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AZELASTINE AND RELATED AGENTS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Azelastine hydrochloride and bepotastine besilate are relatively selective histamine H1-receptor antagonists.

Specific Substances

    A) AZELASTINE
    1) A-5610
    2) Azelastine hydrochloride
    3) E-0659
    4) W-2979M
    5) 4-(p-Chlorobenzyl)-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1(2H)-phthalazinone monohydrochloride
    6) CAS 58581-89-8 (azelastine)
    7) CAS 79307-93-0 (azelastine hydrochloride)
    BEPOTASTINE
    1) Bepotastine besilate
    2) CAS 125602-71-3 (bepotastine)
    3) CAS 190786-44-8 (bepotastine besilate)

    1.2.1) MOLECULAR FORMULA
    1) ALCAFTADINE: C19H21N3O
    2) AZELASTINE HYDROCHLORIDE: C22H24ClN3O.HCl
    3) EPINASTINE HYDROCHLORIDE: C16H15N3.HCl
    4) KETOTIFEN FUMARATE: C23H23NO5S
    5) LEVOCABASTINE HYDROCHLORIDE: C26H29FN2O2.HCl
    6) OLOPATADINE HYDROCHLORIDE: C21H23NO3.HCl

Available Forms Sources

    A) FORMS
    1) AZELASTINE
    a) NASAL SPRAY - Each bottle contains 30 mg (1 mg/mL) of azelastine hydrochloride which can deliver a total of 200 metered sprays. Each spray delivers an average of 137 mcg (0.137 mL of the solution) of azelastine hydrochloride (Prod Info ASTELIN(R) nasal spray, 2003).
    b) OPHTHALMIC SOLUTION - 6 mL bottle of azelastine hydrochloride ophthalmic solution (0.05%) (Prod Info OPTIVAR(R) ophthalmic solution, 2003).
    2) BEPOTASTINE
    a) OPHTHALMIC SOLUTION - 1.5% bepotastine besilate ophthalmic solution in a 10 mL bottle (Prod Info BEPREVE(TM) ophthalmic solution, 2009).
    B) USES
    1) AZELASTINE
    a) Azelastine nasal spray is used to treat symptoms of seasonal allergic rhinitis such as rhinorrhea, sneezing, and nasal pruritus in adults and children 5 years and older, and to treat symptoms of vasomotor rhinitis, such as rhinorrhea, nasal congestion and post nasal drip in adults and children 12 years and older (Prod Info ASTELIN(R) nasal spray, 2003).
    b) Azelastine ophthalmic solution is used to treat itching of the eyes associated with allergic conjunctivitis (Prod Info OPTIVAR(R) ophthalmic solution, 2003).
    2) BEPOTASTINE
    a) Bepotastine ophthalmic solution is used to treat itching of the eyes associated with allergic conjunctivitis (Prod Info BEPREVE(TM) ophthalmic solution, 2009).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Azelastine nasal spray is used to treat symptoms of seasonal allergic rhinitis, such as rhinorrhea, sneezing, and nasal pruritus in adults and children 5 years and older, and to treat symptoms of vasomotor rhinitis, such as rhinorrhea, nasal congestion, and post nasal drip in adults and children 12 years and older. Azelastine and bepotastine ophthalmic solutions are used to treat itching of the eyes associated with allergic conjunctivitis.
    B) PHARMACOLOGY: Azelastine and bepotastine are histamine H1-receptor antagonist. They are inhibitors of the release of histamine and other mediators from cells (eg, mast cells) involved in the allergic response.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) AZELASTINE: NASAL: MOST COMMON: Bitter taste, nasal discomfort/burning, headache, epistaxis, sneezing, sinusitis, and somnolence. OTHER EFFECTS: Rash, nasopharyngitis, weight gain, dry mouth, vomiting, abdominal discomfort, dryness of the nose, fatigue, cough, rhinitis, and dyspnea. AZELASTINE: OPHTHALMIC: MOST COMMON: Eye burning/stinging, headaches, and bitter taste. OTHER EFFECTS: Asthma, conjunctivitis, dyspnea, eye pain, fatigue, influenza-like symptoms, pharyngitis, pruritus, rhinitis, and temporary blurring. BEPOTASTINE: OPHTHALMIC: Alterations in taste, eye irritation, nasopharyngitis, and headache.
    E) WITH POISONING/EXPOSURE
    1) Overdose data are limited. The signs and symptoms of an acute overdose are also expected to be similar to excessive pharmacologic effects. AZELASTINE: Since each bottle of a nasal spray contains 30 mg of azelastine hydrochloride (Astelin(R)), acute overdose in adults is unlikely to result in clinically significant adverse events, other than increased somnolence. In studies, adults did not experience increased incidence of serious adverse events following single doses of the oral formulation of azelastine hydrochloride (up to 16 mg).
    0.2.20) REPRODUCTIVE
    A) Azelastine and bepotastine besilate are classified as FDA pregnancy category C. There are no studies or published case reports on the use of azelastine or bepotastine besilate in pregnant women. However, azelastine and bepotastine besilate have been shown to be embryotoxic, fetotoxic, and teratogenic in animal models.

