Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/2261
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ULTRACET (Tablet)
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dailymed-instance:dosage |
For the short-term (five days or less) management
of acute pain, the recommended dose of ULTRACET is 2 tablets
every 4 to 6 hours as needed for pain relief up to a maximum of 8 tablets
per day.<br/>Individualization of Dose: In patients with creatinine clearances of less than
30 mL/min, it is recommended that the dosing interval of ULTRACET be
increased not to exceed 2 tablets every 12 hours. Dose selection for an elderly
patient should be cautious, in view of the potential for greater sensitivity
to adverse events.
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dailymed-instance:descripti... |
ULTRACET (tramadol hydrochloride/acetaminophen)
Tablets combines two analgesics, tramadol 37.5 mg and acetaminophen 325 mg. 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 299.84. Tramadol hydrochloride is a white,
bitter, crystalline and odorless powder. The
chemical name for acetaminophen is N-acetyl-p-aminophenol. Its structural formula is: The
molecular weight of acetaminophen is 151.17. Acetaminophen is an analgesic
and antipyretic agent which occurs as a white, odorless, crystalline powder,
possessing a slightly bitter taste. ULTRACET tablets
contain 37.5 mg tramadol hydrochloride and 325 mg acetaminophen and are light
yellow in color. Inactive ingredients in the tablet are powdered cellulose,
pregelatinized corn starch, sodium starch glycolate, corn starch, magnesium
stearate, hypromellose, polyethylene glycol, polysorbate 80, titanium dioxide,
iron oxide, and carnauba wax.
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dailymed-instance:clinicalP... |
The following information is based on studies of tramadol
alone or acetaminophen alone, except where otherwise noted:<br/>Pharmacodynamics: Tramadol 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
(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 tramadol. 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.<br/>Acetaminophen: Acetaminophen is a non-opiate, non-salicylate
analgesic.<br/>Pharmacokinetics: Tramadol is administered as a racemate and both
the [-] and [+] forms of both tramadol and M1 are detected in the circulation.
The pharmacokinetics of plasma tramadol and acetaminophen following oral administration
of one ULTRACET tablet are shown in Table 1. Tramadol has
a slower absorption and longer half-life when compared to acetaminophen. A single dose pharmacokinetic study of ULTRACET in
volunteers showed no drug interactions between tramadol and acetaminophen.
Upon multiple oral dosing to steady state, however, the bioavailability of
tramadol and metabolite M1 was lower for the combination tablets compared
to tramadol administered alone. The decrease in AUC was 14% for (+)-tramadol,
10.4% for (-)-tramadol, 11.9% for (+)-M1 and 24.2% for (-)-M1. The cause of
this reduced bioavailability is not clear. Following single or multiple dose
administration of ULTRACET, no significant change in acetaminophen
pharmacokinetics was observed when compared to acetaminophen given alone.<br/>Absorption: The absolute bioavailability of tramadol from
ULTRACET tablets has not been determined. Tramadol hydrochloride
has a mean absolute bioavailability of approximately 75% following administration
of a single 100 mg oral dose of ULTRAM tablets. The mean
peak plasma concentration of racemic tramadol and M1 after administration
of two ULTRACET tablets occurs at approximately two and three
hours, respectively, post-dose. Peak plasma
concentrations of acetaminophen occur within one hour and are not affected
by co-administration with tramadol. Oral absorption of acetaminophen following
administration of ULTRACET occurs primarily in the small
intestine.<br/>Food Effects: When ULTRACET was administered
with food, the time to peak plasma concentration was delayed for approximately
35 minutes for tramadol and almost one hour for acetaminophen. However, peak
plasma concentration or the extent of absorption of either tramadol or acetaminophen
were not affected. The clinical significance of this difference is unknown.<br/>Distribution: The volume of distribution of tramadol was 2.6
and 2.9 L/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. Acetaminophen
appears to be widely distributed throughout most body tissues except fat.
Its apparent volume of distribution is about 0.9 L/kg. A relative small portion
(~20%) of acetaminophen is bound to plasma protein.<br/>Metabolism: Following oral administration, tramadol is extensively
metabolized by a number of pathways, including CYP2D6 and CYP3A4, as well
as by conjugation of parent and metabolites. Approximately 30% of the dose
is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted
as metabolites. The major metabolic pathways appear to be N - and O- demethylation and
glucuronidation or sulfation in the liver. Metabolite M1 (O -desmethyltramadol) is pharmacologically active in animal models.
