Tramadol Hydrochloride: Package Insert and Label Information
TRAMADOL HYDROCHLORIDE- tramadol hydrochloride tablet, film coated, extended release
REMEDYREPACK INC.
WARNING: ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID METABOLISM OF TRAMADOL AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME, INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
Addiction, Abuse, and Misuse
Tramadol Hydrochloride Extended-Release Tablets expose patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing Tramadol Hydrochloride Extended-Release Tablets, and monitor all patients regularly for the development of these behaviors and conditions [see WARNINGS].
Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS):
To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a REMS for these products [see WARNINGS]. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to
- complete a REMS-compliant education program,
- counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products,
- emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist, and
- consider other tools to improve patient, household, and community safety.
Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression may occur with use of Tramadol Hydrochloride Extended-Release Tablets. Monitor for respiratory depression, especially during initiation of Tramadol Hydrochloride Extended-Release Tablets or following a dose increase [see WARNINGS].
Accidental Ingestion
Accidental ingestion of Tramadol Hydrochloride Extended-Release Tablets, especially by children, can result in a fatal overdose of Tramadol Hydrochloride Extended-Release Tablets [see WARNINGS].
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]. Tramadol Hydrochloride Extended-Release Tablets are contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see CONTRAINDICATIONS]. Avoid the use of Tramadol Hydrochloride Extended-Release Tablets in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol [see WARNINGS].
Neonatal Opioid Withdrawal Syndrome
Prolonged use of Tramadol Hydrochloride Extended-Release Tablets during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see WARNINGS].
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 Hydrochloride are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with Tramadol Hydrochloride Extended-Release Tablets requires careful consideration of the effects on the parent drug, tramadol, and the active metabolite, M1 [see WARNINGS, PRECAUTIONS; Drug Interactions].
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 [ see Warnings, Precautions; Drug Interactions].
- Reserve concomitant prescribing of Tramadol Hydrochloride Extended-Release Tablets and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
- Limit dosages and durations to the minimum required.
- Follow patients for signs and symptoms of respiratory depression and sedation.
DESCRIPTION
Tramadol Hydrochloride Extended-Release Tablets, USP are an opioid agonist composed of a matrix delivery system with extended-release characteristics. The chemical name for tramadol hydrochloride, USP is (±) cis -2-[(dimethylamino) methyl]-1-(3 methoxyphenyl) cyclohexanol hydrochloride. Its structural formula is:
The molecular weight of tramadol hydrochloride, USP is 299.84. Tramadol hydrochloride, USP is a white crystalline powder that is freely soluble in water and ethanol. Tramadol Hydrochloride Extended-Release Tablets, USP are for oral administration and contain 100 mg, 200 mg or 300 mg of tramadol hydrochloride, USP. The tablets are white to off-white in color. The inactive ingredients in the tablet are ethylcellulose, hypromellose, magnesium stearate, polyethylene glycol, polyvinyl alcohol, dibasic sodium phosphate anhydrous, talc, and titanium dioxide.
USP dissolution testing is pending.
CLINICAL PHARMACOLOGY
Mechanism of Action
Tramadol Hydrochloride Extended-Release Tablets, contain tramadol, an opioid agonist inhibitor of norepinephrine and serotonin re-uptake. Although the mode of action of tramadol is not completely understood, the analgesic effect of tramadol is believed to be due to 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 -demethylated metabolite (M1) to mu-opioid receptors. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in mu-opioid binding. Tramadol-induced analgesia is only partially antagonized by the opiate 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 hydrochloride administration may produce various 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.
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, and transient elevations in serum amylase.
Effects on the Cardiovascular System
Tramadol produces peripheral vasodilation, which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.
Effects on the Endocrine System
Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see ADVERSE REACTIONS]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.
Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see ADVERSE REACTIONS].
Effects on the Immune System
Opioids have been shown to have a variety of effects on components of the immune system. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.
Concentration–Efficacy Relationships
The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent opioid agonists. The minimum effective analgesic concentration of tramadol for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see DOSAGE AND ADMINISTRATION].
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].
Pharmacokinetics
Tramadol Hydrochloride Extended-Release Tablets are formulated as a racemate and both tramadol and M1 are detected in the circulation.
The pharmacokinetics of tramadol and M1 are dose-proportional over a 100 to 300 mg dose range in healthy subjects.
Absorption
The median time to peak plasma concentrations of tramadol and M1 after multiple-dose administration of a Tramadol Hydrochloride Extended-Release Tablet 200 mg to healthy subjects are attained at about 4 h and 5 h, respectively ( Table 1 and Figure 1).
The pharmacokinetic parameter values of a Tramadol Hydrochloride Extended-Release Tablet 200 mg administered once daily and tramadol immediate-release 50 mg administered every six hours are provided in Table 1. The relative bioavailability of a 200 mg Tramadol Hydrochloride Extended-Release Tablet compared to a 50 mg immediate-release tablet dosed every six hours was approximately 95% in healthy subjects.
