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Tramadol Hydrochloride 50 mg Tablet, Film Coated, 500-count — NDC 59651-441-05 (Billing 59651-0441-05)

by Aurobindo Pharma Limited · 500 TABLET, FILM COATED in 1 BOTTLE

This is a package of 500 tablets of Tramadol Hydrochloride 50 mg Tablet, Film Coated from Aurobindo Pharma Limited, marketed since Sep 2020 and currently FDA-listed.

NDC 59651-0441-05
🏷️ FDA NDC (as labeled) 59651-441-05 billing pads the product segment with a zero
This package
Contains500-count Pack sizes4 compare ↓
Also priced by: Part D plans $0.1012/unit — full pricing hub ↓
Product page 59651-0441-01 Also comes in: 100 tablets 59651-441-01 1000 tablets 59651-441-99 10000 tablets 59651-441-19
Rx only Generic On market CIV 🛡 REMS ⇄ Compare with another NDC
🗂️ FDA directory synced Oct 1, 2026 · this listing last changed Sep 10, 2026 · sources: openFDA · FDA label (DailyMed) · FDA Orange & Purple Book · First Databank · CMS NADAC, ASP, Medicare & Medicaid · RxNorm
📋 All sources & update times →

This page is curated, coded, and maintained by

Compiled from public FDA, CMS, DailyMed, NADAC, and related drug data sources. Editorial policy

⚠️
Other active recalls for Tramadol Hydrochloride (different manufacturers) — 1 · tap to view
These affect other manufacturers’ products for the same ingredient — not necessarily the exact NDC on this page.
Class II · Apr 26, 2024 — Presence of Foreign Tablets: Pharmacist reported a tablet of baclofen in a bottle of 1000-count tramadol (Rubicon Research Private Limited) · FDA recall D-0487-2024
Each entry is an official FDA enforcement report — look up any recall number in the FDA recall database ↗

Identity & classification

Regulatory identifiers FDA, NLM and CMS codes for this package

FDA NDC (as labeled) 59651-441-05
Product NDC 59651-441
11-digit billing NDC 59651044105
RxCUI 835603
UNII 9N7R477WCK
Application # ANDA203494
SPL Set ID e5005d9e-91cb-4ff8-bcf2-b5ee70cf4f3f
Established class (EPC) Opioid Agonist
Mechanism of action Full Opioid Agonists
DEA schedule CIV
Marketing category ANDA
Marketing status On market
FDA listing status Listed (active directory)
Marketing start 2020-09-23
Route ORAL
Dosage form TABLET, FILM COATED
Substance TRAMADOL HYDROCHLORIDE
TE code (Orange Book) AB · RLD · RS
Quick answers
  • RxCUI (RxNorm): 835603
Why two NDCs? The FDA registers this code as 59651-441-05 — a 5-3-2 layout, and that's what's printed on the package and shown on DailyMed. For insurance claims, every NDC is standardized to a uniform 11-digit 5-4-2 format by adding a zero to the product segment → 59651-0441-05. Same drug, same package — only the format differs.
Where does this data come from?
Identifiers from the FDA openFDA NDC Directory and Structured Product Labeling; RxCUI from RxNorm (NLM); GPI from Medi-Span; GCN / HIC / AHFS / legend from First Databank.

RxNorm drug class

This medicine belongs to the Opioid Agonist class.

Pharmacologic class Opioid Agonist
Drug family (ATC) Other opioids
How it works Full Opioid Agonists
Where does this data come from?
Therapeutic classes from RxNorm RxClass (U.S. National Library of Medicine) — Established Pharmacologic Class (FDA), ATC drug family (WHO) and mechanism of action, matched by this product’s RxCUI.

Clinical

📗 Our plain-language guide HelloPharmacist
  • 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...
📖 Read our full Tramadol guide →

Supplement & herbal interactions

🌿 Drug–supplement interaction checker →
Where does this data come from?
Plain-language summary from MedlinePlus (U.S. National Library of Medicine); supplement & herbal interactions and nutrient depletion data from the Natural Medicines database; our full guide is HelloPharmacist editorial content.

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 systemPer eachPer 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 $0.1012 $50.60 / 500 tablets
Where does this data come from?
NADAC (National Average Drug Acquisition Cost) is the CMS weekly pharmacy-acquisition-cost survey — what pharmacies pay. ASP (Average Sales Price) is the CMS Medicare Part B drug-payment file, published quarterly. Medicaid pays is computed by us from CMS State Drug Utilization Data (total reimbursed ÷ units, trailing 12 months) — gross of rebates and inclusive of dispensing fees, so it reflects what Medicaid paid, not an acquisition cost. Medicare drug plans pay is the median negotiated point-of-sale unit cost across plans listing this NDC in the CMS quarterly Prescription Drug Plan pricing files, before rebates. The VA pays is the federal contract price (FSS, and the statutory Big 4 ceiling where listed) from the VA National Acquisition Center pharmaceutical price file. All are free public government data; each measures a different payer, so the figures are not directly comparable.

Packaging — all sizes for this product

Package NDCDescription Marketing startMarketing endStatus
59651-0441-01 59651-441-01 Main listing 100 TABLET, FILM COATED in 1 BOTTLE 2020-09-23 — Active
59651-0441-05 You're viewing this 500 TABLET, FILM COATED in 1 BOTTLE 2020-09-23 — Active
59651-0441-99 59651-441-99 1000 TABLET, FILM COATED in 1 BOTTLE 2020-09-23 — Active
59651-0441-19 59651-441-19 10000 TABLET, FILM COATED in 1 BAG — — Active

You're viewing one of 4 pack sizes for this product.

Pack size FAQ

What quantity is in this package?
This is a 500-count package — 500 tablet, film coated in 1 bottle.
How does this package differ from NDC 59651-0441-01?
Both are Tramadol Hydrochloride 50 mg Tablet, Film Coated — the drug itself is identical. This page's package is the 500-count one, while NDC 59651-0441-01 is the 100 tablets package.
What NDC number is used to bill for this package of Tramadol Hydrochloride 50 mg Tablet, Film Coated?
Use the 11-digit billing form listed in the identifiers section of this page. Pharmacy and medical claims use the 11-digit form; the FDA label may print a shorter form of the same code.

