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:
Proficient Rx LP
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Tramadol hydrochloride tablets are indicated in adults for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses [see Warnings and Precautions (5.1)] , reserve tramadol hydrochloride tablets for use in patients for whom alternative treatment options [e.g., non-opioid analgesics]: Tramadol hydrochloride tablets are contraindicated for: Tramadol hydrochloride tablets are also contraindicated in patients with: Risk Summary Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome. Available data with tramadol hydrochloride tablets in pregnant women are insufficient to inform a drug- associated risk for major birth defects and miscarriage. In animal reproduction studies, tramadol administration during organogenesis decreased fetal weights and reduced ossification in mice, rats, and rabbits at 1.4,
Product summary:
Tramadol hydrochloride tablets, USP 50 mg are available as white capsule shaped film coated tablets, debossed with “377” on one side and plain on the other side. Dispense in a tight container. Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). [see USP Controlled Room Temperature].
Authorization status:
Abbreviated New Drug Application
Authorization number:
71205-303-20, 71205-303-30, 71205-303-40, 71205-303-60, 71205-303-72, 71205-303-78, 71205-303-90

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Medication Guide

Tramadol Hydrochloride Tablets, USP

(TRAM a dol hye” droe cklo' ride"), CIV

Tramadol hydrochloride tablets are:

A strong prescription pain medicine that contains an opioid (narcotic) that is used for the management

pain in adults, when other pain treatments such as non-opioid pain medicines do not treat your pain

well enough or you cannot tolerate them.

An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose

correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.

Important information about tramadol hydrochloride tablets:

Get emergency help right away if you take too much tramadol hydrochloride tablets (overdose). When

you first start taking tramadol hydrochloride tablets, when your dose is changed, or if you take too

much (overdose), serious or life-threatening breathing problems that can lead to death may occur.

Taking tramadol hydrochloride tablets with other opioid medicines, benzodiazepines, alcohol, or other

central nervous system depressants (including street drugs) can cause severe drowsiness, decreased

awareness, breathing problems, coma, and death.

Never give anyone else your tramadol hydrochloride tablets. They could die from taking it. Store

tramadol hydrochloride tablets away from children and in a safe place to prevent stealing or abuse.

Selling or giving away tramadol hydrochloride tablets is against the law.

Important information guiding use in pediatric patients:

Do not give tramadol hydrochloride tablets to a child younger than 12 years of age.

Do not give tramadol hydrochloride tablets to a child younger than 18 years of age after surgery to

remove the tonsils and/or adenoids.

Avoid giving tramadol hydrochloride tablets to children between 12 to 18 years of age who have risk

factors for breathing problems such as obstructive sleep apnea, obesity, or underlying lung problems.

Do not take tramadol hydrochloride tablets if you have:

Severe asthma, trouble breathing, or other lung problems.

A bowel blockage or have narrowing of the stomach or intestines.

An allergy to tramadol.

Taken a Monoamine Oxidase Inhibitor, MAOI, (medicine used for depression) within the last 14 days.

Before taking tramadol hydrochloride tablets, tell your healthcare provider if you have a history of:

head injury, seizures

liver, kidney, thyroid problems

problems urinating

pancreas or gallbladder problems

abuse of street or prescription drugs, alcohol addiction, or mental health problems.

Tell your healthcare provider if you are:

pregnant or planning to become pregnant. Prolonged use of tramadol hydrochloride tablets during

pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not

recognized and treated.

breastfeeding. Not recommended; it may harm your baby.

taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking tramadol

hydrochloride tablets with certain other medicines can cause serious side effects that could lead to

death.

When taking tramadol hydrochloride tablets:

Do not change your dose. Take tramadol hydrochloride tablets exactly as prescribed by your healthcare

provider. Use the lowest dose possible for the shortest time needed.

Take your prescribed dose as indicated by your healthcare provider. The maximum dosage is 1 or 2 tablets

every 4 to 6 hours, as needed for pain relief. Do not take more than your prescribed dose and do not take

more than 8 tablets per day. If you miss a dose, take your next dose at your usual time.

Call your healthcare provider if the dose you are taking does not control your pain.

If you have been taking tramadol hydrochloride tablets regularly, do not stop taking tramadol hydrochloride

tablets without talking to your healthcare provider.

After you stop taking tramadol hydrochloride tablets, ask your pharmacist how to dispose of any unused

tablets.

While taking tramadol hydrochloride tablets DO NOT:

Drive or operate heavy machinery, until you know how tramadol hydrochloride tablets affects you.

Tramadol hydrochloride tablets can make you sleepy, dizzy, or lightheaded.

Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products

containing alcohol during treatment with tramadol hydrochloride tablets may cause you to overdose and die.

The possible side effects of tramadol hydrochloride tablets:

constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your

healthcare provider if you have any of these symptoms and they are severe.

Get emergency medical help if you have:

trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or

throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high

body temperature, trouble walking, stiff muscles, or mental changes such as confusion.

These are not all the possible side effects of tramadol hydrochloride tablets. Call your doctor for

medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more

information go to dailymed.nlm.nih.gov

www.sunpharma.com or call 1-800-818-4555

Distributed by:

Sun Pharmaceutical Industries, Inc.

Cranbury, NJ 08512

Repackaged by:

Proficient Rx LP

Thousand Oaks, CA 91320

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Rev. 06/2019

PGPI0345D

Revised: 3/2020

Document Id: d7d0d9aa-82de-4e29-b09e-c3e9bc8397db

34391-3

Set id: 38bd9c16-f730-4953-a444-68a95498d83c

Version: 3

Effective Time: 20200301

Proficient Rx LP

TRAMADOL HYDROCHLORIDE- tramadol hydrochloride tablet

Proficient Rx LP

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use TRAMADOL HYDROCHLORIDE TABLETS

safely and effectively. See full prescribing information for TRAMADOL HYDROCHLORIDE TABLETS.

TRAMADOL HYDROCHLORIDE tablets, for oral use, C-IV

Initial U.S. Approval: 1995

WARNING: ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION STRATEGY

(REMS); LIFE THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID

METABOLISM OF TRAMADOL AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY

DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH

DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; HEPATOTOXICITY; and RISKS FROM

CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

See full prescribing information for complete boxed warning.

RECENT MAJOR CHANGES

INDICATIONS AND USAGE

Tramadol hydrochloride tabletsare an opioid agonist indicated in adults for the management of pain severe enough to

require an opioid analgesic and for which alternative treatments are inadequate (1).

Limitations of Use (1)

Tramadol hydrochloride tablets expose users to the risks of addiction, abuse and misuse, which can

lead to overdose and death. Assess each patient’s risk prior to prescribing tramadol hydrochloride

tablets, and monitor regularly for these behaviors or conditions. (5.1)

To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse,

the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy

(REMS) for these products. (5.2)

Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially

during initiation or following a dose increase. (5.3)

Accidental ingestion of tramadol hydrochloride tablets, especially by children, can result in a fatal

overdose of tramadol. (5.3)

Life-threatening respiratory depression and death have occurred in children who received tramadol.

Some of the reported cases followed tonsillectomy and/or adenoidectomy; in at least one case, the

child had evidence of being an ultra-rapid metabolizer of tramadol due to a CYP2D6 polymorphism

(5.4 ).

Tramadol hydrochloride tablets are contraindicated in children younger than 12 years of age and in

children younger than 18 years of age following tonsillectomy and/or adenoidectomy (4). Avoid the

use of tramadol hydrochloride tablets in adolescents 12 to 18 years of age who have other risk

factors that may increase their sensitivity to the respiratory depressant effects of tramadol. (5.4)

Prolonged use of tramadol hydrochloride tablets, during pregnancy can result in neonatal opioid

withdrawal syndrome, which may be life threatening if not recognized and treated. If prolonged

opioid use is required in a pregnant woman, advise the patient of the risk of neonatal opioid

withdrawal syndrome and ensure that appropriate treatment will be available. (5.5)

The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors,

or 2D6 inhibitors with tramadol are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors,

or 2D6 inhibitors with tramadol hydrochloride tablets require careful consideration of the effects on

the parent drug, tramadol, and the active metabolite, M1. (5.6, 7)

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS)

depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and

death. Reserve concomitant prescribing for use in patients for whom alternative treatment options

are inadequate; limit dosages and durations to the minimum required; and follow patients for signs

and symptoms of respiratory depression and sedation. (5.7, 7)

Boxed Warning 09/2018

Warnings and Precautions (5) 09/2018

Limitations of Use (1)

Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses (5.1), reserve tramadol

hydrochloride tablets for use in patients for whom alternative treatment options [e.g., non-opioid analgesics]:

DOSAGE AND ADMINISTRATION

DOSAGE FORMS AND STRENGTHS

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

ADVERSE REACTIONS

The most common incidence of treatment-emergent adverse events (≥15.0%) in patients from clinical trials were

dizziness/vertigo, nausea, constipation, headache, somnolence, vomiting and pruritus (6).

To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-406-

7984 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid use with tramadol hydrochloride tablets because

Have not been tolerated or are not expected to be tolerated.

Have not provided adequate analgesia, or are not expected to provide adequate analgesia.

Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals (2.1).

Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain, patient

response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse (2.1).

Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy and

following dosage increases with tramadol hydrochloride tablets and adjust the dosage accordingly (2.1).

The total daily dose may be increased by 50 mg as tolerated every 3 days to reach 200 mg/day (50 mg four times a

day). After titration, tramadol hydrochloride tablets 50 to 100 mg can be administered as needed for pain relief every

4 to 6 hours not to exceed 400 mg/day (2.2, 2.3).

