--------WARNINGS AND PRECAUTIONS-------
`
`• Epistaxis, nasal ulceration, and nasal septal
`
`
`
`perforation. Monitor patients periodically for
`
`signs of adverse effects on the nasal mucosa.
`
`Discontinue if ulcerations or perforations occur.
`
`Avoid use in patients with nasal disease other
`than allergic rhinitis (5.1).
`
`
`• Avoid engaging in hazardous occupations
`
`requiring complete mental alertness and
`coordination such as driving or operating
`
`
`machinery when taking PATANASE Nasal Spray
`(5.2).
`
`
`
`
`
`• Avoid concurrent use of alcohol or other central
`nervous system depressants with PATANASE
`
`
`Nasal Spray (5.2).
`
`
`
`
`--------------ADVERSE REACTIONS--------------­
`
`The most common (>1%) adverse reactions
`included bitter taste, headache, epistaxis,
`pharyngolaryngeal pain, post-nasal drip, cough,
`
`
`and urinary tract infection in patients 12 years of
`
`age and older and epistaxis, headache, upper
`
`
`respiratory tract infection, bitter taste, pyrexia, and
`
`
`rash in patients 6 to 11 years of age (6.1).
`
`To report SUSPECTED ADVERSE
`
`REACTIONS, contact Alcon Laboratories, Inc.
`
`
`at 1-800-757-9195 or FDA at 1-800-FDA-1088 or
`
`www.fda.gov/medwatch.
`
`See 17 for PATIENT COUNSELING
`INFORMATION and FDA-approved patient
`
`labeling.
`Revised: February 2012
`
`
`
`
`
`
`
`
`These highlights do not include all the information
`needed to use PATANASE® Nasal Spray safely and
`effectively. See full prescribing information for
`
`PATANASE Nasal Spray.
`
`PATANASE (olopatadine hydrochloride) Nasal Spray
`
`Initial U.S. Approval: 1996
`
`
`
`---------------INDICATIONS AND USAGE------------------
`
`PATANASE Nasal Spray is an H1 receptor antagonist
`
`
` indicated for the relief of the symptoms of seasonal allergic
`
` rhinitis in adults and children 6 years of age and older. (1)
`
`
`----------DOSAGE AND ADMINISTRATION------------­
`For intranasal use only.
` Recommended dosages:
`
`
`• Adults and adolescents ≥ 12years: Two sprays per
`nostril (665 mcg per spray) twice daily (2.1)
`
`
`
`
`• Children 6 to 11 years: One spray per nostril (665
`
`mcg per spray) twice daily (2.2).
`
`Priming Information: Prime PATANASE Nasal Spray
`
`before initial use and when PATANASE Nasal Spray has
`
`
`
`not been used for more than 7 days (2.3).
`
`---------DOSAGE FORMS AND STRENGTHS------------
`
`
`
`
`Nasal spray 0.6%: 665 mcg of olopatadine hydrochloride in
`each 100- microliter spray. (3) Supplied as a 30.5 g bottle
`
`containing 240 sprays.
`
`--------------CONTRAINDICATIONS-------------­
`None.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3091120
`
`1
`
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`

`

`FULL PRESCRIBING INFORMATION*
`
`1
`INDICATIONS AND USAGE
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Adults and Adolescents 12 years of age and older
`
`
`2.2 Children 6 to 11 years of age
`2.3 Administration Information
`
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Local Nasal Effects
`
`5.2 Activities Requiring Mental Alertness
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Post-Marketing Experience
`
`7 DRUG INTERACTIONS
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`10 OVERDOSAGE
`
`11 DESCRIPTION
`
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of
`
`Fertility
`
`
`13.2 Animal Toxicology
`
`14 CLINICAL STUDIES
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`16.1 How Supplied
`16.2 Storage
`
`
`17 PATIENT COUNSELING INFORMATION
`17.1 Local Nasal Effects and Other Common Adverse Reactions
`17.2. Activities Requiring Mental Alertness
`17.3 Concurrent Use of Alcohol and other Central Nervous System Depressants
`
`17.4. Keep Spray Out of Eyes
`*Sections or subsections omitted from the full prescribing
`
`information are not listed.
`______________________________________________________________________________________
`FULL PRESCRIBING INFORMATION
`
`
`1 INDICATIONS AND USAGE
`
`
`
` PATANASE Nasal Spray is an H1 receptor antagonist indicated for the relief of the symptoms of seasonal
` allergic rhinitis in adults and children 6 years of age and older.
