Tapentadol Hydrochloride 100 mg Tablet, Film Coated, 100-count — NDC 72205-371-91 (Billing 72205-0371-91)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Tapentadol is a centrally-acting synthetic analgesic. The exact mechanism of action is unknown. Although the clinical relevance is unclear, preclinical studies have shown that tapentadol is a mu-opioid receptor (MOR) agonist and a norepinephrine reuptake inhibitor (NRI). Analgesia in animal models is derived from both of these properties.

12.2Pharmacodynamics Effects on the Central Nervous System Tapentadol produces respiratory depression by direct action on the brainstem 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. Tapentadol 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 origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations. Effects on the Gastrointestinal Tract and Other Smooth Muscle Tapentadol 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, and opioid-induced esophageal dysfunction (OIED).

Effects on the Cardiovascular System There was no effect of therapeutic and supratherapeutic doses of tapentadol on the QT interval. In a randomized, double-blind, placebo-and positive-controlled crossover study, healthy subjects were administered five consecutive doses of tapentadol 100 mg every 6 hours, tapentadol 150 mg every 6 hours, placebo and a single oral dose of moxifloxacin. Similarly, tapentadol had no relevant effect on other ECG parameters (heart rate, PR interval, QRS duration, T-wave or U-wave morphology).

Tapentadol 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 (6.2 )].

They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Use of opioids for an extended period of time 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 (6.2 )].

Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. 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 opioid agonists. The minimum effective analgesic concentration of tapentadol 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 (2.1 , 2… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Tapentadol is a centrally-acting synthetic analgesic. The exact mechanism of action is unknown. Although the clinical relevance is unclear, preclinical studies have shown that tapentadol is a mu-opioid receptor (MOR) agonist and a norepinephrine reuptake inhibitor (NRI). Analgesia in animal models is derived from both of these properties.

12.3Pharmacokinetics Absorption The mean absolute bioavailability after single-dose administration (fasting) of tapentadol 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. Food Effect The AUC and C max 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.

Distribution 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%.

Elimination Metabolism 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. Excretion 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. Specific Populations Age: Geriatric Population 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.

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 hepatic impairment group (Child-Pugh Score 5 to 6) and moderate hepatic impairment group (Child-Pugh Score 7 to 9) in comparison to the normal hepatic function group were 1.7 and 4.2, respectively, for AUC; 1.4 and 2.5, respectively, for C max ; and 1.2 and 1.4, respectively, for t 1/2 .

The rate of formation of tapentadol-O-glucuronide was lower in subjects with increased liver impairment. Renal Impairment AUC and C max 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 (CL CR = 50 to <80 mL/min), moderate (CL CR = 30 to <50 mL/min), and severe (CL CR = <30 mL/min) renal impairment, the AUC of tapentadol-O-glucuronide was 1.5-, 2.5-, and 5.5- fold higher compared with normal renal function, respectively. Drug Interaction Studies 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%… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Effects on the Central Nervous System Tapentadol produces respiratory depression by direct action on the brainstem 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. Tapentadol 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 origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations. Effects on the Gastrointestinal Tract and Other Smooth Muscle Tapentadol 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, and opioid-induced esophageal dysfunction (OIED).

Effects on the Cardiovascular System There was no effect of therapeutic and supratherapeutic doses of tapentadol on the QT interval. In a randomized, double-blind, placebo-and positive-controlled crossover study, healthy subjects were administered five consecutive doses of tapentadol 100 mg every 6 hours, tapentadol 150 mg every 6 hours, placebo and a single oral dose of moxifloxacin. Similarly, tapentadol had no relevant effect on other ECG parameters (heart rate, PR interval, QRS duration, T-wave or U-wave morphology).

Tapentadol 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 (6.2 )].

They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Use of opioids for an extended period of time 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 (6.2 )].

Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. 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 opioid agonists. The minimum effective analgesic concentration of tapentadol 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 (2.1 , 2.6 )]. Concentration-Adverse Experience Relationships There is a relationship between increasing tapentadol plasma concentration and increasing frequency of dose-related 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 Dosag… [Excerpted — this section continues on DailyMed.]

14 CLINICAL STUDIES

14.1Clinical Studies in Adult Patients The efficacy and safety of tapentadol tablets in the treatment of acute pain has been established in two randomized, double-blind, placebo-and active-controlled studies of moderate to severe pain from first metatarsal bunionectomy and end-stage degenerative joint disease. Orthopedic Surgery – Bunionectomy A randomized, double-blind, parallel-group, active- and placebo-controlled, multiple-dose study demonstrated the efficacy of 50 mg, 75 mg, and 100 mg tapentadol tablets given every 4 to 6 hours for 72 hours in patients aged 18 to 80 years experiencing moderate to severe pain following unilateral, first metatarsal bunionectomy surgery.

