Watson tramadol hcl 8-04 kr

Tramadol
Hydrochloride
DESCRIPTION
Tramadol hydrochloride tablets are a centrally acting analgesic. The chemical name for tramadolhydrochloride is (±)cis-2-[(Dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol hydro-chloride. Its structural formula is: Molecular formula: C16H25NO2 • HCl Molecular weight: 299.84 Tramadol hydrochloride is a white, bitter, crystalline and odorless powder. It is readily soluble inwater and ethanol and has a pKa of 9.41. The n-octanol/water log partition coefficient (logP) is1.35 at pH 7. Each tablet, for oral administration contains 50 mg of tramadol hydrochloride andis white in color. In addition, each tablet contains the following inactive ingredients: croscarmel-lose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose,polyethylene glycol, polysorbate, pregelatinized starch and titanium dioxide.
CLINICAL PHARMACOLOGY
Pharmacodynamics
Tramadol hydrochloride is a centrally acting synthetic opioid analgesic. Although its mode ofaction is not completely understood, from animal tests, at least two complementary mechanismsappear applicable: binding of parent and M1 metabolite to µ-opioid receptors and weak inhibitionof reuptake of norepinephrine and serotonin.
Opioid activity is due to both low affinity binding of the parent compound and higher affinitybinding of the O-demethylated metabolite M1 to µ-opioid receptors. In animal models, M1 is upto 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 havesome other opioid analgesics. These mechanisms may contribute independently to the overallanalgesic profile of tramadol hydrochloride. Analgesia in humans begins approximately withinone hour after administration and reaches a peak in approximately two to three hours.
Apart from analgesia, tramadol hydrochloride administration may produce a constellation ofsymptoms (including dizziness, somnolence, nausea, constipation, sweating and pruritus) similarto that of other opioids. In contrast to morphine, tramadol has not been shown to cause histaminerelease. At therapeutic doses, tramadol hydrochloride has no effect on heart rate, left-ventricularfunction or cardiac index. Orthostatic hypotension has been observed.
Pharmacokinetics
The analgesic activity of tramadol hydrochloride 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 meanabsolute bioavailability of a 100 mg oral dose is approximately 75%. The mean peak plasmaconcentration of racemic tramadol and M1 occurs at two and three hours, respectively, afteradministration in healthy adults. In general, both enantiomers of tramadol and M1 follow a paral-lel 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 withq.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.
Tramadol
(Multiple Dose)
Tramadol
(Single Dose)
M1
(Multiple Dose)
M1
(Single Dose)
Mean (%CV) Pharmacokinetic Parameters for Racemic Tramadol and M1 Metabolite
a SD = Single dose, MD = Multiple dose, p.o. = Oral administration, i.v. = Intravenous administration, q.i.d. = Four times daily b F represents the oral bioavailability of tramadolc Not applicable Food Effects
Oral administration of tramadol hydrochloride with food does not significantly affect its rate orextent of absorption, therefore, tramadol hydrochloride can be administered without regard tofood.
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 plasmaproteins is approximately 20% and binding also appears to be independent of concentration up to10 mcg/mL. Saturation of plasma protein binding occurs only at concentrations outside theclinically 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 Interactions).
Approximately 7% of the population has reduced activity of the CYP2D6 isoenzyme of
cytochrome P-450. These individuals are "poor metabolizers" of debrisoquine, dextromethor-
phan, 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 micro-
somes 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 concentra-
tions 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 areeliminated primarily by the kidneys. The mean terminal plasma elimination half-lives of racemictramadol and racemic M1 are 6.3 ± 1.4 and 7.4 ± 1.4 hours, respectively. The plasma eliminationhalf-life of racemic tramadol increased from approximately six hours to seven hours uponmultiple dosing.
Special Populations
Renal
Impaired renal function results in a decreased rate and extent of excretion of tramadol and itsactive 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 admin-
istered 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 plasmaclearance was 6.4 mL/min/kg in males and 5.7 mL/min/kg in females following a 100 mg IV doseof 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 curvecompared to males. The clinical significance of this difference is unknown.
Clinical Studies
Tramadol hydrochloride has been given in single oral doses of 50, 75 and 100 mg to patients withpain following surgical procedures and pain following oral surgery (extraction of impactedmolars).
In single-dose models of pain following oral surgery, pain relief was demonstrated in somepatients at doses of 50 mg and 75 mg. A dose of 100 mg tramadol hydrochloride tended to pro-vide analgesia superior to codeine sulfate 60 mg, but it was not as effective as the combination ofaspirin 650 mg with codeine phosphate 60 mg.
