Azelastine Hydrochloride/ Fluticasone Propionate

Registered South African indications:

• Seasonal and perennial allergic rhinitis (including hay fever) and rhino-conjunctivitis in adults if the use of either intranasal antihistamine or corticosteroid alone is not sufficient
• Short term treatment of seasonal allergic rhinitis in children above the age of 6 years if the use of either intranasal antihistamine or corticosteroid alone is not sufficient

Contraindications

Registered contraindications in South Africa & other jurisdictions

• Hypersensitivity to the active ingredients or any of the excipients in this combination product

Cautions

South African recommendations

Caution in the following patient groups

• Pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment

Somnolence

• Somnolence has been reported in some patients using azelastine hydrochloride/ fluticasone propionate in clinical trials
• Patients should be cautioned against engaging in hazardous activities requiring complete mental alertness and motor coordination, such as operating machinery or driving, after administration
• Concurrent use with alcohol or other central nervous system depressants should be avoided due to the risk of further reductions in alertness and central nervous system impairment

Local nasal effects

• Epistaxis was observed more frequently in patients treated with azelastine hydrochloride/ fluticasone propionate than in those who received a placebo
• Nasal ulceration and nasal septal perforation have been reported with intranasal corticosteroids, though no such cases were observed in clinical trials with azelastine hydrochloride/ fluticasone propionate
• Due to the inhibitory effect of corticosteroids on wound healing, patients with recent nasal ulcers, nasal surgery, or nasal trauma should avoid using azelastine hydrochloride/ fluticasone propionate until healing has occurred
• Localised infections of the nose and pharynx with Candida albicans have been reported with intranasal fluticasone propionate. If such an infection develops, appropriate local therapy may be required, and treatment with azelastine hydrochloride/ fluticasone propionate should be discontinued
• Patients using azelastine hydrochloride/ fluticasone propionate over several months or longer should undergo periodic examinations for evidence of Candida infection or other nasal mucosa adverse effects

Glaucoma and cataracts

• Nasal and inhaled corticosteroids may lead to the development of glaucoma and/or cataracts
• Close monitoring is recommended for patients with vision changes or a history of increased intraocular pressure, glaucoma, or cataracts
• In a clinical study of adolescent and adult patients with perennial allergic or vasomotor rhinitis, one patient in the azelastine hydrochloride/ fluticasone propionate group had increased intraocular pressure at six months
• Posterior subcapsular cataracts were observed in:
  • Three patients in the azelastine hydrochloride/ fluticasone propionate group at six months and one patient at 12 months (end of treatment)
  • Three patients in the fluticasone propionate group at 12 months (end of treatment)

Immunosuppression

• Patients using immunosuppressive medicines such as corticosteroids are more susceptible to infections
• Chickenpox and measles can be more severe or even fatal in susceptible individuals using corticosteroids
• Children or adults who have not had these diseases or been properly immunised should take extra precautions to avoid exposure
• The dose, route, and duration of corticosteroid administration affecting the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known
• If exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated
• If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated
• If chickenpox develops, antiviral treatment may be indicated
• Corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculous infections of the respiratory tract, untreated fungal or bacterial infections, systemic viral or parasitic infections, or ocular herpes simplex due to the risk of worsening infections

Hypothalamic-Pituitary-Adrenal (HPA) axis effects

• Higher-than-recommended doses or use in susceptible individuals may result in systemic corticosteroid effects such as hypercorticism and adrenal suppression
• If these effects occur, azelastine hydrochloride/ fluticasone propionate should be discontinued gradually, following accepted procedures for stopping oral corticosteroid therapy
• Concomitant use of intranasal and inhaled corticosteroids may increase the risk of signs or symptoms of hypercorticism and HPA axis suppression
• Replacing a systemic corticosteroid with a topical corticosteroid may be accompanied by signs of adrenal insufficiency and in addition some patients may experience symptoms of withdrawal, e.g., joint and/or muscular pain, lassitude, and depression
• Patients previously on prolonged systemic corticosteroid therapy and transferred to topical corticosteroids should be carefully
  monitored for acute adrenal insufficiency in response to stress
• Patients with asthma or other conditions requiring long-term systemic corticosteroid therapy should avoid rapid tapering, as this may exacerbate symptoms

