TRAMADOL HYDROCHLORIDE- tramadol hydrochloride tablet

United States - English - NLM (National Library of Medicine)

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Active ingredient:
TRAMADOL HYDROCHLORIDE (UNII: 9N7R477WCK) (TRAMADOL - UNII:39J1LGJ30J)
Available from:
Dispensing Solutions, Inc.
INN (International Name):
TRAMADOL HYDROCHLORIDE
Composition:
TRAMADOL HYDROCHLORIDE 50 mg
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Tramadol hydrochloride tablets, USP are indicated for the management of moderate to moderately severe pain in adults. Tramadol hydrochloride tablets should not be administered to patients who have previously demonstrated hypersensitivity to tramadol, any other component of this product or opioids. Tramadol hydrochloride is contraindicated in any situation where opioids are contraindicated, including acute intoxication with any of the following: alcohol, hypnotics, narcotics, centrally acting analgesics, opioids or psychotropic drugs. Tramadol may worsen central nervous system and respiratory depression in these patients. Tramadol has mu-opioid agonist activity. Tramadol Hydrochloride Tablet can be abused and may be subject to criminal diversion. Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. Drug addiction is characterized by behaviors that include one or more of the following: impaired control over
Product summary:
Tramadol hydrochloride tablet, USP 50 mg are available as white capsule shaped film coated tablets, debossed with “377” on one side and plain on the other side. NDC 66336-0915-60 NDC 66336-0915-62 Dispense in tight container. Store at 25°C (77°F); excursions permitted to 15 - 30°C (59 -86°F).
Authorization status:
Abbreviated New Drug Application
Authorization number:
66336-915-60, 66336-915-62

TRAMADOL HYDROCHLORIDE- tramadol hydrochloride tablet

Dispensing Solutions, Inc.

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Tramadol Hydrochloride Tablets, USP

50 mg - Rx only

DESCRIPTION

Tramadol hydrochloride tablet, USP is a centrally acting analgesic. The chemical name for tramadol

hydrochloride, USP is (±)cis-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol

hydrochloride. Its structural formula is:

Molecular formula is C

H NO HCl

The molecular weight of tramadol hydrochloride, USP is 299.8. Tramadol hydrochloride, USP 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 pH7. Tramadol hydrochloride

tablets, USP for oral administration contain 50 mg of tramadol hydrochloride, USP. In addition, each

tablet contains the following inactive ingredients: pregelatinized starch, lactose anhydrous, magnesium

stearate, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, titanium dioxide.

CLINICAL PHARMACOLOGY

Pharmacodynamics

Tramadol hydrochloride 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 µ-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 µ-opioid receptors. 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. 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 hydrochloride tablets. Analgesia in humans begins approximately within one hour

after administration and reaches a peak in approximately two to three hours.

Apart from analgesia, tramadol hydrochloride tablets administration may produce a constellation of

Apart from analgesia, tramadol hydrochloride tablets administration may produce a constellation of

symptoms (including dizziness, somnolence, nausea, constipation, sweating and pruritus) similar to that

of other opioids. In contrast to morphine, tramadol has not been shown to cause histamine release. At

therapeutic doses, tramadol hydrochloride tablets have no effect on heart rate, left-ventricular function

or cardiac index. Orthostatic hypotension has been observed.

Pharmacokinetics

The analgesic activity of tramadol hydrochloride tablets 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. Linear

pharmacokinetics have been observed following multiple doses of 50 and 100 mg to steady-state.

Absorption:

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 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 with four

times per day 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 four times per day.

Table 1 Mean (%CV) Pharmacokinetic Parameters for Racemic Tramadol and M1 Metabolite

Population/

Dosage Regimen

Parent

Drug/

Metabolite

Peak

Conc.

(ng/mL)

Time

to

Peak

(hrs )

Clearance/F

(mL/min/kg)

t

(hrs )

a

b

1/2

a SD = Single dose, MD = Multiple dose, p.o. = Oral

administration, i.v. = Intravenous administration,

qid = Four times daily

b F represents the oral bioavailability of tramadol

c Not applicable

d Not measured

Healthy Adults,

100 mg q.i.d.,

MD p.o.

Tramadol

592 (30)

(61)

5.90 (25)

(15)

110 (29)

2.4 (46)

7.0 (14)

Healthy Adults,

100 mg

SD p.o.

Tramadol

308 (25)

(63)

8.50 (31)

(20)

55.0 (36)

3.0 (51)

6.7 (16)

Geriatric,

(> 75 yrs)

50 mg SD p.o.