Laboratory Monitoring

    A) No specific laboratory tests are necessary unless otherwise clinically indicated.
    B) Monitor serum electrolytes in patients with significant vomiting.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe vomiting.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Significant toxicity is not expected after an overdose.
    C) DECONTAMINATION
    1) PREHOSPITAL: Due to rapid absorption and limited expected toxicity, gastrointestinal decontamination is not routinely recommended.
    2) HOSPITAL: Toxicity after acute ingestion is unlikely. Gastrointestinal decontamination is generally unnecessary.
    D) AIRWAY MANAGEMENT
    1) Should not be required in these cases.
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION PROCEDURE
    1) Hemodialysis is not recommended given the low toxicity of these drugs.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home. Children with no or mild symptoms may be managed at home following the inadvertent ingestion of third generation antihistamines.
    2) OBSERVATION CRITERIA: Following the ingestion of greater than 3 to 5 times the therapeutic dose, patients should be observed for excessive sedation for several hours (up to 12 hours postingestion).
    3) ADMISSION CRITERIA: Patients with significant persistent central nervous system toxicity should be admitted.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    H) PITFALLS
    1) If significant toxicity develops the diagnosis should be reconsidered. When managing a suspected overdose, the possibility of multidrug involvement should be considered.
    I) PHARMACOKINETICS
    1) AZELASTINE: Tmax: Nasal: 2 to 3 hours; oral: 4 to 5 hours. bioavailability - intranasal: 40%; oral: 80%. Protein binding: 88% and 97%. Vd: 14.5 L/kg. Excretion: 25%. Elimination half-life: 22 hours. Metabolites N-desmethylazelastine (oral): 54 hours. BEPOTASTINE: Protein binding: about 55%. Excretion: 75% to 90% excreted unchanged in the urine. Feces: 75% (less than 10% unchanged).
    J) DIFFERENTIAL DIAGNOSIS
    1) Includes overdose ingestions of other antihistamines or CNS infection.

Range Of Toxicity

    A) TOXICITY: Overdose data is limited. Since each bottle of a nasal spray contains 30 mg of azelastine hydrochloride, acute overdose in adults is unlikely to result in clinically significant adverse events, other than increased somnolence. In studies, adults did not experience increased incidence of serious adverse events following single doses of the oral formulation of azelastine hydrochloride (up to 16 mg).
    B) THERAPEUTIC DOSE: AZELASTINE: ADULTS AND CHILDREN (12 YEARS OR OLDER): ALLERGIC OR VASOMOTOR RHINITIS: Two sprays (azelastine 137 mcg/spray) per nostril twice daily. CHILDREN (5 to 11 YEARS): One spray (137 mcg) per nostril twice daily. ALLERGIC CONJUNCTIVITIS: ADULTS AND CHILDREN 3 YEARS AND OLDER: Instill one drop of azelastine 0.05% into each affected eye twice a day. BEPOTASTINE: ADULTS AND CHILDREN (2 YEARS OR OLDER): One drop of bepotastine 1.5% into each affected eye twice daily.