Use of cytochrome P450 3A4 inhibitors

• Ritonavir and other strong CYP3A4 inhibitors can significantly increase fluticasone propionate exposure, leading to reduced serum cortisol concentrations
• Cases of clinically significant medicine interactions have been reported with fluticasone propionate and ritonavir, causing systemic corticosteroid effects such as Cushing’s syndrome and adrenal suppression
• Co-administration of azelastine hydrochloride/ fluticasone propionate and ritonavir is not recommended
• Use caution when co-administering azelastine hydrochloride/ fluticasone propionate with other potent CYP3A4 inhibitors, such as ketoconazole

Effect on growth

• Corticosteroids may cause growth retardation in paediatric patients
• Routine monitoring of growth is recommended in paediatric patients receiving azelastine hydrochloride/ fluticasone propionate

Benzalkonium chloride content

• Azelastine hydrochloride/ fluticasone propionate contains benzalkonium chloride, which may cause nasal irritation, swelling of the nasal mucosa, and bronchospasm, particularly with long-term use

Effects on ability to drive and use machines

• Azelastine hydrochloride/ fluticasone propionate has minor influence on the ability to drive and use machines
• In isolated cases fatigue, weariness, exhaustion, dizziness or weakness that may also be caused by the disease itself, may occur when using azelastine hydrochloride/ fluticasone propionate. In these cases, the ability to drive and use machines may be impaired. Alcohol may enhance this effect

Recommendations in other jurisdictions

Caution in the following patient groups

• Pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment

Treatment duration and medical advice

• Treatment should be stopped, or a doctor should be consulted if there is no improvement within 7 days
• If symptoms improve but are not adequately controlled within 7 days, the advice of a doctor or pharmacist should be sought
• This medicine should not be used continuously for more than 3 months without consulting a doctor

Precautions before use

• Medical advice should be sought before using this medicine in cases of:
  • Concomitant use of other corticosteroid products, such as tablets, creams, ointments, asthma medications, similar nasal sprays, or eye/nose drops
  • Fever or infection in the nasal passages or sinuses
  • Recent injury or surgery to the nose, or existing ulceration in the nose

Drug interactions

• Clinically significant interactions between fluticasone propionate and ritonavir have been reported, leading to systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression
• The concomitant use of fluticasone propionate and ritonavir should be avoided unless the potential benefit outweighs the risk of systemic corticosteroid side effects

Systemic corticosteroid effects

• Systemic effects of nasal corticosteroids may occur, particularly at high doses for prolonged periods, though they are less likely than with oral corticosteroids and may vary in individual patients and between different corticosteroid preparations
• Potential systemic effects include:
  • Cushing’s syndrome and Cushingoid features
  • Adrenal suppression
  • Growth retardation in children and adolescents
  • Cataract and glaucoma
  • Psychological or behavioural effects such as psychomotor hyperactivity, sleep disorders, anxiety, depression, or aggression, particularly in children

Use in liver disease

• Azelastine hydrochloride/ fluticasone propionate undergoes extensive first-pass metabolism, meaning systemic exposure to fluticasone propionate is likely to be increased in patients with severe liver disease
• This may result in a higher frequency of systemic adverse effects, so caution is advised

Adrenal suppression risk

• Treatment with higher than recommended doses of nasal corticosteroids may result in clinically significant adrenal suppression
• If higher than recommended doses are used, additional systemic corticosteroid cover should be considered during periods of stress or elective surgery

Dose considerations

• The dose should be reduced to the lowest effective dose that maintains symptom control
• Higher than recommended doses have not been tested for azelastine hydrochloride/ fluticasone propionate
• The total systemic burden of corticosteroids should be considered when other corticosteroid treatments are prescribed concurrently

Visual disturbances

• Visual disturbance may occur with systemic and topical corticosteroids
• If a patient experiences blurred vision or other visual disturbances, referral to an ophthalmologist is recommended to assess possible causes such as cataract, glaucoma, or central serous chorioretinopathy (CSCR)
• Close monitoring is warranted in patients with a history of increased ocular pressure, glaucoma, or cataracts

