CARBINOXAMINE: 44 Adverse Event Reports & Safety Profile

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

AND USAGE Carbinoxamine Maleate extended-release oral suspension 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 Carbinoxamine Maleate extended-release oral suspension is an H1 receptor antagonist 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)

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

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

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)

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.

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, a 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 2 years of age who were taking carbinoxamine-containing drug products; therefore, Carbinoxamine Maleate Extended-Release Oral Suspension is contraindicated in children younger than 2 years of age.

5.2 Somnolence and Impaired Mental Alertness 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. Advise patients to avoid engaging in hazardous tasks requiring mental alertness and motor coordination after ingestion of Carbinoxamine Maleate Extended-Release Oral Suspension. Avoid concurrent use of Carbinoxamine Maleate Extended-Release Oral Suspension with alcohol or other central nervous system depressants because additional impairment of central nervous system performance may occur.

5.3 Concomitant Medical Conditions Carbinoxamine Maleate Extended-Release Oral Suspension 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 Carbinoxamine Maleate Extended-Release Oral Suspension contains sodium metabisulfite, a sulfite that may cause allergictype 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.

PRECAUTIONS General As many other antihistamines, carbinoxamine maleate has an atropine-like action and, therefore, should be used with caution in patients with: increased intraocular pressure, hyperthyroidism, cardiovascular disease, hypertension. Antihistamines such as carbinoxamine maleate should not be used to treat lower respiratory tract symptoms, including asthma. Information for Patients Carbinoxamine maleate may cause drowsiness; alcohol, sedatives, and tranquilizers may increase the drowsiness effect. Avoid alcoholic beverages while taking this product. Do not take this product if you are taking sedatives or tranquilizers, without first consulting your doctor. Use caution when driving a motor vehicle or operating machinery.

Drug Interactions

Monoamine oxidase inhibitors prolong and intensify the anticholinergic (drying) effects of antihistamines. Carbinoxamine maleate has additive effects with alcohol and other CNS depressants (hypnotics, sedatives, tranquilizers, etc.). Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term studies in animals have been performed to determine the possible effects of carbinoxamine maleate on carcinogenesis, mutagenesis, and fertility.

Pregnancy Teratogenic Effects Pregnancy

Category C Animal reproductive studies have not been conducted with carbinoxamine maleate. It is also not known whether carbinoxamine maleate can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Carbinoxamine maleate should be given to a pregnant woman only if clearly needed.

Nursing Mothers

Because of the higher risk of antihistamines for infants generally and for newborns and prematures in particular, use of carbinoxamine maleate is contraindicated in nursing mothers (see CONTRAINDICATIONS ).

Pediatric Use

Carbinoxamine maleate is contraindicated in children younger than 2 years of age (see CONTRAINDICATIONS ). Neonates have an increased susceptibility to anticholinergic side effects, such as CNS excitation, which may lead to convulsions. Carbinoxamine maleate may diminish mental alertness in children. In the young child, particularly, they may produce excitation.

Geriatric Use

Carbinoxamine maleate is more likely to cause dizziness, sedation, and hypotension in elderly patients (approximately 60 years or older). Sedating drugs may also cause confusion and over sedation in the elderly. Therefore, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

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)