Clinical Effects

Summary Of Exposure

    A) USES: Azelastine nasal spray is used to treat symptoms of seasonal allergic rhinitis, such as rhinorrhea, sneezing, and nasal pruritus in adults and children 5 years and older, and to treat symptoms of vasomotor rhinitis, such as rhinorrhea, nasal congestion, and post nasal drip in adults and children 12 years and older. Azelastine and bepotastine ophthalmic solutions are used to treat itching of the eyes associated with allergic conjunctivitis.
    B) PHARMACOLOGY: Azelastine and bepotastine are histamine H1-receptor antagonist. They are inhibitors of the release of histamine and other mediators from cells (eg, mast cells) involved in the allergic response.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) AZELASTINE: NASAL: MOST COMMON: Bitter taste, nasal discomfort/burning, headache, epistaxis, sneezing, sinusitis, and somnolence. OTHER EFFECTS: Rash, nasopharyngitis, weight gain, dry mouth, vomiting, abdominal discomfort, dryness of the nose, fatigue, cough, rhinitis, and dyspnea. AZELASTINE: OPHTHALMIC: MOST COMMON: Eye burning/stinging, headaches, and bitter taste. OTHER EFFECTS: Asthma, conjunctivitis, dyspnea, eye pain, fatigue, influenza-like symptoms, pharyngitis, pruritus, rhinitis, and temporary blurring. BEPOTASTINE: OPHTHALMIC: Alterations in taste, eye irritation, nasopharyngitis, and headache.
    E) WITH POISONING/EXPOSURE
    1) Overdose data are limited. The signs and symptoms of an acute overdose are also expected to be similar to excessive pharmacologic effects. AZELASTINE: Since each bottle of a nasal spray contains 30 mg of azelastine hydrochloride (Astelin(R)), acute overdose in adults is unlikely to result in clinically significant adverse events, other than increased somnolence. In studies, adults did not experience increased incidence of serious adverse events following single doses of the oral formulation of azelastine hydrochloride (up to 16 mg).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) AZELASTINE
    a) In controlled multiple-dose studies, eye burning/stinging was reported in approximately 30% of patients being treated with ophthalmic azelastine for up to 56 days. Eye pain, conjunctivitis, and temporary blurring were also reported in 1% to 10% patients; however, some of these effects were similar to the underlying disease being studied (Prod Info OPTIVAR(R) ophthalmic solution, 2003).
    b) PEDIATRICS: During placebo-controlled trials, 5.1% of children (5 to 12 years of age) receiving intranasal azelastine (n=176) reported conjunctivitis as compared with 1.8% in the placebo groups (Prod Info ASTELIN(R) intranasal spray, 2007).
    2) BEPOTASTINE
    a) Eye irritation was reported in 2% to 5% of patients who received bepotastine ophthalmic solution during clinical trials (Prod Info BEPREVE(TM) ophthalmic solution, 2009).
    3.4.5) NOSE
    A) WITH THERAPEUTIC USE
    1) AZELASTINE
    a) Alterations in taste perception and nasal burning are the most common adverse effects reported following the use of nasal azelastine (TenEick et al, 2001).
    b) The incidence of nasal burning ranges from 4% to 5% (Prod Info ASTELIN(R) intranasal spray, 2007; Anon, 1996a; McTavish & Sorkin, 1989a).
    c) Dryness of the nose has occurred in less than 5% of patients treated with intranasal or oral azelastine (McTavish & Sorkin, 1989a).
    2) BEPOTASTINE
    a) Nasopharyngitis was reported in 2% to 5% of patients who received bepotastine ophthalmic solution during clinical trials (Prod Info BEPREVE(TM) ophthalmic solution, 2009).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) EPISTAXIS
    1) WITH THERAPEUTIC USE
    a) AZELASTINE: Epistaxis has been reported in less than 5% of patients treated with oral or intranasal azelastine (Prod Info ASTELIN(R) intranasal spray, 2007; McTavish & Sorkin, 1989a).
    B) ASTHMA
    1) WITH THERAPEUTIC USE
    a) AZELASTINE
    1) PEDIATRICS: During placebo-controlled trials, 4.5% of children (5 to 12 years of age) receiving intranasal azelastine (n=176) reported asthma as compared with 4.1% in the placebo groups (Prod Info ASTELIN(R) intranasal spray, 2007).
    2) In controlled multiple-dose studies, asthma and dyspnea were also reported in 1% to 10% patients. However, some of these effects were similar to the underlying disease being studied (Prod Info OPTIVAR(R) ophthalmic solution, 2003).
    C) COUGH
    1) WITH THERAPEUTIC USE
    a) AZELASTINE (CHILDREN): During placebo-controlled trials, 11.4% of children (5 to 12 years of age) receiving intranasal azelastine (n=176) reported cough as compared with 8.3% in the placebo groups (Prod Info ASTELIN(R) intranasal spray, 2007).
    D) SNEEZING
    1) WITH THERAPEUTIC USE
    a) AZELASTINE: During placebo-controlled trials, 3.1% of patients receiving intranasal azelastine (n=391) reported paroxysmal sneezing as compared with 1.1% in the placebo groups (n=353) (Prod Info ASTELIN(R) intranasal spray, 2007).
    E) RHINITIS
    1) WITH THERAPEUTIC USE
    a) AZELASTINE
    1) PEDIATRICS: During placebo-controlled trials, 17% of children (5 to 12 years of age) receiving intranasal azelastine (n=176) reported rhinitis/cold symptoms as compared with 9.5% in the placebo groups (Prod Info ASTELIN(R) intranasal spray, 2007).
    2) During placebo-controlled trials, 2.3% of patients receiving intranasal azelastine (n=391) reported rhinitis as compared with 1.4% in the placebo groups (n=353) (Prod Info ASTELIN(R) intranasal spray, 2007).
    3) In controlled multiple-dose studies, rhinitis and influenza-like symptoms were also reported in 1% to 10% patients. However, some of these effects were similar to the underlying disease being studied (Prod Info OPTIVAR(R) ophthalmic solution, 2003).
    F) PHARYNGITIS
    1) WITH THERAPEUTIC USE
    a) AZELASTINE
    1) During placebo-controlled trials, 3.8% of patients receiving intranasal azelastine (n=391) reported pharyngitis as compared with 2.8% in the placebo groups (n=353) (Prod Info ASTELIN(R) intranasal spray, 2007).
    2) In controlled multiple-dose studies, pharyngitis was reported in 1% to 10% of patients. However, some of these effects were similar to the underlying disease being studied (Prod Info OPTIVAR(R) ophthalmic solution, 2003).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DROWSY
    1) WITH THERAPEUTIC USE
    a) AZELASTINE: During placebo-controlled trials, 11.5% of patients receiving intranasal azelastine (n=391) reported somnolence as compared with 5.4% in the placebo groups (n=353) (Prod Info ASTELIN(R) nasal spray, 2003).
    B) FATIGUE
    1) WITH THERAPEUTIC USE
    a) AZELASTINE
    1) During placebo-controlled trials, 2.3% of patients receiving intranasal azelastine (n=391) reported fatigue as compared with 1.4% in the placebo groups (n=353) (Prod Info ASTELIN(R) intranasal spray, 2007).
    2) In controlled multiple-dose studies, fatigue was also reported in 1% to 10% patients (Prod Info OPTIVAR(R) ophthalmic solution, 2003).
    C) HEADACHE
    1) WITH THERAPEUTIC USE
    a) AZELASTINE
    1) During placebo-controlled trials, 14.8% of patients receiving intranasal azelastine (n=391) reported headache as compared with 12.7% in the placebo groups (n=353) (Prod Info ASTELIN(R) intranasal spray, 2007).
    2) Headache has also been reported in approximately 15% of patients being treated with ophthalmic azelastine for up to 56 days (Prod Info OPTIVAR(R) ophthalmic solution, 2003).
    b) BEPOTASTINE
    1) Headaches were reported in 2% to 5% of patients who received bepotastine ophthalmic solution during clinical trials (Prod Info BEPREVE(TM) ophthalmic solution, 2009).
    D) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) AZELASTINE: During placebo-controlled trials, 2% of patients receiving intranasal azelastine (n=391) reported dizziness as compared with 1.4% in the placebo groups (n=353) (Prod Info ASTELIN(R) intranasal spray, 2007).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) WEIGHT GAIN FINDING
    1) WITH THERAPEUTIC USE
    a) AZELASTINE
    1) Weight gain has been observed in less than 5% of patients treated with intranasal or oral azelastine (Anon, 1996a; McTavish & Sorkin, 1989a). During placebo-controlled trials, 2% of patients receiving intranasal azelastine (n=391) reported a weight increase as compared with 0% in the placebo groups (n=353) (Prod Info ASTELIN(R) intranasal spray, 2007).
    B) GASTROINTESTINAL TRACT FINDING
    1) WITH THERAPEUTIC USE
    a) AZELASTINE
    1) Dry mouth and nose, nausea, vomiting, abdominal discomfort, and altered appetite have been observed in less than 5% of patients treated with oral or intranasal azelastine (McTavish & Sorkin, 1989a).
    2) During placebo-controlled trials, 2.8% of patients receiving intranasal azelastine (n=391) reported nausea as compared with 1.1% in the placebo groups (n=353) (Prod Info ASTELIN(R) intranasal spray, 2007).
    C) DISORDER OF TASTE
    1) WITH THERAPEUTIC USE
    a) AZELASTINE
    1) Alterations in taste perception and nasal burning are the most common adverse effects reported following the use of nasal azelastine (TenEick et al, 2001).
    2) During placebo-controlled trials, 19.7% of patients receiving intranasal azelastine (n=391) reported bitter taste as compared with 0.6% in the placebo groups (n=353) (Prod Info ASTELIN(R) intranasal spray, 2007). Approximately 10% of patients being treated with ophthalmic azelastine for up to 56 days reported a bitter taste (Prod Info OPTIVAR(R) ophthalmic solution, 2003).
    3) Overall, bitter or metallic taste has been reported in 2% to 32% of patients using azelastine nasal spray or oral tablets. The bitter taste is usually transient (Anon, 1996a; McTavish & Sorkin, 1989a; Gould et al, 1988; Ollier et al, 1986) . This taste disorder has been observed several hours after taking oral azelastine, and is exacerbated following ingestion of liquids, especially cold drinks (Gould et al, 1988; Meltzer et al, 1988).
    b) BEPOTASTINE
    1) A mild taste was the most common adverse effect reported during bepotastine clinical trials, occurring in approximately 25% of patients following instillation of bepotastine ophthalmic solution (Prod Info BEPREVE(TM) ophthalmic solution, 2009).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) AZELASTINE
    1) Skin rash (type unspecified) has been reported in less than 5% of patients treated with oral or intranasal azelastine (McTavish & Sorkin, 1989a).
    2) Pruritus was reported in 1% to 10% of patients being treated with ophthalmic azelastine for up to 56 days (Prod Info OPTIVAR(R) ophthalmic solution, 2008).

