Azelastine

381.9

381.90

611-699-2

DTXSID6022638

Oil

S01GX07|R - Respiratory system|S - Sensory organs

2933990090

35.9

4.9

white crystal powder

1.3±0.1 g/cm3

225 °C (hydrochloride salt)

533.9±60.0 °C at 760 mmHg

276.7±32.9 °C

1.642

H2O: Sparingly soluble (hydrochloride salt)

Store at controlled room temperature 20-25 deg C (68-77 deg F). Protect from freezing.

5.51X10-11 mm Hg at 25 deg C (est)

LD50 orl-rat: 310 mg/kg ARZNAD 31,1184,81

Henry's Law constant = 2.57X10-10 atm-cu m/mol at 25 °C (est)

Crystals from alcohol/water. Two distinct crystalline forms have been identified /Azelastine monohydrate/|Crystals from alcohol, mp 225-229 °C /Azelestine hydrochloride/|Hydroxyl radical reaction rate constant = 1.26X10-10 cu cm/molec-sec at 25 °C (est)

III

6.1(b)

1557

R50/53:Very Toxic to aquatic organisms, may cause long-term adverse effects in the aquatic environment . R23/25:Toxic by inhalation and if swallowed .

S61-S60-S45-S28A-S20/21-S28

CY5950000

N-T,N,T

P261, P264, P270, P271, P280, P301+P312, P302+P352, P304+P312, P304+P340, P312, P321, P322, P330, P332+P313, P362, P363, P403+P233, P405, P501

H302

SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.|SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including azelastine hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Azelastine hydrochloride/

|Warning|H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]|P201, P202, P261, P264, P270, P271, P273, P280, P281, P301+P312, P302+P352, P304+P312, P304+P340, P308+P313, P312, P321, P322, P330, P332+P313, P362, P363, P403+P233, P405, and P501|Aggregated GHS information provided by 2 companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Overdosage of intranasal or ophthalmic azelastine is unlikely to result in clinically significant adverse effects aside from increased drowsiness. If overdose does occur, employ general supportive measures. Oral ingestion of antihistamines, including non-oral formulations of azelastine, can cause serious adverse effects in children - for this reason, these products should be kept out of the reach of children. The oral LD50 in rats is 580 mg/kg.

Concurrent use of Astelin Nasal Spray with alcohol or other CNS depressants should be avoided because additional reductions in alertness and additional impairment of CNS performance may occur.|Cimetidine increased the mean Cmax and AUC of orally administered azelastine hydrochloride by approximately 65%. Ranitidine hydrochloride had no effect on azelastine pharmacokinetics.|Interaction studies investigating the cardiac effects, as measured by the corrected QT interval (QTc), of concomitantly administered oral azelastine hydrochloride and erythromycin or ketoconazole were conducted. Oral erythromycin had no effect on azelastine pharmacokinetics or QTc based on analyses of serial electrocardiograms. Ketoconazole interfered with the measurement of azelastine plasma concentrations; however, no effects on QTc were observed.

The manufacturer states that azelastine ophthalmic solution should not be used for the symptomatic management of contact lens-related irritation. Patients should be advised not to wear contact lenses if their eye(s) are red.|Patients who are, or may become, pregnant should be told that this product should be used in pregnancy or during lactation only if the potential benefit justifies the potential risks to the fetus or nursing infant.

In-vitro studies in human plasma indicate that the plasma protein binding of azelastine and desmethylazelastine are approximately 88% and 97%, respectively.

Intranasal azelastine is indicated for the symptomatic treatment of seasonal allergic rhinitis in patients 5 years and older and for the symptomatic treatment of vasomotor rhinitis in patients 12 years and older. Ophthalmic azelastine solution is indicated for the treatment of itchy eyes associated with allergic conjunctivitis.

