OLOPATADINE: 8,787 Adverse Event Reports & Safety Profile

Olopatadine hydrochloride nasal solution (nasal spray), 665 mcg is a metered-spray solution for nasal administration. Olopatadine hydrochloride, the active component of olopatadine hydrochloride nasal solution (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 g/mol, and its molecular formula is C 21 H 23 NO 3

• HCl with the following chemical structure: Olopatadine hydrochloride nasal solution (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 µL of the aqueous solution containing 665 mcg of olopatadine hydrochloride, which is equivalent to 600 mcg of olopatadine (base) [ see Dosage Forms and Strengths ( 3 ) ] . Olopatadine hydrochloride nasal solution (nasal spray) also contains benzalkonium chloride (0.01%), dibasic sodium phosphate, edetate disodium, hydrochloric acid and/or sodium hydroxide (to adjust pH), purified water and sodium chloride.

AND USAGE Olopatadine hydrochloride nasal solution (nasal spray) is indicated for the relief of the symptoms of seasonal allergic rhinitis in adults and pediatric patients 6 years of age and older. Olopatadine hydrochloride nasal solution (nasal spray) is an H 1 receptor antagonist indicated for the relief of the symptoms of seasonal allergic rhinitis in adults and pediatric patients 6 years of age and older.

AND ADMINISTRATION For nasal use only. Recommended dosages:

• Adults and Adolescents ≥ 12 Years : Two sprays per nostril (665 mcg per spray) twice daily ( 2.1 ).
• Pediatric Patients 6 to 11 Years : One spray per nostril (665 mcg per spray) twice daily ( 2.2 ).
• Priming Information : Prime olopatadine hydrochloride nasal solution (nasal spray) before initial use and when olopatadine hydrochloride nasal solution (nasal spray) has not been used for more than 7 days ( 2.3 ).

2.1 Adults and Adolescents Twelve Years of Age and Older The recommended dosage is two sprays per nostril twice daily.

2.2 Pediatric Patients Six to Eleven Years of Age The recommended dosage is one spray per nostril twice daily.

2.3 Administration Information Administer olopatadine hydrochloride nasal solution (nasal spray) by the nasal route only. Priming : Before initial use, prime olopatadine hydrochloride nasal solution (nasal spray) by releasing 5 sprays or until a fine mist appears. The correct amount of medication cannot be assured before the initial priming. Re-priming (as needed): When olopatadine hydrochloride nasal solution (nasal spray) has not been used for more than 7 days, re-prime by releasing 2 sprays. Avoid spraying olopatadine hydrochloride nasal solution (nasal spray) into the eyes.

Discard

Instructions : Discard nasal device after 240 sprays (enough for 30 days of dosing) have been used even though the bottle is not completely empty. The correct amount of medication cannot be assured after 240 sprays have been used.

CONTRAINDICATIONS Olopatadine hydrochloride ophthalmic solution USP, 0.1% is contraindicated in persons with a known hypersensitivity to olopatadine hydrochloride, USP or any components of olopatadine hydrochloride ophthalmic solution USP, 0.1%.