Formation of M1 is dependent on CYP2D6 and as such is subject to inhibition,
which may affect the therapeutic response . Approximately 7% of the population
has reduced activity of the CYP2D6 isoenzyme of cytochrome P450. These individuals
are "poor metabolizers" of debrisoquine, dextromethorphan, tricyclic antidepressants,
among other drugs. Based on a population PK analysis of Phase 1 studies in
healthy subjects, concentrations of tramadol were approximately 20% higher
in "poor metabolizers" versus "extensive metabolizers", while M1 concentrations
were 40% lower. In vitro drug interaction
studies in human liver microsomes indicates that inhibitors of CYP2D6 such
as fluoxetine and its metabolite norfluoxetine, amitriptyline and quinidine
inhibit the metabolism of tramadol to various degrees. The full pharmacological
impact of these alterations in terms of either efficacy or safety is unknown.
Concomitant use of SEROTONIN re-uptake INHIBITORS and MAO INHIBITORS may enhance
the risk of adverse events, including seizure and serotonin syndrome. Acetaminophen is primarily metabolized in the liver by
first-order kinetics and involves three principal separate pathways: In adults, the majority of acetaminophen is conjugated
with glucuronic acid and, to a lesser extent, with sulfate. These glucuronide-,
sulfate-, and glutathione-derived metabolites lack biologic activity. In premature
infants, newborns, and young infants, the sulfate conjugate predominates.<br/>Elimination: Tramadol is eliminated primarily through metabolism
by the liver and the metabolites are eliminated primarily by the kidneys.
The plasma elimination half-lives of racemic tramadol and M1 are approximately
5���6 and 7 hours, respectively, after administration of ULTRACET.
The apparent plasma elimination half-life of racemic tramadol increased to
7���9 hours upon multiple dosing of ULTRACET. The half-life of acetaminophen is about 2 to 3 hours in
adults. It is somewhat shorter in children and somewhat longer in neonates
and in cirrhotic patients. Acetaminophen is eliminated from the body primarily
by formation of glucuronide and sulfate conjugates in a dose-dependent manner.
Less than 9% of acetaminophen is excreted unchanged in the urine.<br/>Special Populations:<br/>Renal: The pharmacokinetics of ULTRACET in
patients with renal impairment has not been studied. Based on studies using
tramadol alone, excretion of tramadol and metabolite M1 is reduced in patients
with creatinine clearance of less than 30 mL/min, adjustment of dosing regimen
in this patient population is recommended . The total amount of tramadol and M1 removed during a 4-hour dialysis
period is less than 7% of the administered dose based on studies using tramadol
alone.<br/>Hepatic: The pharmacokinetics and tolerability of ULTRACET in
patients with impaired hepatic function has not been studied. Since tramadol
and acetaminophen are both extensively metabolized by the liver, the use of
ULTRACET in patients with hepatic impairment is not recommended
(see PRECAUTIONS and DOSAGE
AND ADMINISTRATION).<br/>Geriatric: A population pharmacokinetic analysis of data
obtained from a clinical trial in patients with chronic pain treated with
ULTRACET which included 55 patients between 65 and 75 years
of age and 19 patients over 75 years of age, showed no significant changes
in pharmacokinetics of tramadol and acetaminophen in elderly patients with
normal renal and hepatic function .<br/>Gender: Tramadol clearance was 20% higher in female subjects
compared to males on four phase I studies of ULTRACET in
50 male and 34 female healthy subjects. The clinical significance of this
difference is unknown.<br/>Pediatric: Pharmacokinetics of ULTRACET tablets
has not been studied in pediatric patients below 16 years of age.
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dailymed-instance:activeIng... | |
dailymed-instance:supply |
ULTRACET (tramadol hydrochloride/acetaminophen)
Tablets with tramadol 37.5 mg and acetaminophen 325 mg are light yellow, coated,
capsule-shaped tablets imprinted "O-M" on one side and "650" on the other
are available as follows: Dispense in a tight container. Store at 25��C (77��F);
excursions permitted to 15���30��C (59���86��F).
