Azelastine Hydrochloride

Astelin (azelastine hydrochloride) Nasal Spray, 137 micrograms (mcg), is an antihistamine formulated as a metered-spray solution for intranasal administration. Azelastine hydrochloride occurs as a white, almost odorless, crystalline powder with a bitter taste. It has a molecular weight of 418.37. It is sparingly soluble in water, methanol, and propylene glycol and slightly soluble in ethanol, octanol, and glycerine. It has a melting point of about 225°C and the pH of a saturated solution is between 5.0 and 5.4. Its chemical name is (±)-1-(2H)-phthalazinone,4-[(4chlorophenyl) methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-, monohydrochloride. Its molecular formula is C22H24ClN3O•HCl with the following chemical structure:

Astelin Nasal Spray contains 0.1% azelastine hydrochloride in an aqueous solution at pH 6.8 ± 0.3. It also contains benzalkonium chloride (125 mcg/mL), edetate disodium, hypromellose, citric acid, dibasic sodium phosphate, sodium chloride, and purified water.

After priming [see DOSAGE AND ADMINISTRATION], each metered spray delivers a 0.137 mL mean volume containing 137 mcg of azelastine hydrochloride (equivalent to 125 mcg of azelastine base). The bottle can deliver 200 metered sprays.

There have been no reported overdosages with Astelin Nasal Spray. Acute overdosage by adults with this dosage form is unlikely to result in clinically significant adverse reactions, other than increased somnolence, since one bottle of Astelin Nasal Spray contains 30 mg of azelastine hydrochloride. Clinical trials in adults with single doses of the oral formulation of azelastine hydrochloride (up to 16 mg) have not resulted in increased incidence of serious adverse reactions. General supportive measures should be employed if overdosage occurs. There is no known antidote to Astelin Nasal Spray. Oral ingestion of antihistamines has the potential to cause serious adverse effects in young children. Accordingly, Astelin Nasal Spray should be kept out of the reach of children.

Mechanism Of Action

Azelastine hydrochloride, a phthalazinone derivative, exhibits histamine H1-receptor antagonist activity in isolated tissues, animal models, and humans. Astelin Nasal Spray is administered as a racemic mixture with no difference in pharmacologic activity noted between the enantiomers in in vitro studies. The major metabolite, desmethylazelastine, also possesses H1-receptor antagonist activity.

Pharmacodynamics

In a placebo-controlled study (95 subjects with allergic rhinitis), there was no evidence of an effect of Astelin Nasal Spray (2 sprays per nostril twice daily for 56 days) on cardiac repolarization as represented by the corrected QT interval (QTc) of the electrocardiogram. Following multiple dose oral administration of azelastine 4 mg or 8 mg twice daily, the mean change in QTc was 7.2 msec and 3.6 msec, respectively.

Interaction studies investigating the cardiac repolarization effects of concomitantly administered oral azelastine hydrochloride and erythromycin or ketoconazole were conducted. These drugs had no effect on QTc based on analysis of serial electrocardiograms. At a dose approximately 8 times the maximum recommended dose, azelastine hydrochloride does not prolong the QTc interval to any clinically relevant extent.

Pharmacokinetics

After intranasal administration, the systemic bioavailability of azelastine hydrochloride is approximately 40%. Maximum plasma concentrations (Cmax) are achieved in 23 hours.

Azelastine hydrochloride administered intranasally at doses above two sprays per nostril twice daily for 29 days resulted in greater than proportional increases in Cmax and area under the curve (AUC) for azelastine.

Based on intravenous and oral administration, the steady-state volume of distribution is 14.5 L/kg. In vitro studies with human plasma indicate that the plasma protein binding of azelastine and its metabolite, desmethylazelastine, are approximately 88% and 97%, respectively.

Azelastine is oxidatively metabolized to the principal active metabolite, desmethylazelastine, by the cytochrome P450 enzyme system. The specific P450 isoforms responsible for the biotransformation of azelastine have not been identified. After intranasal dosing of azelastine hydrochloride to steady-state, plasma concentrations of desmethylazelastine range from 20-50% of azelastine concentrations. Limited data indicate that the metabolite profile is similar when azelastine hydrochloride is administered via the intranasal or oral route.

Based on intravenous and oral administration, the elimination half-life and plasma clearance are 22 hours and 0.5 L/h/kg, respectively. Approximately 75% of an oral dose of radiolabeled azelastine hydrochloride was excreted in the feces with less than 10% as unchanged azelastine.

