Carbinoxamine Maleate Extended-Release Oral Suspension

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Somnolence and Impaired Mental Alertness [see Warnings and Precautions (5.2)] Allergic Reactions due to Sulfites, including Anaphylaxis [see Warnings and Precautions (5.4)] The most frequent adverse reactions include: sedation, sleepiness, dizziness, disturbed coordination, epigastic distress, and thickening of bronchial secretions. In clinical use, younger children and older adults may be particularly sensitive to adverse reactions [see Pediatric Use (8.4) and Geriatric Use (8.5)]. The following adverse reactions, listed by body system, have been identified in case reports and during the use of carbinoxamine in observational studies. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole : Urticaria, drug rash, anaphylactic shock, photosensitivity, excessive perspiration, chills, dryness of mouth, nose and throat. Cardiovascular : Hypotension, headache, palpitations, tachycardia, extrasystoles. Central Nervous System : Fatigue, confusion, restlessness, excitation, nervousness, tremor, irritability, insomia, euphoria, paresthesia, blurred vision, diplopia, vertigo, tinnitus, acute labyrinthitis, hysteria, neuritis, convulsions. Gastrointestinal : Anorexia, nausea, vomiting, diarrhea, constipation. Hematologic : Hemolytic anemia, thrombocytopenia, agranulocytosis. Laboratory : Increase in uric acid levels. Respiratory : Tightness of chest and wheezing, nasal stuffiness. Urogenital : Urinary frequency, difficult urination, urinary retention, early menses. Most common adverse reactions are: sedation, sleepiness, dizziness, disturbed coordination, epigastric distress, and thickening of bronchial secretions. (6) To report SUSPECTED ADVERSE REACTIONS, contact Neos Therapeutics at 1-855-298-8246 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

4 CONTRAINDICATIONS Carbinoxamine Maleate Extended-Release Oral Suspension is contraindicated in: children younger than 2 years of age because deaths have been reported in this age group [see Warnings and Precautions (5.1)]. patients who are hypersensitive to carbinoxamine maleate or any of the inactive ingredients in Carbinoxamine Maleate Extended-Release Oral Suspension [see Warnings and Precautions (5.4)]. patients who are taking monoamine oxidase inhibitors (MAOI) [see Drug Interactions (7)]. Children younger than 2 years of age (4) Patients with known hypersensitivity to the drug or any of the inactive ingredients (4) Monoamine oxidase inhibitors (MAOI) (4)

11 DESCRIPTION Each 5 mL of Carbinoxamine Maleate extended-release oral suspension contains carbinoxamine complexed with polistirex equivalent to 4 mg carbinoxamine maleate and the following inactive ingredients: citric acid anhydrous, strawberry-banana flavor, glycerin, high fructose corn syrup, methylparaben, modified food starch, polysorbate 80, polyvinyl acetate, povidone, propylparaben, purified water, sodium metabisulfite, sodium polystyrene sulfonate, sucrose, triacetin, and xanthan gum. Carbinoxamine maleate is freely soluble in water. The chemical name is 2-[(4-chlorophenyl)-2- pyridinylmethoxy]-N, N-dimethylethanamine (Z)-2-butenedioate (1:1), which has the following structure: C16H19ClN2O·C4H4O4 MW = 406.86 The drug-polistirex complex is formed with the active ingredient (carbinoxamine maleate, USP) and sodium polystyrene sulfonate, USP, which has the following structure: structure 1 Structure 2

2 DOSAGE AND ADMINISTRATION Adults and Adolescents 12 years of age and older (2.3): 7.5 mL to 20 mL (6 to 16 mg) every 12 hours Pediatric patients 2-11 years of age (approximately 0.2 to 0.4 mg/kg/day) (2.4): 2 to 3 years – 3.75 mL to 5 mL (3 to 4 mg) every 12 hours 4 to 5 years – 3.75 mL to 10 mL (3 to 8 mg) every 12 hours 6 to 11 years – 7.5 mL to 15 mL (6 to 12 mg) every 12 hours 2.1 Overview The dosage of Carbinoxamine Maleate Extended-Release Oral Suspension should be individualized based on the severity of the condition and the response of the patient. Start with lower doses and increase as needed and tolerated. 2.2 Administration Administer Carbinoxamine Maleate Extended-Release Oral Suspension by the oral route only. Measure Carbinoxamine Maleate Extended-Release Oral Suspension with an accurate milliliter measuring device. A household teaspoon is not an accurate measuring device and could lead to overdosage. A pharmacist can provide an appropriate measuring device and can provide instructions for measuring the correct dose. 2.3 Recommended Dosage for Adults and Adolescents 12 years of age and older: 7.5 mL to 20 mL (6 mg to 16 mg) every 12 hours administered orally 2.4 Recommended Dosage for Pediatric Patients 2 to 11 years of age (approximately 0.2 to 0.4 mg/kg/day): 2 to 3 years: 3.75 mL to 5 mL (3 mg to 4 mg) every 12 hours administered orally 4 to 5 years: 3.75 mL to 10 mL (3 mg to 8 mg) every 12 hours administered orally 6 to 11 years: 7.5 mL to 15 mL (6 mg to 12 mg) every 12 hours administered orally

