Tramadol

What is tramadol?

Tramadol is a narcotic-like pain reliever.

Tramadol is used to treat moderate to severe pain in adults.

The extended-release form of tramadol is for around-the-clock treatment of pain. The extended-release form of tramadol is not for use on an as-needed basis for pain.

Important Information

Seizures have been reported in patients taking tramadol. Your risk of seizures is higher if you are taking higher doses of tramadol over what is recommended. Seizure risk is also higher in those with a seizure disorder or those taking certain antidepressants or opioid medications.

Tramadol should not be used if you are suicidal or prone to addiction.

You should not take tramadol if you have severe breathing problems, a blockage in your stomach or intestines, or if you have recently used alcohol, sedatives, tranquilizers, narcotic medication, or an MAO inhibitor (isocarboxazid, linezolid, methylene blue injection, phenelzine, rasagiline, selegiline, tranylcypromine, and others).

Tramadol can slow or stop your breathing, and may be habit-forming. MISUSE OF THIS MEDICINE CAN CAUSE ADDICTION, OVERDOSE, OR DEATH, especially in a child or other person using the medicine without a prescription.

Tramadol should not be given to a child younger than 12 years old. Ultram ER should not be given to anyone younger than 18 years old.

Taking tramadol during pregnancy may cause life-threatening withdrawal symptoms in the newborn.

Fatal side effects can occur if you use this medicine with alcohol, or with other drugs that cause drowsiness or slow your breathing.

Before taking this medicine

You should not take tramadol if you are allergic to it, or if you have:

  • severe asthma or breathing problems;
  • a blockage in your stomach or intestines;
  • if you have recently used alcohol, sedatives, tranquilizers, or narcotic medications; or
  • if you have used an MAO inhibitor in the past 14 days (such as isocarboxazid, linezolid, methylene blue injection, phenelzine, rasagiline, selegiline, or tranylcypromine).

Tramadol should not be given to a child younger than 12 years old. Ultram ER should not be given to anyone younger than 18 years old.

Do not give this medicine to anyone younger than 18 years old who recently had surgery to remove the tonsils or adenoids.

Avoid giving this medicine to children between 12 to 18 years of age who have conditions that may cause breathing problems.

Seizures have occurred in some people taking tramadol. Talk with your doctor about your seizure risk, which may be higher if you have ever had:

  • a head injury, epilepsy or other seizure disorder;
  • f you also use certain antidepressants, muscle relaxants, opioids, or other medications.

If you use tramadol while you are pregnant, your baby could become dependent on the drug. This can cause life-threatening withdrawal symptoms in the baby after it is born. Babies born dependent on habit-forming medicine may need medical treatment for several weeks. Tell your doctor if you are pregnant or plan to become pregnant.

Do not breast-feed while taking tramadol. This medicine can pass into breast milk and cause drowsiness, breathing problems, or death in a nursing baby.

To make sure tramadol is safe for you, tell your doctor if you have ever had:

  • liver or kidney disease;
  • a stomach disorder; or
  • mental illness, or suicide attempt.

How should I take tramadol?

Take tramadol exactly as prescribed. Follow all directions on your prescription label. Tramadol can slow or stop your breathing, especially when you start using this medicine or whenever your dose is changed. Never take this medicine in larger amounts, or for longer than prescribed. Tell your doctor if the medicine seems to stop working as well in relieving your pain.

Tramadol may be habit-forming, even at regular doses. Never share this medicine with another person, especially someone with a history of drug abuse or addiction. MISUSE OF PAIN MEDICATION CAN CAUSE ADDICTION, OVERDOSE, OR DEATH, especially in a child or other person using the medicine without a prescription. Selling or giving away this medicine is against the law.

Stop taking all other around-the-clock narcotic pain medications when you start taking tramadol.

Tramadol can be taken with or without food, but take it the same way each time.

Do not crush, break, or open an extended-release tablet or capsule (ConZip, Ultram ER). Swallow it whole to avoid exposure to a potentially fatal dose.

Never crush or break a tablet inhale the powder or mix it into a liquid to inject the drug into your vein. This practice has resulted in death.

If you use the tramadol extended-release tablet, the tablet shell may pass into your stools (bowel movements). This is normal and does not mean that you are not receiving enough of the medicine.

Do not stop using this medicine suddenly, or you could have unpleasant withdrawal symptoms. Ask your doctor how to safely stop using this medicine.

Store at room temperature away from moisture and heat. Keep track of your medicine. Tramadol is a drug of abuse and you should be aware if anyone is using your medicine improperly or without a prescription.

Do not keep leftover opioid medication. Just one dose can cause death in someone using this medicine accidentally or improperly. Ask your pharmacist where to locate a drug take-back disposal program. If there is no take-back program, flush the unused medicine down the toilet.

What happens if I miss a dose?

Since tramadol is used for pain, you are not likely to miss a dose. Skip any missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. A tramadol overdose can be fatal, especially in a child or other person using the medicine without a prescription. Overdose symptoms may include slow heart rate, severe drowsiness, cold and clammy skin, very slow breathing, or coma.

What should I avoid while taking tramadol?

Do not drink alcohol. Dangerous side effects or death could occur.

This medicine may impair your thinking or reactions. Avoid driving or operating machinery until you know how this medicine will affect you. Dizziness or severe drowsiness can cause falls or other accidents.

Tramadol side effects

Get emergency medical help if you have signs of an allergic reaction to tramadol (hives, difficult breathing, swelling in your face or throat) or a severe skin reaction (fever, sore throat, burning in your eyes, skin pain, red or purple skin rash that spreads and causes blistering and peeling).

Like other narcotic medicines, tramadol can slow your breathing. Death may occur if breathing becomes too weak.

A person caring for you should seek emergency medical attention if you have slow breathing with long pauses, blue colored lips, or if you are hard to wake up.

Call your doctor at once if you have:

  • noisy breathing, sighing, shallow breathing;
  • a slow heart rate or weak pulse;
  • a light-headed feeling, like you might pass out;
  • seizure (convulsions);
  • missed menstrual periods;
  • impotence, sexual problems, loss of interest in sex; or
  • nausea, vomiting, loss of appetite, dizziness, worsening tiredness or weakness.

Seek medical attention right away if you have symptoms of serotonin syndrome, such as: agitation, hallucinations, fever, sweating, shivering, fast heart rate, muscle stiffness, twitching, loss of coordination, nausea, vomiting, or diarrhea.

Serious side effects may be more likely in older adults and those who are overweight, malnourished, or debilitated.

Long-term use of opioid medication may affect fertility (ability to have children) in men or women. It is not known whether opioid effects on fertility are permanent.

Common tramadol side effects may include:

  • headache, dizziness, drowsiness, tired feeling;
  • constipation, diarrhea, nausea, vomiting, stomach pain;
  • feeling nervous or anxious;
  • itching, sweating, flushing (warmth, redness, or tingly feeling;.
  • dry mouth

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect tramadol?

Narcotic (opioid) medication can interact with many other drugs and cause dangerous side effects or death. Be sure your doctor knows if you also use:

  • other narcotic medications – opioid pain medicine or prescription cough medicine;
  • a sedative like Valium – diazepam, alprazolam, lorazepam, Ativan, Klonopin, Restoril, Tranxene, Versed, Xanax, and others;
  • drugs that make you sleepy or slow your breathing – a sleeping pill, muscle relaxer, tranquilizer, antidepressant, or antipsychotic medicine;
  • drugs that affect serotonin levels in your body – medicine for depression, Parkinson’s disease, migraine headaches, serious infections, or prevention of nausea and vomiting;
  • antibiotics and antifungals including erythromycin, linezolid, and ketoconazole;
  • migraine medications (triptans);
  • drugs that affect blood clotting, like warfarin

This list is not complete. Other drugs may interact with tramadol, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

Further information

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use tramadol only for the indication prescribed.

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

In Summary

Commonly reported side effects of tramadol include: pruritus, agitation, anxiety, constipation, diarrhea, hallucination, nausea, tremor, vomiting, and diaphoresis. Other side effects include: insomnia. See below for a comprehensive list of adverse effects.

For the Consumer

Applies to tramadol: oral capsule extended release, oral suspension, oral tablet, oral tablet disintegrating, oral tablet extended release

Along with its needed effects, tramadol may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking tramadol:

Less Common

  • Abnormal or decreased touch sensation
  • blisters under the skin
  • bloating
  • blood in the urine
  • blood pressure increased
  • blurred vision
  • change in walking and balance
  • chest pain or discomfort
  • chills
  • darkened urine
  • difficult urination
  • dizziness or lightheadedness when getting up from a lying or sitting position
  • fainting
  • fast heartbeat
  • frequent urge to urinate
  • gaseous abdominal or stomach pain
  • indigestion
  • irregular heartbeat
  • loss of memory
  • numbness and tingling of the face, fingers, or toes
  • pain in the arms, legs, or lower back, especially pain in the calves or heels upon exertion
  • pain or discomfort in the arms, jaw, back, or neck
  • pains in the stomach, side, or abdomen, possibly radiating to the back
  • pale, bluish-colored or cold hands or feet
  • recurrent fever
  • seeing, hearing, or feeling things that are not there
  • seizures
  • severe cramping
  • severe nausea
  • severe redness, swelling, and itching of the skin
  • stomach fullness
  • sweating
  • trembling and shaking of the hands or feet
  • trouble performing routine tasks
  • weak or absent pulses in the legs
  • yellow eyes or skin

Get emergency help immediately if any of the following symptoms of overdose occur while taking tramadol:

Symptoms of Overdose

  • Change in consciousness
  • decreased awareness or responsiveness
  • difficulty with breathing
  • lack of muscle tone
  • lightheadedness
  • loss of consciousness
  • pinpointed pupils of the eyes
  • severe sleepiness
  • slow or irregular heartbeat
  • unusual tiredness

Some side effects of tramadol may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More Common

  • Agitation
  • constipation
  • cough
  • diarrhea
  • discouragement
  • drowsiness
  • dry mouth
  • feeling of warmth
  • feeling sad or empty
  • feeling unusually cold
  • fever
  • general feeling of discomfort or illness
  • headache
  • heartburn
  • irritability
  • itching or skin rash
  • joint pain
  • loss of appetite
  • loss of interest or pleasure
  • loss of strength or weakness
  • muscle aches and pains
  • nausea
  • redness of the face, neck, arms, and occasionally, upper chest
  • restlessness
  • runny nose
  • shivering
  • sleepiness or unusual drowsiness
  • sore throat
  • stomach pain
  • stuffy nose
  • sweating
  • tiredness
  • trouble concentrating
  • unusual feeling of excitement
  • weakness