Severe Renal Impairment: increase the tramadol hydrochloride tablets dosing interval to 12 hours, and limit

maximum daily dose to 200 mg (2.2).

Severe hepatic impairment: Recommended dose is 50 mg every 12 hours.

Do not abruptly discontinue tramadol hydrochloride tablets in a physically-dependent patient (2.2).

Tablets: 50 mg (3).

Children younger than 12 years of age (4).

Post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy

(4).

Significant respiratory depression (4).

Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment (4).

Known or suspected gastrointestinal obstruction, including paralytic ileus (4).

Hypersensitivity to tramadol, any other component of this product or opioids (4).

Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days (4).

Serotonin Syndrome: May be life-threatening. Can occur with use of tramadol alone, with concomitant use of

serotonergic drugs, with drugs that impair metabolism of serotonin or tramadol (5.8).

Risk of Seizure: Can occur at the recommended dose of tramadol. Concomitant use with other drugs may increase

seizure risk. Risk may increase in patients with epilepsy, a history of seizures, and in patients with a recognized risk

for seizures (5.9).

Risk of Suicide: Do not prescribe for suicidal or addiction-prone patients (5.10).

Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off the

opioid (5.11).

Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or

Debilitated Patients: Monitor closely, particularly during initiation and titration (5.12).

Severe Hypotension: Monitor during dosage initiation and titration. Avoid use of tramadol hydrochloride tablets in

patients with circulatory shock (5.13).

Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness:

Monitor for sedation and respiratory depression. Avoid use of tramadol hydrochloride tablets in patients with

impaired consciousness or coma (5.14).

they may reduce analgesic effect of tramadol hydrochloride tablets or precipitate withdrawal symptoms (7).

USE IN SPECIFIC POPULATIONS

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 3/2020

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION

STRATEGY(REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL

INGESTION; ULTRA-RAPID METABOLISM OF TRAMADOL AND OTHER RISK

FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN;

NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS

AFFECTING CYTOCHROME P450 ISOENZYMES; and RISKS FROM CONCOMITANT

USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosage and Administration Instructions

2.2 Initial Dosage

2.3 Titration and Maintenance of Therapy

2.4 Discontinuation of Tramadol Hydrochloride Tablets

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Addiction, Abuse and Misuse

5.2 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

5.3 Life-Threatening Respiratory Depression

5.4 Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-threatening Respiratory

Depression in Children

5.5 Neonatal Opioid Withdrawal Syndrome

5.6 Risks of Interactions with Drugs Affecting Cytochrome P450 Isoenzymes

5.7 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

5.8 Serotonin Syndrome Risk

5.9 Increased Risk of Seizure

5.10 Suicide Risk

5.11 Adrenal Insufficiency

5.12 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in

Elderly, Cachectic, or Debilitated Patients

5.13 Severe Hypotension

5.14 Risks of use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or

Impaired Consciousness

5.15 Risks of Use in Patients with Gastrointestinal Conditions

5.16 Anaphylaxis and Other Hypersensitivity Reactions

5.17 Withdrawal

5.18 Driving and Operating Machinery

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

Pregnancy: May cause fetal harm (8.1).

Lactation: Breastfeeding not recommended (8.2).

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal and Hepatic Impairment

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

9.2 Abuse

9.3 Dependence

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

Titration Trials

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

Sections or subsections omitted from the full prescribing information are not listed.

WARNING: ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND

MITIGATION STRATEGY(REMS); LIFE-THREATENING RESPIRATORY

DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID METABOLISM OF

TRAMADOL AND OTHER RISK FACTORS FOR LIFE-THREATENING

RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL

SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450

ISOENZYMES; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES

OR OTHER CNS DEPRESSANTS

ADDICTION, ABUSE AND MISUSE

Tramadol hydrochloride tablets expose patients and other users to the risks of opioid

addiction, abuse and misuse, which can lead to overdose and death. Assess each patient’s

risk prior to prescribing tramadol hydrochloride tablets, and monitor all patients regularly

for the development of these behaviors and conditions [see Warnings and Precautions (5.1)].

OPIOID ANALGESIC RISK EVALUATION AND MITIGATION STRATEGY (REMS)

To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and

misuse, the Food and Drug Administration (FDA) has required a REMS for these products

[see Warnings and Precautions (5.2)]. Under the requirements of the REMS, drug companies

with approved opioid analgesic products must make REMS-compliant education programs

available to healthcare providers. Healthcare providers are strongly encouraged to

LIFE-THREATENING RESPIRATORY DEPRESSION

Serious, life-threatening, or fatal respiratory depression may occur with use of tramadol

hydrochloride tablets. Monitor for respiratory depression, especially during initiation of

tramadol hydrochloride tablets or following a dose increase [see Warnings and Precautions

(5.3)].

ACCIDENTAL INGESTION

Accidental ingestion of tramadol hydrochloride tablets, especially by children, can be fatal

[see Warnings and Precautions (5.3)].

ULTRA-RAPID METABOLISM OF TRAMADOL AND OTHER RISK FACTORS FOR

LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN

Life-threatening respiratory depression and death have occurred in children who received

tramadol. Some of the reported cases followed tonsillectomy and/or adenoidectomy; in at

least one case, the child had evidence of being an ultra-rapid metabolizer of tramadol due to

a CYP2D6 polymorphism [see Warnings and Precautions (5.4)]. Tramadol hydrochloride

tablets are contraindicated in children younger than 12 years of age and in children younger

than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications

(4)]. Avoid the use of tramadol hydrochloride tablets in adolescents 12 to 18 years of age

who have other risk factors that may increase their sensitivity to the respiratory depressant

effects of tramadol [see Warnings and Precautions (5.4)].

NEONATAL OPIOID WITHDRAWAL SYNDROME

complete a REMS-compliant education program,

counsel patients and/or their caregivers, with every prescription, on safe use, serious

risks, storage, and disposal of these products,

emphasize to patients and their caregivers the importance of reading the

MedicationGuide every time it is provided by their pharmacist, and

consider other tools to improve patient, household, and community safety.

Prolonged use of tramadol hydrochloride tablets during pregnancy can result in neonatal

opioid withdrawal syndrome, which may be life-threatening if not recognized and treated,

and requires management according to protocols developed by neonatology experts. If

opioid use is required for a prolonged period in a pregnant woman, advise the patient of the

risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be

available [see Warnings and Precautions (5.5)].

INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES

The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4

inhibitors, or 2D6 inhibitors with tramadol are complex. Use of cytochrome P450 3A4

inducers, 3A4 inhibitors, or 2D6 inhibitors with tramadol hydrochloride tablets require

careful consideration of the effects on the parent drug, tramadol, and the active metabolite,

M1 [see Warnings and Precautions (5.6); Drug Interactions (7)].

RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS

DEPRESSANTS

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS)

depressants, including alcohol, may result in profound sedation, respiratory depression,

coma, and death [see Warnings and Precautions (5.7); Drug Interactions (7)].

1 INDICATIONS AND USAGE

Tramadol hydrochloride tablets are indicated in adults for the management of pain severe enough to

require an opioid analgesic and for which alternative treatments are inadequate.

Limitations of Use

Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses [see

Warnings and Precautions (5.1)], reserve tramadol hydrochloride tablets for use in patients for whom

alternative treatment options [e.g., non-opioid analgesics]:

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosage and Administration Instructions

Reserve concomitant prescribing of tramadol hydrochloride tablets and

benzodiazepines or other CNS depressants for use in patients for whom alternative

treatment options are inadequate.

Limit treatment to the minimum effective dosages and durations.

Follow patients for signs and symptoms of respiratory depression and sedation.

Have not been tolerated or are not expected to be tolerated.

Have not provided adequate analgesia or are not expected to provide adequate analgesia.

Do not use tramadol hydrochloride tablets concomitantly with other tramadol-containing products.

Do not administer tramadol hydrochloride tablets at a dose exceeding 400 mg per day.

Use the lowest effective dosage for the shor test duration consistent with individual patient

treatment goals [see Warnings and Precautions (5.1)].

Initiate the dosing regimen for each patient individually, taking into account the patient's severity

of pain, patient response, prior analgesic treatment experience, and risk factors for addiction,

abuse, and misuse [see Warnings and Precautions (5.1)].

2.2 Initial Dosage

Initiating Treatment with Tramadol Hydrochloride Tablets

For patients 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 four times a day).

After titration, tramadol hydrochloride tablets 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,

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.

Conversion from Tramadol Hydrochloride Tablets to Extended-Release Tramadol

The relative bioavailability of tramadol hydrochloride tablets compared to extended-release tramadol is

unknown, so conversion to extended-release formulations must be accompanied by close observation

for signs of excessive sedation and respiratory depression.

Dosage Modification in Patients with Hepatic Impairment

The recommended dose for adult patients with severe hepatic impairment is 50 mg every 12 hours.

Dosage Modification in Patients with Renal Impairment

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.

Dosage Modification in Geriatric Patients

Do not exceed a total dose of 300 mg/day in patients over 75 years old.

2.3 Titration and Maintenance of Therapy

Individually titrate tramadol hydrochloride tablets to a dose that provides adequate analgesia and

minimizes adverse reactions. Continually reevaluate patients receiving tramadol hydrochloride tablets to

assess the maintenance of pain control and the relative incidence of adverse reactions, as well as to

monitor for the development of addiction, abuse, or misuse [see Warnings and Precautions (5.1)].

Frequent communication is important among the prescriber, other members of the healthcare team, the

patient, and the caregiver/family during periods of changing analgesic requirements, including initial

titration.

