Consumer medicine information

Dymista 125/50 Nasal Spray

Azelastine; Fluticasone propionate

BRAND INFORMATION

Brand name

Dymista 125/50

Active ingredient

Azelastine; Fluticasone propionate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Dymista 125/50 Nasal Spray.

SUMMARY CMI

DYMISTA® 125/50 Nasal Spray

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using DYMISTA 125/50 Nasal Spray?

DYMISTA 125/50 Nasal Spray contains the active ingredient azelastine (as hydrochloride) and fluticasone propionate. DYMISTA 125/50 Nasal Spray is used to relieve the symptoms of allergies, for example: symptoms relating to the nose - runny nose, sneezing, itchy or blocked nose and symptoms relating to the eyes - itchy, watery and red eyes.

For more information, see Section 1. Why am I using DYMISTA 125/50 Nasal Spray? in the full CMI.

2. What should I know before I use DYMISTA 125/50 Nasal Spray?

Do not use if you have ever had an allergic reaction to azelastine (as hydrochloride) or fluticasone propionate or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use DYMISTA 125/50 Nasal Spray? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with DYMISTA 125/50 Nasal Spray and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use DYMISTA 125/50 Nasal Spray?

  • Spray one spray into each nostril in the morning and evening. This medicine is not recommended for children under 12 years of age.

More instructions can be found in Section 4. How do I use DYMISTA 125/50 Nasal Spray? in the full CMI.

5. What should I know while using DYMISTA 125/50 Nasal Spray?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using DYMISTA 125/50 Nasal Spray.
  • DYMISTA 125/50 Nasal Spray is suitable for long term use. Continue using your medicine for as long as your doctor tells you to.
Things you should not do
  • If you miss a dose, do not use a double dose to make up for the dose that you missed.
Driving or using machines
  • DYMISTA 125/50 Nasal Spray is unlikely to make you feel drowsy. However, if you are drowsy, do not drive a car or operate machinery.
Looking after your medicine
  • Keep DYMISTA 125/50 Nasal Spray in a cool dry place where the temperature stays below 25°C.
  • Do not refrigerate or freeze this medicine.
  • Discard DYMISTA 125/50 Nasal Spray after 6 months of first opening the bottle.

For more information, see Section 5. What should I know while using DYMISTA 125/50 Nasal Spray? in the full CMI.

6. Are there any side effects?

There are a number of side effects associated with this medicine. It is important to be aware of them so that you can identify any symptoms if they occur (see the full CMI for more details). The most common and serious side effects are irritated nose (can cause mild stinging, itching or sneezing), a bitter or unpleasant taste in your mouth, unpleasant smell, cough, dry throat or throat irritation, sore throat, nose bleeds, nausea and headache.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

DYMISTA® 125/50 Nasal Spray

Active ingredient(s): azelastine (as hydrochloride)/fluticasone propionate


Consumer Medicine Information (CMI)

This leaflet provides important information about using DYMISTA. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using DYMISTA.

Where to find information in this leaflet:

1. Why am I using DYMISTA 125/50 Nasal Spray?
2. What should I know before I use DYMISTA 125/50 Nasal Spray?
3. What if I am taking other medicines?
4. How do I use DYMISTA 125/50 Nasal Spray?
5. What should I know while using DYMISTA 125/50 Nasal Spray?
6. Are there any side effects?
7. Product details

1. Why am I using DYMISTA 125/50 Nasal Spray?

DYMISTA 125/50 Nasal Spray is sprayed into the nose to treat allergic rhinitis (hayfever and other allergies) and rhinoconjunctivitis (allergy-induced symptoms in the nose and eyes) in adults and children 12 years and older where use of a combination (intranasal antihistamine and glucocorticoid) is appropriate.

DYMISTA 125/50 Nasal Spray relieves the symptoms of allergies, for example: symptoms relating to the nose - runny nose, sneezing, itchy or blocked nose and symptoms relating to the eyes - itchy, watery and red eyes.

Hayfever is an inflammation or swelling of the nose lining (which may cause blockage, runny nose, itching and/ or sneezing).

You may have symptoms only during spring or summer. This type of allergy is generally due to various pollens. Some people may experience symptoms all year round. This is usually caused by house dust mites, pets or moulds.

This medicine contains two active ingredients: azelastine hydrochloride and fluticasone propionate.

Azelastine hydrochloride belongs to a group of medicines called antihistamines. Antihistamines work by preventing the effects of substances such as histamine that the body produces as part of an allergic reaction. This reduces symptoms of an allergic rhinitis.

Fluticasone propionate belongs to a group of medicines called corticosteroids which are used to help reduce inflammation.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another purpose.

2. What should I know before I use DYMISTA 125/50 Nasal Spray?

Warnings

Do not use DYMISTA 125/50 Nasal Spray if:

  • you are allergic to azelastine hydrochloride or fluticasone propionate, or any of the ingredients listed at the end of this leaflet.
  • this medicine has expired or if the packaging is torn or shows signs of tampering.