Less Common

  • Abnormal dreams
  • appetite decreased
  • back pain
  • bladder pain
  • blistering, crusting, irritation, itching, or reddening of the skin
  • bloody or cloudy urine
  • body aches or pain
  • change in hearing
  • clamminess
  • cold flu-like symptoms
  • confusion
  • cough producing mucus
  • cracked, dry, or scaly skin
  • decreased interest in sexual intercourse
  • difficult, burning, or painful urination
  • difficulty with moving
  • disturbance in attention
  • ear congestion
  • ear drainage
  • earache or pain in the ear
  • excessive gas
  • falls
  • false or unusual sense of well-being
  • feeling hot
  • feeling jittery
  • general feeling of bodily discomfort
  • goosebumps
  • headache, severe and throbbing
  • hoarseness
  • hot flashes
  • inability to have or keep an erection
  • itching, pain, redness, swelling, tenderness, or warmth on the skin
  • joint sprain, stiffness, or swelling
  • loss in sexual ability, desire, drive, or performance
  • loss of voice
  • lower back or side pain
  • muscle aching or cramping
  • muscle injury
  • muscle pain, stiffness, spasms, or twitching
  • nasal congestion
  • neck pain
  • night sweats
  • pain in the limbs
  • pain or tenderness around the eyes and cheekbones
  • pain, swelling, or redness in the joints
  • skin discoloration
  • swelling
  • swelling of the hands, ankles, feet, or lower legs
  • tightness of the chest
  • trouble in holding or releasing urine
  • trouble with sleeping
  • weight increased or decreased

For Healthcare Professionals

Applies to tramadol: oral capsule extended release, oral tablet, oral tablet disintegrating, oral tablet extended release

General

The most common adverse reactions include nausea, constipation, dry mouth, somnolence, dizziness, and vomiting.

Psychiatric

CNS stimulation has been reported as a composite of nervousness, anxiety, agitation, tremor, spasticity, euphoria, emotional lability, and hallucinations. During clinical trials, tolerance development was mild and the reports of a withdrawal syndrome were rare. Symptoms of a withdrawal syndrome have included: panic attacks, severe anxiety, hallucinations, paraesthesias, tinnitus and unusual CNS symptoms (i.e. confusion, delusions, personalization, derealization, and paranoia).

Very common (10% or more): CNS stimulation (up to 14%)

Common (1% to 10%): Anxiety, euphoria, nervousness, sleep disorder, insomnia, depression, agitation, apathy, depersonalization

Uncommon (0.1% to 1%): Emotional lability

Rare (less than 0.1%): Hallucinations, nightmares, dependency

Very rare (less than 0.01%): Withdrawal syndrome

Hypersensitivity

Rare (less than 0.1%): Anaphylaxis, allergic reactions such as dyspnea, bronchospasm, wheezing, angioneurotic edema, swollen skin

Gastrointestinal

Very common (10% or more): Nausea (up to 40%), constipation (up to 46%), vomiting (up to 17%), dyspepsia (up to 13%)

Common (1% to 10%): Dry mouth, diarrhea, abdominal pain, flatulence, sore throat, gastroenteritis viral

Uncommon (0.1% to 1%): Toothache, appendicitis, pancreatitis

Nervous system

Epileptiform seizures primarily occurred following administration of high doses or following concomitant treatment with drugs that lower the seizure threshold or trigger seizures.

Serotonin syndrome has been reported during concomitant use of opioids with serotonergic drugs.

Very common (10% or more): Dizziness (up to 28%), somnolence (up to 25%), headache (up to 32%),

Common (1% to 10%): Confusion, coordination disturbance, tremor, paresthesia, hypoesthesia

Uncommon (0.1% to 1%): Migraine, sedation, syncope, disturbance in attention

Rare (less than 0.1%): Epileptiform seizures

Postmarketing reports: Seizures

Opioids:

Postmarketing reports: Serotonin syndrome

Dermatologic

Very common (10% or more): Pruritus (up to 11%)

Common (1% to 10%): Sweating, rash, dermatitis

Uncommon (0.1% to 1%): Cellulitis, piloerection, clamminess, urticaria, toxic epidermal necrolysis, Stevens Johnson-syndrome, hair disorder, skin disorder

Genitourinary

Common (1% to 10%): Menopausal symptoms, urinary frequency, urinary retention, urinary tract infection

Uncommon (0.1% to 1%): Difficulty in micturition, hematuria, dysuria, cystitis, sexual function abnormality

Cardiovascular

Reports of QT prolongation and/or torsade de pointes have been received. In many cases, patients were taking another drug associated with QT prolongation, had risk factors for QT prolongation such as hypokalemia, or in the overdose setting.

Very common (10% or more): Flushing (up to 15.8%)

Common (1% to 10%): Vasodilation, postural hypotension, chest pain

Uncommon (0.1% to 1%): Palpitations, myocardial infarction, lower limb edema, peripheral swelling, hypertension, increased heart rate, peripheral ischemia, EKG abnormality, hypotension, tachycardia

Rare (less than 0.1%): Bradycardia

Postmarketing reports: QT prolongation/torsade de pointes

Other

Very common (10% or more): Asthenia (up to 12%)

Common (1% to 10%): Malaise, weakness, pain, feeling hot, influenza like illness, rigors, lethargy, pyrexia

Uncommon (0.1% to 1%): Tinnitus, vertigo, ear infection

Metabolic

Common (1% to 10%): Anorexia, decreased weight, increased blood glucose

Uncommon (0.1% to 1%): Gout

Rare (less than 0.1%): Changes in appetite

Endocrine

Very rare (less than 0.01%): Syndrome of inappropriate antidiuretic hormone secretion

Opioids:

Postmarketing reports: Adrenal insufficiency; androgen deficiency

Hematologic

Uncommon (0.1% to 1%): Anemia, ecchymosis

Hepatic

Uncommon (0.1% to 1%): Cholelithiasis, cholecystitis, ALT and AST increased, abnormal liver function tests[Ref]

Ocular

Common (1% to 10%): Miosis, visual disturbance, blurred vision

Uncommon (0.1% to 1%): Lacrimation disorder

Frequency not reported: Mydriasis

Renal

Uncommon (0.1% to 1%): blood urea nitrogen increased

Musculoskeletal

Common (1% to 10%): Hypertonia, arthralgia, back pain, limb pain, neck pain, muscle cramps, muscle spasms, joint stiffness, muscle twitching, myalgia, aggravated osteoarthritis

Uncommon (0.1% to 1%): Joint swelling, joint sprain, muscle injury, leg cramps

Rare (less than 0.1%): Involuntary muscle contractions

References

1. Cerner Multum, Inc. “UK Summary of Product Characteristics.” O 0

2. Cerner Multum, Inc. “Australian Product Information.” O 0

3. “Product Information. Ultram ER (traMADol).” PriCara Pharmaceuticals, Raritan, NJ.

4. “Product Information. Ultram (tramadol).” McNeil Pharmaceutical, Raritan, NJ.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Some side effects may not be reported. You may report them to the FDA.

Applies to the following strengths: 50 mg; 100 mg/24 hours; 200 mg/24 hours; 300 mg/24 hours; 150 mg/24 hours

Usual Adult Dose for:

  • Pain
  • Chronic Pain

Usual Geriatric Dose for:

  • Pain
  • Chronic Pain

Usual Pediatric Dose for:

  • Pain

Additional dosage information:

  • Renal Dose Adjustments
  • Liver Dose Adjustments
  • Dose Adjustments
  • Precautions
  • Dialysis
  • Other Comments

Usual Adult Dose for Pain

Adults (17 years or older): 50 to 100 mg orally every 4 to 6 hours as needed for pain
-For patients not requiring rapid onset of analgesic effect: Initial dose: 25 mg orally once a day; titrate in 25 mg increments every 3 days to reach a dose of 25 mg four times a day; thereafter increase by 50 mg as tolerated every 3 days
Maximum dose: 400 mg per day

Comments:
-Doses should be individualized; for patients not requiring rapid analgesia, tolerability may be increased by a slow dose titration.
-The US FDA warns against use of tramadol in pediatric patients; product labeling for immediate-release tramadol describes adult patients as 17 years or older.
-Tramadol should not be used postoperatively in patients up to 18 years after tonsillectomy and/or adenoidectomy or in adolescents up to 18 years who are obese or have conditions that may increase the risk of breathing problems.

Use: For the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

Usual Adult Dose for Chronic Pain

Extended-Release (ER):
18 years or older (tramadol-naive): 100 mg orally once a day
-Individually titrate in 100 mg increments every 5 days to an effective dose that minimizes adverse reactions
-Maximum Dose: 300 mg/day

For patients CURRENTLY receiving Immediate-Release (IR) Tramadol:
Initial Dose: Calculate 24-hour IR requirement and initiate with a total daily ER dose rounded down to the next lowest 100 mg increment orally once a day

Conversion from OTHER Opioids: Discontinue all other around the clock opioid drugs prior to initiating therapy
-Initial dose: 100 mg ER orally once a day
-Individually titrate in 100 mg increments every 5 days to an effective dose that minimizes adverse reactions
-Maximum Dose: 300 mg/day

Comments:
-Due to limitations of dose selection with ER formulations, some patients may not be able to convert from the IR to ER.
-The ER products should not be used with other tramadol products and should not be taken more often than once a day.
-Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of therapy and following dose increases.
-For patients with moderate to moderately severe chronic pain not requiring rapid onset of analgesic effect, tolerability can be improved by initiating slowly, possibly with the immediate-release product.
-This drug is not recommended for patients less than 18 years old.

Use: For the management of pain severe enough to require around-the-clock long-term opioid treatment for which alternative treatment options are inadequate.

Usual Geriatric Dose for Pain

Dose selection should be cautious generally starting at the low end of the dose range

Over 75 years:
Maximum dose of Immediate-release: 300 mg per day

Comments:
-Respiratory depression is the chief risk for elderly patients treated with opioids; titrate dose slowly and monitor closely for signs of central nervous system and respiratory depression.
-Because this drug is substantially excreted by the kidney, consider monitoring renal function.

Usual Geriatric Dose for Chronic Pain

Dose selection should be cautious generally starting at the low end of the dose range

Over 75 years:
Maximum dose of Immediate-release: 300 mg per day

Comments:
-Respiratory depression is the chief risk for elderly patients treated with opioids; titrate dose slowly and monitor closely for signs of central nervous system and respiratory depression.
-Because this drug is substantially excreted by the kidney, consider monitoring renal function.

