Tapentadol

9.34-10.45

pKa1 = 9.60 (tertiary amine); pKa2 = 10.28 (phenol)

152.1 Ų [M+H]+ [CCS Type: TW; Method: Major Mix IMS/Tof Calibration Kit (Waters)]

150.4 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

This chemical does not meet GHS hazard criteria for 50% (1 of 2) of reports.

Warning

H302 (50%): Harmful if swallowed [Warning Acute toxicity, oral]；H361 (50%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]；H411 (50%): Toxic to aquatic life with long lasting effects [Hazardous to the aquatic environment, long-term hazard]

P203, P264, P270, P273, P280, P301+P317, P318, P330, P391, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 2 reports by companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.；Reported as not meeting GHS hazard criteria per 1 of 2 reports by companies.；There is 1 notification provided by 1 of 2 reports by companies with hazard statement code(s).；Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown. For more detailed information, please visit ECHA C&L website.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including tapentadol hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Tapentadol hydrochloride/

Schedule II shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. Each drug or substance has been assigned the Controlled Substances Code Number set forth opposite it. ... Opiates. Unless specifically excepted or unless in another schedule any of the following opiates, including its isomers, esters, ethers, salts and salts of isomers, esters and ethers whenever the existence of such isomers, esters, ethers, and salts is possible within the specific chemical designation, dextrorphan and levopropoxyphene excepted: Tapentadol (DEA Code Number: 9780) is included on this list.

CDC Guideline for Prescribing Opioids for Chronic Pain - United States, 2016; This guideline provides recommendations for primary care clinicians who are prescribing opioids for chronic pain outside of active cancer treatment, palliative care, and end-of-life care. The guideline addresses 1) when to initiate or continue opioids for chronic pain; 2) opioid selection, dosage, duration, follow-up, and discontinuation; and 3) assessing risk and addressing harms of opioid use. CDC developed the guideline using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework, and recommendations are made on the basis of a systematic review of the scientific evidence while considering benefits and harms, values and preferences, and resource allocation. CDC obtained input from experts, stakeholders, the public, peer reviewers, and a federally chartered advisory committee. It is important that patients receive appropriate pain treatment with careful consideration of the benefits and risks of treatment options. This guideline is intended to improve communication between clinicians and patients about the risks and benefits of opioid therapy for chronic pain, improve the safety and effectiveness of pain treatment, and reduce the risks associated with long-term opioid therapy, including opioid use disorder, overdose, and death.[Dowell D et al; Morbidity and Mortality Weekly Report (MMWR) 65 (1):1-49 (2016); Available from, as of March 22, 2016: http://www.cdc.gov/mmwr/volumes/65/rr/rr6501e1.htm]

Raffa RB et al; Expert Opin Pharmacother 13 (10): 1437-49 (2012)

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

Potential pharmacologic interaction (potentially serious, sometimes fatal serotonin syndrome) when tapentadol is used concurrently with other serotonergic drugs (including serotonin [5-hydroxytryptamine; 5-HT] type 1 receptor agonists ["triptans"], selective serotonin-reuptake inhibitors (SSRIs), selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs), tricyclic antidepressants), or drugs that impair the metabolism of serotonin.

Potential pharmacologic interaction (potentially serious, sometimes fatal serotonin syndrome and potential adverse cardiovascular effects secondary to increased norepinephrine levels). Tapentadol is contraindicated in patients who are receiving or have recently (i.e., within 2 weeks) received a monoamine oxidase (MAO) inhibitor.

Naproxen increased the area under the plasma concentration-time curve (AUC) of tapentadol by 17% when a single 80-mg dose of tapentadol was administered concomitantly with the third of 4 doses of naproxen (500 mg twice daily) in healthy individuals; this change was not considered to be clinically relevant and dosage adjustments are not necessary.

Potential pharmacologic interaction (additive CNS depressant effects, impairment of mental and/or physical abilities required to perform hazardous tasks, respiratory depression, hypotension, profound sedation, coma, death) when tapentadol is used concomitantly with alcohol; concomitant use should be avoided.

For more Interactions (Complete) data for Tapentadol (6 total), please visit the HSDB record page.