Check with your doctor if you:

  • have any other medical conditions
    - Recent injury or surgery to your nose or mouth
    - Infection in your nose or sinus
    - Ulcer or open sores in your nose
    - Active or inactive tuberculosis
    - Severe liver disease
    - Increased/ high pressure in the eye (glaucoma) and/ or cataracts.
  • take any medicines for any other condition
  • have allergies to any other medicines, foods, preservatives or dyes

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

It is not known if DYMISTA 125/50 Nasal Spray passes into the breast milk and could affect your baby. Your doctor can discuss with you the benefits and risks involved with using this medicine while you are breast-feeding.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

In particular, tell your doctor if you are taking:

  • A medicine or medicines that depress the central nervous system. Concurrent use with DYMISTA 125/50 Nasal Spray may cause sleepiness or drowsiness.
  • Ritonavir, an antiviral medicine
  • Ketoconazole, an antifungal medicine
  • Cimetidine, a medicine that inhibits stomach acid production

Some medicines may interfere with DYMISTA 125/50 Nasal Spray and affect how it works.

These medicines may be affected by DYMISTA 125/50 Nasal Spray or may affect how well it works. You may need different amounts of your medicine, or you may need to use a different medicine. Your doctor or pharmacist will advise you.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect DYMISTA 125/50 Nasal Spray.

4. How do I use DYMISTA 125/50 Nasal Spray?

How much to use

Adults and children 12 years and older

  • One spray into each nostril in the morning and evening.

Children under 12 years

  • This medicine is not recommended for children under 12 years.

Continue using your medicine for as long as your doctor tells you to.

DYMISTA 125/50 Nasal Spray is suitable for long term use.

How to use with DYMISTA 125/50 Nasal Spray

Use only in your nose.

If you do not understand the instructions in this leaflet, ask your doctor or pharmacist for help.

Preparing the spray

  1. Gently blow your nose before using the medicine.
  2. Shake the bottle for 5 seconds and then remove the protective cap.
  3. The first time DYMISTA 125/50 Nasal Spray is used, prime the pump by squirting it into the air.
  4. Prime the pump by putting two fingers on either side of the spray pump and place your thumb on the bottom of the bottle.
  5. Press down and release the pump 6 times until a fine mist appears.
  6. The pump is now primed and ready to use.
  7. If the nasal spray has not been used for more than 7 days, you will need to prime the pump until a fine mist appears again.

Using the spray

  1. Blow your nose to clear your nostrils.
  2. Keep your head tilted downwards towards your toes. Do not tilt head backwards.
  3. Hold the bottle upright and carefully insert the spray tip into one nostril.
  4. Close other nostril with your finger, rapidly press down once and sniff gently at the same time.
  5. Breathe out through your mouth.
  6. Repeat in your other nostril.
  7. Breathe in gently, and do not tilt your head back after dosing. This will stop the medicine going into your throat and causing an unpleasant taste.
  8. After each use, wipe the spray tip with a clean tissue or cloth and then replace the protective cap.

If you forget to use DYMISTA 125/50 Nasal Spray

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose you missed.

Always use DYMISTA 125/50 Nasal Spray exactly as your doctor has told you.

If you use too much DYMISTA 125/50 Nasal Spray

If you think that you have used too much DYMISTA 125/50 Nasal Spray on one occasion, there is nothing to worry about.

However, if you use too much of it over a long time (months or years), you may start to get unwanted side effects inside your nose and body.

Discuss any worries you may have about this with your doctor or pharmacist.

You should immediately:

  • phone the Poisons Information Centre
    (Australia telephone 13 11 26) for advice, or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using DYMISTA 125/50 Nasal Spray?

Things you must do

If you become pregnant while you are using this medicine, tell your doctor.

Your doctor can discuss with you the risks of using it while you are pregnant.

Remind any doctor, dentist or pharmacist you visit that you are using DYMISTA 125/50 Nasal Spray.

Things you should not do

  • Do not give this medicine to anyone else, even if their symptoms seem to be the same as yours.
  • Do not use it to treat any other complaints unless your doctor tells you to.
  • Do not give this medicine to a child under the age of 12 years.
  • Do not exceed the recommended dose.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how DYMISTA 125/50 Nasal Spray affects you.

DYMISTA 125/50 Nasal Spray is unlikely to make you feel drowsy. However, if you are tired, drowsy, dizzy or light-headed, do not drive a car or operate machinery

Looking after your medicine

  • Keep DYMISTA 125/50 Nasal Spray in a cool dry place where the temperature stays below 25°C.
  • Do not refrigerate or freeze this medicine.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

Cleaning instructions

  1. Remove the clear dust cap. Gently grip the sides of the white plastic spray tip and pull upwards to lift the plastic spray away from the glass bottle.

  1. Wash the dust cap and plastic spray tip in warm tap water.

  1. If plastic spray tip is blocked do not try to unblock DYMISTA 125/50 Nasal Spray with a sharp object.
This can damage the nasal spray and stop you from getting the right dose of DYMISTA.

  1. Allow to dry completely.

  1. When dry, place the clear protective cap onto the plastic spray tip. Then carefully place the spray tip back onto the DYMISTA 125/50 Nasal Spray bottle and press down firmly.
  2. Re-prime the pump before using DYMISTA 125/50 Nasal Spray again.

When to discard your medicine

Discard after 6 months of first opening the bottle.

Do not use this medicine after the expiry date.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects with DYMISTA 125/50 Nasal Spray, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about these side effects.

