Floresp Az Nasal Spray

Azelastine Hydrochloride & Fluticasone Furoate Nasal Spray

Each spray delivers :

Azelastine Hydrochloride IP 140 mcg

Fluticasone Furoate 27.5 mcg

Composition :

Azelastine Hydrochloride IP 0.1% w/w

Fluticasone Furoate 0.0197% w/w

Preservative :

Benzalkonium Chloride Solution IP 0.02% w/w

Excipients q.s.

Nasal spray

4.1 Therapeutic indication

For the relief of the symptoms of seasonal allergic rhinitis in patients 12 years of age and older.

4.2 Posology and method of administration

Adults and adolescents (12 years and over)

One spray/nostril twice daily

Hepatic impairment

Azelastine Hydrochloride : Following oral administration, pharmacokinetic parameters were not influenced by age, gender, or hepatic impairment

Fluticasone furoate : Since fluticasone furoate undergoes extensive first-pass metabolism by the hepatic cytochrome P450 isozyme, CYP3A4, the pharmacokinetics of fluticasone furoate may be altered in patients with hepatic impairment. The systemic exposure would be expected to be higher than that observed had the study been conducted after multiple doses and/or in patients with severe hepatic impairment. Therefore, use fluticasone furoate nasal spray with caution in patients with severe hepatic impairment.

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

fluticasone furoate : Fluticasone furoate is not detectable in urine from healthy subjects following intranasal dosing. Less than 1% of dose-related material is excreted in the urine. No dosage adjustment is required in patients with renal impairment.

Method of administration

Floresp AZ nasal spray is for administration by the intranasal route only.

The device should be cleaned after each use and the cap replaced.

Directions for use

Following are directions for the use of FLORESP-AZ nasal spray.

Using your nasal spray :

STEP 1

Blow your nose gently

STEP 2

Shake the bottle gently and then remove the protective dust cap.

Hold the bottle as shown with your forefinger and middle finger on either side of the nozzle and your thumb underneath the bottle.

STEP 3

If using for the first time or if you have not used it for a week or more, test the spray.

Testing the spray : With the nozzle pointing away from you, press down a few times as shown until a fine mist comes out of the nozzle.

STEP 4

Close one nostril and hold the bottle as shown in step 2. Tilt your head forward slightly and keeping the bottle upright, carefully insert the tip of the nozzle in the other nostril.

STEP 5

Start to breathe in through your nose and while breathing in, press down with your fingers once to release a spray

STEP 6

Breathe out through your mouth. Repeat steps 5 and 6 to inhale a second spray.

STEP 7

Repeat steps 4,5 and 6 for the other nostril.

STEP 8

Wipe the nozzle with a clean handkerchief/tissue and replace the protective dust cap.

Cleaning your nasal spray :

Pull the nozzle upwards to detach form the bottle.

Soak the nozzle and the dust cap in warm water for few minutes

Rinse the nozzle and the dust cap under clean running water

Shake off excess water and allow nozzle and cap to dry at room temperature before refitting onto the bottle.

4.3 Contraindications

Hypersensitivity to the active substances or to any of the excipients

4.4 Special warnings and precautions for use Azelastine Hydrochloride

Concurrent use of Azelastine HCl Nasal Solution (Nasal Spray) with alcohol or other central nervous system depressants should be avoided because additional reductions in alertness and additional impairment of central nervous system performance may occur.

Fluticasone furoate Systemic corticosteroid effects

Systemic effects of nasal corticosteroid may occur, particularly at high doses prescribed for prolonged periods. These effects are much less likely to occur than with oral corticosteroids and may vary in individual patients and between different corticosteroid preparations. Potential systemic effects may include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, cataract, glaucoma and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children). Treatment with higher than recommended doses of nasal corticosteroids may result in clinically significant adrenal suppression. 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. Fluticasone furoate 110 micrograms once daily was not associated with hypothalamic-pituitary-adrenal (HPA) axis suppression in adult, adolescent or paediatric subjects. However the dose of intranasal fluticasone furoate should be reduced to the lowest dose at which effective control of the symptoms of rhinitis is maintained. As with all intranasal corticosteroids, the total systemic burden of corticosteroids should be considered whenever other forms of corticosteroid treatment are prescribed concurrently

If there is any reason to believe that adrenal function is impaired, care must be taken when transferring patients from systemic steroid treatment to fluticasone furoate.