If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain

before increasing the tramadol hydrochloride tablets dosage. If unacceptable opioid-related adverse

reactions are observed, consider reducing the dosage. Adjust the dosage to obtain an appropriate

balance between management of pain and opioid-related adverse reactions.

2.4 Discontinuation of Tramadol Hydrochloride Tablets

When a patient who has been taking tramadol hydrochloride tablets regularly and may be physically

dependent no longer requires therapy with tramadol hydrochloride tablets, taper the dose gradually, by

25% to 50% every 2 to 4 days, while monitoring carefully for signs and symptoms of withdrawal. If the

patient develops these signs or symptoms, raise the dose to the previous level and taper more slowly,

Monitor patients closely for respiratory depression, especially within the first 24-72 hours of

initiating therapy and following dosage increases with tramadol hydrochloride tablets and adjust

the dosage accordingly [see Warnings and Precautions (5.3)].

either by increasing the interval between decreases, decreasing the amount of change in dose, or both.

Do not abruptly discontinue tramadol hydrochloride tablets in a physically-dependent patient. [see

Warnings and Precautions (5.1); Drug Abuse and Dependence (9)].

3 DOSAGE FORMS AND STRENGTHS

Tramadol hydrochloride tablets, USP - 50 mg are white, capsule-shaped, film coated tablets debossed

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

4 CONTRAINDICATIONS

Tramadol hydrochloride tablets are contraindicated for:

Tramadol hydrochloride tablets are also contraindicated in patients with:

5 WARNINGS AND PRECAUTIONS

5.1 Addiction, Abuse and Misuse

Tramadol hydrochloride tablets contain tramadol, a Schedule IV controlled substance. As an opioid,

tramadol hydrochloride tablets expose users to the risks of addiction, abuse, and misuse [see Drug

Abuse and Dependence (9)].

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately

prescribed tramadol hydrochloride tablets. Addiction can occur at recommended dosages and if the

drug is misused or abused.

Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing tramadol

hydrochloride tablets, and monitor all patients receiving tramadol hydrochloride tablets for the

development of these behaviors and conditions. Risks are increased in patients with a personal or family

history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major

depression). The potential for these risks should not, however, prevent the proper management of pain

in any given patient. Patients at increased risk may be prescribed opioids such as tramadol

hydrochloride tablets, but use in such patients necessitates intensive counseling about the risks and

proper use of tramadol hydrochloride tablets along with intensive monitoring for signs of addiction,

abuse, and misuse.

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal

diversion. Consider these risks when prescribing or dispensing tramadol hydrochloride tablets.

Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and

all children younger than 12 years of age [see Warnings and Precautions (5.4)].

post-operative management in children younger than 18 years of age following tonsillectomy

and/or adenoidectomy [see Warnings and Precautions (5.4)].

Significant respiratory depression [see Warnings and Precautions (5.3)].

Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative

equipment [see Warnings and Precautions (5.12)].

Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and

Precautions (5.15)].

Hypersensitivity to tramadol, any other component of this product or opioids [see Warnings and

Precautions (5.16)].

Concurrent use of monoamine oxidase inhibitors (MAOIs) or use within the last 14 days [see Drug

Interactions (7)].

advising the patient on the proper disposal of unused drug [see Patient Counselling Information (17)].

Contact local state professional licensing board or state controlled substances authority for information

on how to prevent and detect abuse or diversion of this product.

5.2 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the

Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS)

for these products. Under the requirements of the REMS, drug companies with approved opioid

analgesic products must make REMS-compliant education programs available to healthcare providers.

Healthcare providers are strongly encouraged to do all of the following:

To obtain further information on the opioid analgesic REMS and for a list of accredited REMS

CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. FDA Blueprint can be

found at www.fda.gov/OpioidAnalgesicREMSBlueprint.

5.3 Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids,

even when used as recommended. Respiratory depression, if not immediately recognized and treated,

may lead to respiratory arrest and death. Management of respiratory depression may include close

observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical

status [see Overdosage (10)]. Carbon dioxide (CO ) retention from opioid-induced respiratory

depression can exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of

tramadol hydrochloride tablets, the risk is greatest during the initiation of therapy or following a

dosage increase. Monitor patients closely for respiratory depression, especially within the first 24 to

72 hours of initiating therapy with and following dosage increases of tramadol hydrochloride tablets.

To reduce the risk of respiratory depression, proper dosing and titration of tramadol hydrochloride

tablets are essential [see Dosage and Administration (2)]. Overestimating the tramadol hydrochloride

tablets dosage when converting patients from another opioid product can result in a fatal overdose with

the first dose.

Accidental ingestion of even one dose of tramadol hydrochloride tablets, especially by children, can

result in respiratory depression and death due to an overdose of tramadol.

5.4 Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-threatening

Respiratory Depression in Children

Life-threatening respiratory depression and death have occurred in children who received tramadol.

Tramadol and codeine are subject to variability in metabolism based upon CYP2D6 genotype (described

below), which can lead to increased exposure to an active metabolite. Based upon post-marketing

reports with tramadol or with codeine, children younger than 12 years of age may be more susceptible

Complete a REMS-compliant education program offered by an accredited provider of continuing

education (CE) or another education program that includes all the elements of the FDA Education

Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain.

Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with

patients and/or their caregivers every time these medicines are prescribed. The Patient

Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG.

Emphasize to patients and their caregivers the importance of reading the Medication Guide that

they will receive from their pharmacist every time an opioid analgesic is dispensed to them.

Consider using other tools to improve patient, household, and community safety, such as patient-

prescriber agreements that reinforce patient-prescriber responsibilities.

to the respiratory depressant effects of tramadol. Furthermore, children with obstructive sleep apnea

who are treated with opioids for post-tonsillectomy and/or adenoidectomy pain may be particularly

sensitive to their respiratory depressant effect. Because of the risk of life-threatening respiratory

depression and death:

Nursing Mothers

Tramadol is subject to the same polymorphic metabolism as codeine, with ultra-rapid metabolizers of

CYP2D6 substrates being potentially exposed to life-threatening levels of the active metabolite O-

desmethyltramadol (M1). At least one death was reported in a nursing infant who was exposed to high

levels of morphine in breast milk because the mother was an ultra-rapid metabolizer of codeine. A baby

nursing from an ultra-rapid metabolizer mother taking tramadol hydrochloride tablets could potentially

be exposed to high levels of M1, and experience life-threatening respiratory depression. For this

reason, breastfeeding is not recommended during treatment with tramadol hydrochloride tablets [see Use

in Specific Populations (8.2)].

CYP2D6 Genetic Variability: Ultra-rapid Metabolizer

Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (e.g., gene

duplications denoted as *1/*1xN or *1/*2xN). The prevalence of this CYP2D6 phenotype varies widely

and has been estimated at 1 to 10% for Whites (European, North American), 3 to 4% for Blacks (African

Americans), 1 to 2% for East Asians (Chinese, Japanese, Korean), and may be greater than 10% in cer

tain racial/ethnic groups (i.e., Oceanian, Northern African, Middle Eastern, Ashkenazi Jews, Puerto

Rican). These individuals convert tramadol into its active metabolite, O-desmethyltramadol (M1), more

rapidly and completely than other people. This rapid conversion results in higher than expected serum

M1 levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have

life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme

sleepiness, confusion, or shallow breathing) [see Overdosage (10)]. Therefore, individuals who are

ultra-rapid metabolizers should not use tramadol hydrochloride tablets.

5.5 Neonatal Opioid Withdrawal Syndrome

Prolonged use of tramadol hydrochloride tablets during pregnancy can result in withdrawal in the

neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be

life- threatening if not recognized and treated, and requires management according to protocols

developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal

syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the

risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see

Use in Specific Populations (8.1) and Patient Counseling Information (17)].

Tramadol hydrochloride tablets are contraindicated for all children younger than 12 years of age

[see Contraindications (4)].

Tramadol hydrochloride tablets are contraindicated for post-operative management in pediatric

patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [see

Contraindications (4)].

Avoid the use of tramadol hydrochloride tablets in adolescents 12 to 18 years of age who have

other risk factors that may increase their sensitivity to the respiratory depressant effects of

tramadol unless the benefits outweigh the risks. Risk factors include conditions associated with

hypoventilation such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary

disease, neuromuscular disease, and concomitant use of other medications that cause respiratory

depression.

As with adults, when prescribing opioids for adolescents, healthcare providers should choose the

lowest effective dose for the shortest period of time and inform patients and caregivers about

these risks and the signs of opioid overdose [see Use in Specific Populations (8.4), Overdosage

(10)].

5.6 Risks of Interactions with Drugs Affecting Cytochrome P450 Isoenzymes

The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors,

or 2D6 inhibitors on levels of tramadol and M1 from tramadol hydrochloride tablets are complex. Use

of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with tramadol hydrochloride

tablets require careful consideration of the effects on the parent drug, tramadol which is a weak

serotonin and norepinephrine reuptake inhibitor and μ-opioid agonist, and the active metabolite, M1,

which is more potent than tramadol in μ-opioid receptor binding [see Drug Interactions (7)].

Risks of Concomitant Use or Discontinuation of Cytochrome P450 2D6 Inhibitors

The concomitant use of tramadol hydrochloride tablets with all cytochrome P450 2D6 inhibitors (e.g.,

amiodarone, quinidine) may result in an increase in tramadol plasma levels and a decrease in the levels

of the active metabolite, M1. A decrease in M1 exposure in patients who have developed physical

dependence to tramadol, may result in signs and symptoms of opioid withdrawal and reduced efficacy.