Less serious side effects

Less serious side effectsWhat to do
  • irritated nose. This can cause mild stinging, itching or sneezing
  • a bitter or unpleasant taste in your mouth
  • unpleasant smell
  • cough, dry throat or throat irritation
  • sore throat
  • nose bleeds
  • nausea
  • headache
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • sleepiness or drowsiness
  • feeling weary, exhausted or weak
  • damage of the skin and mucous membrane in the nose
  • blurred vision or increased pressure in your eye.
  • sudden signs of allergy such as rash, itching or hives on the skin, swelling of the face, lips, tongue or other parts of the body, shortness of breath, wheezing or trouble breathing.
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What DYMISTA 125/50 Nasal Spray contains

Active ingredient
(main ingredient)
  • azelastine hydrochloride
  • fluticasone propionate
Other ingredients
(inactive ingredients)
  • glycerol
  • microcrystalline cellulose
  • carmellose sodium
  • phenethyl alcohol
  • disodium edetate
  • benzalkonium chloride
  • polysorbate 80
  • purified water.
Potential allergensAntimicrobial preservatives: Benzalkonium and phenethyl alcohol

Do not take this medicine if you are allergic to any of these ingredients.

What DYMISTA 125/50 Nasal Spray looks like

DYMISTA 125/50 Nasal Spray (AUST R 203131) is a white suspension.

This medicine comes in an amber coloured glass bottle fitted with a spray pump, applicator and a protective cap. Handle with care.

The 4 mL bottle contains 28 sprays. The 17 mL bottle contains 120 sprays.

Who distributes DYMISTA 125/50 Nasal Spray

Viatris Pty Ltd
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.viatris.com.au
Phone: 1800 274 276

This leaflet was prepared in November 2021.

DYMISTA® is a Viatris company trade mark

Dymista_cmi\Nov21/00

Published by MIMS March 2022

BRAND INFORMATION

Brand name

Dymista 125/50

Active ingredient

Azelastine; Fluticasone propionate

Schedule

S4

 

1 Name of Medicine

Azelastine (as hydrochloride) and fluticasone propionate.

2 Qualitative and Quantitative Composition

Dymista 125/50 nasal spray is a fixed combination product containing the following active ingredients: azelastine hydrochloride and fluticasone propionate. Each g of suspension contains 1 mg azelastine hydrochloride and 0.365 mg fluticasone propionate. One spray (137 mg) contains 125 microgram of azelastine (as the base) and 50 microgram of fluticasone propionate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Dymista 125/50.

A white, homogeneous and redispersible suspension.
It is available as a metered-spray suspension for intranasal administration.

4 Clinical Particulars

4.1 Therapeutic Indications

Symptomatic treatment of moderate to severe allergic rhinitis and rhino-conjunctivitis in adults and children 12 years and older where use of a combination (intranasal antihistamine and glucocorticoid) is appropriate.

4.2 Dose and Method of Administration

Duration of treatment.

Dymista 125/50 nasal spray is suitable for long-term use. There is no restriction regarding duration of use.

Dosage.

Adults and adolescents (e.g. 12 years and older).

One spray in each nostril twice daily (morning and evening).

Children below 12 years.

Dymista 125/50 nasal spray is not recommended for use in children below 12 years of age as safety and efficacy has not been established in this age group.

Elderly.

No dose adjustment is required in this population (see Section 5.2 Pharmacokinetic Properties, Special populations, Age; Section 4.4 Special Warnings and Precautions for Use, Use in the elderly).

Renal and hepatic impairment.

No dose adjustment is required in patients with renal impairment or mild to moderate hepatic impairment (see Section 5.2 Pharmacokinetic Properties, Special populations, Renal impairment; Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment).
Caution is required when treating patients with severe hepatic impairment (see Section 5.2 Pharmacokinetic Properties, Special populations, Hepatic impairment; Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment).

Method of administration.

Dymista 125/50 nasal spray is for administration by the nasal route only.

Preparing the spray.

Shake the bottle gently before each use for about 5 seconds. Then, remove the protective cap.
Prior to first use, Dymista 125/50 nasal spray must be primed by pressing down and releasing the pump 6 times until a fine mist appears. If Dymista 125/50 nasal spray has not been used for more than 7 days, reprime by pressing down and releasing the pump a number of times until a fine mist is produced.

Using the spray.

After blowing the nose, spray the suspension once into each nostril keeping the head tilted downward. After each use, wipe the spray tip and replace the protective cap.

4.3 Contraindications

Hypersensitivity to the active substance(s) or to any of the excipients.

4.4 Special Warnings and Precautions for Use

Somnolence.

In clinical studies, the occurrence of somnolence has been reported in some patients taking Dymista 125/50 (see Section 4.8 Adverse Effects (Undesirable Effects)). The overall incidence of somnolence was much lower than that reported for oral antihistamines. Even so, patients should be cautioned against engaging in hazardous occupations requiring complete mental alertness and motor coordination such as operating machinery or driving a motor vehicle after administration of Dymista 125/50 until they know how they react to the nasal spray. When administered orally in combination, azelastine hydrochloride 4.4 mg tablets and alcohol showed sedative effects. As no specific information is available with the nasal spray, caution is required if Dymista 125/50 is used concomitantly with alcohol or other CNS depressants (see Section 4.7 Effects on Ability to Drive and Use Machines; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Central nervous system depressants).

Local effects.