Visual disturbance

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision 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.

Growth retardation

Growth retardation has been reported in children receiving nasal corticosteroids at licensed doses. A reduction in growth velocity has been observed in children treated with fluticasone furoate 110 micrograms daily for one year. Therefore, children should be maintained on the lowest possible efficacious dose which delivers adequate symptom control. It is recommended that the growth of children receiving prolonged treatment with nasal corticosteroids is regularly monitored. If growth is slowed, therapy should be reviewed with the aim of reducing the dose of nasal corticosteroid if possible, to the lowest dose at which effective control of symptoms is maintained. In addition, consideration should be given to referring the patient to a paediatric specialist.

Patients on ritonavir

Concomitant administration with ritonavir is not recommended because of the risk of increased systemic exposure of fluticasone furoate.

4.5 Drugs interactions

Azelastine hydrochloride

Central nervous system depressants

Concurrent use of Azelastine HCl Nasal Solution (Nasal Spray), with alcohol or other central nervous system depressants should be avoided because reductions in alertness and impairment of central nervous system performance may occur.

Erythromycin and ketoconazole

Interaction studies investigating the cardiac effects, as measured by the corrected QT interval (QTc), of concomitantly administered oral azelastine hydrochloride and erythromycin or ketoconazole were conducted. Oral erythromycin (500 mg three times daily for 7 days) had no effect on azelastine pharmacokinetics or QTc based on analyses of serial electrocardiograms. Ketoconazole (200 mg twice daily for 7 days) interfered with the measurement of azelastine plasma concentrations on the analytic HPLC; however, no effects on QTc were observed

Cimetidine

Cimetidine (400 mg twice daily) increased the mean Cmax and AUC of orally administered azelastine hydrochloride (4 mg twice daily) by approximately 65%

Fluticasone furoate

Interaction with CYP3A inhibitors

Fluticasone furoate is rapidly cleared by extensive first pass metabolism mediated by the cytochrome P450 3A4. Based on data with another glucocorticoid (fluticasone propionate), that is metabolised by CYP3A4, coadministration with ritonavir is not recommended because of the risk of increased systemic exposure of fluticasone furoate. Caution is recommended when co-administering fluticasone furoate with potent CYP3A inhibitors including cobicistat-containing products as an increase in the risk of systemic side effects is expected. Co-administration 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. In a drug interaction study of intranasal fluticasone furoate with the potent CYP3A4 inhibitor ketoconazole there were more subjects with measurable fluticasone furoate concentrations in the ketoconazole group (6 of the 20 subjects) compared to placebo (1 out of 20 subjects). This small increase in exposure did not result in a statistically significant difference in 24 hour serum cortisol levels between the two groups. The enzyme induction and inhibition data suggest that there is no theoretical basis for anticipating metabolic interactions between fluticasone furoate and the cytochrome P450 mediated metabolism of other compounds at clinically relevant intranasal doses. Therefore, no clinical studies have been conducted to investigate interactions of fluticasone furoate on other drugs.

4.6 Use in special populations

Pregnancy

There are no adequate and well-controlled studies in pregnant women. This combination should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus

Azelastine hydrochloride has been shown to cause developmental toxicity in mice, rats, and rabbits.Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully monitored. In animal studies glucocorticoids have been shown to induce malformations including cleft palate and intra-uterine growth retardation. This is not likely to be relevant for humans given recommended nasal doses which results in minimal systemic exposure.