Reproductive

    3.20.1) SUMMARY
    A) Azelastine and bepotastine besilate are classified as FDA pregnancy category C. There are no studies or published case reports on the use of azelastine or bepotastine besilate in pregnant women. However, azelastine and bepotastine besilate have been shown to be embryotoxic, fetotoxic, and teratogenic in animal models.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) AZELASTINE
    a) At the time of this review, no data were available to assess the teratogenic potential of this agent during pregnancy in humans (Prod Info ASTELIN(R) nasal spray, 2012; Prod Info ASTEPRO(R) nasal spray, 2013; Prod Info OPTIVAR(R) ophthalmic solution, 2009).
    B) ANIMAL STUDIES
    1) AZELASTINE
    a) In animal studies, malformations (cleft palate; short or absent tail; fused, absent, or branched ribs), delayed ossification were observed in mice given a maternally toxic oral dose of 68.6 mg/kg (approximately 170 to 280 times the maximum recommended daily intranasal dose and 57,000 times the maximum recommended daily ocular dose in adults on a mg/m(2) basis). Malformations (oligo- and brachydactylia), delayed ossification, and skeletal variations were observed in rats given an oral dose of 30 mg/kg (approximately 150 to 240 times the maximum recommended intranasal dose and 25,000 times the recommended ocular dose in adults on a mg/m(2) basis). (Prod Info ASTELIN(R) nasal spray, 2012; Prod Info ASTEPRO(R) nasal spray, 2013; Prod Info OPTIVAR(R) ophthalmic solution, 2009).
    b) Delayed ossification was observed in rabbits given maternally toxic doses of 30 mg/kg and greater (approximately 300 to 500 times the maximum recommended daily intranasal dose in adults on a mg/m(2) basis) (Prod Info ASTELIN(R) nasal spray, 2012; Prod Info ASTEPRO(R) nasal spray, 2013).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) AZELASTINE
    a) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy in humans (Prod Info ASTELIN(R) nasal spray, 2012; Prod Info ASTEPRO(R) nasal spray, 2013; Prod Info OPTIVAR(R) ophthalmic solution, 2009).
    B) PREGNANCY CATEGORY
    1) The manufacturers have classified azelastine and bepotastine besilate as FDA pregnancy category C (Prod Info ASTELIN(R) nasal spray, 2012; Prod Info ASTEPRO(R) nasal spray, 2013; Prod Info BEPREVE(TM) ophthalmic solution, 2009; Prod Info OPTIVAR(R) ophthalmic solution, 2009).
    C) PREGNANCY COMPLICATIONS
    1) An analysis of 17,776 pregnancies in the Swedish Medical Birth Registry found that infants born to mothers who used antihistamines during pregnancy had a malformation rate equal to that normally expected (3.17% for antihistamine use versus 3.16% in the general population). A slightly reduced rate of cardiovascular defects was also seen in the offspring of women using antihistamines during pregnancy. Reduced risks of premature births, low birth weight, and small size for gestational age were also seen with use of antihistamines. The most common antihistamines used by women in this study were clemastine, promethazine, cyclizine, meclizine, cetirizine, terfenadine, and loratadine (Kallen, 2002).
    D) ANIMAL STUDIES
    1) AZELASTINE
    a) In animal studies, embryo-fetal death and decreased fetal weight were observed in mice given a maternally toxic oral dose of 68.6 mg/kg (approximately 170 to 280 times the maximum recommended daily intranasal dose and 57,000 times the maximum recommended daily ocular dose in adults on a mg/m(2) basis). Embryo-fetal death and decreased fetal weight were observed in rats at a maternally toxic dose of 68.6 mg/kg (340 to 560 times the maximum recommended daily human intranasal dose and 57,000 times the maximum recommended ocular dose on a mg/m(2) basis) (Prod Info ASTELIN(R) nasal spray, 2012; Prod Info ASTEPRO(R) nasal spray, 2013; Prod Info OPTIVAR(R) ophthalmic solution, 2009).
    b) Abortion and decreased fetal weight were observed in rabbits given maternally toxic doses of 30 mg/kg and greater (approximately 300 to 500 times the maximum recommended daily intranasal dose in adults on a mg/m(2) basis) (Prod Info ASTELIN(R) nasal spray, 2012; Prod Info ASTEPRO(R) nasal spray, 2013).
    2) BEPOTASTINE
    a) In animal studies, when rats were given an oral dose of 1000 mg/kg/day during perinatal and lactation periods, there was an increase in stillbirths and a decrease in growth and development (Prod Info BEPREVE(TM) ophthalmic solution, 2009).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) BREAST MILK
    a) It is not known whether azelastine or bepotastine besilate are excreted into human breast milk and the effects in the nursing infant from exposure to the drug have not been determined (Prod Info ASTELIN(R) nasal spray, 2012; Prod Info ASTEPRO(R) nasal spray, 2013; Prod Info BEPREVE(TM) ophthalmic solution, 2009; Prod Info OPTIVAR(R) ophthalmic solution, 2009).
    B) ANIMAL STUDIES
    1) BEPOTASTINE
    a) In rat studies, the maximum concentration of radioactivity in milk was 0.4 mcg-equivalents/mL at 1 hour after a single 3-mg/kg oral dose of radiolabeled bepotastine besilate was given to nursing rats 11 days after delivery. The concentration was below detectable limits at 48 hours following administration. The milk concentration was higher than the maternal blood plasma concentration at all time points of measurement (Prod Info BEPREVE(TM) ophthalmic solution, 2009).
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects on human fertility from exposure to azelastine or bepotastine (Prod Info ASTELIN(R) nasal spray, 2012; Prod Info ASTEPRO(R) nasal spray, 2013; Prod Info BEPREVE(TM) ophthalmic solution, 2009; Prod Info OPTIVAR(R) ophthalmic solution, 2009).
    B) ANIMAL STUDIES
    1) AZELASTINE
    a) In animal studies, the duration of estrous cycles was prolonged and copulatory activity and the number of pregnancies were decreased in rats given doses up to 68.6 mg/kg (approximately 340 to 560 times the maximum recommended intranasal or 57,000 times the maximum recommended ocular adult dose based on a mg/m(2) basis). The numbers of corpora lutea and implantations were decreased (Prod Info ASTELIN(R) nasal spray, 2012; Prod Info ASTEPRO(R) nasal spray, 2013; Prod Info OPTIVAR(R) ophthalmic solution, 2009).
    2) BEPOTASTINE
    a) There was a slight decrease in fertility index and surviving fetuses when oral bepotastine was given to male and female rats at dose of 1000 mg/kg/day. No adverse effects on fertility were observed when rats were given 200 mg/kg/day of oral bepotastine besilate (approximately 3300 times that of topical ocular use in humans) (Prod Info BEPREVE(TM) ophthalmic solution, 2009).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) Studies in rats and mice have shown that azelastine is not carcinogenic. This conclusion was reached after 24 months of oral administration of azelastine, with doses for rats up to 30 mg/kg/day and doses for mice up to 25 mg/kg/day (approximately 240 and 100 times greater than the maximum daily recommended nasal human dose, respectively). In addition, based on a 30 microliter drop size, these doses represent the equivalent of approximately 25,000 and 21,000 times greater than the maximum daily recommended ocular human dose, respectively (Prod Info OPTIVAR(R) ophthalmic solution, 2003; Prod Info ASTELIN(R) nasal spray, 2003).

