Prescription Drug Information: FLUTICASONE (Page 3 of 4)

12.1 Mechanism of Action

Fluticasone propionate is a synthetic trifluorinated corticosteroid with anti-inflammatory activity. Fluticasone propionate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor that is 18 times that of dexamethasone, almost twice that of beclomethasone-17-monopropionate (BMP), the active metabolite of beclomethasone dipropionate, and over 3 times that of budesonide. Data from the McKenzie vasoconstrictor assay in man are consistent with these results. The clinical significance of these findings is unknown.

The precise mechanism through which fluticasone propionate affects rhinitis symptoms is not known. Corticosteroids have been shown to have a wide range of effects on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in inflammation. In 7 trials in adults, Fluticasone Propionate Nasal Spray has decreased nasal mucosal eosinophils in 66% of patients (35% for placebo) and basophils in 39% of patients (28% for placebo). The direct relationship of these findings to long-term symptom relief is not known.

12.2 Pharmacodynamics

HPA Axis Effect

The potential systemic effects of Fluticasone Propionate Nasal Spray on the HPA axis were evaluated. Fluticasone Propionate Nasal Spray given as 200 mcg once daily or 400 mcg twice daily was compared with placebo or oral prednisone 7.5 or 15 mg given in the morning. Fluticasone Propionate Nasal Spray at either dosage for 4 weeks did not affect the adrenal response to 6-hour cosyntropin stimulation, while both dosages of oral prednisone significantly reduced the response to cosyntropin.

Cardiac Electrophysiology

A study specifically designed to evaluate the effect of Fluticasone Propionate on the QT interval has not been conducted.

12.3 Pharmacokinetics

The activity of Fluticasone Propionate Nasal Spray is due to the parent drug, fluticasone propionate. Due to the low bioavailability by the intranasal route, the majority of the pharmacokinetic data was obtained via other routes of administration.

Absorption

Indirect calculations indicate that fluticasone propionate delivered by the intranasal route has an absolute bioavailability averaging less than 2%. Trials using oral dosing of labeled and unlabeled drug have demonstrated that the oral systemic bioavailability of fluticasone propionate is negligible (<1%), primarily due to incomplete absorption and presystemic metabolism in the gut and liver. After intranasal treatment of patients with rhinitis for 3 weeks, fluticasone propionate plasma concentrations were above the level of detection (50 pg/mL) only when recommended doses were exceeded and then only in occasional samples at low plasma levels.

Distribution

Following intravenous administration, the initial disposition phase for fluticasone propionate was rapid and consistent with its high lipid solubility and tissue binding. The volume of distribution averaged 4.2 L/kg.

The percentage of fluticasone propionate bound to human plasma proteins averaged 99%. Fluticasone propionate is weakly and reversibly bound to erythrocytes and is not significantly bound to human transcortin.

Elimination

Following intravenous dosing, fluticasone propionate showed polyexponential kinetics and had a terminal elimination half-life of approximately 7.8 hours. The total blood clearance of fluticasone propionate is high (average: 1,093 mL/min), with renal clearance accounting for less than 0.02% of the total.

Metabolism: The only circulating metabolite detected in man is the 17β-carboxylic acid derivative of fluticasone propionate, which is formed through the CYP3A4 pathway. This metabolite had less affinity (approximately 1/2,000) than the parent drug for the glucocorticoid receptor of human lung cytosol in vitro and negligible pharmacological activity in animal studies. Other metabolites detected in vitro using cultured human hepatoma cells have not been detected in man.

Excretion: Less than 5% of a radiolabeled oral dose was excreted in the urine as metabolites, with the remainder excreted in the feces as parent drug and metabolites.

Special Populations

Fluticasone propionate nasal spray was not studied in any special populations, and no gender-specific pharmacokinetic data have been obtained.