Special Populations

Hepatic Impairment: Following oral administration, pharmacokinetic parameters were not influenced by hepatic impairment.

Renal Impairment: Based on oral, single-dose studies, renal insufficiency (creatinine clearance < 50 mL/min) resulted in a 70-75% higher Cmax and AUC compared to normal subjects. Time to maximum concentration was unchanged.

Age: Following oral administration, pharmacokinetic parameters were not influenced by age.

Gender: Following oral administration, pharmacokinetic parameters were not influenced by gender.

Race: The effect of race has not been evaluated.

Drug-Drug Interactions

Erythromycin: No significant pharmacokinetic interaction was observed with the coadministration of orally administered azelastine (4 mg twice daily) with erythromycin (500 mg three times daily for 7 days). In this study, co-administration of orally administered azelastine with erythromycin resulted in Cmax of 5.36 ± 2.6 ng/mL and AUC of 49.7 ± 24 ng•h/mL for azelastine, whereas, administration of azelastine alone resulted in Cmax of 5.57 ± 2.7 ng/mL and AUC of 48.4 ± 24 ng•h/mL for azelastine.

Cimetidine and Ranitidine: In a multiple-dose, steady-state drug interaction trial in healthy subjects, cimetidine (400 mg twice daily) increased orally administered mean azelastine (4 mg twice daily) concentrations by approximately 65%. No pharmacokinetic interaction was observed with co-administration of orally administered azelastine (4 mg twice daily) with ranitidine hydrochloride (150 mg twice daily). Oral co-administration of azelastine with ranitidine resulted in Cmax of 8.89 ±3.28 ng/mL and AUC of 88.22 ± 40.43 ng•h/mL for azelastine, whereas, azelastine when administered alone resulted in Cmax of 7.83 ± 4.06 ng/mL and AUC of 80.09 ± 43.55 ng•h/mL for azelastine.

Theophylline: No significant pharmacokinetic interaction was observed with the coadministration of an oral 4 mg dose of azelastine hydrochloride twice daily and theophylline 300 mg or 400 mg twice daily.

Clinical Studies

Seasonal Allergic Rhinitis

The efficacy and safety of Astelin Nasal Spray were evaluated in three placebo-controlled clinical trials of Astelin Nasal Spray including 322 patients with seasonal allergic rhinitis who received two sprays per nostril twice a day for up to 4 weeks. These trials included 55 pediatric patients ages 12 to 16 years. Assessment of efficacy was based on the 12-hour reflective Total Symptom Complex (TSC) and Major Symptom Complex (MSC). The MSC was calculated as the average of individual symptoms of nose blows, sneezes, runny nose/sniffles, itchy nose, and watery eyes as assessed by patients on a 0-5 categorical scale. Astelin Nasal Spray two sprays per nostril twice daily demonstrated a greater decrease in the MSC than placebo (Table 3).

Table 3: Mean Change from Baseline in Reflective MSC* in Adults and Adolescents ≥ 12 Years with Seasonal Allergic Rhinitis Treated with Astelin Nasal Spray Two Sprays Per Nostril Twice Daily Versus Placebo

In dose-ranging trials, administration of Astelin Nasal Spray two sprays per nostril twice daily resulted in a statistically significant decrease in symptoms compared to saline placebo within 3 hours after initial dosing and persisted over the 12-hour dosing interval.

The efficacy and safety of Astelin Nasal Spray were evaluated in two placebo-controlled clinical trials of Astelin Nasal Spray including 275 patients with seasonal allergic rhinitis who received one spray per nostril twice a day for up to 2 weeks. Assessment of efficacy was based on the 12hour reflective Total Nasal Symptom Score [rTNSS]. rTNSS is calculated as the sum of the patients scoring of four individual nasal symptoms (runny nose, sneezing, itchy nose, and nasal congestion) as assessed by patients on a 0-3 categorical scale. The primary efficacy endpoint was the change from Baseline to Day 14 in rTNSS. The mean change from baseline in rTNSS was greater in patients receiving Astelin Nasal Spray one spray per nostril twice daily than those receiving placebo (Table 4).

Table 4: Mean Change from Baseline in Reflective TNSS* in Adults and Adolescents ≥ 12 years with Seasonal Allergic Rhinitis Treated with Astelin Nasal Spray One Spray Per Nostril Twice Daily Versus Placebo

Two-week studies comparing the efficacy (and safety) of Astelin Nasal Spray two sprays per nostril twice daily versus one spray per nostril twice daily were not conducted.