Therapeutic equivalents

ProductLabelerPackNADAC/unitTEStatusPrice vs. this
Tramadol Hydrochloride 50 mg 00093-3301-01 Teva 100 tablets $0.025 AB Availability likely —
Tramadol Hydrochloride 50 mg 00904-7496-61 Major 1 tablet $0.025 AB Availability likely —
Tramadol Hydrochloride 50 mg 16571-0716-01 Rising 100 tablets $0.025 AB Availability likely —
Tramadol Hydrochloride 50 mg 29300-0355-01 Unichem 100 tablets $0.025 AB Availability likely —
Tramadol Hydrochloride 50 mg 60219-2348-01 Amneal 100 tablets $0.025 AB Availability likely —
Tramadol Hydrochloride 50 mg 60687-0795-01 American 1 tablet $0.025 AB Availability likely —
tramadol hydrochloride 50 mg 64380-0791-01 Strides 100 tablets $0.025 AB Availability likely —
Tramadol Hydrochloride 50 mg 64980-0614-01 Rising 100 tablets $0.025 AB Availability likely —
Tramadol Hydrochloride 50 mg 72888-0080-00 Advagen 1000 tablets $0.025 AB Availability likely —
Tramadol Hydrochloride 50 mg 52817-0195-00 TRUPHARMA 1000 tablets $0.033 AB FDA listed —
Tramadol Hydrochloride 50 mg 27808-0301-01 Cranbury 100 tablets — AB FDA listed —
Tramadol Hydrochloride 50 mg 50090-5789-00 A-S 30 tablets — AB FDA listed —
Tramadol Hydrochloride 50 mg 50090-5790-01 A-S 90 tablets — AB FDA listed —
Tramadol Hydrochloride 50 mg 51407-0007-01 Golden 100 tablets — AB FDA listed —
Tramadol Hydrochloride 50 mg 55700-0997-01 Quality 120 tablets — AB FDA listed —
Tramadol Hydrochloride 50 mg 58118-2348-08 Clinical 30 tablets — AB FDA listed —
Tramadol Hydrochloride 50 mgthis 59651-0441-05 Aurobindo 500 tablets — AB FDA listed —
tramadol hydrochloride 50 mg 60760-0588-30 ST. 30 tablets — AB Discontinued —
Tramadol Hydrochloride 50 mg 60760-0727-09 St. 9 tablets — AB FDA listed —
Tramadol Hydrochloride 50 mg 60760-0772-09 ST. 9 tablets — AB FDA listed —
Tramadol Hydrochloride 50 mg 63187-0063-15 Proficient 15 tablets — AB FDA listed —
Tramadol Hydrochloride 50 mg 65162-0627-01 Amneal 10 tablets — AB FDA listed —
Tramadol Hydrochloride 50 mg 67046-1209-03 Coupler 30 tablets — AB FDA listed —
Tramadol Hydrochloride 50 mg 67296-1834-01 RedPharm 10 tablets — AB FDA listed —
tramadol hydrochloride 50 mg 68071-3644-03 NuCare 30 tablets — AB FDA listed —
tramadol hydrochloride 50 mg 68071-3655-02 NuCare 12 tablets — AB FDA listed —
Tramadol Hydrochloride 50 mg 68071-4119-01 NuCare 120 tablets — AB FDA listed —
Tramadol Hydrochloride 50 mg 68788-4035-01 Preferred 100 tablets — AB FDA listed —
Tramadol Hydrochloride 50 mg 68788-4040-01 Preferred 100 tablets — AB FDA listed —
Tramadol Hydrochloride 50 mg 68788-4114-01 Preferred 90 tablets — AB FDA listed —
Tramadol Hydrochloride 50 mg 68788-8121-01 Preferred 100 tablets — AB FDA listed —
tramadol hydrochloride 50 mg 68788-8717-01 Preferred 100 tablets — AB FDA listed —
Tramadol Hydrochloride 50 mg 69238-2348-01 Amneal 100 tablets — AB FDA listed —
Tramadol Hydrochloride 50 mg 70518-3824-00 REMEDYREPACK 30 tablets — AB FDA listed —
tramadol hydrochloride 50 mg 70518-4248-00 REMEDYREPACK 30 tablets — AB FDA listed —
Tramadol Hydrochloride 50 mg 71205-0740-15 Proficient 15 tablets — AB FDA listed —
tramadol hydrochloride 50 mg 71335-2518-00 Bryant 50 tablets — AB FDA listed —
tramadol hydrochloride 50 mg 71335-2612-01 Bryant 8 tablets — AB FDA listed —
Tramadol Hydrochloride 50 mg 71335-2721-01 Bryant 8 tablets — AB FDA listed —
Tramadol Hydrochloride 50 mg 71335-3147-00 Bryant 50 tablets — AB FDA listed —
Tramadol Hydrochloride 50 mg 71335-9658-00 Bryant 50 tablets — AB FDA listed —
Tramadol Hydrochloride 50 mg 71610-0006-15 Aphena 15 tablets — AB FDA listed —
Tramadol Hydrochloride 50 mg 71610-0865-15 Aphena 15 tablets — AB FDA listed —
Tramadol Hydrochloride 50 mg 72189-0311-12 DirectRx 12 tablets — AB FDA listed —
Tramadol Hydrochloride 50 mg 76420-0733-00 Asclemed 1000 tablets — AB FDA listed —
Tramadol HCL 50 mg 80425-0057-01 Advanced 30 tablets — AB FDA listed —
Tramadol Hydrochloride 50 mg 80425-0274-01 Advanced 15 tablets — AB FDA listed —
Tramadol Hydrochloride 50 mg 80425-0276-01 Advanced 15 tablets — AB FDA listed —
Tramadol Hydrochloride 50 mg 80425-0501-01 Advanced 15 tablets — AB FDA listed —
Tramadol Hydrochloride 50 mg 80425-0548-01 Advanced 15 tablets — AB FDA listed —
tramadol hydrochloride 50 mg 82804-0114-15 Proficient 15 tablets — AB FDA listed —
Tramadol Hydrochloride 50 mg 82804-0142-15 Proficient 15 tablets — AB FDA listed —
tramadol hydrochloride 50 mg 82868-0052-30 Northwind 30 tablets — AB FDA listed —
Tramadol Hydrochloride 50 mg 87063-0117-01 Asclemed 100 tablets — AB FDA listed —
Tramadol Hydrochloride 50 mg 80425-0588-01 Advanced 15 tablets — AB FDA listed —
Tramadol Hydrochloride 50 mg 82868-0110-30 Northwind 30 tablets — AB FDA listed —
Tramadol Hydrochloride 50 mg 70518-4713-00 REMEDYREPACK 30 tablets — AB FDA listed —
Tramadol Hydrochloride 50 mg 87441-0089-01 Unit 30 tablets — AB FDA listed —
About this product: this is a generic version of the medicine. FDA equivalence ratings are shown when available, and other versions are listed above, least expensive first.
Where does this data come from?
Equivalents are other NDCs of the same ingredient, form and route from the openFDA NDC Directory, ranked least-expensive-first by NADAC. Therapeutic-equivalence (AB) ratings come from the FDA Orange Book; biologics use the FDA Purple Book for biosimilar & interchangeable status.

Availability & generic status

🏛️
2020
On the market since
Sep 2020
📍
2026
Currently FDA-listed
6 years listed
🔓
·
Generic on the market
this product is a generic
✅This is a generic drug

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?
Patents and exclusivity from the FDA Orange Book (small-molecule drugs), refreshed from public FDA data. Generic launch timing is an estimate, not a guarantee.

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.

Loading inactive ingredients from the official FDA label in the background. No external source is being called by this page request.
Where does this data come from?
Source: official FDA Structured Product Labeling (SPL) via DailyMed and the openFDA label index. Structured IACT rows and label-wide narrative are kept separate; availability and product-level specificity depend on the submitted label.

Inactive ingredient FAQ

Are inactive ingredients the same for every manufacturer?
No. Inactive ingredients can differ by manufacturer, dosage form, strength, and package / product version.
Why might an inactive ingredient be missing?
Some SPLs do not provide a complete structured inactive-ingredient list, and older or unusual labels may only include the information in narrative text.
Can inactive ingredients matter?
Yes. They can matter for allergies, intolerances, dyes, gluten / lactose concerns, preservatives, and formulation differences — but confirm with a pharmacist or the manufacturer when it’s clinically important.

Manufacturer & labeler

LabelerAurobindo Pharma Limited
Application holderAUROBINDO PHARMA LTD
FDA applicationANDA203494 (ANDA)
Labeler code59651
First marketedSep 2020
DEA scheduleCIV
Product typeHuman Prescription Drug
Portfolio1,456 products on file
The labeler markets the product; the application holder owns the FDA approval. They’re often the same company but can differ (e.g. a repackager or an authorized generic). A mailing address / phone appears here when the manufacturer includes it in the product’s FDA label (not all do).
Where does this data come from?
Labeler, application holder and registered establishment from the FDA openFDA NDC Directory and Drugs@FDA; address/contact from the product’s FDA label.