Drug Interactions

Inhibitors of Cytochrome P450 3A4: Ritonavir: Fluticasone propionate is a substrate of CYP3A4. Coadministration of fluticasone propionate and the strong CYP3A4 inhibitor, ritonavir, is not recommended based upon a multiple-dose, crossover drug interaction trial in 18 healthy subjects. Fluticasone propionate aqueous nasal spray (200 mcg once daily) was coadministered for 7 days with ritonavir (100 mg twice daily). Plasma fluticasone propionate concentrations following fluticasone propionate aqueous nasal spray alone were undetectable (<10 pg/mL) in most subjects, and when concentrations were detectable, peak levels (Cmax ) averaged 11.9 pg/mL (range: 10.8 to 14.1 pg/mL) and AUC(0–τ) averaged 8.43 pg•h/mL (range: 4.2 to 18.8 pg•h/mL). Fluticasone propionate Cmax and AUC(0–τ) increased to 318 pg/mL (range: 110 to 648 pg/mL) and 3,102.6 pg•h/mL (range: 1,207.1 to 5,662.0 pg•h/mL), respectively, after coadministration of ritonavir with fluticasone propionate aqueous nasal spray. This significant increase in plasma fluticasone propionate exposure resulted in a significant decrease (86%) in serum cortisol AUC.

Ketoconazole: Coadministration of orally inhaled fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily) resulted in a 1.9-fold increase in plasma fluticasone propionate exposure and a 45% decrease in plasma cortisol AUC, but had no effect on urinary excretion of cortisol.

Erythromycin: In a multiple-dose drug interaction study, coadministration of orally inhaled fluticasone propionate (500 mcg twice daily) and erythromycin (333 mg 3 times daily) did not affect fluticasone propionate pharmacokinetics.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis & Mutagenesis & Impairment of Fertility

Fluticasone propionate demonstrated no tumorigenic potential in mice at oral doses up to 1,000 mcg/kg (approximately 20 times the MRHDID in adults and approximately 10 times the MRHDID in children on a mcg/m2 basis) for 78 weeks or in rats at inhalation doses up to 57 mcg/kg (approximately 2 times the MRHDID in adults and approximately equivalent to the MRHDID in children on a mcg/m2 basis) for 104 weeks.

Fluticasone propionate did not induce gene mutation in prokaryotic or eukaryotic cells in vitro. No significant clastogenic effect was seen in cultured human peripheral lymphocytes in vitro or in the mouse micronucleus test.

No evidence of impairment of fertility was observed in male and female rats at subcutaneous doses up to 50 mcg/kg (approximately 2 times the MRHDID in adults on a mcg/m2 basis). Prostate weight was significantly reduced at a subcutaneous dose of 50 mcg/kg.

14 CLINICAL STUDIES

Perennial Nonallergic Rhinitis: Three randomized, double-blind, parallel-group, vehicle placebo-controlled trials were conducted in 1,191 subjects to investigate regular use of Fluticasone Propionate Nasal Spray in subjects with perennial nonallergic rhinitis. These trials evaluated subject-rated total nasal symptom scores (TNSS) that included nasal obstruction, postnasal drip, rhinorrhea in subjects treated for 28 days of double-blind therapy and in 1 of the 3 trials for 6 months of open-label treatment. Two of these trials demonstrated that subjects treated with Fluticasone Propionate Nasal Spray (100 mcg twice daily) exhibited statistically significant decreases in TNSS compared with subjects treated with vehicle.

16 HOW SUPPLIED/STORAGE AND HANDLING

Fluticasone Propionate Nasal Spray, 50 mcg is supplied in an amber glass bottle fitted with a white metering atomizing pump, white nasal adapter, and transparent dust cap in a box of 1 (NDC 55700-680-16) with FDA-approved Patient Labeling (see Patient Instructions for Use for proper actuation of the device). Each bottle contains a net fill weight of 16 g and will provide 120 actuations. Each actuation delivers 50 mcg of fluticasone propionate in 100 mg of formulation through the nasal adapter. The correct amount of medication in each spray cannot be assured after 120 sprays even though the bottle is not completely empty. The bottle should be discarded when the labeled number of actuations has been used.

Store between 4° and 30°C (39° and 86°F).