Usual Pediatric Dose for Pain

Tramadol is not recommended for use in pediatric patients

17 years or older: See Adult Dose

Renal Dose Adjustments

Immediate-release:
-CrCl less than 30 mL/min: Increase dosing interval to every 12 hours; Maximum dose should not exceed 200 mg per day

Extended-release:
-CrCl less than 30 mL/min: Use is not recommended

Liver Dose Adjustments

Immediate-release:
-Patients with cirrhosis: 50 mg orally every 12 hours

Extended-release:
-Severe hepatic impairment (Child-Pugh Class C): Use is not recommended

Dose Adjustments

Concomitant use of Drugs affecting CYP450 Isoenzymes:
-CYP450 3A4 inhibitors/inducers and CYP450 2D6 inhibitors: Interactions are complex, consult drug interaction monographs

For patients who have received this drug for an extended-period:
-Gradually decrease dose by 25% to 50% every 2 to 4 days
-If patient develops signs or symptoms of withdrawal, raise the dose to the previous level and taper more slowly by either increasing the interval between decreases, decreasing the amount of change in dose, or both.
-Do not abruptly discontinue therapy, especially for patients receiving extended-release product.

Precautions

US BOXED WARNINGS: ADDICTION, ABUSE AND MISUSE; 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 CYP450 ISOENZYMES; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS:
-Addiction, Abuse, and Misuse: Use of this drug exposes patients and other users to the risks of opioid addiction and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing and monitor all patients regularly for the development of these behaviors or conditions.
-Life-Threatening Respiratory Depression: Serious life-threatening or fatal respiratory depression may occur. Monitor for respiratory depression, especially during initiation or following a dose increase.
-Accidental Ingestion of/exposure to even one dose, especially by children, can result in a fatal overdose.
-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 occurred following tonsillectomy and/or adenoidectomy, and in at least 1 case, the child had evidence of being an ultra-rapid metabolizer of tramadol due to a CYP450 2D6 polymorphism. This drug is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid use 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.

-Neonatal Opioid Withdrawal Syndrome may result from prolonged maternal opioid use during pregnancy; it may be life-threatening if not recognized and treated; management according to protocols developed by neonatology experts will be required. If opioid use is needed for a prolonged period in a pregnant woman, she should be advised of the risk of neonatal opioid withdrawal syndrome and ensure appropriate treatment be available.
-Concomitant use or discontinuation of CYP450 isoenzymes including CYP450 3A4 inducers, CYP450 3A4 inhibitors, or CYP450 2D6 inhibitors are complex; concomitant use requires careful consideration of the effects on the parent drug, tramadol, and the active metabolite, M1.
-Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for 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.

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

US Controlled Substance: Schedule IV

Dialysis

Hemodialysis patients can receive their regular dose on dialysis days since only 7% of dose is removed
Peritoneal dialysis: No data available

Other Comments

OTHER COMMENTS:
Administration advice:
-Take orally with or without food

Extended release capsules and tablets:
-Swallow whole; do not crush, chew, split, or dissolve
-May take with or without food, but should be taken in a consistent manner once a day

General:
-During periods of changing analgesic requirements, including initial dose titration, frequent communication among members of the healthcare team, patients, and caregivers, is important; patients who experience breakthrough pain may require dose adjustments or if receiving the extended-release (ER) product, may need rescue medication with an immediate-release analgesic.
-Seizures and/serotonin syndrome may occur when used concomitantly with serotonergic agents (SSRIs, SNRIs, and triptans) or with drugs that significantly reduce the metabolic clearance of tramadol.
-Taking this drug in excessive doses, either alone or in combination with other CNS depressants, including alcohol, is a major cause of drug-related deaths.
-Extended-release products should be prescribed by healthcare professionals knowledgeable in the use of potent opioids for the management of chronic pain; this drug should not be used for longer than therapeutically necessary; evaluate continued use at regular intervals.

Monitoring:
-Monitor closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy and with each dose increase.
-Monitor regularly for the development of addiction, abuse, and misuse.
-Consider monitoring renal function in elderly patients.

Patient advice:
-Patients should understand that taking this medication exposes them to the risk of addiction.
-Patients should understand the risks of life-threatening respiratory depression, and be informed as to when this risk is greatest.
-This drug may cause drowsiness, dizziness, or impair thinking or motor skills; patients should avoid driving or operating machinery until adverse effects are determined.
-Patients should be instructed to avoid alcohol, not to exceed the recommended dose, and to speak with their healthcare provider regarding all concomitant medications including starting or stopping any products while taking this drug.
-Patients should be instructed to report bowel problems and signs and symptoms of adrenal insufficiency.
-Advise patient to speak to physician or health care professional if pregnant, intend to become pregnant, or are breastfeeding.
-Women of child bearing potential should understand that prolonged use during pregnancy can result in neonatal opioid withdrawal syndrome and that prompt recognition and treatment will be necessary.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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 Extended-Release Capsules exposes 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 Extended-Release Capsules and monitor all patients regularly for the development of these behaviors and conditions. 

Opiod 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. 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

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 Medication Guide every time it is provided by their pharmacist, and

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

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression may occur with use of Tramadol Hydrochloride Extended-Release Capsules. Monitor for respiratory depression, especially during initiation of Tramadol Hydrochloride Extended-Release Capsules or following a dose increase. Instruct patients to swallow Tramadol Hydrochloride Extended-Release Capsules intact, and not to split, break, chew, crush, or dissolve the contents of the capsules to avoid exposure to a potentially fatal dose of tramadol.

Accidental Ingestion

Accidental ingestion of/exposure to even one dose of Tramadol Hydrochloride Extended-Release Capsules especially by children, can result in a fatal overdose of tramadol.

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 occurred following tonsillectomy and/or adenoidectomy, and at least one case, the child had evidence of being an ultra-rapid metabolizer of tramadol due to a CYP2D6 polymorphism. Tramadol Hydrochloride Extended-Release Capsules are contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of Tramadol Hydrochloride Extended-Release Capsules 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.

Neonatal Opioid Withdrawal Syndrome

Prolonged use of Tramadol Hydrochloride Extended-Release Capsules 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.

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 Extended-Release Capsules requires careful consideration of the effects on the parent drug, tramadol, and the active metabolite, M1.

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.

Reserve concomitant prescribing of Tramadol Hydrochloride Extended-Release Capsules and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.

Limit dosages and durations to the minimum required.

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

1       INDICATIONS AND USAGE

Tramadol Hydrochloride Extended-Release Capsules are indicated for the management of pain severe enough to require daily, around-the-clock, long term opioid treatment and for which alternative treatment options are inadequate.

Limitation of Use

  • Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release/long-acting opioid formulations, reserve  Tramadol Hydrochloride Extended-Release Capsules for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.
  • Tramadol Hydrochloride Extended-Release Capsules are not indicated as an as-needed (prn) analgesic.

2       DOSAGE AND ADMINISTRATION

2.1       Important Dosage and Administration Instructions

Tramadol Hydrochloride Extended-Release Capsules should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.

  • Do not use Tramadol Hydrochloride Extended-Release Capsules concomitantly with other tramadol products.
  • Do not administer Tramadol Hydrochloride Extended-Release Capsules at a dose exceeding 300 mg per day.
  • Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals.
  • 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.
  • Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy and following dosage increases with Tramadol Hydrochloride Extended-Release Capsules and adjust the dosage accordingly.
  • Instruct patients to swallow Tramadol Hydrochloride Extended-Release Capsules whole, and to take it with liquid. Breaking, chewing, splitting, or dissolving Tramadol Hydrochloride Extended-Release Capsules will result in uncontrolled delivery of tramadol and can lead to overdose or death.
  • Tramadol Hydrochloride Extended-Release Capsules may be taken without regard to food. It is recommended that Tramadol Hydrochloride Extended-Release Capsules be taken in a consistent manner.

2.2       Initial Dosage

Patients Not Currently on a Tramadol Product

The initial dose of Tramadol Hydrochloride Extended-Release Capsules are 100 mg once daily.

Patients Currently on Tramadol Immediate-Release (IR) Products

Calculate the 24-hour tramadol IR dose and initiate a total daily dose of Tramadol Hydrochloride Extended-Release Capsules rounded down to the next lowest 100 mg increment. The dose may subsequently be individualized according to patient need.

Due to limitations in flexibility of dose selection with Tramadol Hydrochloride Extended-Release Capsules, some patients maintained on tramadol IR products may not be able to convert to Tramadol Hydrochloride Extended-Release Capsules.

Conversion from Other Opioids to Tramadol Hydrochloride Extended-Release Capsules

Discontinue all other around-the-clock opioid drugs when Tramadol Hydrochloride Extended-Release Capsules therapy is initiated. There are no established conversion ratios for conversion from other opioids to Tramadol Hydrochloride Extended-Release Capsules defined by clinical trials. Initiate dosing using Tramadol Hydrochloride Extended-Release Capsules 100 mg once a day.

2.3       Titration and Maintenance Therapy

Individually titrate Tramadol Hydrochloride Extended-Release Capsules by 100 mg every five days to a dose that provides adequate analgesia and minimizes adverse reactions. The maximum daily dose of Tramadol Hydrochloride Extended-Release Capsules 300 mg per day.

Continually reevaluate patients receiving  Tramadol Hydrochloride Extended-Release Capsules to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse. 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. During chronic therapy, periodically reassess the continued need for the use of opioid analgesics.

Patients who experience breakthrough pain may require a dosage adjustment of Tramadol Hydrochloride Extended-Release Capsules, or may need rescue medication with an appropriate dose of an immediate-release analgesic. If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the Tramadol Hydrochloride Extended-Release Capsules 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 Extended-Release Capsules

When a patient no longer requires therapy with Tramadol Hydrochloride Extended-Release Capsules, 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, either by increasing the interval between doses, decreasing the amount of change in dose, or both. Do not abruptly discontinue Tramadol Hydrochloride Extended-Release Capsules.

3       DOSAGE FORMS AND STRENGTHS

Extended-release capsules are available as: 

150 mg Capsules: White capsule imprinted with gold ink “G 322” on cap and “150” between lines on the body

4       CONTRAINDICATIONS

Tramadol Hydrochloride Extended-Release Capsules are contraindicated for:

• all children younger than 12 years of age

• post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectom.