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 and Impaired Mental Alertness [ see Warnings and Precautions ( 5.2 ) ] 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 Perrigo at 1-866-634-9120 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience 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. The safety data described below reflect exposure to olopatadine hydrochloride nasal solution (nasal spray) in 2770 patients with seasonal or perennial allergic rhinitis in 10 controlled clinical trials of 2 weeks to 12 months duration. Olopatadine hydrochloride nasal solution (nasal spray) is not indicated for use in patients with perennial allergic rhinitis. The safety data from adults and adolescents are based upon 6 placebo-controlled clinical trials (3.7 pH vehicle nasal spray or 7.0 pH vehicle nasal spray) in which 1834 patients with seasonal or perennial allergic rhinitis (652 males and 1182 females) 12 years of age and older were treated with olopatadine hydrochloride nasal solution (nasal spray) two sprays per nostril twice daily. There were 1180 patients (olopatadine hydrochloride nasal solution (nasal spray), 587; vehicle nasal spray, 593) that participated in 3 efficacy and safety trials of 2 weeks duration. There were 2840 patients (olopatadine hydrochloride nasal solution (nasal spray), 1247; 3.7 pH vehicle nasal spray, 1251; 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 olopatadine hydrochloride nasal solution (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 olopatadine hydrochloride nasal solution (nasal spray) and vehicle nasal spray. Overall, 4.7% of the 1834 adult and adolescent patients across all 6 studies treated with olopatadine hydrochloride nasal solution (nasal spray), 3.5% of the 1844 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 to 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 olopatadine hydrochloride nasal solution (nasal spray) one or two sprays per nostril twice daily for 2 weeks. The racial distribution of pediatric patients receiving olopatadine hydrochloride nasal solution (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 olopatadine hydrochloride nasal solution (nasal spray) and vehicle nasal spray. Overall, 1.4% of the 870 pediatric patients across all 3 studies treated with olopatadine hydrochloride nasal solution (nasal spray) and 1.3% of the 872 pediatric patients treated with vehicle nasal spray discontinued due to adverse reactions. Adults and Adolescents 12 Years of Age and Older in Short-Term (2-week)

Trials

There were 1180 patients 12 years of age and older (olopatadine hydrochloride nasal solution (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 olopatadine hydrochloride nasal solution (nasal spray)) that occurred more frequently in patients treated with olopatadine hydrochloride nasal solution (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 Olopatadine Hydrochloride Nasal Solution (Nasal Spray) in Adolescent and Adult Patients 12 Years of Age and Older With Seasonal Allergic Rhinitis Adverse Reaction Adult and Adolescent Patients 12 Years and Older Olopatadine Hydrochloride Nasal Solution (Nasal Spray) N = 587 Vehicle Nasal Spray N = 593 Bitter taste 75 (12.8%) 5 (0.8%)

Headache

26 (4.4%) 24 (4.0%)

Epistaxis

19 (3.2%) 10 (1.7%)

Pharyngolaryngeal Pain

13 (2.2%) 8 (1.3%) Post-nasal drip 9 (1.5%) 5 (0.8%)

Cough

8 (1.4%) 3 (0.5%) Urinary tract infection 7 (1.2%) 3 (0.5%) CPK elevation 5 (0.9%) 2 (0.3%) Dry mouth 5 (0.9%) 1 (0.2%)

Fatigue

5 (0.9%) 4 (0.7%)

Influenza

5 (0.9%) 1 (0.2%)

Nasopharyngitis

5 (0.9%) 4 (0.7%)

Somnolence

5 (0.9%) 2 (0.3%) Throat irritation 5 (0.9%) 0 (0.0%) 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 1742 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 olopatadine hydrochloride nasal solution (nasal spray). One study evaluated the safety of olopatadine hydrochloride nasal solution (nasal spray) at doses of one and two sprays per nostril twice daily in 1188 patients, in which 298 were exposed to olopatadine hydrochloride nasal solution (nasal spray) 1 spray, 296 were exposed to olopatadine hydrochloride nasal solution (nasal spray) 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 to 11 years of age treated with olopatadine hydrochloride nasal solution (nasal spray) one spray per nostril) that occurred more frequently with olopatadine hydrochloride nasal solution (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 Olopatadine Hydrochloride Nasal Solution (Nasal Spray) in Pediatric Patients 6 to 11 Years of Age With Seasonal Allergic Rhinitis Adverse Reaction Pediatric Patients 6 to 11 Years of Age Olopatadine Hydrochloride Nasal Solution (Nasal Spray)

One

Spray per Nostril N = 298 Vehicle Nasal Spray One Spray per Nostril N = 297 Epistaxis Headache Upper respiratory tract infection Bitter taste 17 (5.7%) 13 (4.4%) 8 (2.6%) 3 (1.0%) 11 (3.7%) 11 (3.7%) 0 0 Pyrexia 4 (1.3%) 3 (1.0%)

Rash

4 (1.3%) 0 There were no differences in the incidence of adverse reactions based on gender, race, or ethnicity. Long-Term (12 month)

