncoated - Oral - 50 mg
100's $60.00 ULTRAM, Mc Neil Pharm 00045-0659-60
100's $66.00 ULTRAM, U.D., Mc Neil Pharm 00045-0659-10

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