Tramadol Hydrochloride 100 mg Tablet, Extended Release, 30-count — NDC 68071-1671-3 (Billing 68071-1671-03)
This is a package of 30 tablets of Tramadol Hydrochloride 100 mg Tablet, Extended Release from NuCare Pharmaceuticals,Inc., marketed since Aug 2014 and currently FDA-listed. It is this product's only package size.
Other active recalls for Tramadol Hydrochloride (different manufacturers) — 1 · tap to view
Identity & classification
Regulatory identifiers FDA, NLM and CMS codes for this package
- RxCUI (RxNorm): 833709
Where does this data come from?
- FDA openFDA NDC Directory · synced Oct 1, 2026
- FDA label on DailyMed · label index refreshed Oct 1, 2026
- RxNorm (NLM RxNav) · catalog refreshed Oct 1, 2026
- Medi-Span GPI (licensed)
- First Databank (licensed) · refreshed Oct 1, 2026
RxNorm drug class
This medicine belongs to the Opioid Agonist class.
Where does this data come from?
- RxClass (NLM) · catalog refreshed Oct 1, 2026
Clinical
Tramadol is used to relieve certain types of pain. Tramadol is in a class of medications called opiate (narcotic) analgesics. It works by changing the way the brain and nervous system respond to pain.
Read the full MedlinePlus article ↗- It treats pain that is severe enough to need an opioid when other options haven’t worked or can’t be tolerated. Extended-release forms are for ongoing, around-the-clock pain, not a...
- Take it by mouth exactly as prescribed. If you have extended-release tablets, swallow them whole, never crush, chew or cut them. Don’t take it with other tramadol products.
- Dizziness, nausea, constipation, headache, sleepiness, itching and dry mouth are common. Call your doctor for seizures, severe dizziness, or agitation, fever and shaking. Slow brea...
- Avoid alcohol. Mixing tramadol with alcohol, sleep aids, benzodiazepines or other opioids can cause dangerous sedation and slowed breathing. Tell me about any antidepressants, MAOI...
Patient education
Supplement & herbal interactions
Where does this data come from?
- MedlinePlus (NLM) · refreshed Oct 1, 2026
- FDA label on DailyMed · label index refreshed Oct 1, 2026
Ask a licensed pharmacist directly — free, answered by our team.
Pricing
A drug doesn't have one price. Each row is a different public payment system, and none is what you'd pay at the counter — that depends on your insurance. The ⓘ on each row explains what it measures.
| Price system | Per each | Per package |
|---|---|---|
| Retail pharmacies payNADAC · weekly | Not in the retail survey — common for institutional, discontinued, or low-volume packs. | |
| Medicaid paysCMS SDUD · 12 mo | No recent Medicaid claims on file for this NDC — rare and low-volume NDCs are suppressed in the public data. | |
| Medicare drug plans payPart D · Q2 2026 | $1.97 | $59.02 / 30 tablets |
Where does this data come from?
- CMS NADAC weekly file
- CMS ASP pricing files · refreshed Sep 20, 2026
- CMS Medicaid State Drug Utilization Data · refreshed Oct 2, 2026
- CMS Part D plan pricing files · refreshed Sep 24, 2026
- VA National Acquisition Center price file
Packaging — all sizes for this product
| Package NDC | Description | Marketing start | Marketing end | Status |
|---|---|---|---|---|
| 68071-1671-03 You're viewing this Main listing | 30 TABLET, EXTENDED RELEASE in 1 BOTTLE | 2019-09-30 | — | Active |
Therapeutic equivalents
| Product | Labeler | Pack | NADAC/unit | TE | Status | Price vs. this |
|---|---|---|---|---|---|---|
| Tramadol Hydrochloride 100 mg 33342-0269-07 | Macleods | 30 tablets | $0.894 | AB1 | Availability likely | — |
| Tramadol Hydrochloride 100 mg 47335-0859-08 | Sun | 100 tablets | — | — | FDA listed | — |
| Tramadol Hydrochloride 100 mg 50090-5107-00 | A-S | 30 tablets | — | AB1 | FDA listed | — |
| Tramadol Hydrochloride 100 mg 55700-0996-30 | Quality | 30 tablets | — | AB1 | FDA listed | — |
| Tramadol Hcl Er 100 mg 61919-0818-30 | DIRECT | 30 tablets | — | AB1 | FDA listed | — |
| Tramadol Hydrochloride 100 mg 63187-0597-30 | Proficient | 30 tablets | — | — | FDA listed | — |
| Tramadol Hydrochloride 100 mg 63629-8323-01 | Bryant | 30 tablets | — | AB1 | Discontinued | — |
| Tramadol Hydrochloride 100 mg 67046-1527-03 | Coupler | 30 tablets | — | AB1 | FDA listed | — |
| Tramadol Hydrochloride 100 mgthis 68071-1671-03 | NuCare | 30 tablets | — | AB1 | FDA listed | — |
| Tramadol Hydrochloride 100 mg 68180-0697-01 | Lupin | 100 tablets | — | AB1 | FDA listed | — |
| Tramadol Hydrochloride 100 mg 68788-8367-02 | Preferred | 20 tablets | — | AB1 | FDA listed | — |
| Tramadol Hydrochloride 100 mg 70518-0942-00 | REMEDYREPACK | 30 tablets | — | AB1 | FDA listed | — |
| Tramadol Hydrochloride 100 mg 71205-0463-30 | Proficient | 30 tablets | — | AB1 | FDA listed | — |
| Tramadol Hydrochloride 100 mg 71335-1675-01 | Bryant | 30 tablets | — | — | FDA listed | — |
| Tramadol Hydrochloride 100 mg 76420-0244-30 | Asclemed | 30 tablets | — | — | FDA listed | — |
| Tramadol Hydrochloride 100 mg 76420-0536-30 | Asclemed | 30 tablets | — | AB1 | FDA listed | — |
| Tramadol HCL ER 100 mg 80425-0108-01 | Advanced | 30 tablets | — | AB1 | FDA listed | — |
| Tramadol HCL ER 100 mg 80425-0141-01 | Advanced | 30 tablets | — | — | FDA listed | — |
| Tramadol Hydrochloride 100 mg 82804-0298-30 | Proficient | 30 tablets | — | AB1 | FDA listed | — |
| Tramadol Hydrochloride 100 mg 47335-0531-08 | Sun | 100 tablets | — | — | FDA listed | — |
Where does this data come from?
