AZELASTINE
DESCRIPTION:
AZEP (azelastine hydrochloride) Nasal Spray, 137 micrograms (mcg), is an
antihistamine formulated as a metered spray solution for intranasal
administration. Azelastine hydrochloride occurs as a white, almost odorless,
crystalline powder with a bitter taste. It has a molecular weight of 418.37. It
is sparingly soluble in water, methanol, and propylene glycol and slightly
soluble in ethanol, octanol, and glycerine. It has a melting point of about 225
deg C and the pH of a saturated solution is between 5.0 and 5.4. Its chemical
name is (+/- )-1-(2H)-phthalazinone,4-((4-chlorophenyl)methyl) -2-(hexahydro-1-
methyl-1H-azepin-4-yl)-, monohydrochloride. Its molecular formula is
C22H24CIN3O.HCl.
AZEP Nasal Spray contains 0.1% azelastine hydrochlor ide in an aqueous
solution at pH 6.8 +/- 0.3. It also contains benzalkonium chloride (125 mcg/mL),
edetate disodium, hydroxypropyl methyl cellulose, citric acid, dibasic sodium
phosphate, sodium chloride, and purified water.
After priming, each metered spray delivers a 0.137 mL mean volume containing 137
mcg of azelastine hydrochloride (equivalent to 125 mcg of azelastine base). Each
bottle can deliver 100 metered sprays.
ACTIONS/CLINICAL PHARMACOLOGY:
Azelastine hydrochloride, a phthalazinone derivative, exhibits histamine H1-
receptor antagonist activity in isolated tissues, animal models, and humans.
AZEP Nasal Spray is administered as a racemic mixture with no difference
in pharmacologic activity noted between the enantiomers in in-vitro studies. The
major metabolite, desmethylazelastine, also possesses H1-receptor antagonist
activity.
PHARMACOKINETICS AND METABOLISM
After intranasal administration, the systemic bioavailability of azelastine
hydrochloride is approximately 40%. Maximum plasma concentrations (Cmax) are
achieved in 2-3 hours. Based on intravenous and oral administration, the
elimination half-life, steady-state volume of distribution, and plasma clearance
are 22 hours, 14.5 L/kg, and 0.5 L/h/kg, respectively. Approximately 75% of an
oral dose of radiolabeled azelastine hydrochloride was excreted in the feces
with less than 10% as unchanged azelastine. 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; however, clinical
interaction studies with the known CYP3A4 inhibitor erythromycin failed to
demonstrate a pharmacokinetic interaction. In a multiple-dose, steady-state drug
interaction study in normal volunteers, cimetidine (400 mg twice daily), a non-
specific P450 inhibitor, raised orally administered mean azelastine (4 mg twice
daily) concentrations by approximately 65%.
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. When azelastine hydrochloride is administered orally,
desmethylazelastine has an elimination half-life of 54 hours. Limited data
indicate that the metabolite profile is similar when azelastine hydrochloride is
administered via the intranasal or oral route.
In vitro studies with human plasma indicate that the plasma protein binding of
azelastine and desmethylazelastine are approximately 88% and 97%, respectively.
Azelastine hydrochloride administered intranasally at doses above two sprays per
nostril for 29 days resulted in greater than proportional increases in Cmax and
area under the curve (AUC) for azelastine.
Studies in healthy subjects administered oral doses of azelastine hydrochloride
demonstrated linear responses in Cmax and AUC.
SPECIAL POPULATIONS
Following oral administration, pharmacokinetic parameters were not influenced by
age, gender, or hepatic impairment.
Based on oral, single-dose studies, renal insufficiency (creatine clearance <50
mL/min) resulted in a 70-75% higher Cmax and AUC compared to normal subjects.
Time to maximum concentration was unchanged.
Oral azelastine has been safely administered to over 1400 asthmatic subjects,
supporting the safety of administering AZEP Nasal Spray to allergic
rhinitis patients with asthma.