Tramadol Hydrochloride Extended-Release Capsules are also contraindicated in patients with:

• Significant respiratory depression

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

• Known or suspected gastrointestinal obstruction, including paralytic ileus

• Hypersensitivity to tramadol (e.g., anaphylaxis)

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

5       WARNINGS AND PRECAUTIONS

5.1       Addiction, Abuse, and Misuse

 Tramadol Hydrochloride Extended-Release Capsules contains tramadol, a Schedule IV controlled substance. As an opioid, Tramadol Hydrochloride Extended-Release Capsules exposes users to the risks of addiction, abuse and misuse. Because extended-release products such as Tramadol Hydrochloride Extended-Release Capsules deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of tramadol present.

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Tramadol Hydrochloride Extended-Release Capsules. 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 Extended-Release Capsules, and monitor all patients receiving Tramadol Hydrochloride Extended-Release Capsules 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 are increased risk may be prescribed opioids such as  Tramadol Hydrochloride Extended-Release Capsules, but use in such patients necessitates intensive counseling about the risks and proper use of  Tramadol Hydrochloride Extended-Release Capsules along with intensive monitoring for signs of addiction, abuse and misuse.

Abuse or misuse of  Tramadol Hydrochloride Extended-Release Capsules by splitting, breaking, chewing, crushing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of tramadol and can result in overdose and death.

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispense Tramadol Hydrochloride Extended-Release Capsules. Strategies to reduce these risks include prescribing the drug in smallest appropriate quantity and advising the patient on the proper disposal of unused drug 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. Prescribers are strongly encouraged to do all of the following:

• 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/OpioidAnalgesicREMSPCD.

• 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 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. The 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. Carbon dioxide (CO2) 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 Extended-Release Capsules, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with and following dosage increases of Tramadol Hydrochloride Extended-Release Capsules.

To reduce the risk of respiratory depression, proper dosing and titration of Tramadol Hydrochloride Extended-Release Capsules are essential. Overestimating the Tramadol Hydrochloride Extended-Release Capsules 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 Extended-Release Capsules, 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 postmarketing reports with tramadol or with codeine, children younger than 12 years of age may be more susceptible 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:

  • Tramadol Hydrochloride Extended-Release Capsules are contraindicated for all children younger than 12 years of age.
  • Tramadol Hydrochloride Extended-Release Capsules are contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy.
  • Avoid the use of Tramadol Hydrochloride Extended-Release Capsules 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.

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 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 Extended-Release Capsules could potentially be exposed to high levels of MI, and experience life-threatening respiratory depression. For this reason, breastfeeding is not recommended during treatment with Tramadol Hydrochloride Extended-Release Capsules.

CYP2D6 Genetic Variability: Ultra-rapid metabolizer

Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (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 certain 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). Therefore, individuals who are ultra-rapid metabolizers should not use Tramadol Hydrochloride Extended-Release Capsules.

5.5       Neonatal Opioid Withdrawal Syndrome

Prolonged use of Tramadol Hydrochloride Extended-Release Capsules 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.

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 Extended-Release Capsules are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with Tramadol Hydrochloride Extended-Release Capsules requires 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.

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

The concomitant use of Tramadol Hydrochloride Extended-Release Capsules 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 Extended-Release Capsules 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 Extended-Release Capsules are used in conjunction with inhibitors of CYP2D6.

Cytochrome P450 3A4 Interaction

The concomitant use of  Tramadol Hydrochloride Extended-Release Capsules 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 Extended-Release Capsules 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 Extended-Release Capsules 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 Extended-Release Capsules are used in conjunction with inhibitors and inducers of CYP3A4.

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 Extended-Release Capsules 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.

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 Extended-Release Capsules 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.

5.8       Serotonin Syndrome Risk

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported with the use of tramadol, including Tramadol Hydrochloride Extended-Release Capsules, 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). 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 Extended-Release Capsules if serotonin syndrome is suspected.

5.9       Increased Risk of Seizures

Seizures have been reported in patients receiving tramadol within the recommended dosage range. Spontaneous post-marketing reports indicate that seizure risk is increased with doses of tramadol above the recommended range.

Concomitant use of tramadol increases the seizure risk in patients taking:

  • Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) antidepressants or anorectics,
  • Tricyclic antidepressants (TCAs), and other tricyclic compounds (e.g., cyclobenzaprine, promethazine, etc.),
  • Other opioids,
  • MAO inhibitors,
  • Neuroleptics, or
  • Other drugs that reduce the seizure threshold.

Risk of seizures 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 overdose, naloxone administration may increase the risk of seizure.

5.10       Suicide Risk

  • Do not prescribe Tramadol Hydrochloride Extended-Release Capsules for patients who are suicidal or addiction-prone.  Consideration should be given to the use of non-narcotic analgesics in patients who are suicidal or depressed.
  • Prescribe Tramadol Hydrochloride Extended-Release Capsules with caution for patients with a history of misuse and/or are currently taking CNS-active drugs including tranquilizers or antidepressant drugs, or alcohol in excess, and patients who suffer from emotional disturbance or depression.
  • Inform patients not to exceed the recommended dose and to limit their intake of alcohol.

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 Extended-Release Capsules 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 Extended-Release Capsules 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 dosages of Tramadol Hydrochloride Extended-Release Capsules.

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.

Monitor such patients closely, particularly when initiating and titrating Tramadol Hydrochloride Extended-Release Capsules and when Tramadol Hydrochloride Extended-Release Capsules are given concomitantly with other drugs that depress respiration. Alternatively, consider the use of non-opioid analgesics in these patients.

5.13       Severe Hypotension

Tramadol Hydrochloride Extended-Release Capsules 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). Monitor these patients for signs of hypotension after initiating or titrating the dosage of Tramadol Hydrochloride Extended-Release Capsules. In patients with circulatory shock, Tramadol Hydrochloride Extended-Release Capsules may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Tramadol Hydrochloride Extended-Release Capsules 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 CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), Tramadol Hydrochloride Extended-Release Capsules may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with Tramadol Hydrochloride Extended-Release Capsules.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Tramadol Hydrochloride Extended-Release Capsules in patients with impaired consciousness or coma.

5.15       Risks of Use in Patients with Gastrointestinal Conditions

Tramadol Hydrochloride Extended-Release Capsules are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The tramadol in Tramadol Hydrochloride Extended-Release Capsules 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 hypersensitive reactions have been reported in patients receiving therapy with tramadol. When these events do occur it is often following the first dose. Other reported hypersensitivity 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 Extended-Release Capsules. If anaphylaxis or other hypersensitivity occurs, stop administration of Tramadol Hydrochloride Extended-Release Capsules immediately, discontinue Tramadol Hydrochloride Extended-Release Capsules 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.

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 Extended-Release Capsules. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms.

When discontinuing Tramadol Hydrochloride Extended-Release Capsules, gradually taper the dosage. Do not abruptly discontinue Tramadol Hydrochloride Extended-Release Capsules.

5.18       Risks of Driving and Operating Machinery

 Tramadol Hydrochloride Extended-Release Capsules 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 Extended-Release Capsules and know how they will react to the medication.

6       ADVERSE REACTIONS

The following serious or otherwise important adverse reactions are described in greater detail, in other sections:

  • Addiction, Abuse, and Misuse
  • Life-Threatening Respiratory Depression
  • Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-Threatening Respiratory Depression in Children
  • Neonatal Opioid Withdrawal Syndrome
  • Interactions with Benzodiazepines and Other CNS Depressants
  • Serotonin Syndrome
  • Seizures
  • Suicide
  • Adrenal Insufficiency
  • Severe Hypotension
  • Gastrointestinal Adverse Reactions
  • Hypersensitivity Reactions
  • Withdrawal

6.1       Clinical Trials Experience

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 Extended-Release Capsules were administered to a total of 1987 patients in clinical trials. These included four double-blind and one long-term, open-label study in patients with osteoarthritis of the hip and knee. A total of 812 patients were 65 years or older. Adverse reactions with doses from 100 mg to 300 mg in the four pooled, randomized, double-blind, placebo-controlled studies in patients with chronic non-malignant pain are presented in the following table (see Table 1).

Table 1: Incidence (%) of patients with adverse reaction rates ≥ 5% from four double-blind, placebo controlled studies in patients with moderate to moderately severe chronic pain by dose (N=1917).

TRAMADOL HYDROCHLORIDE EXTENDED-RELEASE CAPSULESPLACEBO
Preferred Term100 mg
(N=429)
n (%)
200 mg
(N=434)
n (%)
300 mg
(N=1054)
n (%)
(N=646)
n (%)
Headache99 (23.1)96 (22.1)200 (19.0)128 (19.8)
Nausea69 (16.1)93 (21.4)265 (25.1)37 (5.7)
Somnolence50 (11.7)60 (13.8)170 (16.1)26 (4.0)
Dizziness41 (9.6)54 (12.4)143 (13.6)31 (4.8)
Constipation40 (9.3)59 (13.6)225 (21.3)27 (4.2)
Vomiting28 (6.5)45 (10.4)98 (9.3)12 (1.9)
Arthralgia23 (5.4)20 (4.6)53 (5.0)33 (5.1)
Dry Mouth20 (4.7)36 (8.3)138 (13.1)22 (3.4)
Sweating18 (4.2)23 (5.3)71 (6.7)4 (0.6)
Asthenia15 (3.5)26 (6.0)91 (8.6)17 (2.6)
Pruritus13 (3.0)25 (5.8)77 (7.3)12 (1.9)
Anorexia9 (2.1)23 (5.3)60 (5.7)1 (0.2)
Insomnia9 (2.1)9 (2.1)53 (5.0)11 (1.7)

The following adverse reactions were reported from all chronic pain studies (N=1917). The lists below include adverse reactions not otherwise noted in Table 1.

Adverse reactions with incidence rates of 1.0% to <5.0%

Cardiac disorders: hypertension

Gastrointestinal disorders: dyspepsia, flatulence

General disorders: abdominal pain, accidental injury, chills, fever, flu syndrome, neck pain, pelvic pain

Investigations: hyperglycemia, urine abnormality

Metabolism and nutrition disorders: peripheral edema, weight loss

Musculoskeletal, connective tissue and bone disorders: myalgia

Nervous system disorders: paresthesia, tremor, withdrawal syndrome

Psychiatric disorders: agitation, anxiety, apathy, confusion, depersonalization, depression, euphoria, nervousness

Respiratory, thoracic and mediastinal disorders: bronchitis, pharyngitis, rhinitis, sinusitis

Skin and subcutaneous tissue disorders: rash

Urogenital disorders: prostatic disorder, urinary tract infection

Vascular disorders: vasodilatation

Adverse reactions with incidence rates of 0.5% to <1.0% at any dose and serious adverse reactions reported in at least two patients.

