TRAMCETA LP

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 hydrochloride is 299.84.

It is a white, crystalline powder that is freely soluble in water and methanol, very slightly soluble in acetone 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 mg, 200 mg or 300 mg of tramadol hydrochloride, USP in an extended-release formulation.

The tablets are white in color and contain the inactive ingredients pregelatinized maize starch, hypromellose, mannitol, magnesium stearate, cellulose acetate and polyethylene glycol.

Imprinting ink contains, shellac glaze, iron oxide black, N-butyl alcohol, ammonium hydroxide and propylene glycol.

USP dissolution test 4. tramadol-structure.

Tramadol hydrochloride extended-release tablets are indicated for the management of severe and persistent pain that requires an opioid analgesic and that cannot be adequately treated with alternative options, including immediate-release opioids.

Limitations of

• Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosages or duration, and persist over the course of therapy, , reserve opioid analgesics, including tramadol hydrochloride extended-release 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 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 severe and persistent pain that requires an opioid analgesic and that cannot be adequately treated with alternative options, including immediate-release opioids.

Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosages or duration and persist over the course of therapy, reserve opioids analgesics, including tramadol hydrochloride extended-release 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 extended-release tablets are not indicated as an as-needed (prn) analgesic.

Tramadol hydrochloride extended-release tablets contain 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. 12.2 Pharmacodynamics Effects on the Central Nervous System Tramadol produces respiratory depression by direct action on brain stem respiratory centers.

The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.

Tramadol causes miosis, even in total darkness.

Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings).

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

Effects on the Gastrointestinal Tract and Other Smooth Muscle Tramadol causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum.

Digestion of food in the small intestine is delayed and propulsive contractions are decreased.

Propulsive peristaltic waves in the colon are decreased, while tone 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).

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.

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.

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.

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 extended-release agonist opioids.

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.

Concentration–Adverse Reaction Relationships There is a relationship between increasing tramadol plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression.

In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions. 12.3 Pharmacokinetics The analgesic activity of tramadol is due to both parent drug and the M1 metabolite.

Tramadol hydrochloride extended-release 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 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.

In healthy subjects, the bioavailability of a tramadol hydrochloride extended-release tablet 200 mg administered once daily relative to a 50 mg immediate-release (IR) tablet administered every six hours was approximately 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.

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 tablet 200 mg administered once daily and tramadol HCl IR 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 Tramadol hydrochloride 50 mg Tablet Tramadol hydrochloride extended-release 200 mg Tablet Tramadol hydrochloride 50 mg Tablet Once-Daily Every 6 Hours Once-Daily Every 6 Hours AUC 0-24 (ng∙h/mL) 5975 6613 1890 2095 C max (ng/mL) 335 383 95 104 C min (ng/mL) 187 228 69 82 T max (h) 12 1.5 15 1.9 % Fluctuation 61 59 34 26 AUC 0-24: 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 IR Tablets Every 6 Hours.

After a single dose administration of 200 mg tramadol hydrochloride extended-release tablet with a high fat meal, the C max and AUC 0-∞ of tramadol decreased 28% and 16%, respectively, compared to fasting conditions.

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.

The volume of distribution of tramadol was 2.6 and 2.9 L/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.

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 administration of tramadol hydrochloride extended-release tablets are approximately 7.9 and 8.8 hours, respectively.

Tramadol is extensively metabolized after oral administration.

The metabolic pathways appear to be

N – demethylation (mediated by CYP3A4 and CYP2D6), O – demethylation (mediated by CYP2D6) and glucuronidation or sulfation in the liver.

CYP2D6 metabolite, O-desmethyl tramadol, (denoted M1) is observed to be 6 times more potent than tramadol in producing analgesia and 200 times more potent in μ-opioid binding in animal models.

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.

Pharmacokinetics of tramadol was studied in patients with mild or moderate hepatic impairment after receiving multiple doses of tramadol hydrochloride extended-release tablets 100 mg. The exposure of (+).

• and (-)-tramadol was similar in mild and moderate hepatic impairment patients in comparison to patients with normal hepatic function.

However, exposure of active metabolite (+).