10 OVERDOSAGE Overdosage with carbinoxamine may cause central nervous system depression or stimulation, hallucinations, convulsions, and death. Atropine-like signs and symptoms – dry mouth; fixed, dilated pupils; flushing; and gastrointestinal symptoms may also occur. The treatment of overdosage consists of discontinuation of Carbinoxamine Maleate extended-release oral suspension and institution of symptomatic and supportive therapy. Vital signs (including respiration, pulse, blood pressure, and temperature) and EKG should be monitored. Induction of vomiting is not recommended. Activated charcoal should be given and gastric lavage should be considered after ingestion of a potentially life-threatening amount of drug. In the presence of severe anticholinergic effects, physostigmine may be useful. Vasopressors may be used to treat hypotension.

7 DRUG INTERACTIONS Do not use Carbinoxamine Maleate extended-release oral suspension in patients who are taking monoamine oxidase inhibitors (MAOIs), which prolong and intensify the anticholinergic (drying) effects of antihistamines. Avoid use of Carbinoxamine Maleate extended-release oral suspension with alcohol and other CNS depressants (hypnotics sedatives, tranquilizers, etc.) due to additive effects. Monoamine oxidase inhibitors (MAOIs): Prolong and intensify the anticholinergic (drying) effects. (4 and 7) Alcohol and CNS depressants (hypnotics sedatives, tranquilizers, etc.): Avoid concomitant use due to additive adverse effects. (7)

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Carbinoxamine is an H1 receptor antagonist (antihistamine) that exhibits anticholinergic (drying) and sedative properties. Antihistamines compete with histamine for receptor sites on effector cells. 12.3 Pharmacokinetics Carbinoxamine Maleate extended-release oral suspension after single-dose administration of 16 mg was bioequivalent to the reference carbinoxamine immediate-release oral solution after the administration of two doses of 8 mg six hours apart under fasting conditions. The carbinoxamine mean (SD) peak plasma concentration (Cmax) was 28.7 (5.3) ng/mL at 6.7 hours after Carbinoxamine Maleate extended-release oral suspension administration. The plasma half-life of carbinoxamine was 17.0 hours. There was no effect of food on the pharmacokinetic parameters. Carbinoxamine Maleate extended-release oral suspension after multiple-dose administration of 16 mg every 12 hours for 8 days was bioequivalent to the reference carbinoxamine immediate-release oral solution after multiple-dose administration of 8 mg every 6 hours. The mean (SD) steady-state Cmax was 72.9 (24.4) ng/mL at 5.6 hours after Carbinoxamine Maleate extended-release oral suspension administration. Carbinoxamine mean (SD) minimum plasma concentration at steady-state was 51.8 (20.3) ng/mL.

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3 DOSAGE FORMS AND STRENGTHS Extended-release oral suspension: 4 mg carbinoxamine maleate per 5 mL Extended-release oral suspension: 4 mg carbinoxamine maleate per 5 mL (3)

Carbinoxamine Maleate Extended-Release Oral Suspension Carbinoxamine Maleate XANTHAN GUM POLYSORBATE 80 GLYCERIN HIGH FRUCTOSE CORN SYRUP TRIACETIN SODIUM METABISULFITE CARBINOXAMINE MALEATE CARBINOXAMINE PROPYLPARABEN SODIUM POLYSTYRENE SULFONATE METHYLPARABEN WATER SUCROSE POVIDONE ANHYDROUS CITRIC ACID Strawberry Banana

13 NONCLINCAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term studies in animals have been performed to determine the possible effects of carbinoxamine on carcinogenesis, mutagenesis, and fertility.