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`
`Administer PATANASE Nasal Spray by the intranasal route only.
`
`
`
`2.1 Adults and Adolescents 12 years of age and older: The recommended dosage is two sprays per
`
`
`
`
`nostril twice daily.
`
`2.2 Children 6 to 11 years of age: The recommended dosage is one spray per nostril twice daily.
`
`
`
`
`
`
`
`
`Reference ID: 3091120
`
`2
`
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`

`
`
`
`2.3 Administration Information
`
`
`Priming: Before initial use, prime PATANASE Nasal Spray by releasing 5 sprays or until a fine mist
`
`
`
`
`
`appears. When PATANASE Nasal Spray has not been used for more than 7 days, re-prime by releasing 2
`sprays. Avoid spraying PATANASE Nasal Spray into the eyes.
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`PATANASE Nasal Spray is a nasal spray solution supplied in a white plastic bottle with a metered-dose
`
`manual spray pump, a white nasal applicator, and a blue overcap. Each spray (100 microliters) delivers
`
`665 mcg of olopatadine hydrochloride.
`
`4 CONTRAINDICATIONS
`
`None.
`
` 5 WARNINGS AND PRECAUTIONS
`
`5.1 Local Nasal Effects
`Epistaxis and Nasal Ulceration: In placebo (vehicle nasal spray)-controlled clinical trials of 2 weeks to 12
`months duration, epistaxis and nasal ulcerations were reported [see Adverse Reactions (6)].
`
`
`
`Nasal Septal Perforation:
`
`Three placebo (vehicle nasal spray)-controlled long term (12 months) safety trials were conducted. In the
`
`first safety trial, patients were treated with an investigational formulation of PATANASE Nasal Spray
`
`
`containing povidone (not the commercially marketed formulation) or a vehicle nasal spray containing
`
`
`
`
`
`povidone. Nasal septal perforations were reported in one patient treated with the investigational
`
`formulation of PATANASE Nasal Spray and 2 patients treated with the vehicle nasal spray. In the second
`
`
`
`safety trial with PATANASE Nasal Spray, which does not contain povidone, there were no reports of nasal
`
`
`
`
`
`septal perforation. In the third safety trial, one patient exposed to the 3.7 pH vehicle nasal spray (containing
`
`
`
`
`
`no povidone) reported a nasal septal perforation [see Adverse Reactions (6)].
`
`
`
`
`
`Before starting PATANASE Nasal Spray, conduct a nasal examination to ensure that patients are free of
`nasal disease other than allergic rhinitis. Perform nasal examinations periodically for signs of adverse
`
`effects on the nasal mucosa and consider stopping PATANASE Nasal Spray if patients develop nasal
`
`ulcerations.
`
`5.2 Activities Requiring Mental Alertness
`
`
`In clinical trials, the occurrence of somnolence has been reported in some patients taking PATANASE
`
`
`
`Nasal Spray [see Adverse Reactions (6)]. Patients should be cautioned against engaging in hazardous
`
`
`occupations requiring complete mental alertness and motor coordination such as driving or operating
`
`machinery after administration of PATANASE Nasal Spray. Concurrent use of PATANASE Nasal Spray
`
`
`with alcohol or other central nervous system depressants should be avoided because additional reductions
`
`in alertness and additional impairment of central nervous system performance may occur.
`
`
`6 ADVERSE REACTIONS
`
`The most clinically significant adverse reactions described in other sections of labeling include;
`
`
`
`• Epistaxis, Nasal Ulceration, and Nasal Septal Perforation [see Warnings and Precautions (5.1)]
`
`
`• Somnolence [see Warnings and Precautions (5.2)]
`
`
`
`
`
`
`
`
`Reference ID: 3091120
`
`3
`
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`

` 6.1 Clinical Trials Experience
`
`
`
` The safety data described below reflect exposure to PATANASE Nasal Spray in 2,770 patients with
`
` seasonal or perennial allergic rhinitis in 10 controlled clinical trials of 2 weeks to 12 months duration.
