Tonmya

Description

Cyclobenzaprine hydrochloride, USP is a white to off-white crystalline tricyclic amine salt powder, chemically identified as 1-Propanamine, 3-(5H-dibenzoa,dcyclohepten-5-ylidene)-N,N-dimethyl-, hydrochloride. Its molecular formula is C20H21N ∙ HCl, and it has a molecular weight of 311.85 g/mol. The compound exhibits a pK of 6.8 and is freely soluble in water, with solubility being pH independent. Each sublingual tablet contains 2.8 mg of cyclobenzaprine hydrochloride, which is equivalent to 2.47 mg of cyclobenzaprine. The formulation includes the following inactive ingredients: colloidal silicon dioxide, corn starch, crospovidone (Type A), D&C Yellow No.10, dibasic potassium phosphate, mannitol, and sodium stearyl fumarate.

Uses and Indications

TONMYA is indicated for the treatment of fibromyalgia in adults.

There are no teratogenic or nonteratogenic effects associated with this drug.

Dosage and Administration

The recommended dosage of TONMYA is 5.6 mg, administered sublingually once daily at bedtime.

For the initial treatment period, from Days 1 to 14, the starting dose is 2.8 mg, which corresponds to one sublingual tablet, taken once daily at bedtime. Following this period, from Day 15 onward, the target dose is 5.6 mg, equivalent to two sublingual tablets, administered once daily at bedtime. The maximum recommended dosage is 5.6 mg once daily.

Prior to sublingual administration, it is essential to ensure that the mouth is moist by taking sips of water. The tablets must not be swallowed whole, cut, crushed, or chewed to ensure proper absorption.

For geriatric patients, the recommended dosage is 2.8 mg, administered sublingually once daily at bedtime.

In patients with hepatic impairment, the recommended dosage for those with mild hepatic impairment is also 2.8 mg, administered sublingually once daily at bedtime. The use of TONMYA is not recommended for patients with moderate or severe hepatic impairment.

Contraindications

Use of TONMYA is contraindicated in the following situations:

• Patients with hypersensitivity to cyclobenzaprine or any inactive ingredient in TONMYA.

• Concomitant use with monoamine oxidase (MAO) inhibitors or within 14 days following their discontinuation, due to the risk of hypertensive crisis.

• During the acute recovery phase of myocardial infarction, and in patients with arrhythmias, heart block, conduction disturbances, or congestive heart failure, as these conditions may be exacerbated by cyclobenzaprine.

• Patients with hyperthyroidism, as cyclobenzaprine may further complicate the management of this condition.

Warnings and Precautions

Based on animal studies, TONMYA has been associated with embryofetal toxicity, specifically the potential to cause neural tube defects when administered two weeks prior to conception and throughout the first trimester of pregnancy. Healthcare professionals are advised to inform females of reproductive potential about this risk and to recommend the use of effective contraception during treatment and for two weeks following the final dose.

The risk of serotonin syndrome, a potentially life-threatening condition, has been documented with the use of cyclobenzaprine in conjunction with other serotonergic agents. Should symptoms indicative of serotonin syndrome arise, it is imperative to immediately discontinue the use of TONMYA alongside the serotonergic medication and initiate supportive symptomatic treatment. If the concurrent use of TONMYA and other serotonergic drugs is deemed clinically necessary, careful monitoring is essential, particularly during the initiation of treatment or when increasing dosages.

Adverse reactions similar to those observed with tricyclic antidepressants (TCAs) have been reported, including arrhythmias, sinus tachycardia, and conduction time prolongation, which may lead to myocardial infarction and stroke. Additionally, TCAs can lower the seizure threshold and are associated with serious central nervous system (CNS) reactions. In the event that clinically significant CNS symptoms manifest, discontinuation of TONMYA should be considered.

Caution is advised when prescribing TONMYA to patients with a history of urinary retention, angle-closure glaucoma, or increased intraocular pressure, as well as to those taking anticholinergic medications, due to the potential for atropine-like adverse reactions.

Patients should be made aware that TONMYA monotherapy may induce CNS depression. It is recommended that patients refrain from operating motor vehicles or engaging in hazardous activities until they are confident that the effects of TONMYA will not impair their ability to perform such tasks safely.

