TRAMADOL LS

Tramadol is a centrally acting synthetic opioid analgesic and SNRI (serotonin/norepinephrine reuptake-inhibitor) that is structurally related to codeine and morphine.

Due to its good tolerability profile and multimodal mechanism of action, tramadol is generally considered a lower-risk opioid option for the treatment of moderate to severe pain.

It is considered a

Step 2 option on the World Health Organization's pain ladder and has about 1/10th of the potency of morphine.

Tramadol differs from other traditional opioid medications in that it doesn't just act as a μ-opioid agonist, but also affects monoamines by modulating the effects of neurotransmitters involved in the modulation of pain such as serotonin and norepinpehrine which activate descending pain inhibitory pathways.

Tramadol's effects on serotonin and norepinephrine mimic the effects of other SNRI antidepressants such as duloxetine and venlafaxine.

Tramadol exists as a racemic mixture consisting of two pharmacologically active enantiomers that both contribute to its analgesic property through different mechanisms and are also themselves metabolized into active metabolites: (+)-tramadol and its primary metabolite (+)-O-desmethyl-tramadol (M1) are agonists of the μ opioid receptor while (+)-tramadol inhibits serotonin reuptake and (-)-tramadol inhibits norepinephrine reuptake.

These pathways are complementary and synergistic, improving tramadol's ability to modulate the perception of and response to pain. 12, 25 Tramadol has also been shown to affect a number of other pain modulators within the central nervous system as well as non-neuronal inflammatory markers and immune mediators. 17, 18, 20, 26, 16 Due to the broad spectrum of targets involved in pain and inflammation, it's not surprising that the evidence has shown that tramadol is effective for a number of pain types including neuropathic pain, post-operative pain, lower back pain, as well as pain associated with labour, osteoarthritis, fibromyalgia, and cancer.

Due to its

SNRI activity, tramadol also has anxiolytic, antidepressant, and anti-shivering effects which are all frequently found as comorbidities with pain.

Similar to other opioid medications, tramadol poses a risk for development of tolerance, dependence and abuse.

If used in higher doses, or with other opioids, there is a dose-related risk of overdose, respiratory depression, and death. 22, 37 However, unlike other opioid medications, tramadol use also carries a risk of seizure and serotonin syndrome, particularly if used with other serotonergic medications. 23, 24.

Tramadol is approved for the management of moderate to severe pain in adults. 30, 37 Tramadol is also used off-label in the treatment of premature ejaculation.

Tramadol modulates the descending pain pathways within the central nervous system through the binding of parent and M1 metabolite to μ-opioid receptors and the weak inhibition of the reuptake of norepinephrine and serotonin. 7, 6 Apart from analgesia, tramadol 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.

Tramadol produces respiratory depression by direct action on brain stem respiratory centres.

The respiratory depression involves both a reduction in the responsiveness of the brain stem centres to increases in CO2 tension and to electrical stimulation.

Tramadol depresses the cough reflex by a direct effect on the cough centre in the medulla.

Antitussive effects may occur with doses lower than those usually required for analgesia.

Tramadol causes miosis, even in total darkness.

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

Marked mydriasis rather than miosis may be seen with hypoxia in the setting oxycodone overdose.

Seizures have been reported in patients receiving tramadol within the recommended dosage range.

Spontaneous post-marketing reports indicate that seizure risk is increased with doses of tramadol above the recommended range.

Risk of convulsions may also increase in patients with epilepsy, those with a history of seizures or in patients with a recognized risk for seizure (such as head trauma, metabolic disorders alcohol and drug withdrawal, CNS infections), or with concomitant use of other drugs known to reduce the seizure threshold.

Tramadol can cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs (e.g., anti-depressants, migraine medications).

Treatment with the serotoninergic drug should be discontinued if such events (characterized by clusters of symptoms such as hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes including confusion, irritability, extreme agitation progressing to delirium and coma) occur and supportive symptomatic treatment should be initiated.

Tramadol should not be used in combination with MAO inhibitors or serotonin-precursors (such as L-tryptophan, oxitriptan) and should be used with caution in combination with other serotonergic drugs (triptans, certain tricyclic antidepressants, lithium, St. John's Wort) due to the risk of serotonin syndrome.