Phthalazines; Anti-Inflammatory Agents, Non-Steroidal; Platelet Aggregation Inhibitors; Bronchodilator Agents; Histamine H1 Antagonists, Non-Sedating; Lipoxygenase Inhibitors|Oral azelastine has been safely administered to over 1400 asthmatic subjects, supporting the safety of administering Astelin Nasal Spray to allergic rhinitis patients with asthma.|Astelin Nasal Spray is indicated for the treatment of the symptoms of seasonal allergic rhinitis such as rhinorrhea, sneezing, and nasal pruritus in adults and children 5 years and older, and for the treatment of the symptoms of vasomotor rhinitis, such as rhinorrhea, nasal congestion and postnasal drip in adults and children 12 years and older. /Include in US product label/|Azelastine is used for the symptomatic treatment of ocular itching associated with allergic conjunctivitis. This indication is based on environmental studies (duration 2-8 weeks) in which therapy with azelastine ophthalmic solution was more effective than vehicle in providing relief of ocular itching in children and adults with allergic conjunctivitis.|THERAPEUTIC CATEGORY: Antihistaminic

Astelin Nasal Spray is contraindicated in patients with a known hypersensitivity to azelastine hydrochloride or any of its components.|... The occurrence of somnolence has been reported in some patients taking Astelin Nasal Spray; due caution should therefore be exercised when driving a car or operating potentially dangerous machinery while using Astelin Nasal Spray. Concurrent use of Astelin Nasal Spray with alcohol or other CNS depressants should be avoided because additional reductions in alertness and additional impairment of CNS performance may occur.|The manufacturer states that there was no evidence of an effect on cardiac repolarization in patients who received azelastine hydrochloride nasal spray (548 mcg twice daily for 56 days) in a placebo-controlled study. Although 3- to 7-millisecond increases in mean QTc intervals were observed with higher oral dosages of the drug, such increases were not considered to be clinically important.|The principal adverse effects of intranasal azelastine are local (e.g., bitter taste, nasal burning, pharyngitis, paroxysmal sneezing), but adverse systemic effects (e.g., somnolence, headache) also can occur. Anaphylactoid reactions, application site reaction, chest pain, aggravated condition, confusion, diarrhea, dyspnea, facial edema, involuntary muscle contractions, paresthesia, parosmia, pruritus, rash, tolerance, urinary retention, vision abnormality, and xerophthalmia have occurred in patients receiving azelastine nasal spray; a causal relationship between these events and the drug have not been established.|For more Drug Warnings (Complete) data for Azelastine (16 total), please visit the HSDB record page.

Azelastine antagonizes the actions of histamine, resulting in the relief of histamine-mediated allergy symptoms. Onset of action occurs within 15 minutes with intranasal formulations and as quickly as 3 minutes with ophthalmic solutions. Intranasal formulations have a relatively long-duration of action, with peak effects observed 4-6 hours after the initial dose and efficacy maintained over the entirety of the standard 12 hour dosing interval.

Agents that are used to treat allergic reactions. Most of these drugs act by preventing the release of inflammatory mediators or inhibiting the actions of released mediators on their target cells. (From AMA Drug Evaluations Annual, 1994, p475) (See all compounds classified as Anti-Allergic Agents.)|Agents that cause an increase in the expansion of a bronchus or bronchial tubes. (See all compounds classified as Bronchodilator Agents.)|Compounds that bind to and inhibit that enzymatic activity of LIPOXYGENASES. Included under this category are inhibitors that are specific for lipoxygenase subtypes and act to reduce the production of LEUKOTRIENES. (See all compounds classified as Lipoxygenase Inhibitors.)|A class of non-sedating drugs that bind to but do not activate histamine receptors (DRUG INVERSE AGONISM), thereby blocking the actions of histamine or histamine agonists. These antihistamines represent a heterogenous group of compounds with differing chemical structures, adverse effects, distribution, and metabolism. Compared to the early (first generation) antihistamines, these non-sedating antihistamines have greater receptor specificity, lower penetration of BLOOD-BRAIN BARRIER, and are less likely to cause drowsiness or psychomotor impairment. (See all compounds classified as Histamine H1 Antagonists, Non-Sedating.)

