SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Rhinocort® Aqua 64 micrograms, nasal spray

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each actuation contains: Budesonide 64 micrograms (1.28 mg/ml).

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Nasal spray, suspension

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Seasonal and perennial allergic rhinitis and vasomotor rhinitis. Treatment of nasal polyps

4.2    Posology and method of administration

Posology

Dosage should be individualised.

Rhinitis (Adults including the elderly)

Recommended start dose	Once daily dosing	Twice daily dosing
256 micrograms per day	Two applications of 64 micrograms into each nostril each morning or If good effect is	One application of 64 micrograms into each nostril morning and evening

The patient should be informed that the full effect of Rhinocort is not achieved until after a few days treatment. Treatment of seasonal rhinitis should, if possible, start before exposure to allergens. Treatment can be continued for up to 3 months.

Patients should be reminded of the importance of taking this medicine regularly.

The dose should be titrated to the lowest dose at which effective control of symptoms is achieved.

Paediatric population: There are insufficient data to recommend the use of Rhinocort Aqua in children. However, it is unlikely that the risk/benefit ratio in children is different from that in adults.

Method of administration

For nasal inhalation.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Special care is demanded in treatment of patients transferred from oral steroids to Rhinocort where disturbances of the hypothalamic-pituitary-adrenal (HPA) axis could be expected.

Special care is needed in patients with fungal and viral infections of the airways and in patients with active or quiescent pulmonary tuberculosis.

Concomitant treatment of seasonal rhinitis may sometimes be necessary to counteract eye symptoms caused by the allergy. In continuous long-term treatment, the nasal mucosa should be inspected regularly e.g. every 6 months.

Reduced liver function affects the elimination of corticosteroids, causing lower elimination rate and higher systemic exposure. Be aware of possible systemic side effects.

Systemic effects of nasal corticosteroids 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).

Paediatric population

The long-term effects of nasal glucocorticosteroids in children are not fully known. Physicians should closely follow the growth of children taking glucocorticosteroids for longer term by any route, and weigh the benefits of the glucocorticosteroid therapy against the possibility of growth suppression. 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 also be given to referring the patient to a paediatric specialist.

Treatment with higher than recommended doses may result in clinically significant adrenal suppression. If there is evidence for higher than recommended doses being used, additional systemic corticosteroid cover should be considered during periods of stress or elective surgery.

In vivo studies have shown that oral administration of itraconazole and ketoconazole (known inhibitors of CYP3A4 activity in the liver and in the intestinal mucosa, see also section 4.5 Interactions) may cause an increase in the systemic exposure to budesonide. This is of limited clinical importance for short-term (1-2 weeks) treatment with itraconazole or ketoconazole, but should be taken into consideration during long-term treatment.

4.5 Interaction with other medicinal products and other forms of interaction

Rhinocort has not been observed to interact with any drug used for the treatment of rhinitis.

The metabolism of budesonide is primarily mediated by CYP3A4, a subfamily of cytochrome P450. Inhibitors of this enzyme, e.g. itraconazole and ketoconazole, can therefore increase systemic exposure to budesonide several times. Since there is no data to support a dosage recommendation, the combination should be avoided. If this is not possible, the period between treatments should be as long as possible and a reduction of the Rhinocort dose could also be considered. However, the use of itraconazole or ketoconazole concomitant with Rhinocort Aqua for shorter periods is of limited importance, see section 4.4 Special warnings and precautions for use.

Raised plasma concentrations of and enhanced effects of corticosteroids have been observed in women also treated with oestrogens and contraceptive steroids, but no effect has been observed with Rhinocort and concomitant intake of low dose combination oral contraceptives.

Because adrenal function may be suppressed, an ACTH stimulation test for diagnosing pituitary insufficiency might show false results (low values).

4.6 Fertility, pregnancy and lactation Pregnancy

Results from prospective epidemiological studies and from worldwide post marketing experience indicate no increased risk for overall congenital malformations from the use of inhaled or intranasal budesonide during early pregnancy. As with other drugs the administration of Rhinocort during pregnancy requires that the benefits for the mother are weighed against the risk for the foetus.