- FDA openFDA NDC Directory · synced Oct 1, 2026
- FDA Orange Book · refreshed Sep 3, 2026
- CMS NADAC weekly file
Availability & generic status
This product is an FDA-approved generic. Other versions of the same drug are listed under Therapeutic equivalents, least expensive first.
Where does this data come from?
- FDA Orange Book · refreshed Sep 3, 2026
What it looks like
Where does this data come from?
- FDA label on DailyMed · label index refreshed Oct 1, 2026
Inactive Ingredients / Excipients
Inactive ingredients, also called excipients, are components of the drug product other than the active ingredient. They may include fillers, dyes, coatings, preservatives, flavors, or other formulation ingredients.
💡 Tap an ingredient (hover on desktop) to see what it is and why it’s used.
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UNII OP1R32D61U
Microcrystalline cellulose is a purified form of cellulose, a natural fiber from plant sources. It acts as a binder and filler in tablets and capsules, helping hold ingredients together and give the medicine its shape and size.
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UNII 4W5IH7FLNY
A clear, oily liquid derived from sebacic acid and butanol. It works as a plasticizer and solvent in pharmaceutical coatings and films, helping them stay flexible and smooth.
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UNII 7Z8S9VYZ4B
Ethylcellulose is a plant-derived thickener and film-former made by chemically modifying cellulose. It's used as a binder to hold tablet ingredients together, a coating to control how quickly medicine is released, or a thickener in liquid formulations.
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UNII XM0M87F357
A dark iron oxide compound that gives medicines their black or dark color. It's used as a colorant in tablets and capsules to help identify the product and make it visually distinctive.
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UNII FZ989GH94E
Povidone is a synthetic polymer made from a plastic-like material. It acts as a binder to hold tablet ingredients together and as a disintegrant to help the tablet break apart in your stomach so the medicine can be absorbed.
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UNII 6DC9Q167V3
Propylene glycol is a clear liquid derived from petroleum or vegetable sources. It acts as a solvent, humectant, and preservative in medicines, helping dissolve active ingredients and maintain product stability.
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UNII 46N107B71O
Shellac is a natural resin secreted by the lac beetle. It's used as a coating on tablets and capsules to control how quickly the medicine dissolves and to improve appearance and stability.
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UNII ETJ7Z6XBU4
Silicon dioxide is a naturally occurring mineral used as a glidant and anti-caking agent. It helps powder ingredients flow smoothly and prevents clumping during manufacturing and storage.
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UNII 7CV7WJK4UI
Sodium stearyl fumarate is a synthetic compound made from stearyl alcohol and fumaric acid. It acts as a lubricant and glidant in tablets and capsules, helping ingredients flow smoothly during manufacturing and preventing sticking.
9 inactive ingredients listed in the exact product block matched to this NDC.
Where does this data come from?
ingredient classCode="IACT" elements from the exact product block matched by this NDC. Label-section narrative from DailyMed / the openFDA label index is shown separately when available.- FDA label on DailyMed · label index refreshed Oct 1, 2026
- FDA openFDA NDC Directory · synced Oct 1, 2026
Inactive ingredient FAQ
Are inactive ingredients the same for every manufacturer?
Why might an inactive ingredient be missing?
Can inactive ingredients matter?
Manufacturer & labeler
Where does this data come from?
- FDA openFDA NDC Directory · synced Oct 1, 2026
- Drugs@FDA
Full prescribing information FDA SPL
🚨 Boxed Warning ▾
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 tablet 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 tablets, and monitor all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions ( 5.1 )] . Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a REMS for these products [see Warnings and Precautions ( 5.2 )] . Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers.
Healthcare providers are strongly encouraged to • • 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 tablets.
Monitor for respiratory depression, especially during initiation of tramadol hydrochloride extended-release tablets or following a dose increase. Instruct patients to swallow tramadol hydrochloride extended-release tablets intact, and not to cut, break, chew, crush, or dissolve the tablets to avoid exposure to a potentially fatal dose of tramadol [see Warnings and Precautions ( 5.3 )] . Accidental Ingestion Accidental ingestion of even one dose of tramadol hydrochloride extended-release tablets, especially by children, can result in a fatal overdose of tramadol [see Warnings and Precautions ( 5.3 )] .
Ultra-Rapid Metabolism Of Tramadol And Other Risk Factors For Life-Threatening Respiratory Depression In Children Life-threatening respiratory depression and death have occurred in children who received tramadol. Some of the reported cases followed tonsillectomy and/or adenoidectomy; in at least one case, the child had evidence of being an ultra-rapid metabolizer of tramadol due to a CYP2D6 polymorphism [see Warnings and Precautions ( 5.4 )] . Tramadol hydrochloride extended-release tablets are contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications ( 4 )] .
Avoid the use of tramadol hydrochloride extended-release tablets in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol. [see Warnings and Precautions ( 5.4 )] Neonatal Opioid Withdrawal Syndrome Prolonged use of tramadol hydrochloride extended-release tablets during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts.
If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be availab… [Excerpted — this section continues on DailyMed.]