The effect of increased tramadol levels may be an increased risk for serious adverse events including

seizures and serotonin syndrome.

Discontinuation of a concomitantly used cytochrome P450 2D6 inhibitor may result in a decrease in

tramadol plasma levels and an increase in active metabolite M1 levels, which could increase or prolong

adverse reactions related to opioid toxicity and may cause potentially fatal respiratory depression.

Follow patients receiving tramadol hydrochloride tablets and any CYP2D6 inhibitor for the risk of

serious adverse events including seizures and serotonin syndrome, signs and symptoms that may reflect

opioid toxicity, and opioid withdrawal when tramadol hydrochloride tablets are used in conjunction with

inhibitors of CYP2D6 [see Drug Interactions (7)].

Cytochrome P450 3A4 Interaction

The concomitant use of tramadol hydrochloride tablets with cytochrome P450 3A4 inhibitors, such as

macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease

inhibitors (e.g., ritonavir) or discontinuation of a cytochrome P450 3A4 inducer such as rifampin,

carbamazepine, and phenytoin, may result in an increase in tramadol plasma concentrations, which could

increase or prolong adverse reactions, increase the risk for serious adverse events including seizures

and serotonin syndrome, and may cause potentially fatal respiratory depression.

The concomitant use of tramadol hydrochloride tablets with all cytochrome P450 3A4 inducers or

discontinuation of a cytochrome P450 3A4 inhibitor may result in lower tramadol levels. This may be

associated with a decrease in efficacy, and in some patients, may result in signs and symptoms of opioid

withdrawal.

Follow patients receiving tramadol hydrochloride tablets and any CYP3A4 inhibitor or inducer for the

risk for serious adverse events including seizures and serotonin syndrome, signs and symptoms that may

reflect opioid toxicity and opioid withdrawal when tramadol hydrochloride tablets are used in

conjunction with inhibitors and inducers of CYP3A4 [see Drug Interactions (7)].

5.7 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of

tramadol hydrochloride tablets with benzodiazepines or other CNS depressants (e.g., non-

benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics,

antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of

these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines

increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of

similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of

other CNS depressant drugs with opioid analgesics [see Drug Interactions (7)].

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an

opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In

patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or

other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response.

If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant,

prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow

patients closely for signs and symptoms of respiratory depression and sedation.

Advise both patients and caregivers about the risks of respiratory depression and sedation when

tramadol hydrochloride tablets are used with benzodiazepines or other CNS depressants (including

alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of

concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients

for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for

overdose and death associated with the use of additional CNS depressants including alcohol and illicit

drugs [see Drug Interactions (7); and Patient Counseling Information (17)].

5.8 Serotonin Syndrome Risk

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported with the use

of tramadol, particularly during concomitant use with serotonergic drugs. Serotonergic drugs include

selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors

(SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the

serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and drugs that impair

metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders

and also others, such as linezolid and intravenous methylene blue) [see Drug Interactions (7)]. This may

occur within the recommended dosage range.

Serotonin syndrome symptoms 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, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting,

diarrhea). The onset of symptoms generally occurs within several hours to a few days of concomitant

use, but may occur later than that. Discontinue tramadol hydrochloride tablets if serotonin syndrome is

suspected.

5.9 Increased Risk of Seizure

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 increase the seizure risk in patients taking [see Drug

Interactions (7)]:

Risk of seizure 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.

Selective serotonin re-uptake inhibitors (SSRI antidepressants or anorectics),

Tricyclic antidepressants (TCAs), and other tricyclic compounds (e.g., cyclobenzaprine,

promethazine, etc.),

Other opioids,

MAO inhibitors [see Warnings and Precautions (5.8); Drug Interactions (7)].

Neuroleptics, or

Other drugs that reduce the seizure threshold.

5.10 Suicide Risk

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

5.11 Adrenal Insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than

one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs

including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal

insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal

insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the

patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until

adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid

without recurrence of adrenal insufficiency. The information available does not identify any particular

opioids as being more likely to be associated with adrenal insufficiency.

5.12 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in

Elderly, Cachectic, or Debilitated Patients

The use of tramadol hydrochloride tablets in patients with acute or severe bronchial asthma in an

unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Patients with Chronic Pulmonary Disease:

Tramadol hydrochloride tablets -treated patients with significant chronic obstructive pulmonary disease

or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or

pre-existing respiratory depression are at increased risk of decreased respiratory drive including

apnea, even at recommended dosage of tramadol hydrochloride tablets [see Warnings and Precautions

(5.3)].

Elderly, Cachectic, or Debilitated Patients:

Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated

patients because they may have altered pharmacokinetics or altered clearance compared to younger,

healthier patients [see Warnings and Precautions (5.3)].

Monitor such patients closely, particularly when initiating and titrating tramadol hydrochloride tablets

and when tramadol hydrochloride tablets are given concomitantly with other drugs that depress

respiration [see Warnings and Precautions (5.7); Drug Interactions (7)]. Alternatively, consider the use of

non-opioid analgesics in these patients.

5.13 Severe Hypotension

Tramadol hydrochloride tablets may cause severe hypotension including orthostatic hypotension and

syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood

pressure has already been compromised by a reduced blood volume or concurrent administration of

certain CNS depressant drugs (e.g. phenothiazines or general anesthetics) [see Drug Interactions (7)].

Monitor these patients for signs of hypotension after initiating or titrating the dosage of tramadol

hydrochloride tablets. In patients with circulatory shock, tramadol hydrochloride tablets may cause

Consideration should be given to the use of non-narcotic analgesics in patients who are suicidal

or depressed [see Drug Abuse and Dependence (9)].

Prescribe tramadol hydrochloride tablets with caution for patients with a history of misuse and/or

are currently taking CNS-active drugs including tranquilizers or antidepressant drugs, alcohol in

excess, and patients who suffer from emotional disturbance or depression [see Drug Interactions

(7)].

Inform patients not to exceed the recommended dose and to limit their intake of alcohol [see

Dosage and Administration (2),Warnings and Precautions (5.7)].

vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of tramadol

hydrochloride tablets in patients with circulatory shock.

5.14 Risks of use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury,

or Impaired Consciousness

In patients who may be susceptible to the intracranial effects of CO retention (e.g., those with evidence

of increased intracranial pressure or brain tumors), tramadol hydrochloride tablets may reduce

respiratory drive, and the resultant CO retention can further increase intracranial pressure. Monitor

such patients for signs of sedation and respiratory depression, particularly when initiating therapy with

tramadol hydrochloride tablets. Opioids may also obscure the clinical course in a patient with a head

injury. Avoid the use of tramadol hydrochloride tablets in patients with impaired consciousness or

coma.

5.15 Risks of Use in Patients with Gastrointestinal Conditions

Tramadol hydrochloride tablets are contraindicated in patients with known or suspected gastrointestinal

obstruction, including paralytic ileus [see Contraindications (4)].

The tramadol in tramadol hydrochloride tablets may cause spasm of the sphincter of Oddi. Opioids may

cause increases in serum amylase. Monitor patients with biliary tract disease, including acute

pancreatitis for worsening symptoms.

5.16 Anaphylaxis and Other Hypersensitivity Reactions

Serious and rarely fatal anaphylactic 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 hypersensitivity reactions to

tramadol and other opioids may be at increased risk and therefore should not receive tramadol

hydrochloride tablets [see Contraindications (4)]. If anaphylaxis or other hypersensitivity occurs, stop

administration of tramadol hydrochloride tablets immediately, discontinue tramadol hydrochloride

tablets permanently, and do not rechallenge with any formulation of tramadol. Advise patients to seek

immediate medical attention if they experience any symptoms of a hypersensitivity reaction. [see

Contraindications (4); Patient Counselling Information (17)].

5.17 Withdrawal

Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial

agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic,

including tramadol hydrochloride tablets. In these patients, mixed agonist/antagonist and partial agonist

analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [see Drug

Interactions (7)].

When discontinuing tramadol hydrochloride tablets in a physically-dependent patient, gradually taper the

dosage [see Dosage and Administration (2.4)]. Do not abruptly discontinue tramadol hydrochloride

tablets in these patients [see Drug Abuse and Dependence (9.3)].

5.18 Driving and Operating Machinery

Tramadol hydrochloride tablets may impair the mental or physical abilities needed to perform

potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive

or operate dangerous machinery unless they are tolerant to the effects of tramadol hydrochloride tablets

and know how they will react to the medication [see Patient Counselling Information (17)].

6 ADVERSE REACTIONS

The following serious adverse reactions are described, or described in greater detail, in other

The following serious adverse reactions are described, or described in greater detail, in other

sections:

6.1 Clinical Trials Experience

Table 1: 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

Dizziness/Vertigo

Nausea

Constipation

Headache

Somnolence

Vomiting

Pruritus

“CNS Stimulation”

Asthenia

Sweating

Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)]

Life-Threatening Respiratory Depression[see Warnings and Precautions (5.3)]

Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-threatening

Respiratory Depression in Children [see Warnings and Precautions (5.4)]

Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.5)]

Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions (5.7)]

Serotonin Syndrome [see Warnings and Precautions (5.8)]

Seizures [see Warnings and Precautions (5.9)]

Suicide [see Warnings and Precautions (5.10)]

Adrenal Insufficiency [see Warnings and Precautions (5.11)]

Severe Hypotension [see Warnings and Precautions (5.13)]

Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.15)]

Hypersensitivity Reactions [see Warnings and Precautions (5.16)]

Withdrawal [see Warnings and Precautions (5.17)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates

observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials

of another drug and may not reflect the rates observed in practice.

