Tapentadol

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).

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.

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.

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