Nursing mothers

It is not known whether azelastine hydrochloride or fluticasone furoate is excreted in human milk. Hence, caution should be exercised while prescribing this combination to nursing mothers and should only be considered if the expected benefit to the mother is greater than any possible risk to the child.

4.7 Effects on ability to drive and use machines

The occurrence of somnolence has been reported in some patients taking intranasal azelastine hydrochloride. In these cases, the ability to drive and use machines may be impaired by Floresp AZ nasal spray. Alcohol may enhance this effect.

4.8 Undesirable effects

Azelastine hydrochloride

Commonly (1 - 10 %) : a substance-specific bitter taste may be experienced after administration (often due to incorrect method of application, namely tilting the head too far backwards during administration) which, in rare cases, may lead to nausea. Uncommonly (0.1 - 1 %) : a mild, transient irritation of the inflamed nasal mucosa may occur with symptoms such as stinging, itching, sneezing and epistaxis. In very rare cases (< 0.01 %) : hypersensitivity reactions (such as rash, pruritus, urticaria) were reported.

Fluticasone furoate

The most commonly reported adverse reactions during treatment with fluticasone furoate are epistaxis, nasal ulceration and headache. The most serious undesirable effects are rare reports of hypersensitivity reactions, including anaphylaxis (less than 1 case per 1000 patients). The following convention has been used for the classification of frequencies : 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).

• Immune system disorders : Rare- Hypersensitivity reactions including anaphylaxis, angioedema, rash, and urticaria.

• Nervous system disorders : Common- Headache.

• Eye disorders : Not known- Transient ocular changes, vision blurred.

• Respiratory, thoracic and mediastinal disorders : Very common- *Epistaxis, Common- Nasal ulceration, dyspnoea**, Uncommon- Rhinalgia, nasal discomfort (including nasal burning, nasal irritation, and nasal soreness), nasal dryness. Very rare- Nasal septum perforation, Not known- Bronchospasm.

• Musculoskeletal and connective tissue disorders (Children) : Not known- ***Growth retardation.

Epistaxis

*Epistaxis was generally mild to moderate in intensity. In adults and adolescents, the incidence of epistaxis was higher in longer-term use (more than 6 weeks) than in short-term use (up to 6 weeks).

Systemic effects Systemic effects of nasal corticosteroids may occur, particularly when prescribed at high doses for prolonged periods. Growth retardation has been reported in children receiving nasal corticosteroids.

**Dyspnoea cases were reported in more than 1% of patients during clinical trials with fluticasone furoate; similar rates were also observed in placebo groups.

Paediatric population

The safety in children under 6 years has not been well established. Frequency, type and severity of adverse reactions observed in the paediatric population are similar to those in the adult population.

Epistaxis

*In paediatric clinical studies of up to 12 weeks duration the incidence of epistaxis was similar between patients receiving fluticasone furoate and patients receiving placebo.

Growth retardation

***In a one-year clinical study assessing growth in pre-pubescent children receiving 110 micrograms of fluticasone furoate once daily, an average treatment difference of -0.27 cm per year in growth velocity was observed compared to placebo.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via email to : medico@zuventus.com

4.9 Overdose

Azelastine hydrochloride

The results of animal studies show that toxic doses can produce CNS symptoms, e.g. excitation, tremor, convulsions. Should these occur in humans, symptomatic and supportive treatment should be instigated as there is no specific antidote. Gastric lavage is recommended if the overdose is recent. With the nasal route of administration overdosage reactions are not anticipated.

Fluticasone furoate

In a bioavailability study, intranasal doses of up to 2640 micrograms per day were administered over three days with no adverse systemic reactions observed. Acute overdose is unlikely to require any therapy other than observation.

5.0 Pharmacological properties

5.1 Mechanism of action

Azelastine, a phthalazinone derivative of novel structure, is classified as a potent long acting anti-allergic compound with particularly strong H1 antagonist properties. Fluticasone furoate is a synthetic trifluorinated corticosteroid that possesses a very high affinity for the glucocorticoid receptor and has a potent anti-inflammatory action.