`
`
`
`
`
`The safety data from adults and adolescents are based upon 6 placebo (3.7 pH vehicle nasal spray or 7.0 pH
`
`
`
`
`
` vehicle nasal spray)-controlled clinical trials in which 1,834 patients with seasonal or perennial allergic
`
` rhinitis (652 males and 1,182 females) 12 years of age and older were treated with PATANASE Nasal
`
`
`
`
`
` Spray two sprays per nostril twice daily. There were 1,180 patients (PATANASE Nasal Spray, 587;
`
`
`
`
`
` vehicle nasal spray, 593) that participated in 3 efficacy and safety trials of 2 weeks duration. There were
`
`
` 2,840 patients (PATANASE Nasal Spray, 1,247; 3.7 pH vehicle nasal spray, 1,251; 7.0 pH vehicle nasal
`
`
`
`
` spray, 342) that participated in 3 long-term clinical trials of 1 year duration. The racial distribution of adult
`
`
`
`and adolescent patients receiving PATANASE Nasal Spray was 77% white, 9% black, and 14% other. The
`
`
`incidence of discontinuation due to adverse reactions in these controlled clinical trials was comparable for
`
`
`
`
`
`PATANASE Nasal Spray and vehicle nasal spray. Overall, 4.7% of the 1,834 adult and adolescent patients
`
`
`
`
`
`across all 6 studies treated with PATANASE Nasal Spray, 3.5% of the 1,844 patients treated with 3.7 pH
`
`
`
`
`vehicle nasal spray discontinued due to adverse reactions, and 2.9% of the 342 patients treated with 7.0 pH
`
`
`
`vehicle nasal spray discontinued due to adverse reactions.
`
`
`
`
`
` The safety data from pediatric patients 6-11 years of age are based upon 3 clinical trials in which 870
`
`
` children with seasonal allergic rhinitis (376 females and 494 males) were treated with PATANASE Nasal
`
`
` Spray 1 or 2 sprays per nostril twice daily for 2 weeks. The racial distribution of pediatric patients
`
`
`
` receiving PATANASE Nasal Spray was 68.6% white, 16.6% black, and 14.8% other. The incidence of
`
`
`discontinuation due to adverse reactions in these controlled clinical trials was comparable for PATANASE
`
`
`
`Nasal Spray and vehicle nasal spray. Overall, 1.4% of the 870 pediatric patients across all 3 studies treated
`
`
`
`
`with PATANASE Nasal Spray and 1.3% of the 872 pediatric patients treated with vehicle nasal spray
`
`discontinued due to adverse reactions.
`
`
`
`
`
`Safety information for pediatric patients 2 to 5 years of age is obtained from one vehicle-controlled study of
`
`2 weeks duration [See Pediatric Use (8.4)].
`
`
`
`
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in
`
`
` the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and
`
`
`
`
`
`may not reflect the rates observed in practice.
`
`
`Adults and Adolescents 12 Years of Age and Older in Short-Term (2-week) Trials:
`
`
`
`There were 1,180 patients 12 years of age and older (PATANASE Nasal Spray, 587; vehicle nasal spray,
`
`593) that participated in 3 efficacy and safety trials of 2 weeks duration. Table 1 presents the most common
`
`
`
`
`
`
`adverse reactions (0.9% or greater in patients treated with PATANASE Nasal Spray) that occurred more
`
`
`
`
`frequently in patients treated with PATANASE Nasal Spray compared with vehicle nasal spray in the 3
`
`
`clinical trials of 2 weeks duration.
`
`
`
`
`
`
`
`Table 1: Adverse Reactions Occurring at an Incidence of 0.9% or Greater in Controlled Clinical
`
`
`Trials of 2 Weeks Duration with PATANASE Nasal Spray in Adolescent and Adult Patients 12 Years
`
`
`of Age and Older with Seasonal Allergic Rhinitis
`
`
`Adverse Reaction
`Bitter taste
`Headache
`Epistaxis
`
`Pharyngolaryngeal Pain
`
`Post-nasal drip
`
`Cough
`Urinary tract infection
`
`CPK elevation
`
`Adult and Adolescent Patients 12 Years and Older
`
`PATANASE Nasal Spray
`Vehicle Nasal Spray
`N = 587
`N = 593
`
`75 (12.8%)
`5 (0.8%)
`
`
`26 (4.4%)
`24 (4.0%)
`
`
`19 (3.2%)
`10 (1.7%)
`
`
`13 (2.2%)
`8 (1.3%)
`
`
`9 (1.5%)
`5 (0.8%)
`
`
`8 (1.4%)
`3 (0.5%)
`
`
`7 (1.2%)
`3 (0.5%)
`
`
`5 (0.9%)
`2 (0.3%)
`
`Reference ID: 3091120
`
`4
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`
` 5 (0.9%)
`
`5 (0.9%)
`
`5 (0.9%)
`
`5 (0.9%)
`
`5 (0.9%)
`5 (0.9%)
`
`
` 1 (0.2%)
`
`4 (0.7%)
`
`1 (0.2%)
`
`4 (0.7%)
`
`2 (0.3%)
`0 (0.0%)
`
` Dry mouth
`
`Fatigue
`Influenza
`Nasopharyngitis
`Somnolence
`
`Throat irritation
`
`
`There were no differences in the incidence of adverse reactions based on gender or race. Clinical trials did
`
`
`
`
`not include sufficient numbers of patients 65 years of age and older to determine whether they respond
`
`differently from younger subjects.