IDENTIFICATION AND USE: Tapentadol is a Schedule II Controlled Substance that is indicated for the relief of moderate to severe acute pain (under the drug name Nucynta). HUMAN EXPOSURE AND TOXICITY: Serious, life-threatening, or fatal respiratory depression may occur with use of Nucynta ER. Potentially serious, sometimes fatal serotonin syndrome may occur with the use of tapentadol. Manifestations of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or GI symptoms (e.g., nausea, vomiting, diarrhea). The co-ingestion of alcohol with Nucynta ER may result in increased plasma tapentadol levels and a potentially fatal overdose of tapentadol. Accidental ingestion of even one dose of Nucynta ER, especially by children, can result in a fatal overdose of tapentadol. Prolonged use of Nucynta ER during pregnancy can result in neonatal opioid withdrawal syndrome. ANIMAL STUDIES: In a study of pre- and postnatal development in rats, tapentadol was administered orally to pregnant and lactating rats during the late gestation and early postnatal period (resulting in up to 2.28 times the plasma exposure at the Maximum Recommended Human Dose (MRHD) on an AUC basis). Treatment-related developmental delay was observed, including incomplete ossification, and significant reductions in pup body weights and body weight gains at doses associated with maternal toxicity. At maternal tapentadol doses > or = 150 mg/kg/day, a dose-related increase in pup mortality was observed to postnatal Day 4. Tapentadol HCl was evaluated for teratogenic effects in pregnant rats and rabbits following intravenous and subcutaneous exposure during the period of embryofetal organogenesis. Evidence of embryofetal toxicity in rats included transient delays in skeletal maturation (i.e., reduced ossification) at the 40 mg/kg/d

/HUMAN EXPOSURE STUDIES/ Modulatory descending pathways, originating at supraspinal sites that converge at dorsal horn neurons, influence pain perception in humans. Defects in descending pain control are linked to chronic pain states and its restoration may be a valuable analgesic tool. Conditioned pain modulation (CPM) is a surrogate marker of descending inhibition that reduces the perception of pain from a primary test stimulus during application of a conditioning stimulus. Here the effects of the analgesics tapentadol, a combined mu-opioid receptor agonist and noradrenaline reuptake inhibitor, and morphine, a strong mu-opioid receptor agonist, were tested on CPM in a randomized, double-blind, placebo-controlled crossover trial in 12 healthy pain-free volunteers, to understand possible differences in mechanism of action between these opioids. On three occasions CPM responses were obtained 60-90 and 120-150 min following intake of tapentadol (100 mg immediate release tablet), morphine (40 mg immediate release tablet) or placebo. At both time points, CPM was detectable after treatment with placebo and tapentadol (peak pain ratings reduced by 20-30% after application of the conditioning stimulus) but not after morphine. Compared to placebo morphine displayed significantly less CPM: mean treatment difference 18.2% (95% CI 3.4 to 32.9%) at 60-90 min after drug intake and 19.5% (95% CI 5.7 to 33.2%) at 120-150 min after drug intake (p = 0.001). No difference in CPM between placebo and tapentadol was detected: mean treatment difference 1.5% (95% CI -11.6 to 14.6%) at 60-90 min after drug intake and 1.5% (95% CI -16.0 to 18.9%) at 120-150 min after drug intake (p = 0.60). Our data show that in volunteers morphine affects CPM, while tapentadol was without effect despite identical experimental conditions. These data confirm that tapentadol's main mechanism of action is distinct from that of morphine and likely related to the effect of adrenergic stimulation on descending co

/SIGNS AND SYMPTOMS/ Serious, life-threatening, or fatal respiratory depression may occur with use of Nucynta ER. Monitor for respiratory depression, especially during initiation of Nucynta ER or following a dose increase. Instruct patients to swallow Nucynta ER tablets whole; crushing, chewing, or dissolving Nucynta ER tablets can cause rapid release and absorption of a potentially fatal dose of tapentadol.

