Patanase - Scientific Information
|Class:||Nasal antihistamines and decongestants|
|Ingredients:||Olopatadine hydrochloride, Benzalkonium chloride, Dibasic sodium phosphate, Sodium chloride, Edetate disodium, Sodium hydroxide and/or Hydrochloric acid and Purified water.|
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:
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 Forms and Strengths]. 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.
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.
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.
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.
Healthy Subjects: Olopatadine was absorbed with individual peak plasma concentrations observed between 30 minutes and 1 hour after twice daily intranasal administration of Patanase Nasal Spray. The mean ( ± SD) steady-state peak plasma concentration (Cmax) of olopatadine was 16.0 ± 8.99 ng/mL. Systemic exposure as indexed by area under the curve (AUC0-12) averaged 66.0 ± 26.8 ng·h/mL. The average absolute bioavailability of intranasal olopatadine is 57%. The mean accumulation ratio following multiple intranasal administration of Patanase Nasal Spray was about 1.3.
Seasonal Allergic Rhinitis (SAR) Patients: Systemic exposure of olopatadine in SAR patients after twice daily intranasal administration of Patanase Nasal Spray was comparable to that observed in healthy subjects. Olopatadine was absorbed with peak plasma concentrations observed between 15 minutes and 2 hours. The mean steady-state Cmax was 23.3 ± 6.2 ng/mL and AUC0-12 averaged 78.0 ± 13.9 ng·h/mL.
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.
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.
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.
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.
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 Patanase Nasal Spray is warranted in patients with renal impairment.
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.
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 Patanase 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 Patanase Nasal Spray twice daily for a minimum of 14 days. The mean Cmax and AUC 0-12 of olopatadine were 13.4 ± 4.6 ng/mL and 75.0± 26.4 ng·hr/mL respectively. The mean C max 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.
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).
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 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 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 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 1.
|Treatment||N||Baseline||Change from Baseline||Difference from Placebo|
|Study 1||Patanase Nasal Spray 0.6%||183||8.71||-3.63||-0.96||(-1.42, -0.51)||<0.0001|
|Patanase Nasal Spray 0.4%||188||8.90||-3.38||-0.71||(-1.17, -0.26)||0.0023|
|Vehicle Nasal Spray||191||8.75||-2.67|
|Study 2||Patanase Nasal Spray 0.6%||220||9.17||-2.90||-0.98||(-1.37, -0.59)||<0.0001|
|Patanase Nasal Spray 0.4%||228||9.26||-2.63||-0.72||(-1.11, -0.33)||0.0003|
|Vehicle Nasal Spray||223||9.07||-1.92|
Itchy eyes and watery eyes were evaluated as secondary endpoints but eye redness was not evaluated. In two of the studies, patients treated with Patanase 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 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.
Pediatric Patients 6 to 11 Years 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 Patanase 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 Patanase 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 2.
|Treatment||N||Baseline||Change from Baseline||Difference from Placebo|
|Patanase Nasal Spray 0.6%, 1 spray per nostril twice daily||294||8.99||-2.24||-0.55||(- 0.90, - 0.19)||0.0015|
|Vehicle Nasal Spray, 1 spray per nostril twice daily||294||9.09||-1.70|
Itchy eyes and watery eyes were evaluated as secondary endpoints in the same study but eye redness was not evaluated. Patients treated with Patanase Nasal Spray had significantly greater decreases in reflective symptom scores for itchy eyes and watery eyes, compared to vehicle nasal spray.