Tramadol

208 (31)

(19)

6.89 (25)

(23)

Hepatic Impaired

50 mg

SD p.o.

Tramadol

217 (11)

(16)

4.23 (56)

13.3

(11)

19.4 (12)

9.8 (20)

18.5 (15)

Renal Impaired

CL 10-30 mL/min

100 mg SD i.v.

Tramadol

4.23 (54)

10.6

(31)

11.5 (40)

Renal Impaired

CL <5 mL/min

100 mg SD i.v.

Tramadol

3.73 (17)

11.0

(29)

16.9 (18)

Food Effects:

Oral administration of tramadol hydrochloride tablets with food does not significantly affect its rate or

extent of absorption, therefore, tramadol hydrochloride tablets can be administered without regard to

food.

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.

Metabolism:

Tramadol is extensively metabolized after oral administration 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 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 l 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 (see WARNINGS) and serotonin syndrome.

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.

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 4-hour dialysis period is less than 7% of the administered 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 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.

Clinical Studies

Tramadol hydrochloride tablets have been given in single oral doses of 50, 75, and 100 mg to patients

with pain following surgical procedures 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 tramadol hydrochloride tablets tended to provide

analgesia superior to codeine sulfate 60 mg, but it was not as effective as the combination of aspirin

650 mg with codeine phosphate 60 mg.

Tramadol hydrochloride tablets have been studied in three long-term controlled trials involving a total

of 820 patients, with 530 patients receiving tramadol hydrochloride tablets. Patients with a variety of

chronic painful conditions were studied in double-blind trials of one to three months duration. Average

daily doses of approximately 250 mg of tramadol hydrochloride tablets in divided doses were generally

comparable 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 two to three

doses of acetaminophen 500 mg with oxycodone hydrochloride 5 mg (TYLOX ) daily. [TYLENOL

is the registered trademark of McNeil Consumer Healthcare and TYLOX is the registered trademark

of RW Johnson].

Titration Trials

In a randomized, blinded clinical study with 129 to 132 patients per group, a 10-day titration to a daily

tramadol hydrochloride dose of 200 mg (50 mg four times per day), attained in 50 mg increments every

3 days, was found to result in fewer discontinuations due to dizziness or vertigo than titration over only

4 days or no titration.

Figure 2:Protocol CAPSS-047

Time to Discontinuation Due to Nausea/Vomiting

INDICATIONS AND USAGE

Tramadol hydrochloride tablets, USP are indicated for the management of moderate to moderately

severe pain in adults.

CONTRAINDICATIONS

Tramadol hydrochloride tablets should not be administered to patients who have previously

demonstrated hypersensitivity to tramadol, any other component of this product or opioids. Tramadol

hydrochloride is contraindicated in any situation where opioids are contraindicated, including acute

intoxication with any of the following: alcohol, hypnotics, narcotics, centrally acting analgesics,

opioids or psychotropic drugs. Tramadol may worsen central nervous system and respiratory

depression in these patients.

WARNINGS

Seizure Risk

Seizures have been reported in patients receiving tramadol hydrochloride tablets within the

recommended dosage range. Spontaneous post-marketing reports indicate that seizure risk is

increased with doses of tramadol hydrochloride tablets above the recommended range.

Concomitant use of tramadol hydrochloride tablets 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 tablets may enhance the seizure risk in patients taking:

MAO inhibitors (see also WARNINGS - Use with MAO inhibitors, and Serotonin Re-Uptake

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 tablets overdose,

naloxone administration may increase the risk of seizure.

Suicide Risk

Do not prescribe tramadol hydrochloride tablets for patients who are suicidal or addiction-prone.

Prescribe tramadol hydrochloride tablets with caution for patients who are taking tranquilizers or

antidepressant drug and patients who use alcohol in excess and who suffer from emotional

disturbance or depression.

The judicious prescribing of tramadol is essential to the safe use of this drug. With patients who are

depressed or suicidal, consideration should be given to the use of non-narcotic analgesics.

Tramadol-related deaths have occurred in patients with previous histories of emotional disturbances or

suicidal ideation or attempts as well as histories of misuse of tranquilizers, alcohol, and other CNS-

active drugs (see WARNINGS, Risk of Overdosage).

Serotonin Syndrome Risk

The development of a potentially life-threatening serotonin syndrome may occur with the use of

tramadol products, including tramadol hydrochloride tablets, particularly with concomitant use

of serotonergic drugs such as SSRIs, SNRIs, TCAs, MAOIs, and triptans, with drugs which

impair metabolism of serotonin (including MAOIs), and with drugs which impair metabolism of

tramadol (CYP2D6 and CYP3A4 inhibitors). This may occur within the recommended dose (see

CLINICAL PHARMACOLOGY, Pharmacokinetics).