Genotoxicity

    A) No evidence of mutagenicity caused by azelastine was found in the Ames test, DNA repair test, mouse lymphoma forward mutation assay, mouse micronucleus test, or chromosomal aberration test in rat bone marrow (Prod Info ASTELIN(R) nasal spray, 2003; Prod Info OPTIVAR(R) ophthalmic solution, 2003).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) No specific laboratory tests are necessary unless otherwise clinically indicated.
    B) Monitor serum electrolytes in patients with significant vomiting.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with significant persistent central nervous system toxicity should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic or has mild symptoms can be managed at home.
    B) Children may be managed at home following the accidental ingestion of large quantities of third generation antihistamines. Following the ingestion of greater than 3 to 5 times the therapeutic dose, patients should be observed for excessive sedation for several hours (up to 12 hours postingestion) (TenEick et al, 2001).
    C) Since each bottle of a nasal spray contains 30 mg of azelastine hydrochloride, acute overdose in adults is unlikely to result in clinically significant adverse events, other than increased somnolence. In studies, adults did not experience increased incidence of serious adverse events following single doses of the oral formulation of azelastine hydrochloride (up to 16 mg) (Prod Info ASTELIN(R) nasal spray, 2003).
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Following the ingestion of greater than 3 to 5 times the therapeutic dose, patients should be observed for excessive sedation for several hours (up to 12 hours postingestion).

Monitoring

    A) No specific laboratory tests are necessary unless otherwise clinically indicated.
    B) Monitor serum electrolytes in patients with significant vomiting.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Although azelastine has not been associated with oral toxicity, inadvertent ingestion of azelastine nasal drops or ophthalmic solution may occur. Due to rapid absorption and limited expected toxicity, gastrointestinal decontamination is not routinely recommended. Since each bottle of a nasal spray contains 30 mg of azelastine hydrochloride, acute overdose in adults is unlikely to result in clinically significant adverse events, other than increased somnolence. In studies, adults did not experience increased incidence of serious adverse events following single doses of the oral formulation of azelastine hydrochloride (up to 16 mg).
    6.5.2) PREVENTION OF ABSORPTION
    A) Toxicity after acute ingestion is unlikely. Gastrointestinal decontamination is generally unnecessary.
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) No specific laboratory tests are necessary unless otherwise clinically indicated.
    2) Monitor serum electrolytes in patients with significant vomiting.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis is not recommended given the low toxicity of these drugs.

Range Of Toxicity

Summary

    A) TOXICITY: Overdose data is limited. Since each bottle of a nasal spray contains 30 mg of azelastine hydrochloride, acute overdose in adults is unlikely to result in clinically significant adverse events, other than increased somnolence. In studies, adults did not experience increased incidence of serious adverse events following single doses of the oral formulation of azelastine hydrochloride (up to 16 mg).
    B) THERAPEUTIC DOSE: AZELASTINE: ADULTS AND CHILDREN (12 YEARS OR OLDER): ALLERGIC OR VASOMOTOR RHINITIS: Two sprays (azelastine 137 mcg/spray) per nostril twice daily. CHILDREN (5 to 11 YEARS): One spray (137 mcg) per nostril twice daily. ALLERGIC CONJUNCTIVITIS: ADULTS AND CHILDREN 3 YEARS AND OLDER: Instill one drop of azelastine 0.05% into each affected eye twice a day. BEPOTASTINE: ADULTS AND CHILDREN (2 YEARS OR OLDER): One drop of bepotastine 1.5% into each affected eye twice daily.

