TONMYA Cyclobenzaprine Hydrochloride 2.8 mg Tablet, Orally Disintegrating, 60-count — NDC 70792-102-60 (Billing 70792-0102-60)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action The mechanism of action of cyclobenzaprine for the treatment of fibromyalgia in adults is unknown. In in vitro pharmacology studies, cyclobenzaprine demonstrated functional antagonism of 5-HT 2A , α 1 -adrenergic, H 1 -histaminergic, and M 1 -muscarinic acetylcholine receptors. In addition, pharmacological studies in animals demonstrated a similarity between the effects of cyclobenzaprine and the structurally related TCAs, including reserpine antagonism, norepinephrine potentiation, potent peripheral and central anticholinergic effects, and sedation.

12.2Pharmacodynamics The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of cyclobenzaprine have not been fully characterized.

12.3Pharmacokinetics Following single-dose sublingual administration of 2.8 mg and 5.6 mg of TONMYA in healthy adult subjects (n=16), C max , AUC 0-tau, and AUC 0-inf of cyclobenzaprine increased in an approximately dose-proportional manner. In a multiple-dose study of 5.6 mg of TONMYA administered sublingually once daily for 20 days in healthy subjects (n=26), approximately 2.5-fold accumulation of plasma cyclobenzaprine exposure was observed at steady-state. Absorption The median time to peak plasma cyclobenzaprine concentration (T max ) was approximately 4.3 hours for the 2.8 mg and 5.6 mg once daily TONMYA dosages.

Food Effect: A food effect study was conducted in healthy adult subjects (n=16) with a single sublingual 5.6 mg TONMYA dose. When TONMYA was administered with food, there was approximately 10% decrease in peak plasma concentration (C max ) compared to the fasted state with no effect on exposure (AUC 0-tau and AUC 0-inf ). These changes are not clinically significant.

Elimination TONMYA has a single dose elimination half-life of approximately 36 hours (range 28-59 hours; n=16). Metabolism: Cyclobenzaprine is extensively metabolized. Cytochromes P-450 3A4, 1A2, and, to a lesser extent, 2D6 mediate N-demethylation, one of the oxidative pathways for cyclobenzaprine metabolism.

Excretion: Cyclobenzaprine is excreted primarily as glucuronides via the kidney. Specific Populations Geriatric Patients: After cyclobenzaprine extended-release capsules dosing, the plasma cyclobenzaprine AUC was increased by 40% and the half-life of cyclobenzaprine was prolonged in geriatric subjects greater than 65 years of age compared to younger adult subjects 18 to 45 years of age (50 hours vs. 32 hours, respectively) [see Use in Specific Populations (8.5) ].

There were no notable differences in C max or T max in this study. Hepatic Impairment: In a pharmacokinetic study of immediate-release cyclobenzaprine tablets in 15 patients with mild hepatic impairment (HI) (Child-Pugh A) and 1 patient with moderate HI (Child-Pugh B), both AUC and C max were approximately double the values seen in subjects with normal hepatic function. The pharmacokinetics of cyclobenzaprine in patients with moderate HI (1 patient only) and severe HI is not known [see Use in Specific Populations (8.6) ] .

12.1Mechanism of Action The mechanism of action of cyclobenzaprine for the treatment of fibromyalgia in adults is unknown. In in vitro pharmacology studies, cyclobenzaprine demonstrated functional antagonism of 5-HT 2A , α 1 -adrenergic, H 1 -histaminergic, and M 1 -muscarinic acetylcholine receptors. In addition, pharmacological studies in animals demonstrated a similarity between the effects of cyclobenzaprine and the structurally related TCAs, including reserpine antagonism, norepinephrine potentiation, potent peripheral and central anticholinergic effects, and sedation.

12.3Pharmacokinetics Following single-dose sublingual administration of 2.8 mg and 5.6 mg of TONMYA in healthy adult subjects (n=16), C max , AUC 0-tau, and AUC 0-inf of cyclobenzaprine increased in an approximately dose-proportional manner. In a multiple-dose study of 5.6 mg of TONMYA administered sublingually once daily for 20 days in healthy subjects (n=26), approximately 2.5-fold accumulation of plasma cyclobenzaprine exposure was observed at steady-state. Absorption The median time to peak plasma cyclobenzaprine concentration (T max ) was approximately 4.3 hours for the 2.8 mg and 5.6 mg once daily TONMYA dosages.