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 1 reports the cumulative incidence rate of adverse reactions by

7, 30 and 90 days for the most frequent reactions (5% or more by 7 days). The most frequently

reported events were in the central nervous system and gastrointestinal system. Although the

reactions listed in the table are felt to be probably related to 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 tablets groups.

Sweating

Dyspepsia

Dry Mouth

Diarrhea

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 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 exist.

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

of tramadol and/or reported in post-marketing experience with tramadol-containing products.

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 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.

Gastrointestinal: Gastrointestinal bleeding, Hepatitis, Stomatitis, Liver failure.

Laboratory Abnormalities: Creatinine increase, Elevated liver enzymes, Hemoglobin decrease,

Proteinuria.

Sensory: Cataracts, Deafness, Tinnitus.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of tramadol

hydrochloride tablets. Because these reactions are reported voluntarily from a population of uncertain

size, it is not always possible to reliably estimate their frequency or establish a causal relationship to

drug exposure.

Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been

reported during concomitant use of opioids with serotonergic drugs.

Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often

following greater than one month of use.

Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see

Clinical Pharmacology (12.2)].

QT prolongation/torsade de pointes: Cases of QT prolongation and/or torsade de pointes have been

reported with tramadol use. Many of these cases were reported in patients taking another drug labeled

for QT prolongation, in patients with a risk factor for QT prolongation (e.g., hypokalemia), or in the

overdose setting.

Eye disorders – mydriasis

Metabolism and nutrition disorders – Cases of hypoglycemia have been reported very rarely in patients

taking tramadol. Most reports were in patients with predisposing risk factors, including diabetes or renal

insufficiency, or in elderly patients.

Nervous system disorders – movement disorder, speech disorder

Psychiatric disorders – delirium

7 DRUG INTERACTIONS

Table 2: Clinically Significant Drug Interactions with Tramadol Hydrochloride Tablets

Inhibitors of CYP2D6

Clinical Impact:

The concomitant use of tramadol hydrochloride tablets and CYP2D6 inhibitors

may result in an increase in the plasma concentration of tramadol and a decrease in

the plasma concentration of M1, particularly when an inhibitor is added after a

stable dose of tramadol hydrochloride tablets is achieved. Since M1 is a more

potent µ-opioid agonist, decreased M1 exposure could result in decreased

therapeutic effects, and may result in signs and symptoms of opioid withdrawal in

patients who had developed physical dependence to tramadol. Increased tramadol

exposure can result in increased or prolonged therapeutic effects and increased

risk for serious adverse events including seizures and serotonin syndrome. After

stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the tramadol

plasma concentration will decrease and the M1 plasma concentration will

increase. This could increase or prolong therapeutic effects but also increase

adverse reactions related to opioid toxicity, such as potentially fatal respiratory

depression [see Clinical Pharmacology (12.3)].

Intervention:

If concomitant use of a CYP2D6 inhibitor is necessary, follow patients closely

for adverse reactions including opioid withdrawal, seizures and serotonin

syndrome.

If a CYP2D6 inhibitor is discontinued, consider lowering tramadol hydrochloride

tablets dosage until stable drug effects are achieved. Follow patients closely for

adverse events including respiratory depression and sedation.

Examples:

Quinidine, fluoxetine, paroxetine and bupropion

Inhibitors of CYP3A4

Clinical Impact:

The concomitant use of tramadol hydrochloride tablets and CYP3A4 inhibitors

can increase the plasma concentration of tramadol and may result in a greater

amount of metabolism via CYP2D6 and greater levels of M1. Follow patients

closely for increased risk of serious adverse events including seizures and

serotonin syndrome, and adverse reactions related to opioid toxicity including

potentially fatal respiratory depression, particularly when an inhibitor is added

after a stable dose of tramadol hydrochloride tablets is achieved.

After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the

tramadol plasma concentration will decrease [see Clinical Pharmacology (12.3)],

resulting in decreased opioid efficacy or a withdrawal syndrome in patients who

had developed physical dependence to tramadol.

Intervention:

If concomitant use is necessary, consider dosage reduction of tramadol

hydrochloride tablets until stable drug effects are achieved. Follow patients

closely for seizures and serotonin syndrome, and signs of respiratory depression

and sedation at frequent intervals.

If a CYP3A4 inhibitor is discontinued, consider increasing the tramadol

hydrochloride tablets dosage until stable drug effects are achieved and follow

patients for signs and symptoms of opioid withdrawal.

Examples:

Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g.

ketoconazole), protease inhibitors (e.g., ritonavir)

CYP3A4 Inducers

Clinical Impact:

The concomitant use of tramadol hydrochloride tablets and CYP3A4 inducers can

decrease the plasma concentration of tramadol [see Clinical Pharmacology (12.3)],

resulting in decreased efficacy or onset of a withdrawal syndrome in patients

who have developed physical dependence to tramadol.

After stopping a CYP3A4 inducer, as the effects of the inducer decline, the

tramadol plasma concentration will increase [see Clinical Pharmacology (12.3)],

which could increase or prolong both the therapeutic effects and adverse

reactions, and may cause seizures, serotonin syndrome, and/or potentially fatal

respiratory depression.

Intervention:

If concomitant use is necessary, consider increasing the tramadol hydrochloride

tablets dosage until stable drug effects are achieved. Follow patients for signs of

opioid withdrawal.

If a CYP3A4 inducer is discontinued, consider tramadol hydrochloride tablets

dosage reduction and monitor for seizures and serotonin syndrome, and signs of

sedation and respiratory depression.

Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly

reduced analgesic effect of tramadol. 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.

Examples:

Rifampin, carbamazepine, phenytoin

Benzodiazepines and Other Central Nervous System (CNS) Depressants

Clinical Impact:

Due to additive pharmacologic effect, the concomitant use of benzodiazepines or

other CNS depressants, including alcohol, increases the risk of respiratory

depression, profound sedation, coma, and death.

Intervention:

Reserve concomitant prescribing of these drugs for use in patients for whom

alternative treatment options are inadequate. Limit dosages and durations to the

minimum required. Follow patients closely for signs of respiratory depression

and sedation [see Warnings and Precautions (5.7)].

Examples:

Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle

relaxants, general anesthetics, antipsychotics, other opioids, and alcohol.

Serotonergic Drugs

Clinical Impact:

The concomitant use of opioids with other drugs that affect the serotonergic

neurotransmitter system has resulted in serotonin syndrome.

Intervention:

If concomitant use is warranted, carefully observe the patient, particularly during

treatment initiation and dose adjustment. Discontinue tramadol hydrochloride

tablets immediately if serotonin syndrome is suspected.

Examples:

Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine

reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3

receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g.,

mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those

intended to treat psychiatric disorders and also others, such as linezolid and

intravenous methylene blue).

Monoamine Oxidase Inhibitors (MAOIs)

Clinical Impact:

MAOI interactions with opioids may manifest as serotonin syndrome [see

Warnings and Precautions (5.9)] or opioid toxicity (e.g., respiratory depression,

coma) [see Warnings and Precautions (5.3)].

Intervention:

Do not use tramadol hydrochloride tablets in patients taking MAOIs or within 14

days of stopping such treatment.

Examples:

phenelzine, tranylcypromine, linezolid

Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics

Clinical Impact:

May reduce the analgesic effect of tramadol hydrochloride tablets and/or

precipitate withdrawal symptoms.

Intervention:

Avoid concomitant use.

Examples:

butorphanol, nalbuphine, pentazocine, buprenorphine

Muscle Relaxants

Clinical Impact:

Tramadol may enhance the neuromuscular blocking action of skeletal muscle

relaxants and produce an increased degree of respiratory depression.

Intervention:

Monitor patients for signs of respiratory depression that may be greater than

otherwise expected and decrease the dosage of tramadol hydrochloride tablets

and/or the muscle relaxant as necessary.

Diuretics

Clinical Impact:

Opioids can reduce the efficacy of diuretics by inducing the release of

antidiuretic hormone.

Intervention:

Monitor patients for signs of diminished diuresis and/or effects on blood

pressure and increase the dosage of the diuretic as needed.

Anticholinergic Drugs

Clinical Impact:

The concomitant use of anticholinergic drugs may increase risk of urinary

retention and/or severe constipation, which may lead to paralytic ileus.

Intervention:

Monitor patients for signs of urinary retention or reduced gastric motility when

tramadol hydrochloride tablets are used concomitantly with anticholinergic

drugs.

Digoxin

Clinical Impact:

Post-marketing surveillance of tramadol has revealed rare reports of digoxin

toxicity.

Intervention:

Follow patients for signs of digoxin toxicity and adjust dosage of digoxin as

needed.

Warfarin

Clinical Impact:

Post-marketing surveillance of tramadol has revealed rare reports of alteration of

warfarin effect, including elevation of prothrombin times.

Intervention:

Monitor the prothrombin time of patients on warfarin for signs of an interaction

and adjust the dosage of warfarin as needed.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome.

Available data with tramadol hydrochloride tablets in pregnant women are insufficient to inform a drug-

associated risk for major birth defects and miscarriage.

In animal reproduction studies, tramadol administration during organogenesis decreased fetal weights

and reduced ossification in mice, rats, and rabbits at 1.4, 0.6, and 3.6 times the maximum recommended

human daily dosage (MRHD). Tramadol decreased pup body weight and increased pup mortality at 1.2

and 1.9 times the MRHD [see Data]. Based on animal data, advise pregnant women of the potential risk

to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is

unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In

the U.S. general population, the estimated background risk of major birth defects and miscarriage in

clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in

respiratory depression and physical dependence in the neonate and neonatal opioid withdrawal syndrome

shortly after birth.