Serotonin syndrome may include mental-status changes (e.g., agitation, hallucinations, coma),

autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular

aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea,

vomiting, diarrhea).

Anaphylactoid Reactions

Serious and rarely fatal anaphylactoid reactions have been reported in patients receiving therapy with

tramadol hydrochloride tablets. 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

tablets (see CONTRAINDICATIONS).

Respiratory Depression

Administer tramadol hydrochloride tablets cautiously in patients at risk for respiratory depression. In

these patients alternative non-opioid analgesics should be considered. When large doses of tramadol

hydrochloride tablets 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 should be used with caution and in reduced dosages when administered to patients receiving

CNS depressants such as alcohol, opioids, anesthetic agents, narcotics, phenothiazines, tranquilizers or

sedative hypnotics. Tramadol increases the risk of CNS and respiratory depression in these patients.

Interactions with Alcohol and Drugs of Abuse

Tramadol may be expected to have additive effects when used in conjunction with alcohol, other

opioids, or illicit drugs that cause central nervous system depression.

Increased Intracranial Pressure or Head Trauma

Tramadol hydrochloride tablets should be used with caution in patients with increased intracranial

pressure 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 suspicion for adverse

drug reaction when evaluating altered mental status in these patients if they are receiving tramadol

hydrochloride tablets. (See WARNINGS, Respiratory Depression)

Use in Ambulatory Patients

Tramadol may impair the mental and or physical abilities required for the performance of potentially

hazardous tasks such as driving a car or operating machinery. The patients using this drug should be

cautioned accordingly.

Use with MAO Inhibitors and serotonin re-uptake inhibitors

Use tramadol hydrochloride tablets with great caution in patients taking monoamine oxidase inhibitors.

Animal studies have shown increased deaths with combined administration. Concomitant use of tramadol

hydrochloride tablets with MAO inhibitors or SSRI's increases the risk of adverse events, including

seizure and serotonin syndrome.

Misuse, Abuse and Diversion

Tramadol has mu-opioid agonist activity. Tramadol hydrochloride tablets can be sought by drug

abusers and people with addiction disorders and may be subject to criminal diversion. The possibility of

illegal or illicit use should be considered when prescribing or dispensing Tramadol hydrochloride

tablets in situations where the physician or pharmacist is concerned about an increased risk of misuse,

abuse, or diversion. Misuse or abuse poses a significant risk to the abuser that could result in overdose

and death (see DRUG ABUSE AND DEPENDENCE and OVERDOSAGE).

Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. The

development of addiction to opioid analgesics in properly managed patients with pain has been reported

to be rare. However, data are not available to establish the true incidence of addiction in chronic pain

patients.

Risk of Overdosage

Patients taking tramadol should be warned not to exceed the dose recommended by their physician.

Tramadol products in excessive doses, either alone or in combination with other CNS depressants,

including alcohol, are a cause of drug-related deaths. Patients should be cautioned about the

concomitant use of tramadol products and alcohol because of potentially serious CNS additive effects

of these agents. Because of its added depressant effects, tramadol should be prescribed with caution

for those patients whose medical condition requires the concomitant administration of sedatives,

tranquilizers, muscle relaxants, antidepressants, or other CNS depressant drugs. Patients should be

advised of the additive depressant effects of these combinations.

Serious potential consequences of overdosage with tramadol hydrochloride tablets are central nervous

system depression, respiratory depression and death. Some deaths have occurred as a consequence of

the accidental ingestion of excessive quantities of tramadol alone or in combination with other drugs. In

treating an overdose, primary attention should be given to maintaining adequate ventilation along with

general supportive treatment (see OVERDOSAGE).

Withdrawal

Withdrawal symptoms may occur if tramadol hydrochloride tablets are discontinued abruptly. (See also

DRUG ABUSE and DEPENDENCE) Reported symptoms have included anxiety, sweating, insomnia,

rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely

hallucinations. Other symptoms that have been reported less frequently with tramadol hydrochloride

tablets discontinuation include panic attacks, severe anxiety, and paresthesias. Clinical experience

suggests that withdrawal symptoms may be avoided by tapering tramadol hydrochloride tablets at the

time of discontinuation.

PRECAUTIONS

Acute Abdominal Conditions

The administration of tramadol hydrochloride tablets may complicate the clinical assessment of patients

with 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 it may

take several days for elevated plasma concentrations to develop.

