NDA 21-861
`Page 6
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`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 patients 12 years of age and older. (1)
`
` --------------DOSAGE AND ADMINISTRATION------------­
`
`For intranasal use only.
`
`
`
`The recommended dose of PATANASE Nasal Spray in patients 12 years and older is two sprays per nostril twice
`
`
`daily (2).
`
`
`Priming Information: Prime PATANASE Nasal Spray before initial use and when PATANASE Nasal Spray has not
`
`been used for more than 7 days. (2.2)
`
`-------------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.
`---------------WARNINGS AND PRECAUTIONS-------------
`• Epistaxis, nasal ulceration, and nasal septal perforation. Monitor patients periodically for signs of adverse effects
`
`
`on the nasal mucosa. Avoid use in patients with nasal disease other than allergic rhinitis (5.1).
`• Avoid engaging in hazardous occupations requiring complete mental alertness 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 adverse reactions (>1%) included bitter taste, headache, epistaxis, pharyngolaryngeal pain, post­
`nasal drip, cough, and urinary tract infection (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: 2008
`______________________________________________________________________________________
`FULL PRESCRIBING INFORMATION*
`
`
`1 INDICATIONS AND USAGE
`1.1 Seasonal Allergic Rhinitis
`
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Adults and Adolescents 12 years of age and
`older
`2.2 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
`
`APOTEX EX1039
`
`Page 1
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`
`NDA 21-861
`Page 7
`
`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
`14.1 Seasonal Allergic Rhinitis
`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
`
`
`1.1 Seasonal Allergic Rhinitis: PATANASE Nasal Spray is indicated for the relief of the symptoms of seasonal
`
`
`
`
`
`allergic rhinitis in patients 12 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 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 6 months
`duration, epistaxis and nasal ulcerations were reported [see Adverse Reactions (6)].
`
`
`
`
`Nasal Septal Perforation:
`
`Page 2
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`
`NDA 21-861
`Page 8
`
`Two placebo (vehicle nasal spray)-controlled long term (6 and 12 months) safety trials were conducted. In the 12­
`
`
`
`month 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 a 6-month trial with PATANASE Nasal Spray, which does
`not contain povidone, there were no reports of 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
`
`
`Use of PATANASE Nasal Spray has been associated with epistaxis, nasal ulceration, and somnolence [see
`Warnings and Precautions (5.1 and 5.2)].
`
`
`
`6.1 Clinical Trials Experience
`
`The safety data described below reflect exposure to PATANASE Nasal Spray two sprays per nostril twice- daily in
`
`
`1,491 patients 12 years of age and older (513 males and 978 females) with seasonal or perennial allergic rhinitis in 5
`
`
`
`placebo (vehicle nasal spray)-controlled clinical trials of 2 weeks to 12 months duration. There were 1,180 patients
`(PATANASE Nasal Spray, 587; vehicle nasal spray, 593) that participated in 3 trials of 2 weeks duration, and 1,814
`
`
`
`patients (PATANASE Nasal Spray, 904; vehicle nasal spray, 910) that participated in 2 long-term (6 months and 12
`
`
`
`
`months) clinical trials. The racial and ethnic distribution of the 1,491 patients with exposure to PATANASE Nasal
`
`
`
`
`Spray was 76% white, 8% black, 12% Hispanic, and 3% 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, 3.9% of the 1,491 patients across all 5 studies treated with PATANASE Nasal Spray and 3.2% of the 1,503
`patients treated with vehicle nasal spray discontinued due to adverse reactions.
`
`
`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 (PATANASE Nasal Spray, 587; vehicle nasal spray, 593) with seasonal allergic rhinitis
`that participated in 3 clinical 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.
`
`
`
`
`
`
`
`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
`
`
`PATANASE Nasal Spray
`N = 587
`75 (12.8%)
`
`26 (4.4%)
`
`19 (3.2%)
`
`13 (2.2%)
`
`9 (1.5%)
`
`Vehicle Nasal Spray
`N = 593
`
`5 (0.8%)
`
`24 (4.0%)
`
`10 (1.7%)
`
`8 (1.3%)
`
`5 (0.8%)
`
`Page 3
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`

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`8 (1.4%)
`
`
`7 (1.2%)
`
`5 (0.9%)
`
`5 (0.9%)
`
`5 (0.9%)
`
`5 (0.9%)
`
`5 (0.9%)
`
`5 (0.9%)
`5 (0.9%)
`
`NDA 21-861
`Page 9
`
`Cough
`
`Urinary tract infection
`
`CPK elevation
`
`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.