Full prescribing information FDA SPL

The complete FDA label for this product — the official prescribing information, verbatim, section by section. Very long sections are excerpted here and marked; the full text is on DailyMed (linked in the sources below). Jump with a chip, search within the label, or expand everything.
🚨 Boxed Warning 🎯 Indications and Usage ⏱️ Dosage and Administration 💊 Dosage Forms and Strengths ⛔ Contraindications ⚠️ Warnings and Cautions 🤒 Adverse Reactions 🔄 Drug Interactions 👥 Use in Specific Populations 🤰 Pregnancy 🧒 Pediatric Use 🧓 Geriatric Use 🆘 Overdosage 🧬 Clinical Pharmacology 🧬 Mechanism of Action 📦 How Supplied / Storage and Handling 📋 Description 💬 Information for Patients 💬 Medication Guide 🧬 Pharmacokinetics 🧬 Pharmacodynamics 🔬 Clinical Studies 🔒 Drug Abuse and Dependence 🔒 Controlled Substance 🧪 Nonclinical Toxicology 📄 Carcinogenesis, Mutagenesis, Impairment of Fertility 📄 Recent Major Changes 📄 Package Label / Principal Display Panel
🚨 Boxed Warning ~3 min read ▾

WARNING: SERIOUS LIFE-THREATENING RISKS FROM USE OF TRAMADOL HYDROCHLORIDE TABLETS Addiction, Abuse, and Misuse Because the use of tramadol hydrochloride tablets 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 and reassess all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.1) ] . Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of tramadol hydrochloride tablets, especially during initiation or following a dosage increase.

To reduce the risk of respiratory depression, proper dosing and titration of tramadol hydrochloride tablets are essential [see Warnings and Precautions (5.2) ] . Accidental Ingestion Accidental ingestion of even one dose of tramadol hydrochloride tablets, especially by children, can result in a fatal overdose of tramadol [see Warnings and Precautions (5.2) ] . 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 tablets and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate [see Warnings and Precautions (5.3) , Drug Interactions (7) ] . Neonatal Opioid Withdrawal Syndrome (NOWS) Advise pregnant women using opioids for an extended period of time of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery [see Warnings and Precautions (5.4) ].

Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) Healthcare providers are strongly encouraged to complete a REMS compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription [see Warnings and Precautions (5.5) ]. 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 (5.6) ]. Tramadol hydrochloride tablets are contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications (4) ]. Avoid the use of tramadol hydrochloride tablets in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol [see Warnings and Precautions (5.6) ].

Interactions with Drugs Affecting Cytochrome P450 Isoenzymes The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with tramadol are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with tramadol hydrochloride tablets requires careful consideration of the effects on the parent drug, tramadol, and the active metabolite, M1 [see Warnings and Precautions (5.7) ; Drug Interactions (7) ]. WARNING: SERIOUS LIFE-THREATENING RISKS FROM USE OF TRAMADOL HYDROCHLORIDE TABLETS See full prescribing information for complete boxed warning.

Tramadol hydrochloride tablets exposes users to the risks of addiction, abuse and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing tramadol hydrochloride tablets , and monitor regularly for these behaviors… [Excerpted — this section continues on DailyMed.]

🎯 Indications and Usage 196 words ▾

1 INDICATIONS AND USAGE Tramadol hydrochloride tablets are indicated in adults for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. Limitations of Use: Because of the risks of addiction, abuse, misuse, ov erdo se, and death, which can occur at any dosage or duration and persist over the course of therapy [see Warnings and Precautions (5.1) ] , reserve opioid analgesics, including tramadol hydrochloride tablets, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.

Tramadol hydrochloride tablets are an opioid agonist indicated in adults for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate ( 1 ). Limitations of Use: Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy, reserve opioid analgesics, including tramadol hydrochloride tablets, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.

( 1 , 5.1 )

⏱️ Dosage and Administration ~3 min read ▾

2 DOSAGE AND ADMINISTRATION Tramadol hydrochloride tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. ( 2.1 ) Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of tramadol hydrochloride tablets for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.

( 2.1 , 5 ) Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. ( 2.1 ) Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse.

( 2.1 , 5.1 ) Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with tramadol hydrochloride tablets. Consider this risk when selecting an initial dose and when making dose adjustments. ( 2.1 , 5.2 ) Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse ( 2.1 ).

Discuss opioid overdose reversal agents and options for acquiring them with the patient and/or caregiver, both when initiating and renewing treatment with tramadol hydrochloride tablets, especially if the patient has additional risk factors for overdose, or close contacts at risk for exposure and overdose. ( 2.2 , 5.1 , 5.2 , 5.3 ) Start at 25 mg/day and titrate in 25 mg increments as separate doses every 3 days to reach 100 mg/day (25 mg four times a day). Thereafter the total daily dose may be increased by 50 mg as tolerated every 3 days to reach 200 mg/day (50 mg four times a day).

After titration, tramadol hydrochloride tablets 50 to 100 mg can be administered as needed for pain relief every 4 to 6 hours not to exceed 400 mg/day ( 2.3 , 2.4 ). Severe Renal Impairment : increase the tramadol hydrochloride tablets dosing interval to 12 hours, and limit maximum daily dose to 200 mg ( 2.3 ). Severe hepatic impairment : Recommended dose is 50 mg every 12 hours.

Periodically reassess patients receiving tramadol hydrochloride tablets to evaluate the continued need for opioid analgesics to maintain pain control, for the signs or symptoms of adverse reactions, and for the development of addiction, abuse, or misuse. (2.4) Do not rapidly reduce or abruptly discontinue tramadol hydrochloride tablets in a physically dependent patient because rapid reduction or abrupt discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. ( 2.5 , 5.18 ).

2.1Important Dosage and Administration Instructions Do not use tramadol hydrochloride tablets concomitantly with other tramadol-containing products. Do not administer tramadol hydrochloride tablets at a dose exceeding 400 mg per day. Tramadol hydrochloride tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks.

Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see Warnings and Precautions (5) ]. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of tramadol hydrochloride tablets for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. Many acute pain conditions (e.g., the pain that oc… [Excerpted — this section continues on DailyMed.]

💊 Dosage Forms and Strengths 48 words ▾

3 DOSAGE FORMS AND STRENGTHS Tramadol hydrochloride tablets USP, 50 mg (equivalent to 43.9 mg of tramadol) are white to off-white, capsule shaped coated tablet debossed 'T' on one side and ‘0’ & ‘3’ separated with score line (functional) on other side. Tablets: 50 mg ( 3 ).

⛔ Contraindications ~1 min read ▾

4 CONTRAINDICATIONS Tramadol hydrochloride tablets are contraindicated for: all children younger than 12 years of age [see Warnings and Precautions (5.6) ] . postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Warnings and Precautions (5.6) ] . Tramadol hydrochloride tablets are also contraindicated in patients with: Significant respiratory depression [see Warnings and Precautions (5.2) ] . 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 (5.16) ] . Hypersensitivity to tramadol, any other component of this product or opioids [see Warnings and Precautions (5.17) ] . 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 the absence of resuscitative equipment ( 4 ). Known or suspected gastrointestinal obstruction, including paralytic ileus ( 4 ). Hypersensitivity to tramadol, any other component of this product or opioids ( 4 ).