🎯 Indications and Usage ▾
1 INDICATIONS AND USAGE Tramadol hydrochloride extended-release tablets 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. Limitations 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 opioid formulations [see Warnings and Precautions ( 5.1 )] , reserve tramadol hydrochloride extended-release tablets 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 tablets are not indicated as an as-needed (prn) analgesic. Tramadol hydrochloride extended-release tablets are an opioid agonist 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. ( 1 ) Limitations 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 opioid formulations, reserve tramadol hydrochloride extended-release tablets 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.
( 1 ) Tramadol hydrochloride extended-release tablets are not indicated as an as-needed (prn) analgesic. ( 1 )
⏱️ Dosage and Administration ▾
2 DOSAGE AND ADMINISTRATION To be prescribed only by healthcare providers knowledgeable in use of potent opioids for management of chronic pain. ( 2.1 ) Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals ( 2.1 ). Individualize dosing based on the severity of pain, patient response, prior analgesic experience, and risk factors for addiction, abuse, and misuse.
( 2.1 ) Do not exceed a daily dose of 300 mg tramadol. Do not use with other tramadol products. ( 2.1 ) For opioid-naÏve and opioid non-tolerant patients, initiate tramadol hydrochloride extended-release tablets at a dose of 100 mg once daily, then titrate up by 100 mg increments every 5 days according to need and tolerance.
( 2.2 ) For patients currently on tramadol IR, calculate total 24-hr IR dose, and initiate tramadol hydrochloride extended-release tablets at a dose rounded down to next lower 100 mg increment; then adjust dose according to need and tolerance. See full prescribing information for instructions on conversion, titration, and maintenance of therapy. ( 2.2 , 2.3 ) Do not abruptly discontinue tramadol hydrochloride extended-release tablets in a physically-dependent patient.
( 2.4 )
2.1Important Dosage and Administration Instructions Tramadol hydrochloride extended-release tablets 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 tablets concomitantly with other tramadol products [see Warnings and Precautions ( 5.6 ), ( 5.14 )] . Do not administer tramadol hydrochloride extended-release tablets at a dose exceeding 300 mg per day.
Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions ( 5.7 )] . Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions ( 5.1 )] Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy and following dosage increases with tramadol hydrochloride extended-release tablets and adjust the dosage accordingly [see Warnings and Precautions ( 5.3 )] .
Instruct patients to swallow tramadol hydrochloride extended-release tablets whole [see Patient Counseling Information ( 17 )] , and to take it with liquid. Crushing, chewing, splitting, or dissolving tramadol hydrochloride extended-release tablets will result in uncontrolled delivery of tramadol and can lead to overdose or death [see Warnings and Precautions ( 5.1 )] . Tramadol hydrochloride extended-release tablets may be taken without regard to food, It is recommended that tramadol hydrochloride extended-release tablets be taken in a consistent manner [see Clinical Pharmacology ( 12.3 )] .
2.2Initial Dosage Patients Not Currently on a Tramadol Product The initial dose of tramadol hydrochloride extended-release tablets is 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 tablets rounded down to the next lower 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 tablets, some patients maintained on tramadol IR products may not be able to convert to tramadol hydrochloride extended-release tablets. Conversion from Other Opioids to Tramadol Hydrochloride Extended-Release Tablets Discontinue all other around-the-clock opioid drugs when tramadol hydrochloride extended-release tablets therapy is initiated. There are no established conversion ratios for conversion from other opioids to tramadol hy… [Excerpted — this section continues on DailyMed.]
💊 Dosage Forms and Strengths ▾
3 DOSAGE FORMS AND STRENGTHS Extended-release tablets are available as: 100 mg tablets: White to off-white circular, biconvex, beveled edge coated tablets imprinted with 'L010' on one side and plain on the other side. 200 mg tablets: White to off-white circular, biconvex, beveled edge coated tablets imprinted with 'L011' on one side and plain on the other side. 300 mg tablets: White to off-white circular, biconvex, beveled edge coated tablets imprinted with 'L012' on one side and plain on the other side.
Extended-release tablets 100 mg, 200 mg, and 300 mg (non-scored) ( 3 )
⛔ Contraindications ▾
4 CONTRAINDICATIONS Tramadol hydrochloride extended-release tablets are contraindicated for: all children younger than 12 years of age [see Warnings and Precautions ( 5.4 )] post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Warnings and Precautions ( 5.4 )] . Tramadol hydrochloride extended-release tablets are also contraindicated in patients with: Significant respiratory depression [see Warnings and Precautions ( 5.3 )] Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions ( 5.12 )] Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions ( 5.15 )] Hypersensitivity to tramadol (e.g., anaphylaxis) [see Warnings and Precautions (5.16), Adverse Reactions ( 6.2 )] Concurrent use of monoamine oxidase inhibitors (MAOIs) or use within the last 14 days [see Drug Interactions ( 7 )].
Children younger than 12 years of age ( 4 ) Postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. ( 4 ) Significant respiratory depression ( 4 ) Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment ( 4 ) Known or suspected gastrointestinal obstruction, including paralytic ileus ( 4 ) Hypersensitivity to tramadol ( 4 ) Concurrent use of monoamine oxidase inhibitors (MAOIs) or use within the last 14 days ( 4 )
⚠️ Warnings and Cautions ▾
5 WARNINGS AND PRECAUTIONS Serotonin Syndrome with Concomitant Use of Serotonergic Drugs : Potentially life-threatening condition could result from concomitant serotonergic drug administration. Discontinue tramadol hydrochloride extended-release tablets if serotonin syndrome is suspected. ( 5.8 ) Risk of Seizure : Present within recommended dosage range.
