| | See TERMINOLOGY & ABBREVIATIONS |
|IMPORTANT SAFETY INFORMATION
WARNING: ABUSE POTENTIAL, LIFE-THREATENING RESPIRATORY DEPRESSION, ACCIDENTAL EXPOSURE, and INTERACTION WITH ALCOHOL
Tapentadol, an opioid agonist and Schedule II controlled substance (in the U.S.) with an abuse liability similar to other opioid agonists, legal or illicit. Assess each patient's risk for opioid abuse or addiction prior to prescribing Tapentadol ER formulation. The risk for opioid abuse is increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (eg, major depressive disorder). Routinely monitor all patients receiving Tapentadol ER formulation for signs of misuse, abuse, and addiction during treatment.
Life-threatening Respiratory Depression
Respiratory depression, including fatal cases, may occur with use of Tapentadol ER formulation, even when the drug has been used as recommended and not misused or abused. Proper dosing and titration are essential, and Tapentadol ER formulation should only be prescribed by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain. Monitor for respiratory depression, especially during initiation of Tapentadol ER formulation or following a dose increase. Instruct patients to swallow Tapentadol ER formulation tablets whole. Crushing, dissolving, or chewing Tapentadol ER formulation can cause rapid release and absorption of a potentially fatal dose of tapentadol.
Accidental ingestion of Tapentadol ER formulation, especially in children, can result in a fatal overdose of tapentadol.
Interaction With Alcohol
The co-ingestion of alcohol with Tapentadol ER formulation may result in an increase of plasma levels and potentially fatal overdose of tapentadol. Instruct patients not to consume alcoholic beverages or use prescription or nonprescription products that contain alcohol while on Tapentadol ER formulation.
|Indication(s) & Dosage
Tapentadol is indicated for the relief of moderate to severe acute pain in patients 18 years of age or older.
As with many centrally-acting analgesic medications, the dosing regimen should be individualized according to the severity of pain being treated, the previous experience with
similar drugs and the ability to monitor the patient.
The dose is 50 mg, 75 mg, or 100 mg every 4 to 6 hours depending upon pain intensity. On the first day of dosing, the second dose may be administered as soon as one hour after the first dose, if adequate pain relief is not attained with the first dose. Subsequent dosing is 50 mg, 75 mg, or 100 mg every 4 to 6 hours and should be adjusted to maintain adequate analgesia with acceptable tolerability.
Daily doses greater than 700 mg on the first day of therapy and 600 mg on subsequent days have not been studied and are not recommended.
||May be given with or without food after every 4-6 hrs. A second dose as soon as 1 hour after the first dose on first day of treatment may be administered to control pain. Should be swallowed whole and not to open/chew or crush.
Experience with Tapentadol overdose is very limited. Preclinical data suggest that symptoms similar to those of other centrally acting analgesics with mu-opioid agonist activity are to be expected upon intoxication with tapentadol. In principle, these symptoms may particularly appear in the clinical setting: miosis, vomiting, cardiovascular collapse, consciousness disorders up to coma, convulsions and respiratory depression up to respiratory arrest.
Management of Overdose
Management of overdose should be focused on treating symptoms of mu-opioid agonism. Primary attention should be given to re-establishment of a patent airway and institution of assisted or controlled ventilation when overdose of Tapentadol is suspected. Supportive measures (including oxygen and vasopressors) should be employed in the management of irculatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation.
Pure opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. Respiratory depression following an overdose may outlast the duration of action of the opioid antagonist. Administration of an opioid antagonist is not a substitute for continuous monitoring of airway, breathing, and circulation following an opioid overdose. If the response to opioid antagonists is suboptimal or only brief in nature, an additional antagonist should be administered as directed by the manufacturer of the product.
Gastrointestinal decontamination may be considered in order to eliminate unabsorbed drug. Gastrointestinal decontamination with activated charcoal or by gastric lavage is only
recommended within 2 hours after intake. Gastrointestinal decontamination at a later time point may be useful in case of intoxication with exceptionally large quantities. Before attempting gastrointestinal decontamination, care should be taken to secure the airway.
Impaired Pulmonary Function
Like other drugs with mu-opioid agonist activity, Tapentadol is contraindicated in patients with significant respiratory depression in unmonitored settings or the absence of resuscitative equipment. Tapentadol is also contraindicated in patients with acute or severe bronchial asthma or hypercapnia in unmonitored settings or the absence of resuscitative equipment.