Cardiac disorders: EKG abnormal, hypotension, tachycardia

Gastrointestinal disorders: gastroenteritis

General disorders: neck rigidity, viral infection

Hematologic/Lymphatic disorders; anemia, ecchymoses

Metabolism and nutrition disorders: blood urea nitrogen increased, GGT increased, gout, SGPT increased

Musculoskeletal disorders: arthritis, arthrosis, joint disorder, leg cramps

Nervous system disorders: emotional lability, hyperkinesia, hypertonia, thinking abnormal, twitching, vertigo

Respiratory disorders: pneumonia

Skin and subcutaneous tissue disorders: hair disorder, skin disorder, urticaria

Special Senses: eye disorder, lacrimation disorder

Urogenital disorders: cystitis, dysuria, sexual function abnormality, urinary retention

6.2       Postmarketing Experience

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

Anaphylaxis: Anaphylaxis has been reported with ingredients contained in Tramadol Hydrochloride Extended-Release Capsules.

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

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 overdose setting.

7       DRUG INTERACTIONS

Table 2 includes clinically significant drug interactions with Tramadol Hydrochloride Extended-Release Capsules.

Table 2: Clinically Significant Drug Interactions with Tramadol Hydrochloride Extended-Release Capsules

Inhibitors of CYP2D6
Clinical Impact:The concomitant use of Tramadol Hydrochloride Extended-Release Capsules 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 Extended-Release Capsules are 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  which could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity, and may cause potentially fatal respiratory depression.
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 Extended-Release Capsules dosage until stable drug effects are achieved. Follow patients closely for adverse events including respiratory depression and sedation.
ExamplesQuinidine, fluoxetine, paroxetine and bupropion
Inhibitors of CYP3A4
Clinical Impact:The concomitant use of Tramadol Hydrochloride Extended-Release Capsules 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 Extended-Release Capsules are achieved.
After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease, resulting in decreased opioid efficacy and possibly signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol.
Intervention:If concomitant use is necessary, consider dosage reduction of Tramadol Hydrochloride Extended-Release Capsules 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 Extended-Release Capsules dosage until stable drug effects are achieved and follow patients for signs and symptoms of opioid withdrawal.
ExamplesMacrolide 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 Extended-Release Capsules and CYP3A4 inducers can decrease the plasma concentration of tramadol, 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, which could increase or prolong both the therapeutic effects and adverse reactions, and may cause seizures and serotonin syndrome, and potentially fatal respiratory depression.
Intervention:If concomitant use is necessary, consider increasing the Tramadol Hydrochloride Extended-Release Capsules dosage until stable drug effects are achieved. Follow patients for signs of opioid withdrawal.
If a CYP3A4 inducer is discontinued, consider Tramadol Hydrochloride Extended-Release Capsules 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 Extended-Release Capsules 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, can increase the risk of hypotension, 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.
Examples:Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, 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 Extended-Release Capsules 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 or opioid toxicity (e.g., respiratory depression, coma) .
Intervention:Do not use Tramadol Hydrochloride Extended-Release Capsules 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 Extended-Release Capsules 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 Extended-Release Capsules 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 Extended-Release Capsules 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 Extended-Release Capsules 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 2-4% and 15-20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents 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 of neonatal opioid withdrawal syndrome and manage accordingly.

Neonatal seizures, neonatal withdrawal syndrome, fetal death and still birth have been reported with tramadol during post-approval use of tramadol immediate-release products.

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 Extended-Release Capsules are not recommended for use in pregnant women during or immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including Tramadol Hydrochloride Extended-Release Capsules 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 Extended-Release Capsules, 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 (75 mg/kg) at maternally toxic dosages, but was not teratogenic at these dose levels. These doses on a mg/m2 basis are 1.9, 0.8, and 4.9 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 2.3, 2.6, and 19 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 (1.6 times the MRHD) or greater had decreased weights, and pup survival was decreased early in lactation at 80 mg/kg (2.6 times the MRHD).

8.2       Lactation 

Risk Summary

Tramadol Hydrochloride Extended-Release Capsules 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. 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 Extended-Release Capsules.

Clinical Considerations

If infants are exposed to Tramadol Hydrochloride Extended-Release Capsules 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.

8.4       Pediatric Use

The safety and effectiveness of Tramadol Hydrochloride Extended-Release Capsules in pediatric patients have not been established.

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

  •  Tramadol Hydrochloride Extended-Release Capsules are contraindicated for all children younger than age 12 years of age.
  •  Tramadol Hydrochloride Extended-Release Capsules are contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy.
  • Avoid the use of Tramadol Hydrochloride Extended-Release Capsules 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

Eight hundred and twelve elderly (65 years of age or older) subjects were exposed to Tramadol Hydrochloride Extended-Release Capsules in clinical trials. Of those subjects, two hundred and forty were 75 years of age and older. In general, higher incidence rates of adverse events were observed for patients older than 65 years of age compared with patients 65 years and younger, particularly for the following adverse events: nausea, constipation, somnolence, dizziness, dry mouth, vomiting, asthenia, pruritus, anorexia sweating, fatigue, weakness, postural hypotension and dyspepsia. For this reason, Tramadol Hydrochloride Extended-Release Capsules should be used with great caution in patients older than 75 years of age.

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 Extended-Release Capsules slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression.

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       Hepatic Impairment

Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver.  Tramadol Hydrochloride Extended-Release Capsules has not been studied in patients with hepatic impairment. The limited availability of dose strengths of Tramadol Hydrochloride Extended-Release Capsules does not permit the dosing flexibility required for safe use in patients with severe hepatic impairment (Child-Pugh Class C). Therefore, Tramadol Hydrochloride Extended-Release Capsules should not be used in patients with severe hepatic impairment.

8.7       Renal Impairment

 Tramadol Hydrochloride Extended-Release Capsules has not been studied in patients with renal impairment. Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. The limited availability of dose strengths of Tramadol Hydrochloride Extended-Release Capsules does not permit the dosing flexibility required for safe use in patients with severe renal impairment (Child-Pugh Class C). Therefore, Tramadol Hydrochloride Extended-Release Capsules should not be used in patients with severe renal impairment.

9       DRUG ABUSE AND DEPENDENCE

9.1       Controlled Substance

 Tramadol Hydrochloride Extended-Release Capsules contains tramadol, a Schedule IV controlled substance.

9.2       Abuse

Tramadol Hydrochloride Extended-Release Capsules contains tramadol, a substance with a high potential for abuse similar to other opioids, and can be abused and is subject to misuse, addiction, and criminal diversion.

The high drug content in extended-release formulations adds to the risk of adverse outcomes from abuse and misuse.

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 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 healthcare providers. “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 Extended-Release Capsules, 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 Extended-Release Capsules

Tramadol Hydrochloride Extended-Release Capsules are for oral use only. The abuse of Tramadol Hydrochloride Extended-Release Capsules poses a risk of overdose and death. The risk is increased with concurrent use of Tramadol Hydrochloride Extended-Release Capsules with alcohol and other central nervous system depressants. With intravenous abuse, the inactive ingredients in Tramadol Hydrochloride Extended-Release Capsules can result in local tissue necrosis, infection, pulmonary granulomas, embolism and death, and increased risk of endocarditis and valvular heart injury. 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 opioids 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 (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.

Tramadol Hydrochloride Extended-Release Capsules should not be abruptly discontinued in a physically-dependent patient. If Tramadol Hydrochloride Extended-Release Capsules are abruptly discontinued in a physically-dependent patient, 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.

10       OVERDOSAGE

Clinical Presentation

Acute overdosage with Tramadol Hydrochloride Extended-Release Capsules 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, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations.

Treatment of Overdose

In case of overdosage, priorities are the reestablishment 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 arrhythmias will require advanced life-support techniques.

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 Extended-Release Capsules 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 Extended-Release Capsules, carefully monitor the patient until spontaneous respiration is reliably reestablished.  Tramadol Hydrochloride Extended-Release Capsules will continue to release tramadol and add to the tramadol load for 24 to 48 hours or longer following ingestion, necessitating prolonged monitoring. 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 Extended-Release Capsules are an opioid agonist   in an extended-release oral formulation. The chemical name for tramadol hydrochloride USP is (±)cis-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochloride. Its structural formula is:

C16 H25 NO2 . HCl

The molecular weight of tramadol hydrochloride USP is 299.8. It is a white, bitter, crystalline and odorless powder that 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 Extended-Release Capsules contain a total dose of tramadol hydrochloride 150 mg in a combination of immediate-release and extended-release components.

DosageImmediate-releaseExtended-release
150 mg37.5 mg112.5 mg

Tramadol Hydrochloride Extended-Release Capsules are white in color. Inactive ingredients include gelatin, titanium dioxide, shellac, yellow iron oxide, lactose monohydrate 200 mesh, microcrystalline cellulose, povidone K30, corn starch, sodium starch glycolate, magnesium stearate, sucrose stearate, hypromellose, talc, polysorbate 80, Eudragit NE 30D, and simethicone emulsion.

12       CLINICAL PHARMACOLOGY

12.1       Mechanism of Action

Tramadol Hydrochloride Extended-Release Capsules contains tramadol, an opioid agonist, and an inhibitor of reuptake of norepinephrine and serotonin. Although its mode of action is not completely understood, from animal tests, at least two complementary mechanisms appear applicable: binding of parent and M1 metabolite to µ-opioid receptors and weak inhibition of reuptake of norepinephrine and serotonin.

Opioid activity of tramadol 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.

Tramadol has been shown to inhibit reuptake of norepinephrine and serotonin in vitro, as have some other opioid analgesics. These mechanisms may contribute independently to the overall analgesic profile of tramadol. The relationship between exposure of tramadol and M1 and efficacy has not been evaluated in clinical studies.

Apart from analgesia, tramadol administration may produce a constellation of symptoms (including dizziness, somnolence, nausea, constipation, sweating and pruritus) similar to that of other opioids. In contrast to morphine, tramadol has not been shown to cause histamine release. At therapeutic doses, tramadol has no effect on heart rate, left ventricular function or cardiac index. Orthostatic hypotension has been observed.

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 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 is 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 histamine release and/or 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.

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.

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 agonist opioids. The minimum effective analgesic concentration of [drug substance] 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.

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.

12.3       Pharmacokinetics

The analgesic activity of tramadol is due to both parent drug and the M1 metabolite.   Tramadol Hydrochloride Extended-Release Capsules are administered as a racemate and both tramadol and M1 are detected in the circulation.  The Cmax and AUC of Tramadol Hydrochloride Extended-Release Capsules have been observed to be dose-proportional over an oral dose range of 100 to 300 mg in healthy subjects.