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

⚠️ Warnings and Cautions ~3 min read ▾

5 WARNINGS AND PRECAUTIONS Opioid-Induced Hyperalgesia and Allodynia : Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation. ( 5.8 ) Serotonin Syndrome : May be life-threatening.

Can occur with use of tramadol alone, with concomitant use of serotonergic drugs, with drugs that impair metabolism of serotonin or tramadol ( 5.9 ). Risk of Seizure : Can occur at the recommended dose of tramadol. Concomitant use with other drugs may increase seizure risk.

Risk may increase in patients with epilepsy, a history of seizures, and in patients with a recognized risk for seizures ( 5.10 ). Risk of Suicide : Do not prescribe for suicidal or addiction-prone patients ( 5.11 ). Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients : Regularly evaluate closely, particularly during initiation and titration ( 5.12 ).

Adrenal Insufficiency : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off the opioid ( 5.13 ). Severe Hypotension : Regularly evaluate during dosage initiation and titration. Avoid use of tramadol hydrochloride tablets in patients with circulatory shock ( 5.14 ).

Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness : Regularly evaluate for sedation and respiratory depression. Avoid use of tramadol hydrochloride tablets in patients with impaired consciousness or coma ( 5.15 ).

5.1Addiction, Abuse and Misuse Tramadol hydrochloride tablets contains tramadol, a Schedule IV controlled substance. As an opioid, tramadol hydrochloride tablets exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9) ] . Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed tramadol hydrochloride tablets.

Addiction can occur at recom mende d doses and if the drug is misused or abused. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use [see Adverse Reactions (6.2) ].

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing tramadol hydrochloride tablets, and reassess all patients receiving tramadol hydrochloride tablets for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient.

Patients at increased risk may be prescribed opioids such as tramadol hyd rochl oride tablets but use in such patients necessitates intensive counseling about the risks and proper use of tramadol hydrochloride tablets along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2) , Warnings and Precautions (5.2) ] . Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use.

Consider these risks when prescribing or dispensing tramadol hydrochloride tablets. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and proper disposal of unused drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent… [Excerpted — this section continues on DailyMed.]

🤒 Adverse Reactions ~3 min read ▾

6 ADVERSE REACTIONS The following serious adverse reactions are described, or 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 (5.2) ] Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-threatening Respiratory Depression in Children [see Warnings and Precautions (5.6) ] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.4) ] Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions (5.3) ] Opioid-Induced Hyperalgesia and Allodynia [See Warnings and Precautions (5.8) ] Serotonin Syndrome [see Warnings and Precautions (5.9) ] Seizures [see Warnings and Precautions (5.10) ] Suicide [see Warnings and Precautions (5.11) ] Adrenal Insufficiency [see Warnings and Precautions (5.13) ] Severe Hypotension [see Warnings and Precautions (5.14) ] Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.16) ] Hypersensitivity Reactions [see Warnings and Precautions (5.17) ] Withdrawal [see Warnings and Precautions (5.18) ] The most common incidence of treatment-emergent adverse events (≥15.0%) in patients from clinical trials were dizziness/vertigo, nausea, constipation, headache, somnolence, vomiting and pruritus (6).

To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 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 tablets was administered to 550 patients during the double-blind or open-label extension periods in U.S. studies of chronic nonmalignant pain. Of these patients, 375 were 65 years old or older.

Table 1 reports the cumulative incidence rate of adverse reactions by 7, 30 and 90 days for the most frequent reactions (5% or more by 7 days). The most frequently reported events were in the central nervous system and gastrointestinal system. Although the reactions listed in the table are felt to be probably related to tramadol hydrochloride tablets administration, the reported rates also include some events that may have been due to underlying disease or concomitant medication.

The overall incidence rates of adverse experiences in these trials were similar for tramadol hydrochloride tablets and the active control groups, TYLENOL with Codeine #3 (acetaminophen 300 mg with codeine phosphate 30 mg), and aspirin 325 mg with codeine phosphate 30 mg, however, the rates of withdrawals due to adverse events appeared to be higher in the tramadol hydrochloride tablets groups. Table 1: Cumulative Incidence of Adverse Reactions for Tramadol Hydrochloride Tablets in Chronic Trials of Nonmalignant Pain (N=427) 1 “CNS Stimulation” is a composite of nervousness, anxiety, agitation, tremor, spasticity, euphoria, emotional lability and hallucinations Up to 7 Days Up to 30 Days Up to 90 Days Dizziness/Vertigo 26% 31% 33% Nausea 24% 34% 40% Constipation 24% 38% 46% Headache 18% 26% 32% Somnolence 16% 23% 25% Vomiting 9% 13% 17% Pruritus 8% 10% 11% “CNS Stimulation” 1 7% 11% 14% Asthenia 6% 11% 12% Sweating 6% 7% 9% Dyspepsia 5% 9% 13% Dry Mouth 5% 9% 10% Diarrhea 5% 6% 10% Incidence 1% to Less than 5% Possibly Causally Related The following lists adverse reactions that occurred with an incidence of 1% to less than 5% in clinical trials, and for which the possibility of a causal relationship with tramadol hydrochloride tablets exists.

Body as a Whole : Malaise. Cardiovascular : Vasodilation. Central Nervous System : Anxiety, Confusion, Coordination disturbance, Euphoria, Miosis, Nervousness, Sleep disorder.

Gastrointestinal : Abdominal pain, Anorexia, Flatulence. Musculoskeletal : Hypertonia. S… [Excerpted — this section continues on DailyMed.]

🔄 Drug Interactions ~3 min read ▾

7 DRUG INTERACTIONS Table 2: Clinically Significant Drug Interactions with Tramadol Hydrochloride Tablets Inhibitors of CYP2D6 Clinical Impact: The concomitant use of tramadol hydrochloride tablets and CYP2D6 inhibitors may result in an increase in the plasma concentration of tramadol and a decrease in the plasma concentration of M1, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride tablets 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. This could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity, such as potentially fatal respiratory depression [see Clinical Pharmacology (12.3) ] .

Intervention: If concomitant use of a CYP2D6 inhibitor is necessary, evaluate patients at frequent intervals for adverse reactions including opioid withdrawal, seizures and serotonin syndrome. If a CYP2D6 inhibitor is discontinued, consider lowering tramadol hydrochloride tablets dosage until stable drug effects are achieved. Evaluate patients at frequent intervals for adverse events including respiratory depression and sedation.

Examples: Quinidine, fluoxetine, paroxetine and bupropion Inhibitors of CYP3A4 Clinical Impact: The concomitant use of tramadol hydrochloride tablets and CYP3A4 inhibitors can increase the plasma concentration of tramadol and may result in a greater amount of metabolism via CYP2D6 and greater levels of M1. Follow patients closely for increased risk of serious adverse events including seizures and serotonin syndrome, and adverse reactions related to opioid toxicity including potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride tablets are achieved.

After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease [see Clinical Pharmacology (12.3) ] , resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to tramadol. Intervention: If concomitant use is necessary, consider dosage reduction of tramadol hydrochloride tablets until stable drug effects are achieved. Inform patients and caregivers of this potential interaction, educate them on the signs and symptoms of seizures, serotonin syndrome, and signs of respiratory depression and sedation.

If a CYP3A4 inhibitor is discontinued, consider increasing the tramadol hydrochloride tablets dosage until stable drug effects are achieved and evaluate patients at frequent intervals for signs and symptoms of opioid withdrawal. Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir) CYP3A4 Inducers Clinical Impact: The concomitant use of tramadol hydrochloride tablets and CYP3A4 inducers can decrease the plasma concentration of tramadol [see Clinical Pharmacology (12.3) ] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to tramadol.