Risk is increased with higher than recommended doses and concomitant use of SSRIs, SNRIs, anorectics, tricyclic antidepressants and other tricyclic compounds, other opioids, MAOIs, neuroleptics, other drugs that reduce seizure threshold, in patients with epilepsy or at risk for seizures. ( 5.9 , 7 ) Risk of Suicide : Do not use tramadol hydrochloride extended-release tablets in suicidal or addiction-prone patients. Use with caution in those taking tranquilizers, antidepressants or abuse alcohol.
( 5.10 ) Adrenal Insufficiency : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.11 ) Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients : Monitor closely, particularly during initiation and titration. ( 5.12 ) Severe Hypotension : Monitor during dosage initiation and titration.
Avoid use of tramadol hydrochloride extended-release tablets in patients with circulatory shock. ( 5.13 ) Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness : Monitor for sedation and respiratory depression. Avoid use of tramadol hydrochloride extended-release tablets in patients with impaired consciousness or coma.
( 5.14 )
5.1Addiction, Abuse, and Misuse Tramadol hydrochloride extended-release tablet contains tramadol, a Schedule IV controlled substance. As an opioid, tramadol hydrochloride extended-release tablet exposes users to the risks of addiction, abuse, and misuse. Because extended-release products such as tramadol hydrochloride extended-release tablets 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 [see Drug Abuse and Dependence ( 9 )] .
Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed tramadol hydrochloride extended-release tablets. Addiction can occur at recommended dosages and if the drug is misused or abused. Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing tramadol hydrochloride extended-release tablets, and monitor all patients receiving tramadol hydrochloride extended-release tablets for the development of these behaviors and conditions.
Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as tramadol hydrochloride extended-release tablets, but use in such patients necessitates intensive counseling about the risks and proper use of tramadol hydrochloride extended-release tablets along with intensive monitoring for signs of addiction, abuse, and misuse.
Abuse or misuse of tramadol hydrochloride extended-release tablets by cutting, breaking, chewing, crushing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of tramadol and can result in overdose and death [see Overdosage ( 10 )] . Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing tramadol hydrochloride extended-release tablets.
Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see Patient Counseling Inf… [Excerpted — this section continues on DailyMed.]
🤒 Adverse Reactions ▾
6 ADVERSE REACTIONS The following serious adverse reactions are described in greater detail, in other sections: Addiction, Abuse, and Misuse [see Warnings and Precautions ( 5.1 )] Life-Threatening Respiratory Depression [see Warnings and Precautions ( 5.3 )] Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-Threatening Respiratory Depression in Children [see Warnings and Precautions ( 5.4 )] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.5 )] Interactions with Benzodiazepines and Other CNS Depressants [see Warnings and Precautions ( 5.7 )] Serotonin Syndrome [see Warnings and Precautions ( 5.8 )] Seizures [see Warnings and Precautions ( 5.9 )] Suicide [see Warnings and Precautions ( 5.10 )] Adrenal Insufficiency [see Warnings and Precautions ( 5.11 )] Severe Hypotension [see Warnings and Precautions ( 5.13 )] Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.15 )] Hypersensitivity Reactions [see Warnings and Precautions( 5.16 )] Withdrawal [see Warnings and Precautions ( 5.17 )] Most common adverse reactions (≥10% and ≥2 x placebo rate): Dizziness, constipation, nausea, headache, somnolence, flushing, pruritus, vomiting, insomnia, dry mouth.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical 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 tablet was administered to a total of 3108 patients during studies conducted in the U.S. These included four double-blind studies in patients with osteoarthritis and/or chronic low back pain and one open-label study in patients with chronic non-malignant pain.
A total of 901 patients were 65 years or older. The frequency of adverse reactions generally increased with doses from 100 mg to 400 mg in the two pooled, twelve-week, randomized, double-blind, placebo-controlled studies in patients with chronic non-malignant pain (see Table 1). The most common adverse reactions from Table 1 occurring in ≥10% and ≥2 x placebo rate of the patients treated with tramadol hydrochloride extended-release tablets are dizziness (not vertigo), nausea, constipation, headache, somnolence, flushing, pruritus, vomiting, insomnia, and dry mouth.
Table 1: Incidence (%) of patients with adverse reaction rates ≥ 5% from two 12-week placebo-controlled studies in patients with moderate to moderately severe chronic pain by dose (N=1811). MedDRA Preferred Term Tramadol Hydrochloride Extended - Release Tablets Placebo 100 mg ( N = 403 ) n (%) 200 mg ( N = 400 ) n (%) 300 mg ( N = 400 ) n (%) 400 mg ( N = 202 ) n (%) ( N = 406 ) n (%) Dizziness (not vertigo) 64 (16) 81 (20) 90 (23) 57 (28) 28 (7) Nausea 61 (15) 90 (23) 102 (26) 53 (26) 32 (8) Constipation 49 (12) 68 (17) 85 (21) 60 (30) 17 (4) Headache 49 (12) 62 (16) 46 (12) 32 (16) 43 (11) Somnolence 33 (8) 45 (11) 29 (7) 41 (20) 7 (2) Flushing 31 (8) 40 (10) 35 (9) 32 (16) 18 (4) Pruritus 25 (6) 34 (9) 30 (8) 24 (12) 4 (1) Vomiting 20 (5) 29 (7) 34 (9) 19 (9) 11 ( 3) Insomnia 26 (7) 32 (8) 36 (9) 22 (11) 13 (3) Dry Mouth 20 (5) 29 (7) 39 (10) 18 (9) 6 (2) Diarrhea 15 (4) 27 (7) 37 (9) 10 (5) 17 (4) Asthenia 14 (4) 24 (6) 26 (7) 13 (6) 7 (2) Postural hypotension 7 (2) 17 (4) 8 (2) 11 (5) 9 (2) Sweating increased 6 (2) 8 (2) 15 (4) 13 (6) 1 (0) Anorexia 3 (1) 7 (2) 21 (5) 12 (6) 1 (0) Adverse reactions With Incidence Rates of 1.0% to <5.0% During Clinical Trials The following adverse reactions were reported from all the chronic pain studies (N=3108).