Neonatal opioid withdrawal syndrome can present as irritability, hyperactivity and abnormal sleep

pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and

severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of

use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe

newborns for symptoms and signs of neonatal opioid withdrawal syndrome and manage accordingly [see

Warnings and Precautions (5.5)].

Neonatal seizures, neonatal withdrawal syndrome, fetal death and still birth have been reported during

post-marketing.

Labor or Delivery

Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in

neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced

respiratory depression in the neonate. Tramadol hydrochloride tablets are not recommended for use in

pregnant women during or immediately prior to labor, when other analgesic techniques are more

appropriate. Opioid analgesics, including tramadol hydrochloride tablets, can prolong labor through

actions which temporarily reduce the strength, duration, and frequency of uterine contractions.

However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which

tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess

sedation and respiratory depression.

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.

Data

Animal Data

Tramadol has been shown to be embryotoxic and fetotoxic in mice, (120 mg/kg), rats (25 mg/kg) and

rabbits 2 (75 mg/kg) at maternally toxic dosages, but was not teratogenic at these dose levels. These

doses on a mg/m basis are 1.4, 0.6, and 3.6 times the maximum recommended human daily dosage

(MRHD) for mouse, rat and rabbit, respectively.

No drug-related teratogenic effects were observed in progeny of mice (up to 140 mg/kg), rats (up to 80

mg/kg) or rabbits (up to 300 mg/kg) treated with tramadol by various routes. Embryo and fetal toxicity

consisted primarily of decreased fetal weights, decreased 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, 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 MRHD, respectively.

Tramadol was evaluated in pre- and post-natal studies in rats. Progeny of dams receiving oral (gavage)

dose levels of 50 mg/kg 1.2 times the MRHD) or greater had decreased weights, and pup survival was

decreased early in lactation at 80 mg/kg (1.9 times the MRHD).

8.2 Lactation

Risk Summary

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.

Tramadol and its metabolite, O-desmethyltramadol (M1), are present in human milk. There is no

information on the effects of the drug on the breastfed infant or the effects of the drug on milk

production. The M1 metabolite is more potent than tramadol in mu opioid receptor binding [see Clinical

Pharmacology (12)]. Published studies have reported tramadol and M1 in colostrum with administration

of tramadol to nursing mothers in the early post-partum period. Women who are ultra-rapid metabolizers

of tramadol may have higher than expected serum levels of M1, potentially leading to higher levels of

M1 in breast milk that can be dangerous in their breastfed infants. In women with normal tramadol

metabolism, the amount of tramadol secreted into human milk is low and dose-dependent. Because of the

potential for serious adverse reactions, including excess sedation and respiratory depression in a

breastfed infant, advise patients that breastfeeding is not recommended during treatment with tramadol

hydrochloride tablets [see Warnings and Precautions (5.4)].

Clinical Considerations

If infants are exposed to tramadol hydrochloride tablets through breast milk, they should be monitored

for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants

when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.

Data

Following a single IV 100 mg dose of tramadol, the cumulative excretion in breast milk within 16 hours

post dose was 100 mcg of tramadol (0.1% of the maternal dose) and 27 mcg of M1.

8.3 Females and Males of Reproductive Potential

Infertility

Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is

not known whether these effects on fertility are reversible [see Adverse Reactions (6.2)].

8.4 Pediatric Use

The safety and effectiveness of tramadol hydrochloride tablets in pediatric patients have not been

established.

Life-threatening respiratory depression and death have occurred in children who received tramadol [see

Warnings and Precautions (5.4)]. In some of the reported cases, these events followed tonsillectomy

and/or adenoidectomy, and one of the children had evidence of being an ultra-rapid metabolizer of

tramadol (i.e., multiple copies of the gene for cytochrome P450 isoenzyme 2D6). Children with sleep

apnea may be particularly sensitive to the respiratory depressant effects of tramadol. Because of the

risk of life-threatening respiratory depression and death:

Avoid the use of tramadol hydrochloride tablets in adolescents 12 to 18 years of age who have other

risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol unless

the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation such as

postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular

disease, and concomitant use of other medications that cause respiratory depression.

8.5 Geriatric Use

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.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after

large initial doses were administered to patients who were not opioid-tolerant or when opioids were

co-administered with other agents that depress respiration. Titrate the dosage of tramadol

hydrochloride tablets slowly in geriatric patients starting at the low end of the dosing range and monitor

closely for signs of central nervous system and respiratory depression [see Warnings and Precautions

(5.12)].

Tramadol is known to be substantially excreted by the kidney, and the risk of adverse reactions to this

drug may be greater in patients with impaired renal function. Because elderly patients are more likely to

have decreased renal function, care should be taken in dose selection, and it may be useful to monitor

renal function.

8.6 Renal and Hepatic Impairment

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 (2.2)]. Metabolism of tramadol and M1 is reduced in

patients with severe hepatic impairment based on a study in patients with advanced cirrhosis of the liver.

In patients with severe hepatic impairment, dosing reduction is recommended [see Dosage and

Administration (2.2)].

Tramadol hydrochloride tablets are contraindicated for all children younger than 12 years of age

[see Contraindications (4)].

Tramadol hydrochloride tablets are contraindicated for post-operative management in pediatric

patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [see

Contraindications (4)].

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.

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Tramadol hydrochloride tablets contain tramadol, a Schedule IV controlled substance.

9.2 Abuse

Tramadol hydrochloride tablets contain tramadol, a substance with a high potential for abuse similar to

other opioids. Tramadol hydrochloride tablets can be abused and is subject to misuse, addiction, and

criminal diversion [see Warnings and Precautions (5.1)].

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.

Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its

rewarding psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after

repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use,

persisting in its use despite harmful, or potentially harmful, consequences, a higher priority given to

drug use than to other activities and obligations, increased tolerance, and sometimes a physical

withdrawal.

“Drug-seeking” behavior is very common in persons with substance use disorders. 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” (visiting multiple prescribers to obtain additional prescriptions) is common among

drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate

pain relief can be appropriate behavior in a patient with poor pain control.

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

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

of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true

addiction.

Tramadol hydrochloride tablets, like other opioids, can be diverted for non-medical use into illicit

channels of distribution. Careful record-keeping of prescribing information, including quantity,

frequency, and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and

proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Risks Specific to Abuse of Tramadol Hydrochloride Tablets

Tramadol hydrochloride tablets are intended for oral use only. Abuse of tramadol hydrochloride tablets

pose a risk of overdose and death. The risk is increased with concurrent abuse of tramadol

hydrochloride tablets with alcohol and other central nervous system depressants.

Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis

and HIV.

9.3 Dependence

Both tolerance and physical dependence can develop during chronic opioid therapy. 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). Tolerance may occur to both the desired and undesired

effects of drugs, and may develop at different rates for different effects.

Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage

reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with

opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (pentazocine,

butorphanol, nalbuphine), or partial agonists (buprenorphine). Physical dependence may not occur to a

clinically significant degree until after several days to weeks of continued opioid usage.

Tramadol hydrochloride tablets should not be abruptly discontinued in a physically-dependent patient

[see Dosage and Administration (2)]. If tramadol hydrochloride tablets are abruptly discontinued in a

physically dependent patient, a withdrawal syndrome may occur. Some or all of the following can

characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia,

and mydriasis. Other signs and 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.

Infants born to mothers physically dependent on opioids will also be physically dependent and may

exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1)].

10 OVERDOSAGE

Clinical Presentation

Acute overdosage with tramadol hydrochloride tablets can be manifested by respiratory depression,

somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin,

constricted pupils, and, in some cases, pulmonary edema, bradycardia, QT prolongation, hypotension,

partial or complete airway obstruction, atypical snoring, seizures, and death. Marked mydriasis rather

than miosis may be seen with hypoxia in overdose situations.

Deaths due to overdose have been reported with abuse and misuse of tramadol [see Warnings and

Precautions (5.1); Drug Abuse and Dependence (9.2)]. 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.

Treatment of Overdose

In case of overdose, priorities are the re-establishment of a patent and protected airway and institution

of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen

and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac

arrest or serious arrhythmias will require advanced life-supporting measures.

The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression

resulting from opioid overdose. For clinically significant respiratory or circulatory depression

secondary to tramadol overdose, administer an opioid antagonist. Opioid antagonists should not be

administered in the absence of clinically significant respiratory or circulatory depression secondary to

tramadol overdose.

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 tablets 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.

Because the duration of opioid reversal is expected to be less than the duration of action of tramadol in

tramadol hydrochloride tablets, carefully monitor the patient until spontaneous respiration is reliably re-

established. If the response to an opioid antagonist is suboptimal or only brief in nature, administer

additional antagonist as directed by the product's prescribing information.

In an individual physically dependent on opioids, administration of the recommended usual dosage of the

antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms

experienced will depend on the degree of physical dependence and the dose of the antagonist

administered. If a decision is made to treat serious respiratory depression in the physically dependent

patient, administration of the antagonist should be begun with care and by titration with smaller than usual

doses of the antagonist.

11 DESCRIPTION

Tramadol hydrochloride tablets, USP, for oral use, are an opioid agonist. The chemical name for

tramadolhydrochloride is (±)cis-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol

hydrochloride.

