Karbinal ER

6 ADVERSE REACTIONS The following clinically significant adverse reactions are descrived elsewhere in the labeling: Somnolense and Impaired Mental Alertness [see Warnings and Precautions (5.2) ]. Allergic Reactions due to Sulfites, including Anaphylaxis [see Warnings and Precautions (5.2)]. The most frequent adverse reactions include: sedation, sleepiness, dizziness, disturbed coordination, epigastric 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, insomnia, 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 Cerecor, Inc., at 1-866-416-9637 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

4 CONTRAINDICATIONS Karbinal ER 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 Karbinal ER [see Warnings and Precautions (5.1)] 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 Karbinal ER 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: The drug-polistirex complex is formed with the active ingredient (carbinoxamine maleate, USP) and sodium polystyrene sulfonate, USP, which has the following structure: Chemical Structure Chemical Structure

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 Karbinal ER 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 Karbinal ER by the oral route only. Measure Karbinal ER 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 correct dose. 2.3 Recommended Dosage for Adults and Adolescents 12 years of age and older: 7.5 mL to 20 mL (6 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 to 4 mg) every 12 hours administered orally 4 to 5 years: 3.75 mL to 10 mL (3 to 8 mg) every 12 hours administered orally 6 to 11 years: 7.5 mL to 15 mL (6 to 12 mg) every 12 hours administered orally

1 INDICATIONS AND USAGE Karbinal ER is indicated for adults and pediatric patients 2 years of age and older for the symptomatic treatment of: Seasonal and perennial allergic rhinitis Vasomotor rhinitis Allergic conjunctivitis due to inhalant allergens and foods Mild, uncomplicated allergic skin manifestations of urticaria and angioedema Dermatographism As therapy for anaphylactic reactions adjunctive to epinephrine and other standard measures after the acute manifestations have been controlled Amelioration of the severity of allergic reactions to blood or plasma Karbinal ER is indicated for adults and pediatric patients 2 years of age and older for the symptomatic treatment of: Seasonal and perennial allergic rhinitis ( 1 ) Vasomotor rhinitis ( 1 ) Allergic conjunctivitis due to inhalant allergens and foods ( 1 ) Mild, uncomplicated allergic skin manifestations of urticaria and angioedema ( 1 ) Dermatographism ( 1 ) As therapy for anaphylactic reactions adjunctive to epinephrine and other standard measures after the acute manifestations have been controlled ( 1 ) Amelioration of the severity of allergic reactions to blood or plasma ( 1 )

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 Karbinal ER 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 of Karbinal ER in patients who are taking monoamine oxidase inhibitors (MAOIs), which prolong and intensify the anticholinergic (drying) effects of antihistamines. Avoid use of Karbinal ER 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 H 1 receptor antagonist (antihistamine) that exhibits anticholinergic (drying) and sedative properties. Antihistamines compete with histamine for receptor sites on effector cells. 12.3 Pharmacokinetics Karbinal ER 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 (C max ) was 28.7 (5.3) ng/mL at 6.7 hours after Karbinal ER administration. The plasma half-life of carbinoxamine was 17.0 hours. There was no effect of food on the pharmacokinetic parameters. Karbinal ER 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 C max was 72.9 (24.4) ng/mL at 5.6 hours after Karbinal ER administration. Carbinoxamine mean (SD) minimum plasma concentration at steady-state was 51.8 (20.3) ng/mL.

12.1 Mechanism of Action Carbinoxamine is an H 1 receptor antagonist (antihistamine) that exhibits anticholinergic (drying) and sedative properties. Antihistamines compete with histamine for receptor sites on effector cells.

12.3 Pharmacokinetics Karbinal ER 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 (C max ) was 28.7 (5.3) ng/mL at 6.7 hours after Karbinal ER administration. The plasma half-life of carbinoxamine was 17.0 hours. There was no effect of food on the pharmacokinetic parameters. Karbinal ER 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 C max was 72.9 (24.4) ng/mL at 5.6 hours after Karbinal ER administration. Carbinoxamine mean (SD) minimum plasma concentration at steady-state was 51.8 (20.3) ng/mL.

20230105

13

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 )

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

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.

13. NONCLINICAL 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

Karbinal ER

Carbinoxamine Maleate

23594-101

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL - 480 mL Bottle Label NDC 23594-101-05 Karbinal ™ ER (carbinoxamine maleate) Extended-release Oral Suspension 4 mg/5 ml Shake Well Before Use Dose every 12 hours Dispense with an accurate milliliter measuring device Strawberry Banana Flavored Rx only 16 fl oz. (480 mL) karbinal-16oz Manufactured by: Tris Pharma, Inc. Monmouth Junction, NJ 08852 Distributed by: Aytu Therapeutics Englewood, CO 80112 www.aytubio.com LB8594 Rev 01 06/2021

Contraindications, Nursing Mothers (4) Removed 3/2021

17. Patient Counseling Information Administration Advise patients to measure Karbinal ER 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. Karbinal ER 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)] . MAOIs Advise patients to not use MAOIs while taking Karbinal ER. MAOIs may prolong and intensify the anticholinergic (drying) effects [see Contraindications (4.4) and Drug Interactions (7)] . Lactation Advise women that breastfeeding is not recommended during treatment with Karbinal ER [see Warnings and Precautions (5.1) and Use in Specific Populations (8.2 and 8.4)] .

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

8.5 Geriatric Use Karbinal ER may cause dizziness, hypotension, confusion, or over-sedation in the elderly. Start elderly patients on lower doses and observe closely.

8.4 Pediatric Use Karbinal ER is contraindicated in pediatric patients younger than 2 years of age becuase deaths have been reported in this patient population who were taking carbinoxamine-containing drug products. The safety and effectiveness of Karbinal ER in pediatric patients aged 2 years and older hve been established and I based on demonstration of bioequivalence to the immediate-release reference product [see Clinical Phamacology (12.3)] . Carbinoxamine may diminish mental alertness or produce sedation in children. Paradoxical reactions with excitation are more likely in younger children.

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 out comes. However, published dat a 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 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 out comes. However, published dat a 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 breastmilk. There are post-marketing 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 wit h Karbinal ER [see Warnings and Precautions (5.1)] and use in Specific Populations (8.4)]. 8.4 Pediatric Use Karbinal ER is contraindicated in pediatric patients younger than 2 years of age becuase deaths have been reported in this patient population who were taking carbinoxamine-containing drug products. The safety and effectiveness of Karbinal ER in pediatric patients aged 2 years and older hve been established and I based on demonstration of bioequivalence to the immediate-release reference product [see Clinical Phamacology (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 Karbinal ER may cause dizziness, hypotension, confusion, or over-sedation in the elderly. Start elderly patients on lower doses and observe closely.

16. HOW SUPPLIED/STORAGE AND HANDLING Karbinal ER 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 23594-101-05 Bottles of 16 fl oz (480 mL) NDC 23594-101-01 Bottles of 1 fl oz (30 mL) Physician Samples Store at 25°C (77°F); excursions permitted from 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature.] Dispense in tight, light-resistant container with child-resistant closure.

Store at 25°C (77°F); excursions permitted from 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature.] Dispense in tight, light-resistant container with child-resistant closure.