Oral mucosal adverse reactions have been reported more frequently in patients treated with TONMYA compared to those receiving placebo. To mitigate the risk of oral sensory changes, such as hypoesthesia, patients should be advised to moisten their mouths with sips of water prior to the administration of TONMYA. In cases of severe oral mucosal reactions, consideration should be given to discontinuing the medication.

Side Effects

In clinical trials, a significant proportion of patients treated with TONMYA experienced oral mucosal adverse reactions, with 43% reporting at least one treatment-emergent reaction compared to 8% of those receiving placebo. The most common oral mucosal adverse reactions included oral hypoesthesia, abnormal product taste, oral paresthesia, tongue discomfort, oral discomfort, glossodynia, oral pain, and aphthous ulcers. Notably, 82% of these reactions began within minutes of dosing, and 88% occurred after nearly every dose. While almost two-thirds of these reactions lasted less than 60 minutes, 63% of those lasting longer than 60 minutes were still present the following morning. Severe oral mucosal adverse reactions were reported in 0.7% of TONMYA-treated patients, including paresthesia, glossitis, hypoesthesia, oral pain, and dry mouth. Discontinuation due to oral mucosal adverse reactions was more frequent in TONMYA-treated patients (4.5%) compared to placebo-treated patients (0.5%).

Common adverse reactions observed in long-term safety trials (occurring in more than 5% of participants) included oral hypoesthesia (45%), somnolence (18%), abnormal product taste (7%), and oral paresthesia (7%). In another trial, additional common adverse reactions included fatigue (7%), sinusitis (7%), and hypoesthesia oral (15%).

Postmarketing experience has revealed other adverse reactions, including drowsiness, dry mouth, dizziness, fatigue, asthenia, nausea, constipation, dyspepsia, unpleasant taste, blurred vision, headache, nervousness, and confusion.

Serious adverse reactions have been reported across various systems. Cardiovascular events included tachycardia, arrhythmia, vasodilatation, palpitation, hypotension, hypertension, myocardial infarction, heart block, and stroke. Gastrointestinal reactions encompassed vomiting, anorexia, diarrhea, gastrointestinal pain, gastritis, and rare reports of hepatitis, jaundice, and cholestasis. Neurological and psychiatric adverse reactions included seizures, ataxia, vertigo, dysarthria, tremors, hypertonia, convulsions, disorientation, insomnia, and various mood disturbances. Other serious reactions involved hypersensitivity reactions such as anaphylaxis and angioedema, as well as hematologic issues like purpura and leukopenia.

In cases of overdose, the most common adverse reactions included drowsiness and tachycardia, while less frequent manifestations were tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Rare but critical manifestations of overdose included cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, neuroleptic malignant syndrome, rhabdomyolysis, and death.

Drug Interactions

There are currently no documented drug interactions associated with this medication. Additionally, there is no information available regarding interactions with laboratory tests. As such, no specific recommendations for dosage adjustments or monitoring are warranted at this time.

Packaging & NDC

The table below lists all NDC Code configurations of Tonmya (cyclobenzaprine hydrochloride), the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

The safety and effectiveness of TONMYA have not been established in pediatric patients. Therefore, its use in this population is not recommended.

Geriatric Use

Elderly patients, defined as those 65 years of age and older, were not represented in the clinical trials of TONMYA for fibromyalgia, as no participants in this age group were included. Consequently, there is insufficient data to determine whether geriatric patients respond differently to TONMYA compared to younger adults.

Pharmacokinetic studies indicate that after administration of cyclobenzaprine extended release capsules, elderly patients exhibit significantly increased plasma concentrations and a prolonged half-life of cyclobenzaprine compared to younger patients. This heightened exposure necessitates careful consideration when prescribing TONMYA to this population.

Due to the increased plasma levels of cyclobenzaprine in patients aged 65 and older, the recommended dosage for these individuals is 2.8 mg once daily at bedtime. This dosage is lower than that recommended for younger adult patients, underscoring the importance of dose adjustments and monitoring in geriatric patients to mitigate potential risks associated with higher drug exposure.

Pregnancy

Based on animal data, TONMYA may cause fetal harm when administered to a pregnant woman. In studies involving rabbits, an increased incidence of neural tube defects, including splayed vertebral arches and spina bifida occulta, was observed when pregnant rabbits were treated with oral cyclobenzaprine during embryogenesis at a dose of 30 mg/kg/day, which is approximately 0.2 times the maximum recommended human dose (MRHD) of TONMYA, without evidence of maternal toxicity. Additionally, in rat studies, decreased pup body weight and survival were noted at cyclobenzaprine doses of ≥10 mg/kg/day (approximately ≥0.8 times the MRHD of TONMYA) when administered orally during pregnancy and lactation.

