INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Karbinal ER is indicated for adults and pediatric patients years of age and older for the symptomatic treatment of:Seasonal and perennial allergic rhinitisVasomotor rhinitisAllergic conjunctivitis due to inhalant allergens and foodsMild, uncomplicated allergic skin manifestations of urticaria and angioedemaDermatographismAs 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. 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 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) 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).

LACTATION SECTION.

8.2 Lactation. Risk SummaryBased 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 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 Karbinal ER [see Warnings and Precautions (5.1)] and use in Specific Populations (8.4)].

ADVERSE REACTIONS SECTION.

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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Body as 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. Somnolense and Impaired Mental Alertness [see Warnings and Precautions (5.2) ]. Allergic Reactions due to Sulfites, including Anaphylaxis [see Warnings and Precautions (5.2)]. 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.

CLINICAL PHARMACOLOGY SECTION.

12. CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Carbinoxamine is an 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 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 days was bioequivalent to the reference carbinoxamine immediate-release oral solution after multiple-dose administration of mg every hours. The mean (SD) steady-state 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.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Karbinal ER is contraindicated in:children younger than 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 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 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 years of age 4) Patients with known hypersensitivity to the drug or any of the inactive ingredients 4) Monoamine oxidase inhibitors (MAOI) 4) Children younger than years of age 4) Patients with known hypersensitivity to the drug or any of the inactive ingredients 4) Monoamine oxidase inhibitors (MAOI) 4).

DESCRIPTION SECTION.

11. DESCRIPTION. Each mL of Karbinal ER Extended-release Oral Suspension contains carbinoxamine complexed with polistirex equivalent to 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.

DOSAGE & ADMINISTRATION SECTION.

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 hoursPediatric patients 2-11 years of age (approximately 0.2 to 0.4 mg/kg/day) 2.4): to years 3.75 mL to mL (3 to mg) every 12 hours4 to years 3.75 mL to 10 mL (3 to mg) every 12 hours6 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. household teaspoon is not an accurate measuring device and could lead to overdosage. 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 to 11 years of age (approximately 0.2 to 0.4 mg/kg/day): 2 to years: 3.75 mL to mL (3 to mg) every 12 hours administered orally4 to years: 3.75 mL to 10 mL (3 to mg) every 12 hours administered orally6 to 11 years: 7.5 mL to 15 mL (6 to 12 mg) every 12 hours administered orally.

DRUG INTERACTIONS SECTION.

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.. 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) 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).

HOW SUPPLIED SECTION.

16. HOW SUPPLIED/STORAGE AND HANDLING. Karbinal ER Oral Suspension contains mg carbinoxamine maleate per mL. It is 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 fl oz (30 mL) Physician Samples Store at 25C (77F); excursions permitted from 15 to 30C (59 to 86F). [See USP Controlled Room Temperature.]Dispense in tight, light-resistant container with child-resistant closure.

OVERDOSAGE SECTION.

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 potentially life-threatening amount of drug. In the presence of severe anticholinergic effects, physostigmine may be useful. Vasopressors may be used to treat hypotension.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 480 mL Bottle LabelNDC 23594-101-05Karbinal(TM) ER (carbinoxamine maleate)Extended-release Oral Suspension mg/5 mlShake Well Before UseDose every 12 hoursDispense with an accurate milliliter measuring device Strawberry Banana FlavoredRx 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 Aytu BioPharma logo.

PATIENT COUNSELING INFORMATION.

17. Patient Counseling Information. Administration. Advise patients to measure Karbinal ER with an accurate milliliter measuring device. 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 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 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)].

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Karbinal ER is contraindicated in pediatric patients younger than 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 years and older hve been established and 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.

PHARMACOKINETICS SECTION.

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 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 days was bioequivalent to the reference carbinoxamine immediate-release oral solution after multiple-dose administration of mg every hours. The mean (SD) steady-state 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.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryPublished data over decades of use of antihistamines, including carbinoxamine, have not identified drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal out comes. However, published dat 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 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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. 8.2) Contraindicated in children younger than 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) Lactation: Advise not to breastfeed. 8.2) Contraindicated in children younger than 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 SummaryPublished data over decades of use of antihistamines, including carbinoxamine, have not identified drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal out comes. However, published dat 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 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 SummaryBased 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 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 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 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 years and older hve been established and 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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Activities requiring mental alertness: Avoid engaging in hazardous tasks requiring complete mental alertness such as driving or operating machinery. 5.2) Anticholinergic actions: Use with caution in patients with increased intraocular pressure, narrow angle glaucoma, hyperthyroidism, cardiovascular disease, hypertension, stenosing peptic ulcer, symptomatic prostatic hypertrophy, bladder neck obstruction, pyloroduodenal obstruction. 5.3) Contains sodium metabisulfite, sulfite that may cause anaphylaxis including life-threatening or less severe asthmatic episodes in susceptible individuals. 5.4) Activities requiring mental alertness: Avoid engaging in hazardous tasks requiring complete mental alertness such as driving or operating machinery. 5.2) Anticholinergic actions: Use with caution in patients with increased intraocular pressure, narrow angle glaucoma, hyperthyroidism, cardiovascular disease, hypertension, stenosing peptic ulcer, symptomatic prostatic hypertrophy, bladder neck obstruction, pyloroduodenal obstruction. 5.3) Contains sodium metabisulfite, sulfite that may cause anaphylaxis including life-threatening or less severe asthmatic episodes in susceptible individuals. 5.4) 5.1 Pediatric Mortality. Deaths have been reported in children less than years of age who were taking carbinoxamine-containing drug products; therefore, Karbinal ER is contraindicated in children younger than years of age.. 5.2 Somnolence and Impaired Mental Alertness. Karbinal ER may produce marked drowsiness and impair the mental or physical abilities required for the performance of potentially hazardous tasks such as driving car or operating machinery. Advise patients to avoid engaging in hazardous tasks requiring mental alertness and motor coordination after ingestion of Karbinal ER. Avoid concurrent use of Karbinal ER with alcohol or other central nervous system depressants because additional impairment of central nervous system performance may occur.. 5.3 Concomitant Medical Conditions. Karbinal ER has anticholinergic (atropine-like) properties and, therefore, should be used with caution in patients with: increased intraocular pressure, narrow angle glaucoma, hyperthyroidism, cardiovascular disease, hypertension, stenosing peptic ulcer, symptomatic prostatic hypertrophy, bladder neck obstruction, or pyloroduodenal obstruction.. 5.4 Allergic Reactions due to Sulfites, including Anaphylaxis. Karbinal ER contains sodium metabisulfite, sulfite that may cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in susceptible individuals. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic individuals.