Breast-feeding

Budesonide is excreted in breast milk. However, at therapeutic doses of Rhinocort no effects on the breast fed child are anticipated. Rhinocort can be used during breast feeding.

Maintenance treatment with inhaled Rhinocort (200 or 400 micrograms twice daily) in asthmatic nursing women results in negligible systemic exposure to budesonide in breast-fed infants.

In a pharmacokinetic study, the estimated daily infant dose was 0.3% of the daily maternal dose for both dose levels, and the average plasma concentration in infants was estimated to be 1/600th of the concentrations observed in maternal plasma, assuming complete infant oral bioavailability. Budesonide concentrations in infant plasma samples were all less than the limit of quantification.

Based on data from inhaled budesonide and the fact budesonide exhibits linear PK properties within the therapeutic dosage intervals after nasal, inhaled, oral and rectal administrations at therapeutic doses of budesonide, exposure to the breast-fed child is anticipated to be low.

4.7 Effects on ability to drive and use machines

Rhinocort Aqua has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Tabulated list of adverse reactions

Adverse reactions, which have been associated with budesonide, are given below, listed by system organ class and frequency. Frequencies are defined as: very common (>1/10), common (>1/100 and <1/10), uncommon (>1/1000 and <1/100), rare (>1/10 000 and <1/1000), very rare (<1/10 000) and not known (cannot be estimated from the available data).

Immune system disorders	Uncommon	Immediate and delayed hypersensitivity reactions including urticaria, rash, dermatitis angioedema and pruritus
	Rare	Anaphylactic reaction
Endocrine disorders	Rare	Signs and symptoms of systemic corticosteroid effects, including adrenal suppression and growth retardation
Eye disorders	Not known	Raised intraocular pressure or Glaucoma Cataract
Respiratory, thoracic and mediastinal disorders	Common	Haemorrhagic secretion and epistaxis Nasal Irritation (sneezing, stinging and dryness)
	Rare	Nasal septum perforation Nasal ulcer Dysphonia
	Very rare	Ulceration of mucous membrane

Musculoskeletal and connective tissue disorders	Uncommon	Muscle spasm
Injury, poisoning and procedural complications	Rare	Contusion*

* based on mechanistic plausibility and extrapolation from other budesonide/corticosteroi d formulations.

In rare cases, signs or symptoms of systemic glucocorticosteroid-side effects may occur with nasal glucocorticosteroids, probably depending on dose, exposure time, concomitant and previous corticosteroid exposure, and individual sensitivity (see section 4.4).

Paediatric population

Growth retardation has been reported in children receiving intranasal steroids. Due to the risk of growth retardation in the paediatric population, growth should be monitored as described in section 4.4.

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 the Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Acute overdose with Rhinocort even in excessive doses, is not expected to be a clinical problem.

Inhalation of high doses of corticosteroids may lead to suppression of the hypothalamic-pituitary-adrenal (HPA) axis function.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Decongestants and other nasal preparations for topical use, corticosteroids. ATC code: R01A D05

Budesonide is a non-halogenated glucocorticosteroid with a high local antiinflammatory action within the respiratory tract.

5.2 Pharmacokinetic properties

Bioavailablity of oral budesonide in man is low (11-13%) due to an extensive first pass metabolism in the liver.

The systemic availability of budesonide from Rhinocort Aqua, with reference to the metered dose is 33%. In adults the maximal plasma concentration after administration of 256 micrograms budesonide from Rhinocort Aqua is 0.64 nM and is reached within 0.7 hours. The AUC after administration of 256 micrograms budesonide from Rhinocort Aqua is 2.7 nmol xh /L in adults.