• and (-)-M1 decreased ~50% with increased severity of the hepatic impairment (from normal to mild and moderate).

The pharmacokinetics of tramadol after the administration of tramadol hydrochloride extended-release tablets has not been studied in patients with severe hepatic impairment (Child-Pugh Class C).

After the administration of tramadol

IR tablets to patients with advanced cirrhosis of the liver, tramadol exposure was increased and the tramadol and M1 half-lives were longer than patients with normal hepatic function.

Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1.

The pharmacokinetics of tramadol were studied in patients with mild or moderate renal impairment after receiving multiple doses of tramadol hydrochloride extended-release tablets 100 mg. There is no consistent trend observed for tramadol exposure related to renal function in patients with mild (CL cr: 50 to 80 mL/min) or moderate (CL cr: 30 to 50 mL/min) renal impairment in comparison to patients with normal renal function.

However, exposure of M1 increased to 40% with increased severity of the renal impairment (from normal to mild and moderate).

Tramadol hydrochloride extended-release tablets have not been studied in patients with severe renal im.

The following serious or otherwise important adverse reactions are described in greater detail, in other sections: Addiction, Abuse, and Misuse Life-Threatening Respiratory Depression Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-Threatening Respiratory Depression in Children Neonatal Opioid Withdrawal Syndrome Interactions with Benzodiazepines and Other CNS Depressants Opioid-Induced Hyperalgesia and Allodynia Serotonin Syndrome Seizures Suicide Adrenal Insufficiency Severe Hypotension Gastrointestinal Adverse Reactions Hypersensitivity Reactions Withdrawal Most common adverse reactions (≥10% and ≥2 x placebo rate): Dizziness, constipation, nausea, headache, somnolence, flushing, pruritus, vomiting, insomnia, dry mouth.

To report SUSPECTED ADVERSE

REACTIONS, contact Sun Pharmaceutical Industries, Inc.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Tramadol hydrochloride extended-release tablets were 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.

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 81 90 57 28 Nausea 61 90 102 53 32 Constipation 49 68 85 60 17 Headache 49 62 46 32 43 Somnolence 33 45 29 41 7 Flushing 31 40 35 32 18 Pruritus 25 34 30 24 4 Vomiting 20 29 34 19 11 Insomnia 26 32 36 22 13 Dry Mouth 20 29 39 18 6 Diarrhea 15 27 37 10 17 Asthenia 14 24 26 13 7 Postural hypotension 7 17 8 11 9 Sweating increased 6 8 15 13 1 Anorexia 3 7 21 12 1 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 throat General disorders: weakness, pain, feeling hot, influenza like illness, fall, rigors, lethargy, pyrexia, chest pain.

Infections and infestations: nasopharyngitis, upper respiratory tract infection, sinusitis, influenza, gastroenteritis viral, urinary tract infection, bronchitis.

Investigations: blood creatine phosphokinase increased, weight decreased Metabolism and nutrition disorders: appetite decreased Musculoskeletal, connective tissue and bone disorders: arthralgia, back pain, pain in limb, neck pain Nervous system disorders: tremor, paresthesia, hypoesthesia Psychiatric disorders: nervousness, anxiety, depression, restlessness Respiratory, thoracic and mediastinal disorders: sneezing, cough, rhinorrhea, nasal congestion, dyspnea, sinus congestion Skin and subcutaneous tissue disorders: sweating increased, dermatitis Vascular disorders: hot flushes, vasodilatation Adverse Reactions With Incidence Rates of 0.5% to <1.0% and Serious Adverse Reactions Reported in at Least 2 patients During Clinical Trials Cardiac disorders: palpitations, myocardial infarction Ear and labyrinth disorders: tinnitus, vertigo Gastrointestinal disorders: flatulence, toothache, constipation aggravated, appendicitis, pancreatitis General disorders: feeling jittery, edema lower limb, shivering, joint swelling, malaise, drug withdrawal syndrome, peripheral swelling Hepato-biliary disorders: cholelithiasis, cholecystitis.

Infections and infestations: cellulitis, ear infection, gastroenteritis, pneumonia, viral infection Injury and poisoning: joint sprain, muscle injury.

