DESCRIPTION SECTION

11 DESCRIPTION

Olopatadine hydrochloride nasal spray, 665 mcg is a metered-spray solution for nasal administration. Olopatadine hydrochloride, the active component of olopatadine hydrochloride 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 C21H23NO3 • HCl with the following chemical structure:

Olopatadine hydrochloride 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 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.

CLINICAL PHARMACOLOGY SECTION

12 CLINICAL PHARMACOLOGY

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 Electrophysiology

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 two 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 Patients: Systemic exposure of olopatadine in seasonal allergic rhinitis (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.

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.

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.

Specific Populations

Patients with 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.

Patients with Renal Impairment

The mean Cmax values for olopatadine following single nasal 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). The mean plasma AUC0-12 was 2-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.

Male and Female Patients

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.

Racial or Ethnic Groups

The effects of race on olopatadine pharmacokinetics have not been adequately investigated.

Pediatric Patients 6 to 11 Years of Age

The systemic pharmacokinetics of olopatadine, olopatadine N-oxide and N-desmethyl 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 (one 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 olopatadine 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.

DOSAGE & ADMINISTRATION SECTION

Highlight: 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 spray before initial use and when olopatadine hydrochloride nasal spray has not been used for more than 7 days (2.3).

2 DOSAGE AND ADMINISTRATION

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 spray by the nasal route only.

Priming: Before initial use, prime olopatadine hydrochloride 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 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.

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.

NONCLINICAL TOXICOLOGY SECTION

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity

Olopatadine demonstrated no tumorigenic potential in mice at oral doses up to 500 mg/kg/day (approximately 460 times the MRHDID on a mg/m2 basis) for 78 weeks or in rats at oral doses up to 200 mg/kg/day (approximately 370 times the MRHDID on a mg/m2 basis) for 104 weeks.

Mutagenesis

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.

Impairment of Fertility

Olopatadine administered at an oral dose of 400 mg/kg/day, (approximately 730 times the MRHDID for adults on an mg/m2 basis) produced toxicity in male and female rats, and resulted in a decrease in the fertility index and reduced implantation rate. No effects on reproductive function were observed at 50 mg/kg/day (approximately 90 times the MRHDID on a mg/m2 basis).

INFORMATION FOR PATIENTS SECTION

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

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)].

Somnolence and Impaired Mental Alertness

Somnolence has been reported in some patients taking olopatadine hydrochloride nasal spray. Caution patients 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)].

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)].

Keep Spray Out of Eyes

Inform patients to avoid spraying olopatadine hydrochloride nasal spray in their eyes [see Dosage and Administration (2.3)].

Made in Israel

Manufactured By Padagis
Yeruham, Israel

Distributed By
Padagis
Allegan, MI 49010 ● www.padagis.com

Rev 11-21

4S000 RC J5

SPL PATIENT PACKAGE INSERT SECTION

Patient Package Insert

have nose problems, such as nose bleeds, or sores in the nose. 

are pregnant or planning to become pregnant. It is not known if olopatadine hydrochloride nasal spray will harm your unborn baby. 

are breastfeeding or plan to breastfeed. It is not known if olopatadine passes into your breast milk. You and your healthcare provider should decide if you will use olopatadine hydrochloride nasal spray if you plan to breastfeed.

See the**“Instructions for Use”** at the end of this Patient Information leaflet for information about the right way to use olopatadine hydrochloride nasal spray. 

Olopatadine hydrochloride nasal spray is for use in**your nose only. Do not spray it in your eyes or mouth.**

Use olopatadine hydrochloride nasal spray exactly as your healthcare provider tells you to use it. 

Do not use more than your healthcare provider tells you. 

If you use too much olopatadine hydrochloride nasal spray, call your healthcare provider or pharmacist right away 

Throw away olopatadine hydrochloride nasal spray after 240 sprays (about 30 days) after the first priming. Even though the bottle may not be completely empty, you may not get the correct dose of medicine if you continue to use it.

Olopatadine hydrochloride nasal spray can cause sleepiness or drowsiness.   

**Do not** drink alcohol or take any medicines that may cause you to feel sleepy while using olopatadine hydrochloride nasal spray. It may make your sleepiness worse.

**nosebleeds.**

**sores in the nose.**

**hole in the cartilage between the nose (nasal septum perforation).** A whistling sound when you breathe may be a symptom of nasal septum perforation. 

**sleepiness or drowsiness.**

bad or bitter taste

headache

throat pain

nose congestion

cough

urinary tract infection

headache

upper respiratory tract infection

bad or bitter taste

fever

rash

Store olopatadine hydrochloride nasal spray at room temperature between 39°F to 77°F (4°C to 25°C). 

Do not use your olopatadine hydrochloride nasal spray after the expiration date on the label or box.

This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 11/2021

INSTRUCTIONS FOR USE SECTION

Instructions for Use

Use olopatadine hydrochloride nasal spray exactly how your healthcare provider tells you to use it. 

Your olopatadine hydrochloride nasal spray bottle must be shaken and primed before you use it for the first time and when you have not used it for more than 7 days. 

Throw away olopatadine hydrochloride nasal spray after 240 sprays after the first priming. Even though the bottle may not be completely empty, you may not get the correct dose of medicine if you continue to use it.

Support the bottom of the bottle with your thumb (see**Figure B**). Prime the bottle by pressing and releasing the shoulders of the bottle down firmly 5 times or until you see a fine mist come out of the nasal applicator. 

Now your pump is primed and ready to use. 

If you do not use olopatadine hydrochloride nasal spray for more than 7 days, you will need to prime the bottle again by pressing and releasing the shoulders of the bottle down firmly 2 times or until you see a fine mist come out of the nasal applicator.

Store olopatadine hydrochloride nasal spray at room temperature between 39°F to 77°F (4°C to 25°C). 

Do not use olopatadine hydrochloride nasal spray after the expiration date on the label or box.

For more information, go to [www.padagis.com](http://www.padagis.com) or call 1-866-634-9120. 4S000 RC J5

This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: 11/2021