Systemic bioavailability of azelastine hydrochloride following intranasal administration is approximately 40%, reaching Cmax within 2-3 hours. When administered at doses greater than the recommended maximum, greater than proportional increases in both Cmax and AUC were observed.|After an oral dose of radio-labeled azelastine hydrochloride, approximately 75% was excreted in the feces, with less than 10% as unchanged azelastine hydrochloride.|After intravenous and oral administration, the steady-state volume of distribution is 14.5 L/kg.|Based on intravenous and oral administration, azelastine demonstrated a plasma clearance of 0.5 L/h/kg.|After intranasal administration, the systemic bioavailability of azelastine hydrochloride is approximately 40%. Maximum plasma concentrations (Cmax) are achieved in 2-3 hours.|Based on oral, single-dose studies, renal insufficiency (creatinine clearance <50 mL/min) resulted in a 70-75% higher Cmax and AUC compared to normal subjects. Time to maximum concentration was unchanged.|Based on intravenous and oral administration, the steady-state volume of distribution, and plasma clearance are 14.5 L/kg, and 0.5 L/hr/kg, respectively.|In vitro studies with human plasma indicate that the plasma protein binding of azelastine and desmethylazelastine are approximately 88% and 97%, respectively.|For more Absorption, Distribution and Excretion (Complete) data for Azelastine (10 total), please visit the HSDB record page.

Azelastine hydrochloride is oxidatively metabolized to its main, and biologically active, metabolite desmethylazelastine by the cytochrome P450 enzyme system. Though labels for azelastine state that specific CYP enzyme involvement has not been elucidated, it has been suggested that the N-demethylation of azelastine is primarily catalyzed by CYP3A4, CYP2D6, and CYP1A2.|Azelastine is oxidatively metabolized to the principal active metabolite, desmethylazelastine, by the cytochrome P450 enzyme system. The specific P450 isoforms responsible for the biotransformation of azelastine have not been identified|The major active metabolite, desmethylazelastine, was not measurable (below assay limits) after single-dose intranasal administration of azelastine hydrochloride. After intranasal dosing of azelastine hydrochloride to steady-state, plasma concentrations of desmethylazelastine range from 20-50% of azelastine concentrations.|The ... pharmacokinetics of azelastine hydrochloride after single and multiple dosing (4.4 mg as tablet, tau = 12 hr) were investigated in 14 volunteers (6 female, 8 male) older than 65 years (70 +/- 5 years, mean +/- SD). ... The RIA co-detects besides azelastine the pharmacodynamically active metabolite N-demethyl-azelastine and thus, the parameters describe the pharmacokinetic behaviour as a resultant from both compounds, i.e. the "active principle". N-Demethylated metabolites are known to have longer half-lives usually than their parent compounds and thus, accumulate in a higher degree during multiple dosing.

Based on intravenous and oral administration, azelastine demonstrated an elimination half-life of 22 hours. Its primary active metabolite, desmethylazelastine, has an elimination half-life of 54 hours.|Based on intravenous and oral administration, the elimination half-life is 22 hours ...|When azelastine hydrochloride is administered orally, desmethylazelastine has an elimination half-life of 54 hours.