`
`
`Long-Term (6- and 12-month) Safety Trials:
`
`In a 6-month, placebo (vehicle nasal spray)-controlled, safety trial, 445 patients 12 years of age and older with
`
`perennial allergic rhinitis were treated with PATANASE Nasal Spray 2 sprays per nostril twice daily, and 445
`
`patients were treated with vehicle nasal spray. The most frequently reported adverse reaction was epistaxis, which
`
`occurred in 19% of patients treated with PATANASE Nasal Spray and 23% in patients treated with vehicle nasal
`
`
`
`
`spray. Epistaxis resulted in discontinuation of 0.7% of patients treated with PATANASE Nasal Spray and 0.2% of
`
`
`
`patients treated with vehicle nasal spray. Nasal ulcerations occurred in 9% of patients treated with PATANASE
`
`
`Nasal Spray and 6% of patients treated with vehicle nasal spray. Nasal ulcerations resulted in discontinuation of
`
`
`
`0.4% of patients treated with PATANASE Nasal Spray and no 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 compared to none treated with vehicle nasal spray. Weight increase was reported in 5
`
`
`
`
`patients treated with PATANASE Nasal Spray and in no patients treated with vehicle nasal spray.
`
`In a 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.
`
`6.2 Post-Marketing Experience
`
`
`
`
`In addition to the adverse reactions reported during clinical trials, adverse events have also been identified during
`post-approval use of olopatadine oral formulations (2.5 and 5 mg tablets) in other countries. Because these events
`
`
`
`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 most frequently reported adverse reaction was
`
`
`
`
`somnolence. Additional common adverse reactions included hypersensitivity reactions, dizziness, headache,
`
`
`malaise, thirst, abdominal pain, diarrhea, nausea, abnormal hepatic function, white blood cell disorders, occult blood
`in urine, and increased blood cholesterol.
`
`
`
`7 DRUG INTERACTIONS
`
`
`
`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. Olopatadine
`did not inhibit the in vitro metabolism of specific substrates for CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1
`
`
`
`and CYP3A4. Based on these data, drug interactions involving P450 inhibition are not expected. Due to the modest
`protein binding of olopatadine (55%), drug interactions through displacement from plasma proteins are not
`expected.
`
`3 (0.5%)
`
`
`3 (0.5%)
`
`2 (0.3%)
`
`1 (0.2%)
`
`4 (0.7%)
`
`1 (0.2%)
`
`4 (0.7%)
`
`2 (0.3%)
`0 (0.0%)
`
`
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`Page 4
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`NDA 21-861
`Page 10
`
`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
`
`
`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
`
`
`
`Safety and effectiveness in pediatric patients below the age of 12 years have not yet been established.
`
`8.5 Geriatric Use
`
`
`
`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 experience has not
`
`
`
`
`identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly
`
`
`
`
`
`patient should be cautious, reflecting the greater frequency of decreased 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
`
`on an mg/m2 basis), or in dogs at an oral dose of 5 g/kg (approximately 28,000 times the MRHD for adults on a
`
`
`
`mg/m2 basis). The 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 on a mg/m2 basis, respectively).
`
`
`
`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:
`
`Page 5
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`
`NDA 21-861
`Page 11
`
`
`
`
`N
`
`O
`
`CO2H
`HCl
`
`
`
`
`
`
`
`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.
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`Olopatadine is an antihistamine with selective H1 -receptor antagonist activity: its principal effects are mediated via
`
`inhibition of H1 receptors. 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 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
`
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`Page 6
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`NDA 21-861
`Page 12
`
`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 was recovered in
`
`
`
`
`
`urine with 17% in the feces. Of the drug-related material recovered within the first 24 hours in the urine, 86% was
`
`
`unchanged olopatadine with the balance comprised of olopatadine N-oxide and N-desmethyl olopatadine.
`
`
`
`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.
`
`
`
`
`Renal Impairment: The mean Cmax values for olopatadine following single intranasal doses were not markedly
`
`
`
` different between healthy subjects (18.1 ng/mL) and patients with mild, moderate and severe renal impairment
`
`
`(range 15.5 to 21.6 ng/mL). Mean plasma AUC0-12 was two-fold higher in patients with severe impairment
`
`
`
`
`
`(creatinine clearance <30 mL/min/1.73 m2). In these patients, peak steady-state plasma concentrations of
`
`
`olopatadine are approximately 10-fold lower than those observed after higher 20 mg oral doses, twice daily, which
`
`
`were safe and well-tolerated. These findings indicate that no adjustment of the dosing regimen of PATANASE Nasal
`
`
`
`
`Spray is warranted in patients with renal impairment.