Like drugs with mu-opioid agonist activity, Tapentadol is contraindicated in any patient who has or is suspected of having paralytic ileus.
Monoamine Oxidase Inhibitors
Tapentadol is contraindicated in patients who are receiving monoamine oxidase (MAO) inhibitors or who have taken them within the last 14 days due to potential additive effects on norepinephrine levels which may result in adverse cardiovascular events.
|Warning & Precautions
Respiratory depression is the primary risk of mu-opioid agonists. Respiratory depression occurs more frequently in elderly or debilitated patients and in those suffering from conditions accompanied by hypoxia, hypercapnia, or upper airway obstruction, in whom even moderate therapeutic doses may significantly decrease pulmonary ventilation.
Tapentadol should be administered with caution to patients with conditions accompanied by hypoxia, hypercapnia or decreased respiratory reserve such as: asthma, chronic obstructive pulmonary disease or cor pulmonale, severe obesity, sleep apnea syndrome, myxedema, kyphoscoliosis, central nervous system (CNS) depression, or coma. In such patients, even usual therapeutic doses of Tapentadol may increase airway resistance and decrease respiratory drive to the point of apnea. Alternative non-mu-opioid agonist analgesics should be considered and Tapentadol should be employed only under careful medical supervision at the lowest effective dose in such patients. If respiratory depression occurs, it should be treated as any mu-opioid agonist-induced respiratory depression.
Patients receiving other mu-opioid agonist analgesics, general anesthetics, phenothiazines, other tranquilizers, sedatives, hypnotics, or other CNS depressants (including alcohol) concomitantly with Tapentadol may exhibit additive CNS depression. Interactive effects resulting in respiratory depression, hypotension, profound sedation, coma or death may result if these drugs are taken in combination with Tapentadol. When such combined therapy is contemplated, a dose reduction of one or both agents should be considered.
Head Injury and Increased Intracranial Pressure
Opioid analgesics can raise cerebrospinal fluid pressure as a result of respiratory depression with carbon dioxide retention. Therefore, Tapentadol should not be used in patients who may be susceptible to the effects of raised cerebrospinal fluid pressure such as those with evidence of head injury and increased intracranial pressure. Opioid analgesics may obscure the clinical course of patients with head injury due to effects on pupillary response and consciousness. Tapentadol should be used with caution in patients with head injury, intracranial lesions, or other sources of preexisting increased intracranial pressure.
Misuse and Abuse
Tapentadol is a mu-opioid agonist and is a Schedule II controlled substance. Such drugs are sought by drug abusers and people with addiction disorders. Diversion of Schedule II products is an act subject to criminal penalty. Tapentadol can be abused in a manner similar to other opioid agonists, legal or illicit. This
should be considered when prescribing or dispensing Tapentadol in situations where the physician or pharmacist is concerned about an increased risk of misuse and abuse. Concerns about abuse and addiction should not prevent the proper management of pain. However, all patients treated with mu-opioid agonists require careful monitoring for signs of abuse and addiction, since use of mu-opioid agonist analgesic products carry the risk of addiction even under appropriate medical use. Tapentadol may be abused by crushing, chewing, snorting or injecting the product. These practices pose a significant risk to the abuser that could result in overdose and death.
Driving and Operating Machinery
Patients should be cautioned that Tapentadol may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. This is to be expected especially at the beginning of treatment, at any change of dosage as well as in combination with alcohol or tranquilizers.
Interactions with Alcohol and Drugs of Abuse
Due to its mu-opioid agonist activity, Tapentadol may be expected to have additive effects when used in conjunction with alcohol, opioids, or illicit drugs that cause central nervous system depression, respiratory depression, hypotension, and profound sedation, coma or death.
Tapentadol has not been systematically evaluated in patients with a seizure disorder, and such patients were excluded from clinical studies. Tapentadol should be prescribed with care in patients with a history of a seizure disorder or any condition that would put the patient at risk of seizures.