Instances of nasal ulceration and nasal septal perforation have been reported in patients following the intranasal application of corticosteroids. There were no instances of nasal ulceration or nasal septal perforation observed in clinical studies with Dymista 125/50.
Because of the inhibitory effect of corticosteroids on wound healing, patients who have experienced recent nasal ulcers, surgical operation or injury to the nose or mouth should not use Dymista 125/50 until healing has occurred.
Local infections of the nasal airways should be appropriately treated but do not constitute a specific contraindication to treatment with Dymista 125/50. Candidiasis of the throat can occur in patients treated with intranasal steroids. Special care should be taken when treating patients who may be susceptible to candida infections (e.g. diabetics).

Visual disturbance.

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision, increased intra-ocular pressure or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts.

Hypothalamic-pituitary-adrenal (HPA) axis effects.

Intranasal steroid products are designed to deliver drug directly to the nasal mucosa in order to minimise overall systemic glucocorticoid exposure and side effects. Systemic effects such as HPA axis suppression, reduction of bone density and retardation of growth rate in children may occur with intranasal steroids, particularly at high doses prescribed for prolonged periods of time. If there is evidence for higher than recommended doses being used, then additional systemic corticosteroid cover should be considered during periods of stress or elective surgery.
The lowest dose of fluticasone propionate nasal spray that causes suppression of the HPA axis or effects on bone mineral density or growth retardation has not yet been established. However, the systemic bioavailability of fluticasone propionate is low (estimated at 1.26% using high doses), when given as fluticasone propionate nasal spray, and this limits the potential for such systemic side effects. Measurement of serum cortisol and 24 hour urinary cortisol in the clinical studies in adults did not suggest any HPA axis suppression with recommended doses. Studies of effects on the HPA axis in children have not been conducted.
Care must be taken while transferring patients from systemic steroid treatment to Dymista 125/50 if there is any reason to suppose that their adrenal function is impaired.

Respiratory conditions.

In patients who have tuberculosis or untreated infections of the respiratory tract, the possible benefits of the treatment with Dymista 125/50 should be weighed against possible risk.

Use of cytochrome P450 3A4 inhibitors.

Care should be taken when co-administering known, strong CYP3A4 inhibitors, e.g. ritonavir and ketoconazole, as there is potential for increased systemic exposure to fluticasone propionate (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 5.2 Pharmacokinetic Properties, Metabolism).

Effect on growth.

Retardation of growth rate in children may occur with intranasal steroids, particularly at high doses prescribed for prolonged periods of time (see Section 4.4 Special Warnings and Precautions for Use, Paediatric use).

Use in hepatic impairment.

See Section 5.2 Pharmacokinetic Properties, Special populations, Hepatic impairment.

Use in renal impairment.

See Section 5.2 Pharmacokinetic Properties, Special populations, Renal impairment.

Use in the elderly.

See Section 5.2 Pharmacokinetic Properties, Special populations, Age.

Paediatric use.

Safety and effectiveness of Dymista 125/50 in pediatric patients below the age of 12 years have not been established.
Retardation of growth rate in children may occur with intranasal steroids, particularly at high doses prescribed for prolonged periods of time (see Section 4.4 Special Warnings and Precautions for Use, Effect on growth).

Effects on laboratory tests.

No effects are known.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No formal drug interaction studies have been performed with Dymista 125/50. The drug interactions of Dymista 125/50 are expected to reflect those of the individual components as described below.

Central nervous system depressants.

When administered orally in combination, azelastine hydrochloride 4.4 mg tablets and alcohol showed sedative effects. As no specific information is available with the nasal spray, caution is required if Dymista 125/50 is used concomitantly with alcohol or other CNS depressants (see Section 4.4 Special Warnings and Precautions for Use, Somnolence; Section 4.7 Effects on Ability to Drive and Use Machines).

Cytochrome P450 inhibitors.

Under normal circumstances, very low plasma concentrations of fluticasone propionate are achieved after intranasal dosing, due to extensive first pass metabolism and high systemic clearance mediated by cytochrome P450 3A4 in the gut and liver. Hence, clinically significant drug interactions mediated by fluticasone propionate are unlikely.
Co-treatment with CYP3A4 inhibitors, including cobicistat-containing products is expected to increase the risk of systemic side effects. The combination should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid side-effects, in which case patients should be monitored for systemic corticosteroid side-effects.

Ritonavir.

A drug interaction study in healthy subjects has shown that ritonavir (a highly potent cytochrome P450 3A4 inhibitor) can greatly increase fluticasone propionate plasma concentrations, resulting in markedly reduced serum cortisol concentrations. During postmarketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing's syndrome and adrenal suppression. Therefore, concomitant use of fluticasone propionate and ritonavir should be avoided, unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.

Ketoconazole.

Studies have shown that other inhibitors of cytochrome P450 3A4 produce negligible (erythromycin) and minor (ketoconazole) increases in systemic exposure to fluticasone propionate without notable reductions in serum cortisol concentrations. Nevertheless, care is advised when co-administering potent cytochrome P450 3A4 inhibitors (e.g. ketoconazole), as there is potential for increased systemic exposure to fluticasone propionate (see Section 5.2 Pharmacokinetic Properties, Metabolism; Section 4.4 Special Warnings and Precautions for Use, Use of cytochrome P450 3A4 inhibitors).

Cimetidine.