After stopping a CYP3A4 inducer, as the effects of the inducer decline, the tramadol plasma concentration will increase [see Clinical Pharmacology (12.3) ] , which could increase or prolong both the therapeutic effects and adverse reactions, and may cause seizures, serotonin syndrome, and/or potentially fatal respiratory depression. Intervention: If concomitant use is necessary, consider increasing… [Excerpted — this section continues on DailyMed.]

👥 Use in Specific Populations ~3 min read ▾

8 USE IN SPECIFIC POPULATIONS Pregnancy : May cause fetal harm ( 8.1 ). Lactation : Breastfeeding not recommended ( 8.2 ).

8.1Pregnancy Risk Summary Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.4) ]. Available data with tramadol hydrochloride tablets in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, tramadol administration during organogenesis decreased fetal weights and reduced ossification in mice, rats, and rabbits at 1.4, 0.6, and 3.6 times the maximum recommended human daily dosage (MRHD).

Tramadol decreased pup body weight and increased pup mortality at 1.2 and 1.9 times the MRHD [see Data] . Based on animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in respiratory depression and physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.

Neonatal opioid withdrawal syndrome can present as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms and signs of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.4) ] .

Neonatal seizures, neonatal withdrawal syndrome, fetal death and still birth have been reported during postmarketing. Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid overdose reversal agent, such as naloxone or nalmefene, must be available for reversal of opioid-induced respiratory depression in the neonate.

Tramadol hydrochloride tablets are not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including tramadol hydrochloride tablets, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor.

Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Tramadol has been shown to cross the placenta. The mean ratio of serum tramadol in the umbilical veins compared to maternal veins was 0.83 for 40 women given tramadol during labor.

The effect of tramadol hydrochloride tablets, if any, on the later growth, development, and functional maturation of the child is unknown. Data Animal Data Tramadol has been shown to be embryotoxic and fetotoxic in mice, (120 mg/kg), rats (25 mg/kg) and rabbits (75 mg/kg) at maternally toxic dosages, but was not teratogenic at these dose levels. These doses on a mg/m 2 basis are 1.4, 0.6, and 3.6 times the maximum recommended human daily dosage (MRHD) for mouse, rat and rabbit, respectively.

No drug-related teratogenic effects were observed in progeny of mice (up to 140 mg/kg), rats (up to 80 mg/kg) or rabbits (up to 300 mg/kg) treated with tramadol by various routes. Embryo and fetal toxicity consisted pr… [Excerpted — this section continues on DailyMed.]

🤰 Pregnancy ~3 min read ▾

8.1Pregnancy Risk Summary Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.4) ]. Available data with tramadol hydrochloride tablets in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, tramadol administration during organogenesis decreased fetal weights and reduced ossification in mice, rats, and rabbits at 1.4, 0.6, and 3.6 times the maximum recommended human daily dosage (MRHD).

Tramadol decreased pup body weight and increased pup mortality at 1.2 and 1.9 times the MRHD [see Data] . Based on animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in respiratory depression and physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.

Neonatal opioid withdrawal syndrome can present as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms and signs of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.4) ] .

Neonatal seizures, neonatal withdrawal syndrome, fetal death and still birth have been reported during postmarketing. Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid overdose reversal agent, such as naloxone or nalmefene, must be available for reversal of opioid-induced respiratory depression in the neonate.

Tramadol hydrochloride tablets are not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including tramadol hydrochloride tablets, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor.

Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Tramadol has been shown to cross the placenta. The mean ratio of serum tramadol in the umbilical veins compared to maternal veins was 0.83 for 40 women given tramadol during labor.

The effect of tramadol hydrochloride tablets, if any, on the later growth, development, and functional maturation of the child is unknown. Data Animal Data Tramadol has been shown to be embryotoxic and fetotoxic in mice, (120 mg/kg), rats (25 mg/kg) and rabbits (75 mg/kg) at maternally toxic dosages, but was not teratogenic at these dose levels. These doses on a mg/m 2 basis are 1.4, 0.6, and 3.6 times the maximum recommended human daily dosage (MRHD) for mouse, rat and rabbit, respectively.

No drug-related teratogenic effects were observed in progeny of mice (up to 140 mg/kg), rats (up to 80 mg/kg) or rabbits (up to 300 mg/kg) treated with tramadol by various routes. Embryo and fetal toxicity consisted primarily of decreased fetal weights, decreased skeletal ossification and increased supernumerary ribs at maternally toxic do… [Excerpted — this section continues on DailyMed.]

🧒 Pediatric Use 212 words ▾

8.4Pediatric Use The safety and effectiveness of tramadol hydrochloride tablets in pediatric patients have not been established. Life-threatening respiratory depression and death have occurred in children who received tramadol [see Warnings and Precautions (5.6) ] . 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 tablets are contraindicated for all children younger than 12 years of age [see Contraindications (4) ] . Tramadol hydrochloride tablets are contraindicated for postoperative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications (4) ] .

Avoid the use of tramadol hydrochloride tablets in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression.

🧓 Geriatric Use ~1 min read ▾

8.5Geriatric Use A total of 455 elderly (65 years of age or older) subjects were exposed to tramadol hydrochloride tablets in controlled clinical trials. Of those, 145 subjects were 75 years of age and older. In studies including geriatric patients, treatment-limiting adverse events were higher in subjects over 75 years of age compared to those under 65 years of age.

Specifically, 30% of those over 75 years of age had gastrointestinal treatment-limiting adverse events compared to 17% of those under 65 years of age. Constipation resulted in discontinuation of treatment in 10% of those over 75. Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration.

Titrate the dosage of tramadol hydrochloride tablets slowly in geriatric patients starting at the low end of the dosing range and frequently reevaluate the patient 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 regularly evaluate renal function.

🆘 Overdosage ~2 min read ▾

10 OVERDOSAGE Clinical Presentation Acute overdosage with tramadol hydrochloride tablets can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and in some cases, pulmonary edema, bradycardia, hypotension, hypoglycemia, 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) ] . Toxic leukoencephalopathy has been reported after opioid overdose and can present hours, days, or weeks after apparent recovery from the initial intoxication.

Deaths due to overdose have been reported with abuse and misuse of tramadol [see Warnings and Precautions (5.1) ; Drug Abuse and Dependence (9.2) ] . Review of case reports has indicated that the risk of fatal overdose is further increased when tramadol is abused concurrently with alcohol or other CNS depressants, including other opioids. Treatment of Overdose In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed.

Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or serious arrhythmias will require advanced life-supporting measures. Because strategies for the management of overdose are continually evolving, it is advisable to contact a poison control center (where available) to determine the latest recommendations for the management of an overdose.

For clinically significant respiratory or circulatory depression secondary to morphine overdose, administer an opioid overdose reversal agent such as naloxone or nalmefene. While an opioid overdose reversal agent will reverse some, but not all, symptoms caused by overdosage with tramadol, the risk of seizures is also increased with reversal agent administration. In animals, convulsions following the administration of toxic doses of tramadol hydrochloride could be suppressed with barbiturates or benzodiazepines but were increased with naloxone.

Naloxone administration did not change the lethality of an overdose in mice. Hemodialysis is not expected to be helpful in an overdose because it removes less than 7% of the administered dose in a 4-hour dialysis period. Because the duration of opioid reversal is expected to be less than the duration of action of tramadol in tramadol hydrochloride tablets, carefully monitor the patient until spontaneous respiration is reliably re-established.