Serotonin Syndrome Risk
The development of a potentially life-threatening serotonin syndrome may occur with use of Serotonin and Norepinephrine Reuptake Inhibitor (SNRI) products, including Tapentadol, particularly with concomitant use of serotonergic drugs such as Selective Serotonin Reuptake Inhibitors (SSRIs), SNRIs, tricyclic antidepressants (TCAs), MAOIs and triptans, and with drugs that impair metabolism of serotonin (including MAOIs). This may occur within the recommended dose. 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 gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
Withdrawal symptoms may occur if Tapentadol is discontinued abruptly. These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely, hallucinations. Withdrawal symptoms may be reduced by tapering Tapentadol.
A study of Tapentadol in subjects with hepatic impairment showed higher serum concentrations than in those with normal hepatic function. Tapentadol should be used with
caution in patients with moderate hepatic impairment. Tapentadol has not been studied in patients with severe hepatic impairment and, therefore, use in this population is not recommended.
Use in Pancreatic/Biliary Tract Disease
Like other drugs with mu-opioid agonist activity, Tapentadol may cause spasm of the sphincter of Oddi and should be used with caution in patients with biliary tract disease, including acute pancreatitis.
|Adverse Drug Reactions
The following treatment-emergent adverse events are discussed in more detail in other sections of the labeling:
- Respiratory Depression
- CNS Depression
Because clinical studies are conducted under widely varying conditions, adverse event rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. A treatment-emergent adverse event refers to any untoward medical event associated with the use of the drug in humans, whether or not considered drug-related. Based on data from nine Phase 2/3 studies that administered multiple doses (seven
placebo- and/or active-controlled, one noncontrolled and one Phase 3 active-controlled safety study) the most common adverse events (reported by <10% in any Tapentadol dose group) were: nausea, dizziness, vomiting and somnolence. The most common reasons for discontinuation due to adverse events in the studies described
above (reported by <1% in any Tapentadol dose group) were dizziness (2.6% vs. 0.5%), nausea (2.3% vs. 0.6%), vomiting (1.4% vs. 0.2%), somnolence (1.3% vs. 0.2%) and headache (0.9% vs. 0.2%) for Tapentadol- and placebo-treated patients, respectively. Seventy-six percent of Tapentadol-treated patients from the nine studies experienced adverse events.
Tapentadol was studied in multiple-dose, active- or placebo-controlled studies, or noncontrolled studies (n = 2178), in single-dose studies (n = 870), in open-label study extension (n = 483) and in Phase 1 studies (n = 597). Of these, 2034 patients were treated with doses of 50 mg to 100 mg of Tapentadol dosed every 4 to 6 hours.The data described below reflect exposure to Tapentadol in 3161 patients, including 449 exposed for 45 days. Tapentadol was studied primarily in placebo- and active-controlled studies (n = 2266, and n = 2944, respectively). The population was 18 to 85 years old (mean age 46 years), 68% were female, 75% white and 67% were postoperative. Most patients received Tapentadol doses of 50 mg, 75 mg, or 100 mg every 4 to 6 hours.
Other Adverse Reactions Observed During the Premarketing Evaluation of Tapentadol
The following adverse drug reactions occurred in <1% of Tapentadol-treated patients in the pooled safety data from nine Phase 2/3 studies that administered multiple doses (seven were placebo- and/or active-controlled, one noncontrolled, and one Phase 3 active-controlled safety study):
Cardiac disorders: heart rate increased, heart rate decreased.
Eye disorders: visual disturbance
Gastrointestinal disorders: abdominal discomfort, impaired gastric emptying
General disorders and administration site conditions: irritability, edema, drug withdrawal syndrome, feeling drunk
Immune system disorders: hypersensitivity Investigations: gamma-glutamyltransferase increased, alanine aminotransferase increased, aspartate aminotransferase increased
Musculoskeletal and connective tissue disorders: involuntary muscle contractions, sensation of heaviness.
Nervous system disorders: hypoesthesia, paresthesia, disturbance in attention, sedation, dysarthria, depressed level of consciousness, memory impairment, ataxia, presyncope, syncope, coordination abnormal, seizure Psychiatric disorders: euphoric mood, disorientation, restlessness, agitation, nervousness, thinking abnormal
Renal and urinary disorders: urinary hesitation, pollakiuria Respiratory, thoracic and mediastinal disorders: oxygen saturation decreased, cough,
dyspnea, respiratory depression Skin and subcutaneous tissue disorders: urticaria Vascular disorders: blood pressure decreased In the pooled safety data, the overall incidence of adverse reactions increased with increased dose of Tapentadol, as did the percentage of patients with adverse reactions of nausea, dizziness, vomiting, somnolence, and pruritus.