PHARMACODYNAMICS
In a placebo-controlled study (95 subjects with allergic rhinitis), there was no
evidence of an effect of AZEP Nasal Spray (2 sprays per nostril twice
daily for 56 days) on cardiac repolarization as represented by the corrected QT
interval (QTc) of the electrocardiogram. At higher oral exposures (>/=4 mg twice
daily), a non-clinically significant mean change on the QTc (3-7 millisecond
increase) was observed.
Interaction studies investigating the cardiac repolarization effects of
concomitantly administered oral azelastine hydrochloride and erythromycin or
ketoconazole were conducted. Oral erythromycin had no effect on azelastine
pharmacokinetics or QTc based on analysis of serial electrocardiograms.
Ketoconazole interfered with the measurement of azelastine plasma levels;
however, no effects on QTc were observed (see PRECAUTIONS, Drug Interactions).
CLINICAL STUDIES:
CLINICAL TRIALS
U.S. placebo-controlled trials of AZEP Nasal Spray, included 322 patients
with seasonal allergic rhinitis who received two sprays per nostril twice a day
for up to 4 weeks. These trials included 55 pediatric patients ages 12 to 16
years. AZEP Nasal Spray significantly improved a complex of symptoms which
included rhinorrhea, sneezing, and nasal pruritus.
In dose-ranging trials, AZEP Nasal Spray administration resulted in a
decrease in symptoms which reached statistical significance from saline placebo
within 3 hours after initial dosing and persisted over the 12-hour dosing
interval.
There were no findings on nasal examination in an 8-week study that suggested
any adverse effect of azelastine on the nasal mucosa.
INDICATIONS AND USAGE:
AZEP 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 12 years and older.
CONTRAINDICATIONS:
AZEP Nasal Spray is contraindicated in patients with a known
hypersensitivity to azelastine hydrochloride or any of its components.
PRECAUTIONS:
ACTIVITIES REQUIRING MENTAL ALERTNESS: In clinical trials, the occurrence of
somnolence has been reported in some patients taking AZEP Nasal Spray: due
caution should therefore be exercised when driving a car or operating
potentially dangerous machinery. Concurrent use of AZEP Nasal Spray with
alcohol or other CNS depressants should be avoided because additional reductions
in alertness and additional impairment of CNS performance may occur.
INFORMATION FOR PATIENTS: Patients should be instructed to use AZEP Nasal
Spray only as prescribed. For the proper use of the nasal spray and to attain
maximum improvement, the patient should read and follow carefully the
accompanying patient instructions. Patients should be instructed to prime the
delivery system before initial use and after storage for 3 or more days (see
PATIENT INSTRUCTIONS FOR USE). Patients should also be instructed to store the
bottle upright at room temperature with the pump tightly closed and away from
children.
Patients should be advised against the concurrent use of AZEP Nasal Spray
with other antihistamines without consulting a physician. 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. Patients should be advised to
assess their individual responses to AZEP Nasal Spray before engaging in
any activity requiring mental alertness, such as driving a car or operating
machinery. Patients should be advised that the concurrent use of AZEP
Nasal Spray with alcohol or other CNS depressants may lead to additional
reductions in alertness and impairment of CNS performance and should be avoided
(see Drug Interactions ).
DRUG INTERACTIONS: Concurrent use of AZEP 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 (400 mg twice daily) increased the mean Cmax and AUC of orally
administered azelastine hydrochloride (4 mg twice daily) by approximately 65%.
Ranitidine hydrochloride (150 mg twice daily) 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
(500 mg three times daily for seven days) had no effect on azelastine
pharmacokinetics or QTc based on analyses of serial electrocardiograms.
Ketoconazole (200 mg twice daily for 7 days) interfered with the measurement of
azelastine plasma concentrations; however, no effects on QTc were observed.
No significant pharmacokinetic interaction was observed with the
coadministration of an oral 4-mg dose of azelastine hydrochloride twice daily
and theophylline 300 mg or 400 mg twice daily.