The limited observational data available regarding oral cyclobenzaprine use in pregnancy is of insufficient quality to adequately inform a TONMYA-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Therefore, healthcare professionals should advise pregnant women about the potential risks to the fetus associated with maternal exposure to TONMYA. It is recommended that women avoid the use of TONMYA two weeks prior to conception and throughout the first trimester of pregnancy.

It is important to note that all pregnancies carry a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is approximately 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for pregnant women with fibromyalgia remains unknown.

Healthcare professionals are encouraged to report pregnancies to the Tonix Medicines, Inc., Adverse Event reporting line at 1-888-869-7633 (1-888-TNXPMED).

Lactation

A small number of published cases report the transfer of cyclobenzaprine into human milk in low amounts; however, these data cannot be confirmed. Currently, there are no data available regarding the effects of cyclobenzaprine on breastfed infants or its impact on milk production.

Healthcare professionals should consider the developmental and health benefits of breastfeeding alongside the clinical need for TONMYA in lactating mothers. Additionally, potential adverse effects on the breastfed child from TONMYA or from the underlying maternal condition should be taken into account.

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available data regarding dosage adjustments, special monitoring, or safety considerations. Therefore, healthcare professionals should exercise caution when prescribing this medication to patients with reduced kidney function, as the lack of information necessitates careful clinical judgment and monitoring.

Hepatic Impairment

In patients with mild hepatic impairment (Child Pugh A), the recommended dosage of TONMYA is 2.8 mg once daily at bedtime, which is lower than the dosage recommended for patients with normal hepatic function. It is important to note that the use of TONMYA is not recommended in patients with moderate hepatic impairment (Child Pugh B) or severe hepatic impairment (Child Pugh C).

Additionally, cyclobenzaprine exposure (AUC) has been shown to be increased in patients with both mild and moderate hepatic impairment compared to subjects with normal hepatic function. This increased exposure may elevate the risk of adverse reactions associated with TONMYA. Therefore, careful consideration and monitoring are advised for patients with hepatic impairment when prescribing this medication.

Overdosage

In cases of cyclobenzaprine overdose, healthcare professionals should be vigilant for a range of symptoms and take appropriate management steps to mitigate risks.

Common Symptoms of Overdosage The most frequently observed adverse reactions associated with cyclobenzaprine overdose include drowsiness and tachycardia. Other less common manifestations may present as tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations.

Severe and Rare Manifestations Rare but potentially life-threatening symptoms can include cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, neuroleptic malignant syndrome, rhabdomyolysis, and even death. Clinicians should be particularly attentive to changes in the electrocardiogram (ECG), especially alterations in the QRS axis or width, as these are significant indicators of cyclobenzaprine toxicity.

Management Recommendations Due to the rapid onset of toxicity symptoms following an overdose, immediate hospital monitoring is recommended. It is common for multiple drugs, including alcohol, to be ingested in deliberate cyclobenzaprine overdoses, necessitating comprehensive evaluation and management.

Upon presentation, the following steps should be taken:

• Obtain an ECG and initiate cardiac monitoring to assess for dysrhythmias.

• Protect the patient's airway and establish an intravenous line.

• Monitor for signs of central nervous system (CNS) or respiratory depression, hypotension, cardiac dysrhythmias, and seizures.

It is important to note that monitoring plasma cyclobenzaprine levels should not guide the management of the overdose. Dialysis is generally considered ineffective due to the low plasma concentrations of cyclobenzaprine.

Specific Interventions A maximal limb-lead QRS duration of 0.1 seconds may serve as a critical indicator of the overdose's severity. For patients exhibiting dysrhythmias or QRS widening, serum alkalinization to a pH of 7.45 to 7.55 should be initiated using intravenous sodium bicarbonate and hyperventilation. If dysrhythmias persist despite these interventions, lidocaine or phenytoin may be effective.

In cases of CNS depression, early intubation is advised due to the risk of abrupt deterioration. Seizures should be managed with benzodiazepines, and if these are ineffective, alternative anticonvulsants such as phenobarbital or phenytoin may be utilized.