Tapentadol is mainly metabolized by glucuronidation. The following substances have been included in a set of interaction studies without any clinically significant finding: acetaminophen, acetylsalicylic acid, naproxen and probenecid. The pharmacokinetics of tapentadol were not affected when gastric pH or gastrointestinal motility were increased by omeprazole and metoclopramide, respectively.
Drugs Metabolized by Cytochrome P450 Enzymes
In vitro investigations indicate that Tapentadol does not inhibit or induce P450 enzymes. Thus, clinically relevant interactions mediated by the cytochrome P450 system are unlikely to occur.
Drugs That Inhibit or Induce Cytochrome P450 Enzymes
The major pathway of tapentadol metabolism is conjugation with glucuronic acid to produce glucuronides. To a lesser extent, tapentadol is additionally metabolized to N-desmethyl tapentadol (13%) by CYP2C9 and CYP2C19 to hydroxy tapentadol (2%) by CYP2D6, which are further metabolized by conjugation. Since only a minor amount of Tapentadol is metabolized via the oxidative pathway clinically relevant interactions mediated by the cytochrome P450 system are unlikely to occur.
Centrally-Acting Drugs and Alcohol
Patients receiving other opioid agonist analgesics, general anesthetics, phenothiazines, antiemetics, other tranquilizers, sedatives, hypnotics, or other CNS depressants (including alcohol) concomitantly with Tapentadol may exhibit an additive CNS depression. Interactive effects resulting in respiratory depression, hypotension, profound sedation, or coma may result if these drugs are taken in combination with Tapentadol. When such combined therapy is contemplated, a dose reduction of one or both agents should be considered.
Monoamine Oxidase Inhibitors
Tapentadol is contraindicated in patients who are receiving monoamine oxidase (MAO) inhibitors or who have taken them within the last 14 days due to potential additive effects on norepinephrine levels which may result in adverse cardiovascular events [see Contraindications]
|Pregnancy Category (FDA) and use in Specific Population
Category C: Either studies in animals have revealed adverse effects on the foetus (teratogenic or embryocidal or other).Drugs should be given only if the potential benefit justifies the potential risk to the foetus.
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 times the plasma exposure at the maximum recommended human dose (MRHD) of 700 mg/day 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 0.2, 0.6, and 1.85 times the plasma exposure at the MRHD based on an AUC comparison] revealed embryofetal toxicity at doses < 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 < 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.
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 1.7 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 < 150 mg/kg/day, a dose-related increase in pup mortality was observed through postnatal Day 4. There are no adequate and well controlled studies of Tapentadol in pregnant women.
Tapentadol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Labor and Delivery
The effect of tapentadol on labor and delivery in humans is unknown. Tapentadol is not recommended for use in women during and immediately prior to labor and delivery. Due to the mu-opioid receptor agonist activity of Tapentadol, neonates whose mothers have been taking Tapentadol should be monitored for respiratory depression. A specific opioid antagonist, such as naloxone, should be available for reversal of opioid induced respiratory depression in the neonate.
There is insufficient/limited information on the excretion of tapentadol in human or animal breast milk. Physicochemical and available pharmacodynamic/toxicological data on tapentadol point to excretion in breast milk and risk to the suckling child cannot be excluded. Tapentadol should not be used during breast-feeding.
The safety and effectiveness of Tapentadol in pediatric patients less than 18 years of age have not been established. Tapentadol is not recommended in this population.
Of the total number of patients in Phase 2/3 double-blind, multiple-dose clinical studies of Tapentadol, 19% were 65 and over, while 5% were 75 and over. No overall differences in effectiveness were observed between these patients and younger patients. The rate of constipation was higher in subjects greater than or equal to 65 years than those less than 65 years (12% vs. 7%). In general, recommended dosing for elderly patients with normal renal and hepatic function is the same as for younger adult patients with normal renal and hepatic function. Because elderly patients are more likely to have decreased renal and hepatic function, consideration should be given to starting elderly patients with the lower range of recommended doses.