After oral administration of 4.4 mg azelastine hydrochloride twice daily, cimetidine has been shown to increase the plasma levels of azelastine. This is thought to be due to cimetidine inhibiting the metabolism of azelastine by interacting with the hepatic cytochrome P450 system. No interaction was seen following co-medication with ranitidine.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No studies on impairment of fertility were conducted with Dymista 125/50. However, non-clinical studies are available for the individual active component, azelastine.
In male and female rats, azelastine at oral doses of 30 mg/kg/day and greater (resulting in plasma levels which were at least about 400 times above the plasma levels at the recommended therapeutic intranasal dose) caused a decrease in the fertility index, but in long-term toxicity studies up to 2 years there were no drug related alterations in reproductive organs either in males or in females in this species. A clinical study in 21 healthy human females using an intranasal dose of 1.12 mg/day found no effect on ovulation or sexual hormone pattern.
(Category B3)
There is no or insufficient evidence of safety of Dymista 125/50, azelastine or fluticasone propionate in human pregnancy. No studies on the effect on embryofetal development have been conducted with azelastine/ fluticasone combination. Animal reproductive studies of azelastine and fluticasone propionate in mice and rats revealed evidence of teratogenicity as well as other developmental toxic effects. However, equivalent effects have not been reported when these individual compounds have been given to humans during pregnancy. Direct intranasal application ensures minimal systemic exposure. As with other medicines, the use of Dymista 125/50 during pregnancy should only be considered if the expected benefit to the mother is greater than any possible risk to the foetus.
In pregnant rats there was evidence of significant diaplacental transfer of the drug to the foetuses. Azelastine was embryolethal and teratogenic in mice at oral doses greater than 30 mg/kg/day. In rats, azelastine was embryo-toxic at oral doses greater than 3 mg/kg/day, and teratogenicity and embryolethality were seen at doses greater than 30 mg/kg/day. In rabbits, azelastine was teratogenic at oral doses greater than 20 mg/kg/day. In pregnant rats, azelastine demonstrated no peri/ postnatal toxicity at oral doses up to 30 mg/kg/day.
In rats, the no effect doses resulted in plasma levels which were at least about 25 times above the plasma levels at the recommended therapeutic intranasal dose in humans. (The calculation of the safety factor is based on plasma levels derived from oral subchronic toxicity studies).
Reproductive toxicity studies with fluticasone propionate in mice and rats have shown the expected foetotoxic and teratogenic effects at subcutaneous doses of 100 to 150 microgram/kg/day and above. As with previous compounds of this class, these effects are unlikely to be relevant to human therapy.
It is not known whether Dymista 125/50 is excreted in human breast milk. Because many drugs are excreted in human milk, caution should be exercised when Dymista 125/50 is administered to a nursing woman. Since there are no data from well controlled human studies on the use of Dymista 125/50 by nursing mothers, based on data from the individual components, a decision should be made whether to discontinue nursing or to discontinue Dymista 125/50, taking into account the importance of Dymista 125/50 to the mother. No studies in lactating animals have been conducted with the combination azelastine/ fluticasone.
It is not known if azelastine is excreted in human milk.
The excretion of fluticasone propionate into human breast milk has not been investigated. Subcutaneous administration of tritiated drug to lactating rats resulted in measurable radioactivity in both plasma and milk (levels in milk were 3-7 times plasma levels) 1-8 hours post-dosing. However plasma levels in patients following intranasal application of fluticasone propionate at recommended doses are low and the amount of fluticasone ingested by the newborn is estimated to be very small as a consequence of very low maternal plasma concentration.

4.7 Effects on Ability to Drive and Use Machines

Due to the potential occurrence of somnolence (see Section 4.4 Special Warnings and Precautions for Use, Somnolence), patients using Dymista 125/50 should be cautioned against engaging in hazardous occupations requiring complete mental alertness and motor coordination such as driving or operating machinery after administration of Dymista 125/50 until they know how they react to the nasal spray.
Caution is required if Dymista 125/50 is used concomitantly with alcohol or other CNS depressants (see Section 4.4 Special Warnings and Precautions for Use, Somnolence; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Central nervous system depressants).

4.8 Adverse Effects (Undesirable Effects)

In the 4 placebo controlled studies (MP4001, MP4002, MP4004 and MP4006), 1006 patients were treated with Dymista 125/50, 1012 with placebo, 851 with azelastine (AZE) in Dymista 125/50 vehicle, 846 with fluticasone propionate (FLU) in Dymista 125/50 vehicle, 152 with Astelin Nasal Spray (marketed AZE), and 153 with fluticasone propionate from Roxanne Laboratories Inc. (marketed FLU). The mean duration of exposure to each of these products was about 14 days. There were no relevant differences between the treatment groups in the overall rate of premature discontinuations and also the primary reason for discontinuation.
Across all treatment groups, the percentage of subjects with any AEs was low and majority of AEs were mild in nature. The most frequently reported adverse events (AEs) were dysgeusia, epistaxis and headache. However, headache and especially epistaxis were also frequently reported under placebo. Commonly, dysgeusia, a substance-specific unpleasant taste, may be experienced after administration (often due to incorrect method of application, namely tilting the head too far backwards during administration).
Treatment emergent adverse events reported with an incidence of ≥ 1% in the Dymista 125/50 treated group, in the 4 pivotal studies, are shown in Table 1.
Table 2 listed possible adverse reactions for Dymista 125/50, with frequencies corresponding to: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), not known (cannot be estimated from the available data).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