5.2 Pharmacodynamic properties

Data from animal studies show that where high levels of azelastine are achieved both inhibition and release of chemical mediators (e.g. leukotriene, histamine, serotonin) involved in allergic reaction occurs. Corticosteroids have been shown to have a wide range of actions on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in inflammation. Specific effects of fluticasone furoate demonstrated in in vitro and in vivo models included activation of the glucocorticoid response element, inhibition of pro-inflammatory transcription factors such as NFkB, and inhibition of antigen-induced lung eosinophilia in sensitized rats.

Fluticasone furoate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor that is approximately 29.9 times that of dexamethasone and 1.7 times that of fluticasone propionate. The clinical relevance of these findings is unknown.

5.3 Pharmacokinetic properties

Azelastine hydrochloride

Absorption : After intranasal administration of 2 sprays per nostril (548 mcg total dose) of 137 mcg azelastine hydrochloride, the mean azelastine peak plasma concentration (C max) is 200 pg/mL, the mean extent of systemic exposure (AUC) is 5122 pg•hr/mL and the median time to reach Cmax (t max) is 3 hours. The systemic bioavailability of azelastine hydrochloride is approximately 40% after intranasal administration.

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

Metabolism : Azelastine is oxidatively metabolized to the principal active metabolite, desmethylazelastine, by the cytochrome P450 enzyme system. The specific P450 isoforms responsible for the biotransformation of azelastine have not been identified. After a single-dose, intranasal administration of 137 mcg azelastine hydrochloride (548 mcg total dose), the mean desmethylazelastine Cmax is 23 pg/mL, the AUC is 2131 pg•hr/mL and the median tmax is 24 hours. After intranasal dosing of azelastine to steadystate, plasma concentrations of desmethylazelastine range from 20-50% of azelastine concentrations

Elimination : Following intranasal administration of 137 mcg azelastine hydrochloride, the elimination half-life of azelastine is 22 hours while that of desmethylazelastine is 52 hours. Approximately 75% of an oral dose of radiolabeled azelastine hydrochloride was excreted in the feces with less than 10% as unchanged azelastine.

Fluticasone furoate

Absorption : Fluticasone furoate undergoes incomplete absorption and extensive first-pass metabolism in the liver and gut resulting in negligible systemic exposure. The intranasal dosing of 110 micrograms once daily does not typically result in measurable plasma concentrations (<10 pg/mL). The absolute bioavailability for intranasal fluticasone furoate is 0.50 %, such that less than 1 microgram of fluticasone furoate would be systemically available after administration of 110 micrograms.

Distribution : The plasma protein binding of fluticasone furoate is greater than 99 %. Fluticasone furoate is widely distributed with volume of distribution at steady-state of, on average, 608 L.

Biotransformation : Fluticasone furoate is rapidly cleared (total plasma clearance of 58.7 L/h) from systemic circulation principally by hepatic metabolism to an inactive 17β-carboxylic metabolite (GW694301X), by the cytochrome P450 enzyme CYP3A4. The principal route of metabolism was hydrolysis of the S-fluoromethyl carbothioate function to form the 17β-carboxylic acid metabolite. In vivo studies have revealed no evidence of cleavage of the furoate moiety to form fluticasone.

Elimination : Elimination was primarily via the faecal route following oral and intravenous administration indicative of excretion of fluticasone furoate and its metabolites via the bile. Following intravenous administration, the elimination phase half-life averaged 15.1 hours. Urinary excretion accounted for approximately 1 % and 2 % of the orally and intravenously administered dose, respectively.

6.0 Nonclinical properties

6.1 Animal toxicology or pharmacology

Azelastine hydrochloride

Two-year carcinogenicity studies in Crl:CD(SD)BR rats and NMRI mice were conducted to assess the carcinogenic potential of azelastine hydrochloride. No evidence of tumorigenicity was observed in rats at doses up to 30 mg/kg day (approximately 180 and 160 times the MRHDID 2 for adults and children, respectively, on a mg/m basis). No evidence for tumorigenicity was observed in mice at doses up to 25 mg/kg (approximately 75 and 65 times the MRHDID for adults and children, respectively, 2 on a mg/m basis).