Information for Patients

Patients should be informed that tramadol hydrochloride tablets may cause seizures and/or serotonin

syndrome with concomitant use of serotonergic agents (including SSRIs, SNRIs, and triptans) or

drugs that significantly reduce the metabolic clearance of tramadol.

Tramadol hydrochloride tablets may impair mental or physical abilities required for the

performance 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

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.

Serotonergic Drugs

There have been postmarketing reports of serotonin syndrome with use of tramadol and SSRIs/SNRIs or

MAOIs and α2-adrenergic blockers. Caution is advised when tramadol hydrochloride tablet 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 treatment of tramadol hydrochloride tablet 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).

Triptans

Based on the mechanism of action of tramadol and the potential for serotonin syndrome, caution is

advised when tramadol hydrochloride tablet is coadministered with a triptan. If concomitant treatment of

tramadol hydrochloride tablet with a triptan is clinically warranted, careful observation of the patient is

advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin

Syndrome).

Use with Carbamazepine

Patients taking carbamazepine may have a significantly reduced analgesic effect of tramadol

hydrochloride tablets. Because carbamazepine increases tramadol metabolism and because of the

seizure risk associated with tramadol, concomitant administration of tramadol hydrochloride tablets and

carbamazepine is not recommended.

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 tramadol hydrochloride tablets 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.

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. Administration of CYP3A4 inhibitors, such as ketoconazole and

erythromycin, or inducers, such as rifampin and St. John's Wort, with tramadol hydrochloride tablet may

affect the metabolism of tramadol leading to altered tramadol exposure.

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.

Use with Cimetidine

Concomitant administration of tramadol hydrochloride tablets with cimetidine does not result in

clinically significant changes in tramadol pharmacokinetics. Therefore, no alteration of the tramadol

hydrochloride tablets dosage regimen is recommended.

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.

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/m or 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.

Pregnancy

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 doses, but was not

teratogenic at these dose levels. These dosages on a mg/ m basis 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.

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/ m or 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/ m or

1.9 and higher the maximum daily human dose).

There are no adequate and well-controlled studies in pregnant women. Tramadol hydrochloride tablets

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.

Labor and Delivery

Tramadol hydrochloride tablets 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 tablets, if any, on the later growth, development, and functional

maturation of the child is unknown.

Nursing Mothers

Tramadol hydrochloride tablets are 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 post-dose was 100 µg of tramadol (0.1% of the maternal dose) and 27 µg of M1.

Pediatric Use

The safety and efficacy of tramadol hydrochloride tablets in patients under 16 years of age have not

been established. The use of tramadol 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 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. (see CLINICAL PHARMACOLOGY and DOSAGE AND

ADMINISTRATION).

A total of 455 elderly (65 years of age or older) subjects were exposed to tramadol hydrochloride

tablets 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.

ADVERSE REACTIONS

Tramadol hydrochloride tablets were 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 were in the

central nervous system and gastrointestinal system. Although the reactions listed in the table are felt to

be probably related to tramadol hydrochloride tablets 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 tramadol hydrochloride tablets

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 tramadol hydrochloride groups. [TYLENOL is the

registered trademark of McNeil Consumer Healthcare and TYLOX is the registered trademark of RW

Johnson].

Table 2 Cumulative Incidence of Adverse Reactions for Tramadol Hydrochloride Tablets in

Chronic Trials of Nonmalignant Pain (N=427)

Up

to

7

Days

Up to

30

Days

Up to

90

Days

1 “CNS Stimulation” is a composite of nervousness, anxiety, agitation, tremor,

spasticity, euphoria, emotional

lability and hallucinations.

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”

11% 14%

Asthenia

6% 11% 12%

Sweating

Dyspepsia

Dry Mouth

Diarrhea

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 tramadol hydrochloride tablets 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 (see WARNINGS), 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 tramadol hydrochloride tablets during clinical trials and/or reported in

post-marketing experience. A causal relationship between tramadol hydrochloride tablets 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.

DRUG ABUSE AND DEPENDENCE

Abus e

Tramadol has mu-opioid agonist activity. Tramadol Hydrochloride Tablet can be abused and

may be subject to criminal diversion.

Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental

factors influencing its development and manifestations. Drug addiction is characterized by behaviors

that include one or more of the following: impaired control over drug use, compulsive use, use for non-

medical purposes, and continued use despite harm or risk of harm, and craving. Drug addiction is a

treatable disease, utilizing a multidisciplinary approach, but relapse is common.

