Microsoft word - rhinocort aqua spc 14v004 (paed+psur120512)

SUMMARY OF PRODUCT CHARACTERISTICS
TRADE NAME OF THE MEDICINAL PRODUCT

Rhinocort Aqua 32 micrograms/dose nasal spray, suspension
Rhinocort Aqua 64 micrograms/dose nasal spray, suspension
2.
QUALITATIVE AND QUANTITATIVE COMPOSITION
One dose (0.05 ml) contains 32 micrograms or 64 micrograms of budesonide. For a full list of excipients see section 6.1. PHARMACEUTICAL FORM
Nasal spray, suspension CLINICAL PARTICULARS
Therapeutic indications
Seasonal and perennial allergic rhinitis and vasomotor rhinitis. Prophylactically in patients with nasal polyps following polypectomy. Symptomatic treatment in nasal polyposis. Posology and route of administration
The dosage should be adjusted individually. Rhinitis Adults and children from 6 years: The recommended initial dose is 256 micrograms per day. The dose may be administered once daily in the morning or divided into two administrations, morning and evening. This means 128 micrograms (2 x 64 micrograms) into each nostril in the morning or 64 micrograms into each nostril morning and evening. No further effect has been seen with doses higher than 256 micrograms per day. For elderly patients the dosage is the same as for adults. When the desired clinical effect has been achieved, the dose should be reduced to the lowest amount that is needed to control the symptoms. Clinical trials show that a dose of 32 micrograms in each nostril in the morning may be sufficient for some patients. Rhinocort Aqua SPC 14v004 (Paed+PSUR120512) In some patients relief of symptoms is already obtained within 5-7 hours after the start of treatment. The patient should be informed that the full effect is only obtained after several days of treatment (in rare cases only after 2 weeks). Treatment of seasonal allergic rhinitis should therefore, if possible, start before exposure to the allergens. In cases of severe nasal congestion an initial addition of a vasoconstrictor may be required. Supplementary treatment may sometimes be necessary in order to counteract possible ocular symptoms caused by the allergy. For the indication allergic rhinitis, the 32 micrograms/dose strength is available without prescription, for use for a maximum of 3 months. Symptomatic treatment and prevention of nasal polyps The recommended dose is 256 micrograms per day. The dose may be administered once daily in the morning or divided into two administrations, morning and evening. When the desired clinical effect has been achieved, the dose should be reduced to the lowest amount that is needed to control the symptoms.
Previous hypersensitivity to budesonide or to any of the excipients.
Special warnings and precautions for use
In long-term treatment with high doses, systemic effects of glucocorticosteroids such as hypercortisolism, adrenal suppression and/or retarded growth in children may occur (see Paediatric population below). Care must be exercised in the treatment of patients who are being transferred from systemically acting glucocorticosteroids to Rhinocort Aqua and if there is suspected disturbed pituitary-adrenocortical function. In these patients there should be a careful reduction of the systemic steroid dose and testing of hypothalamic-pituitary-adrenocortical function should be considered. They may also need the addition of systemic steroids in connection with periods of stress, e.g. surgery, trauma, etc. Impaired hepatic function affects the elimination of corticosteroids, which leads to a reduced rate of elimination and increased systemic exposure. Pay attention to possible systemic effects. Special caution is needed in patients with active or latent lung tuberculosis, and in patients with fungal or viral infections (e.g. herpes) of the airways. Rhinocort Aqua should not come into contact with the eyes. If Rhinocort Aqua comes into contact with the eyes, rinse immediately with water. Rhinocort Aqua SPC 14v004 (Paed+PSUR120512) Concomitant treatment with ketoconazole or other potent CYP3A4-inhibiting drugs should be avoided. If this is not possible, the time interval between administrations of the agents should be as long as possible (see section 4.5). Systemic effects may occur with nasal corticosteroids, especially at high doses during long periods of treatment. It is less likely that these effects will occur in intranasal treatment than when corticosteroids are administered orally, and these effects may vary between patients and with different corticosteroid preparations. Possible systemic undesirable effects may include Cushing's syndrome, Cushing-like symptoms, adrenal suppression, inhibited growth in height of children and adolescents, cataracts, glaucoma, and more rarely a range of psychological disorders or behavioural disorders including psychomotor hyperactivity, sleep disorders, agitation, depression or aggression (especially in children). Paediatric population Long-term effects of nasal steroids in children have not been elucidated. Treatment with medicines containing cortisone can lead to slower growth. Regular monitoring of height is recommended in children and adolescents receiving long-term treatment with corticosteroids, irrespective of the administration form. If retarded growth is suspected, this should be investigated. The benefits of glucocorticosteroid treatment should be placed in relation to the possible risk of inhibited growth. Interaction with other medicinal products and other forms of interaction