Vasomotor Rhinitis

The efficacy and safety of Astelin Nasal Spray were evaluated in two placebo-controlled clinical trials of Astelin Nasal Spray including 216 patients with vasomotor rhinitis who received two sprays per nostril twice a day for up to 4 weeks. These patients had vasomotor rhinitis for at least one year, negative skin tests to indoor and outdoor aeroallergens, negative nasal smears for eosinophils, and negative sinus X-rays. Astelin Nasal Spray demonstrated a significantly greater decrease in a symptom complex comprised of rhinorrhea, post nasal drip, nasal congestion, and sneezing compared to placebo.

Astelin
[AS-ta-LIN]
(azelastine hydrochloride) Nasal Spray

Important: For use in your nose only.

What is Astelin Nasal Spray?

• Astelin Nasal Spray is a prescription medicine used to treat symptoms of seasonal allergic rhinitis in people age 5 and older and vasomotor rhinitis in people age 12 and older.
• Astelin Nasal Spray may help to reduce your nasal symptoms including stuffy nose, runny nose, itching and sneezing.

It is not known if Astelin Nasal Spray is safe and effective in children with seasonal allergic rhinitis under 5 years of age or in children with vasomotor rhinitis under 12 years of age.

What should I tell my healthcare provider before using Astelin Nasal Spray?

Before using Astelin Nasal Spray, tell your healthcare provider if you are:

• allergic to any of the ingredients in Astelin Nasal Spray. See the end of this leaflet for a complete list of ingredients in Astelin Nasal Spray.
• pregnant, or plan to become pregnant. It is not known if Astelin Nasal Spray will harm your unborn baby.
• breastfeeding, or plan to breastfeed. It is not known if Astelin Nasal Spray passes into your breast milk. You and your healthcare provider should decide if you will use Astelin Nasal Spray if you plan to breastfeed.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Astelin Nasal Spray and other medicines may affect each other, causing side effects.

How should I use Astelin Nasal Spray?

• Read the Instructions for Use at the end of this leaflet for information about the right way to use Astelin Nasal Spray.
• Spray Astelin Nasal Spray in your nose only. Do not spray it into your eyes or mouth.
• Use Astelin Nasal Spray exactly as your healthcare provider tells you to use it.
• Do not use more than your healthcare provider tells you.
• Throw away your Astelin Nasal Spray bottle after using 200 sprays. Even though the bottle may not be completely empty, you may not get the correct dose of medicine.
• If you use too much or a child accidentally swallows Astelin Nasal Spray, call your healthcare provider or go to the nearest hospital emergency room right away.

What should I avoid while using Astelin Nasal Spray?

Astelin Nasal Spray can cause sleepiness:

• Do not drive, operate machinery, or do other dangerous activities until you know how Astelin Nasal Spray affects you.
• Do not drink alcohol or take other medicines that may cause you to feel sleepy while using Astelin Nasal Spray. It may make your sleepiness worse.

What are the possible side effects of Astelin Nasal Spray?

The most common side effects of Astelin Nasal Spray include:

• unusual bitter taste
• headache
• sleepiness
• nose burning, pain or discomfort
• runny nose
• scratchy or sore throat
• nosebleeds
• inflamation or swelling of the sinuses
• sneezing
• nausea
• dry mouth
• fatigue
• dizziness
• weight increase

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all of the possible side effects of Astelin Nasal Spray. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1800-FDA-1088.

How should I store Astelin Nasal Spray?

• Keep Astelin Nasal Spray upright at 68°F to 77°F (20°C to 25°C).
• Do not freeze Astelin Nasal Spray.
• Do not use Astelin Nasal Spray after the expiration date “EXP” on the medicine label and box.

Keep Astelin Nasal Spray and all medicines out of reach of children.

General information about the safe and effective use of Astelin Nasal Spray.

Medicines are sometimes prescribed for conditions other than those listed in a Patient Information leaflet. Do not use Astelin Nasal Spray for a condition for which it was not prescribed. Do not give Astelin Nasal Spray to other people, even if they have the same symptoms that you have. It may harm them.

This Patient Information leaflet summarizes the most important information about Astelin Nasal Spray. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Astelin Nasal Spray that is written for health professionals.

For more information call 1-866-210-5954.

What are the ingredients in Astelin Nasal Spray?

Active ingredient: azelastine hydrochloride

Inactive ingredients: benzalkonium chloride, edetate disodium, hypromellose, citric acid, dibasic sodium phosphate, sodium chloride, and purified water.