/SIGNS AND SYMPTOMS/ Potentially serious, sometimes fatal serotonin syndrome may occur with serotonin- and norepinephrine-reuptake inhibitors (SNRIs), including tapentadol, particularly with concurrent use of other serotonergic drugs (including serotonin [5-hydroxytryptamine; 5-HT] type 1 receptor agonists ["triptans"], selective serotonin-reuptake inhibitors [SSRIs], other SNRIs, tricyclic antidepressants), or drugs that impair the metabolism of serotonin (e.g., MAO inhibitors). Serotonin syndrome may occur within the recommended dosage range for tapentadol. Manifestations of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).

/CASE REPORTS/ This case report describes a 34-year-old male who died as the result of tapentadol toxicity. This case apparently represents the first reported description of a death because of this drug. The toxicologic features of this case, namely concentrations of tapentadol in the femoral blood and heart blood, 1.05 and 3.20 mg/L, respectively, may assist other individuals in evaluating deaths where tapentadol concentration is a factor. Analysis of the blood based upon enzyme-linked immunosorbent assays, liquid chromatography-mass spectrometry, and gas chromatography-mass spectrometry revealed no other substance of significance, only nicotine and cotinine, and the autopsy findings were consistent with an opiate-type drug overdose, and indicated no competing cause of death.

For more Human Toxicity Excerpts (Complete) data for Tapentadol (13 total), please visit the HSDB record page.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

tapentadol

DILI Negative

Oral

DOI:10.1016/j.drudis.2019.09.022

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Tapentadol was administered to rats (diet) and mice (oral gavage) for two years. In mice, tapentadol HCl was administered by oral gavage at dosages of 50, 100 and 200 mg/kg/day (200 mg/kg/day = maximum tolerated dose in mice) for 2 years. Exposures based on mean plasma Cmax were ~4.9x higher than the maximum recommended human daily dose. Exposure based on dose adjusted for body surface area (based on a 500 mg dose of Nucynta Extended-Release to a 50 kg human) was ~1.6x higher in mice than the maximum recommended human daily dose. No increase in tumor incidence was observed at any dose level. In rats, tapentadol HCl was administered in the diet at dosages of 10, 50, 125 and 250 mg/kg/day for two years. Exposure based on dose adjusted for body surface area (based on a 500 mg dose of Nucynta Extended-Release to a 50 kg human) was ~4.0x higher in rats than at the maximum recommended human daily dose. Cmax values were not measured in this carcinogenicity study and therefore a direct Cmax exposure multiple cannot be calculated.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ In mice, tapentadol HCl was administered by oral gavage at dosages of 50, 100 and 200 mg/kg/day (200 mg/kg/day = maximum tolerated dose in mice) for 2 years. Exposures based on mean plasma Cmax were approximately 4.9x higher than the maximum recommended human daily dose. Exposure based on dose adjusted for body surface area (based on a 500 mg dose of Nucynta Extended-Release to a 50 kg human) was approximately 1.6x higher in mice than the maximum recommended human daily dose. No increase in tumor incidence was observed at any dose level.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ In a study of pre- and postnatal development in rats, oral administration of tapentadol at doses of 20, 50, 150, or 300 mg/kg/day to pregnant and lactating rats during the late gestation and early postnatal period [resulting in up to 2.28 times the plasma exposure at the MRHD on an AUC basis] did not influence physical or reflex development, the outcome of neurobehavioral tests or reproductive parameters. Treatment-related developmental delay was observed, including incomplete ossification, and significant reductions in pup body weights and body weight gains at doses associated with maternal toxicity (150 mg/kg/day and above). At maternal tapentadol doses > or = 150 mg/kg/day, a dose-related increase in pup mortality was observed to postnatal Day 4.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Tapentadol HCl was evaluated for teratogenic effects in pregnant rats and rabbits following intravenous and subcutaneous exposure during the period of embryofetal organogenesis. When tapentadol was administered twice daily by the subcutaneous route in rats at dose levels of 10, 20, or 40 mg/kg/day [producing up to 1.36 times the plasma exposure at the maximum recommended human dose (MRHD) of 500 mg/day for Nucynta Extended-Release based on an area under the time-curve (AUC) comparison], no teratogenic effects were observed. Evidence of embryofetal toxicity included transient delays in skeletal maturation (i.e., reduced ossification) at the 40 mg/kg/day dose which was associated with significant maternal toxicity. Administration of tapentadol HCl in rabbits at doses of 4, 10, or 24 mg/kg/day by subcutaneous injection [producing up to 2.48 times the plasma exposure at the MRHD based on an AUC comparison] revealed embryofetal toxicity at doses > or = 10 mg/kg/day. Findings included reduced fetal viability, skeletal delays and other variations. In addition, there were multiple malformations including gastroschisis/thoracogastroschisis, amelia/phocomelia, and cleft palate at doses > or = 10 mg/kg/day and above, and ablepharia, encephalopathy, and spina bifida at the high dose of 24 mg/kg/day. Embryofetal toxicity, including malformations, may be secondary to the significant maternal toxicity observed in the study.