Safety

Trials In a 12-month, placebo-controlled, safety trial (vehicle nasal spray), 890 patients 12 years of age and older with perennial allergic rhinitis were randomized to treatment with olopatadine hydrochloride nasal solution (nasal spray) two sprays per nostril twice daily (445 patients) or vehicle nasal spray (445 patients). In the olopatadine hydrochloride nasal solution (nasal spray) 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 reaction. The most frequently reported adverse reaction was epistaxis, which occurred in 25% of patients treated with olopatadine hydrochloride nasal solution (nasal spray) and 28% in patients treated with vehicle nasal spray. Epistaxis resulted in discontinuation of 0.9% of patients treated with olopatadine hydrochloride nasal solution (nasal spray) and 0.2% of patients treated with vehicle nasal spray. Nasal ulcerations occurred in 10% of patients treated with olopatadine hydrochloride nasal solution (nasal spray) and 9% of patients treated with vehicle nasal spray. Nasal ulcerations resulted in discontinuation of 0.4% of patients treated with olopatadine hydrochloride nasal solution (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 olopatadine hydrochloride nasal solution (nasal spray) and 1 patient treated with vehicle nasal spray. Weight increase was reported in 6 patients treated with olopatadine hydrochloride nasal solution (nasal spray) and 1 patient treated with vehicle nasal spray. Depression or worsening of depression occurred in 9 patients treated with olopatadine hydrochloride nasal solution (nasal spray) and in 5 patients treated with vehicle nasal spray. Three patients, 2 of whom had preexisting histories of depression, who received olopatadine hydrochloride nasal solution (nasal spray) were hospitalized for depression compared to none who received vehicle nasal spray. In a second 12-month, placebo-controlled, safety trial (vehicle nasal spray), 459 patients 12 years of age and older with perennial allergic rhinitis were treated with two sprays per nostril of an investigational formulation of olopatadine hydrochloride nasal solution (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 olopatadine hydrochloride nasal solution (nasal spray) and 2 patients treated with the vehicle nasal spray. Epistaxis was reported in 19% of patients treated with the investigational formulation of olopatadine hydrochloride nasal solution (nasal spray) and 12% of patients treated with vehicle nasal spray. Somnolence was reported in 3 patients treated with the investigational formulation of olopatadine hydrochloride nasal solution (nasal spray) compared to 1 patient treated with vehicle nasal spray. Fatigue was reported in 5 patients treated with the investigational formulation of olopatadine hydrochloride nasal solution (nasal spray) compared to 1 patient treated with vehicle nasal spray. In a third 3-arm, 12-month, placebo-controlled, safety trial (vehicle nasal spray), conducted post approval, 1026 patients 12 years of age and older with perennial allergic rhinitis were randomized to treatment with olopatadine hydrochloride nasal solution (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 two sprays per nostril, twice daily. Overall, 5% of olopatadine hydrochloride nasal solution (nasal spray) patients, 2% of 3.7 pH vehicle patients and 3% of 7.0 pH vehicle patients discontinued due to adverse reactions. The most frequently reported adverse reaction was epistaxis, which occurred in 24% of patients treated with olopatadine hydrochloride nasal solution (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 olopatadine hydrochloride nasal solution (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 olopatadine hydrochloride nasal solution (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 olopatadine hydrochloride nasal solution (nasal spray). Hyposmia and anosmia were each reported by one patient treated with olopatadine hydrochloride nasal solution (nasal spray). Neither somnolence nor weight loss was reported. Depression occurred in 3 patients treated with olopatadine hydrochloride nasal solution (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 Postmarketing Experience During the post approval use of olopatadine hydrochloride nasal solution (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 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 olopatadine hydrochloride nasal solution (nasal spray).

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 olopatadine hydrochloride nasal solution (nasal spray) ( 5.2 ).
• Avoid concurrent use of alcohol or other central nervous system depressants with olopatadine hydrochloride nasal solution (nasal spray) ( 5.2 ).

5.1 Local Nasal Effects Epistaxis and Nasal Ulceration In placebo-controlled clinical trials (vehicle nasal spray) of 2 weeks to 12 months duration, epistaxis and nasal ulcerations were reported [ see Adverse Reactions 6.1 ].