Budesonide has not been observed to interact with medicinal products that are used to treat rhinitis. The metabolism of budesonide is primarily mediated by CYP3A4. Inhibitors of this enzyme, e.g. ketoconazole and itraconazole, may therefore increase systemic exposure to budesonide several times. Oral ketoconazole 200 mg once daily increased the plasma concentrations of oral budesonide (3 mg in a single dose) on average six-fold when administered simultaneously. When oral ketoconazole was administered 12 hours after budesonide, the concentration increased on average three-fold. There is no information about this interaction for nasal budesonide, but also in such cases greatly increased plasma levels are expected. Since there are no data to support a dosage recommendation to be given in cases of nasal administration, the combination must be avoided. If this is not possible, the time interval between administration of ketoconazole and that of budesonide must be as long as possible and a reduction of the budesonide dose may also be considered. Other potent inhibitors of CYP3A4 also probably cause a marked increase in the plasma levels of budesonide. Elevated plasma concentrations and increased effects of corticosteroids have been observed in women who were also treated with oestrogens and contraceptive steroids, but no effect has been observed with budesonide and concomitant intake of combined low dose contraceptive pills. As adrenal function may be inhibited, an ACTH stimulation test for diagnosis of pituitary failure may show an incorrect result (low value). Rhinocort Aqua SPC 14v004 (Paed+PSUR120512) Fertility, pregnancy and lactation
Results from prospective studies and from global experience after market launch do not indicate any increased risk of congenital defects in the use of inhaled or intranasal budesonide in early pregnancy. As with other medicinal products, administration of budesonide during pregnancy requires the benefits to the mother to be weighed against the risks to the foetus. Budesonide is excreted in breast milk. However, at therapeutic doses of budesonide no effects on the suckling child are expected. Budesonide can be used during breast-feeding. Maintenance treatment with inhaled budesonide (200 or 400 micrograms twice daily) in asthmatic, lactating women results in negligible systemic exposure to budesonide in the suckling child. In a pharmacokinetic study the estimated daily dose in the child was 0.3% of the mother's daily dose at both dose levels and the mean plasma concentration in the infant was estimated at a 600th part of the concentrations that were observed in the mother's plasma, assuming complete oral bioavailability in the child. The concentrations of budesonide in the infant's plasma samples were all below the quantification limit. Based on data from the inhaled budesonide and the fact that budesonide shows linear pharmacokinetic properties within the therapeutic dose interval after nasal, inhaled, oral and rectal administration, exposure of the suckling child is expected to be low. Effects on ability to drive and use machines
Rhinocort Aqua does not affect ability to drive or operate machinery. Undesirable effects
Approx. 5 % of treated patients may be expected to experience side effects in the form of local irritation. In below table the undesirable effects are listed according to classification and frequency. Common (≥1/100, <1/10), Uncommon (≥1/1,000, <1/100), Rare (≥1/10,000, <1/1,000) Very rare (<1/10,000), No known frequency (cannot be calculated from available data). Immediate and delayed hypersensitivity reactions, including urticaria, rash, dermatitis angioedema and pruritus. Anaphylactic reaction Endocrine system Signs and symptoms of systemic Rhinocort Aqua SPC 14v004 (Paed+PSUR120512) corticosteroids effects, including inhibited adrenal function and inhibited growth in height No known frequency Cataract Glaucoma Respiratory, thoracic Local irritation, epistaxis, haemorrhagic nasal secretion. Nasal septum perforation, ulceration of mucous membranes. Dysphonia
Systemic effects may occur with nasal corticosteroids, especially at high doses during
long periods of treatment (see section 4.4).
In very rare cases ulcerations of mucous membranes and nasal septum perforation
have occurred during use of nasally applied steroids. The cause of these adverse events
(the steroid, the underlying condition or other factors) is unclear.
Paediatric population
Inhibition of growth in height has been reported in children who are given intranasal
steroids. Because of the risk of inhibition of growth in the paediatric population
growth must be monitored as described in section 4.4.