For more Non-Human Toxicity Excerpts (Complete) data for Tapentadol (8 total), please visit the HSDB record page.

Tapentadol should be used with caution in patients with conditions accompanied by hypoxia, hypercapnia, or decreased respiratory reserve such as asthma, chronic obstructive pulmonary disease, cor pulmonale, severe obesity, sleep apnea, myxedema, kyphoscoliosis, CNS depression, or coma. In such patients, even therapeutic tapentadol doses may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea.

Seizures were reported in less than 1% of tapentadol-treated patients in clinical studies. Because tapentadol has not been systematically evaluated in patients with seizure disorders and because such patients were excluded from clinical studies, the drug should be used with caution in patients with a history of seizures or any condition predisposing the patient to seizures.

Tapentadol should not be used in patients who may be susceptible to effects of elevated cerebrospinal fluid (CSF) pressure, including those with evidence of head injury and increased intracranial pressure, since respiratory depressant effects of opiate agonists include carbon dioxide retention and secondary elevation of CSF pressure, and such effects may be markedly exaggerated in these patients. Opiate agonists also produce effects (e.g., pupillary changes, altered consciousness) that may obscure the clinical course of patients with head injury. Tapentadol should be used with caution in patients with head injury, intracranial lesions, or other sources of preexisting increased intracranial pressure.

Prolonged use of Nucynta ER 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.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

Emergency and supportive measures. 1. Maintain an open airway and assist ventilation if necessary. Administer supplemental oxygen. Treat coma, seizures, hypotension, and noncardiogenic pulmonary edema if they occur. /Opiates and opioids/

For more Antidote and Emergency Treatment (Complete) data for Tapentadol (8 total), please visit the HSDB record page.

◉ Summary of Use during Lactation；Maternal use of oral opioids during breastfeeding can cause infant drowsiness, which may progress to rare but severe central nervous system depression. Newborn infants seem to be particularly sensitive to the effects of even small dosages of narcotic analgesics. Little information is available on the use of tapentadol during breastfeeding. Because it has opioid agonist activity, an alternate drug is preferred, especially when nursing a newborn or preterm infant. Monitor infants for excess sedation and respiratory depression. If tapentadol is required by the mother of a newborn, it is not a reason to discontinue breastfeeding; however, once the mother's milk comes in, it is best to provide pain control with a nonnarcotic analgesic and limit maternal intake of oral tapentadol to 2 to 3 days at a low dose with close infant monitoring. If the baby shows signs of increased sleepiness (more than usual), difficulty breastfeeding, breathing difficulties, or limpness, a physician should be contacted immediately. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breastfeeding is stopped.；◉ Effects in Breastfed Infants；The German manufacturer of tapentadol reports that they received 4 spontaneous reports of infant exposure to tapentadol in breastmilk, with no adverse reactions noted. Neither the age of the infants nor the extent of breastfeeding was reported. The dosage was known in only one of the mothers, which was 100 mg twice daily given rectally.；◉ Effects on Lactation and Breastmilk；Relevant published information was not found as of the revision date.

LD50 Rat iv 40 mg/kg

LD50 Mouse po > 300 mg/kg

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including tapentadol hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Tapentadol hydrochloride/

Schedule II shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. Each drug or substance has been assigned the Controlled Substances Code Number set forth opposite it. ... Opiates. Unless specifically excepted or unless in another schedule any of the following opiates, including its isomers, esters, ethers, salts and salts of isomers, esters and ethers whenever the existence of such isomers, esters, ethers, and salts is possible within the specific chemical designation, dextrorphan and levopropoxyphene excepted: Tapentadol (DEA Code Number: 9780) is included on this list.