Therapeutic Dose

    7.2.1) ADULT
    A) AZELASTINE
    1) ALLERGIC CONJUNCTIVITIS
    a) OPHTHALMIC SOLUTION: Instill one drop of azelastine 0.05% into each affected eye twice a day (Prod Info OPTIVAR(R) ophthalmic solution, 2009).
    2) ALLERGIC RHINITIS
    a) NASAL SPRAY: 1 or 2 sprays of azelastine 0.1% or 0.15% per nostril twice daily (Prod Info ASTEPRO(R) nasal spray, 2015; Prod Info ASTELIN(R) nasal spray, 2012)
    3) VASOMOTOR RHINITIS
    a) NASAL SPRAY: 2 sprays in each nostril twice daily (Prod Info ASTELIN(R) nasal spray, 2012).
    B) AZELASTINE HYDROCHLORIDE/FLUTICASONE PROPIONATE
    1) NASAL SPRAY: 1 spray in each nostril twice daily (Prod Info DYMISTA(R) nasal spray suspension, 2015)
    C) BEPOTASTINE
    1) ALLERGIC CONJUNCTIVITIS: Instill one drop of bepotastine 1.5% into each affected eye twice daily (Prod Info BEPREVE(TM) ophthalmic solution, 2009).
    D) EPINASTINE
    1) ALLERGIC CONJUNCTIVITIS: Instill one drop of epinastine solution into each affected eye twice daily (Prod Info ELESTAT(R) ophthalmic solution, 2011).
    7.2.2) PEDIATRIC
    A) AZELASTINE
    1) ALLERGIC CONJUNCTIVITIS
    a) 3 YEARS AND OLDER
    1) OPHTHALMIC SOLUTION: Instill one drop of azelastine 0.05% into each affected eye twice a day (Prod Info OPTIVAR(R) ophthalmic solution, 2009).
    2) ALLERGIC RHINITIS
    a) 2 TO 5 YEARS
    1) NASAL SPRAY: 1 spray of 0.1% per nostril twice daily (Prod Info ASTEPRO(R) nasal spray, 2015); patients taking Astelin(R) and at least 5 years old, may use 1 spray of 0.1% or 0.15% per nostril twice daily (Prod Info ASTELIN(R) nasal spray, 2012)
    b) 6 TO 11 YEARS
    1) NASAL SPRAY: 1 spray of 0.1% or 0.15% per nostril twice daily (Prod Info ASTEPRO(R) nasal spray, 2015). Patients taking Astelin(R) and at least 5 years old, may use 1 spray per nostril twice daily (Prod Info ASTELIN(R) nasal spray, 2012)
    c) 12 YEARS AND OLDER
    1) NASAL SPRAY: 1 or 2 sprays of azelastine 0.1% or 0.15% per nostril twice daily (Prod Info ASTEPRO(R) nasal spray, 2015; Prod Info ASTELIN(R) nasal spray, 2012), or 2 sprays of azelastine 0.15% per nostril once daily (Prod Info ASTEPRO(R) nasal spray, 2015).
    3) VASOMOTOR RHINITIS
    a) 12 YEARS AND OLDER:
    1) NASAL SPRAY: 2 sprays (137 mcg/spray) per nostril twice daily (Prod Info ASTELIN(R) nasal spray, 2012)
    B) AZELASTINE HYDROCHLORIDE/FLUTICASONE PROPIONATE
    1) NASAL SPRAY
    a) UNDER 6 YEARS: Safety and efficacy have not been established (Prod Info DYMISTA(R) nasal spray suspension, 2015).
    b) 6 YEARS AND OLDER: 1 spray in each nostril twice daily (Prod Info DYMISTA(R) nasal spray suspension, 2015)
    C) BEPOTASTINE
    1) ALLERGIC CONJUNCTIVITIS (2 YEARS OR OLDER): Instill one drop of bepotastine 1.5% into each affected eye twice daily (Prod Info BEPREVE(TM) ophthalmic solution, 2009).
    D) EPINASTINE
    1) ALLERGIC CONJUNCTIVITIS (2 YEARS OR OLDER): Instill one drop of epinastine solution into each affected eye twice daily (Prod Info ELESTAT(R) ophthalmic solution, 2011).
    2) ALLERGIC CONJUNCTIVITIS (UNDER 2 YEARS OF AGE): Safety and efficacy in pediatric patients under the age of 2 years have not been established (Prod Info ELESTAT(R) ophthalmic solution, 2011).

Minimum Lethal Exposure

    A) ANIMAL STUDIES
    1) In animal studies, single oral doses as high as 10 mg/kg (approximately 260 times the maximum recommended daily intranasal dose in adults and children on a mg/m(2) basis) were well-tolerated in dogs; however, single oral doses of 20 mg/kg were lethal (Prod Info ASTEPRO(R) nasal spray, 2010).

