Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3315
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ULTRAM (Tablet, Coated)
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dailymed-instance:dosage |
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.<br/>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.
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dailymed-instance:descripti... |
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
pregelatinized corn starch, modified starch (corn), hypromellose, lactose,
magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate
80, sodium starch glycolate, titanium dioxide and carnauba wax.
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dailymed-instance:clinicalP... |
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��-opioid receptors and weak inhibition
of re-uptake 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 ULTRAM. Analgesia in humans begins approximately within
one hour after administration and reaches a peak in approximately two to threehours. 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.<br/>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.<br/>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 dosesalthough 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 q.i.d.<br/>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.<br/>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.<br/>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 and serotonin syndrome.<br/>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.<br/>Special Populations:<br/>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.<br/>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 .<br/>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).<br/>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.
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dailymed-instance:activeIng... | |
dailymed-instance:supply |
ULTRAM (tramadol hydrochloride) Tablets
- 50 mg are white, capsule-shaped, coated tablet imprinted "ULTRAM" on one
side and "06 59" on the scored side. Bottles of 100
tablets: NDC 0045-0659-60 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:inactiveI... |
dailymed-ingredient:carnauba_wax,
dailymed-ingredient:hypromellose,
dailymed-ingredient:lactose,
dailymed-ingredient:magnesium_stearate,
dailymed-ingredient:microcrystalline_cellulose,
dailymed-ingredient:modified_starch_(corn),
dailymed-ingredient:polyethylene_glycol,
dailymed-ingredient:polysorbate_80,
dailymed-ingredient:pregelatinized_corn_starch,
dailymed-ingredient:sodium_starch_glycolate,
dailymed-ingredient:titanium_dioxine
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Acute Abdominal Conditions: The administration of ULTRAM may complicate
the clinical assessment of patients with acute abdominal conditions.<br/>Use in Renal and Hepatic Disease: Impaired renal function results in a decreased rate and extent
of excretion of tramadol and its active metabolite, M1. In patients with creatinine
clearances of less than 30 mL/min, dosing reduction is recommended . Metabolism of tramadol and M1 is reduced in patients with advanced
cirrhosis of the liver. In cirrhotic patients, dosing reduction is recommended
(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.<br/>Information for Patients:<br/>Drug Interactions:<br/>CYP2D6 and CYP3A4 Inhibitors: Concomitant administration of CYP2D6 and/or CYP3A4 inhibitors
(see
CLINICAL PHARMACOLOGY, Pharmacokinetics), such as quinidine,
fluoxetine, paroxetine and amitriptyline (CYP2D6 inhibitors), and ketoconazole
and erythromycin (CYP3A4 inhibitors), may reduce metabolic clearance of tramadol
increasing the risk for serious adverse events including seizures and serotonin
syndrome.<br/>Serotonergic Drugs: There have been postmarketing reports of serotonin syndrome
with use of tramadol and SSRIs/SNRIs or MAOIs and��2-adrenergic blockers.
Caution is advised when ULTRAM is coadministered with other
drugs that may affect the serotonergic neurotransmitter systems, such as SSRIs,
MAOIs, triptans, linezolid (an antibiotic which is a reversible non-selective
MAOI), lithium, or St. John's Wort. If concomitant treatmentof ULTRAM with
a drug affecting the serotonergic neurotransmitter system is clinically warranted,
careful observation of the patient is advised, particularly during treatment
initiation and dose increases (see WARNINGS,
Serotonin Syndrome).<br/>Triptans: Based on the mechanism of action of tramadol and the potential
for serotonin syndrome, caution is advised when ULTRAM is
coadministered with a triptan. If concomitant treatment of ULTRAM with
a triptan is clinically warranted, careful observation of the patient is advised,
particularly during treatment initiation and dose increases (see WARNINGS, Serotonin
Syndrome).<br/>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.<br/>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.<br/>Potential for Other Drugs to Affect Tramadol: 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.<br/>Potential for Tramadol to Affect Other Drugs: 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.<br/>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.<br/>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.<br/>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/mor 0.36 times the maximum daily human dosage of 246 mg/m)