The structural formula is:

The molecular weight of tramadol hydrochloride 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 pH 7. Tramadol hydrochloride tablets,

USP contain 50 mg of tramadol hydrochloride, USP, and are white in color. Inactive ingredients in the

tablet are pregelatinized starch, lactose anhydrous, magnesium stearate, microcrystalline cellulose,

polyethylene glycol, sodium starch glycolate, titanium dioxide, hypromellose and polysorbate 80.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Tramadol hydrochloride tablets contain tramadol, an opioid agonist and inhibitor of norepinephrine and

serotonin re- uptake. Although the mode of action is not completely understood, the analgesic effect of

tramadol is believed to be due to both binding to μ-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 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 opioid 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 (12.2)].

Analgesia in humans begins approximately within one hour after administration and reaches a peak in

approximately two to three hours.

12.2 Pharmacodynamics

Effects on the Central Nervous System

Tramadol produces respiratory depression by direct action on brain stem respiratory centers. The

respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers

to both increases in carbon dioxide tension and electrical stimulation.

Tramadol administration may produce a constellation of symptoms including nausea and vomiting,

dizziness, and somnolence.

Tramadol causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are

not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar

findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

Effects on the Gastrointestinal Tract and Other Smooth Muscle

Tramadol causes a reduction in motility associated with an increase in smooth muscle tone in the antrum

of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive

contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be

increased to the point of spasm resulting in constipation. Other opioid- induced effects may include a

reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in

serum amylase.

Effects on the Cardiovascular System

Tramadol produces peripheral vasodilation, which may result in orthostatic hypotension or syncope.

Manifestations of peripheral vasodilation may include pruritus, flushing, red eyes, sweating and/or

orthostatic hypotension.

The effect of oral tramadol on the QTcF interval was evaluated in a double-blind, randomized, four-way

crossover, placebo-and positive- (moxifloxacin) controlled study in 68 adult male and female healthy

subjects. At a 600 mg/day dose (1.5-fold the maximum immediate-release daily dose), the study

demonstrated no significant effect on the QTcF interval.

Effects on the Endocrine System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing

hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic

secretion of insulin and glucagon [see Warnings and Precautions (5.11); Adverse Reactions (6)].

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen

deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.

The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various

medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels

have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6)].

Effects on the Immune System

Opioids have been shown to have a variety of effects on components of the immune system in in vitro

and animal models. The clinical significance of these findings is unknown. Overall, the effects of

opioids appear to be modestly immunosuppressive.

Concentration–Efficacy Relationships

The minimum effective analgesic concentration will vary widely among patients, especially among

patients who have been previously treated with potent opioid agonists. The minimum effective analgesic

concentration of tramadol for any individual patient may increase over time due to an increase in pain,

the development of a new pain syndrome and/or the development of analgesic tolerance [see Dosage and

Administration (2)].

Concentration–Adverse Reaction Relationships

There is a relationship between increasing tramadol plasma concentration and increasing frequency of

dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory

depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to

opioid-related adverse reactions [see Dosage and Administration (2)].

12.3 Pharmacokinetics

The analgesic activity of tramadol hydrochloride tablets is due to both parent drug and the M1

metabolite [see Clinical Pharmacology (12.1, 12.2)]. 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.

Abs orption

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 3 below).

Table 3: Mean (%CV) Pharmacokinetic Parameters for Racemic Tramadol and M1 Metabolite

Table 3: 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)

Healthy Adults,

100 mg q.i.d., MD

p.o.

Tramadol

592 (30)

110 (29)

2.3 (61)

2.4 (46)

5.90 (25)

6.7 (15)

7.0 (14)

Healthy Adults,

100 mg SD p.o.

Tramadol

308 (25)

55.0 (36)

1.6 (63)

3.0 (51)

8.50 (31)

5.6 (20)

6.7 (16)

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.

a

b

1/2

Geriatric, (>75 yrs)

50 mg SD p.o.

Tramadol

208 (31)

2.1 (19)

6.89 (25)

7.0 (23)

Hepatic Impaired,

50 mg SD p.o.

Tramadol

217 (11)

19.4 (12)

1.9 (16)

9.8 (20)

4.23 (56)

13.3 (11)

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.

Dis tribution

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 mcg/mL.

Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range.

Elimination

Tramadol is eliminated primarily through metabolism by the liver and the metabolites are eliminated

primarily by the kidneys. The mean (%CV) apparent total clearance of tramadol after a single 100 mg

oral dose is 8.50 (31) mL/min/kg. 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.

Metabolis m

SD = Single dose, MD = Multiple dose, p.o. = Oral administration, i.v. = Intravenous

administration, q.i.d. = Four times daily

F represents the oral bioavailability of tramadol

Not applicable

Not measured

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 Warnings and Precautions (5.4); Drug Interactions

(7)].

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

Special Populations

Hepatic Impairment

Metabolism of tramadol and M1 is reduced in patients with severe hepatic impairment based on a study

inpatients with advanced cirrhosis of the liver, resulting in both a larger area under the concentration

time curve fortramadol and longer tramadol and M1 elimination half-lives (13 hrs. for tramadol and 19

hrs. for M1). In patientswith severe hepatic impairment, adjustment of the dosing regimen is

recommended [see Dosage and Administration (2)].

Renal Impairment

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 (2)]. The total amount of tramadol and M1

removed during a 4- hour dialysis period is less than 7% of the administered dose.

Age: 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 (2.2)].

Sex

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.

Poor / Extensive Metabolizers, CYP2D6

The formation of the active metabolite, M1, is mediated by CYP2D6, a polymorphic enzyme.

Approximately 7% of the population has reduced activity of the CYP2D6 isoenzyme of cytochrome

P450 metabolizing enzyme system. These individuals are “poor metabolizers” of debrisoquine,

dextromethorphan and tricyclic antidepressants, among other drugs. Based on a population PK analysis

of Phase 1 studies with IR tablets in healthy subjects, concentrations of tramadol were approximately

20% higher in “poor metabolizers” versus “extensive metabolizers,” while M1 concentrations were

40% lower.

13 NONCLINICAL TOXICOLOGY

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 [see Warnings and Precautions (5.8) and Drug Interactions (7)].

Excretion

Tramadol metabolites are eliminated primarily by the kidneys. 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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

A slight, but statistically significant, increase in two common murine tumors, pulmonary and hepatic, was

observed in an NMRI mouse carcinogenicity study, particularly in aged mice. Mice were dosed orally

up to 30 mg/kg in the drinking water (0.36 times the MRHD) 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 evidence of carcinogenicity was noted in a rat 2-year carcinogenicity study testing oral

doses of up to 30 mg/kg in the drinking water, 0.73 times the MRHD.

Mutagenesis

Tramadol was mutagenic in the presence of metabolic activation in the mouse lymphoma assay.

Tramadol was not mutagenic in the in vitro bacterial reverse mutation assay using Salmonella and E. coli

(Ames), the mouse lymphoma assay in the absence of metabolic activation, the in vitro chromosomal

aberration assay, or the in vivo micronucleus assay in bone marrow.

Impairment of Fertility

No effects on fertility were observed for tramadol at oral dose levels up to 50 mg/kg in male rats and 75

mg/kg in female rats. These dosages are 1.2 and 1.8 times the maximum recommended human daily dose

based on body surface area, respectively.

14 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.

Titration Trials

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

tramadol hydrochloride tablets 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. In a second study with 54 to 59 patients per group, patients who had

nausea or vomiting when titrated over 4 days were randomized to re-initiate tramadol hydrochloride

tablets therapy using slower titration rates.

Figure 2:

16 HOW SUPPLIED/STORAGE AND HANDLING

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

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

Dispense in a tight container.

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). [see USP

Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Addiction, Abuse, and Misuse

Inform patients that the use of tramadol hydrochloride tablets, even when taken as recommended, can

result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and

Precautions (5.1)]. Instruct patients not to share tramadol hydrochloride tablets with others and to take

steps to protect tramadol hydrochloride tablets from theft or misuse.

Life-Threatening Respiratory Depression

Inform patients of the risk of life-threatening respiratory depression, including information that the risk

is greatest when starting tramadol hydrochloride tablets or when the dosage is increased, and that it can

occur even at recommended dosages [see Warnings and Precautions (5.3)]. Advise patients how to

20's NDC 71205-303-20 Bottles of 20

30's NDC 71205-303-30 Bottles of 30

40's NDC 71205-303-40 Bottles of 40

60's NDC 71205-303-60 Bottles of 60

90's NDC 71205-303-90 Bottles of 90

120's NDC 71205-303-72 Bottles of 120

180's NDC 71205-303-78 Bottles of 180

recognize respiratory depression and to seek medical attention if breathing difficulties develop.

Accidental Ingestion

Inform patients that accidental ingestion, especially by children, may result in respiratory depression or

death [see Warnings and Precautions (5.3)]. Instruct patients to take steps to store tramadol hydrochloride

tablets securely and to dispose of unused tramadol hydrochloride tablets in accordance with the local

state guidelines and/or regulations.

Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-threatening Respiratory

Depression in Children

Advise caregivers that tramadol hydrochloride tablets are contraindicated in children younger than 12

years of age and in children younger than 18 years of age following tonsillectomy and/or

adenoidectomy. Advise caregivers of children ages 12 to 18 years of age receiving tramadol

hydrochloride tablets to monitor for signs of respiratory depression [see Warnings and Precautions

(5.4)].

Interactions with Benzodiazepines and Other CNS Depressants

Inform patients and caregivers that potentially fatal additive effects may occur if tramadol hydrochloride

tablets are used with benzodiazepines, CNS depressants, including alcohol, or some illicit drugs and not

to use these concomitantly unless supervised by a healthcare provider [see Warnings and Precautions

(5.7); Drug Interactions (7)].