With the nasal route of administration, overdose reactions are not anticipated.
Dymista 125/50 nasal spray contains both azelastine and fluticasone propionate; therefore, the risks associated with overdosage for the individual components apply to Dymista 125/50.
With the nasal route of administration, overdosage reactions to azelastine are not anticipated. To date, there has been only one report of incorrect usage: a 2 year old boy drank approximately 10 mL of azelastine nasal spray. This led to a burning sensation in the nose and mouth and to spontaneous vomiting, these events lasting 5-10 minutes. Pulse rate, blood pressure and respiration were normal and stable, and a normal pupil reaction was found. No tissue damage in the mouth or throat occurred. The boy recovered completely.
In the event of overdosage after accidental oral uptake, disturbances of the central nervous system (including drowsiness, confusion, coma, tachycardia and hypotension) are to be expected based on the results of animal experiments. Symptomatic and supportive treatment should be instigated as there is no known antidote.
There are no data available on the effects of acute or chronic overdosage with fluticasone propionate nasal spray. Intranasal administration of 2,400 microgram fluticasone per day (i.e. 12 times the recommended dose) for four days to healthy human volunteers caused a small degree of suppression of adrenal steroid production.
Suppression of adrenal steroid production may give rise to typical signs and symptoms of Cushing's disease, such as buffalo hump, puffiness of face, hypertension and elevated blood glucose. If such a condition were to occur, care should be taken to wean the patient slowly off the steroid due to the probability of adrenal impairment. Recovery from impaired adrenocortical function caused by prolonged steroid therapy is usually slow and has been known to last up to 12 months.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Pharmacotherapeutic group: decongestants and other nasal preparations for topical use, corticosteroids/ fluticasone, combinations, ATC code: R01AD58.
Dymista 125/50 is a novel formulation of azelastine hydrochloride and fluticasone propionate. Therefore, the mechanisms of actions described below for the individual components apply to Dymista 125/50.
Azelastine hydrochloride, a phthalazinone derivative, is classified as a potent long-acting anti-allergic compound with selective H1-antagonist, mast cell stabilizing and anti-inflammatory properties. Data from in vivo (preclinical) and in vitro studies show that azelastine inhibits the synthesis or release of the chemical mediators known to be involved in early and late stage allergic reactions, e.g. leukotrienes, histamine, platelet-activating factor (PAF) and serotonin. The major metabolite, desmethylazelastine, also exhibits H1-receptor antagonist activity. Dymista 125/50 is administered as a racemic mixture. The racemate, R- and S-enantiomers were equally potent at inhibiting eyelid histamine-induced oedema in rats, however the R-enantiomer was 2-fold less active at inhibiting eyeball histamine-induced oedema.
Azelastine nasal spray has a faster onset of action than orally administered antihistamines and nasally administered corticosteroids. A relief of nasal allergic symptoms is observed within 15 minutes after administration. Fluticasone propionate has potent anti-inflammatory activity but when used topically on the nasal mucosa at recommended doses has little or no detectable systemic activity.

Clinical trials.