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 gastric, biliary and pancreatic secretions, spasm of the sphincter of Oddi, and transient elevations in serum amylase.

Opioids may influence the hypothalamic-pituitary-adrenal or -gonadal axes.

Some changes that can be seen include an increase in serum prolactin and decreases in plasma cortisol and testosterone.

Clinical signs and symptoms may be manifest from these hormonal changes.

Hyponatremia has been reported very rarely with the use of tramadol, usually in patients with predisposing risk factors, such as elderly patients and/or patients using concomitant medications that may cause hyponatremia (e.g., antidepressants, benzodiazepines, diuretics).

In some reports, hyponatremia appeared to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and resolved with discontinuation of tramadol and appropriate treatment (e.g., fluid restriction).

During tramadol treatment, monitoring for signs and symptoms of hyponatremia is recommended for patients with predisposing risk factors.

Tramadol administration may result in severe hypotension in patients whose ability to maintain adequate blood pressure is compromised by reduced blood volume, or concurrent administration of drugs such as phenothiazines and other tranquillizers, sedative/hypnotics, tricyclic antidepressants or general anesthetics.

These patients should be monitored for signs of hypotension after initiating or titrating the dose of tramadol.

The maximum placebo-adjusted mean change from baseline in the QTcF interval was 5.5 ms in the 400 mg/day treatment arm and 6.5 ms in the 600 mg/day mg treatment arm, both occurring at the 8h time point.

Both treatment groups were within the 10 ms threshold for QT prolongation.

Post-marketing experience with the use of tramadol containing products included rare reports of QT prolongation reported with an overdose.

Particular care should be exercised when administering tramadol to patients who are suspected to be at an increased risk of experiencing torsade de pointes during treatment with a QTc-prolonging drug.

Like all opioids, tramadol has the potential for abuse and misuse, which can lead to overdose and death.

Therefore, tramadol should be prescribed and handled with caution.

Dependence/Tolerance Physical dependence and tolerance reflect the neuroadaptation of the opioid receptors to chronic exposure to an opioid and are separate and distinct from abuse and addiction.

Tolerance, as well as physical dependence, may develop upon repeated administration of opioids, and are not by themselves evidence of an addictive disorder or abuse.

Patients on prolonged therapy should be tapered gradually from the drug if it is no longer required for pain control.

Withdrawal symptoms may occur following abrupt discontinuation of therapy or upon administration of an opioid antagonist.

Some of the symptoms that may be associated with abrupt withdrawal of an opioid analgesic include body aches, diarrhea, gooseflesh, loss of appetite, nausea, nervousness or restlessness, anxiety, runny nose, sneezing, tremors or shivering, stomach cramps, tachycardia, trouble with sleeping, unusual increase in sweating, palpitations, unexplained fever, weakness and yawning.

Mu-type opioid receptor Agonist

Sodium-dependent noradrenaline transporter Inhibitor Sodium-dependent serotonin transporter Inhibitor + 11 more targets.

Tramadol is administered as a racemate, with both the and forms of both tramadol and the M1 metabolite detected in circulation.

Following administration, racemic tramadol is rapidly and almost completely absorbed, with a bioavailability of 75%.

This difference in absorption and bioavailability can be attributed to the 20-30% first-pass metabolism.

Peak plasma concentrations of tramadol and the primary metabolite M1 occur at two and three hours, respectively.

Following a single oral dose of 100 mg of tramadol, the Cmax was found to be approximately 300 μg/L with a Tmax of 1.6-1.9 hours, while metabolite M1 was found to have a Cmax of 55 μg/L with a Tmax of 3 hours. 12, 30 Steady-state plasma concentrations of both tramadol and M1 are achieved within two days of dosing.

There is no evidence of self-induction.

Following multiple oral doses, Cmax is 16% higher and AUC is 36% higher than after a single dose, demonstrating a potential role of saturable first-pass hepatic metabolism in increasing bioavailability.

Tramadol is rapidly and almost completely absorbed following intramuscular administration.

Following injection of 50 mg of tramadol, Cmax of 166 μg/L was found with a Tmax of 0.75 hours.

Following rectal administration with suppositories containing 100 mg of tramadol, Cmax of 294 μg/L was found with a Tmax of 3.3 hours.