Food Effect: A food effect study was conducted in healthy adult subjects (n=16) with a single sublingual 5.6 mg TONMYA dose. When TONMYA was administered with food, there was approximately 10% decrease in peak plasma concentration (C max ) compared to the fasted state with no effect on exposure (AUC 0-tau and AUC 0-inf ). These changes are not clinically significant.

Elimination TONMYA has a single dose elimination half-life of approximately 36 hours (range 28-59 hours; n=16). Metabolism: Cyclobenzaprine is extensively metabolized. Cytochromes P-450 3A4, 1A2, and, to a lesser extent, 2D6 mediate N-demethylation, one of the oxidative pathways for cyclobenzaprine metabolism.

Excretion: Cyclobenzaprine is excreted primarily as glucuronides via the kidney. Specific Populations Geriatric Patients: After cyclobenzaprine extended-release capsules dosing, the plasma cyclobenzaprine AUC was increased by 40% and the half-life of cyclobenzaprine was prolonged in geriatric subjects greater than 65 years of age compared to younger adult subjects 18 to 45 years of age (50 hours vs. 32 hours, respectively) [see Use in Specific Populations (8.5) ].

There were no notable differences in C max or T max in this study. Hepatic Impairment: In a pharmacokinetic study of immediate-release cyclobenzaprine tablets in 15 patients with mild hepatic impairment (HI) (Child-Pugh A) and 1 patient with moderate HI (Child-Pugh B), both AUC and C max were approximately double the values seen in subjects with normal hepatic function. The pharmacokinetics of cyclobenzaprine in patients with moderate HI (1 patient only) and severe HI is not known [see Use in Specific Populations (8.6) ] .

12.2Pharmacodynamics The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of cyclobenzaprine have not been fully characterized.

14 CLINICAL STUDIES The efficacy of TONMYA for the treatment of fibromyalgia was assessed in three randomized, two-arm, parallel-group, double-blind, placebo-controlled multicenter trials (Trial 1 [NCT04172831], Trial 2 [NCT04508621], and Trial 3 [NCT05273749]). The trials enrolled 1,474 patients aged 18 to 65 (735 TONMYA-treated patients and 739 placebo-treated patients) who met the 2016 American College of Rheumatology (ACR) criteria for diagnosis of fibromyalgia (including generalized pain, defined as pain in at least 4 of 5 regions; symptoms that had been present at a similar level for at least 3 months; and widespread pain index (WPI) ≥7 and symptom severity scale (SSS) score ≥5, OR WPI between 4 to 6 and SSS scale score ≥9).

In the trials, 95% of patients were female, 83% of patients were not Hispanic or Latino, and the percentage of White, Black, and Asian patients were 86%, 9%, and 1%, respectively. The mean age was 49 years (range 18 to 65 years), and the mean duration of fibromyalgia was 9 years (range 0 to 49 years). Patients were randomized to receive bedtime sublingual treatment of either: 2.8 mg of TONMYA nightly for the first 2 weeks, and then 5.6 mg of TONMYA beginning on the evening of Day 15 through Week 14.

Placebo administered through Week 14. The primary endpoint in all three trials was the change from baseline to Week 14 in the weekly average of daily 24-hour recall pain intensity scores. As measured by the 11-point (0-10) numeric rating scale (NRS), the minimum mean baseline pain score required for enrollment was 4.

Within each trial, at baseline, the TONMYA and placebo groups had similar mean weekly averages of daily diary pain scores. In Trials 1 and 3, TONMYA demonstrated a statistically significant reduction in pain intensity scores as compared to placebo (Table 2). In Trial 2, there was no statistically significant treatment group difference (TONMYA minus placebo).

Results of this trial may not have been generalizable due to the presence of factors outside the conduct of the study. The least squares (LS) mean change from baseline in the weekly average of daily 24-hour recall pain intensity scores at Week 14 in adult patients with fibromyalgia for the TONMYA and placebo groups in Trial 1 and Trial 3 are presented in Table 2. The LS mean change from baseline in the weekly average of daily 24-hour recall pain intensity scores over the weeks of the study in adult patients with fibromyalgia in Trials 1 and 3 are presented in Figure 1.