The lists below include adverse reactions not otherwise noted in Table 1. Eye disorders : vision blurred Gastrointestinal disorders : abdominal pain upper, dyspepsia, abdominal pain, sore th… [Excerpted — this section continues on DailyMed.]
🔄 Drug Interactions ▾
7 DRUG INTERACTIONS Table 2 includes clinically significant drug interactions with tramadol hydrochloride extended-release tablets. Inhibitors of CYP2D6 Clinical Impact: The concomitant use of tramadol hydrochloride extended-release tablets and CYP2D6 inhibitors may result in an increase in the plasma concentration of tramadol and a decrease in the plasma concentration of M1, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride extended-release tablets is achieved. Since M1 is a more potent µ-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol.
Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease and the M1 plasma concentration will increase which could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity, and may cause potentially fatal respiratory depression [see Clinical Pharmacology (12.3)] .
Intervention: If concomitant use of a CYP2D6 inhibitor is necessary, follow patients closely for adverse reactions including opioid withdrawal, seizures, and serotonin syndrome. If a CYP2D6 inhibitor is discontinued, consider lowering tramadol hydrochloride extended-release tablets dosage until stable drug effects are achieved. Follow patients closely for adverse events including respiratory depression and sedation.
Examples Quinidine, fluoxetine, paroxetine and bupropion Inhibitors of CYP3A4 Clinical Impact: The concomitant use of tramadol hydrochloride extended-release tablets and CYP3A4 inhibitors can increase the plasma concentration of tramadol and may result in a greater amount of metabolism via CYP2D6 and greater levels of M1. Follow patients closely for increased risk of serious adverse events including seizures and serotonin syndrome, and adverse reactions related to opioid toxicity including potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride extended-release tablets is achieved.
After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease [see Clinical Pharmacology (12.3)] , resulting in decreased opioid efficacy 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 tablets until stable drug effects are achieved. Follow patients closely for seizures and serotonin syndrome, and signs of respiratory depression and sedation at frequent intervals.
If a CYP3A4 inhibitor is discontinued, consider increasing the tramadol hydrochloride extended-release tablets dosage until stable drug effects are achieved and follow patients for signs and symptoms of opioid withdrawal. Examples Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir) CYP3A4 Inducers Clinical Impact: The concomitant use of tramadol hydrochloride extended-release tablets and CYP3A4 inducers can decrease the plasma concentration of tramadol [see Clinical Pharmacology (12.3)] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to tramadol, [see Warnings and Precautions (5.6)] .
After stopping a CYP3A4 inducer, as the effects of the inducer decline, the tramadol plasma concentration will increase [see Clinical Pharmacology (12.3)] , which could increase or prolong both the therapeutic effects and adverse reactions, and may cause seizures and serotonin s… [Excerpted — this section continues on DailyMed.]
👥 Use in Specific Populations ▾
8 USE IN SPECIFIC POPULATIONS Pregnancy : May cause fetal harm. ( 8.1 ) Lactation : Breastfeeding not recommended. ( 8.2 ) Severe Hepatic or Renal Impairment : Use not recommended. ( 8.6 , 8.7 )
8.1Pregnancy Risk Summary Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions ( 5.5 )] . Available data with tramadol hydrochloride extended-release tablets in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, tramadol administration during organogenesis decreased fetal weights and reduced ossification in mice, rats, and rabbits at 1.4, 0.6, and 3.6 times the maximum recommended human daily dosage (MRHD).
Tramadol decreased pup body weight and increased pup mortality at 1.2 and 1.9 times the MRHD [see Data] . Based on animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.
All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in 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 and signs of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions ( 5.5 )] .
Neonatal seizures, neonatal withdrawal syndrome, fetal death and stillbirth 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 tablets 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 tablets, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor.
Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Tramadol has been shown to cross the placenta. The mean ratio of serum tramadol in the umbilical veins compared to maternal veins was 0.83 for 40 women given tramadol during labor.
The effect of tramadol hydrochloride extended-release tablets, if any, on the later growth, development, and functional maturation of the child is unknown. Data Animal Data Tramadol has been shown to be embryotoxic and fetotoxic in mice, (120 mg/kg), rats (25 mg/kg) and rabbits (75 mg/kg) at maternally toxic dosages, but was not teratogenic at these dose levels. These doses on a mg/m 2 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… [Excerpted — this section continues on DailyMed.]
🤰 Pregnancy ▾
8.1Pregnancy Risk Summary Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions ( 5.5 )] . Available data with tramadol hydrochloride extended-release tablets in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, tramadol administration during organogenesis decreased fetal weights and reduced ossification in mice, rats, and rabbits at 1.4, 0.6, and 3.6 times the maximum recommended human daily dosage (MRHD).
Tramadol decreased pup body weight and increased pup mortality at 1.2 and 1.9 times the MRHD [see Data] . Based on animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.
All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in 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 and signs of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions ( 5.5 )] .
Neonatal seizures, neonatal withdrawal syndrome, fetal death and stillbirth 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 tablets 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 tablets, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor.
Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Tramadol has been shown to cross the placenta. The mean ratio of serum tramadol in the umbilical veins compared to maternal veins was 0.83 for 40 women given tramadol during labor.