17 PATIENT COUNSELING INFORMATION

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

Local Nasal Effects

Inform patients that treatment with Fluticasone Propionate Nasal Spray may lead to adverse reactions, which include epistaxis and nasal ulceration. Candida infection may also occur with treatment with Fluticasone Propionate Nasal Spray. In addition, Fluticasone Propionate Nasal Spray has been associated with nasal septal perforation and impaired wound healing. Patients who have experienced recent nasal ulcers, nasal surgery, or nasal trauma should not use Fluticasone Propionate Nasal Spray until healing has occurred [see Warnings and Precautions (5.1)].

Glaucoma and Cataracts

Inform patients that glaucoma and cataracts are associated with nasal and inhaled corticosteroid use. Advise patients to notify their healthcare providers if a change in vision is noted while using Fluticasone Propionate Nasal Spray [see Warnings and Precautions (5.2)].

Hypersensitivity Reactions, including Anaphylaxis

Inform patients that hypersensitivity reactions, including anaphylaxis, angioedema, urticaria, contact dermatitis, and rash, may occur after administration of Fluticasone Propionate Nasal Spray. If such reactions occur, patients should discontinue use of Fluticasone Propionate Nasal Spray [see Warnings and Precautions (5.3)].

Immunosuppression

Warn patients who are on immunosuppressant doses of corticosteroids to avoid exposure to chickenpox or measles and if they are exposed to consult their healthcare provider without delay. Inform patients of potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex [see Warnings and Precautions (5.4)].

Reduced Growth Velocity

Advise parents that Fluticasone Propionate Nasal Spray may cause a reduction in growth velocity when administered to pediatric patients. Physicians should closely follow the growth of children and adolescents taking corticosteroids by any route [see Warnings and Precautions (5.7), Pediatric Use (8.4)].

Use Daily for Best Effect

Inform patients that they should use Fluticasone Propionate Nasal Spray on a regular basis. Fluticasone Propionate Nasal Spray, like other corticosteroids, does not have an immediate effect on rhinitis symptoms. Maximum benefit may not be reached for several days. Patients should not increase the prescribed dosage but should contact their healthcare providers if symptoms do not improve or if the condition worsens.

Keep Spray Out of Eyes and Mouth

Inform patients to avoid spraying Fluticasone Propionate Nasal Spray in their eyes and mouth.

Product No.: 7264

Manufactured For:

Wockhardt USA, LLC

Parsippany, NJ 07054

Manufactured By:

Morton Grove Pharmaceuticals, Inc.

Morton Grove, IL 60053

27264

REV. 03/16

Patient Information

Fluticasone Propionate Nasal Spray, USP

50 mcg per spray

Read the Patient Information that comes with Fluticasone Propionate Nasal Spray before you start using it and each time you get a refill. There may be new information. This Patient Information does not take the place of talking to your healthcare provider about your medical condition or treatment.

What is Fluticasone Propionate Nasal Spray?

Fluticasone Propionate Nasal Spray is a prescription medicine used to treat non-allergy nasal symptoms such as runny nose, stuffy nose, sneezing, and nasal itching in adults and children aged 4 years and older.

It is not known if Fluticasone Propionate Nasal Spray is safe and effective in children younger than 4 years of age.

Who should not use Fluticasone Propionate Nasal Spray?

Do not use Fluticasone Propionate Nasal Spray if you are allergic to fluticasone propionate or any of the ingredients in Fluticasone Propionate Nasal Spray. See “What are the ingredients in Fluticasone Propionate Nasal Spray?” below for a complete list of ingredients.

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

Tell your healthcare provider about all of your health conditions, including if you:

  • have or have had nasal sores, nasal surgery, or nasal injury.
  • have eye problems, such as cataracts or glaucoma.
  • have an immune system problem.
  • are allergic to any of the ingredients in Fluticasone Propionate Nasal Spray, any other medicines, or food products. See What are the ingredients in Fluticasone Propionate Nasal Spray? below for a complete list of ingredients.
  • have any type of viral, bacterial, or fungal infection.
  • are exposed to chickenpox or measles.
  • have any other medical conditions.
  • are pregnant or planning to become pregnant. It is not known if Fluticasone Propionate Nasal Spray may harm your unborn baby.
  • are breastfeeding or plan to breastfeed. It is not known if Fluticasone Propionate Nasal Spray passes into your breast milk and if it can harm your baby.