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, 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) in male rats and 75 mg/kg (450 mg/m) in
female rats. These dosages are 1.2 and 1.8 times the maximum daily human dosage
of 246 mg/m, respectively.<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy Category C: Tramadol has been shown to be embryotoxic and fetotoxic in
mice, (120 mg/kg or 360 mg/m), rats (���25 mg/kg or 150 mg/m)
and rabbits (���75 mg/kg or 900 mg/m) at maternally toxic
dosages, but was not teratogenic at these dose levels. These dosages on a
mg/mbasis are 1.4,���0.6, and���3.6 times the maximum
daily human dosage (246 mg/m) 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), rats (up to 80 mg/kg or 480 mg/m)
or rabbits (up to 300 mg/kg or 3600 mg/m) 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),
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), respectively.<br/>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/mor 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/mor 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.<br/>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 . 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.<br/>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��g of tramadol (0.1% of the maternal
dose) and 27��g of M1.<br/>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.<br/>Geriatric Use: In general, dose selection for an elderly patient should
be cautious, usually starting at the low end of the dosing range, reflecting
the greater frequency of decreased hepatic, renal or cardiac function and
of concomitant disease or other drug therapy. In patients over 75 years of
age, daily doses in excess of 300 mg are not recommended . A total of 455 elderly (65 years of age
or older) subjects were exposed to ULTRAM in controlled clinical
trials. Of those, 145 subjects were 75 years of age and older. In
studies including geriatric patients, treatment-limiting adverse events were
higher in subjects over 75 years of age compared to those under 65 years of
age. Specifically, 30% of those over 75 years of age had gastrointestinal
treatment-limiting adverse events compared to 17% of those under 65 years
of age. Constipation resulted in discontinuation of treatment in 10% of those
over 75.
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dailymed-instance:genericMe... |
tramadol hydrochloride
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dailymed-instance:fullName |
ULTRAM (Tablet, Coated)
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dailymed-instance:adverseRe... |
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 werein 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. Incidence 1% to less than
5% possibly causally related: the following lists adverse reactions
that occurred with an incidence of 1% to less than 5% in clinical trials,
and for which the possibility of a causal relationship with ULTRAM exists. Body as a Whole: Malaise. Cardiovascular: Vasodilation. Central Nervous System: Anxiety, Confusion, Coordination
disturbance, Euphoria, Miosis, Nervousness, Sleep disorder. Gastrointestinal: Abdominal pain, Anorexia, Flatulence. Musculoskeletal: Hypertonia. Skin: Rash. Special
Senses: Visual disturbance. Urogenital:Menopausal symptoms, Urinary frequency, Urinary retention. Incidence less than 1%, possibly causally related: the
following lists adverse reactions that occurred with an incidence of less
than 1% in clinical trials and/or reported in post-marketing experience. Body as a Whole: Accidental injury, Allergic reaction,
Anaphylaxis, Death, Suicidal tendency, Weight loss, Serotonin syndrome (mental
status change, hyperreflexia, fever, shivering, tremor, agitation, diaphoresis,
seizures and coma). Cardiovascular: Orthostatic hypotension, Syncope, Tachycardia. Central Nervous System: Abnormal gait, Amnesia,
Cognitive dysfunction, Depression, Difficulty in concentration, Hallucinations,
Paresthesia, Seizure , Tremor. Respiratory: Dyspnea. Skin: Stevens-Johnson syndrome/Toxic epidermal necrolysis, Urticaria,
Vesicles. Special Senses: Dysgeusia. Urogenital: Dysuria, Menstrual disorder. Other
adverse experiences, causal relationship unknown: A variety of other
adverse events were reported infrequently in patients taking ULTRAM during
clinical trials and/or reported in post-marketing experience. A causal relationship
between ULTRAM and these events has not been determined.
However, the most significant events are listed below as alerting information
to the physician. Cardiovascular: Abnormal ECG, Hypertension, Hypotension, Myocardial ischemia, Palpitations,
Pulmonary edema, Pulmonary embolism. Central
Nervous System: Migraine, Speech disorders. Gastrointestinal: Gastrointestinal bleeding, Hepatitis,
Stomatitis, Liver failure. Laboratory
Abnormalities: Creatinine increase, Elevated liver enzymes, Hemoglobin
decrease, Proteinuria. Sensory: Cataracts, Deafness, Tinnitus.
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dailymed-instance:indicatio... |
ULTRAMis indicated for the management of
moderate to moderately severe pain in adults.
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dailymed-instance:routeOfAd... | |
dailymed-instance:name |
ULTRAM
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