Caution with Physostigmine Physostigmine is not recommended except in instances of life-threatening symptoms that do not respond to other therapies, and its use should only occur in close consultation with a poison center.

In summary, prompt recognition of symptoms and immediate management are crucial in addressing cyclobenzaprine overdose to prevent serious complications.

Nonclinical Toxicology

No teratogenic effects were observed in nonclinical studies. Additionally, there were no non-teratogenic effects reported.

Carcinogenesis studies were conducted in CD-1 mice and Sprague-Dawley rats to assess the carcinogenic potential of cyclobenzaprine. In an 81-week study, metastatic hemangiosarcoma was identified in 3 of 21 male mice at a dose of 10 mg/kg/day, which is approximately 9 times the maximum recommended human dose (MRHD) of 5.6 mg of TONMYA on a mg/m² basis. In a separate 105-week study, malignant astrocytoma was observed in 3 of 50 male rats at the same dose of 10 mg/kg/day, approximately 0.3 times the MRHD based on estimated AUC. No tumors were found in female mice or rats.

Cyclobenzaprine was evaluated for mutagenic potential and was found to be neither mutagenic nor clastogenic in various assays, including 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.

In terms of fertility, cyclobenzaprine HCl was administered to male and female rats at doses up to 20 mg/kg/day, given 70 and 14 days prior to mating, respectively. The results indicated no effects on fertility or reproductive performance, with doses approximately 1.1 and 3.8 times the MRHD on an estimated AUC basis for males and females, respectively.

In animal pharmacology and toxicology studies, a 67-week study in rats receiving oral doses of cyclobenzaprine at 10, 20, or 40 mg/kg/day (approximately 0.3 to 4.3 times and 1.2 to 12.4 times the MRHD on an estimated AUC basis) revealed liver findings. These included midzonal vacuolation with lipidosis in males and midzonal and centrilobular hepatocytic enlargement in females, along with centrilobular coagulative necrosis. Microscopic changes in the higher dose groups were noted after 26 weeks, with earlier occurrences in rats that died prior to this time; lower doses did not show these changes until after 26 weeks.

A 26-week study in Cynomolgus monkeys administered oral doses of cyclobenzaprine at 2.5, 5, 10, or 20 mg/kg/day indicated that one monkey at the highest dose of 20 mg/kg/day (69 times the MRHD on a mg/m² basis) was euthanized in week 17 due to morbidity attributed to chronic pancreatitis, cholecystitis, cholangitis, and focal liver necrosis.

Postmarketing Experience

Adverse reactions have been reported in clinical studies and postmarketing experience with cyclobenzaprine immediate-release (IR) and extended-release (ER) products, as well as tricyclic antidepressants (TCAs). Due to the voluntary nature of these reports from a population of uncertain size, it is not always feasible to reliably estimate their frequency or establish a causal relationship to drug exposure.

In a postmarketing surveillance program for cyclobenzaprine IR products, the most frequently reported adverse reactions included drowsiness, dry mouth, and dizziness. Additional adverse reactions reported in 1% to 3% of patients encompassed fatigue/tiredness, asthenia, nausea, constipation, dyspepsia, unpleasant taste, blurred vision, headache, nervousness, and confusion.

Further adverse reactions reported in postmarketing experience with cyclobenzaprine ER or IR products, in clinical studies of cyclobenzaprine IR products (incidence <1%), or in postmarketing experience with other TCAs include:

Body as a Whole: Syncope, malaise, chest pain, edema. Cardiovascular: Tachycardia, arrhythmia, vasodilatation, palpitation, hypotension, hypertension, myocardial infarction, heart block, stroke. Digestive: Vomiting, anorexia, diarrhea, gastrointestinal pain, gastritis, thirst, flatulence, edema of the tongue, abnormal liver function, rare reports of hepatitis, jaundice, cholestasis, paralytic ileus, tongue discoloration, stomatitis, parotid swelling. Endocrine: Inappropriate ADH syndrome. Hematologic and Lymphatic: Purpura, bone marrow depression, leukopenia, eosinophilia, thrombocytopenia. Hypersensitivity: Anaphylaxis, angioedema, pruritus, facial edema, urticaria, rash. Metabolic, Nutritional, and Immune: Elevation and lowering of blood sugar levels, weight gain or loss. Musculoskeletal: Local weakness, myalgia. Nervous System and Psychiatric: Seizures, ataxia, vertigo, dysarthria, tremors, hypertonia, convulsions, muscle twitching, disorientation, insomnia, depressed mood, abnormal sensations, anxiety, agitation, psychosis, abnormal thinking and dreaming, hallucinations, excitement, paresthesia, diplopia, serotonin syndrome, neuroleptic malignant syndrome, decreased or increased libido, abnormal gait, delusions, aggressive behavior, paranoia, peripheral neuropathy, Bell's palsy, alteration in EEG patterns, extrapyramidal symptoms. Respiratory: Dyspnea. Skin: Sweating, photosensitization, alopecia. Special Senses: Ageusia, tinnitus. Urogenital: Urinary frequency and/or retention, impaired urination, dilatation of urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, galactorrhea.