Reporting of suspected adverse reactions:
Reporting suspected adverse reactions is an important way to gather more information
to continuously monitor the benefit/risk balance of the medicinal product. Any
suspected adverse reactions should be reported to Pharmaceutical Services, Ministry
of Health, CY-1475, www.moh.gov.cy/phs Fax: + 357 22608649
Overdose
Acute overdosage with Rhinocort Aqua, even high doses, is not expected to cause any clinical problems. If Rhinocort Aqua is used in high doses for a long period, the systemic effects characteristic of glucocorticosteroids such as hypercortisolism and adrenal suppression may occur. PHARMACOLOGICAL PROPERTIES
Pharmacodynamic properties
Pharmacotherapeutic group: Glucocorticoids ATC code: R01AD05 Mechanism of effectBudesonide is a glucocorticosteroid with a powerful local anti-inflammatory effect. Rhinocort Aqua SPC 14v004 (Paed+PSUR120512) The precise mechanism of action of glucocorticosteroids in the treatment of rhinitis is not fully understood. Anti-inflammatory effects such as inhibited release of inflammatory mediators and inhibition of cytokine-mediated immune response are probably significant. The activity of budesonide, measured as its affinity for glucocorticosteroid receptors, is approx. 15 times higher than that of prednisolone. Clinical effect and safety Budesonide given prophylactically prior to nasal provocation has proved to protect against immigration of eosinophils and hyperreactivity.
At recommended doses, Rhinocort Aqua does not cause any clinically significant
changes either in basal plasma cortisol levels or in the response to stimulation with
ACTH. However, dose-related suppression of plasma and urinary cortisol has been
observed in healthy volunteers following short-term administration of Rhinocort Aqua.
A dose-response relationship has not been demonstrated in clinical trials in children
with seasonal or perennial allergic rhinitis or in adults with perennial allergic rhinitis.
Vasomotor rhinitis (non-allergic perennial rhinitis) has not been documented with
Rhinocort Aqua in the strengths 32 and 64 micrograms/dose.
Paediatric population

Clinical efficacy
The therapeutic efficacy of Rhinocort Aqua nasal spray has been evaluated in several
thousand adults and children. Most studies were carried out with intranasally
administered doses of 32 to 256 μg of Rhinocort Aqua once daily. Examples of
representative studies that evaluated the use of Rhinocort Aqua for the treatment of
children with seasonal and perennial allergic rhinitis are given below. The primary
effect variable was the combined nasal symptom score (CNSS), which is the sum of
the individual nasal symptom scores for three nasal symptoms (blocked nose, runny
nose and sneezing, each of which was estimated on a scale of 0-3).
Seasonal allergic rhinitis
Paediatric population
A 2 week, randomised, double blind, placebo controlled study with parallel groups
evaluated the efficacy and safety of Rhinocort Aqua 16, 32 and 64 µg once daily in
400 children (aged from 2 to 5 years) with allergic rhinitis (seasonal or perennial). A
marked reduction from the baseline value of CNSS was shown in all treatment groups,
including placebo. The difference between Rhinocort Aqua 64 µg and placebo
treatment was not statistically significant.
Perennial allergic rhinitis
Paediatric population
A 6 week, randomised, double blind, placebo controlled study with parallel groups
evaluated the efficacy and safety of Rhinocort Aqua 128 µg once daily in 202 children
(aged from 6 to 16 years) with perennial allergic rhinitis. The primary effect variables
were CNSS and the value of peak nasal inhalation flow (PNIF). Rhinocort Aqua gave
statistically significant greater improvement in CNSS and PNIF than placebo. The
Rhinocort Aqua SPC 14v004 (Paed+PSUR120512) principal effect of Rhinocort Aqua occurred 12 hours after the first dose for CNSS and
48 hours for PNIF.
Clinical safety
Paediatric population

In a randomised, double blind, placebo controlled study of growth 229 pre-pubertal
children aged from 4 to 8 years were given Rhinocort Aqua 64 micrograms once daily
or placebo for 12 months after a 6 month baseline period. In this study the rate of
growth was similar in the treatment groups with Rhinocort Aqua and placebo after 12
months of treatment: the mean difference in the rate of growth (placebo – Rhinocort
Aqua) was 0.27 cm/year (95% confidence interval: −0.07 to 0.62).