`
`
`
`
`
`Pediatric Patients 6 to 11 Years of Age: There were 1,742 pediatric patients 6 to 11 years of age
`
`
`(Olopatadine nasal spray, 870; vehicle nasal spray, 872) with seasonal allergic rhinitis that participated in 3
`
`
`clinical trials of 2 weeks duration. Two of the studies used the investigational formulation of olopatadine
`
`
`
`
`
`nasal spray, and one of the studies used PATANASE Nasal Spray. One study evaluated the safety of
`
`
`
`
`
`
`
`PATANASE Nasal Spray at doses of 1 and 2 sprays per nostril twice daily in 1188 patients, in which 298
`
`were exposed to PATANASE 1 spray, 296 were exposed to PATANASE 2 sprays, 297 were exposed to
`
`vehicle 1 spray, and 297 were exposed to vehicle 2 sprays twice daily for 2 weeks. Table 2 presents the
`
`
`most common adverse reactions (greater than 1.0% in pediatric patients 6-11 years of age treated with
`PATANASE Nasal Spray 1 spray/nostril) that occurred more frequently with PATANASE Nasal Spray
`
`compared with vehicle nasal spray.
`
`
`Table 2. Adverse Reactions Occurring at an Incidence of Greater than 1.0% in a Controlled Clinical
`
`
`Trial of 2 Weeks Duration with PATANASE Nasal Spray in Pediatric Patients 6-11 Years of Age
`With Seasonal Allergic Rhinitis
`
`
`
`
`Pediatric Patients 6 to 11 Years of Age
`PATANASE Nasal Spray 1
`Vehicle Nasal Spray 1
`spray per nostril
`spray per nostril
`N = 298
`N = 297
`
`
`17 (5.7%)
`11 (3.7%)
`
`
`13 (4.4%)
`11 (3.7%)
`
`8 (2.6%)
`0
`
`
`3 (1.0%)
`0
`
`
`4 (1.3%)
`3 (1.0%)
`
`
`4 (1.3%)
`0
`
`Adverse Reaction
`Epistaxis
`Headache
`Upper respiratory tract infection
`Bitter taste
`Pyrexia
`Rash
`
`There were no differences in the incidence of adverse reactions based on gender, race, or ethnicity.
`
`
`
`
`Pediatric Patients 2 to 5 Years of Age: The safety of PATANASE Nasal Spray at a dose of 1 spray per
`
`
`
`nostril twice daily was evaluated in one 2-week vehicle-controlled study in 132 patients (PATANASE
`Nasal Spray, 66; vehicle nasal spray. 66) 2 to 5 years of age with allergic rhinitis [see Pediatric Use (8.4)].