The efficacy of Dymista 125/50 was established in four randomised, double-blind, placebo-controlled studies in subjects with seasonal allergic rhinitis (SAR), namely MP4001, MP4002, MP4004, and MP4006. One further study (3311) was performed to assess the onset of action of Dymista 125/50 using a standardised Environmental Exposure Chamber (EEC) model.
Study MP4001 compared Dymista 125/50 with commercial azelastine nasal spray (Astelin Nasal Spray) and commercial fluticasone propionate nasal spray from Roxane Laboratories Inc available in the US at that time. Studies MP4002, MP4004, and MP4006 compared Dymista 125/50 with the single compounds in the Dymista 125/50 vehicle. All 4 trials had in common 4 treatment groups, the same regimen (1 spray per nostril twice daily), the same duration of treatment (2 weeks), and the same primary and almost the same secondary endpoints. These studies included male and female subjects 12 years of age or older with a minimum 2-year history of SAR.
During the study, nasal symptoms of itchy nose, nasal congestion, runny nose, sneezing, and ocular symptoms of itchy eyes, watery eyes, and eye redness were rated twice daily in a diary, using a 4-point scale from 0 (no symptoms) to 3 (severe symptoms). The scores were summed up to a total nasal symptom score (TNSS) and a total ocular symptom score (TOSS), respectively. In addition, postnasal drip was rated on the same 4-point scale. The Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) was completed by each subject 18 years of age or older, at the start and end of 14-day treatment (or early termination).
The primary efficacy endpoint for all four placebo-controlled studies was the change from baseline in the combined (i.e. AM and PM data added) 12-hour reflective total nasal symptom score (crTNSS) over the 14 day treatment period, tested primarily in the ITT set based on last observation. Secondary efficacy endpoints included the 12-hour AM and PM reflective TNSS, the instantaneous TNSS (iTNSS), the 12-hour reflective score for postnasal drip, the 12-hour reflective TOSS, the instantaneous TOSS, the 12-hour reflective and instantaneous individual nasal and ocular symptoms and the RQLQ score. In studies MP4002, MP4004 and MP4006, an attempt was made to evaluate the onset of action.
The pooled study population was primarily female (62.9%), white (80.3%) and between 18 and 65 years of age (87.3%).
Table 3 shows the primary efficacy results for the individual pivotal studies expressed as absolute change in crTNSS compared with placebo and all active treatments. Across the individual studies, Dymista 125/50 was significantly superior to placebo and the monotherapy components. In addition, each individual component was significantly superior to placebo.
Data from studies MP4004 and MP4006 indicate that the onset of clinically relevant action for Dymista 125/50 occurs within 30 minutes after first application of the combination. In the meta-analysis that pooled data from the 4 efficacy studies, Dymista 125/50 was shown to be statistically significantly superior to both azelastine and fluticasone monoproducts and all active treatments were statistically significantly superior to placebo for almost all secondary efficacy variables including the reflective TNSS confined to daytime (denominated as 12 hr PM) or night time (12 hr AM), the instantaneous TNSS, the reflective TOSS, postnasal drip, and all individual nasal and ocular symptom scores (all p < 0.05) except the comparison Dymista 125/50 with azelastine for eye redness (p = 0.0513). Dymista 125/50 at least doubled the effect of azelastine and fluticasone propionate in reducing nasal and ocular symptoms score.
The RQLQ score for Dymista 125/50 was significantly improved over placebo for overall score and for each individual RQLQ domain in each individual study and in the meta-analysis. Across all studies and in the meta-analysis, the treatment difference in overall score between Dymista 125/50 and placebo exceeded the minimum clinically significant difference of -0.50.
Dymista 125/50 provided substantial allergic rhinitis symptom relief (50% reduction in crTNSS) at least 3 days faster than azelastine and 6 days faster than fluticasone propionate nasal spray. The superior effect of Dymista 125/50 to fluticasone propionate nasal spray was maintained throughout a one year study in patients with chronic persistent allergic rhinitis and nonallergic/ vasomotor rhinitis.
In an Environmental Exposure Chamber (EEC) study (3311) relief of allergic rhinitis symptoms was observed from 5 minutes after first dose of Dymista 125/50 for nasal (TNSS) and 10 minutes for ocular symptoms (TOSS) (p < 0.05).

5.2 Pharmacokinetic Properties

Two pharmacokinetic studies demonstrated that simultaneous intranasal administration of azelastine hydrochloride and fluticasone propionate with Dymista 125/50 does not result in altered systemic absorption of either agent.

Absorption.

After intranasal administration of two sprays per nostril (500 microgram of azelastine and 200 microgram of fluticasone propionate) of Dymista 125/50 nasal spray, the mean (± standard deviation) peak plasma exposure (Cmax) was 194.5 ± 74.4 picogram/mL for azelastine and 10.3 ± 3.9 picogram/mL for fluticasone and the mean total exposure (AUC) was 4217 ± 2618 picogram/mL.hr for azelastine and 97.7 ± 43.1 picogram/mL.hr for fluticasone. The median time to peak exposure (Tmax) from a single dose was 0.5 hours for azelastine and 1.0 hours for fluticasone.
After intranasal administration, the systemic bioavailability of azelastine hydrochloride is approximately 40%. The absolute bioavailability of intranasal fluticasone at high doses (2,400 microgram/day, i.e. 12 times the recommended dose) is estimated as 1.26% (90% CI 0.85, 1.86).

Distribution.

After oral and intravenous administration of azelastine, the mean volume of distribution was 14.5 L/kg. In vitro studies with human plasma indicate that the plasma protein binding of azelastine and desmethylazelastine are approximately 88% and 97%, respectively.
Fluticasone propionate has a large volume of distribution at steady state (approximately 318 L). Plasma protein binding is 91%.

Metabolism.

Azelastine is extensively metabolised, desmethylazelastine being the principal metabolite. No specific isoform of cytochrome P450 was found to be specific in the metabolism of azelastine at low concentrations (6-30 nanogram/mL) in human liver microsomes.
Fluticasone propionate is cleared rapidly from the systemic circulation, principally by hepatic metabolism to an inactive carboxylic acid metabolite, by the cytochrome P450 enzyme CYP3A4. Swallowed fluticasone propionate is also subject to extensive first pass metabolism. Care should be taken when co-administering potent CYP3A4 inhibitors such as ketoconazole and ritonavir as there is potential for increased systemic exposure to fluticasone propionate (see Section 4.4 Special Warnings and Precautions for Use, Use of cytochrome P450 3A4 inhibitors; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Excretion.

Plasma elimination half-lives after a single dose of azelastine are 22 hours for azelastine and 56 hours for the therapeutically active metabolite N-desmethyl azelastine. Up to 74% of radiolabelled oral or intravenous dose is excreted in faeces and 26% in urine. Thirteen percent is excreted in urine as unchanged azelastine.
The elimination rate of intravenous administered fluticasone propionate is linear over the 250-1000 microgram dose range and is characterised by a high plasma clearance (CL = 1.1 L/min). Peak plasma concentrations are reduced by approximately 98% within 3-4 hours and only low plasma concentrations were associated with the 7.8 h terminal half-life. The renal clearance of fluticasone propionate is negligible (< 0.2%) and less than 5% as the carboxylic acid metabolite. The major route of elimination is the excretion of fluticasone propionate and its metabolites in the bile.

Special populations.

