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.

2.3 Administration Information

Priming: Before initial use, prime Olopatadine Hydrochloride Nasal Spray by releasing 5 sprays or until a fine mist appears. When Olopatadine Hydrochloride Nasal Spray has not been used for more than 7 days, re-prime by releasing 2 sprays. Avoid spraying Olopatadine Hydrochloride Nasal Spray into the eyes.

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 Olopatadine Hydrochloride 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 Spray and 2 patients treated with the vehicle nasal spray. In the second safety trial with Olopatadine Hydrochloride 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 Olopatadine Hydrochloride 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 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 Olopatadine Hydrochloride 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 Olopatadine Hydrochloride Nasal Spray. Concurrent use of Olopatadine Hydrochloride 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.

6.2 Post-Marketing Experience

During the post approval use of Olopatadine Hydrochloride 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 Spray.

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, Olopatadine Hydrochloride 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. Olopatadine Hydrochloride 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

The safety and effectiveness of Olopatadine Hydrochloride 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 Olopatadine Hydrochloride Nasal Spray at doses of 1 and 2 sprays per nostril twice daily in 1188 patients, of which, 298 patients were exposed to Olopatadine Hydrochloride 1 spray and 297 patients were exposed to vehicle 1 spray. In this study, the incidence of epistaxis with Olopatadine Hydrochloride Nasal Spray treatment was 5.7%, compared to 3.2% seen in adult and adolescent studies. This study also evaluated the effectiveness of Olopatadine Hydrochloride Nasal Spray in patients 6 through 11 years of age with seasonal allergic rhinitis [see Clinical Studies (14)].

The safety of Olopatadine Hydrochloride 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 patients (28 females and 38 males) were exposed to Olopatadine Hydrochloride Nasal Spray. The racial distribution of patients receiving Olopatadine Hydrochloride Nasal Spray was 66.7% white, 27.3% black, and 6.4% other. Two patients 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 Olopatadine Hydrochloride 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%).

8.5 Geriatric Use

Clinical studies of Olopatadine Hydrochloride 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.

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 Olopatadine Hydrochloride 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 Olopatadine Hydrochloride 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 Olopatadine Hydrochloride Nasal Spray was about 1.3.

Seasonal Allergic Rhinitis (SAR) Patients: Systemic exposure of olopatadine in SAR patients after twice daily intranasal administration of Olopatadine Hydrochloride 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 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 Olopatadine Hydrochloride 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 well-tolerated. These findings indicate that no adjustment of the dosing regimen of Olopatadine Hydrochloride 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: Pediatric Patients 6 to 11 Years of Age: The systemic pharmacokinetics of olopatadine, olopatadine N-oxide and Ndesmethyl olopatadine in patients 6 through 11 years of age were characterized using data from 42 pediatric patients administered Olopatadine Hydrochloride Nasal Spray, one spray per nostril twice daily for a minimum of 14 days. The mean Cmax (15.4 ± 7.3 ng/mL) of olopatadine was approximately 2-fold less than was comparable to that observed in adults (78.0 ± 13.9 ng·h/mL). The Cmax and AUC0-12 of olopatadine N-oxide were comparable to that observed in adults. The Cmax and AUC0-12 of N-desmethyl olopatadine are approximately 18% and 37% higher than that observed in adults, respectively.

Pediatric Patients 2 to 5 Years of Age: The systemic pharmacokinetics of olopatadine, olopatadine N-oxide, and N-desmethyl olopatadine were characterized using population pharmacokinetic methods applied to sparse data (approximately 5 samples per patient) obtained from 66 pediatric patients (2 to less than 6 years of age) administered one-half the recommended adult dose (1 spray per nostril) of Olopatadine Hydrochloride Nasal Spray twice daily for a minimum of 14 days. The mean Cmax and AUC0-12 of olopatadine were 13.4 ± 4.6 ng/mL and 75.0± 26.4 ng*hr/mL respectively. The mean Cmax and AUC0-12 of olopatdine N-oxide and N-desmethyl olopatadine were similar to that of patients 6 to 11 years of age.

Drug Interaction Studies

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 also not expected.