Transitioning from systemic steroids

• If adrenal function is impaired, caution is necessary when transferring patients from systemic steroid treatment to azelastine hydrochloride/ fluticasone propionate

Use in infections or post-surgery

• In patients with tuberculosis, untreated infections, or recent surgery or injury to the nose or mouth, the benefits of treatment should be weighed against the risks
• Nasal infections should be treated with antibacterial or antifungal therapy but do not constitute a contraindication to azelastine hydrochloride/ fluticasone propionate use

Excipients

• Azelastine hydrochloride/ fluticasone propionate contains benzalkonium chloride, which may cause nasal mucosal oedema with long-term use

Ability to drive and use machines

• Azelastine hydrochloride/ fluticasone propionate has minor influence on the ability to drive and use machines
• In isolated cases fatigue, weariness, exhaustion, dizziness or weakness that may also be caused by the disease itself, may occur when using this combination product. In these cases, the ability to drive and use machines may be impaired. Alcohol may enhance this effect

Forms avail. in SA and covered in this monograph: nas

South African registered indications and dosages

Seasonal and perennial allergic rhinitis (including hay fever) and rhino-conjunctivitis if the use of either intranasal antihistamine or corticosteroid alone is not sufficient

Azelastine Hydrochloride/ Fluticasone Propionate
137/50 (µg/actuation)

• Nasal (nas): One actuation in each nostril, twice daily (morning and evening); Treatment duration: Suitable for long-term use, should correspond to the period of allergenic exposure

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Regular use is essential for full therapeutic benefit

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Contact with the eyes should be avoided

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Method of administration
Azelastine hydrochloride/ fluticasone propionate spray is for nasal use only
The bottle should be shaken gently before use for about 5 seconds by tilting it upwards and downwards and the protective cap be removed afterwards. Prior to first use, the spray must be primed by pressing down and releasing the pump 6 times. If the spray has not been used for more than 7 days it must be reprimed once by pressing down and releasing the pump. After blowing the nose the suspension is to be sprayed once into each nostril keeping the head tilted downward. After use the spray tip is to be wiped and the protective cap to be replaced

Paed forms avail. in SA and covered in this monograph: nas

South African registered indications and dosages

Short-term treatment of seasonal allergic rhinitis if the use of either intranasal antihistamine or corticosteroid alone is not sufficient

Azelastine Hydrochloride/ Fluticasone Propionate
137/50 (µg/actuation)

Younger than 6 years

• Not established for use

6 years and older

• See adult dosage

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Azelastine hydrochloride/ fluticasone propionate is not recommended for use in children below 6 years of age as safety and efficacy has not been established in this age group

Pregnancy

South African recommendations

• Caution
• There are no or limited amount of data from the use of azelastine hydrochloride and fluticasone propionate in pregnant women. There are no adequate and well-controlled clinical trials of this combination, or azelastine hydrochloride or fluticasone propionate only in pregnant women
• Animal reproductive studies of azelastine hydrochloride and fluticasone propionate in mice, rats, and/or rabbits revealed evidence of teratogenicity as well as other developmental toxic effects
• Azelastine hydrochloride:
  Azelastine hydrochloride has shown teratogenic effects in experimental animals, such as mice, rats and rabbits. Effects such as embryo-foetal death, malformations (cleft palate; short or absent tail; fused, absent or branched ribs), delayed ossification, and decreased foetal weight and maternal toxicity occurred in mice
  In rats, azelastine hydrochloride caused malformations (oligo- and brachydactylia), delayed ossification and skeletal variations, in the absence of maternal toxicity. Azelastine hydrochloride also caused embryo-foetal death and decreased foetal weight at higher doses. This also caused severe maternal toxicity. In rabbits, azelastine hydrochloride caused abortion, delayed ossification, and decreased foetal weight and also resulted in severe maternal toxicity
• Fluticasone propionate:
  Fluticasone propionate has also shown teratogenic effects. Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. In the rabbit, foetal weight reduction, skeletal variations, omphalocele and cleft palate were observed
  Nonteratogenic Effects: Fluticasone propionate crossed the placenta following oral administration of approximately 4 and 25 times the MRHDID (Maximum Recommended Human Daily Inhalation Dose) in adult rats and rabbits