Dymista 125/50 was not studied in any special populations, and no gender specific pharmacokinetic data have been obtained. The following information is available for the individual active components, azelastine and fluticasone propionate.

Hepatic impairment.

No significant difference was found in t1/2, Cmax or AUC in an oral single dose study of azelastine in 6 patients with hepatic impairment compared to normal subjects. Caution is warranted in extrapolating these data to long-term use (see Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment).
Dymista 125/50 undergoes extensive first-pass metabolism and high systemic clearance mediated by cytochrome P450 3A4 in the gut and liver, therefore the systemic exposure of intranasal fluticasone propionate in patients with severe liver disease is likely to be increased. This may result in a higher frequency of systemic adverse events. Caution is advised when treating these patients (see Section 5.2 Pharmacokinetic Properties, Metabolism; Section 4.4 Special Warnings and Precautions for Use, Use of cytochrome P450 3A4 inhibitors; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Renal impairment.

In a single oral dose study of azelastine in 9 patients, renal insufficiency (creatinine clearance < 50 mL/min) resulted in a 70-75% higher Cmax and AUC compared to normal subjects. However, the number of patients evaluated in this study is too small to draw meaningful conclusions. No information regarding the use of azelastine nasal spray in renally impaired patients is available (see Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment).

Age.

A pharmacokinetic study in elderly patients (n = 15) receiving oral azelastine 4.4 mg twice daily found a prolongation of the Tmax and an increase in Cmax and AUC compared to results in healthy volunteers. There have been no specific studies in the elderly with the nasal spray. In clinical and post-marketing studies of the nasal spray, no increase in the incidence of adverse reactions has been seen in elderly patients.
The efficacy and safety of Dymista 125/50 in children under 12 years of age have not been established (see Section 4.4 Special Warnings and Precautions for Use, Paediatric use).

Race.

The effect of race has not been evaluated.

5.3 Preclinical Safety Data

Genotoxicity.

No studies of genotoxicity were conducted with Dymista 125/50. However, studies are available for the individual active components, azelastine and fluticasone propionate.
Azelastine demonstrated no genotoxic potential in standard assays for gene mutations, chromosomal damage and DNA damage.
Fluticasone propionate has no mutagenic effect in vivo or in vitro. There was no evidence of a mutagenic potential in a standard battery of mutagenicity assays.

Carcinogenicity.

No studies of carcinogenicity were conducted with Dymista 125/50; however, studies are available for the individual active components, azelastine and fluticasone propionate.
Azelastine demonstrated no carcinogenic potential in mice and rats at dietary doses up to 25 and 30 mg/kg/day, respectively.
No evidence of a tumorigenic effect was observed in either a 2 year study in rats receiving doses of fluticasone propionate up to 57 microgram/kg/day by inhalation or in an 18 month study in mice receiving oral doses of fluticasone propionate up to 1 mg/kg/day.

6 Pharmaceutical Particulars

6.1 List of Excipients

Dymista 125/50 nasal spray contains the following inactive ingredients: disodium edetate, glycerol, microcrystalline cellulose, carmellose sodium, polysorbate 80, benzalkonium chloride, phenethyl alcohol, purified water.
Dymista 125/50 contains the antimicrobial preservatives benzalkonium chloride and phenethyl alcohol.

6.2 Incompatibilities

See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C. Do not refrigerate. Do not freeze. Discard after 6 months of first opening the bottle.
Dymista 125/50 nasal spray should be kept out of reach of children.

6.5 Nature and Contents of Container

Dymista 125/50.

Container type: amber glass (type I) bottle fitted with a metered-dose spray pump unit. The spray pump unit consists of a nasal spray pump with a white nasal adapter and clear plastic dust cap.
Pack sizes: 4 mL bottle containing 28 sprays;
4 mL bottle containing 28 sprays (starter pack); and
17 mL bottle containing 120 sprays.
Some pack sizes may not be marketed.

Australian register of therapeutic goods (ARTG).

AUST R 203131 - Dymista 125/50 azelastine (as hydrochloride) 125 microgram and fluticasone propionate 50 microgram nasal spray bottle.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking it to your local pharmacy.

6.7 Physicochemical Properties

Dymista 125/50 nasal spray has a pH of 5.5 - 6.5.

Chemical structure.

Azelastine hydrochloride.


Chemical name: (R,S)-4[(4-chlorophenyl) methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl) -phthalazin-1(2H)-one hydrochloride.
Molecular formula: C22H24ClN3O.HCl.
Molecular weight: 418.37 g mol-1.
Azelastine hydrochloride occurs as a white, odourless, crystalline powder with a bitter taste. It is sparingly soluble in water, and soluble in ethanol and dichloromethane. Azelastine hydrochloride is slightly hygroscopic.

Fluticasone propionate.


Chemical name: 6α,9-difluoro-17-[[(fluoromethyl) sulphanyl]carbonyl] -11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-dien-17α-yl propanoate.
Molecular formula: C25H31F3O5S.
Molecular weight: 500.6 g mol-1.
Fluticasone propionate is a white or almost white powder. It is practically insoluble in water, sparingly soluble in dichloromethane and slightly soluble in alcohol.

CAS number.

Azelastine hydrochloride.

79307-93-0.

Fluticasone propionate.

80474-14-2.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Only Medicine).

Summary Table of Changes