`
`
`Gender: The mean systemic exposure (Cmax and AUC0-12) in female SAR patients following multiple administration
`
`
`
`of olopatadine was 40% and 27% higher, respectively than those values observed in male SAR patients.
`
`
`
`
`
`Race: The effects of race on olopatadine pharmacokinetics have not been adequately investigated.
`
`
`
`
`
`Age: The effects of age on olopatadine pharmacokinetics have not been adequately investigated.
`
`
`
`
`
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`Olopatadine administered orally was not carcinogenic in mice and rats at doses of up to 500 mg/kg/day and 200
`
`
`
`mg/kg/day, respectively (approximately 420 and 340 times the MRHD for adults by intranasal administration on a
`
`
`mg/m2 basis, respectively).
`
`
`There was no evidence of genotoxicity when olopatadine was tested in an in vitro bacteria reverse mutation test
`
`
`
`
`(Ames), an in vitro mammalian chromosome aberration assay or an in vivo mouse micronucleus test.
`
`
`
`
`Olopatadine administered orally to male and female rats at dose of 400 mg/kg/day, (approximately 680 times the
`
` MRHD for adults on a mg/m2 basis) resulted in a decrease in the fertility index and reduced implantation rate. No
`
`
`
`
`effects on fertility were observed at dose of 50 mg/kg/day (approximately 85 times the MRHD for adults on a mg/m2
`
`basis).
`
`13.2 Animal Toxicology
`
`Reproductive Toxicology Studies
`
`
`
`
`
`
`
`Olopatadine was not teratogenic in rabbits and rats at oral doses of up to 400 or 600 mg/kg/day, respectively
`(approximately 1,400 and 1,000 times the MRHD for adults on a mg/m2 basis, respectively). However, a decrease in
`
`
`
`
`the number of live fetuses was observed in rabbits at the oral olopatadine doses of 25 mg/kg (approximately 88
`times the MRHD for adults on a mg/m2 basis) and above, and in rats at oral doses of 60 mg/kg (approximately 100
`
`
`
`
`
`times the MRHD for adults on a mg/m2 basis) and above. In rats, viability and body weights of pups were reduced
`
`on day 4 post partum at the oral doses of 60 mg/kg (approximately 100 times the MRHD for adults on a mg/m2
`
`
`
`
`
` basis) and above, but no effect on viability was observed at the dose of 20 mg/kg (approximately 35 times the
`
`MRHD for adults on a mg/m2 basis).
`
`
`Page 7
`
`

`
`NDA 21-861
`Page 13
`
`
`
`
`
`Treatment
`
`N
`
`Baseline
`
`14 CLINICAL STUDIES
`
`
`14.1 Seasonal Allergic Rhinitis
`
`Adult and Adolescent Patients 12 Years of Age and Older:
`
`
`
`The efficacy and safety of PATANASE Nasal Spray were evaluated in three randomized, double blind, parallel
`group, multicenter, placebo (vehicle nasal spray)-controlled clinical trials of 2 weeks duration in adult and
`adolescent patients, 12 years of age and older with symptoms of seasonal allergic rhinitis. The three clinical trials
`
`
`were conducted in the United States and included 1,598 patients (556 males, and 1,042 females) 12 years of age and
`
`
`
`older. In these three trials 587 patients were treated with PATANASE Nasal Spray 0.6%, 418 patients were treated
`with PATANASE Nasal Spray 0.4%, and 593 patients were treated with vehicle nasal spray. Assessment of efficacy
`
`was based on patient recording of 4 individual nasal symptoms (nasal congestion, rhinorrhea, itchy nose, and
`
`
`sneezing) on a 0 to 3 categorical severity scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe) as reflective or
`
`
`
`instantaneous scores. Reflective scoring required patients to record symptom severity over the previous 12 hours;
`
`the instantaneous scoring required patients to record symptom severity at the time of recording. The primary
`
`efficacy endpoint was the difference from placebo in the percent change from baseline in the sum of morning and
`
`evening reflective total nasal symptom score (rTNSS) averaged for the 2-week treatment period. In all 3 trials,
`
`
`patients treated with PATANASE Nasal Spray, two sprays per nostril, twice-daily, exhibited statistically
`
`
`
`significantly greater decreases in rTNSS compared to vehicle nasal spray. Results for the rTNSS from two
`
`representative trials are shown in Table 2.