If the response to an opioid overdose reversal agent is suboptimal or only brief in nature, administer additional reversal agent as directed by the product’s prescribing information. In an individual physically dependent on opioids, administration of the recommended dosage of the opioid overdose reversal agent 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 reversal agent administered.

If a decision is made to treat serious respiratory depression in the physically-dependent patient, administration of the reversal agent should begin with care and by titration with smaller than usual doses of the reversal agent.

🧬 Clinical Pharmacology ~3 min read ▾

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Tramadol hydrochloride tablets contains tramadol, an opioid agonist and inhibitor of norepinephrine and serotonin re-uptake. Although the mode of action is not completely understood, the analgesic effect of tramadol is believed to be due to both binding to μ-opioid receptors and weak inhibition of re-uptake of norepinephrine and serotonin. Opioid activity is due to both low affinity binding of the parent compound and higher affinity binding of the O -demethylated metabolite M1 to μ-opioid receptors.

In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in μ-opioid binding. Tramadol-induced analgesia is only partially antagonized by the opioid antagonist naloxone in several animal tests. The relative contribution of both tramadol and M1 to human analgesia is dependent upon the plasma concentrations of each compound [see Clinical Pharmacology (12.2) ] .

Analgesia in humans begins approximately within one hour after administration and reaches a peak in approximately two to three hours.

12.2Pharmacodynamics 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 administration may produce a constellation of symptoms including nausea and vomiting, dizziness, and somnolence.

Tramadol causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

Effects on the Gastrointestinal Tract and Other Smooth Muscle Tramadol causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation.

Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, transient elevations in serum amylase, and opioid-induced esophageal dysfunction (OIED). Effects on the Cardiovascular System Tramadol produces peripheral vasodilation, which may result in orthostatic hypotension or syncope. Manifestations of peripheral vasodilation may include pruritus, flushing, red eyes, sweating and/or orthostatic hypotension.

The effect of oral tramadol on the QTcF interval was evaluated in a double-blind, randomized, four-way crossover, placebo- and positive- (moxifloxacin) controlled study in 68 adult male and female healthy subjects. At a 600 mg/day dose (1.5-fold the maximum immediate-release daily dose), the study demonstrated no significant effect on the QTcF interval. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans.

They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon [see Warnings and Precautions (5.13) ; Adverse Reactions (6) ] . Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6) ] .

Effects on the Immune System Opioids have… [Excerpted — this section continues on DailyMed.]

🧬 Mechanism of Action 164 words ▾

12.1Mechanism of Action Tramadol hydrochloride tablets contains tramadol, an opioid agonist and inhibitor of norepinephrine and serotonin re-uptake. Although the mode of action is not completely understood, the analgesic effect of tramadol is believed to be due to both binding to μ-opioid receptors and weak inhibition of re-uptake of norepinephrine and serotonin. Opioid activity is due to both low affinity binding of the parent compound and higher affinity binding of the O -demethylated metabolite M1 to μ-opioid receptors.

In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in μ-opioid binding. Tramadol-induced analgesia is only partially antagonized by the opioid antagonist naloxone in several animal tests. The relative contribution of both tramadol and M1 to human analgesia is dependent upon the plasma concentrations of each compound [see Clinical Pharmacology (12.2) ] .

Analgesia in humans begins approximately within one hour after administration and reaches a peak in approximately two to three hours.

📦 How Supplied / Storage and Handling 85 words ▾

16 HOW SUPPLIED/STORAGE AND HANDLING Tramadol Hydrochloride Tablets USP, 50 mg are white to off-white, capsule shaped coated tablet debossed 'T' on one side and ‘0’ & ‘3’ separated with score line (functional) on other side. Bottles of 100 NDC 59651-441-01 Bottles of 500 NDC 59651-441-05 Bottles of 1,000 NDC 59651-441-99 Dispense in a tight container. Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Store tramadol hydrochloride tablets securely and dispose of properly [see Patient Counseling Information (17) ] .

📋 Description 121 words ▾

11 DESCRIPTION Tramadol hydrochloride tablets, USP for oral use, are an opioid agonist. The chemical name for tramadol hydrochloride is (±) cis -2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochloride. The structural formula is: The molecular weight of tramadol hydrochloride is 299.8.

Tramadol hydrochloride USP is a white, crystalline powder. It is readily soluble in water and ethanol and has a pKa of 9.41. The n-octanol/water log partition coefficient (logP) is 1.35 at pH 7.

Tramadol hydrochloride tablets, USP contain 50 mg of tramadol hydrochloride USP (equivalent to 43.9 mg of tramadol) and are a white, crystalline powder. Inactive ingredients in the tablet are carnauba wax, corn starch, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate, povidone, sodium starch glycolate, and titanium dioxide. structure

💬 Information for Patients ~3 min read ▾

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 tablets securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Inform patients that leaving tramadol hydrochloride tablets unsecured can pose a deadly risk to others in the home [see Warnings and Precautions (5.1 , 5.18) , Drug Abuse and Dependence (9.2) ].

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 Drug Enforcement Administration (DEA)-registered collectors are available, instruct patients to dispose of tramadol hydrochloride tablets by following these four steps: Mix tramadol hydrochloride 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 tablets, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.1 )] . Instruct patients not to share tramadol hydrochloride tablets with others and to take steps to protect tramadol hydrochloride tablets from theft or misuse.

Life-Threatening Respiratory Depression Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting tramadol hydrochloride tablets or when the dosage is increased, and that it can occur even at recommended dosages. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Warnings and Precautions (5.2) ] .

Accidental Ingestion Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions (5.2) ] . Interactions with Benzodiazepines and Other CNS Depressants Inform patients and caregivers that potentially fatal additive effects may occur if tramadol hydrochloride tablets are used with benzodiazepines or other CNS depressants, including alcohol (e.g., non-benzodiazepine, sedative/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids), and not to use these concomitantly unless supervised by a healthcare provider [see Warnings and Precautions (5.3) ; Drug Interactions (7) ] .

Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose.

Discuss with the patient the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program) [see Dosage and Administration (2.2) , Warnings and Precautions (5.3) ] . Educate patients and caregivers on how… [Excerpted — this section continues on DailyMed.]

💬 Medication Guide ~3 min read ▾

MEDICATION GUIDE Tramadol Hydrochloride (tram’ a dol hye’’ droe klor’ ide) Tablets, USP CIV Tramadol hydrochloride tablets are: A strong prescription pain medicine that contains an opioid (narcotic) that is used for the management pain in adults, when other pain treatments such as non-opioid pain medicines do not treat your pain well enough or you cannot tolerate them. An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.

Important information about tramadol hydrochloride tablets: Get emergency help or call 911 right away if you take too much tramadol hydrochloride tablets (overdose). When you first start taking tramadol hydrochloride tablets, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur. Ask your healthcare provider about medicines like naloxone or nalmefene that can be used in an emergency to reverse an opioid overdose.

Taking tramadol hydrochloride tablets with other opioid medicines, benzodiazepines, gabapentinoids (gabapentin or pregabalin), alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death. Never give anyone else your tramadol hydrochloride tablets. They could die from taking it.

Selling or giving away tramadol hydrochloride tablets is against the law. Store tramadol hydrochloride 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 tablets to a child younger than 12 years of age.

Do not give tramadol hydrochloride tablets to a child younger than 18 years of age after surgery to remove the tonsils and/or adenoids. Avoid giving tramadol hydrochloride tablets to children between 12 to 18 years of age who have risk factors for breathing problems such as obstructive sleep apnea, obesity, or underlying lung problems. Do not take tramadol hydrochloride tablets if you have: Severe asthma, trouble breathing, or other lung problems.