Instructions for Use

Astelin
[AS-ta-LIN]
(azelastine hydrochloride) Nasal Spray

Important: For use in your nose only.

For the correct dose of medicine:

• Keep your head tilted downward when spraying into your nostril.
• Change nostrils each time you use the spray.
• Breathe gently and do not tip your head back after using the spray. This will keep the medicine from running down into your throat. You may get a bitter taste in your mouth.

Figure A identifies the parts of your Astelin Nasal Spray pump

Figure A

Before you use Astelin Nasal Spray for the first time, you will need to prime the bottle. Priming your Astelin Nasal Spray

Remove the blue dust cover over the tip of the pump and the blue safety clip just under the “shoulders” of the pump (See Figure B).

Figure B

Hold the bottle upright with 2 fingers on the shoulders of the spray pump unit and

• put your thumb on the bottom of the bottle. Press upward with your thumb and release for the pumping action. Repeat this until you see a fine mist (See Figure C).
• To get a fine mist you must pump the spray fast and use firm pressure against the bottom of the bottle. If you see a stream of liquid, the pump is not working correctly and you may have nasal discomfort.
• This should happen in 4 sprays or less.

Now your pump is primed and ready to use.

Figure C

• Do not use Astelin Nasal Spray unless you see a fine mist after you do the priming sprays. If you do not see a fine mist, clean the tip of the spray nozzle. See the “Cleaning the Spray Tip of your Astelin Nasal Spray” section below.
• If you do not use Astelin Nasal Spray for 3 or more days, you will need to prime the pump with 2 sprays or until you see a fine mist.

Using your Astelin Nasal Spray

Step 1. Blow your nose to clear your nostrils.

Step 2. Keep your head tilted downward toward your toes.

Step 3. Place the spray tip about ¼ inch to ½ inch into 1 nostril. Hold bottle upright and aim the spray tip toward the back of your nose (See Figure D).

Figure D

Step 4. Close your other nostril with a finger. Press the pump 1 time and sniff gently at the same time, keeping your head tilted forward and down (See Figure E).

Figure E

Step 5. Repeat Step 3 and Step 4 in your other nostril.

Step 6. If your healthcare provider tells you to use 2 sprays in each nostril, repeat Steps 2 through 4 above for the second spray in each nostril.

Step 7. Breathe in gently, and do not tilt your head back after using Astelin Nasal Spray. This will help to keep the medicine from going into your throat.

Step 8. When you finish using your Astelin Nasal Spray, wipe the spray tip with a clean tissue or cloth. Put the safety clip and dust cover back on the bottle.

Cleaning the Spray Tip of your Astelin Nasal Spray

• If the spray tip opening is clogged, do not use a pin or pointed object to unclog the tip. Unscrew the spray pump unit from the bottle by turning it to the left (counter-clockwise) (See Figure F).
• Soak only the spray pump unit in warm water. Squirt the spray unit several times while holding it under water. Use the pumping action to clear the opening in the tip (See Figure G).

Figure F

Figure G

• Let the spray pump unit air dry. Make sure it is dry before you put it back onto the bottle.
• Put the spray pump unit back into the open bottle and tighten it by turning clockwise (to the right).
• To keep the medicine from leaking out, use firm pressure when you put the pump back onto the bottle.
• After cleaning, follow the instructions for priming.

This Patient Information and Instructions for Use has been approved by the U.S. Food and Drug Administration.

OPTIVAR® is indicated for the treatment of itching of the eye associated with allergic conjunctivitis.

To report SUSPECTED ADVERSE REACTIONS, contact Meda Pharmaceuticals Inc. at 1-800- 526-3840 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

In controlled multiple-dose studies where patients were treated for up to 56 days, the most frequently reported adverse reactions were transient eye burning/stinging (approximately 30%), headaches (approximately 15%) and bitter taste (approximately 10%). The occurrence of these events was generally mild.

The following events were reported in 1–10% of patients: asthma, conjunctivitis, dyspnea, eye pain, fatigue, influenza-like symptoms, pharyngitis, pruritus, rhinitis and temporary blurring. Some of these events were similar to the underlying disease being studied.

Metabolized by CYP isoenzymes.a

Specific Drugs

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

This medication may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Drinking alcohol can increase certain side effects of azelastine.

Azelastine is an antihistamine that reduces the natural chemical histamine in the body. Histamine can produce symptoms of itching or watery eyes.

Azelastine ophthalmic (for the eyes) is used to treat itchy eyes caused by allergies (hay fever).

Azelastine ophthalmic may also be used for purposes not listed in this medication guide.