Patients who qualified for the study with a baseline pain score of >4 on an 11-point rating scale ranging from 0 to 10 were randomized to 1 of 5 treatments. Patients were allowed to take a second dose of study medication as soon as 1 hour after the first dose on study Day 1, with subsequent dosing every 4 to 6 hours. If rescue analgesics were required, the patients were discontinued for lack of efficacy.

Efficacy was evaluated by comparing the sum of pain intensity difference over the first 48 hours (SPID48) versus placebo. Tapentadol tablets at each dose provided a greater reduction in pain compared to placebo based on SPID48 values. For various degrees of improvement from baseline to the 48-hour endpoint, Figure 1 shows the fraction of patients achieving that level of improvement.

The figures are cumulative, such that every patient that achieves a 50% reduction in pain from baseline is included in every level of improvement below 50%. Patients who did not complete the 48-hour observation period in the study were assigned 0% improvement. Figure 1.

Percentage of Patients Achieving Various Levels of Pain Relief as Measured by Pain Severity at 48 Hours Compared to Baseline- Post Operative Bunionectomy The proportions of patients who showed reduction in pain intensity at 48 hours of 30% or greater, or 50% or greater were significantly higher in patients treated with tapentadol tablets at each dose versus placebo. End-Stage Degenerative Joint Disease A randomized, double-blind, parallel-group, active- and placebo-controlled, multiple-dose study evaluated the efficacy and safety of 50 mg and 75 mg tapentadol tablets given every 4 to 6 hours during waking hours for 10 days in patients aged 18 to 80 years, experiencing moderate to severe pain from end stage degenerative joint disease of the hip or knee, defined as a 3-day mean pain score of ≥5 on an 11-point pain intensity scale, ranging from 0 to 10.

Pain scores were assessed twice daily and assessed the pain the patient had experienced over the previous 12 hours. Patients were allowed to continue non-opioid analgesic therapy for which they had been on a stable regimen before screening throughout the study. Eighty-three percent (83%) of patients in the tapentadol treatment groups and the placebo group took such analgesia during the study.

The 75 mg treatment group was dosed at 50 mg for the first day of the study, followed by 75 mg for the remaining nine days. Patients requiring rescue analgesics other than study medication were discontinued for lack of efficacy. Efficacy was evaluated by comparing the sum of pain intensity difference (SPID) versus placebo over the first five days of treatment.

Tapentadol tablets 50 mg and 75 mg provided improvement in pain compared with placebo based on the 5-Day SPID. For various degrees of improvement from baseline to the Day 5 endpoint, Figure 2 shows the fraction of patients achieving that level of improvement. The figures are cumulative, such that every patient that achieves a 50% reduction in pain from baseline is included in every level of improvement below 50%.

Patients who did not complete the 5-day observation period in the study were assigned 0% improvement. Figure 2. Percentage of Patients Achieving Various Levels of Pain Relief as Measured by Av… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis 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 for 2 years (up to 0.2 times the plasma exposure at the maximum recommended human dose [MRHD] on an area under the time-curve [AUC] basis). No increase in tumor incidence was observed at any dose level.

In rats, tapentadol HCl was administered in diet at dosages of 10, 50, 125 and 250 mg/kg/day for two years (up to 0.2 times in the male rats and 0.6 times in the female rats the MRHD on an AUC basis). No increase in tumor incidence was observed at any dose level. Mutagenesis Tapentadol did not induce gene mutations in bacteria, but was clastogenic with metabolic activation in a chromosomal aberration test in V79 cells.

The test was repeated and was negative in the presence and absence of metabolic activation. The one positive result for tapentadol was not confirmed in vivo in rats, using the two endpoints of chromosomal aberration and unscheduled DNA synthesis, when tested up to the maximum tolerated dose. Impairment of Fertility Tapentadol HCl was administered intravenously to male or female rats at dosages of 3, 6, or 12 mg/kg/day (representing exposures of up to approximately 0.4 times the exposure at the MRHD on an AUC basis, based on extrapolation from toxicokinetic analyses in a separate 4-week intravenous study in rats).

Tapentadol did not alter fertility at any dose level. Maternal toxicity and adverse effects on embryonic development, including decreased number of implantations, decreased numbers of live conceptuses, and increased pre-and post-implantation losses occurred at dosages ≥6 mg/kg/day.

13.2Animal Toxicology and/orPharmacology In toxicological studies with tapentadol, the most common systemic effects of tapentadol were related to the mu-opioid receptor agonist and norepinephrine reuptake inhibition pharmacodynamic properties of the compound. Transient, dose-dependent and predominantly CNS-related findings were observed, including impaired respiratory function and convulsions, the latter occurring in the dog at plasma levels (C max ) which are in the range associated with the maximum recommended human dose (MRHD).