`
`Table 2: Mean Reflective Total Nasal Symptom Score (rTNSS) Over 2 Weeks in Seasonal Allergic
`
`
`Rhinitis Trials
`
`
`Difference from Placebo
`
`Change
`from
`
`Baseline
`
`-3.63
`
`
`
`PATANASE Nasal Spray 0.6%
`
`
`PATANASE Nasal Spray 0.4%
`
`Vehicle Nasal Spray
`
`PATANASE Nasal Spray 0.6%
`
`
`183
`
`188
`191
`220
`
`
`8.71
`
`8.90
`8.75
`9.17
`
`
`Estimate
`-0.96
`
`
`p-value
`95% CI
`
`(-1.42, -0.51) <0.0001
`
`-3.38
`-2.67
`-2.90
`
`-0.71
`
`-0.98
`
`
`0.0023
`(-1.17, -0.26)
`
`
`
`(-1.37, -0.59) <0.0001
`
`
`PATANASE Nasal Spray 0.4%
`
`Vehicle Nasal Spray
`
`228
`223
`
`9.26
`9.07
`
`-2.63
`-1.92
`
`-0.72
`
`
`(-1.11, -0.33)
`
`
`
`0.0003
`
`
`
`
`In the 2-week seasonal allergic trials, onset of action was also evaluated by instantaneous TNSS assessments twice-
`
`
`
`
`daily after the first dose of study medication. In these trials, onset of action was seen after 1 day of dosing. Onset of
`
`
`
`action was evaluated in three environmental exposure unit studies with single doses of PATANASE Nasal Spray. In
`
`
`these studies, patients with seasonal allergic rhinitis were exposed to high levels of pollen in the environmental
`
`
`
`
`exposure unit and then treated with either PATANASE Nasal Spray or vehicle nasal spray, two sprays in each
`
`
`nostril, after which they self-reported their allergy symptoms hourly as instantaneous scores for the subsequent 12
`
`
`
`hours. PATANASE Nasal Spray 0.6% was found to have an onset of action of 30 minutes after dosing in the
`environmental exposure unit.
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`16.1 How Supplied
`PATANASE Nasal Spray, 665 mcg is supplied in a white plastic bottle with a metered-dose manual spray pump, a
`
`
`
`
`
`white nasal applicator and a blue overcap in a box of 1 (NDC 0065-0332-30). Each trade size bottle contains 30.5 g
`of clear, colorless liquid and will provide 240 metered sprays. After priming [see Dosage and Administration (2)],
`
`each spray delivers a fine mist containing 665 mcg of olopatadine hydrochloride in 100 microliters of formulation
`through the nozzle.
`
`
`Before initial use, prime PATANASE Nasal Spray by releasing 5 sprays or until a fine mist appears. After periods of
`
`
`
`
`non-use greater than 7 days, re-prime PATANASE Nasal Spray by releasing 2 sprays. The correct amount of
`
`
`
`
`
`
`medication cannot be assured before the initial priming and after 240 sprays have been used, even though the bottle
`
`
`
`Study
`1
`
`
`
`Study
`2
`
`
`
`Page 8
`
`

`
`NDA 21-861
`Page 14
`
`is not completely empty. The nasal device should be discarded after 240 sprays (enough for 30 days of dosing) have
`
`
`
`been used.
`
`Net content 30.5 g, 240 sprays: NDC 0065-0332-30 (trade size)
`
`
`
`16.2 Storage
`Store at 4° to 25° C ( 39° to 77° F). Rx Only.
`
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`
`See FDA-approved Patient Labeling accompanying the product.
`
`
`17.1 Local Nasal Effects and Other Common Adverse Reactions
`Patients should be informed that treatment with PATANASE Nasal Spray may lead to adverse reactions, which
`
`
`include epistaxis and nasal ulcerations. [see Warnings and Precautions (5.1)] Other common adverse reactions
`
`
`reported with use of PATANASE Nasal Spray include bitter taste, headache, pharyngolaryngeal pain, post-nasal
`
`
`drip, cough, and urinary tract infection [see Adverse Reactions (6)].
`
`
`
`
`17.2. Activities Requiring Mental Alertness
`Somnolence has been reported in some patients taking PATANASE Nasal Spray. 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 [see Warnings and Precautions
`
`
`(5.2)].
`
`17.3 Concurrent Use of Alcohol and other Central Nervous System Depressants
`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 [see Warnings and Precautions (5.2)].
`
`17.4. Keep Spray Out of Eyes
`
`Patients should be informed to avoid spraying PATANASE Nasal Spray in their eyes.
`
`
`
`
`
`
`Revised: March 2008
`
`
`Mfd for:
`
`ALCON LABORATORIES, INC.
`
`For