Nasal Septal Perforation

Three placebo-controlled long term (12 months) safety trials (vehicle nasal spray) were conducted. In the first safety trial, patients were treated with an investigational formulation of olopatadine hydrochloride nasal solution (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 olopatadine hydrochloride nasal solution (nasal spray) and 2 patients treated with the vehicle nasal spray. In the second safety trial with olopatadine hydrochloride nasal solution (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 ( 6.1 ) ]. Before starting olopatadine hydrochloride nasal solution (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 olopatadine hydrochloride nasal solution (nasal spray) if patients develop nasal ulcerations.

5.2 Somnolence and Impaired Mental Alertness In clinical trials, the occurrence of somnolence has been reported in some patients taking olopatadine hydrochloride nasal solution (nasal spray) [ see Adverse Reactions ( 6.1 ) ]. 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 olopatadine hydrochloride nasal solution (nasal spray). Concurrent use of olopatadine hydrochloride nasal solution (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.

PRECAUTIONS INFORMATION FOR PATIENTS To prevent contaminating the dropper tip and solution, care should be taken not to touch the eyelids or surrounding areas with the dropper tip of the bottle. Keep bottle tightly closed when not in use. Patients should be advised not to wear a contact lens if their eye is red. Olopatadine hydrochloride ophthalmic solution USP, 0.1% should not be used to treat contact lens related irritation. The preservative in Olopatadine hydrochloride ophthalmic solution USP, 0.1%, benzalkonium chloride, may be absorbed by soft contact lenses. Patients who wear soft contact lenses and whose eyes are not red should be instructed to wait at least ten minutes after instilling Olopatadine hydrochloride ophthalmic solution USP, 0.1% before they insert their contact lenses.

Carcinogenesis And Mutagenesis And Impairment Of Fertility

Olopatadine administered orally was not carcinogenic in mice and rats in doses up to 500 mg/kg/day and 200 mg/kg/day, respectively. Based on a 40 μL drop size, these doses were 78,125 and 31,250 times higher than the maximum recommended ocular human dose (MROHD). No mutagenic potential was observed when olopatadine was tested in an in vitro bacterial reverse mutation (Ames) test, an in vitro mammalian chromosome aberration assay or an in vivo mouse micronucleus test. Olopatadine administered to male and female rats at oral doses of 62,500 times MROHD level resulted in a slight decrease in the fertility index and reduced implantation rate; no effects on reproductive function were observed at doses of 7,800 times the maximum recommended ocular human use level.

Pregnancy

Pregnancy Category C. Olopatadine was found not to be teratogenic in rats and rabbits. However, rats treated at 600 mg/kg/day, or 93,750 times the MROHD and rabbits treated at 400 mg/kg/day, or 62,500 times the MROHD, during organogenesis showed a decrease in live fetuses. There are, however, no adequate and well controlled studies in pregnant women. Because animal studies are not always predictive of human responses, this drug should be used in pregnant women only if the potential benefit to the mother justifies the potential risk to the embryo or fetus.

Nursing Mothers

Olopatadine has been identified in the milk of nursing rats following oral administration. It is not known whether topical ocular administration could result in sufficient systemic absorption to produce detectable quantities in the human breast milk. Nevertheless, caution should be exercised when Olopatadine hydrochloride ophthalmic solution USP, 0.1% is administered to a nursing mother.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 3 years have not been established.

Geriatric Use

No overall differences in safety or effectiveness have been observed between elderly and younger patients.

INTERACTIONS Formal drug-drug interaction studies were not conducted for olopatadine hydrochloride nasal solution (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 Clinical Pharmacology ( 12.3 ) ].

Active Ingredient Purpose Olopatadine (0.2%)...................................... Antihistamine (equivalent to olopatadine hydrochloride, USP 0.222%)

INACTIVE INGREDIENTS benzalkonium chloride 0.015% (preservative), boric acid, hydrochloric acid/sodium hydroxide (to adjust pH), hydroxypropyl-gamma-cyclodextrin, hypromellose, mannitol, polyethylene glycol 400, povidone, and purified water.