Table 2: Primary Efficacy Endpoint: Mean Change from Baseline in Weekly Average of Daily 24-Hour Recall Pain Intensity Scores at Week 14 in Adult Patients with Fibromyalgia (Trials 1 and 3) Placebo TONMYA Visit/ Statistics Value Change from baseline Value Change from baseline CI = confidence interval; LS = least squares; SD = standard deviation; SE = standard error Trial 1 Baseline N 255 248 Mean (SD) 6.0 (1.08) 6.1 (1.06) (Minimum, Maximum) (4, 9) (4, 9) Week 14 LS mean (SE) LS means, differences and CIs were based on a mixed model for repeated measures with fixed, categorical effects of treatment, center, study week, and treatment-by-study week interaction, as well as the fixed covariates of baseline value and baseline value-by-study week interactions.

An unstructured covariance matrix was used. 4.6 (0.12) -1.5 (0.12) 4.2 (0.12) -1.9 (0.12) 95% CI (4.3, 4.8) (-1.7, -1.3) (3.9, 4.4) (-2.1, -1.7) Difference in LS mean (SE) -0.4 (0.16) 95% CI for difference in LS mean (-0.7, -0.1) p-value for difference 0.010 Trial 3 Baseline N 225 231 Mean (SD) 5.9 (1.08) 5.9 (1.05) (Minimum, Maximum) (4, 9) (4, 9) Week 14 LS mean (SE) 4.7 (0.12) -1.2 (0.12) 4.1 (0.12) -1.8 (0.12) 95% CI (4.5, 5.0) (-1.4, -0.9) (3.8, 4.3) (-2.0, -1.6) Difference in LS mean (SE) -0.7 (0.16) The difference in the LS mean (i.e., -0.7) was due to a rounding effect: the change from baseline was -1.82 in the TONMYA group and -1.16 in the placebo group, and the difference in LS mean between the groups was -0.66.

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13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies were conducted in CD-1 mice and Sprague-Dawley rats with oral cyclobenzaprine to evaluate its carcinogenic potential. In an 81-week carcinogenicity study, metastatic hemangiosarcoma was seen in 3 of 21 male mice at 10 mg/kg/day (approximately 9 times the maximum recommended human dose (MRHD) of 5.6 mg of TONMYA on a mg/m 2 basis). In a 105-week carcinogenicity study, malignant astrocytoma was seen in 3 of 50 male rats at 10 mg/kg/day (approximately 0.3 times the MRHD on an estimated AUC basis).

There were no tumor findings in female mice or rats. Mutagenesis Cyclobenzaprine was not mutagenic or clastogenic in the following assays: in vitro Ames bacterial mutation assays, an in vitro Chinese hamster ovary (CHO) cell chromosomal aberration test, an in vitro CHO cell micronucleus test, and in vivo mouse bone marrow micronucleus assays. Impairment of Fertility Cyclobenzaprine HCl, when administered 70 and 14 days prior to mating to male and female rats, respectively, had no effects on fertility or reproductive performance at oral doses up to 20 mg/kg/day (approximately 1.1 and 3.8 times in males and females, respectively, the MRHD on an estimated AUC basis).

13.2Animal Toxicology and/or Pharmacology In a 67-week study with rats that received cyclobenzaprine at oral doses of 10, 20, or 40 mg/kg/day (approximately 0.3 to 4.3 times and 1.2 to 12.4 times in males and females, respectively, the maximum recommended human dose (MRHD) of 5.6 mg of TONMYA on an estimated AUC basis), there were findings in the liver consisting of midzonal vacuolation with lipidosis for males and midzonal and centrilobular hepatocytic enlargement for females. In addition, there were findings of centrilobular coagulative necrosis.

In the higher dose groups, these microscopic changes were seen after 26 weeks and even earlier in rats that died prior to 26 weeks; at lower doses, these changes were not seen until after 26 weeks. In a 26-week study with Cynomolgus monkeys that received cyclobenzaprine at oral of doses of 2.5, 5, 10, or 20 mg/kg/day, one monkey at 20 mg/kg/day (69 times the MRHD on mg/m 2 basis) was euthanized in week 17. Morbidity for this animal was attributed to findings of chronic pancreatitis, cholecystitis, cholangitis, and focal liver necrosis.