Effect on plasma hydrocortisone concentration:
At recommended doses Rhinocort Aqua causes no clinically relevant changes in basal
plasma hydrocortisone concentrations or in ACTH stimulation. In healthy volunteer
subjects dose-dependent suppression of hydrocortisone concentrations was seen in
plasma and urine after short term administration of Rhinocort Aqua.
Pharmacokinetic properties
Absorption
The systemic availability of budesonide from Rhinocort Aqua is 33 % of the measured
dose.
The peak plasma concentration in adults from 256 micrograms of budesonide from
Rhinocort Aqua is 0.64 nmol/l, and is reached within 0.7 hours. The AUC (area under
the curve) after administration of 256 micrograms of budesonide from Rhinocort Aqua
is 2.7 nmol x hours/litre in adults.
Distribution
Budesonide has a volume of distribution of approx. 3 l/kg. Binding to plasma proteins
is approx. 85-90 %.

Metabolism
Budesonide undergoes extensive ( 90%) first pass metabolism in the liver to
metabolites with low glucocorticosteroid activity. The glucocorticosteroid activity of
the principal metabolites, 6-beta-hydroxybudesonide and 16-alpha-
hydroxyprednisolone, is less than 1 % of that of budesonide. The metabolism of
budesonide is primarily mediated by CYP3A, a subfamily of cytochrome P450.
Budesonide does not undergo local metabolism in the nose.
Elimination
The metabolites are excreted unchanged or in conjugated form , primarily via the
kidneys. No intact budesonide was detected in urine.
Budesonide has high systemic clearance ( 1.2 l/min) and the half-life in plasma after intravenous administration is on average approx. 4 hours. Linearity The kinetics of budesonide are dose-proportional at clinically relevant doses. Rhinocort Aqua SPC 14v004 (Paed+PSUR120512) Paediatric population Budesonide has a systemic clearance of about 0.5 l/min in children with asthma at the age of 4-6 years. Clearance per kilo body weight in children is about 50% higher than in adults. The terminal half life of budesonide after inhalation is about 2.3 hours in children with asthma. This is about the same as in adults. The area under the curve (AUC) after administration of 256 micrograms budesonide from Rhinocort Aqua is 5.5 nmol × hours/litre in children, which indicates higher systemic glucocorticosteroid exposure in children than in adults. At clinically recommended doses the pharmacokinetics of budesonide are dose-proportional and plasma exposure is correlated to the patient's weight. This should therefore be taken into account when paediatric doses are set. Preclinical safety data
Conventional studies with regard to general toxicity, genotoxicity and carcinogenicity did not show any particular risks for humans. In reproduction studies in animals corticosteroids, such as budesonide, were shown to be able to cause malformations of various kinds (cleft palate, skeletal malformation). However, the experimental animal results do not appear to have any relevance for humans with recommended doses of Rhinocort Aqua. Pharmaceutical Particulars
List of excipients
Microcrystalline cellulose Carmellose sodium Anhydrous glucose Polysorbate 80 Disodium edetate Potassium sorbate (E 202) Hydrochloric acid The amount of preservative, potassium sorbate (E 202), is 1.2 mg/ml in both strengths. Shelf-life
Special precautions for storage
Do not store above 30 ºC. Do not freeze. Rhinocort Aqua SPC 14v004 (Paed+PSUR120512) Nature and contents of container
Brown glass bottles fitted with a spray pump and nasal applicator. Pack sizes: Rhinocort Aqua 32 μg/dose 120 doses Rhinocort Aqua 64 μg/dose 120 doses Special precautions for disposal and other handling
Before Rhinocort Aqua is used for the first time, the nasal applicator must be primed
with the drug. Therefore, shake the bottle, and spray into the air until there is an even
mist. The effect of this lasts for approx. 24 hours. If a longer period elapses before the
next dose is taken, the nasal applicator must be primed with the drug again. This time
it is sufficient to spray just once into the air.
How the patient should take Rhinocort Aqua is described in detail in the package
leaflet.
MARKETING AUTHORISATION HOLDER
AstraZeneca AB, S-151 85 Södertälje, Sweden. MARKETING AUTHORISATION NUMBER(S)
Rhinocort Aqua 32 μg/dose 18341 Rhinocort Aqua 64 μg/dose 18340 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
31 August 1999/15 November 2005 DATE OF REVISION OF THE TEXT
Rhinocort Aqua SPC 14v004 (Paed+PSUR120512)

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