Recommendations in other jurisdictions

• Caution
• There are no or limited amount of data from the use of azelastine hydrochloride and fluticasone propionate in pregnant women. Therefore, azelastine hydrochloride/ fluticasone propionate should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus
• The label should include a warning that medical opinion should be sought, before using this medicine, in the case of pregnancy

Breastfeeding

South African recommendations

• Caution
• It is not known whether azelastine hydrochloride/ fluticasone propionate is excreted in human breast milk. Caution should be exercised when azelastine hydrochloride/ fluticasone propionate is administered to breastfeeding women

Recommendations in other jurisdictions

• Caution
• It is unknown whether nasally administered azelastine hydrochloride/metabolites or fluticasone propionate/metabolites are excreted in human breast milk
• Azelastine hydrochloride/ fluticasone propionate should be used during lactation only if the potential benefit justifies the potential risk to the newborns/infant
• The label should include a warning that medical opinion should be sought, before using this medicine, in the case of breastfeeding

Fertility

South African recommendations

• There are only limited data with regard to fertility

Recommendations in other jurisdictions

• There are only limited data on the effect of azelastine hydrochloride and fluticasone propionate with regard to fertility

Recommendations below are applicable to South Africa and other jurisdictions

• Caution; no information available

Recommendations below are applicable to South Africa and other jurisdictions

• Caution; no information available

Recommendations below are applicable to South Africa and other jurisdictions

• No dose adjustment recommended

Immune System Disorders

Very rare

• Hypersensitivity including anaphylactic reactions
• Angioedema (oedema of the face or tongue and skin rash)
• Bronchospasm

Nervous System Disorders

Common

• Headache
• Dysgeusia (unpleasant taste)
• Unpleasant smell

Very rare

• Dizziness
• Somnolence (drowsiness, sleepiness)

Eye Disorders*

Very rare

• Glaucoma
• Increased intraocular pressure
• Cataract

Not known

• Blurred vision

Respiratory, Thoracic and Mediastinal Disorders

Very common

• Epistaxis

Uncommon

• Nasal discomfort (including nasal irritation, stinging, itching)
• Sneezing
• Nasal dryness
• Cough
• Dry throat
• Throat irritation

Very rare

• Nasal septal perforation**
• Mucosal erosion

Not known

• Nasal ulcers

Gastrointestinal Disorders

Rare

• Dry mouth

Very rare

• Nausea

Skin and Subcutaneous Tissue Disorders

Very rare

• Rash
• Pruritus
• Urticaria

General Disorders and Administration Site Conditions

Very rare

• Fatigue (weariness, exhaustion)
• Weakness

* A very small number of spontaneous reports have been identified following prolonged treatment with intranasal fluticasone propionate
** Nasal septal perforation has been reported following the use of intranasal corticosteroids

Azelastine Hydrochloride

• Sedative or central nervous medications

Other interactions

• Alcohol

Fluticasone Propionate

• Ritonavir
• CYP 3A4 inhibitors
• Cobicistat-containing products
• Ketoconazole
• Erythromycin

• Growth (adolescents and children)

Additional observations

• Signs/symptoms of HPA axis suppression/adrenal insufficiency
• Possible eosinophilic conditions (including eosinophilic granulomatosis with polyangiitis [formerly known as Churg-Strauss])
• Glaucoma and/or cataracts especially in patients with a change in vision
• Infection
• Adverse nasal effects (eg, nasal septal perforation, nasal ulceration, epistaxis, localised Candida albicans infections)

Azelastine hydrochloride and fluticasone propionate have different modes of action and show synergistic effects in terms of improvement of allergic rhinitis and rhino-conjunctivitis symptoms.

Azelastine Hydrochloride
Azelastine, a phthalazinone derivative is classified as a potent long-acting anti-allergic compound with selective H₁-antagonist, mast cell stabilising 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. A relief of nasal allergic symptoms is observed within 15 minutes after administration.

Fluticasone Propionate
Fluticasone propionate is a synthetic trifluorinated corticosteroid that possesses a very high affinity for the glucocorticoid receptor and has a potent anti-inflammatory action, e.g. 3-5-fold more potent than dexamethasone in cloned human glucocorticoid receptor binding and gene expression assays.