Tell your healthcare provider about all the medicines you take , including prescription and over-the-counter medicines, vitamins, and herbal supplements. Fluticasone Propionate Nasal Spray and certain other medicines may interact with each other. This may cause serious side effects. Especially, tell your healthcare provider if you take antifungal or anti-HIV medicines.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.

How should I use Fluticasone Propionate Nasal Spray?

Read the step-by-step instructions for using Fluticasone Propionate Nasal Spray at the end of this Patient Information.

  • Fluticasone Propionate Nasal Spray is for use in your nose only. Do not spray it in your eyes or mouth.
  • Children should use Fluticasone Propionate Nasal Spray with an adult’s help, as instructed by the child’s healthcare provider.
  • Use Fluticasone Propionate Nasal Spray exactly as your healthcare provider tells you. Do not use Fluticasone Propionate Nasal Spray more often than prescribed.
  • Fluticasone Propionate Nasal Spray may take several days of regular use for your rhinitis symptoms to get better. If your symptoms do not improve or get worse, call your healthcare provider.
  • You will get the best results if you keep using Fluticasone Propionate Nasal Spray regularly each day without missing a dose. After you begin to feel better, your healthcare provider may decrease your dose. Do not stop using Fluticasone Propionate Nasal Spray unless your healthcare provider tells you to do so.

What are the possible side effects of Fluticasone Propionate Nasal Spray? Fluticasone Propionate Nasal Spray may cause serious side effects, including:

Symptoms of an infection may include:

  • nose problems. Nose problems may include:
    • nose bleeds.
    • sores (ulcers) in your nose.
    • a certain fungal infection in your nose, mouth, and/or throat (thrush).
    • hole in the cartilage of your nose (nasal septal perforation).
    • Symptoms of nasal septal perforation may include:
      • crusting in the nose
      • nose bleeds
      • runny nose
      • whistling sound when you breathe
    • slow wound healing. You should not use Fluticasone Propionate Nasal Spray until your nose has healed if you have a sore in your nose, have had surgery on your nose, or if your nose has been injured.
  • eye problems including glaucoma and cataracts. You should have regular eye exams while you use Fluticasone Propionate Nasal Spray.
  • serious allergic reactions. Call your healthcare provider or get emergency medical care if you get any of the following signs of a serious allergic reaction:
    • rash
    • hives
    • swelling of your face, mouth, and tongue
    • breathing problems
  • weakened immune system and increased chance of getting infections (immunosuppression). Taking medicines that weaken your immune system makes you more likely to get infections and can make certain infections worse. These infections may include tuberculosis (TB), ocular herpes simplex infections, and infections caused by fungi, bacteria, viruses, and parasites. Avoid contact with people who have a contagious disease such as chickenpox or measles while using Fluticasone Propionate Nasal Spray. If you come in contact with someone who has chickenpox or measles call your healthcare provider right away.
  • Symptoms of an infection may include:
  • fever
  • pain
  • aches
  • chills
  • feeling tired
  • nausea
  • vomiting
  • lowered steroid hormone levels (adrenal insufficiency). Adrenal insufficiency happens when your adrenal glands do not make enough steroid hormones. This can happen when you stop taking oral corticosteroid medicines (such as prednisone) and start taking medicine containing an inhaled steroid (such as Fluticasone Propionate Nasal Spray). Symptoms of adrenal insufficiency may include:
    • feeling tired
    • lack of energy
    • weakness
    • nausea and vomiting
    • low blood pressure
  • slowed growth in children. A child’s growth should be checked often.

The most common side effects of Fluticasone Propionate Nasal Spray include:

  • headache
  • sore throat
  • nose bleeds
  • nose burning or itching
  • nausea and vomiting
  • trouble breathing
  • cough

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

These are not all the side effects with Fluticasone Propionate Nasal Spray. Ask your healthcare provider or pharmacist for more information.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How do I store Fluticasone Propionate Nasal Spray?