Azelastine hydrochloride showed no genotoxic effects in the Ames test, DNA repair test, mouse lymphoma forward mutation assay, mouse micronucleus test, or chromosomal aberration test in rat bone marrow. There were no effects on male or female fertility and reproductive performance in male and female rats at oral doses up to 30 mg/kg (approximately 180 times the MRHDID 2 in adults on a mg/m basis). At 68.6 mg/kg 2 (approximately 410 times the MRHDID on a mg/m basis), the duration of estrous cycles was prolonged and copulatory activity and the number of pregnancies were decreased. The numbers of corpora lutea and implantations were decreased; however, pre-implantation loss was not increased.

Fluticasone furoate

Findings in general toxicology studies were similar to those observed with other glucocorticoids and are associated with exaggerated pharmacological activity. These findings are not likely to be relevant for humans given recommended nasal doses which results in minimal systemic exposure. No genotoxic effects of fluticasone furoate have been observed in conventional genotoxicity tests. Further, there were no treatment-related increases in the incidence of tumours in two year inhalation studies in rats and mice.

FLORESP-AZ nasal spray is an antihistamine-corticosteroid combination available as a metered spray formulation for intranasal administration. It contains azelastine hydrochloride, which is a second generation H1 receptorantagonist with potent topical activity, and fluticasone furoate, a synthetic corticosteroid with anti-inflammatory properties.

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

FLORESP-AZ sales pack contains 70 metered doses.

8.4 Storage and handing instructions

• Store below 30°C. Protect from light. Do not freeze.

• Keep out of reach of children.

• SHAKE WELL BEFORE EACH USE.

• FOR NASAL USE ONLY.

• Refer enclosed leaflet for dosage & administration.

• Local Nasal Effects : Patients should be informed that treatment with Floresp AZ Nasal Spray may lead to adverse reactions, which include epistaxis and nasal ulceration. Candida infection may also occur with treatment with Floresp AZ Nasal Spray. In addition, nasal corticosteroids are associated with nasal septal perforation and impaired wound healing. Patients who have experienced recent nasal ulcers, nasal surgery, or nasal trauma should not use Floresp AZ Nasal Spray until healing has occurred

• Cataracts and Glaucoma : Patients should be informed that glaucoma and cataracts are associated with nasal and inhaled corticosteroid use. Patients should inform his/her health care provider if a change in vision is noted while using Floresp AZ Nasal Spray

• Hypersensitivity Reactions, Including Anaphylaxis : Patients should be aware that hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria, may occur after administration of Floresp AZ Nasal Spray. If such reactions occur, patients should discontinue use of Floresp AZ Nasal Spray

• Immunosuppression : Patients who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles and, if exposed, to consult their physician without delay. Patients should be informed of potential worsening of existing tuberculosis, fungal, bacterial, viral or parasitic infections, or ocular herpes simplex

• Use Daily for Best Effect : Patients should use Floresp AZ Nasal Spray on a regular basis for optimal effect.

• Keep Spray Out of Eyes : Patients should be informed to avoid spraying Floresp AZ Nasal Spray in their eyes.

• Potential Drug Interactions : Patients should be advised that coadministration of Floresp AZ Nasal Spray and ritonavir is not recommended and to be cautious if coadministrating with ketoconazole.

• Do not drive, operate machinery, or do other dangerous activities until you know how Floresp AZ affects you.

• Do not drink alcohol or take other medicines that may cause you to feel sleepy while using Floresp AZ, it may make your sleepiness worse.

• Do not take this medicine, if you are allergic to Fluticasone furoate or Azelastine Hydrochloride.

• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

• If you have any further questions, ask your doctor or pharmacist.