Table 1 . Mean (%CV) Steady-State Pharmacokinetic Parameter Values (n=26). | ||||
Pharmacokinetic Parameter | Tramadol | M1 Metabolite | ||
Tramadol Hydrochloride Extended-Release 200 mg Tablet Once-Daily | Immediate- Release Tramadol
| Tramadol Hydrochloride Extended-Release 200 mg Tablet Once-Daily | Immediate-
| |
AUC 0-24 (ng·h/mL) | 5991 (22) | 6399 (28) | 1361 (27) | 1438 (23) |
C max (ng/mL) | 345 (21) | 423 (23) | 71 (27) | 79 (22) |
C min (ng/mL) | 157 (31) | 190 (34) | 41 (30) | 50 (29) |
T max (hr)* | 4.0 (3.0 to 9.0) | 1.0 (1.0 to 3.0) | 5.0 (3.0 to 20) | 1.5 (1.0 to 3.0) |
Fluctuation (%) | 77 (26) | 91 (22) | 53 (29) | 49 (26) |
*T max is presented as Median (Range) | ||||
Steady-state plasma concentrations are reached within approximately 48 hours.
Figure 1. Mean Tramadol Plasma Concentrations at Steady State Following Five Days of Oral Administration of A Tramadol Hydrochloride Extended-Release Tablet 200 mg Once Daily and Immediate-Release Tramadol 50 mg Every 6 Hours.
Figure 2. Mean M1 Plasma Concentrations at Steady State Following Five Days of Oral Administration of A Tramadol Hydrochloride Extended-Release Tablet 200 mg Once Daily and Immediate-Release Tramadol 50 mg Every 6 Hours
Food Effect
Coadministration with a high fat meal did not significantly affect AUC (overall exposure to tramadol); however, C max (peak plasma concentration) increased 67% following a single 300 mg tablet administration and 54% following a single 200 mg tablet administration. Tramadol Hydrochloride Extended-Release Tablets were administered without regard to food in all clinical trials.
Distribution
The volume of distribution of tramadol is 2.6 and 2.9 L/kg in males and females, respectively, following a 100 mg intravenous dose. The binding of tramadol to human plasma proteins is approximately 20%. Protein 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
After single administration of Tramadol Hydrochloride Extended-Release Tablets, the mean terminal plasma elimination half-lives of racemic tramadol and racemic M1 are 6.5 ± 1.5 and 7.5 ± 1.4 hours, respectively.
Metabolism
Tramadol is extensively metabolized after oral administration. The major metabolic pathways appear to be N- and O- demethylation and glucuronidation or sulfation in the liver. N -demethylation is mediated by CYP3A4 and CYP2B6. One metabolite ( O – desmethyltramadol, denoted M1) is pharmacologically active in animal models. Formation of M1 is dependent on CYP2D6 and as such is subject to inhibition and polymorphism, which may affect the therapeutic response [see PRECAUTIONS — Drug Interactions].
Excretion
Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The remainder is excreted either as unidentified or as unextractable metabolites.
Special Populations
Hepatic Impairment
The metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver, resulting in both a larger area under the concentration time curve (AUC) for tramadol and longer mean tramadol and M1 elimination half-lives (13 hours for tramadol and 19 hours for M1) after the administration of tramadol immediate-release tablets. Tramadol Hydrochloride Extended-Release Tablets have not been studied in patients with hepatic impairment. The limited availability of dose strengths and once daily dosing of Tramadol Hydrochloride Extended-Release Tablets do not permit the dosing flexibility required for safe use in patients with hepatic impairment. Therefore, Tramadol Hydrochloride Extended-Release Tablets should not be used in patients with hepatic impairment [see WARNINGS, Use in Renal and Hepatic Disease and DOSAGE AND ADMINISTRATION].
Renal Impairment
Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1 in patients taking an immediate-release formulation of tramadol. Tramadol Hydrochloride Extended-Release Tablets have not been studied in patients with renal impairment. The limited availability of dose strengths and once daily dosing of Tramadol Hydrochloride Extended-Release Tablets do not permit the dosing flexibility required for safe use in patients with severe renal impairment. Therefore, Tramadol Hydrochloride Extended-Release Tablets should not be used in patients with severe renal impairment (creatinine clearance less than 30 mL/min) [see WARNINGS, Use in Renal and Hepatic Disease and DOSAGE AND ADMINISTRATION]. The total amount of tramadol and M1 removed during a 4-hour dialysis period is less than 7% of the administered dose.
Geriatric Patients
Healthy elderly subjects aged 65 to 75 years administered an immediate-release formulation of tramadol, have plasma concentrations and elimination half-lives comparable to those observed in healthy subjects less than 65 years of age. In subjects over 75 years, mean maximum plasma concentrations are elevated (208 vs. 162 ng/mL) and the mean elimination half-life is prolonged (7 vs. 6 hours) compared to subjects 65 to 75 years of age. Adjustment of the daily dose is recommended for patients older than 75 years [see DOSAGE AND ADMINISTRATION].
Sex
Following a 100 mg IV dose of tramadol, plasma clearance was 6.4 mL/min/kg in males and 5.7 mL/min/kg in females. Following a single oral dose of immediate-release tramadol, and after adjusting for body weight, females had a 12% higher peak tramadol concentration and a 35% higher area under the concentration-time curve compared to males. The clinical significance of this difference is unknown.
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