Maximum Tolerated Exposure

    A) Overdose data is limited. The signs and symptoms of an acute overdose are expected to be similar to excessive pharmacologic effects. Since each bottle of a nasal spray contains 30 mg of azelastine hydrochloride, acute overdose in adults is unlikely to result in clinically significant adverse events, other than increased somnolence. In studies, adults did not experience increased incidence of serious adverse events following single doses of the oral formulation of azelastine hydrochloride (up to 16 mg) (Prod Info ASTEPRO(R) nasal spray, 2010).
    B) In animal studies, single oral doses as high as 10 mg/kg (approximately 260 times the maximum recommended daily intranasal dose in adults and children on a mg/m(2) basis) were well-tolerated in dogs; however, single oral doses of 20 mg/kg were lethal (Prod Info ASTEPRO(R) nasal spray, 2010).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) AZELASTINE - Azelastine hydrochloride is a phthalazinone derivative and a relatively selective histamine H1-receptor antagonist. It is an inhibitor of the release of histamine and other mediators from cells (e.g., mast cells) involved in the allergic response. In addition, the inhibition of other mediators involved in allergic reactions (eg; leukotrienes and PAF) has been observed in in-vitro studies using human cell lines. Decreased chemotaxis and activation of eosinophils has also been observed. Desmethylazelastine, the major metabolite, has H1-receptor antagonist activity (Prod Info ASTELIN(R) nasal spray, 2003; Prod Info OPTIVAR(R) ophthalmic solution, 2003).
    B) BEPOTASTINE - Bepotastine besilate 1.5% ophthalmic solution acts topically as a histamine-1 receptor antagonist. Additionally, bepotastine besilate 1.5% ophthalmic solution inhibits the release of histamine from mast cells (Prod Info BEPREVE(TM) ophthalmic solution, 2009)

Physicochemical

Physical Characteristics

    A) ALCAFTADINE: White to yellow powder; ophthalmic solution osmolality is approximately 290 milliosmoles/kg (Prod Info LASTACAFT(TM) ophthalmic solution, 2010).
    B) AZELASTINE HYDROCHLORIDE: White, almost odorless, crystalline powder with a bitter taste (Prod Info ASTEPRO(R) nasal spray, 2013; Prod Info ASTELIN(R) nasal spray, 2012) that is sparingly soluble in water, methanol, and propylene glycol, and slightly soluble in ethanol, octanol, and glycerine; melting point is 225 degrees C (Prod Info ASTEPRO(R) nasal spray, 2013; Prod Info ASTELIN(R) nasal spray, 2012; Prod Info OPTIVAR(R) ophthalmic solution, 2009); ophthalmic solution osmolarity is approximately 271 to 312 milliosmoles/L (Prod Info OPTIVAR(R) ophthalmic solution, 2009).
    C) EMEDASTINE DIFUMARATE: White crystalline fine powder that is soluble in water; ophthalmic solution osmolality is approximately 300 milliosmoles/kg (Prod Info EMADINE(R) ophthalmic solution, 2003).
    D) EPINASTINE HYDROCHLORIDE: Ophthalmic solution osmolality of 250 to 310 milliosmoles/kg (Prod Info ELESTAT(R) ophthalmic solution, 2004).
    E) KETOTIFEN: Stable in slightly acidic solution (Prod Info ZADITEN(R) oral tablets, 1998).
    F) KETOTIFEN FUMARATE: Fine crystalline, yellowish gray powder with a faintly bitter taste that is readily soluble in water (Prod Info ZADITEN(R) oral tablets, 1998); ophthalmic solution osmolality is 210 to 300 milliosmoles/kg (Prod Info ketotifen fumarate ophthalmic solution, 2005).
    G) LEVOCABASTINE HYDROCHLORIDE: White to almost white powder that is freely soluble in dimethylsulfoxide, soluble in N,N-dimethylformamide and methanol, and slightly soluble in propylene glycol, polyethylene glycol, and ethanol; in aqueous medium solubility is a function of pH, with minimum solubility at pH 4.1 to 9.8; melting point is greater than 300 degrees C (Prod Info LIVOSTIN(R) ophthalmic suspension, 2001).
    H) OLOPATADINE HYDROCHLORIDE: White crystalline powder that is soluble in water (Prod Info PATADAY(TM) ophthalmic solution, 2006; Prod Info PATANASE(R) nasal spray, 2009); ophthalmic solution osmolality is 300 milliosmoles/kg (Prod Info PATADAY(TM) ophthalmic solution, 2006).

Ph

    A) ALCAFTADINE: approximately 7 (Prod Info LASTACAFT(TM) ophthalmic solution, 2010)
    B) AZELASTINE HYDROCHLORIDE: 5 to 6.5 (ophthalmic solution) (Prod Info OPTIVAR(R) ophthalmic solution, 2009); 5 to 5.4 (nasal spray, saturated) (Prod Info ASTEPRO(R) nasal spray, 2013); 6.5 to 7.1 (nasal spray, aqueous) (Prod Info ASTELIN(R) nasal spray, 2012)
    C) EMEDASTINE DIFUMARATE: approximately 7.4 (Prod Info EMADINE(R) ophthalmic solution, 2003)
    D) EPINASTINE HYDROCHLORIDE: approximately 7 (Prod Info ELESTAT(R) ophthalmic solution, 2004)
    E) KETOTIFEN FUMARATE: 4.4 to 5.8 (Prod Info ketotifen fumarate ophthalmic solution, 2005)
    F) LEVOCABASTINE HYDROCHLORIDE: 6 to 8 (Prod Info LIVOSTIN(R) ophthalmic suspension, 2001)
    G) OLOPATADINE HYDROCHLORIDE: approximately 7 (ophthalmic solution) (Prod Info PATADAY(TM) ophthalmic solution, 2006); approximately 3.7 (nasal spray) (Prod Info PATANASE(R) nasal spray, 2009)

Molecular Weight

    A) ALCAFTADINE: 307.39 (Prod Info LASTACAFT(TM) ophthalmic solution, 2010)
    B) AZELASTINE HYDROCHLORIDE: 418.37 (Prod Info ASTEPRO(R) nasal spray, 2013; Prod Info ASTELIN(R) nasal spray, 2012; Prod Info OPTIVAR(R) ophthalmic solution, 2009)
    C) EMEDASTINE DIFUMARATE: 534.57 (Prod Info EMADINE(R) ophthalmic solution, 2003)
    D) EPINASTINE HYDROCHLORIDE: 285.78 (Prod Info ELESTAT(R) ophthalmic solution, 2004)
    E) KETOTIFEN FUMARATE: 425.5 (Prod Info ketotifen fumarate ophthalmic solution, 2005)
    F) LEVOCABASTINE HYDROCHLORIDE: 456.99 (Prod Info LIVOSTIN(R) ophthalmic suspension, 2001)
    G) OLOPATADINE HYDROCHLORIDE: 373.88 (Prod Info PATADAY(TM) ophthalmic solution, 2006)