`
`
`
`
`
`
`Reference ID: 3091120
`
`5
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`

`
`
`
`
` Long-Term (12-month) Safety Trials:
`
`In a 12-month, placebo (vehicle nasal spray)-controlled, safety trial, 890 patients 12 years of age and older
`
` with perennial allergic rhinitis were randomized to treatment with PATANASE Nasal Spray 2 sprays per
` nostril twice daily (445 patients) or vehicle nasal spray (445 patients). ). In the PATANASE and vehicle
`
`
`
`
`
`
`
` nasal spray groups, 72% and 74% of patients, respectively, completed the trial. Overall, 7% and 5%,
`
`
` respectively, discontinued study participation due to an adverse event. The most frequently reported
`
`
` adverse reaction was epistaxis, which occurred in 25% of patients treated with PATANASE Nasal Spray
`
`
`
` and 28% in patients treated with vehicle nasal spray. Epistaxis resulted in discontinuation of 0.9% of
`
`
`
` patients treated with PATANASE Nasal Spray and 0.2% of patients treated with vehicle nasal spray. Nasal
`
`
`
`
` ulcerations occurred in 10% of patients treated with PATANASE Nasal Spray and 9% of patients treated
`
`
`
`
` with vehicle nasal spray. Nasal ulcerations resulted in discontinuation of 0.4% of patients treated with
`
`
`
` PATANASE Nasal Spray and 0.2% patients treated with vehicle nasal spray. There were no patients with
`
`
`
` nasal septal perforation in either treatment group. Somnolence was reported in 1 patient treated with
`
`
`PATANASE Nasal Spray and 1 patient treated with vehicle nasal spray. Weight increase was reported in 6
`
`
`
`
` patients treated with PATANASE Nasal Spray and 1 patient treated with vehicle nasal spray. Depression
`
` or worsening of depression occurred in 9 patients treated with PATANASE Nasal Spray and in 5 patients
`
`
`
`
`
`
` treated with vehicle nasal spray. Three patients, two of whom had pre-existing histories of depression, who
`
`
`
`
`
` received PATANASE Nasal Spray were hospitalized for depression compared to none who received
`
`
`
` vehicle nasal spray.
`
`In a second 12-month, placebo (vehicle nasal spray)-controlled, safety trial, 459 patients 12 years of age
`
`
`and older with perennial allergic rhinitis were treated with 2 sprays per nostril of an investigational
`
`
`formulation of PATANASE Nasal Spray containing povidone (not the commercially marketed formulation)
`
`
`
`
`
`and 465 patients were treated with 2 sprays of a vehicle nasal spray containing povidone. Nasal septal
`
`
`
`
`
`perforations were reported in one patient treated with the investigational formulation of PATANASE Nasal
`
`
`Spray and 2 patients treated with the vehicle nasal spray. Epistaxis was reported in 19% of patients treated
`
`
`
`
`
`
`with the investigational formulation of PATANASE Nasal Spray and 12% of patients treated with vehicle
`
`
`nasal spray. Somnolence was reported in 3 patients treated with the investigational formulation of
`
`
`
`PATANASE Nasal Spray compared to 1 patient treated with vehicle nasal spray. Fatigue was reported in 5
`
`
`
`patients treated with the investigational formulation of PATANASE Nasal Spray compared to 1 patient
`
`treated with vehicle nasal spray.
`
`In a third 3-arm 12-month, placebo (vehicle nasal spray)-controlled, safety trial conducted post approval,
`
`1,026 patients 12 years of age and older with perennial allergic rhinitis were randomized to treatment with
`
`
`PATANASE Nasal Spray (343 patients), a 3.7 pH vehicle nasal spray (341 patients), or a 7.0 pH vehicle
`
`
`
`
`
`nasal spray (342 patients). All treatments were administered as 2 sprays per nostril, twice daily. Overall,
`
`5% of PATANASE Nasal Spray patients, 2% of 3.7 pH vehicle patients and 3% of 7.0 pH vehicle patients
`
`
`
`
`
`
`discontinued due to adverse events. The most frequently reported adverse event was epistaxis, which
`
`
`
`
`
`
` occurred in 24% of patients treated with PATANASE Nasal Spray, 20% of patients treated with 3.7 pH
` vehicle nasal spray, and 23% of patients treated with 7.0 pH vehicle nasal spray. Epistaxis resulted in the
`
`discontinuation of 2 patients treated with PATANASE Nasal Spray and 1 patient treated with 7.0 pH
`
`
`
`
`
`vehicle nasal spray. Nasal septal perforation was reported for one patient treated with the 3.7 pH vehicle
`
`
`
`
`
` nasal spray. Nasal ulcerations occurred in 9% of patients treated with PATANASE Nasal Spray, 8% of
`
`
`
`
`
`patients treated with 3.7 pH vehicle nasal spray, and 9% of patients treated with 7.0 pH vehicle nasal spray.
`
`
`
`
`
`
`
`
`Nasal ulceration resulted in the discontinuation of 1 patient treated with PATANASE Nasal Spray.
`
`
`Hyposmia and anosmia were each reported by one patient treated with PATANASE Nasal Spray. Neither
`
` somnolence nor weight loss was reported. Depression occurred in 3 patients treated with PATANASE
`
` Nasal Spray, 2 patients treated with 3.7 pH vehicle nasal spray, and 3 patients treated with 7.0 pH vehicle
`
`
`
`
`
`nasal spray.