Tramadol hydrochloride has been studied in three long-term controlled trials involving a total of820 patients, with 530 patients receiving tramadol hydrochloride. Patients with a variety of chronicpainful conditions were studied in double-blind trials of one to three months duration. Averagedaily doses of approximately 250 mg of tramadol hydrochloride in divided doses were generallycomparable 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 twoto three doses of acetaminophen 500 mg with oxycodone hydrochloride 5 mg (TYLOX®) daily.
Tylenol® with Codeine #3 and Tylox® are the registered trademarks of Johnson RW.
Titration Trials
In a randomized, blinded clinical study with 129 to 132 patients per group, a 10-day titration to adaily tramadol hydrochloride 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 overonly 4 days or no titration. Figure 2: Time to Discontinuation Due to Nausea/Vomiting Percent Discontinuing
Days in Double-Blind
INDICATIONS AND USAGE
Tramadol hydrochloride tablets are indicated for the management of moderate to moderatelysevere pain in adults.
CONTRAINDICATIONS
Tramadol hydrochloride should not be administered to patients who have previously demonstratedhypersensitivity to tramadol, any other component of this product or opioids. Tramadolhydrochloride is contraindicated in any situation where opioids are contraindicated, includingacute intoxication with any of the following: alcohol, hypnotics, narcotics, centrally actinganalgesics, opioids or psychotropic drugs. Tramadol hydrochloride may worsen central nervoussystem and respiratory depression in these patients.
WARNINGS
Seizure Risk
Seizures have been reported in patients receiving tramadol hydrochloride within the rec-
ommended dosage range. Spontaneous post-marketing reports indicate that seizure risk is
increased with doses of tramadol hydrochloride above the recommended range.
Concomitant use of tramadol hydrochloride 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 tramadol hydrochloride 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 tramadol hydrochloride over-
dose, naloxone administration may increase the risk of seizure.
Anaphylactoid Reactions
Serious and rarely fatal anaphylactoid reactions have been reported in patients receiving therapy
with tramadol hydrochloride. 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
tramadol hydrochloride (see CONTRAINDICATIONS).
Respiratory Depression
Administer tramadol hydrochloride cautiously in patients at risk for respiratory depression. In
these patients alternative non-opioid analgesics should be considered. When large doses of
tramadol hydrochloride 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
Tramadol hydrochloride should be used with caution and in reduced dosages when administeredto patients receiving CNS depressants such as alcohol, opioids, anesthetic agents, narcotics,phenothiazines, tranquilizers or sedative hypnotics. Tramadol hydrochloride increases the risk ofCNS and respiratory depression in these patients.
Increased Intracranial Pressure or Head Trauma
Tramadol hydrochloride should be used with caution in patients with increased intracranial pres-
sure 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 suspi-
cion for adverse drug reaction when evaluating altered mental status in these patients if they are
receiving tramadol hydrochloride tablets. (See Respiratory Depression.)
Use in Ambulatory Patients
Tramadol hydrochloride may impair the mental and or physical abilities required for the per-formance of potentially hazardous tasks such as driving a car or operating machinery. The patientusing this drug should be cautioned accordingly.
Use with MAO Inhibitors and Serotonin Re-uptake Inhibitors
Use tramadol hydrochloride with great caution in patients taking monoamine oxidase inhibitors.
Animal studies have shown increased deaths with combined administration. Concomitant use of tramadol hydrochloride with MAO inhibitors or SSRI’s increases the risk of adverse events,including seizure and serotonin syndrome.
Withdrawal
Withdrawal symptoms may occur if tramadol hydrochloride 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. Other symptoms that have been seen less frequently with tramadol hydrochloride
discontinuation include: panic attacks, severe anxiety, and paresthesias. Clinical experience
suggests that withdrawal symptoms may be avoided by tapering tramadol hydrochloride at the
time of discontinuation.
Physical Dependence and Abuse
Tramadol hydrochloride may induce psychic and physical dependence of the morphine-type
(µ-opioid) (see DRUG ABUSE AND DEPENDENCE). Tramadol hydrochloride should not be
used in opioid-dependent patients. Tramadol hydrochloride 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 tramadol hydrochloride 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 tramadol hydrochloride may complicate the clinical assessment of patientswith 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 itmay take several days for elevated plasma concentrations to develop.
Information for Patients
• Tramadol hydrochloride tablets may impair mental or physical abilities required for the per- formance of potentially hazardous tasks such as driving a car or operating machinery. • Tramadol hydrochloride tablets should not be taken with alcohol containing beverages. • Tramadol hydrochloride tablets 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 ofother drugs when tramadol is administered concomitantly at therapeutic doses. Tramadol does notappear to induce its own metabolism in humans, since observed maximal plasma concentrationsafter multiple oral doses are higher than expected based on single-dose data. Tramadol is a mildinducer of selected drug metabolism pathways measured in animals.