Absorption

After a single dose administration of Tramadol Hydrochloride Extended-Release Capsules, Tmax occurs around 10-12 hours.

The mean Cmax and AUC of  Tramadol Hydrochloride Extended-Release Capsules after a 300 mg single dose was 308 ng/mL and 6777 ng.hr/mL, respectively under fasting conditions.  Tramadol Hydrochloride Extended-Release Capsules are bioequivalent to a reference extended-release tramadol product following a single 300 mg dose under fasting conditions.

At steady-state, Tramadol Hydrochloride Extended-Release Capsules at 200 mg has been observed to be bioequivalent to a reference extended-release tramadol product at 200 mg under fasting conditions (Table 3). Following administration of Tramadol Hydrochloride Extended-Release Capsules 200 mg capsules, steady-state plasma concentrations of both tramadol and M1 are achieved within four days of once daily dosing.

Table 3.
Mean (%CV) Steady-State Pharmacokinetic Parameter Values (N= 38)
TramadolO-Desmethyltramadol 
(M1 Metabolite)
ParameterTramadol hydrochloride Extended-Release Capsules 200 mg A Reference Extended-Release Tramadol Product 200 mgTramadol hydrochloride Extended-Release Capsules 200 mg A Reference Extended-Release Tramadol Product
200 mg
AUC0-24 (ng.hr/mL)5678 (27%)5563 (32%)1319 (34%)1302 (40%)
Cmax (ng/mL)332 (25%)350 (31%)70 (34%)74 (41%)
Cmin
(ng/mL)
128 (39%)125 (45%)35 (34%)33 (42%)
Tmax5.9 (66%)10 (30%)11 (37%)13 (29%)
% Fluctuation88 (19%)101 (30%)64 (22%)76 (30%)

AUC0-24: Area Under the Curve in a 24-hour dosing interval

Cmax: Peak Concentration in a 24-hour dosing interval

Cmin: Trough Concentration in a 24-hour dosing interval

Tmax: Time to Peak Concentration

Food Effect

The rate and extent of absorption of Tramadol Hydrochloride Extended-Release Capsules (300 mg) are similar following oral administration with or without food. Therefore, Tramadol Hydrochloride Extended-Release Capsules can be administered without regard to meals.

Distribution

The volume of distribution of tramadol was 2.6 and 2.9 liters/kg in male and female subjects, respectively, following a 100 mg intravenous tramadol 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 plasma elimination half-lives of racemic tramadol and racemic M1 after administration of Tramadol Hydrochloride Extended-Release Capsules are approximately 10 and 11 hours, respectively.

Metabolism

Tramadol is extensively metabolized after oral administration. The major metabolic pathways appear to be N – (mediated by CYP3A4 and CYP2B6) and O – (mediated by CYP2D6) 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 and polymorphism, which may affect the therapeutic response.

Excretion

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.

Special Populations

Hepatic Impairment

Pharmacokinetics of tramadol was studied in patients with mild or moderate hepatic impairment after receiving multiple doses of an extended-release tramadol product at 100 mg. The exposure of (+)- and (-)-tramadol was similar in mild and moderate hepatic impairment patients in comparison to patients with normal hepatic function. However, exposure of (+)- and (-)-M1 decreased ~50% with increased severity of the hepatic impairment (from normal to mild and moderate). The pharmacokinetics of tramadol has not been studied in patients with severe hepatic impairment. After the administration of tramadol immediate-release tablets to patients with advanced cirrhosis of the liver, tramadol area under the plasma concentration time curve was larger and the tramadol and M1 half-lives were longer than subjects with normal hepatic function. The limited availability of dose strengths of Tramadol Hydrochloride Extended-Release Capsules does not permit the dosing flexibility required for safe use in patients with severe hepatic impairment. Therefore, Tramadol Hydrochloride Extended-Release Capsules should not be used in patients with severe hepatic impairment.

Renal Impairment

Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. The pharmacokinetics of tramadol was studied in patients with mild or moderate renal impairment after receiving multiple doses of an extended-release tramadol product at 100 mg. There is no consistent trend observed for tramadol exposure related to renal function in patients with mild (CLcr: 50-80 mL/min) or moderate (CLcr: 30-50 mL/min) renal impairment in comparison to patients with normal renal function (CLcr > 80 mL/min). However, exposure of M1 increased 20-40% with increased severity of the renal impairment (from normal to mild and moderate). The pharmacokinetics of tramadol has not been studied in patients with severe renal impairment (CLcr < 30 mL/min). The limited availability of dose strengths of Tramadol Hydrochloride Extended-Release Capsules does not permit the dosing flexibility required for safe use in patients with severe renal impairment. Therefore, Tramadol Hydrochloride Extended-Release Capsules should not be used in patients with severe renal impairment. The total amount of tramadol and M1 removed during a 4-hour dialysis period is less than 7% of the administered dose.

Sex

Based on pooled multiple-dose pharmacokinetics studies for an extended-release tramadol product in 166 healthy subjects (111 males and 55 females), the dose-normalized AUC values for tramadol were somewhat higher in females than in males. There was a considerable degree of overlap in values between male and female groups. Dosage adjustment based on sex is not recommended.

Age: Geriatric Population

The effect of age on pharmacokinetics of Tramadol Hydrochloride Extended-Release Capsules have not been studied. Healthy elderly subjects aged 65 to 75 years administered an immediate-release formulation of tramadol, have plasma concentrations and elimination half-lives comparable to those observed in healthy subjects younger than 65 years of age. In subjects over 75 years, mean maximum plasma concentrations are elevated (208 vs. 162 ng/mL) and the mean 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.

Drug Interaction Studies

Potential for Tramadol to Affect Other Drugs

In vitro studies indicate that tramadol is unlikely to inhibit the CYP3A4-mediated metabolism of other drugs when tramadol is administered concomitantly at therapeutic doses. Tramadol does not appear to induce its own metabolism in humans, since observed maximal plasma concentrations after multiple oral doses are higher than expected based on single-dose data.

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 P-450 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.

CYP2D6 Inhibitors

In vitro drug interaction studies in human liver microsomes indicate that concomitant administration with inhibitors of CYP2D6 such as fluoxetine, paroxetine, and amitriptyline could result in some inhibition of the metabolism of tramadol.

Quinidine

Tramadol is metabolized to active metabolite M1 by CYP2D6. Coadministration of quinidine, a selective inhibitor of CYP2D6, with tramadol ER resulted in a 50-60% increase in tramadol exposure and a 50-60% decrease in M1 exposure. The clinical consequences of these findings are unknown.

To evaluate the effect of tramadol, a CYP2D6 substrate on quinidine, an in vitro drug interaction study in human liver microsomes was conducted. The results from this study indicate that tramadol has no effect on quinidine metabolism.

CYP3A4 Inhibitors and Inducers

Since tramadol is also metabolized by CYP3A4, administration of CYP3A4 inhibitors, such as ketoconazole and erythromycin, or CYP3A4 inducers, such as rifampin and St. John’s Wort, with  Tramadol Hydrochloride Extended-Release Capsules may affect the metabolism of tramadol leading to altered tramadol exposure.

Cimetidine

Concomitant administration of tramadol immediate-release tablets with cimetidine, a weak CPY3A4 inhibitor, does not result in clinically significant changes in tramadol pharmacokinetics. No alteration of the Tramadol Hydrochloride Extended-Release Capsules dosage regimen with cimetidine is recommended.

Carbamazepine

Carbamazepine, a CYP3A4 inducer, increases tramadol metabolism. Patients taking carbamazepine may have a significantly reduced analgesic effect of tramadol. Concomitant administration of Tramadol Hydrochloride Extended-Release Capsules and carbamazepine is not recommended.

13       NONCLINICAL TOXICOLOGY

13.1       Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Carcinogenicity assessment has been conducted in mice, rats and p53(+/-) heterozygous mice. 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 (0.5 times the maximum recommended daily human dosage or 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 (1 times the MRHD). In a second rat study, no evidence of carcinogenicity was noted in rats at oral doses up to 75 mg/kg/day for males and 100 mg/kg/day for females (approximately 2 fold the maximum recommended human daily dose MRHD) for two years. However, the excessive decrease in body weight gain observed in the rat study might have reduced their sensitivity to any potential carcinogenic effect of the drug. No carcinogenic effect of tramadol was observed in p53(+/–)-heterozygous mice at oral doses up to 150 mg/kg/day for 26 weeks.

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 Extended-Release Capsules are bioequivalent under fasting conditions to another extended-release tramadol product which demonstrated efficacy in two of four clinical trials of patients with chronic pain. To qualify for inclusion into these studies, patients were required to have moderate to moderately severe pain as defined by a pain intensity score of ≥40 mm, off previous medications, on a 0 – 100 mm visual analog scale (VAS).

In one 12-week randomized, double-blind, placebo-controlled study, patients with moderate to moderately severe pain due to osteoarthritis of the knee and/or hip were administered doses from 100 mg to 400 mg daily. Treatment with the extended-release tramadol product was initiated at 100 mg once daily for four days then increased by 100 mg per day increments every five days to the randomized fixed dose. Between 51% and 59% of patients in active treatment groups completed the study and 56% of patients in the placebo group completed the study. Discontinuations due to adverse events were more common in the extended-release tramadol product 200 mg, 300 mg and 400 mg treatment groups (20%, 27%, and 30% of discontinuations, respectively) compared to 14% of the patients treated with the extended-release tramadol product 100 mg and 10% of patients treated with placebo.

Pain, as assessed by the WOMAC Pain subscale, was measured at 1, 2, 3, 6, 9, and 12 weeks and change from baseline assessed. A responder analysis based on the percent change in WOMAC Pain subscale demonstrated a statistically significant improvement in pain for the 100 mg and 200 mg treatment groups compared to placebo (see Figure 2).

Figure 2

In one 12-week randomized, double-blind, placebo-controlled flexible-dosing trial of the extended-release tramadol product in patients with osteoarthritis of the knee, patients titrated to an average daily dose of approximately 270 mg/day. Forty-nine percent of patients randomized to the active treatment group completed the study, while 52% of patients randomized to placebo completed the study. Most of the early discontinuations in the active treatment group were due to adverse events, accounting for 27% of the early discontinuations in contrast to 7% of the discontinuations from the placebo group. Thirty-seven percent of the placebo-treated patients discontinued the study due to lack of efficacy compared to 15% of active-treated patients. The active treatment group demonstrated a statistically significant decrease in the mean Visual Analog Scale (VAS) score, and a statistically significant difference in the responder rate, based on the percent change from baseline in the VAS score, measured at 1, 2, 4, 8, and 12 weeks, between patients receiving the extended-release tramadol product and placebo (see Figure 3).