The absolute bioavailability was found to be higher than oral administration (77% vs 75%), likely due to reduced first-pass metabolism with rectal administration compared to oral administration.

The volume of distribution of tramadol is reported to be in the range of 2.6-2.9 L/kg. 30, 37 Tramadol has high tissue affinity; the total volume of distribution after oral administration was 306 L and 203 L after parenteral administration.

Tramadol crosses the blood-brain barrier with peak brain concentrations occurring 10 minutes following oral administration.

It also crosses the placental barrier with umbilical concentrations being found to be ~80% of maternal concentrations.

Tramadol undergoes extensive first-pass metabolism in the liver by N.

• demethylation and conjugation.

From the extensive metabolism, there have been identified at least 23 metabolites.

There are two main metabolic pathways: the O-demethylation of tramadol to produce O-desmethyl-tramadol (M1) catalyzed by CYP2D6 and the N-demethylation to N-desmethyl-tramadol (M2) catalyzed by CYP3A4 and CYP2B6. 12, 30, 37 The wide variability in the pharmacokinetic properties between patients can partly be ascribed to polymorphisms within the gene for CYP2D6 that determine its enzymatic activity.

CYP2D6*1 is considered the wild-type allele associated with normal enzyme activity and the "extensive metabolizer" phenotype; 90-95% of Caucasians are considered "extensive metabolizers" (with normal CYP2D6 function) while the remaining 5-10% are considered "poor metabolizers" with reduced or non-functioning enzyme.

CYP2D6 alleles associated with non-functioning enzyme include 3, 4, 5, and 6 while alleles associated with reduced activity include 9, 10, 17, and 41.

Poor metabolizers have reduced activity of the CYP2D6 enzyme and therefore less production of tramadol metabolites M1 and M2, which ultimately results in a reduced analgesic effect as tramadol interacts with the μ-opioid receptor primarily via M1.

There are also large differences in the frequency of these alleles between different ethnicities: 3, 4, 5, 6, and 41 are more common among Caucasians while 17 is more common in Africans for example.

Compared to 5-10% of Caucasians, only ~1% of Asians are considered poor metabolizers, however Asian populations carry a much higher frequency (51%) of the CYP2D6*10 allele, which is relatively rare in Caucasian populations and results in higher exposure to tramadol.

Some individuals are considered "ultra-rapid metabolizers", such as those carrying CYP2D6 gene duplications (CYP2D6*DUP) or multiplications.

These individuals are at risk of intoxication or exaggerated effects of tramadol due to higher concentrations of its active metabolite (M1).

The occurrence of this phenotype is seen in approximately 1% to 2% of East Asians (Chinese, Japanese, Korean), 1% to 10% of Caucasians, 3% to 4% of African-Americans, and may be >10% in certain racial/ethnic groups (ie, Oceanian, Northern African, Middle Eastern, Ashkenazi Jews, Puerto Rican).

FDA label recommends avoiding the use of tramadol in these individuals. 30, 37 Hover over products below to view reaction partners Tramadol O-Desmethyltramadol N,O-didesmethyltramadol N,N,O-tridesmethyl-tramadol O-Desmethyl-tramado glucuronide N-Desmethyltramadol N,N-didesmethyltramadol N,N,O-tridesmethyl-tramadol N,O-didesmethyltramadol.

Tramadol is eliminated primarily through metabolism by the liver and the metabolites are excreted primarily by the kidneys, accounting for 90% of the excretion while the remaining 10% is excreted through feces. 30, 37, 6 Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites.

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. 30, 37.

Tramadol reported a half-life of 5-6 hours while the M1 metabolite presents a half-life of 8 hours.

In clinical trials, the clearance rate of tramadol ranged from 3.73 ml/min/kg in renal impairment patients to 8.50 ml/min/kg in healthy adults. 30, 37.

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The reported

LD50 for tramadol, when administered Oral in mice, is 350 mg/kg.

In carcinogenic studies, there are reports of murine tumors which cannot be concluded to be carcinogenic in humans.

On the other hand, tramadol showed no evidence to be mutagenic in different assays and does not have effects on fertility.

However, there are clear reports of embryotoxicity and fetotoxicity. 30, 37.

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.