Investigations: alanine aminotransferase increased, blood pressure increased, aspartate aminotransferase increased, heart rate increased, blood glucose increased, liver function tests abnormal Musculoskeletal, connective tissue and bone disorders: muscle cramps, muscle spasms, joint stiffness, muscle twitching, myalgia, osteoarthritis aggravated Nervous system disorders: migraine, sedation, syncope, disturbance in attention, dizziness aggravated Psychiatric disorders: euphoric mood, irritability, libido decreased, sleep disorder, agitation, disorientation, abnormal dreams Renal and urinary disorders: difficulty in micturition, urinary frequency, hematuria, dysuria, urinary retention Respiratory, thoracic and mediastinal disorders: yawning Skin and subcutaneous tissue disorders: contusion, piloerection, clamminess, night sweats, urticaria Vascular disorders: hypertension aggravated, hypertension, peripheral ischemia 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of tramadol.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Serotonin syndrome

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

Adrenal insufficiency

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

Anaphylaxis has been reported with ingredients contained in tramadol hydrochloride extended-release tablets.

Androgen deficiency

Cases of androgen deficiency have occurred with use of opioids for an extended period of time.

Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration QT prolongation/torsade de pointes: Cases of QT prolongation and/or torsade de pointes have been reported with tramadol use.

Many of these cases were reported in patients taking another drug labeled for QT prolongation, in patients with a risk factor for QT prolongation (e.g., hypokalemia), or in overdose setting.

Metabolism and nutrition disorders

Hyponatremia: cases of severe hyponatremia and/or SIADH have been reported in patients taking tramadol, most often in females over the age of 65, and within the first week of therapy.

Cases of hypoglycemia have been reported in patients taking tramadol.

Most reports were in patients with predisposing risk factors, including diabetes or renal insufficiency, or in elderly patients.

Opioid-induced esophageal dysfunction (OIED): Cases of OIED have been reported in patients taking opioids, and may occur more frequently in patients taking higher doses of opioid, and/or in patients taking opioids longer term.

A prospective, observational cohort study estimated the risks of addiction, abuse, and misuse in patients initiating long-term use of Schedule II opioid analgesics between and 2021.

Study participants included in one or more analyses had been enrolled in selected insurance plans or health systems for at least one year, were free of at least one outcome at baseline, completed a minimum number of follow-up assessments, and either: 1) filled multiple extended-release/long-acting opioid analgesic prescriptions during a 90-day period (n=978); or 2) filled any Schedule II opioid analgesic prescriptions covering at least of 90 days (n=1,244).

Those included also had no dispensing of the qualifying opioids in the previous 6 months.

• approximately 1% to 6% of participants across the two cohorts newly met criteria for addiction, as assessed with two validated interview based measures of moderate-to-severe opioid use disorder based on Diagnostic and Statistical Manual of Mental.

Disorders, Fifth Edition (DSM-5) criteria, and.

• approximately 9% and 22% of participants across the two cohorts newly met criteria for prescription opioid abuse and misuse [defined in Drug Abuse and Dependence ], respectively, as measured with a validated self-reported instrument.

A retrospective, observational cohort study estimated the risk of opioid involved overdose or opioid overdose-related death in patients with new long-term use of Schedule II opioid analgesics from 2006 through 2016 (n=220,249).

Included patients had been enrolled in either one of two commercial insurance programs, one managed care program, or one Medicaid program for at least 9 months.

New long-term use was defined as having Schedule II opioid analgesic prescriptions covering at least 70 days’ supply over the 3 months prior to study entry and none during the preceding 6 months.

Patients were excluded if they had an opioid-involved overdose in the 9 months prior to study entry.

Overdose was measured using a validated medical code-based algorithm with linkage to the National Death Index database.

The 5-year cumulative incidence estimates for opioid-involved overdose or opioid overdose-related death ranged from approximately 1.5% to 4% across study sites, counting only the first event during follow-up.

Approximately 17% of first opioid overdoses observed over the entire study period (5 - to 11 years, depending on the study site) were fatal.

Higher baseline opioid dose was the strongest and most consistent predictor of opioid-involved overdose or opioid overdose-related death.