N02AX06

N - Nervous system；N02 - Analgesics；N02A - Opioids；N02AX - Other opioids；N02AX06 - Tapentadol

QN - Nervous system；QN02 - Analgesics；QN02A - Opioids；QN02AX - Other opioids；QN02AX06 - Tapentadol

Tapentadol is an opioid agonist that exerts physiological effects commonly caused by the opioid drug class. These effects include miosis, reduced gastrointestinal motility, and peripheral vasodilation. Tapentadol produces respiratory depression by reducing the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation. Tapentadol has a high potential for misuse and abuse, which can lead to the development of substance use disorder. Abuse of tapentadol poses a risk of overdose and death, which increases with alcohol or other central nervous system depressants.

Tapentadol is a centrally-acting synthetic analgesic. Although their clinical relevance is unclear, tapentadol is believed to have two main mechanisms of action. Tapentadol is a selective mu-opioid receptor (MOR) agonist: it binds to MOR with an affinity greater than or equal to ten-fold affinity compared to delta- and kappa-opioid receptors. Tapentadol also inhibits noradrenaline reuptake, thereby increasing noradrenaline levels and activating alpha-2 receptors to promote analgesia. Tapentadol is a weak serotonin reuptake inhibitor; however, this action does not contribute to its analgesic effect.

Treatments for neuropathic pain are either not fully effective or have problematic side effects. Combinations of drugs are often used. Tapentadol is a newer molecule that produces analgesia in various pain models through two inhibitory mechanisms, namely central mu-opioid receptor (MOR) agonism and noradrenaline reuptake inhibition. These two components interact synergistically, resulting in levels of analgesia similar to opioid analgesics such as oxycodone and morphine, but with more tolerable side effects. The right central nucleus of the amygdala (CeA) is critical for the lateral spinal ascending pain pathway, regulates descending pain pathways and is key in the emotional-affective components of pain. Few studies have investigated the pharmacology of limbic brain areas in pain models. Here we determined the actions of systemic tapentadol on right CeA neurones of animals with neuropathy and which component of tapentadol contributes to its effect. Neuronal responses to multimodal peripheral stimulation of animals with spinal nerve ligation or sham surgery were recorded before and after two doses of tapentadol. After the higher dose of tapentadol either naloxone or yohimbine were administered. Systemic tapentadol resulted in dose-dependent decrease in right CeA neuronal activity only in neuropathy. Both naloxone and yohimbine reversed this effect to an extent that was modality selective. The interactions of the components of tapentadol are not limited to the synergy between the MOR and a2-adrenoceptors seen at spinal levels, but are seen at this supraspinal site where suppression of responses may relate to the ability of the drug to alter affective components of pain.

The terminal half-life is about four hours after oral administration.

The average terminal half-life of tapentadol is 4 hours following oral administration.

In humans, about 97% of the parent compound is metabolized. Tapentadol is mainly metabolized by Phase II pathways, and only a small amount is metabolized by Phase I oxidative pathways; thus, drug metabolism mediated by cytochrome P450 system is of less importance than phase II conjugation. The major pathway of tapentadol metabolism is conjugation with glucuronic acid to produce glucuronides. After oral administration, approximately 70% of the drug, of which 55% is the O-glucuronide metabolite and 15% is the sulfate metabolite, is excreted in urine. About 3% of the dose was excreted in urine as the unchanged parent drug. Tapentadol can also undergo CYP2C9- and CYP2C19-mediated demethylation to form N-desmethyl tapentadol, which accounts for 13% of the dose. About 2% of tapentadol can also undergo CYP2D6-mediated hydroxylation to form Hydroxy tapentadol. N-desmethyl tapentadol and Hydroxy tapentadol can further be glucuronidated. Metabolites of tapentadol do not contribute to the pharmacological activity of tapentadol.