A bowel blockage or have narrowing of the stomach or intestines. An allergy to tramadol. Taken a Monoamine Oxidase Inhibitor, MAOI, (medicine used for depression) within the last 14 days.

Before taking tramadol hydrochloride tablets, tell your healthcare provider if you have a history of: head injury, seizures liver, kidney, thyroid problems problems urinating pancreas or gallbladder problems abuse of street or prescription drugs, alcohol addiction, opioid overdose, or mental health problems. Tell your healthcare provider if you are: noticing your pain getting worse. If your pain gets worse after you take tramadol hydrochloride tablets, do not take more of tramadol hydrochloride tablets without first talking to your healthcare provider.

Talk to your healthcare provider if the pain that you have increases, if you feel more sensitive to pain, or if you have new pain after taking tramadol hydrochloride tablets. pregnant or planning to become pregnant . Use of tramadol hydrochloride tablets for an extended period of time 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. living in a household where there are small children or someone who has abused street or prescription drugs. taking prescription or over-the-counter medicines, vitamins, or herbal supplements.

Taking tramadol hydrochloride tablets with certain other medicines can cause serious side effects that could lead to death. When taking tramadol hydrochloride tablets: Do not change your dose. Take tramadol hydrochloride tablets exactly as prescribed by your healthcare provider.

Use the lowest do… [Excerpted — this section continues on DailyMed.]

🧬 Pharmacokinetics ~3 min read ▾

12.3Pharmacokinetics The analgesic activity of tramadol hydrochloride tablets are due to both parent drug and the M1 metabolite [see Clinical Pharmacology (12.1 , 12.2) ] . Tramadol is administered as a racemate and both the [-] and [+] forms of both tramadol and M1 are detected in the circulation. Linear pharmacokinetics have been observed following multiple doses of 50 and 100 mg to steady-state.

Absorption The mean absolute bioavailability of a 100 mg oral dose is approximately 75%. The mean peak plasma concentration of racemic tramadol and M1 occurs at two and three hours, respectively, after administration in healthy adults. In general, both enantiomers of tramadol and M1 follow a parallel time course in the body following single and multiple doses although small differences (~ 10%) exist in the absolute amount of each enantiomer present.

Steady-state plasma concentrations of both tramadol and M1 are achieved within two days with four times per day dosing. There is no evidence of self-induction (see Figure 1 and Table 3 below). Figure 1: Mean Tramadol and M1 Plasma Concentration Profiles after a Single 100 mg Oral Dose and after Twenty-Nine 100 mg Oral Doses of Tramadol HCl given four times per day.

Table 3: Mean (%CV) Pharmacokinetic Parameters for Racemic Tramadol and M1 Metabolite a SD = Single dose, MD = Multiple dose, p.o.= Oral administration, i.v.= Intravenous administration, q.i.d. = Four times daily b F represents the oral bioavailability of tramadol c Not applicable d Not measured Population/Dosage Regimen a Parent Drug/ Metabolite Peak Conc.(ng/mL) Time to Peak (hrs) Clearance/F b (mL/min/Kg) t 1/2 (hrs) Healthy Adults, 100 mg qid, MD p.o. Tramadol M1 592 (30) 110 (29) 2.3 (61) 2.4 (46) 5.90 (25) c 6.7 (15) 7.0 (14) Healthy Adults, 100 mg SD p.o.

Tramadol M1 308 (25) 55.0 (36) 1.6 (63) 3.0 (51) 8.50 (31) c 5.6 (20) 6.7 (16) Geriatric, (>75 yrs) 50 mg SD p.o. Tramadol M1 208 (31) d 2.1 (19) d 6.89 (25) c 7.0 (23) d Hepatic Impaired, 50 mg SD p.o. Tramadol M1 217 (11) 19.4 (12) 1.9 (16) 9.8 (20) 4.23 (56) c 13.3 (11) 18.5 (15) Renal Impaired, CLcr10 to 30 mL/min 100 mg SD i.v.

Tramadol M1 c c c c 4.23 (54) c 10.6 (31) 11.5 (40) Renal Impaired, CLcr<5 mL/min 100 mg SD i.v. Tramadol M1 c c c c 3.73 (17) c 11.0 (29) 16.9 (18) Food Effects Oral administration of tramadol hydrochloride tablets with food does not significantly affect its rate or extent of absorption, therefore, tramadol hydrochloride tablets can be administered without regard to food. Distribution The volume of distribution of tramadol was 2.6 and 2.9 liters/kg in male and female subjects, respectively, following a 100 mg intravenous dose.

The binding of tramadol to human plasma proteins is approximately 20% and binding also appears to be independent of concentration up to 10 mcg/mL. Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range. Elimination Tramadol is eliminated primarily through metabolism by the liver and the metabolites are eliminated primarily by the kidneys.

The mean (%CV) apparent total clearance of tramadol after a single 100 mg oral dose is 8.50 (31) mL/min/kg. The mean terminal plasma elimination half-lives of racemic tramadol and racemic M1 are 6.3 ± 1.4 and 7.4 ± 1.4 hours, respectively. The plasma elimination half-life of racemic tramadol increased from approximately six hours to seven hours upon multiple dosing.

Metabolism Tramadol is extensively metabolized after oral administration by a number of pathways, including CYP2D6 and CYP3A4, as well as by conjugation of parent and metabolites. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The remainder is excreted either as unidentified or as unextractable metabolites.

The major metabolic pathways appear to be N - and O -demethylation and glucuronidation or sulfation in the liver. One metabolite ( O -desmethyltramadol, denoted M1) is pharmacologically act… [Excerpted — this section continues on DailyMed.]

🧬 Pharmacodynamics ~3 min read ▾

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 administration may produce a constellation of symptoms including nausea and vomiting, dizziness, and somnolence.

Tramadol causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

Effects on the Gastrointestinal Tract and Other Smooth Muscle Tramadol causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation.

Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, transient elevations in serum amylase, and opioid-induced esophageal dysfunction (OIED). Effects on the Cardiovascular System Tramadol produces peripheral vasodilation, which may result in orthostatic hypotension or syncope. Manifestations of peripheral vasodilation may include pruritus, flushing, red eyes, sweating and/or orthostatic hypotension.

The effect of oral tramadol on the QTcF interval was evaluated in a double-blind, randomized, four-way crossover, placebo- and positive- (moxifloxacin) controlled study in 68 adult male and female healthy subjects. At a 600 mg/day dose (1.5-fold the maximum immediate-release daily dose), the study demonstrated no significant effect on the QTcF interval. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans.

They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon [see Warnings and Precautions (5.13) ; Adverse Reactions (6) ] . Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6) ] .

Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

Concentration–Efficacy Relationships The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with opioid agonists. The minimum effective analgesic concentration of tramadol for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance [see Dosage and Administration (2) ] . Concentration–Adverse Reaction Relationships There is a relationship between increasing tramadol plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression.

In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration (2) ]… [Excerpted — this section continues on DailyMed.]

🔬 Clinical Studies ~2 min read ▾

14 CLINICAL STUDIES Tramadol hydrochloride tablets has been given in single oral doses of 50, 75 and 100 mg to patients with pain following surgical procedures and pain following oral surgery (extraction of impacted molars). In single-dose models of pain following oral surgery, pain relief was demonstrated in some patients at doses of 50 mg and 75 mg. A dose of 100 mg tramadol hydrochloride tablets tended to provide analgesia superior to codeine sulfate 60 mg, but it was not as effective as the combination of aspirin 650 mg with codeine phosphate 60 mg.