In patients with severe renal impairment, the safety and effectiveness of Tapentadol has not been established. Tapentadol is not recommended in this population.
Administration of Tapentadol resulted in higher exposures and serum levels to tapentadol in subjects with impaired hepatic function compared to subjects with normal hepatic function. Tapentadol should be used with caution in patients with moderate hepatic impairment.
Tapentadol has not been studied in patients with severe hepatic impairment, therefore, use of Tapentadol is not recommended in this population.
||Store at 20-25°C (68-77°F).
Mechanism of Action
Tapentadol is a centrally-acting synthetic analgesic. Although its exact mechanism is unknown, analgesic efficacy is thought to be due to mu-opioid agonist activity and the inhibition of norepinephrine reuptake.
Tapentadol is a centrally-acting synthetic analgesic. It is 18 times less potent than morphine in binding to the human mu-opioid receptor and is 2-3 times less potent in producing analgesia in animal models. Tapentadol has been shown to inhibit norepinephrine reuptake in the brains of rats resulting in increased norepinephrine concentrations. In preclinical models, the analgesic activity due to the mu-opioid receptor agonist activity of tapentadol can be antagonized by selective mu-opioid antagonists (e.g., naloxone), whereas the norepinephrine reuptake inhibition is sensitive to norepinephrine modulators. Tapentadol exerts its analgesic effects without a pharmacologically active metabolite.
Effects on the cardiovascular system: There was no effect of therapeutic and supratherapeutic doses of tapentadol on the QT interval.
Mean absolute bioavailability after single-dose administration (fasting) 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 hour) 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 is widely distributed throughout the body. Following intravenous administration, the volume of distribution (Vz) for tapentadol is 540 +/- 98 L. The plasma protein binding is low and amounts to approximately 20%.
Metabolism and Elimination
In humans, the metabolism of tapentadol is extensive. 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 contributes to the analgesic activity.
Tapentadol and its metabolites are excreted almost exclusively (99%) via the kidneys. The terminal half-life is on average 4 hours after oral administration. The total clearance is 1530 +/- 177 ml/min.
The mean exposure (AUC) to tapentadol was similar in elderly subjects compared to young adults, with a 16% lower mean Cmax observed in the elderly subject group compared to young adult subjects.
AUC and Cmax of tapentadol were comparable in subjects with varying degrees of renal function (from normal to severely impaired). In contrast, increasing exposure (AUC) to
tapentadol-O-glucuronide was observed with increasing degree of renal impairment. In subjects with mild, moderate, and severe renal impairment, the AUC of tapentadol-O-glucuronide are 1.5-, 2.5-, and 5.5-fold higher compared with normal renal function, respectively. Hepatic Impairment Administration of Tapentadol resulted in higher exposures and serum levels to tapentadol in subjects with impaired hepatic function compared to subjects with normal hepatic function. The ratio of tapentadol pharmacokinetic parameters for the mild and moderate hepatic impairment groups in comparison to the normal hepatic function group were 1.7 and 4.2, respectively, for AUC; 1.4 and 2.5, respectively, for Cmax; and 1.2 and 1.4, respectively, for t1/2. The rate of formation of tapentadol-O-glucuronide was lower in subjects with increased liver impairment.
Pharmacokinetic Drug Interactions
Tapentadol is mainly metabolized by Phase 2 glucuronidation, a high capacity/low affinity system, therefore, clinically relevant interactions caused by Phase 2 metabolism are unlikely to occur. Naproxen and probenecid increased the AUC of tapentadol by 17% and 57%, respectively. These changes are not considered clinically relevant and no change in dose is required.
No changes in the pharmacokinetic parameters of tapentadol were observed when acetaminophen and acetylsalicylic acid were given concomitantly. In vitro studies did not reveal any potential of tapentadol to either inhibit or induce cytochrome P450 enzymes. Thus, clinically relevant interactions mediated by the cytochrome P450 system
are unlikely to occur. The pharmacokinetics of tapentadol were not affected when gastric pH or gastrointestinal motility were increased by omeprazole and metoclopramide, respectively. Plasma protein binding of tapentadol is low (approximately 20%). Therefore, the likelihood of pharmacokinetic drug-drug interactions by displacement from the protein binding site is low.
||N02AX06 - tapentadol; Belongs to the class of other opioids. Used to relieve pain.