GERIATRIC USE: U.S. placebo-controlled clinical trials included 11 patients
above the age of 60 years who were treated with AZEP Nasal Spray. While
this number is very small and no substantial conclusions can be drawn, the
adverse events in this group were similar to patients under age 60 years.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY: Carcinogenicity studies in
rats and mice with oral azelastine hydrochloride for 24 months at doses up to 30
mg/kg/day and 25 mg/kg/day, respectively (240 and 100 times the maximum
recommended human daily intranasal dose on a mg/M(square) basis), revealed no
evidence of carcinogenicity.
Azelastine hydrochloride showed no genotoxic effects in the Ames test, DNA
repair test, mouse lymphoma forward mutation assay, mouse micronucleus test, or
chromosomal aberration test in rat bone marrow.
Reproduction and fertility studies in rats showed no effects on male or female
fertility at oral doses of up to 30 mg/kg/day (240 times the maximum recommended
human daily intranasal dose on a mg/m(square) basis). At 68.6 mg/kg/day (550
times the maximum recommended human daily intranasal dose on a mg/M(square)
basis), the duration of estrous cycles was prolonged and copulatory activity and
the number of pregnancies were decreased. The numbers of corpora lutea and
implantations were decreased; however, the implantation ratio was not affected.
PREGNANCY CATEGORY C: Azelastine hydrochloride has been shown to be embryotoxic,
fetotoxic, and teratogenic (external and skeletal abnormalities) in mice at an
oral dose of 68.6 mg/kg/day (280 times the maximum recommended human daily
intranasal dose on a mg/m(square) basis).
At an oral dose of 30 mg/kg/day (240 times the maximum recommended human daily
intranasal dose on a mg/m(square) basis), delayed ossification (undeveloped
metacarpus), and the incidence of 14th rib were increased in rats. At 68.6
mg/kg/day (550 times the maximum recommended human daily intranasal dose on a
mg/m(square) basis) azelastine hydrochloride caused abortion and fetotoxic
effects in rats.
The relevance to humans of these skeletal findings noted at only high drug
exposure levels is unknown.
There are no adequate and well-controlled clinical studies in pregnant women.
AZEP Nasal Spray should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus.
NURSING MOTHERS: It is not known whether azelastine hydrochloride is excreted in
human milk. Because many drugs are excreted in human milk, caution should be
used when AZEP Nasal Spray is administered to a nursing woman.
PEDIATRIC USE: Safety and efficacy of AZEP Nasal Spray in pediatric
patients below the age of 12 years have not been established.
DRUG INTERACTIONS:
Concurrent use of AZEP 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 (400 mg twice daily) increased the mean Cmax and AUC of orally
administered azelastine hydrochloride (4 mg twice daily) by approximately 65%.
Ranitidine hydrochloride (150 mg twice daily) 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
(500 mg three times daily for seven days) had no effect on azelastine
pharmacokinetics or QTc based on analyses of serial electrocardiograms.
Ketoconazole (200 mg twice daily for 7 days) interfered with the measurement of
azelastine plasma concentrations; however, no effects on QTc were observed.
No significant pharmacokinetic interaction was observed with the
coadministration of an oral 4-mg dose of azelastine hydrochloride twice daily
and theophylline 300 mg or 400 mg twice daily.
(See Also PRECAUTIONS.)
ADVERSE REACTIONS:
Adverse experience information for AZEP Nasal Spray is derived from six
well-controlled, 2-day to 8-week clinical studies which included 391 patients
who received AZEP Nasal Spray at a dose of 2 sprays per nostril twice
daily. In placebo-controlled efficacy trials, the incidence of discontinuation
due to adverse reactions in patients receiving AZEP Nasal Spray was not
significantly different from vehicle placebo (2.2% vs 2.8%, respectively).
In these clinical studies, adverse events that occurred statistically
significantly more often in patients treated with AZEP Nasal Spray versus
vehicle placebo included bitter taste (19.7% vs 0.6%), somnolence (11.5% vs
5.4%), weight increase (2.0% vs 0%), and myalgia (1.5% vs 0%).