`
`
`There were no long-term clinical trials in children below 12 years of age.
`
`
`
`6.2 Post-Marketing Experience
`During the post approval use of PATANASE Nasal Spray, the following adverse reactions have been
`
`
`
`
`
`
`identified. 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. The
`
`
`
`
`
`Reference ID: 3091120
`
`6
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`
`
`most common adverse reactions reported include dizziness, dysgeusia, epistaxis, headache, nasal
`
`discomfort, oropharyngeal pain, and somnolence. Additionally, hyposmia and anosmia have been reported
`with the use of PATANASE Nasal Spray.
`
`
`
`7 DRUG INTERACTIONS
`
`
`
`
`
`
`Formal drug-drug interaction studies were not conducted for PATANASE Nasal Spray. Drug interactions
`
`
`with inhibitors of liver enzymes are not anticipated because olopatadine is eliminated predominantly by
`
`
`
`renal excretion. Drug interactions involving P450 inhibition and plasma protein binding are also not
`expected. [See ClinicalPharmacology (12.3)].
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`Pregnancy Category C:
`
`
`No adequate and well-controlled studies in pregnant women have been conducted. Animal reproductive
`
`studies in rats and rabbits revealed treatment-related effects on fetuses or pups. Because animal studies are
`
`
`
`not always predictive of human responses, PATANASE Nasal Spray should be used in pregnant women
`
`
`only if the potential benefit to the mother justifies the potential risk to the embryo or fetus.
`
`
`
`
`A decrease in the number of live fetuses was observed in rabbits and rats at the oral olopatadine doses
`approximately 88 times and 100 times the maximum recommended human dose (MRHD) and above,
`respectively, for adults on a mg/m2 basis. In rats, viability and body weights of pups were reduced on day 4
`
`
`
` post partum at the oral dose approximately 100 times the MRHD for adults on a mg/m2 basis, but no effect
`
`
`on viability was observed at the dose approximately 35 times the MRHD for adults on a mg/m2 basis.
`
`
`8.3 Nursing Mothers
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`Olopatadine has been identified in the milk of nursing rats following oral administration. It is not known
`
`whether topical nasal administration could result in sufficient systemic absorption to produce detectable
`
`
`quantities in human breast milk. PATANASE Nasal Spray should be used by nursing mothers only if the
`
`potential benefit to the patient outweighs the potential risks to the infant.
`
`
`8.4 Pediatric Use
`
`
`
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`The safety and effectiveness of PATANASE Nasal Spray has not been established for patients under 6
`
`
`
`
`
`years of age. The safety of olopatadine nasal spray was evaluated in 3 vehicle-controlled 2-week studies in
`870 patients 6 to 11 years of age [see Adverse Reactions (6.1)]. Doses studied included 1 and 2 sprays per
`
`
`
`
`nostril twice daily. One of these studies evaluated the safety of PATANASE Nasal Spray at doses of 1 and
`
`
`
`
`2 sprays per nostril twice daily in 1188 patients, of which, 298 patients were exposed to PATANASE 1
`
`
`
`spray and 297 patients were exposed to vehicle 1 spray. In this study, the incidence of epistaxis with
`
`PATANASE treatment was 5.7%, compared to 3.2% seen in adult and adolescent studies. This study also
`
`
`
`evaluated the effectiveness of PATANASE Nasal Spray in patients 6 through 11 years of age with seasonal
`allergic rhinitis [see Clinical Studies (14.1)].
`
`
`The safety of PATANASE Nasal Spray at a dose of 1 spray per nostril twice daily was evaluated in one 2­
`
`
`
`week vehicle-controlled study in 132 children ages 2 to 5 years of age with allergic rhinitis. In this trial, 66
`
`
`
`
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`patients ( 28 females and 38 males) were exposed to PATANASE Nasal Spray. The racial distribution of
`
`
`
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`patients receiving PATANASE Nasal Spray was 66.7% white, 27.3% black, and 6.4% other. Two patients
`
`
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`exposed to vehicle nasal spray discontinued due to an adverse reaction (1 patient with pneumonia and 1
`
`
`
`patient with rhinitis) compared to no patients exposed to PATANASE Nasal Spray. The most common
`(greater than 1.0%) adverse events reported were diarrhea (9.1%), epistaxis (6.1%), rhinorrhea (4.5%),
`
`bitter taste (3.0%) and wheezing (3.0%). Diarrhea was reported less frequently (< 1%) in the 6 to 11 year
`
`old age group.