Figure 3

Four randomized, placebo-controlled clinical trials of Tramadol Hydrochloride Extended-Release Capsules were conducted, none of which demonstrated efficacy but which differed in design from the preceding clinical studies described. Two trials were 12-week randomized placebo-controlled trials of Tramadol Hydrochloride Extended-Release Capsules 100 mg/day, 200 mg/day, and 300 mg/day versus placebo in patients with moderate to moderately severe osteoarthritis pain of the hip and knee. The other two 12 week trials were similar in design, but only studied Tramadol Hydrochloride Extended-Release Capsules 300 mg/day. In this fixed-dose design, subjects were required to titrate to a fixed dose, even if their pain responded to a lower titration dose.

16 HOW SUPPLIED/STORAGE AND HANDLING

Tramadol Hydrochloride Extended-Release Capsules (tramadol hydrochloride) capsules are supplied as opaque white hard gelatin capsules, imprinted as follows.

150 mg Capsules:       White capsule imprinted with gold ink “G 322” on cap and “150” between lines on the body

Bottle of 500 capsules: NDC 69420-5150-01

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]. Keep out of reach of children.

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 Extended-Release Capsules even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death. Instruct patients not to share Tramadol Hydrochloride Extended-Release Capsules with others and to take steps to protect Tramadol Hydrochloride Extended-Release Capsules 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 Extended-Release Capsules or when the dosage is increased, and that it can occur even at recommended dosages. Advise patients how to 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. Instruct patients to take steps to store Tramadol Hydrochloride Extended-Release Capsules securely and to dispose of unused Tramadol Hydrochloride Extended-Release Capsules 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 Extended-Release Capsules are contraindicated in all 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 to18 years of age receiving Tramadol Hydrochloride Extended-Release Capsules to monitor for signs of respiratory depression.

Interactions with Benzodiazepines and Other CNS Depressants

Inform patients and caregivers that potentially fatal additive effects may occur if Tramadol Hydrochloride Extended-Release Capsules are used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider.

Serotonin Syndrome

Inform patients that tramadol could cause a rare but potentially life-threatening condition, particularly during concomitant use with 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.

Seizures

Inform patients that Tramadol Hydrochloride Extended-Release Capsules may cause seizures with concomitant use of serotonergic agents (including SSRIs, SNRIs, and triptans) or drugs that significantly reduce the metabolic clearance of tramadol.

MAOI Interaction

Inform patients not to take Tramadol Hydrochloride Extended-Release Capsules while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking Tramadol Hydrochloride Extended-Release Capsules.

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.

Important Administration Instructions

Instruct patients how to properly take Tramadol Hydrochloride Extended-Release Capsules, including the following:

  • Tramadol Hydrochloride Extended-Release Capsules are designed to work properly only if swallowed intact. Taking cut, broken, chewed, crushed, or dissolved Tramadol Hydrochloride Extended-Release Capsules can result in a fatal overdose.
  • 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, hepatic toxicity, and death.
  • Tramadol Hydrochloride Extended-Release Capsules should not be taken with alcohol containing beverages.
  • Do not discontinue Tramadol Hydrochloride Extended-Release Capsules without first discussing the need for a tapering regimen with the prescriber.

Hypotension

Inform patients that Tramadol Hydrochloride Extended-Release Capsules 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).

Anaphylaxis

Inform patients that anaphylaxis has been reported with ingredients contained in Tramadol Hydrochloride Extended-Release Capsules. Advise patients how to recognize such a reaction and when to seek medical attention.

Pregnancy

Neonatal Opioid Withdrawal Syndrome

Inform female patients of reproductive potential that prolonged use of Tramadol Hydrochloride Extended-Release Capsules during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated.

Embryo-Fetal Toxicity

Inform female patients of reproductive potential that Tramadol Hydrochloride Extended-Release Capsules can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy.

Lactation

Advise women that breastfeeding is not recommended during treatment with Tramadol Hydrochloride Extended-Release Capsules.

Infertility

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

Driving or Operating Heavy Machinery

Inform patients that Tramadol Hydrochloride Extended-Release Capsules 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.

Constipation

Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention.

Disposal of Unused Tramadol Hydrochloride Extended-Release Capsules 

Advise patients to properly dispose of unused Tramadol Hydrochloride Extended-Release Capsules. Advise patients to throw the drug in the household trash following these steps. 1) Remove them from their original containers and mix them 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, or to dispose of in accordance with local state guidelines and/or regulations.

Manufactured by:       Galephar P.R., Inc.
Juncos, Puerto Rico 00777

Manufactured for::             SA3, LLC
Los Angeles, CA 90064 USA

Rev. 09/2018

Medication Guide
Tramadol Hydrochloride Extended-Release Capsules, CIV
Tramadol Hydrochloride Extended-Release Capsules are:

  • A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage pain severe enough to require daily around-the-clock, long-term treatment with an opioid, when other pain treatments such as non-opioid pain medicines or immediate-release opioid medicines do not treat your pain well enough or you cannot tolerate them.
  • A long-acting (extended-release) 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.
  • Not for use to treat pain that is not around-the-clock.
Important information about Tramadol Hydrochloride Extended-Release Capsules:

  • Get emergency help right away if you take too much Tramadol Hydrochloride Extended-Release Capsules (overdose). When you first start taking Tramadol Hydrochloride Extended-Release Capsules, 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 Extended-Release Capsules 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 Extended-Release Capsules. They could die from taking it. Store Tramadol Hydrochloride Extended-Release Capsules away from children and in a safe place to prevent stealing or abuse. Selling or giving away Tramadol Hydrochloride Extended-Release Capsules are against the law.
Important Information Guiding Use in Pediatric Patients:

  • Do not give Tramadol Hydrochloride Extended-Release Capsules to a child younger than 12 years of age.
  • Do not give Tramadol Hydrochloride Extended-Release Capsules to a child younger than 18 years of age after surgery to remove the tonsils and/or adenoids.
  • Avoid giving Tramadol Hydrochloride Extended-Release Capsules 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 Extended-Release Capsules if you have:

  • severe asthma, trouble breathing, or other lung problems.
  • a bowel blockage or have narrowing of the stomach or intestines.
Before taking Tramadol Hydrochloride Extended-Release Capsules, 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 Extended-Release Capsules 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 Extended-Release Capsules with certain other medicines can cause serious side effects that could lead to death.
When taking Tramadol Hydrochloride Extended-Release Capsules:

  • Do not change your dose. Take Tramadol Hydrochloride Extended-Release Capsules exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed.
  • Take your prescribed dose once a day at the same time every day. Do not take more than your prescribed dose. If you miss a dose, take your next dose at your usual time.
  • Swallow Tramadol Hydrochloride Extended-Release Capsules whole. Do not split, break, chew, crush, dissolve, snort, or inject Tramadol Hydrochloride Extended-Release Capsules because this may cause you to overdose and die.
  • Call your healthcare provider if the dose you are taking does not control your pain.
  • Do not stop taking Tramadol Hydrochloride Extended-Release Capsules without talking to your healthcare provider.
  • After you stop taking Tramadol Hydrochloride Extended-Release Capsules, dispose the unused Tramadol Hydrochloride Extended-Release Capsules in accordance with the local state guidelines and/or regulations.
While taking  Tramadol Hydrochloride Extended-Release Capsules DO NOT:

  • Drive or operate heavy machinery, until you know how Tramadol Hydrochloride Extended-Release Capsules affects you. Tramadol Hydrochloride Extended-Release Capsules 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 Extended-Release Capsules may cause you to overdose and die.
The possible side effects of Tramadol Hydrochloride Extended-Release Capsules:

  • constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain, seizure.  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 Extended-Release Capsules. Call your doctor for medical advice about side effects. You may report side effects to SA3, LLC at Vertical Pharmaceuticals, LLC at (877) 958-3784 or FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov
Manufactured for: SA3, LLC, Los Angeles, CA 90064 USA, call 1-877-958-3784

This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued: 09/2018

PRINCIPAL DISPLAY PANEL

NDC 69420-5150-01
Tramadol
Hydrochloride
Extended-Release Capsules
150 mg per capsule
Once daily
500 Capsules
Rx Only

TRAMADOL HYDROCHLORIDE  tramadol hydrochloride capsule, extended release
Product Information
Product TypeHUMAN PRESCRIPTION DRUG LABELItem Code (Source)NDC:69420-5150
Route of AdministrationORALDEA ScheduleCIV
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
TRAMADOL HYDROCHLORIDE (TRAMADOL)TRAMADOL HYDROCHLORIDE150 mg
Inactive Ingredients
Ingredient NameStrength
GELATIN
TITANIUM DIOXIDE
SHELLAC
FERRIC OXIDE YELLOW
LACTOSE MONOHYDRATE
CELLULOSE, MICROCRYSTALLINE
POVIDONE K30
STARCH, CORN
MAGNESIUM STEARATE
SUCROSE STEARATE
HYPROMELLOSES
TALC
POLYSORBATE 80
ETHYL ACRYLATE AND METHYL METHACRYLATE COPOLYMER (2:1; 750000 MW)
Product Characteristics
ColorWHITE (opaque white)Scoreno score
ShapeCAPSULESize19mm
FlavorImprint CodeG;322;150
Contains
Packaging
#Item CodePackage Description
1NDC:69420-5150-1500 CAPSULE, EXTENDED RELEASE in 1 BOTTLE
Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
NDA AUTHORIZED GENERICNDA02237007/01/2015

How it works

  • Tramadol is a man-made, pain-relieving medicine that may be used for the treatment of moderate-to-severe pain.
  • Although experts aren’t exactly sure how tramadol works, studies have suggested that tramadol and its active metabolite bind to mu opioid receptors in the central nervous system (the brain and spinal cord). It also appears to weakly inhibit the reuptake of serotonin and norepinephrine, increasing levels of these two neurotransmitters in the nerve synapse.
  • Tramadol belongs to the group of medicines known as narcotic analgesics.

Upsides

  • Tramadol may be used for the treatment of moderate-to-severe pain such as that caused by cancer, osteoarthritis, and other musculoskeletal diseases. Tramadol is often prescribed after surgery.
  • Tramadol may also be effective for nerve-related pain.
  • Tramadol may be less likely than other narcotic analgesics to cause respiratory depression.
  • Generic tramadol is available.