Study exclusion criteria may have selected patients at lower risk of overdose, and substantial loss to follow-up (approximately 80%) also may have biased estimates.

The risk estimates from the studies described above may not be generalizable to all patients receiving opioid analgesics, such as those with exposures shorter or longer than the duration evaluated in the studies.

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.

Toxic leukoencephalopathy has been reported after opioid overdose and can present hours, days, or weeks after apparent recovery from the initial intoxication.

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 measures.

For clinically significant respiratory or circulatory depression secondary to tramadol 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 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 to 48 hours or longer following ingestion, necessitating prolonged monitoring.

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 usual 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 be initiated with care and by titration with smaller than usual doses of the reversal agent.

Tramadol hydrochloride extended-release tablets are contraindicated for: all children younger than 12 years of age post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy.

Tramadol hydrochloride extended-release tablets are also contraindicated in patients with: Significant respiratory depression Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment Known or suspected gastrointestinal obstruction, including paralytic ileus Hypersensitivity to tramadol (e.g., anaphylaxis) Concurrent use of monoamine oxidase inhibitors (MAOIs) or use within the last 14 days.

Children younger than 12 years of age Postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy.

Significant respiratory depression

Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment Known or suspected gastrointestinal obstruction, including paralytic ileus Hypersensitivity to tramadol Concurrent use of monoamine oxidase inhibitors (MAOIs) or use within the last 14 days.

Tramadol hydrochloride extended-release tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting 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.

Reserve titration to higher doses of tramadol hydrochloride extended-release 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.

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.

Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with tramadol hydrochloride extended-release tablets.

Consider this risk when selecting an initial dose and when making dose adjustments.

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 extended-release tablets, especially if the patient has additional risk factors for overdose, or close contacts at risk for exposure and overdose.

Tramadol hydrochloride extended-release tablets should be taken once daily, at approximately the same time every day. 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.

For patients converting from other opioid analgesics, discontinue all opioid analgesics other than as needed for breakthrough pain and 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.

Do not exceed a daily dose of 300 mg tramadol.

Do not use with other tramadol products.

Periodically reassess patients receiving tramadol hydrochloride extended-release 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.

Do not rapidly reduce or abruptly discontinue tramadol hydrochloride extended-release 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. 2.1 Important Dosage and Administration Instructions Tramadol hydrochloride extended-release tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.

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

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 of time consistent with individual patient treatment goals.

Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of tramadol hydrochloride extended-release 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.

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 Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with tramadol hydrochloride extended-release tablets.

Tramadol hydrochloride extended-release tablets should be taken once daily, at approximately the same time every day. Instruct patients to swallow tramadol hydrochloride extended-release tablets whole, 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.

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. 2.2 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.

The presence of risk factors for overdose should not prevent the management of pain in any patient.

Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program) .

There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics.

Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent. 2.3 Initial Dosage It is safer to underestimate a patient’s 24-hour tramadol requirements and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour tramadol dosage and manage an adverse reaction due to an overdose.

While useful tables of opioid equivalents are readily available, there is inter-patient variability in the potency of opioid drugs and opioid formulations.

Frequently reevaluate patients for signs and symptoms of opioid withdrawal and for signs of oversedation/toxicity after converting patients to Tramadol Hydrochloride Extended-Release Tablets.

Use of Tramadol Hydrochloride Extended-Release Tablets

The initial dose of tramadol hydrochloride extended-release tablets is 100 mg once daily.

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 should be taken once daily.

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 Opioid Analgesics to Tramadol Hydrochloride Extended-Release Tablets When tramadol hydrochloride extended-release tablets therapy is initiated, discontinue all opioid analgesics other than those used on an as needed basis for breakthrough pain when appropriate.

There are no established conversion ratios for conversion from other opioids to tramadol hydrochloride extended-release tablets defined by clinical trials.

Initiate dosing using tramadol hydrochloride extended-release tablets 100 mg once a day. 2.4 Titration and Maintenance of Therapy Individually titrate tramadol hydrochloride extended-release tablets by 100 mg every five days to a dose that provides adequate analgesia and minimizes adverse reactions.