`
`
`The incidence of epistaxis was higher in the pediatric population (5.7% in 6 -11 year old patients and 6.1%
`
`in 2-5 year old patients) compared to the adult and adolescent population (3.2%).
`
`
`
`Reference ID: 3091120
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`7
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`8.5 Geriatric Use
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`Clinical studies of PATANASE Nasal Spray did not include sufficient numbers of patients aged 65 years
`
`
`
`
`
`and older to determine whether they respond differently from younger patients. Other reported clinical
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`
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`experience has not identified differences in responses between the elderly and younger patients. In general,
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`dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased
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`
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`hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.
`
`
`10 OVERDOSAGE
`
`
`
`
`There have been no reported overdosages with PATANASE Nasal Spray.
`
`Acute overdosage with this dosage form is unlikely due to the configuration of the primary container
`
`
`closure system. However, symptoms of antihistamine overdose may include drowsiness in adults and,
`
`
`
`initially, agitation and restlessness, followed by drowsiness in children. There is no known specific
`
`
`
`antidote to PATANASE Nasal Spray. Should overdose occur, symptomatic or supportive treatment is
`recommended, taking into account any concomitantly ingested medications.
`
`
`No mortality was observed in rats at an intranasal dose of 3.6 mg/kg (approximately 6 times the MRHD for
`adults and adolescents ≥12 years of age and 7 times the MRHD for children 6-11 years of age on a mg/m2
`
`
`basis), or in dogs at an oral dose of 5 g/kg (approximately 28,000 times the MRHD for adults and
`
`
`
`
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`adolescents ≥12 years of age and 33,000 the MRHD for children 6-11 years of age on a mg/m2 basis). The
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`oral median lethal dose (MLD) in mice and rats were 1,490 mg/kg and 3,870 mg/kg respectively
`
`
`(approximately 1,200 times and 6,500 times the MRHD for adults and adolescents ≥12 years of age and
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`
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`1,500 times and 7,700 times the MRHD for children 6-11 years of age, on a mg/m2 basis, respectively).
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`
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`For additional information about overdose treatment, call a poison control center (1-800-222-1222).
`
`
`11 DESCRIPTION
`
`PATANASE (olopatadine hydrochloride) Nasal Spray, 665 micrograms (mcg) is a metered-spray solution
`
`
`
`for intranasal administration. Olopatadine hydrochloride, the active component of PATANASE Nasal
`
`
`
`
`Spray, is a white, water-soluble crystalline powder. The chemical name for olopatadine hydrochloride is
`
`
`(Z)-11-[3-(dimethylamino)propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid hydrochloride. It has
`a molecular weight of 373.88, and its molecular formula is C21H23NO3 • HCl with the following chemical
`structure:
`
`
`
`N
`
`CO2H
`HCl
`
`O
`
`
`
`
`
`
`
`
`
` PATANASE Nasal Spray contains 0.6% w/v olopatadine (base) in a nonsterile aqueous solution with pH of
`
`
`approximately 3.7. After initial priming (5 sprays), each metered spray from the nasal applicator delivers
` 100 microliters of the aqueous solution containing 665 mcg of olopatadine hydrochloride, which is
`
`
` equivalent to 600 mcg of olopatadine (base) [see Dosage and Administration]. PATANASE Nasal Spray
`
`
`
`also contains benzalkonium chloride (0.01%), dibasic sodium phosphate, edetate disodium, sodium
`
`
` chloride, hydrochloric acid and/or sodium hydroxide (to adjust pH), and purified water.
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`
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`Reference ID: 3091120
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`12 CLINICAL PHARMACOLOGY
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`12.1 Mechanism of Action
`Olopatadine is a histamine H1 -receptor antagonist. The antihistaminic activity of olopatadine has been
`
`
`documented in isolated tissues, animal models, and humans.