NDA022556

Carbinoxamine Maleate Extended-Release Oral Suspension

Carbinoxamine Maleate

62542-101

HUMAN PRESCRIPTION DRUG

ORAL

​17 PRINCIPAL DISPLAY PANEL - 480 mL Bottle Label ​PRINCIPAL DISPLAY PANEL - 480 mL Bottle Label NDC 62542-101-05 Carbinoxamine Maleate Extended-Release Oral Suspension 4 mg/5ml Shake Well Before Use Dose every 12 hours Dispense with an accurate millimeter measuring device Strawberry Banana Flavored Rx only 16 fl oz. (480 mL) Carbinoxamine Maleate Label

Administration Advise patients to measure Carbinoxamine Maleate extended-release oral suspension with an accurate milliliter measuring device. A household teaspoon is not an accurate measuring device and could lead to overdosage [see Dosage and Administration (2.2)]. Activities Requiring Mental Alertness Advise patients to use caution when driving a motor vehicle or operating machinery. Carbinoxamine Maleate extended-release oral suspension may produce marked drowsiness and impair the mental or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery [see Warnings and Precautions (5.2)]. Alcohol, Sedatives, and Tranquilizers Advise patients to avoid the use of alcoholic beverages, sedatives, and tranquilizers while taking Carbinoxamine Maleate extended-release oral suspension because additional reduction in mental alertness may occur [see Warnings and Precautions (5.2) and Drug Interactions (7)]. MAOIs Advise patients to not use MAOIs while taking Carbinoxamine Maleate extended-release oral suspension. MAOIs may prolong and intensify the anticholinergic (drying) effects [see Contraindications (4) and Drug Interactions (7)]. Lactation Advise women that breastfeeding is not recommended during treatment with Carbinoxamine Maleate extended-release oral suspension [see Warnings and Precautions (5.1) and Use in Specific Populations (8.2)]. Manufactured by: Tris Pharma, Inc. Monmouth Junction, NJ 08852 www.trispharma.com For: Neos Therapeutics LP Denver, CO 80237 LB8788 Rev. 00 05/2024 Neos Logo

14 CLINICAL STUDIES The effectiveness and safety of Carbinoxamine Maleate extended-release oral suspension is based on demonstration of bioequivalence to the immediate-release reference product [see Pharmacokinetics (12.3)].

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. (8.2) Contraindicated in children younger than 2 years of age. (4 and 8.4) May cause sedation or excitation in young children. (8.4) May cause dizziness, sedation, and hypotension in elderly patients. Start elderly patients on lower doses and observe closely for confusion and over-sedation. (8.5) 8.1 Pregnancy Risk Summary Published data over decades of use of antihistamines, including carbinoxamine, have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. However, published data specifically evaluating the risk of carbinoxamine were not found. Animal reproductive studies have not been conducted with carbinoxamine maleate. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. 8.2 Lactation Risk Summary Based on the physical properties of carbinoxamine, it is likely that carbinoxamine is present in breastmilk. There are published reports of drowsiness and irritability in infants exposed to antihistamines via breast milk. There are postmarketing reports of deaths in children under 2 years of age exposed to carbinoxamine by oral administration. There are no available data on the effects on milk production. It is not recommended to breastfeed during treatment with Carbinoxamine Maleate extended-release oral suspension [see Warnings and Precautions (5.1) and Use in Specific Populations (8.4)]. 8.4 Pediatric Use Carbinoxamine Maleate extended-release oral suspension is contraindicated in pediatric patients younger than 2 years of age because deaths have been reported in this patient population who were taking carbinoxamine-containing drug products [see Contraindications (4) and Warnings and Precautions (5.1)]. The safety and effectiveness of Carbinoxamine Maleate extended-release oral suspension in pediatric patients aged 2 years and older have been established and is based on demonstration of bioequivalence to the immediate-release reference product [see Clinical Pharmacology (12.3)]. Carbinoxamine may diminish mental alertness or produce sedation in children. Paradoxical reactions with excitation are more likely in younger children. 8.5 Geriatric Use Carbinoxamine Maleate extended-release oral suspension may cause dizziness, hypotension, confusion, or over-sedation in the elderly. Start elderly patients on lower doses and observed closely.

16 HOW SUPPLIED/STORAGE AND HANDLING Carbinoxamine Maleate extended-release oral suspension contains 4 mg carbinoxamine maleate per 5 mL. It is a light beige to tan viscous suspension with strawberry banana flavor and is supplied as follows: NDC 62542-101-05 Bottles of 16 fl oz (480 mL) Store at 25ºC (77ºF); excursions permitted from 15ºC to 30ºC (59ºF to 86ºF). [See USP Controlled Room Temperature]. Dispense in tight, light-resistant container with child-resistant closure.