The following adverse events were reported with frequencies >/=2% in the
AZEP Nasal Spray treatment group and more frequently than placebo in
short-term (=2 days) and long-term (2-8 weeks) clinical trials.
AZEP Vehicle
ADVERSE EVENT Nasal Spray Placebo
n=391 n=353
--------------------------------------------------------------------------------------------------------------------------
Bitter Taste* 19.7 0.6
Headache 14.8 12.7
Somnolence* 11.5 5.4
Nasal Burning 4.1 1.7
Pharyngitis 3.8 2.8
Dry Mouth 2.8 1.7
Paroxysmal Sneezing 3.1 1.1
Nausea 2.8 1.1
Rhinitis 2.3 1.4
Fatigue 2.3 1.4
Dizziness 2.0 1.4
Epistaxis 2.0 1.4
Weight Increase* 2.0 0.0
-----------------------------------------------------------------------------------------------------------------------------
* P<0.05, Fisher's Exact Test (two-tailed)
The following events were observed infrequently (<2% and exceeding placebo
incidence) in patients who received AZEP Nasal Spray (2 sprays/nostril
twice daily) in U.S. clinical trials.
Cardiovascular: flushing, hypertension, tachycardia.
Dermatological: contact dermatitis, eczema, hair and follicle infection,
furunculosis.
Digestive: constipation, gastroenteritis, glossitis, ulcerative stomatitis,
vomiting, increased SGPT, aphthous stomatitis.
Metabolic and Nutritional: increased appetite.
Musculoskeletal: myalgia, temporomandibular dislocation.
Neurological: hyperkinesia, hypoesthesia, vertigo.
Psychological: anxiety, depersonalization, depression, nervousness, sleep
disorder, thinking abnormal.
Respiratory: bronchospasm, coughing, throat burning, laryngitis.
Special senses: conjunctivitis, eye abnormality, eye pain, watery eyes, taste
loss.
Urogenital: albuminuria, amenorrhea, breast pain, hematuria, increased urinary
frequency.
Whole body: allergic reaction, back pain, herpes simplex, viral infection,
malaise, pain in extremities, abdominal pain.
In controlled trials involving nasal and oral azelastine hydrochloride
formulations, there were infrequent occurrences of hepatic transaminase
elevations. The clinical relevance of these reports has not been established.
OVERDOSAGE:
There have been no reports of overdosages with AZEP Nasal Spray. Acute
overdosage with this dosage form is unlikely to result in clinically significant
adverse events, other than increased somnolence, since one bottle of AZEP
Nasal Spray contains 17 mg of azelastine hydrochloride. Clinical studies with
single doses of the oral formulation of azelastine hydrochloride (up to 16 mg)
have not resulted in increased incidence of serious adverse events. General
supportive measures should be employed if overdosage occurs. Oral doses greater
than 120 mg/kg (480 times the maximum recommended human daily intranasal dose on
a mg/M(square) basis) produced significant mortality in mice. Responses seen
prior to mortality were tremor, convulsions, decreased muscle tone, and
salivation. Single doses as high as 10 mg/kg (270 times the recommended human
daily intranasal dose on a mg/M(square) basis) were well tolerated in dogs, but
single doses of 20 mg/kg were lethal.
DOSAGE AND ADMINISTRATION:
The recommended dose of AZEP Nasal Spray in adults and children 12 years
and older is two sprays per nostril twice daily. Before initial use, the child-
resistant screw cap on the bottle should be replaced with the pump unit and the
delivery system should be primed with 4 sprays or until a fine mist appears.
When 3 or more days have elapsed since the last use, the pump should be reprimed
with 2 sprays or until a fine mist appears.
CAUTION: AVOID SPRAYING IN THE EYES.
Directions for Use: Illustrated patients instructions for proper use accompany
each package of AZEP Nasal Spray.
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