The effect of tramadol hydrochloride extended-release tablets, if any, on the later growth, development, and functional maturation of the child is unknown. Data Animal Data Tramadol has been shown to be embryotoxic and fetotoxic in mice, (120 mg/kg), rats (25 mg/kg) and rabbits (75 mg/kg) at maternally toxic dosages, but was not teratogenic at these dose levels. These doses on a mg/m 2 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 os… [Excerpted — this section continues on DailyMed.]
🧒 Pediatric Use ▾
8.4Pediatric Use The safety and effectiveness of tramadol hydrochloride extended-release tablets in pediatric patients have not been established. Life-threatening respiratory depression and death have occurred in children who received tramadol [see Warnings and Precautions ( 5.4 )] . In some of the reported cases, these events followed tonsillectomy and/or adenoidectomy, and one of the children had evidence of being an ultra-rapid metabolizer of tramadol (i.e., multiple copies of the gene for cytochrome P450 isoenzyme 2D6).
Children with sleep apnea may be particularly sensitive to the respiratory depressant effects of tramadol. Because of the risk of life-threatening respiratory depression and death: Tramadol hydrochloride extended-release tablets are contraindicated for all children younger than 12 years of age [see Contraindications ( 4 )] . Tramadol hydrochloride extended-release tablets are contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications ( 4 )].
Avoid the use of tramadol hydrochloride extended-release tablets in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression. [see Warnings and Precautions ( 5.4 )].
🧓 Geriatric Use ▾
8.5Geriatric Use Nine-hundred-one elderly (65 years of age or older) subjects were exposed to tramadol hydrochloride extended-release tablets in clinical trials. Of those subjects, 156 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: constipation, fatigue, weakness, postural hypotension and dyspepsia.
For this reason, tramadol hydrochloride extended-release tablets should be used with caution in patients over 65 years of age, and with even greater caution in patients older than 75 years of age [see Dosage and Administration ( 2.4 ), Clinical Pharmacology ( 12.3 )] . 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 tablets slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions ( 5.12 )] . Tramadol is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
🆘 Overdosage ▾
10 OVERDOSAGE Clinical Presentation Acute overdosage with tramadol hydrochloride extended-release tablets can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, QT prolongation, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology ( 12.2 )] .
Treatment of Overdose In case of overdose, 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 tablets could be suppressed with barbiturates or benzodiazepines but were increased with naloxone. Naloxone administration did not change the lethality of an overdose in mice.
Hemodialysis is not expected to be helpful in an overdose because it removes less than 7% of the administered dose in a 4-hour dialysis period. Because the duration of opioid reversal is expected to be less than the duration of action of tramadol in tramadol hydrochloride extended-release tablets, carefully monitor the patient until spontaneous respiration is reliably reestablished. Tramadol hydrochloride extended-release tablets 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 initiated with care and by titration with smaller than usual doses of the antagonist.
🧬 Clinical Pharmacology ▾
12 CLINICAL PHARMACOLOGY
12.1Mechanism of Action Tramadol hydrochloride extended-release tablet contains tramadol, an opioid agonist and an inhibitor of reuptake of norepinephrine and serotonin. Although the mode of action of tramadol is not completely understood, the analgesic effect of tramadol is believed to be due to both binding to µ-opioid receptors and weak inhibition of 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-desmethyl 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. 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.
12.2Pharmacodynamics 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 may be increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.
Effects on the Cardiovascular System Tramadol produces peripheral vasodilation, which may result in orthostatic hypotension or syncope. Manifestations of 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 [see Adverse Reactions ( 6.2 )] . 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 op… [Excerpted — this section continues on DailyMed.]
🧬 Mechanism of Action ▾
12.1Mechanism of Action Tramadol hydrochloride extended-release tablet contains tramadol, an opioid agonist and an inhibitor of reuptake of norepinephrine and serotonin. Although the mode of action of tramadol is not completely understood, the analgesic effect of tramadol is believed to be due to both binding to µ-opioid receptors and weak inhibition of 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-desmethyl 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. 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.
📦 How Supplied / Storage and Handling ▾
16 HOW SUPPLIED/STORAGE AND HANDLING Tramadol hydrochloride extended-release tablets USP are supplied in the following package and dose strength forms: 100 mg tablets (white to off-white circular, biconvex, beveled edge, coated) imprinted with L010 on one side and plain on the other side. NDC 68071-1671-3 BOTTLES OF 30 Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Store tramadol hydrochloride extended-release tablets securely and dispose of properly [see Precautions/Information for Patients ].
📋 Description ▾
11 DESCRIPTION Tramadol hydrochloride is an opioid agonist in an extended-release tablet formulation for oral use. The chemical name is (±) cis-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochloride. Its structural formula is: The molecular weight of tramadol HCl is 299.84.
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 tablets USP contain 100, 200 or 300 mg of tramadol HCl in an extended-release formulation.
The tablets are white to off-white in color and contain the inactive ingredients: colloidal silicon dioxide, dibutyl sebacate, ethyl cellulose, microcrystalline cellulose, povidone, and sodium stearyl fumarate. The imprinting ink contains shellac, iron oxide black and propylene glycol. Tramadol hydrochloride extended-release tablets USP meet USP Dissolution Test 3. image-1
💬 Information for Patients ▾
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Storage and Disposal: Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store tramadol hydrochloride extended-release tablets securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home [see Warnings , Drug Abuse and Dependence ] . Inform patients that leaving tramadol hydrochloride extended-release tablets unsecured can pose a deadly risk to others in the home.
Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Inform patients that medicine take-back options are the preferred way to safely dispose of most types of unneeded medicines. If no take back programs or DEA-registered collectors are available, instruct patients to dispose of tramadol hydrochloride extended-release tablets by following these four steps: Mix tramadol hydrochloride extended-release tablets (do not crush) with an unpalatable substance such as dirt, cat litter, or used coffee grounds; Place the mixture in a container such as a sealed plastic bag; Throw the container in the household trash; Delete all personal information on the prescription label of the empty bottle Inform patients that they can visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines.