Downsides

If you are between the ages of 18 and 60, take no other medication or have no other medical conditions, side effects you are more likely to experience include:

  • A headache, nausea, dizziness, constipation, vomiting, joint pains, dry mouth, sweating, and an itchy skin are commonly reported side effects.
  • Sedation, which may affect a person’s ability to drive or operate machinery, or perform hazardous tasks is also commonly reported. Alcohol may enhance this effect.
  • May cause dependence, addiction, and slowed breathing. Tramadol may be misused and sought after by drug abusers. Tolerance may develop to its effect.
  • Seizures have been reported with tramadol use. The risk is increased in people taking certain types of antidepressants (such as SSRIs, SNRIs, TCAs, MAO inhibitors), other opioids, antipsychotics, other drugs that reduce the seizure threshold, with a pre-existing seizure disorder, head trauma, excessive alcohol use, or with a metabolic disorder predisposing to an increased risk of seizures.
  • Do not take tramadol if you are also using alcohol, drugs with sedative properties, or other narcotic medications; dangerous or fatal side effects, such as slowed breathing, can occur.
  • Seniors over the age of 65 years may be more sensitive to the side effects of tramadol. Tramadol should be initiated cautiously, and extended-release tramadol is best avoided.
  • May not be suitable for some people including those with a history of depression or prone to addiction. Tramadol may increase the risk of suicidal thoughts or behaviors.
  • Tramadol may not be appropriate for people at risk for respiratory depression, with head trauma, increased intracranial pressure, or with an acute abdominal disease.
  • The dosage of tramadol may require adjusting in liver or kidney disease.
  • Withdrawal symptoms (such as anxiety, sweating, insomnia, nausea, diarrhea, pain, piloerection [bristling of hairs]) have been reported when tramadol has been abruptly stopped following dosing for extended periods of time. The dosage of tramadol should always be tapered off slowly on discontinuation.
  • Tramadol may interact with a number of other drugs including antidepressants, antipsychotics, St John’s Wort, bupropion, triptans, or other drugs that are metabolized by CYP 2D6 or CYP3A4 hepatic enzymes.
  • The metabolism of tramadol may be slowed by people who are poor metabolizers at CYP 2D6. While concentrations of tramadol may be higher in these people, concentrations of the active metabolite of tramadol may be lower, resulting in insufficient pain relief.
  • Interaction or overdosage may cause serotonin syndrome (symptoms include mental status changes [such as agitation, hallucinations, coma, delirium]), fast heart rate, dizziness, flushing, muscle tremor or rigidity and stomach symptoms (including nausea, vomiting, and diarrhea).
  • Rarely, anaphylaxis (a potentially fatal allergic reaction) has occurred with tramadol use, usually following the initial dose. Itchy skin, a rash, difficulty breathing, and other allergy-type symptoms may be more common. Do not use in people with a history of an allergic reaction to codeine or another opioid.
  • Tramadol is not FDA-approved for use in children under the age of 12 (immediate-release capsules) or 18 (extended-release capsules).

Notes: In general, seniors or children, people with certain medical conditions (such as liver or kidney problems, heart disease, diabetes, seizures) or people who take other medications are more at risk of developing a wider range of side effects. For a complete list of all side effects, click here.

Bottom Line

  • Tramadol is a strong pain relief medicine effective for both general and nerve-related pain. Tramadol can cause dependence and use may be limited by side effects such as nausea and sedation. Pain-relieving effects or side effects may be altered in some people due to genetic variation or drug interactions.

Tips

  • Tramadol may be taken with or without food.
  • The long-acting formulation must be swallowed whole; do not crush or chew as you may receive a dangerous or fatal dose. Extended-release tramadol capsules are intended to be taken only once a day. Do not increase the dosage of tramadol unless your doctor has advised you to do so.
  • May make you sleepy and affect your ability to drive or operate machinery. Refrain from driving or potentially hazardous tasks until you are sure tramadol is not having this effect.
  • Avoid alcohol. Alcohol may enhance the side effects of tramadol and increase the risk of seizures.
  • Can cause nausea. Taking an antiemetic (anti-sickness medicine) with tramadol can counteract this effect. Starting treatment with low doses or taking with food may also help to lessen nausea.
  • If you have been taking tramadol for long periods of time, do not stop it suddenly. Your doctor will advise you the best way to taper down the dosage over several weeks.
  • Tell a doctor immediately if you experience an allergic reaction to tramadol, excessive sweating, feel agitated or confused, develop a fever or diarrhea, find it difficult to control your limbs, or notice spasmodic jerky contractions of your muscles.
  • Keep out of reach of children and pets. Keep your medicine in a safe, private storage area, out of view of any person that may illegally misuse it.
  • Do not use if pregnant or breastfeeding unless specifically recommended by your doctor.

Response and Effectiveness

  • Peak levels of immediate-release tramadol are reached approximately two hours after oral administration. Peak levels of extended-release tramadol capsules occur within 10 to 12 hours. There is a lot of variability in the way people respond to tramadol – some people may require higher or lower dosages than others for the same level of pain relief.
  • Starting at the lowest possible dose and increasing the dose slowly may lessen side effects like nausea, dizziness, and headache.
  • When stopping treatment with tramadol, it’s best to slowly discontinue the medicine to avoid withdrawal symptoms. Your doctor will give you a schedule.

A total of 946 drugs are known to interact with tramadol.

  • 491 major drug interactions
  • 447 moderate drug interactions
  • 8 minor drug interactions

Show all medications in the database that may interact with tramadol.

Check for interactions with tramadol

Common medications checked in combination with tramadol

  • Advil (ibuprofen)
  • Aleve (naproxen)
  • Ambien (zolpidem)
  • aspirin (Aspir 81, Ecotrin, Acetylsalicylic Acid, Aspirin Low Strength, Bayer Aspirin, Aspir-Low, Ascriptin, Ecotrin Adult Low Strength, Bufferin, Aspiritab, Arthritis Pain, Fasprin, Halfprin, Easprin, Durlaza, Aspirtab, St. Joseph 81 mg Chewable Aspirin, Aspergum, Low Dose ASA, Buffered Aspirin, Ecotrin Maximum Strength, Ascriptin Enteric, Acuprin 81, St. Joseph 81 mg Aspirin Enteric Safety-Coated, Aspirin Lite Coat, Bayer Aspirin Regimen, Aspi-Cor, Empirin, Bayer Children’s Aspirin, Bufferin Extra Strength, St. Joseph Aspirin, Bayer Women’s Aspirin With Calcium, Miniprin, Migralex, Ascriptin Maximum Strength, Arthritis Foundation Pain Reliever, Bayer Aspirin with Heart Advantage, Bufferin Low Dose, Medi-Seltzer, Sloprin, ZORprin, Bayer Aspirin Extra Strength Plus, Buffex, Entercote, Extra Strength Bayer, Genacote, Gennin-FC, Genprin, Litecoat Aspirin, Minitabs, Tri-Buffered Aspirin, Entaprin, Bufferin Arthritis Strength, Therapy Bayer, Stanback Analgesic, Norwich Aspirin, Ecpirin, Zero-Order Release, YSP Aspirin, Heartline, Bayer Advanced Aspirin, Buffasal)
  • Aspirin Low Strength (aspirin)
  • Benadryl (diphenhydramine)
  • Celebrex (celecoxib)
  • Cymbalta (duloxetine)
  • Fish Oil (omega-3 polyunsaturated fatty acids)
  • Flexeril (cyclobenzaprine)
  • gabapentin (Neurontin, Gralise, Gabarone, Fanatrex)
  • hydrocodone (Hysingla ER, Zohydro ER, Vantrela ER)
  • ibuprofen (Advil, Motrin, IBU, Advil Liqui-Gels, Proprinal, Motrin IB, Children’s Motrin, IBU-200, Advil Migraine, Ibu-8, Motrin Childrens, Nuprin, Motrin Migraine Pain, Ibuprofen PMR, NeoProfen, Caldolor, Advil Children’s, Addaprin, Motrin Infant Drops, Advil Infant’s Concentrated Drops, Rufen, Genpril, A-G Profen, Ibu-Tab, Haltran, Menadol, Midol IB, Saleto-200, Q-Profen, Saleto-400, Saleto-600, Saleto-800, Advil Junior Strength, Midol Maximum Strength Cramp Formula, Actiprofen, Childrens Ibuprofen Berry, PediaCare Infants’ IB Ibuprofen Pain Reliever/Fever Reducer, Ibu-4, PediaCare Children’s IB Ibuprofen Pain Reliever/Fever Reducer, Ibu-6, Motrin Junior Strength, Help I Have An Aching Body, Children’s ElixSure IB, Cap-Profen, Motrin Pediatric, Advil Film-Coated)
  • Lipitor (atorvastatin)
  • Lyrica (pregabalin)
  • meloxicam (Mobic, Vivlodex, Qmiiz ODT)
  • naproxen (Aleve, Naprosyn, Naproxen Sodium DS, Anaprox, Anaprox-DS, Naprelan, EC-Naprosyn, Flanax Pain Reliever, Aflaxen, All Day Pain Relief, Comfort Pac with Naproxen, Leader Naproxen Sodium, Pamprin All Day Relief, Midol Extended Relief, All Day Relief)
  • Neurontin (gabapentin)
  • Nexium (esomeprazole)
  • Norco (acetaminophen / hydrocodone)
  • Percocet (acetaminophen / oxycodone)
  • prednisone (Deltasone, Rayos, Sterapred, Sterapred DS, Prednicot, Meticorten, Orasone, Liquid Pred, Prednicen-M)
  • Singulair (montelukast)
  • Suboxone (buprenorphine / naloxone)
  • Synthroid (levothyroxine)
  • Tylenol (acetaminophen)
  • Vitamin B12 (cyanocobalamin)
  • Vitamin C (ascorbic acid)
  • Vitamin D3 (cholecalciferol)
  • warfarin (Coumadin, Jantoven)
  • Xanax (alprazolam)
  • Zoloft (sertraline)
  • Zyrtec (cetirizine)

Tramadol alcohol/food interactions

There is 1 alcohol/food interaction with tramadol

Tramadol disease interactions

There are 9 disease interactions with tramadol which include:

  • acute alcohol intoxication
  • drug dependence
  • liver disease
  • renal dysfunction
  • seizure disorders
  • acute abdominal conditions
  • intracranial pressure
  • respiratory depression
  • suicidal