References

General Bibliography

    1) Anon: FDC Reports: Carter-Wallace Azelastine nasal spray approved Nov 1 - The Pink Sheet. ;58:T&G, 1996a.
    2) Gould CAL, Ollier S, Aurich R, et al: A study of the clinical efficacy of azelastine in patients with extrinsic asthma, and its effect on airway responsiveness. Br J Clin Pharmacol 1988; 26:515-525.
    3) Kallen B: Use of antihistamine drugs in early pregnancy and delivery outcome. J Matern Fetal Neonatal Med 2002; 11(3):146-152.
    4) McTavish D & Sorkin EM: Azelastine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential. Drugs 1989; 38:778-800.
    5) McTavish D & Sorkin EM: Azelastine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential. Drugs 1989a; 38:778-800.
    6) Meltzer EO, Storms WW, Pierson WE, et al: Efficacy of azelastine in perennial allergic rhinitis: clinical and rhinomanometric evaluation. J Allergy Clin Immunol 1988; 82:447-455.
    7) Naradzay J & Barish RA: Approach to ophthalmologic emergencies. Med Clin North Am 2006; 90(2):305-328.
    8) Ollier S, Gould CAL, & Davies RJ: The effect of single and multiple dose therapy with azelastine on the immediate asthmatic response to allergen provocation testing. J Allergy Clin Immunol 1986; 78:358-364.
    9) Peate WF: Work-related eye injuries and illnesses. Am Fam Physician 2007; 75(7):1017-1022.
    10) Product Information: ASTELIN(R) intranasal spray, azelastine hcl intranasal spray. MedPointe Pharmaceuticals, Somerset, NJ, 2007.
    11) Product Information: ASTELIN(R) nasal spray, azelastine hcl nasal spray. MedPointe Pharmaceuticals, Somerset, NJ, 2003.
    12) Product Information: ASTELIN(R) nasal spray, azelastine HCl nasal spray. Meda Pharmaceuticals Inc. (per DailyMed), Somerset, NJ, 2012.
    13) Product Information: ASTEPRO(R) nasal spray, azelastine HCl 0.1%, 0.15% nasal spray. Meda Pharmaceuticals Inc, Somerset, NJ, 2010.
    14) Product Information: ASTEPRO(R) nasal spray, azelastine HCl nasal spray. MEDA Pharmaceuticals (per manufacturer), Somerset, NJ, 2013.
    15) Product Information: ASTEPRO(R) nasal spray, azelastine HCl nasal spray. Meda Pharmaceuticals (per FDA), Somerset, NJ, 2015.
    16) Product Information: BEPREVE(TM) ophthalmic solution, bepotastine besilate ophthalmic solution. ISTA Pharmaceuticals, Inc, Irvine, CA, 2009.
    17) Product Information: DYMISTA(R) nasal spray suspension, azelastine hydrochloride fluticasone propionate nasal spray suspension. Meda Pharmaceuticals Inc (per FDA), Somerset , NJ, 2015.
    18) Product Information: ELESTAT(R) ophthalmic solution, epinastine hcl ophthalmic solution. Allergan,Inc., Irvine, CA, 2004.
    19) Product Information: ELESTAT(R) ophthalmic solution, epinastine HCl 0.05% ophthalmic solution. Allergan, Inc. (per FDA), Irvine, CA, 2011.
    20) Product Information: EMADINE(R) ophthalmic solution, emedastine difumarate ophthalmic solution. Alcon Laboratories,Inc., Fort Worth, TX, 2003.
    21) Product Information: LASTACAFT(TM) ophthalmic solution, alcaftadine ophthalmic solution. Vistakon Pharmaceuticals, LLC, Jacksonville, FL, 2010.
    22) Product Information: LIVOSTIN(R) ophthalmic suspension, levocabastine hydrochloride ophthalmic suspension. Novartis Opthalmics, Mississauga, Ontario, 2001.
    23) Product Information: OPTIVAR(R) ophthalmic solution, azelastine hcl ophthalmic solution. MedPointe Pharmaceuticals, Somerset, NJ, 2003.
    24) Product Information: OPTIVAR(R) ophthalmic solution, azelastine HCl 0.05% ophthalmic solution. Meda Pharmaceuticals Inc. (per DailyMed), Somerset, NJ, 2009.
    25) Product Information: OPTIVAR(R) ophthalmic solution, azelastine hcl ophthalmic solution. Meda Pharmaceuticals, Inc., Somerset, NJ, 2008.
    26) Product Information: PATADAY(TM) ophthalmic solution, olopatadine hcl ophthalmic solution. Alcon Laboratories,Inc, Fort Worth, TX, 2006.
    27) Product Information: PATANASE(R) nasal spray, olopatadine hydrochloride nasal spray. Alcon Laboratories, Inc., Fort Worth, TX, 2009.
    28) Product Information: ZADITEN(R) oral tablets, ketotifen fumarate oral tablets. Novartis Pharmaceuticals, Quebec, Canada, 1998.
    29) Product Information: ketotifen fumarate ophthalmic solution, ketotifen fumarate ophthalmic solution. Apotex Inc, Toronto, ON, 2005.
    30) Spector SL, Perhach JL, Rohr AS, et al: Pharmacodynamic evaluation of azelastine in subjects with asthma. J Allergy Clin Immunol 1987; 80:75-80.
    31) TenEick AP, Blumer JL, & Reed MD: Safety of antihistamines in children. Drug Saf 2001; 24(2):119-147.