5.3 Preclinical safety data

The acute toxicity of budesonide is low and of the same order of magnitude and type as that of the reference glucocorticoids studied (beclomethasone dipropionate, flucinolone acetonide). Results from subacute and chronic toxicity studies show that the systemic effects of budesonide are less severe than or similar to those observed after administration of the other glucocorticosteroids e.g. decreased body weight gain and atrophy of lymphoid tissues and adrenal cortex. An increased incidence of brain gliomas in male rats in a carcinogenicity study could not be verified in a repeat study, in which the incidence of gliomas did not differ between any of the groups on active treatment (budesonide, prednisolone, triamcinolone acetonide) and the control groups. Liver changes (primary hepatocellular neoplasms) found in male rats in the original carcinogenicity study were noted again in the repeat study with budesonide as well as with the reference glucocorticosteroids. These effects are most probably related to a receptor effect and thus represent a class effect.

Available clinical experience shows no indication that budesonide or other glucocorticosteroids induce brain gliomas or primary heptocellular neoplasms in man. Budesonide has been used successfully in the treatment of seasonal allergic rhinitis for several years.

In animal reproduction studies, corticosteroids such as budesonide have been shown to induce malformations (cleft palate, skeletal malformations). However these animal experimental results do not appear to be relevant in humans at the recommended doses.

Animal studies have also identified an involvement of excess prenatal glucocorticosteroids in increased risk for intrauterine growth retardation, adult cardiovascular disease and permanent changes in glucocorticoid receptor density, neurotransmitter turnover and behaviour at exposures below the teterogenic dose range.

6 PHARMACEUTICAL PARTICULARS

List of excipients

Disodium edetate

Potassium sorbate (E202)

Glucose anhydrous Microcrystalline cellulose (E460) Carboxymethylcellulose sodium (E466) Polysorbate 80 (E433)

Hydrochloric acid Purified water

6.2 Incompatibilities

Not applicable.

6.3    Shelf life

2 years.

Use within 2 months of starting treatment.

6.4    Special precautions for storage

Do not store above 30°C. Do not refrigerate or freeze.

For storage conditions after first opening of the medicinal product, see section 6.3.

6.5    Nature and contents of container

Rhinocort Aqua is an aqueous solution of budesonide in either a 10 ml or 20 ml amber/brown glass (type II) bottle. Each bottle is fitted with a spray pump and contains either 120 or 240 actuations. Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Before using Rhinocort Aqua for the first time the nozzle must be primed (filled with the medicine). To do this the bottle is shaken and the protective cap removed. The bottle is then held upright and the nozzle pumped up and down several times (5-10 times) spraying into the air, until an even mist is seen. The priming effect remains for approximately 24 hours. If a longer period of time passes before the next dose is taken, the nozzle must be loaded with medicine again. This time it is sufficient to spray just once into the air.

a. The patient is then instructed to blow their nose. Next, the bottle needs to be shaken and the protective cap removed.

b.    The bottle is then held upright, with one finger held on either side of the nozzle.

c.    The tip of the nozzle is inserted into the nostril and the nozzle pressed down once (or more as instructed by the doctor). The spray is then administered into the other nostril in the same way. Note: it is not necessary to inhale at the same time as spraying.

d.    The nozzle needs to be wiped with a clean tissue after use and the protective cap replaced. The bottle should be stored in an upright position.

e.    Keeping the Rhinocort Aqua nozzle clean

The plastic nozzle of Rhinocort Aqua should be cleaned regularly and at any time the spray of medicine is not coming out as it should. If this happens, first the nozzle should be checked to ensure that it is primed with medicine (see earlier). If, after the nozzle is primed again, the pump is still not working, the nozzle should be cleaned by using the following instructions:

The plastic nozzle is removed with a clean tissue and washed in warm, not hot, water. The nozzle is then rinsed thoroughly, dried and then replaced onto the top of the bottle. The nozzle should not be unblocked with a pin or other sharp object. After cleaning, the nozzle must be primed (filled with medicine) again before use.

No special requirements for disposal.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7    MARKETING AUTHORISATION HOLDER

AstraZeneca UK Ltd 600 Capability Green Luton, LU1 3LU, UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 17901/0074

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 12 December 2003

Date of the latest renewal: 30 July 2012

10 DATE OF REVISION OF THE TEXT

16/09/2016