`
`
`12.2 Pharmacodynamics
`Cardiac effects: In a placebo-controlled cardiovascular safety study, 32 healthy volunteers received 20 mg
`
`oral solution of olopatadine twice daily for 14 days (8-fold greater daily dose than the recommended daily
`
`
`
`nasal dose). The mean QTcF (QT corrected by Fridericia’s correction method for heart rate) change from
`
`baseline was -2.7 msec and -3.8 msec for olopatadine, and placebo, respectively. In this study, 8 subjects
`treated with olopatadine had a QTcF change from baseline of 30 – 60 msec, 1 subject had a QTcF change
`
`
`
`from baseline greater than 60 msec, and no subjects had QTcF values greater than 500 msec. Eight subjects
`
`
`treated with placebo had a QTcF change from baseline of 30 – 60 msec, no subjects had a QTcF change
`
`from baseline greater than 60 msec, and no subjects had QTcF values greater than 500 msec. In a 12­
`
`
`month study in 429 perennial allergic rhinitis patients treated with PATANASE Nasal Spray 2 sprays per
`
`nostril twice daily, no evidence of any effect of olopatadine hydrochloride on QT prolongation was
`
`observed.
`
`
`12.3 Pharmacokinetics
`The pharmacokinetic properties of olopatadine were studied after administration by the nasal, oral,
`
`intravenous, and topical ocular routes. Olopatadine exhibited linear pharmacokinetics across the routes
`
`studied over a large dose range.
`
`
`Absorption:
`Healthy Subjects: Olopatadine was absorbed with individual peak plasma concentrations observed between
`
`
`
`30 minutes and 1 hour after twice daily intranasal administration of PATANASE Nasal Spray. The mean
`
`( ± SD) steady-state peak plasma concentration (Cmax) of olopatadine was 16.0 ± 8.99 ng/mL. Systemic
`
`
`
`exposure as indexed by area under the curve (AUC0-12) averaged 66.0 ± 26.8 ng·h/mL. The average
`
`absolute bioavailability of intranasal olopatadine is 57%. The mean accumulation ratio following multiple
`
`intranasal administration of PATANASE Nasal Spray was about 1.3.
`
`Seasonal Allergic Rhinitis (SAR) Patients: Systemic exposure of olopatadine in SAR patients after twice
`
`daily intranasal administration of PATANASE Nasal Spray was comparable to that observed in healthy
`
`
`
`
`
`subjects. Olopatadine was absorbed with peak plasma concentrations observed between 15 minutes and
`2 hours. The mean steady-state Cmax was 23.3 ± 6.2 ng/mL and AUC0-12 averaged 78.0 ± 13.9 ng·h/mL.
`
`
`
`
`Distribution: The protein binding of olopatadine was moderate at approximately 55% in human serum,
`
`
`and independent of drug concentration over the range of 0.1 to 1000 ng/mL. Olopatadine was bound
`
`
`
`
`predominately to human serum albumin.
`
`Metabolism: Olopatadine is not extensively metabolized. Based on plasma metabolite profiles following
`
`
`oral administration of [14C] olopatadine, at least six minor metabolites circulate in human plasma.
`
`
`
`Olopatadine accounts for 77% of peak plasma total radioactivity and all metabolites amounted to <6%
`
`
`combined. Two of these have been identified as the olopatadine N-oxide and N-desmethyl olopatadine. In
`
`in vitro studies with cDNA-expressed human cytochrome P450 isoenzymes (CYP) and flavin-containing
`
`
`monooxygenases (FMO), N-desmethyl olopatadine (Ml) formation was catalyzed mainly by CYP3A4,
`
`while olopatadine N-oxide (M3) was primarily catalyzed by FMO1 and FMO3. Olopatadine at
`
`concentrations up to 33,900 ng/mL did not inhibit the in vitro metabolism of specific substrates for
`
`
`
`
`CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4. The potential for olopatadine and its
`
`
`metabolites to act as inducers of CYP enzymes has not been evaluated.
`
`Elimination: The plasma elimination half-life of olopatadine is 8 to 12 hours. Olopatadine is mainly
`
`eliminated through urinary excretion. Approximately 70% of a [14C] olopatadine hydrochloride oral dose
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`Reference ID: 3091120
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`was recovered in urine with 17% in the feces. Of the drug-related material recovered within the first
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`
`24 hours in the urine, 86% was unchanged olopatadine with the balance comprised of olopatadine N-oxide
`
`
`and N-desmethyl olopatadine.
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`
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`Special Population:
`
`Hepatic Impairment: No specific pharmacokinetic study examining the effect of hepatic impairment was
`
`
`
`conducted. Since metabolism of olopatadine is a minor route of elimination, no adjustment of the dosing
`
`
`
`regimen of PATANASE Nasal Spray is warranted in patients with hepatic impairment.
`
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`Renal Impairment: The mean Cmax values for olopatadine following single intranasal doses were not
`
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` ma