Patient Counseling

Healthcare providers should advise patients to read the FDA-approved patient labeling (Patient Information) thoroughly. It is important to instruct patients not to swallow whole, cut, crush, or chew TONMYA. To minimize the risk of oral numbness, patients should moisten their mouths with sips of water prior to administering TONMYA.

In the event that a dose is missed, patients should take the next dose at the regularly scheduled time the following evening and should not take two doses to compensate for the missed dose. Patients must be informed to stop taking TONMYA and notify their healthcare provider immediately if they experience any symptoms of an allergic reaction, such as difficulty breathing, hives, swelling of the face or tongue, or itching.

Healthcare providers should caution patients against taking TONMYA with MAO inhibitors or within 14 days after discontinuation of a MAO inhibitor. Additionally, patients should be made aware of the risk of serotonin syndrome when using TONMYA in conjunction with other medications, including SSRIs, SNRIs, TCAs, tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. Patients should be informed of the signs and symptoms of serotonin syndrome and instructed to seek medical care immediately if they experience these symptoms.

Patients should also be advised to stop taking TONMYA and notify their healthcare provider right away if they experience symptoms of arrhythmias or tachycardia. It is essential to inform patients that TONMYA may enhance the impairment effects of alcohol, and similar effects may occur if taken with other CNS depressants.

Healthcare providers should encourage patients to report any severe oral mucosal adverse reactions to their healthcare provider. Patients should be cautioned about operating a motor vehicle or hazardous machinery until it is reasonably certain that TONMYA therapy will not adversely affect their ability to engage in such activities. It is recommended that patients take TONMYA at approximately the same time each night.

Female patients of reproductive potential should be informed that TONMYA may cause fetal harm and should notify their healthcare providers of any known or suspected pregnancy. They should also be advised to use effective contraception during treatment with TONMYA and for two weeks following the final dose. Furthermore, patients who are exposed to TONMYA during pregnancy should be instructed to contact Tonix Medicines, Inc., at 1-888-869-7633 (1-888-TNXPMED).

Storage and Handling

The product is supplied in its original container, which must be used for both storage and dispensing. It is essential to protect the product from moisture during handling. The polyester coil should be removed upon first use and discarded appropriately. Additionally, the desiccant canister must remain in the bottle throughout the entire period of use to ensure product integrity.

Storage conditions require the product to be maintained at a USP controlled room temperature of 20°C to 25°C (68°F to 77°F), with permissible excursions between 15°C to 30°C (59°F to 86°F).

Additional Clinical Information

The postmarketing experience and clinical studies of cyclobenzaprine immediate-release (IR) and extended-release (ER) products, as well as tricyclic antidepressants (TCAs), have identified a range of adverse reactions. Commonly reported reactions include drowsiness, dry mouth, dizziness, fatigue, asthenia, nausea, constipation, dyspepsia, unpleasant taste, blurred vision, headache, nervousness, and confusion.

Additional adverse reactions, with an incidence of less than 1%, encompass a variety of systems. Cardiovascular effects may include tachycardia, arrhythmia, and hypotension, while gastrointestinal issues can involve vomiting and abnormal liver function. Neurological and psychiatric effects range from seizures and ataxia to anxiety and psychosis. Other notable reactions include hypersensitivity responses such as anaphylaxis and angioedema, as well as metabolic changes like fluctuations in blood sugar levels. Clinicians should be aware of these potential adverse effects when prescribing cyclobenzaprine.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Tonmya as submitted by Tonix Medicines, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)