  • Store Fluticasone Propionate between 39°F and 86°F (4°C and 30°C).

Keep Fluticasone Propionate Nasal Spray and all medicines out of the reach of children.

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

Medicines are sometimes prescribed for purposes not mentioned in a Patient Information leaflet. Do not use Fluticasone Propionate Nasal Spray for a condition for which it was not prescribed. Do not give your Fluticasone Propionate Nasal Spray to other people, even if they have the same condition that you have. It may harm them.

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

For more information about Fluticasone Propionate Nasal Spray, call 1-800-346-6854.

What are the ingredients in Fluticasone Propionate Nasal Spray?

Active ingredient: fluticasone propionate.

Inactive ingredients: microcrystalline cellulose, carboxymethylcellulose sodium, dextrose, 0.02% w/w benzalkonium chloride, polysorbate 80, and 0.25% w/w phenylethyl alcohol.

Instructions for Use

Fluticasone Propionate Nasal Spray

USP 50 mcg per spray

Fluticasone Propionate Nasal Spray is for use in your nose only.

Read this information before you start using your Fluticasone Propionate Nasal Spray.

Image FIGURE A Your Fluticasone Propionate Nasal Spray must be primed before you use it for the first time and when you have not used it for a week or more. How to prime your Fluticasone Propionate Nasal Spray • Shake the bottle gently and then remove the dust cover (See Figure A). • Hold the bottle as shown (See Figure B) with the nasal applicator pointing away from you and with your forefinger and middle finger on either side of the nasal applicator and your thumb underneath the bottle.
Image FIGURE B Press down and release 6 times until a fine spray appears (See Figure B). The pump is now ready for use.
Image FIGURE C Using your Fluticasone Propionate Nasal Spray: Step 1. Blow your nose to clear your nostrils Step 2. Close 1 nostril. Tilt your head forward slightly and, keeping the bottle upright, carefully insert the nasal applicator into the other nostril (See Figure C). Step 3. Start to breathe in through your nose, and while breathing in press firmly and quickly down 1 time on the applicator to release the spray. To get a full dose, use your forefinger and middle finger to spray while supporting the base of the bottle with your thumb. Avoid spraying in your eyes. Breathe in gently through the nostril. Step 4. Breathe out through your mouth. Step 5. If a second spray is required in that nostril, repeat steps 2 through 4. Step 6. Repeat steps 2 through 5 in the other nostril. Step 7. Wipe the nasal applicator with a clean tissue and replace the dust cover (See Figure D).
Image FIGURE D
Do not use this bottle for more than the labeled number of sprays even though the bottle is not completely empty. Before you throw the bottle away, you should talk to your healthcare provider to see if a refill is needed. Do not take extra doses or stop taking Fluticasone Propionate Nasal Spray without talking to your healthcare provider.

Cleaning your Fluticasone Propionate Nasal Spray:

Your nasal spray should be cleaned at least 1 time each week.

  1. Remove the dust cover and then gently pull upwards to free the nasal applicator.
  2. Wash the applicator and dust cover under warm tap water. Allow to dry at room temperature.
  3. Place the applicator and dust cover back on the bottle.
  4. If the nasal applicator becomes blocked, it can be removed and left to soak in warm water. Rinse the nasal applicator with cold tap water. Dry the nasal applicator and place it back on the bottle. Do not try to unblock the nasal applicator by inserting a pin or other sharp object.

Storing your Fluticasone Propionate Nasal Spray:

  • Store Fluticasone Propionate Nasal Spray between 39°F and 86°F (4°C and 30°C).
  • Do not use your Fluticasone Propionate Nasal Spray after the date shown as “EXP” on the label or box.

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

Manufactured For:

Wockhardt USA, LLC

Parsippany, NJ 07054

Manufactured By:

Morton Grove Pharmaceuticals, Inc.

Morton Grove, IL 60053

27264A REV. 03-16

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