Azelastine is primarily a selective antagonist of histamine H1-receptors, with a lesser affinity for H2-receptors, used for the symptomatic treatment of allergies. Histamine H1-receptors are G-protein-coupled receptors with 7 transmembrane spanning domains that are found on nerve endings, smooth muscle cells, and glandular cells. Following allergen exposure in sensitized individuals, IgE-receptor cross-linking on mast cells results in the release of histamine, which binds to H1-receptors and contributes to typical allergic symptoms such as itching, sneezing, and congestion. Though its primary mode of action is thought to be via H1-receptor antagonism, azelastine (like other second-generation antihistamines) appears to affect other mediators of allergic symptomatology. Azelastine has mast cell-stabilizing properties that prevent the release of interleukin-6, tryptase, histamine, and TNF-alpha from mast cells, and has been shown to reduce mediators of mast cell degranulation such as leukotrienes in the nasal lavage of patients with rhinitis, as well as inhibiting their production and release from eosinophils (potentially via inhibition of phospholipase A₂ and leukotriene C₄ synthase). Additionally, patients using oral azelastine were observed to have significantly reduced concentrations of substance P and bradykinin in nasal secretions, both of which may play a role in nasal itching and sneezing in patients with allergic rhinitis.|Azelastine is a histamine H1-receptor antagonist. Azelastine, a phthalazinone derivative, is structurally unrelated to other currently available antihistamines and has been characterized a selective H1-receptor antagonist. Although azelastine has been referred to as a second generation ("nonsedating") antihistamine, adverse CNS effects (e.g., drowsiness) may occur with the drug, particularly at relatively high doses or when administered with CNS depressants (e.g., alcohol). The desmethyl metabolite also possesses antihistaminic activity. In addition, azelastine inhibits other mediators (e.g., leukotrienes, platelet activating factor (PAF)) involved in allergic reactions. Azelastine may inhibit the accumulation of eosinophils at the site of allergic inflammation and prevent eosinophil degranulation.|Azelastine, an orally effective antiasthmatic agent, has been reported to inhibit antihistamine-resistant, leukotriene-mediated allergic bronchoconstriction in guinea pigs. This suggests that azelastine might act through inhibition of leukotriene (LT) C4/D4 synthesis. /Investigators/ have examined the effect of azelastine on allergic and nonallergic histamine secretion and LTC4 formation. Azelastine and the known 5-lipoxygenase inhibitors, nordihydroguaiaretic acid and AA-861, exerted concentration-dependent inhibition of allergic LTC4 formation in chopped lung tissue from actively sensitized guinea pigs and calcium ionophore A23187-stimulated LTC4 synthesis in mixed peritoneal cells from rats. Azelastine also produced concentration-dependent inhibition of allergic and nonallergic histamine secretion from rat peritoneal mast cells. The ability of azelastine to inhibit allergic and nonallergic histamine secretion and LTC4 generation may contribute to its mode of action and its therapeutic efficacy.|Leukotrienes have been proposed as important chemical mediators of allergic inflammation, and there is evidence that azelastine (Astelin) can affect leukotriene-mediated allergic responses. One of the enzymes required for the synthesis of leukotrienes from arachidonic acid is 5-lipoxygenase (5-LO). Azelastine, which is preferentially taken up by the lung and alveolar macrophages, inhibits leukotriene generation in the airways. This property of azelastine may contribute to its therapeutic efficacy in the long-term treatment and management of rhinitis and asthma. Azelastine does not directly inhibit 5-LO in disrupted murine peritoneal cells and rat basophilic leukemia cells (IC50 > 100 microM), but does have moderate 5-LO inhibitory activity in intact murine peritoneal cells (IC50 = 10 microM, 5 min) and in chopped guinea pig liver (IC50 = 14 microM, 2 hr). The generation and release of leukotrienes in human neutrophils and eosinophils is also inhibited by azelastine (IC50 = 0.9-1.1 microM). Furthermore, azelastine is a potent and specific inhibitor of allergen-induced generation of leukotrienes in the nose of the guinea pig (ID50 < 100 ug/kg, im, 20 min) as well as in patients with rhinitis (2 mg, po, 4 hr; ID50 < 30 ug/kg). Azelastine also inhibits allergen-induced, leukotriene-mediated, pyrilamine-resistant bronchoconstriction (oral ID50 = 60 ug/kg, 2 hr and 120 ug/kg, 24 hr). This profile suggests that azelastine may be a novel inhibitor of Ca(2+)-dependent translocation of 5-lipoxygenase from cytosol to the nuclear envelope or a FLAP /5-lipoxygenase activity protein/ inhibitor rather than a direct 5-LO inhibitor.|Azelastine, oxatomide, and ketotifen are used for patients with allergic diseases. These drugs inhibit the release of chemical mediators including the leukotrienes; however, the mechanism involved is unclear. To clarify the mechanism of inhibition, we investigated the effects of three drugs on the function of phospholipase A2, 5-lipoxygenase, leukotriene C4 synthase, and leukotriene A4 hydrolase, which are all catabolic enzymes involved in synthesizing leukotriene C4 and leukotriene B4 in rat basophilic leukemia (RBL)-1 cells. The production of leukotriene C4 and leukotriene B4 was measured by high performance liquid chromatography (HPLC). All three drugs inhibited the production of leukotriene C4 and leukotriene B4 when cells were stimulated with A23187. All three drugs also inhibited the A23187-stimulated release of 3H-arachidonic acid from membrane phospholipids. Azelastine inhibited the production of leukotriene C4, but not leukotriene B4, when either arachidonic acid or leukotriene A4 free acid was used as the substrate in our cell free system. Oxatomide and ketotifen did not inhibit the synthesis of either leukotriene C4 or leukotriene B4 in the same cell free study. Results indicated that oxatomide and ketotifen inhibit the production of leukotriene C4 and leukotriene B4 by inhibiting phospholipase A2 activity, whereas, azelastine inhibits the leukotriene C4 production by inhibiting phospholipase A2 and leukotriene C4 synthase.|For more Mechanism of Action (Complete) data for Azelastine (12 total), please visit the HSDB record page.