Tramadol hydrochloride tablets has been studied in three long-term controlled trials involving a total of 820 patients, with 530 patients receiving tramadol hydrochloride tablets. Patients with a variety of chronic painful conditions were studied in double-blind trials of one to three months duration. Average daily doses of approximately 250 mg of tramadol hydrochloride tablets in divided doses were generally comparable to five doses of acetaminophen 300 mg with codeine phosphate 30 mg (TYLENOL with Codeine #3) daily, five doses of aspirin 325 mg with codeine phosphate 30 mg daily, or two to three doses of acetaminophen 500 mg with oxycodone hydrochloride 5 mg (TYLOX) daily.

Titration Trials In a randomized, blinded clinical study with 129 to 132 patients per group, a 10-day titration to a daily tramadol hydrochloride tablets dose of 200 mg (50 mg four times per day), attained in 50 mg increments every 3 days, was found to result in fewer discontinuations due to dizziness or vertigo than titration over only 4 days or no titration. In a second study with 54 to 59 patients per group, patients who had nausea or vomiting when titrated over 4 days were randomized to re-initiate tramadol hydrochloride tablets therapy using slower titration rates.

A 16-day titration schedule, starting with 25 mg every morning and using additional doses in 25 mg increments every third day to 100 mg/day (25 mg four times per day), followed by 50 mg increments in the total daily dose every third day to 200 mg/day (50 mg four times per day), resulted in fewer discontinuations due to nausea or vomiting and fewer discontinuations due to any cause than did a 10-day titration schedule. Figure 2: Clinical Studies Section

🔒 Drug Abuse and Dependence ~3 min read ▾

9 DRUG ABUSE AND DEPENDENCE

9.1Controlled Substance Tramadol hydrochloride tablets contain tramadol, a Schedule IV controlled substance.

9.2Abuse Tramadol hydrochloride tablets contains tramadol, a substance with potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions (5.1) ]. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Misuse and abuse of tramadol hydrochloride tablets increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death.

The risk is increased with concurrent abuse of tramadol hydrochloride tablets with alcohol and other CNS depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction.

All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of tramadol hydrochloride tablets abuse include those with a history of prolonged use of any opioid, including products containing tramadol, those with a history of drug or alcohol abuse, or those who use tramadol hydrochloride tablets in combination with other abused drugs. “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 provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control.

Tramadol hydrochloride tablets like other opioids, can be diverted for nonmedical 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 reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Risks Specific to Abuse of Tramadol hydrochloride tablets Abuse of tramadol hydrochloride tablets poses a risk of overdose and death. The risk is increased with concurrent use of tramadol hydrochloride tablets with alcohol and/or other CNS depressants. Tramadol hydrochloride tablets are approved for oral use only.

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 use of opioid therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Physical dependence is… [Excerpted — this section continues on DailyMed.]

🔒 Controlled Substance 13 words ▾

9.1Controlled Substance Tramadol hydrochloride tablets contain tramadol, a Schedule IV controlled substance.

🧪 Nonclinical Toxicology 210 words ▾

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis A slight, but statistically significant, increase in two common murine tumors, pulmonary and hepatic, was observed in an NMRI mouse carcinogenicity study, particularly in aged mice. Mice were dosed orally up to 30 mg/kg in the drinking water (0.36 times the MRHD) for approximately two years, although the study was not done with the Maximum Tolerated Dose. This finding is not believed to suggest risk in humans.

No evidence of carcinogenicity was noted in a rat 2-year carcinogenicity study testing oral doses of up to 30 mg/kg in the drinking water, 0.73 times the MRHD. Mutagenesis Tramadol was mutagenic in the presence of metabolic activation in the mouse lymphoma assay. Tramadol was not mutagenic in the in vitro bacterial reverse mutation assay using Salmonella and E. coli (Ames), the mouse lymphoma assay in the absence of metabolic activation, the in vitro chromosomal aberration assay, or the in vivo micronucleus assay in bone marrow.

Impairment of Fertility No effects on fertility were observed for tramadol at oral dose levels up to 50 mg/kg in male rats and 75 mg/kg in female rats. These dosages are 1.2 and 1.8 times the maximum recommended human daily dose based on body surface area, respectively.

📄 Carcinogenesis, Mutagenesis, Impairment of Fertility 207 words ▾

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis A slight, but statistically significant, increase in two common murine tumors, pulmonary and hepatic, was observed in an NMRI mouse carcinogenicity study, particularly in aged mice. Mice were dosed orally up to 30 mg/kg in the drinking water (0.36 times the MRHD) for approximately two years, although the study was not done with the Maximum Tolerated Dose. This finding is not believed to suggest risk in humans.

No evidence of carcinogenicity was noted in a rat 2-year carcinogenicity study testing oral doses of up to 30 mg/kg in the drinking water, 0.73 times the MRHD. Mutagenesis Tramadol was mutagenic in the presence of metabolic activation in the mouse lymphoma assay. Tramadol was not mutagenic in the in vitro bacterial reverse mutation assay using Salmonella and E. coli (Ames), the mouse lymphoma assay in the absence of metabolic activation, the in vitro chromosomal aberration assay, or the in vivo micronucleus assay in bone marrow.

Impairment of Fertility No effects on fertility were observed for tramadol at oral dose levels up to 50 mg/kg in male rats and 75 mg/kg in female rats. These dosages are 1.2 and 1.8 times the maximum recommended human daily dose based on body surface area, respectively.

📄 Recent Major Changes 34 words ▾

Boxed Warning 08/2025 Indications and Usage ( 1 ) 08/2025 Dosage and Administration ( 2.2 , 2.5 ) 08/2025 Warnings and Precautions ( 5.1 , 5.2 , 5.3 , 5.16 , 5.18 ) 08/2025

📄 Package Label / Principal Display Panel 35 words ▾

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 50 mg (100 Tablets Bottle) NDC 59651-441-01 Rx only traMADOL Hydrochloride Tablets, USP CIV 50 mg PHARMACIST: Dispense the Medication Guide provided separately to each patient. AUROBINDO 100 Tablets tramadol-fig3

Source: FDA Structured Product Labeling, mirrored from DailyMed / openFDA. Prefer the government’s original formatting? View this label on DailyMed ↗
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This drug has a REMS. A Risk Evaluation & Mitigation Strategy is an FDA-required safety program. It may require enrollment, counseling, or monitoring to manage a serious risk. See the boxed warning & full label below, and REMS@FDA ↗.

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The pricing shown on our NDC pages comes from CMS NADAC, a voluntary survey of retail community pharmacy invoices. CMS does not publish a NADAC for every NDC — packages outside the retail survey (institutional and hospital products, bulk packages, discontinued items, and many OTC items) may never receive one. A missing price reflects the survey's scope, not this product's actual cost, and does not mean the product is free or unavailable.
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Yes, per the latest FDA NDC Directory data on this page: this package is listed as actively marketed, with no marketing end date reported by Aurobindo Pharma Limited. Listing status can change — the directory data on this page refreshes weekly.
Does this product come in other package sizes?
Yes — the FDA directory lists 3 other package presentations of this same product, including 100 tablets (59651-0441-01), 1000 tablets (59651-0441-99), 10000 tablets (59651-0441-19). Each has its own NDC and its own page — see the package list near the top of this page.
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Aurobindo Pharma Limited is the labeler of record for this NDC — the company under whose FDA-assigned code the package is listed. The labeler may be the manufacturer itself or a distributor marketing the product under its own code.
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← 59651-0440-39 · Aurobindo 59651-0444-01 · Aurobindo →
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