The maximum daily dose of tramadol hydrochloride extended-release tablets is 300 mg per day. Continually reevaluate patients receiving tramadol hydrochloride extended-release tablets to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions as well as to reassess for the development of addiction, abuse, or misuse.

Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration.

During use of opioid therapy for an extended period of time, periodically reassess the continued need for the use of opioid analgesics.

Patients who experience breakthrough pain may require a dosage adjustment of tramadol hydrochloride extended-release tablets, or may need rescue medication with an appropriate dose of an immediate-release analgesic.

If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the tramadol hydrochloride extended-release tablets dosage.

If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after dosage increase), consider reducing the dosage.

Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions. 2.5 Safe Reduction or Discontinuation of Tramadol Hydrochloride Extended-Release Tablets Do not rapidly reduce or abruptly discontinue tramadol hydrochloride extended-release tablets in patients who may be physically dependent on opioids.

Rapid reduction or abrupt discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide.

Rapid reduction or abrupt discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse.

Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances.

When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking tramadol hydrochloride extended-release tablets, there are a variety of factors that should be considered, including the total daily dose of opioid (including tramadol hydrochloride extended-release tablets) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient.

It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic.

When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder.

Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder.

Complex patients with co-morbid pain and substance use disorders may benefit from referral to a specialist.

There are no standard opioid tapering schedules that are suitable for all patients.

Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually.

For patients.

Tramadol hydrochloride extended-release tablets, USP are supplied in the following package and dose strength forms: 100 mg: White, round shape, biconvex, beveled edge, coated tablet with release portal on the center of the tablet on any one side, imprinted “531” with black ink on one side and plain on other side.

Bottles of 30's with Child Resistant Cap …………….

NDC 47335-859-83 Bottles of 100's with Child Resistant Cap …………….

NDC 47335-859-88 Bottles of 100's with Non Child Resistant Cap ……… NDC 47335-859-08 Bottles of 1000's with Non Child Resistant Cap …….

NDC 47335-859-18 200 mg: White, round shape, biconvex, beveled edge, coated tablet with release portal on the center of the tablet on any one side, imprinted “533” with black ink on one side and plain on other side.

NDC 47335-860-83 Bottles of 100's with Child Resistant Cap …………….

NDC 47335-860-88 Bottles of 100's with Non Child Resistant Cap ……… NDC 47335-860-08 Bottles of 1000's with Non Child Resistant Cap …….

NDC 47335-860-18 300 mg: White, round shape, biconvex, beveled edge, coated tablet with release portal on the center of the tablet on any one side, imprinted “537” with black ink on one side and plain on other side.

NDC 47335-861-83 Bottles of 100's with Child Resistant Cap …………….

NDC 47335-861-88 Bottles of 100's with Non Child Resistant Cap ……… NDC 47335-861-08 Bottles of 1000's with Non Child Resistant Cap …….

NDC 47335-861-18 Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) .

Dispense in a tight, light resistant container.

Store tramadol hydrochloride extended-release tablets securely and dispose of properly.

Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome.

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.

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 to 4% and to 20%, respectively.

Fetal/Neonatal Adverse Reactions Use of opioid analgesics for an extended period of time 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.

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

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, 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.

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 ossification, and increased supernumerary ribs at maternally toxic dose levels.

Transient delays in developmental or behavioral parameters were also seen in pups from rat dams allowed to deliver.

Embryo and fetal lethality were reported only in one rabbit study at 300 mg/kg, a dose that would cause extreme maternal toxicity in the rabbit.

The dosages listed for mouse, rat, and rabbit are 2.3, 2.6, and 19 times the MRHD, respectively.

Tramadol was evaluated in pre.

• and post-natal studies in rats.

Progeny of dams receiving oral (gavage) dose levels of 50 mg/kg (1.6 times the MRHD) or greater had decreased weights, and pup survival was decreased early in lactation at 80 mg/kg (2.6 times the MRHD).

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.

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 age 12 years of age.

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.

Avoid the use of tramadol hydrochloride extended-release tablets in adolescents 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. .

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.

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 frequently reevaluate the patient for signs of central nervous system and respiratory depression.

Tramadol is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function.

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to regularly evaluate renal function.