There is no known antidote to azelastine hydrochloride nasal spray.|/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/HUMAN EXPOSURE STUDIES/ ... With three different doses of oral azelastine, /investigators/ have performed a dose-response study to determine its protective effect on the airways against histamine-induced bronchoconstriction in 12 patients with mild, atopic asthma. On 4 separate days, patients undertook standardized inhalation-challenge tests with increasing concentrations of histamine (0.03 to 32 mg/mL) 4 hours after placebo or azelastine, 4.4, 8.8, and 17.6 mg, administered double blind and in random order. On 2 additional days, patients underwent methacholine challenge tests after placebo or azelastine, 17.6 mg. Baseline FEV1 between treatment days and 4 hours after placebo and azelastine did not change significantly. The three doses of azelastine, 4.4, 8.8, and 17.6 mg, increased the concentration of histamine required to cause a 20% fall in FEV1 (PC20) from 0.16 mg/mL geometric mean (GM) after placebo to 1.98 (p less than 0.01), 8.8 (p less than 0.01), and 8.1 (p less than 0.01) mg/mL, respectively. GM potency ratios derived from the PC20 values obtained for each patient indicated that the three increasing doses of azelastine displaced the histamine dose-response curve to the right by factors of 12.8, 54.4, and 50.2. Azelastine had no effect on the airway response to methacholine with GM PC20 values of 0.16 and 0.19 after placebo and azelastine, 17.6 mg. Azelastine is a potent H1histamine-receptor antagonist on human airways in vivo without demonstrable anticholinergic effect.|/SIGNS AND SYMPTOMS/ There have been no reported overdosages with Astelin Nasal Spray. Acute overdosage by adults with this dosage form is unlikely to result in clinically significant adverse events, other than increased somnolence, since one bottle of Astelin Nasal Spray contains 30 mg of azelastine hydrochloride. Clinical studies in adults with single doses of the oral formulation of azelastine hydrochloride (up to 16 mg) have not resulted in increased incidence of serious adverse events.

4-((4-chlorophenyl)methyl)-2- (hexahydro-1-methyl-1H-azepin-4-yl)-1(2H)- phthalazinone HCl

Azelastine hydrochloride preparations: (AHFS, 2011)|Azelastine currently is commercially available in the US as azelastine hydrochloride nasal spray preparation, having a pH of approximately 6.8.|Azelastine also is commercially available as azelastine hydrochloride ophthalmic solution. Azelastine hydrochloride ophthalmic solution is a sterile solution of the drug in water for injection; the solution contains benzalkonium chloride as a preservative and also contains edetate disodium, hydroxypropyl methylcellulose, sorbitol, and sodium hydroxide. Azelastine hydrochloride ophthalmic solution has a pH of approximately 5-6.5 and an osmolarity of approximately 271-312 mOsmL/L.

HPLC determination in plasma.|A manual-injection liquid chromatographic method using fluorescence detection permitted determination of a new antiasthmatic drug, azelastine, and its desmethyl metabolite extracted from human plasma. Reliable quantitation was achieved to at least 0.3 ng/ml for each analyte. No interference was seen in co-chromatography of sixteen other substances, which were potential co-medications (or their metabolites) as used in standard asthma or allergy treatment.

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients