Bronchial asthma.

This pharmaceutical form is indicated for patients who cannot use the spray for inhalation or Turbuhaler for administration of the medical product.

The dosage of Polmena^® Inhalation Suspension is individual. In the case of daily doses up to 1mg the whole dose may be given in one administration. In the case of higher daily doses the dose is divided into two administrations per day.

For children, the highest dose (2 mg per day) should only be administered in case of severe asthma and during a limited period of time.

Initially the dosage:

When treatment is started, during periods of severe asthma and while reducing or discontinuing oral glucocorticosteroids, the recommended dose of Polmena^® Inhalation Suspension is:
Adults (including elderly): usually 1 – 2 mg twice daily. In very severe cases the dosage may be further increased.

Children 12 years and older: Dosage as for adults.

Children 3 months to 12 years: 0.5 – 1 mg twice daily.

Maintenance:
The maintenance dose should be individualized and be the lowest dose which keeps the patient symptoms-free.
Adults (including elderly and children 12 years and older): 0.5 – 1 mg twice daily.

Children 3 months to 12 years: 0.25 – 0.5 mg twice daily.

Dosage table:

*should be diluted to 2 ml with 0.9 % saline or solution for Inhalation, see 6.6.

Following a single dose an effect may be expected after a few hours. The full therapeutic effect is achieved only after several weeks of treatment. Treatment with Polmena^® is prophylactic therapy with no demonstrated effect on acute disorders.

In patients in whom an increased therapeutic effect is desired, in general an increase of the Polmena^® dose is to be recommended in preference to combination treatment with oral corticosteroids because of the lower risk of systemic side effects.

The maintenance dose should be the lowest possible.

Patients dependent on oral steroids:

When transfer from oral steroids is initiated the patient must be in a relatively stable condition. A high dose of Polmena^® is given in combination with the previously used oral steroid dose for 10 days. After that, the oral dose should be gradually reduced by e.g. 2.5 mg prednisolone or equivalent per month to the lowest possible level. The oral steroid can often be discontinued entirely.

Since budesonide given as Polmena^® Inhalation Suspension is deposited in the lungs with the aid of inspiration, it is important that the patient inhales calmly and with even breaths through the mouthpiece of the nebuliser.

There is no experience of treatment of patients with impaired hepatic or renal function. Since budesonide is eliminated predominantly through metabolism in the liver, increased exposure may be expected in patients with severe cirrhosis of the liver.

A face-mask can be used for children who cannot breathe in through the mouthpiece.

Instructions for correct use of Polmena^® Inhalation Suspension

Polmena^® Inhalation Suspension is inhaled with the aid of a jet nebuliser fitted with a mouthpiece or suitable facemask.

To minimise the risk of oropharyngeal candida infection, the patient should rinse their mouth out with water after inhaling.

Note

·                     It is important to instruct the patient/carer to wash the facial skin with water after using the face-mask to prevent facial skin irritation.

·                     Ultrasonic nebulisers must not be used, as they deliver too low a dose of budesonide to the patient.

·                     The nebuliser and compressor (propeller unit) must be adjusted so that the majority of the delivered drops of liquid are in the range of 3 to 5 micrometres.

An in-vitro study has shown that nebulisers of the types Pari Inhalierboy, Pari Master and Aiolos deliver comparable doses of budesonide.

·      The amount of budesonide delivered to a patient varies between 11 and 22 % of the amount administered in the nebuliser, and depends on factors such as:

- Nebulisation time.

- Volume fill.

- Technical performance of the compressor (propeller unit) and the nebulizer.

- Patient’s tidal volume.

- Use of face-mask or mouthpiece.

The air-flow rate through the nebuliser is also important. In order to obtain the maximum available dose of budesonide a flow rate of 5-8 l/min is required. The fill volume should be 2-4 ml.
The available dose for small children is maximised by the use of a closely fitting face- mask.

The single-dose unit must be shaken carefully before being opened.
The nebuliser chamber must be cleaned after every administration. Wash the chamber and mouthpiece or face-mask with warm tap water and use a mild detergent.
Rinse thoroughly and dry the chamber by connecting it to the compressor or air inlet. See also the nebuliser manufacturer’s instructions.

Budesonide is not intended for rapid relief of acute episodes of asthma where an inhaled short-acting bronchodilator is required.

Care is needed in patients transferring from oral steroids, since they may remain at risk of impaired adrenal function for a considerable time. Patients who have required high dose emergency corticosteroid therapy or prolonged treatment at the highest recommended dose of inhaled corticosteroids may also be at risk. These patients may exhibit signs and symptoms of adrenal insufficiency when exposed to severe stress. Additional systemic corticosteroid treatment should be considered during periods of stress or elective surgery.

Systemic effects of inhaled corticosteroids may occur, particularly at high doses prescribed for prolonged periods. These effects are much less likely to occur than with oral corticosteroids. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract, glaucoma, and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children). It is important therefore that the dose of inhaled corticosteroid is titrated to the lowest dose at which effective control of asthma is maintained.

Regular monitoring of growth is recommended in children and adolescents receiving long-term treatment with corticosteroids, irrespective of the administration form. The benefits of corticosteroid treatment must be placed in relation to possible risks of inhibition of growth.

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

Concomitant use of ketoconazole, itraconazole, HIV protease inhibitors or other potent CYP3A4 inhibitors should be avoided. If this is not possible, the period between treatments should be as long as possible (see also section 4.5).

Special caution is necessary in patients with active or quiescent pulmonary tuberculosis, and in patients with fungal or viral infections in the airways.

Oral candidiasis may occur during the therapy with inhaled corticosteroids. This infection may require treatment with appropriate antifungal treatment and in some patients discontinuation of treatment may be necessary (see also section 4.2).

As with other inhalation therapy, paradoxical bronchospasm may occur with an immediate increase in wheezing after dosing. If this occurs, treatment with inhaled budesonide should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.

Patients must be instructed to contact their physician if the effect of the treatment generally diminishes, as repeated inhalations for severe asthma attacks must not delay the initiation of other important therapy. In the event of acute deterioration the treatment should be supplemented with a course of oral steroid for a short period.

During transfer from oral steroid therapy to Polmena^® Inhalation Suspension, patients may experience previous symptoms such as muscle and joint pain. In these cases a temporary increase of the oral steroid dose may be necessary. If, in isolated cases, fatigue, headache, nausea, vomiting or similar symptoms occur, a generally inadequate steroid effect should be suspected.

Replacement of systemic steroid treatment by Polmena^® Inhalation Suspension sometimes reveals allergies, e.g. rhinitis and eczema that were previously controlled by the systemic treatment.

The metabolism of budesonide is primarily mediated by CYP3A4. Inhibitors of this enzyme, e.g. itraconazole, ketoconazole, HIV protease inhibitors can therefore increase systemic exposure to budesonide several times (see section 4.4). Since there are 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 budesonide dose could also be considered. 

Limited data about this interaction for high-dose inhaled budesonide indicate that marked increases in plasma levels (on average four-fold) may occur if itraconazole 200 mg once daily is administered concomitantly with inhaled budesonide (single dose of 1,000 μg).

Raised plasma concentrations of and increased effects of corticosteroids have been observed in women also treated with estrogens and contraceptive steroids, but no effect has been observed with budesonide 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).

Pregnancy

Results from approximately 2,000 pregnancies have not revealed any increased risk of malformations as a result of treatment with budesonide. Animal studies have shown that glucocorticosteroids can induce malformations (see 5.3), but this is judged not to be relevant for humans with the recommended dosage.

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

During pregnancy the aim must be the lowest effective dose of budesonide while taking account of the risk of a worsening of the asthma.

Lactation

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

Polmena^® has no influence on the ability to drive and use machines.

Tabulated list of adverse reactions

Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).

Table 1: Undesirable drug effects by organ system and frequency

On account of the risk of Candida infections in the oropharynx the patient must rinse the mouth with water after every dose.

* Facial skin irritation, as an example of a hypersensitivity reaction, has occurred in some cases when a nebuliser with a face-mask has been used. To prevent irritation, the facial skin should be washed with water after use of the face-mask.

There is an increased risk of pneumonia in patients with newly diagnosed COPD starting treatment with inhaled corticosteroids. However, a weighted analysis of 8 pooled clinical trials involving 4,643 COPD patients treated with budesonide and 3,643 patients randomised to non-inhaled corticosteroid treatments is not demonstrate an increased risk of pneumonia. The results from the first 7 of these 8 trials have been published as a meta-analysis.

** Paediatric population:

Due to the risk of growth retardation in the paediatric population, growth should be monitored regularly, as described in section 4.4.

To report any side effect(s):

•Saudi Arabia:

The National Pharmacovigilance Center (NPC):

SFDA Call Center: 19999

E-mail: npc.drug@sfda.gov.sa

Website: https://ade.sfda.gov.sa

•United Arab of Emirates:

Pharmacovigilance and Medical Device Section

P.O. Box: 1853, Tel: 80011111

Email: pv@mohap.gov.ae

Drug Department, Ministry of Health & Prevention

Dubai-UAE.

•Other GCC States:

Please contact the relevant competent authority.

Acute overdosage with Polmena^®, even in excessive doses, is not expected to be a clinical problem. If it is used chronically in high doses, systemic effects of glucocorticosteroids such as hypercortisolism and adrenal suppression may occur.

Pharmacotherapeutic group: Other drugs for obstructive airway diseases, inhalants, glucocorticoids. ATC Code: R03B A02

Budesonide is a glucocorticosteroid with high local anti-inflammatory effect.

The precise mechanism of action of glucocorticosteroids in the treatment of asthma is not fully understood. Anti-inflammatory effects, such as inhibited release of inflammatory mediator and inhibition of cytokine-mediated immune response are probably important.

The activity of budesonide, measured as affinity for glucocorticosteroid receptors is approx. 15 times higher than that of prednisolone.

Budesonide has shown anti-inflammatory effects such as reduced bronchial obstruction during both the early and the late phase of an allergic reaction. Budesonide reduces histamine and metacholine activity in the airways in hyper-reactive patients.
Studies have shown that the earlier the treatment with budesonide is initiated after the onset of asthma, the better is the lung function that can be expected.
Dose-related suppression of plasma and urinary cortisol have been observed in studies in healthy volunteers treated with budesonide. At recommended doses, budesonide causes a significantly lower effect on the adrenal function than prednisolone 10 mg, as shown by ACTH tests.

In children over the age of 3 years, no systemic effects have been detected with doses up to 400 micrograms per day. In the range 400-800 micrograms per day biochemical signs of a systemic effect may occur. With daily doses in excess of 800 micrograms such signs are common. This information applies to budesonide administered as inhalation spray and inhalation powder.

Asthma itself, like inhaled corticosteroids, can retard growth. Limited data from long- term studies suggest that most children and adolescents treated with inhaled budesonide will ultimately achieve their adult target height. However, an initial small but transient reduction in growth (approximately 1 cm) has been observed. This generally occurs within the first year of treatment.

Inhalation therapy with budesonide is effective in preventing effort-induced asthma.

Absorption

In adults the systemic availability of budesonide following administration of budesonide inhalation suspension via a jet nebuliser is approximately 15% of the nominal dose and 40% to 70% of the dose delivered to the patients. A minor fraction of the systemically available drug comes from swallowed drug. The maximal plasma concentration, occurring about 10 to 30 min after start of nebulisation is approximately 4 nmol/L after a single dose of 2 mg.

Distribution

Budesonide has a volume of distribution of approximately 3 L/kg. Plasma protein binding averages 85 - 90%.

Biotransformation

Budesonide undergoes an extensive degree (≈90%) of biotransformation on first passage through the liver to metabolites of low glucocorticosteroid activity. The glucocorticosteroid activity of the major metabolites, 6β-hydroxybudesonide and 16α-hydroxyprednisolone, is less than 1% of that of budesonide. The metabolism of budesonide is primarily mediated by CYP3A, a subfamily of cytochrome P450.

Elimination

The metabolites of budesonide are excreted as such or in conjugated form mainly via the kidneys. No unchanged budesonide has been detected in the urine. Budesonide has high systemic clearance (approximately 1.2 L/min) in healthy adults, and the terminal half-life of budesonide after iv dosing averages 2 - 3 hours.

Linearity

The kinetics of budesonide are dose-proportional at clinically relevant doses.

In a study, 100 mg ketoconazole taken twice daily, increased plasma levels of concomitantly administered oral budesonide (single dose of 10 mg) on average, by 7.8-fold. Information about this interaction is lacking for inhaled budesonide, but marked increases in plasma levels could be expected.

Paediatric population

Budesonide has a systemic clearance of approximately 0.5 L/min in 4 - 6 years old asthmatic children. Per kg body weight children have a clearance which is approximately 50% greater than in adults. The terminal half-life of budesonide after inhalation is approximately 2.3 hours in asthmatic children. This is about the same as in healthy adults. In 4 - 6 years old asthmatic children, the systemic availability of budesonide following administration of budesonide Inhalation Suspension via a jet nebuliser (Pari LC Jet Plus® with Pari Master® compressor) is approximately 6% of the nominal dose and 26% of the dose delivered to the patients. The systemic availability in children is about half of that in healthy adults.

The maximal plasma concentration, occurring approximately 20 min after start of nebulisation is approximately 2.4 nmol/L in 4 - 6 years old asthmatic children after a 1 mg dose. The exposure (Cmax and AUC) of budesonide following administration of a single 1 mg dose by nebulisation to 4 - 6 year old children is comparable to that in healthy adults given the same delivered dose by the same nebuliser system.

In toxicity studies budesonide caused only the expected glucocorticoid effects. Budesonide has not exhibited any genotoxic effects.

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

Polysorbate 80, sodium chloride, EDTA, citric acid, sodium citrate, water for injection.

None.

Do not store above 30°C, do not freeze.

Store in an upright position and protected from light.

After opening of the pouch, the unused single-dose ampoules should be kept in the pouch to protect them from light.

Single-dose ampoules that are stored in an opened pouch must be used within 3 months.

The contents of an opened single-dose ampoule must be used within 60 minutes. Discard any unused suspension.

Polmena^® 0.5 mg/ml Inhalation Suspension: This product is a suspension containing fine particles. After keeping it in upright position, the fine particles precipitate and it becomes white or off-white suspension after shaking, presented in single-dose low-density polyethylene ampoule, intended for inhalation use.

Pack size: 20 Single-dose ampoules (5 ampoules/Pouch, 4 Pouches/Pack).

No special requirements.