Addiction, Abuse, and Misuse Inform patients that the use of tramadol hydrochloride extended-release tablets, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions ( 5.1 )] . Instruct patients not to share tramadol hydrochloride extended-release tablets with others and to take steps to protect tramadol hydrochloride extended-release tablets from theft or misuse. Life-Threatening Respiratory Depression Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting tramadol hydrochloride extended-release tablets or when the dosage is increased, and that it can occur even at recommended dosages [see Warnings and Precautions ( 5.3 )].
Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop. Accidental Ingestion Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions ( 5.3 )] . Instruct patients to take steps to store tramadol hydrochloride extended-release tablets securely and to dispose of unused tramadol hydrochloride extended-release tablets in accordance with the local state guidelines and/or regulations.
Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-threatening Respiratory Depression in Children Advise caregivers that tramadol hydrochloride extended-release tablets are contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Advise caregivers of children 12 to 18 years of age receiving tramadol hydrochloride extended-release tablets to monitor for signs of respiratory depression [see Warnings and Precautions ( 5.4 )] .
Interactions with Benzodiazepines and Other CNS Depressants Inform patients and caregivers that potentially fatal additive effects may occur if tramadol hydrochloride extended-release tablets are used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider [see Warnings and Precautions ( 5.7 ), Drug Interactions ( 7 )] . Serotonin Syndrome Inform patients that 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… [Excerpted — this section continues on DailyMed.]
💬 Medication Guide ▾
Medication Guide Tramadol Hydrochloride Extended-Release Tablets , CIV (tram' a dol hye'' droe klor' ide) Tramadol hydrochloride extended-release tablets 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 tablets: Get emergency help right away if you take too much tramadol hydrochloride extended-release tablets (overdose) .
When you first start taking tramadol hydrochloride extended-release tablets, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur. Taking tramadol hydrochloride extended-release tablets with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death. Never give anyone else your tramadol hydrochloride extended-release tablets.
They could die from taking it. Selling or giving away tramadol hydrochloride extended-release tablets is against the law. Store tramadol hydrochloride extended-release tablets securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home.
Important Information Guiding Use in Pediatric Patients: Do not give tramadol hydrochloride extended-release tablets to a child younger than 12 years of age. Do not give tramadol hydrochloride extended-release tablets to a child younger than 18 years of age after surgery to remove the tonsils and/or adenoids. Avoid giving tramadol hydrochloride extended-release tablets to children between 12 to 18 years of age who have risk factors for breathing problems such as obstructive sleep apnea, obesity, or underlying lung problems.
Do not take tramadol hydrochloride extended-release tablets 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 tablets, tell your healthcare provider if you have a history of: head injury, seizures problems urinating abuse of street or prescription drugs, alcohol addiction, or mental health problems. liver, kidney, thyroid problems pancreas or gallbladder problems Tell your healthcare provider if you are: pregnant or planning to become pregnant .
Prolonged use of tramadol hydrochloride extended-release tablets during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated. breastfeeding . Not recommended-: it may harm your baby. taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking tramadol hydrochloride extended-release tablets with certain other medicines can cause serious side effects that could lead to death.
When taking tramadol hydrochloride extended-release tablets: Do not change your dose. Take tramadol hydrochloride extended-release tablets 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 tablets whole. Do not cut, break, chew, crush, dissolve, snort, or inject tramadol hydroch… [Excerpted — this section continues on DailyMed.]
🧬 Pharmacokinetics ▾
12.3Pharmacokinetics The analgesic activity of tramadol is due to both parent drug and the M1 metabolite. Tramadol hydrochloride extended-release tablet is administered as a racemate and both the [-] and [+] forms of both tramadol and M1 are detected in the circulation. The pharmacokinetics of tramadol hydrochloride extended-release tablets are approximately dose-proportional over a 100 to 400 mg dose range in healthy subjects.
The observed tramadol AUC values for the 400-mg dose were 26% higher than predicted based on the AUC values for the 200-mg dose. The clinical significance of this finding has not been studied and is not known. Absorption In healthy subjects, the bioavailability of a tramadol hydrochloride extended-release 200 mg tablet administered once daily relative to a 50 mg immediate-release (IR) tablet (tramadol hydrochloride) administered every six hours was approximately 85 to 90%.
Consistent with the extended-release nature of the formulation, there is a lag time in drug absorption following tramadol hydrochloride extended-release tablets administration. The mean peak plasma concentrations of tramadol and M1 after administration of tramadol hydrochloride extended-release tablets to healthy volunteers are attained at about 12 h and 15 h, respectively, after dosing (see Table 3 and Figure 1). Following administration of the tramadol hydrochloride extended-release tablets, steady-state plasma concentrations of both tramadol and M1 are achieved within four days with once daily dosing.
The mean (%CV) pharmacokinetic parameter values for tramadol hydrochloride extended-release tablets 200 mg administered once daily and tramadol HCl IR (tramadol hydrochloride) 50 mg administered every six hours are provided in Table 3. Table 3: Mean (%CV) Steady-State Pharmacokinetic Parameter Values (n=32) Tramadol M1 Metabolite Pharmacokinetic Parameter Tramadol Hydrochloride Extended - Release 200 - mg Tablet Once - Daily Tramadol Hydrochloride 50 - mg Tablet Every 6 Hours Tramadol Hydrochloride Extended - Release 200 - mg Tablet Once - Daily Tramadol Hydrochloride 50 - mg Tablet Every 6 Hours AUC 0 t o 2 4 (ng∙h/mL) 5975 (34) 6613 (27) 1890 (25) 2095 (26) C m a x (ng/mL) 335 (35) 383 (21) 95 (24) 104 (24) C m i n (ng/mL) 187 (37) 228 (32) 69 (30) 82 (27) T m a x (h) 12 (27) 1.5 (42) 15 (27) 1.9 (57) % Fluctuation 61 (57) 59 (35) 34 (72) 26 (47) AUC 0 to 24 : Area Under the Curve in a 24-hour dosing interval; C max : Peak Concentration in a 24- hour dosing interval; C min : Trough Concentration in a 24-hour dosing interval; T max : Time to Peak Concentration Figure 1: Mean Steady-State Tramadol (a) and M1 (b) Plasma Concentrations on Day 8 Post Dose after Administration of 200 mg Tramadol Hydrochloride Extended-Release Tablets Once-Daily and 50 mg Tramadol Hydrochloride Tablets Every 6 Hours.