Tapentadol is a novel, centrally acting analgesic combining mu-opioid receptor (MOR) agonism and noradrenaline (NA) reuptake inhibition in a single molecule. Many classic opioids form active metabolites that contribute to analgesia and/or side effects, and the involved cytochrome P450 enzyme complex can give rise to pharmacokinetic drug-drug interactions and variability in drug efficacy due to enzyme polymorphisms. Here we report on the relevance of tapentadol metabolites. Nine metabolites, including the major metabolite tapentadol-O-glucuronide, had no analgesic effects in the tail-flick test in mice. In the phenylquinone writhing test in mice, only 5 of these metabolites showed analgesic effects. The absence or presence of analgesia correlated with moderate activity (0.5 uM < K(i) < 1.1 uM) at the NA transporter or MOR. However, the systemic exposure for these metabolites found in humans after therapeutic oral doses of tapentadol was far below their respective K(i) values at these binding sites (by a factor of > 45). Thus, it is highly unlikely that tapentadol forms metabolites that contribute in any relevant degree to its analgesic activity.

In humans, about 97% of the parent compound is metabolized. Tapentadol is mainly metabolized via Phase 2 pathways, and only a small amount is metabolized by Phase 1 oxidative pathways. The major pathway of tapentadol metabolism is conjugation with glucuronic acid to produce glucuronides. After oral administration approximately 70% (55% O-glucuronide and 15% sulfate of tapentadol) of the dose is excreted in urine in the conjugated form. A total of 3% of drug was excreted in urine as unchanged drug. Tapentadol is additionally metabolized to N-desmethyl tapentadol (13%) by CYP2C9 and CYP2C19 and to hydroxy tapentadol (2%) by CYP2D6, which are further metabolized by conjugation. Therefore, drug metabolism mediated by cytochrome P450 system is of less importance than phase 2 conjugation. None of the metabolites contribute to the analgesic activity. Tapentadol and its metabolites are excreted almost exclusively (99%) via the kidneys.

H8A007M585

TAPENTADOL

Established Pharmacologic Class [EPC] - Opioid Agonist

Mechanisms of Action [MoA] - Opioid Agonists

Tapentadol is an Opioid Agonist. The mechanism of action of tapentadol is as an Opioid Agonist.

Compounds with activity like OPIATE ALKALOIDS, acting at OPIOID RECEPTORS. Properties include induction of ANALGESIA or NARCOSIS.

Drugs that block the transport of adrenergic transmitters into axon terminals or into storage vesicles within terminals. The tricyclic antidepressants (ANTIDEPRESSIVE AGENTS, TRICYCLIC) and amphetamines are among the therapeutically important drugs that may act via inhibition of adrenergic transport. Many of these drugs also block transport of serotonin.

The mean absolute bioavailability after single-dose administration of tapentadol in a fasted state is approximately 32% due to extensive first-pass metabolism. Maximum serum concentrations of tapentadol are typically observed at around 1.25 hours after dosing. Dose-proportional increases in the Cmax and AUC values of tapentadol have been observed over the 50 to 150 mg dose range. A multiple (every 6 hours) dose study with doses ranging from 75 to 175 mg tapentadol showed a mean accumulation factor of 1.6 for the parent drug and 1.8 for the major metabolite tapentadol- O-glucuronide, which are primarily determined by the dosing interval and apparent half-life of tapentadol and its metabolite. The AUC and Cmax increased by 25% and 16%, respectively, when tapentadol was administered after a high-fat, high-calorie breakfast. Tapentadol may be given with or without food.

Tapentadol and its metabolites are 99% excreted via the kidneys.

Tapentadol is widely distributed throughout the body. Following intravenous administration, the volume of distribution (V_z) for tapentadol is 540 ± 98 L.

The total clearance is 1530 ± 177 mL/min.

Following oral administration, approximately 70% of a dose is excreted in urine as glucuronide or sulfate conjugates and only 3% is excreted unchanged. Tapentadol and its inactive metabolites are eliminated primarily by the kidneys (99%).

Tapentadol and its metabolites are excreted almost exclusively (99%) via the kidneys. ... The total clearance is 1530 +/- 177 mL/min.

Tapentadol is a Schedule II controlled substance.

Schedule II Controlled Substance: (A) The drug or other substance has a high potential for abuse; (B) The drug or other substance has a currently accepted medical use in treatment in the United States or a currently accepted medical use with severe restrictions; and (C) Abuse of the drug or other substances may lead to severe psychological or physical dependence.

MEDICATION