"Drug-seeking" behavior is very common in addicts and drug abusers. Drug-seeking tactics include

emergency calls or visits near the end of office hours, refusal to undergo appropriate examination,

testing or referral, repeated "loss" of prescriptions, tampering with prescriptions and reluctance to

provide prior medical records or contact information for other treating physician(s). "Doctor shopping"

to obtain additional prescriptions is common among drug abusers and people suffering from untreated

addiction.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians

should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of

physical dependence in all addicts. In addition, abuse of tramadol hydrochloride tablet can occur in the

absence of true addiction and is characterized by misuse for non-medical purposes, often in combination

with other psychoactive substances. Concerns about abuse and addiction should not prevent the proper

management of pain. However all patients treated with opioids require careful monitoring for signs of

abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under

appropriate medical use.

Proper assessment of the patient and periodic re-evaluation of therapy are appropriate measures that

help to limit the potential abuse of this product.

Tramadol hydrochloride tablet is intended for oral use only.

Dependence

Tolerance is the need for increasing doses of drugs to maintain a defined effect such as analgesia (in

the absence of disease progression or other external factors). Physical dependence is manifested by

withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist (see

also WARNINGS, Withdrawal).

The opioid abstinence or withdrawal syndrome is characterized by some or all of the following:

restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other

symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal

cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or

heart rate.

Generally, tolerance and/or withdrawal are more likely to occur the longer a patient is on continuous

therapy with tramadol hydrochloride tablet.

OVERDOSAGE

Acute overdosage with tramadol can be manifested by respiratory depression, somnolence progressing

to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, seizures,

bradycardia, hypotension, cardiac arrest, and death. Deaths due to overdose have been reported with

abuse and misuse of tramadol (see WARNINGS, Misuse, Abuse, and Diversion). Review of case

reports has indicated that the risk of fatal overdose is further increased when tramadol is abused

concurrently with alcohol or other CNS depressants, including other opioids.

In the treatment of tramadol overdosage, primary attention should be given to the reestablishment of a

patent airway and institution of assisted or controlled ventilation. Supportive measures (including

oxygen and vasopressors) should be employed in the management of circulatory shock and pulmonary

edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage

or defibrillation.

While naloxone will reverse some, but not all, symptoms caused by overdosage with tramadol,

the risk of seizures is also increased with naloxone administration. In animals convulsions

following the administration of toxic doses of tramadol hydrochloride tablet could be suppressed

with barbiturates or benzodiazepines but were increased with naloxone. 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 the administered 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 tablets can be improved by initiating therapy with the

following titration 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 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.

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 tablet, USP 50 mg are available as white capsule shaped film coated tablets,

debossed with “377” on one side and plain on the other side.

NDC 66336-0915-60

NDC 66336-0915-62

Dispense in tight container.

Store at 25°C (77°F); excursions permitted to 15 - 30°C (59 -86°F).

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL- 50 mg

NDC 66336-0915-XX

NDC 66336-0915-60

NDC 66336-0915-62

Tramadol hydrochloride Tablets

50 mg

Rx Only

TRAMADOL HYDROCHLORIDE

tramadol hydrochloride tablet

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 6 336 -9 15(NDC:576 6 4-377)

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

TRAMADO L HYDRO CHLO RIDE (UNII: 9 N7R477WCK) (TRAMADOL -

UNII:39 J1LGJ30 J)

TRAMADOL

HYDROCHLORIDE

50 mg

Inactive Ingredients

Ingredient Name

Stre ng th

STARCH, CO RN (UNII: O8 232NY3SJ)

ANHYDRO US LACTO SE (UNII: 3SY5LH9 PMK)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

CELLULO SE, MICRO CRYSTALLINE (UNII: OP1R32D6 1U)

PO LYETHYLENE GLYCO LS (UNII: 3WJQ0 SDW1A)

SO DIUM STARCH GLYCO LATE TYPE A PO TATO (UNII: 58 56 J3G2A2)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

Product Characteristics

Color

WHITE (white)

S core

no sco re

S hap e

CAPSULE

S iz e

13mm

Flavor

Imprint Code

Contains

Dispensing Solutions, Inc.

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 6 336 -9 15-6 0

6 0 in 1 BOTTLE

2

NDC:6 6 336 -9 15-6 2

18 0 in 1 BOTTLE

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 759 6 4

0 6 /22/20 0 2

Labeler -

Dispensing Solutions, Inc. (066070785)

Registrant -

PSS World Medical, Inc. (101822682)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Dispensing So lutio ns, Inc.

0 6 6 0 70 78 5

relabel(6 6 336 -9 15, 6 6 336 -9 15)

Revised: 11/2013

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