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dailymed-instance:activeMoi... | |
dailymed-instance:inactiveI... |
dailymed-ingredient:carnauba_wax,
dailymed-ingredient:corn_starch,
dailymed-ingredient:hypromellose,
dailymed-ingredient:iron_oxide,
dailymed-ingredient:magnesium_stearate,
dailymed-ingredient:polyethylene_glycol,
dailymed-ingredient:polysorbate_80,
dailymed-ingredient:powdered_cellulose,
dailymed-ingredient:pregelatinized_corn_starch,
dailymed-ingredient:sodium_starch_glycolate,
dailymed-ingredient:titanium_dioxide
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dailymed-instance:genericMe... |
tramadol hydrochloride and acetaminophen
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dailymed-instance:fullName |
ULTRACET (Tablet)
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dailymed-instance:adverseRe... |
Table 2 reports the incidence rate of treatment-emergent
adverse events over five days of ULTRACET use in clinical
trials (subjects took an average of at least 6 tablets per day). Incidence at
least 1%, causal relationship at least possible or greater: the
following lists adverse reactions that occurred with an incidence of at least
1% in single-dose or repeated-dose clinical trials of ULTRACET. Body as a Whole���Asthenia, fatigue, hot flushes Central and Peripheral Nervous System���Dizziness, headache, tremor Gastrointestinal System���Abdominal
pain, constipation, diarrhea, dyspepsia, flatulence, dry mouth, nausea, vomiting Psychiatric Disorders���Anorexia, anxiety, confusion, euphoria, insomnia, nervousness,
somnolence Skin
and Appendages���Pruritus, rash, increased sweating. Selected Adverse events
occurring at less than 1%: the following lists clinically relevant
adverse reactions that occurred with an incidence of less than 1% in ULTRACET clinical
trials. Body
as a Whole���Chest pain, rigors, syncope, withdrawal syndrome Cardiovascular Disorders���Hypertension, aggravated hypertension, hypotension Central and Peripheral Nervous
System���Ataxia, convulsions, hypertonia, migraine, aggravated
migraine, involuntary muscle contractions, paresthesias, stupor, vertigo Gastrointestinal System���Dysphagia, melena, tongue edema Hearing and Vestibular Disorders���Tinnitus Heart
Rate and Rhythm Disorders���Arrhythmia, palpitation, tachycardia Liver and Biliary System���Hepatic function abnormal Metabolic and Nutritional Disorders���Weight decrease Psychiatric Disorders���Amnesia, depersonalization,
depression, drug abuse, emotional lability, hallucination, impotence, paroniria,
abnormal thinking Red
Blood Cell Disorders���Anemia Respiratory System���Dyspnea Urinary System���Albuminuria, micturition disorder, oliguria, urinary retention Vision Disorders���Abnormal vision Other
clinically significant adverse experiences previously reported with tramadol
hydrochloride. Other events
which have been reported with the use of tramadol products and for which a
causal association has not been determined include: vasodilation, orthostatic
hypotension, myocardial ischemia, pulmonary edema, allergic reactions (including
anaphylaxis and urticaria, Stevens-Johnson syndrome/TENS), cognitive dysfunction,
difficulty concentrating, depression, suicidal tendency, hepatitis liver failure
and gastrointestinal bleeding. Reported laboratory abnormalities included
elevated creatinine and liver function tests. Serotonin syndrome (whose symptoms
may include mental status change, hyperreflexia, fever, shivering, tremor,
agitation, diaphoresis, seizures and coma) has been reported with tramadol
when used concomitantly with other serotonergic agents such as SSRIs and MAOIs. Other clinically significant
adverse experiences previously reported with acetaminophen. Allergic reactions (primarily skin rash) or
reports of hypersensitivity secondary to acetaminophen are rare and generally
controlled by discontinuation of the drug and, when necessary, symptomatic
treatment.
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dailymed-instance:indicatio... |
ULTRACET is indicated for the short-term
(five days or less) management of acute pain.
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dailymed-instance:routeOfAd... | |
dailymed-instance:name |
ULTRACET
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