Food Effects After a single dose administration of 200 mg tramadol hydrochloride extended-release tablet with a high fat meal, the C max and AUC 0 to ∞ of tramadol decreased 28% and 16%, respectively, compared to fasting conditions. Mean T max was increased by 3 hr (from 14 hr under fasting conditions to 17 hr under fed conditions). While tramadol hydrochloride extended-release tablets may be taken without regard to food, it is recommended that it be taken in a consistent manner [see Dosage and Administration ( 2.1 )] .
Distribution The volume of distribution of tramadol was 2.6 and
2.9L/kg in male and female subjects, respectively, following a 100-mg intravenous dose. The binding of tramadol to human plasma proteins is approximately 20% and binding also appears to be independent of concentration up to 10 mcg/mL. Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range.
Elimination Tramadol is eliminated primarily through metabolism by the liver and the metabolites are eliminated primarily by the kidneys. The mean terminal plasma elimination half-lives of racemic tramadol and racemic M1 after a… [Excerpted — this section continues on DailyMed.]
🧬 Pharmacodynamics ▾
12.2Pharmacodynamics 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 may be increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.
Effects on the Cardiovascular System Tramadol produces peripheral vasodilation, which may result in orthostatic hypotension or syncope. Manifestations of 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 [see Adverse Reactions ( 6.2 )] . 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 [see Adverse Reactions ( 6.2 )] . Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models.
The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive. Concentration–Efficacy Relationships The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent opioid agonists.
The minimum effective analgesic concentration of tramadol for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see Dosage and Administration ( 2.1 )] . Concentration–Adverse Reaction Relationships There is a relationship between increasing tramadol plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration ( 2.1 , 2.2 )] .
🔬 Clinical Studies ▾
14 CLINICAL STUDIES Clinical Trial Experience Tramadol hydrochloride extended-release tablets were studied in patients with chronic, moderate to moderately severe pain due to osteoarthritis and/or low back pain in four 12-week, randomized, double-blind, placebo- controlled trials. 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 to 100 mm visual analog scale (VAS). Adequate evidence of efficacy was demonstrated in the following two studies: Study 1: Osteoarthritis of the Knee and/or Hip 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 was initiated at 100 mg QD 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 the tramadol hydrochloride extended-release tablets 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 tramadol hydrochloride extended-release tablets 200 mg, 300 mg and 400 mg treatment groups (20%, 27%, and 30% of discontinuations, respectively) compared to 14% of the patients treated with tramadol hydrochloride extended-release tablets 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 Study 2: Osteoarthritis of the Knee In one 12-week randomized, double-blind, placebo-controlled flexible-dosing trial of tramadol hydrochloride extended-release tablets in patients with osteoarthritis of the knee, patients titrated to an average daily tramadol hydrochloride extended-release tablets dose of approximately 270 mg/day.
Forty-nine percent of patients randomized to tramadol hydrochloride extended-release tablets completed the study, while 52% of patients randomized to placebo completed the study. Most of the early discontinuations in the tramadol hydrochloride extended-release tablets 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 tramadol hydrochloride extended-release tablets-treated patients.
The tramadol hydrochloride extended-release tablets group demonstrated a statistically significant decrease in the mean 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 tramadol hydrochloride extended-release tablets and placebo (see Figure 3). Figure 3 image-4 image-5
🔒 Drug Abuse and Dependence ▾
9 DRUG ABUSE AND DEPENDENCE
9.1Controlled Substance Tramadol hydrochloride extended-release tablet contains tramadol, a scheduled IV controlled substance.
9.2Abuse Tramadol hydrochloride extended-release tablet contains tramadol, a substance with a high potential for abuse similar to other opioids. Tramadol hydrochloride extended-release tablets can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions ( 5.1 )]. 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 tablets, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.
Risks Specific to Abuse of Tramadol Hydrochloride Extended-Release Tablets Tramadol hydrochloride extended-release tablets are for oral use only. The abuse of tramadol hydrochloride extended-release tablets poses a risk of overdose and death. The risk is increased with concurrent use of tramadol hydrochloride extended-release tablets with alcohol and other central nervous system depressants.
With intravenous abuse the inactive ingredients in tramadol hydrochloride extended-release tablets 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.
9.3Dependence 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 de… [Excerpted — this section continues on DailyMed.]
🔒 Controlled Substance ▾
9.1Controlled Substance Tramadol hydrochloride extended-release tablet contains tramadol, a scheduled IV controlled substance.
🧪 Nonclinical Toxicology ▾
13 NONCLINICAL TOXICOLOGY
13.1Carcinogenesis, 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.
📄 Carcinogenesis, Mutagenesis, Impairment of Fertility ▾
13.1Carcinogenesis, 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.
📄 Recent Major Changes ▾
RECENT MAJOR CHANGES Boxed Warning 07/2018 Warnings and Precautions ( 5 ) 07/2018
📄 Package Label / Principal Display Panel ▾
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