Use with Carbamazepine
Patients taking carbamazepine may have a significantly reduced analgesic effect of tramadol
hydrochloride. Because carbamazepine increases tramadol metabolism and because of the seizure
risk associated with tramadol, concomitant administration of tramadol hydrochloride and
carbamazepine is not recommended.
Use with Quinidine
Tramadol is metabolized to M1 by the CYP2D6. Quinidine is a selective inhibitor of that
isoenzyme, so that concomitant administration of quinidine and tramadol hydrochloride 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 adminis-tration with inhibitors of CYP2D6 such as fluoxetine, paroxetine, and amitriptyline could resultin some inhibition of the metabolism of tramadol.
Use with Cimetidine
Concomitant administration of tramadol hydrochloride with cimetidine does not result in clini-
cally significant changes in tramadol pharmacokinetics. Therefore, no alteration of the tramadol
hydrochloride 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 warfarineffect, including elevation of prothrombin times.
Carcinogenesis, Mutagenesis, Impairment of Fertility
A slight, but statistically significant, increase in two common murine tumors, pulmonary andhepatic, was observed in a mouse carcinogenicity study, particularly in aged mice. Mice were dosed orally up to 30 mg/kg (90 mg/m2 or 0.36 times the maximum daily human dosage of 246 mg/m2) for approximately two years, although the study was not done with the MaximumTolerated Dose. This finding is not believed to suggest risk in humans. No such finding occurredin a rat carcinogenicity study (dosing orally up to 30 mg/kg, 180 mg/m2, or 0.73 times the maxi-mum daily human dosage).
Tramadol was not mutagenic in the following assays: Ames Salmonella microsomal activationtest, CHO/HPRT mammalian cell assay, mouse lymphoma assay (in the absence of metabolicactivation), dominant lethal mutation tests in mice, chromosome aberration test in Chinesehamsters, and bone marrow micronucleus tests in mice and Chinese hamsters. Weakly mutagenicresults occurred in the presence of metabolic activation in the mouse lymphoma assay andmicronucleus test in rats. Overall, the weight of evidence from these tests indicates that tramadoldoes 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/m2)in male rats and 75 mg/kg (450 mg/m2) in female rats. These dosages are 1.2 and 1.8 times themaximum daily human dosage of 246 mg/m2, respectively.
Pregnancy
Teratogenic Effects: Pregnancy Category C
Tramadol has been shown to be embryotoxic and fetotoxic in mice, (120 mg/kg or 360 mg/m2),rats (≥25 mg/kg or 150 mg/m2) and rabbits (≥75 mg/kg or 900 mg/m2) at maternally toxicdosages, but was not teratogenic at these dose levels. These dosages on a mg/m2 basis are 1.4,≥0.6, and ≥3.6 times the maximum daily human dosage (246 mg/m2) 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/m2), rats (up to 80 mg/kg or 480 mg/m2) or rabbits (up to 300 mg/kg or 3600 mg/m2)treated with tramadol by various routes. Embryo and fetal toxicity consisted primarily ofdecreased fetal weights, skeletal ossification and increased supernumerary ribs at maternally toxicdose levels. Transient delays in developmental or behavioral parameters were also seen in pupsfrom rat dams allowed to deliver. Embryo and fetal lethality were reported only in one rabbit studyat 300 mg/kg (3600 mg/m2), a dose that would cause extreme maternal toxicity in the rabbit. Thedosages listed for mouse, rat and rabbit are 1.7, 1.9 and 14.6 times the maximum daily humandosage (246 mg/m2), 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/m2 or 1.2 times the maximum daily human tramadoldosage) or greater had decreased weights, and pup survival was decreased early in lactation at 80 mg/kg (480 mg/m2 or 1.9 times the maximum daily human dose).
There are no adequate and well-controlled studies in pregnant women. Tramadol hydrochlorideshould be used during pregnancy only if the potential benefit justifies the potential risk to thefetus. Neonatal seizures, neonatal withdrawal syndrome, fetal death and still birth have beenreported during post-marketing.
Labor and Delivery
Tramadol hydrochloride 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 tramadol hydrochloride, if any, on the later growth, development, and functionalmaturation of the child is unknown.
Nursing Mothers
Tramadol hydrochloride is not recommended for obstetrical preoperative medication or for post-delivery analgesia in nursing mothers because its safety in infants and newborns has not beenstudied. Following a single IV 100 mg dose of tramadol, the cumulative excretion in breast milkwithin 16 hours postdose was 100 mcg of tramadol (0.1% of the maternal dose) and 27 mcg of M1.