Serotonin Syndrome

Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from

concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin

syndrome, and to seek medical attention right away if symptoms develop. Instruct patients to inform their

healthcare provider if they are taking, or plan to take serotonergic medications [see Warnings and

Precautions (5.8)].

Seizures

Inform patients that tramadol hydrochloride tablets may cause seizures with concomitant use of

serotonergic agents (including SSRIs, SNRIs, and triptans) or drugs that significantly reduce the

metabolic clearance of tramadol [see Warnings and Precautions (5.9)].

MAOI Interaction

Inform patients not to take tramadol hydrochloride tablets while using any drugs that inhibit monoamine

oxidase. Patients should not start MAOIs while taking tramadol hydrochloride tablets [see Drug

Interactions (7)].

Adrenal Insufficiency

Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition.

Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting,

anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical

attention if they experience a constellation of these symptoms [see Warnings and Precautions (5.11)].

Important Administration Instructions

Instruct patients how to properly take tramadol hydrochloride tablets. [see Dosage and

Administration (2)].

Advise patients not to adjust the dose of tramadol hydrochloride tablets without consulting with a

physician or other healthcare professional.

If patients have been receiving treatment with tramadol hydrochloride tablets for more than a few

weeks and cessation of therapy is indicated, counsel them on the importance of safely tapering the

dose as abrupt discontinuation of the medication could precipitate withdrawal symptoms. Provide

Hypotension

Inform patients that tramadol hydrochloride tablets may cause orthostatic hypotension and syncope.

Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of

serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or

lying position) [see Warnings and Precautions (5.13)].

Anaphylaxis

Inform patients that anaphylaxis has been reported with ingredients contained in tramadol hydrochloride

tablets. Advise patients how to recognize such a reaction and when to seek medical attention [see

Contraindications (4); Warnings and Precautions (5.16); Adverse Reactions (6)].

Pregnancy

Neonatal Opioid Withdrawal Syndrome

Inform female patients of reproductive potential that prolonged use of tramadol hydrochloride tablets

during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if

not recognized and treated and that the patient should inform their healthcare provider if they have used

opioids at any time during their pregnancy, especially near the time of birth. [see Warnings and

Precautions (5.5); Use in Special Populations (8.1)].

Embryo-Fetal Toxicity

Inform female patients of reproductive potential that tramadol hydrochloride tablets may cause fetal

harm and to inform the healthcare provider of a known or suspected pregnancy [see Use in Special

Populations (8.1)].

Lactation

Advise women that breastfeeding is not recommended during treatment with tramadol hydrochloride

tablets [see Warnings and Precautions (5.4);Use in Special Populations (8.2)].

Infertility

Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these

effects on fertility are reversible [see Use in Special Populations (8.3)].

Driving or Operating Heavy Machinery

Inform patients that tramadol hydrochloride tablets may impair the ability to perform potentially

hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform

such tasks until they know how they will react to the medication [see Warnings and Precautions (5.18)].

Constipation

Advise patients of the potential for severe constipation, including management instructions and when to

seek medical attention [see Adverse Reactions (6)].

Disposal of Unused Tramadol Hydrochloride Tablets

Advise patients to throw the unused tramadol hydrochloride tablets in the household trash following

these steps.

1) Remove the drugs from their original containers and mix with an undesirable substance, such as used

coffee grounds or kitty litter (this makes the drug less appealing to children and pets, and

unrecognizable to people who may intentionally go through the trash seeking drugs).

2) Place the mixture in a sealable bag, empty can, or other container to prevent the drug from leaking or

breaking out of a garbage bag.

a dose schedule to accomplish a gradual discontinuation of the medication [see Dosage and

Administration (2.4)].

Maximum single-dose and 24-hour dose

Advise patients not to exceed 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

[see Dosage and Administration (2); Warnings and Precautions (5.3)].

Distributed By:

Sun Pharmaceutical Industries, Inc.

Cranbury, NJ 08512

Repackaged by:

Proficient Rx LP

Thousand Oaks, CA 91320

PGPI0173L

Rev. 06/2019

Medication Guide

Tramadol Hydrochloride Tablets, USP

(TRAM a dol hye” droe cklo' ride"), CIV

Tramadol hydrochloride tablets are:

Important information about tramadol hydrochloride tablets:

Important information guiding use in pediatric patients:

A strong prescription pain medicine that contains an opioid (narcotic) that is used for the

management pain in adults, when other pain treatments such as non-opioid pain medicines do not

treat your pain well enough or you cannot tolerate them.

An opioid pain medicine that can put you at risk for overdose and death. Even if you take your

dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead

to death.

Get emergency help right away if you take too much tramadol hydrochloride tablets

(overdose). When you first start taking tramadol hydrochloride tablets, when your dose is

changed, or if you take too much (overdose), serious or life-threatening breathing problems that

can lead to death may occur.

Taking tramadol hydrochloride tablets with other opioid medicines, benzodiazepines, alcohol, or

other central nervous system depressants (including street drugs) can cause severe drowsiness,

decreased awareness, breathing problems, coma, and death.

Never give anyone else your tramadol hydrochloride tablets. They could die from taking it. Store

tramadol hydrochloride tablets away from children and in a safe place to prevent stealing or

abuse. Selling or giving away tramadol hydrochloride tablets is against the law.

Do not give tramadol hydrochloride tablets to a child younger than 12 years of age.

Do not give tramadol hydrochloride tablets to a child younger than 18 years of age after surgery

to remove the tonsils and/or adenoids.

Avoid giving tramadol hydrochloride tablets to children between 12 to 18 years of age who have

risk factors for breathing problems such as obstructive sleep apnea, obesity, or underlying lung

problems.

Taken a Monoamine Oxidase Inhibitor, MAOI, (medicine used for depression) within the last 14 days.

Before taking tramadol hydrochloride tablets, tell your healthcare provider if you have a history of:

Tell your healthcare provider if you are:

When taking tramadol hydrochloride tablets:

Do not change your dose. Take tramadol hydrochloride tablets exactly as prescribed by your

healthcare provider. Use the lowest dose possible for the shortest time needed.

Take your prescribed dose as indicated by your healthcare provider. The maximum dosage is 1 or 2

tablets every 4 to 6 hours, as needed for pain relief. Do not take more than your prescribed dose and do

not take more than 8 tablets per day. If you miss a dose, take your next dose at your usual time.

Call your healthcare provider if the dose you are taking does not control your pain.

If you have been taking tramadol hydrochloride tablets regularly, do not stop taking tramadol

hydrochloride tablets without talking to your healthcare provider.

After you stop taking tramadol hydrochloride tablets, ask your pharmacist how to dispose of any unused

tablets.

While taking tramadol hydrochloride tablets DO NOT:

Drive or operate heavy machinery, until you know how tramadol hydrochloride tablets affects you.

Tramadol hydrochloride tablets can make you sleepy, dizzy, or lightheaded.

Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products

containing alcohol during treatment with tramadol hydrochloride tablets may cause you to overdose and

die.

The possible side effects of tramadol hydrochloride tablets:

Do not take tramadol hydrochloride tablets if you have:

Severe asthma, trouble breathing, or other lung problems.

A bowel blockage or have narrowing of the stomach or intestines.

An allergy to tramadol.

head injury, seizures

liver, kidney, thyroid problems

problems urinating

pancreas or gallbladder problems

abuse of street or prescription drugs, alcohol addiction, or mental health problems.

pregnant or planning to become pregnant. Prolonged use of tramadol hydrochloride tablets

during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-

threatening if not recognized and treated.

breastfeeding. Not recommended; it may harm your baby.

taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking

tramadol hydrochloride tablets with certain other medicines can cause serious side effects that

could lead to death.

constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call

your healthcare provider if you have any of these symptoms and they are severe.

Get emergency medical help if you have:

trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or

throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation,

high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.

These are not all the possible side effects of tramadol hydrochloride tablets. Call your doctor for

www.sunpharma.com or call 1-800-818-4555

Distributed by:

Sun Pharmaceutical Industries, Inc.

Cranbury, NJ 08512

Repackaged by:

Proficient Rx LP

Thousand Oaks, CA 91320

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Rev. 06/2019

PGPI0345D

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL

50mg-Tablets

TRAMADOL HYDROCHLORIDE

tramadol hydrochloride tablet

Product Information

Product T ype

HUMAN PRESCRIPTION

DRUG

Ite m Code (Source )

NDC:7120 5-

30 3(NDC:576 6 4-377)

Route of Administration

ORAL

DEA Sche dule

Active Ingredient/Active Moiety

medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For

more information go to dailymed.nlm.nih.gov

Proficient Rx LP

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 )

MICRO CRYSTALLINE CELLULO SE (UNII: OP1R32D6 1U)

PO LYETHYLENE GLYCO L, UNSPECIFIED (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

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:7120 5-30 3-20

20 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 8 /0 1/20 19

2

NDC:7120 5-30 3-30

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 8 /0 1/20 19

3

NDC:7120 5-30 3-40

40 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 8 /0 1/20 19

4

NDC:7120 5-30 3-6 0

6 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 8 /0 1/20 19

5

NDC:7120 5-30 3-9 0

9 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 8 /0 1/20 19

6

NDC:7120 5-30 3-72

120 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 8 /0 1/20 19

7

NDC:7120 5-30 3-78

18 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 8 /0 1/20 19

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 -

Proficient Rx LP (079196022)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Pro ficient Rx LP

0 79 19 6 0 22

REPACK(7120 5-30 3) , RELABEL(7120 5-30 3)

Revised: 3/2020

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