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 and adolescents ≥12 years of age and 500 and 400 times the MRHD for children 6-11 years of age 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).

Adult and Adolescent Patients 12 Years of Age and Older:
The efficacy and safety of Olopatadine Hydrochloride 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 Olopatadine Hydrochloride Nasal Spray 0.6%, 418 patients were treated with Olopatadine Hydrochloride 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 average of morning and evening reflective total nasal symptom score (rTNSS) averaged for the 2-week treatment period. In all 3 trials, patients treated with Olopatadine Hydrochloride 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 3.

Table 3: Mean Reflective Total Nasal Symptom Score (rTNSS) in Adult and Adolescent Patients with Seasonal Allergic Rhinitis

Itchy eyes and watery eyes were evaluated as secondary endpoints but eye redness was not evaluated. In two of the studies, patients treated with Olopatadine Hydrochloride Nasal Spray had significantly greater decreases in reflective symptom scores for itchy eyes and watery eyes, compared to vehicle nasal spray.

In the 2-week seasonal allergy 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 Olopatadine Hydrochloride 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 Olopatadine Hydrochloride 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. Olopatadine Hydrochloride Nasal Spray 0.6% was found to have an onset of action of 30 minutes after dosing in the environmental exposure unit.

Pediatric Patients 6 to 11Years of Age:
There were 3 clinical trials of 2 weeks duration with olopatadine nasal spray in patients 6 to 11 years of age with seasonal allergic rhinitis. Efficacy of Olopatadine Hydrochloride Nasal Spray was evaluated in 2 of the 3 trials. One of the 2 trials that showed efficacy was a randomized, double blind, parallel group, multicenter, placebo (vehicle nasal spray)-controlled clinical trial of 2 weeks duration including 1,188 children ages 6 to < 12 years with seasonal allergic rhinitis. Assessment of efficacy was based on patient/caregiver 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 captured symptom severity over the previous 12 hours; the instantaneous scoring captured symptom severity at the time of recording. The primary efficacy endpoint was the difference from placebo in the percent change from baseline in the average of patient/caregiver-reported morning and evening reflective total nasal symptom score (rTNSS) averaged for the 2-week treatment period. Patients treated with Olopatadine Hydrochloride Nasal Spray, 1 or 2 sprays per nostril twice daily, had statistically significantly greater decreases in rTNSS compared to vehicle nasal spray. Results for rTNSS are shown in Table 4.

Table 4: Mean Reflective Total Nasal Symptom Score (rTNSS) in Pediatric Patients 6-11 Years of Age with Seasonal Allergic Rhinitis

Itchy eyes and watery eyes were evaluated as secondary endpoints in the same study but eye redness was not evaluated. Patients treated with Olopatadine Hydrochloride Nasal Spray had significantly greater decreases in reflective symptom scores for itchy eyes and watery eyes, compared to vehicle nasal spray.

16.1 How Supplied

Olopatadine Hydrochloride 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 61314-320-01). Each 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 Olopatadine Hydrochloride Nasal Spray by releasing 5 sprays or until a fine mist appears. After periods of non-use greater than 7 days, re-prime Olopatadine Hydrochloride 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 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 61314-320-01

16.2 Storage

Store at 4°-25°C (39°-77°F). Rx Only.

17.1 Local Nasal Effects and Other Common Adverse Reactions

Inform patients that treatment with Olopatadine Hydrochloride 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 Olopatadine Hydrochloride Nasal Spray include bitter taste, headache, and pharyngolaryngeal pain [see Adverse Reactions (6)].

17.2. Activities Requiring Mental Alertness

Somnolence has been reported in some patients taking Olopatadine Hydrochloride 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 Olopatadine Hydrochloride Nasal Spray [see Warnings and Precautions (5.2)].

17.3 Concurrent Use of Alcohol and other Central Nervous System Depressants

Advise patients that concurrent use of Olopatadine Hydrochloride 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

Inform patients to avoid spraying Olopatadine Hydrochloride Nasal Spray in their eyes.

Manufactured by
ALCON CUSI, S.A.
08320 El Masnou
Barcelona Spain
for Sandoz Inc.


Princeton, NJ 08540

© 2011, 2013 Novartis