Pediatric Use
The safety and efficacy of tramadol hydrochloride in patients under 16 years of age have not beenestablished. The use of tramadol hydrochloride 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 func-
tion 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 tramadol hydrochloridein 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 subjectsover 75 years of age compared to those under 65 years of age. Specifically, 30% of those over 75years of age had gastrointestinal treatment-limiting adverse events compared to 17% of those under65 years of age. Constipation resulted in discontinuation of treatment in 10% of those over 75.
ADVERSE REACTIONS
Tramadol hydrochloride was administered to 550 patients during the double-blind or open-labelextension periods in U.S. studies of chronic nonmalignant pain. Of these patients, 375 were 65years old or older. Table 2 reports the cumulative incidence rate of adverse reactions by 7, 30 and90 days for the most frequent reactions (5% or more by 7 days). The most frequently reportedevents were in the central nervous system and gastrointestinal system. Although the reactionslisted in the table are felt to be probably related to tramadol hydrochloride administration, thereported rates also include some events that may have been due to underlying disease orconcomitant medication. The overall incidence rates of adverse experiences in these trials weresimilar for tramadol hydrochloride and the active control groups, TYLENOL® with Codeine #3(acetaminophen 300 mg with codeine phosphate 30 mg), and aspirin 325 mg with codeinephosphate 30 mg (Tylenol® with Codeine #3 is the registered trademark of Johnson RW).
However, the rates of withdrawals due to adverse events appeared to be higher in the tramadolhydrochloride groups.
Cumulative Incidence of Adverse Reactions for Tramadol Hydrochloride in Chronic Trials
of Nonmalignant Pain (N = 427)
1 “CNS Stimulation” is a composite of nervousness, anxiety, agitation, tremor, spasticity, euphoria, emotional lability and hallucinations.
Incidence 1% to less than 5%, possibly causally related: The following lists adverse reactions thatoccurred with an incidence of 1% to less than 5% in clinical trials, and for which the possibilityof a causal relationship with tramadol hydrochloride exists.
Central Nervous System: Anxiety, Confusion, Coordination disturbance, Euphoria, Miosis,Nervousness, Sleep disorder. Gastrointestinal: Abdominal pain, Anorexia, Flatulence. Special Senses: Visual disturbance. Urogenital: Menopausal symptoms, Urinary frequency, Urinary retention.
Incidence less than 1%, possibly causally related: The following lists adverse reactions thatoccurred with an incidence of less than 1% in clinical trials and/or reported in post-marketingexperience.
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 (see WARNINGS), Tremor.
Skin: Stevens-Johnson syndrome/Toxic epidermal necrolysis, Urticaria, Vesicles. Urogenital: Dysuria, Menstrual disorder.
Other adverse experiences, causal relationship unknown: A variety of other adverse events were reported infrequently in patients taking tramadolhydrochloride during clinical trials and/or reported in post-marketing experience. A causal rela-tionship between tramadol hydrochloride and these events has not been determined. However, themost 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.
DRUG ABUSE AND DEPENDENCE
Tramadol hydrochloride 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. Tramadol
hydrochloride is associated with craving and tolerance development. Withdrawal symptoms may
occur if tramadol hydrochloride is discontinued abruptly. These symptoms may include: anxiety,
sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms,
piloerection, and rarely hallucinations. Other symptoms that have been seen less frequently with
tramadol hydrochloride discontinuation include: panic attacks, severe anxiety, and paresthesias.
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 tramadol hydrochloride. 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 tramadol hydrochloride, the risk of seizures is also increased withnaloxone administration. In animals convulsions following the administration of toxic doses oftramadol could be suppressed with barbiturates or benzodiazepines but were increased withnaloxone. 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 theadministered 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 tramadol hydrochloride can be improved by initiating therapy with a titra-
tion regimen. 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, tramadol hydrochloride tablets 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.
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, tramadol hydrochloride tablets 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 needusing the lowest beneficial dose. Studies with tramadol in adults have shown that starting at thelowest possible dose and titrating upward will result in fewer discontinuations and increasedtolerability.
• In all patients with creatinine clearance less than 30 mL/min, it is recommended that the
dosing interval of tramadol hydrochloride tablets 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.
HOW SUPPLIED
Tramadol Hydrochloride Tablets, 50 mg are available as white, round, film coated tablets,
debossed with 466 on one side and WATSON on the other. Each tablet contains 50 mg of
tramadol hydrochloride. They are supplied in bottles of 100, 500 and 1000 tablets.
Store at controlled room temperature 15°-30°C (59°-86°F). [See USP.] Dispense in a tight container as defined in the USP.
Watson Laboratories, Inc.

Source: http://www.nohealthinsurance.net/Prescribing/ultram.pdf