4.1. Therapeutic indications

Asmanex Twisthaler 400 micrograms Inhalation Powder is indicated in adults and adolescents 12 years of age and older for regular treatment to control persistent asthma.

4.2. Posology and method of administration

Asmanex Twisthaler 400 micrograms Inhalation Powder should be administered by oral inhalation only. After each dose, patients should be advised to rinse their mouth with water and spit out the contents without swallowing.

Posology

Dosage recommendations are based on severity of asthma (see criteria below).

Patients with persistent mild to moderate asthma: The recommended starting dose for most of these patients is 400 micrograms once daily. Data suggest that better asthma control is achieved if once daily dosing is administered in the evening. Some patients may be more adequately controlled on 400 micrograms daily, given in two divided doses (200 micrograms twice daily). (A formulation of Asmanex Twisthaler 200 micrograms Inhalation Powder is also available.)

The dose of Asmanex Twisthaler 400 micrograms Inhalation Powder should be individualised and titrated to the lowest dose at which effective control of asthma is maintained. Dose reduction to 200 micrograms once daily given in the evening may be an effective maintenance dose for some patients.

Patients with severe asthma: The recommended starting dose is 400 micrograms twice daily, which is the maximum recommended dose. When symptoms are controlled, titrate Asmanex Twisthaler 400 micrograms Inhalation Powder to the lowest effective dose.

In patients with severe asthma and previously receiving oral corticosteroids, Asmanex Twisthaler 400 micrograms Inhalation Powder will be initiated concurrently with the patient's usual maintenance dose of systemic corticosteroid. After approximately one week, gradual withdrawal of the systemic corticosteroid can be initiated by reducing the daily or alternate daily dose. The next reduction is made after an interval of one to two weeks, depending on the response of the patient. Generally, these decrements are not to exceed 2.5 mg of prednisone daily, or its equivalent.

A slow rate of withdrawal is strongly recommended. During withdrawal of oral corticosteroids, patients must be carefully monitored for signs of unstable asthma, including objective measures of airway function, and for adrenal insufficiency (see section 4.4).

The patient should be instructed that Asmanex Twisthaler 400 micrograms Inhalation Powder is not intended to be used “on demand” as a reliever medication to treat acute symptoms and that this product must be taken regularly to maintain therapeutic benefit even when he or she is asymptomatic.

Special populations

Paediatric population

The safety and efficacy of Asmanex Twisthaler 400 mcg in children less than 12 years of age have not been established. No data are available.

Elderly patients older than 65 years of age

No dosage adjustment is necessary.

Method of administration

This product is for inhalation use only.

The patient needs to be instructed how to use the inhaler correctly (see below).

Patients should be in an upright position when inhaling the product.

Prior to removing the cap, be sure the counter and the pointer on the cap are aligned. The inhaler can be opened by removing the white cap while holding unit upright (the maroon-coloured base down), gripping the base, and twisting the cap counterclockwise. The counter will register the number down by one count. Instruct the patient to place the inhaler in the mouth, closing the lips around the mouthpiece, and to breathe in rapidly and deeply. Then, the inhaler is removed from the mouth, and the breath held for about 10 seconds, or as long as is comfortable. The patient is not to breathe out through the inhaler. To close, while holding the unit in an upright position, replace the cap immediately after each inhalation, loading for the next dose by rotating the cap clockwise while gently pressing down until a click sound is heard and the cap is fully closed. The arrow on the cap will be fully aligned with the counter window. After inhalation, patients are advised to rinse their mouth with water and spit out the contents without swallowing. This helps to reduce the risk of candidiasis.

The digital display will indicate when the last dose has been delivered; after dose 01, the counter will read 00 and the cap will lock, at which time the unit must be discarded. The inhaler is to be kept clean and dry at all times. The outside of the mouthpiece can be cleaned with a dry cloth or tissue; do not wash the inhaler; avoid contact with water.

For detailed instructions see Package Leaflet.

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

Oropharyngeal candidiasis

During clinical trials with Asmanex Twisthaler 400 micrograms Inhalation Powder, oral candidiasis, which is associated with the use of this class of medicinal product, occurred in some patients. This infection may require treatment with appropriate antifungal therapy and in some patients discontinuance of Asmanex Twisthaler 400 micrograms Inhalation Powder may be necessary (see section 4.8). After dosing the patient with Asmanex Twisthaler 400 micrograms Inhalation Powder, advise patients to rinse their mouth with water and spit out the contents without swallowing.

Systemic effects of corticosteroids

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 and may vary in individual patients and between different corticosteroid preparations. Possible systemic effects may include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataracts glaucoma, and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children). Therefore, it is important that the dose of inhaled corticosteroid is titrated to the lowest dose at which effective control of asthma is maintained.

Visual disturbance may be reported with systemic and topical (including, intranasal, inhaled and intraocular) 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 of visual disturbances 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.

Transferring from systemic corticosteroid therapy

Particular care is needed for patients who are transferred from systemically active corticosteroids to Asmanex Twisthaler 400 micrograms Inhalation Powder, because deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) axis function.

During dose reduction some patients may experience symptoms of systemic corticosteroid withdrawal, e.g., joint and/or muscular pain, lassitude and depression, despite maintenance or even improvement in pulmonary function. Such patients are to be encouraged to continue with both Asmanex Twisthaler 400 micrograms Inhalation Powder treatment and withdrawal of the systemic corticosteroids, unless objective signs of adrenal insufficiency are present. If evidence of adrenal insufficiency occurs, increase the systemic corticosteroid doses temporarily and thereafter continue withdrawal more slowly.

During periods of stress, including trauma, surgery, or infection, or a severe asthma attack, patients transferred from systemic corticosteroids will require supplementary treatment with a short course of systemic corticosteroids, which is gradually tapered as symptoms subside.

It is recommended that such patients carry a supply of oral corticosteroids and a warning card indicating their need and recommended dosage of systemic corticosteroids during stressful periods. Periodic testing of adrenocortical function, particularly measurement of early morning plasma cortisol levels, is recommended.

Transfer of patients from systemic corticosteroid therapy to Asmanex Twisthaler 400 micrograms Inhalation Powder may unmask pre-existing allergic conditions previously suppressed by systemic corticosteroid therapy. If this occurs, symptomatic treatment is recommended.

Effects on HPA axis function

Use of Asmanex Twisthaler 400 micrograms Inhalation Powder will often permit control of asthma symptoms with less suppression of HPA axis function than therapeutically equivalent oral doses of prednisone. Although mometasone furoate has demonstrated low systemic bioavailability at the recommended dosage, it is absorbed into the circulation and can be systemically active at higher doses. Thus, to maintain its profile of limited potential for HPA axis suppression, recommended doses of Asmanex Twisthaler 400 micrograms Inhalation Powder must not be exceeded and must be titrated to the lowest effective dose for each individual patient.

Acute asthma episodes

As with other inhaled asthma medications, bronchospasm may occur with an immediate increase in wheezing after dosing. If bronchospasm occurs following dosing with the Asmanex Twisthaler 400 micrograms Inhalation Powder, immediate treatment with a fast-acting inhaled bronchodilator is recommended; thus, the patient should be told to keep an appropriate beta2-agonist-containing bronchodilator inhaler on hand at all times. In such cases, treatment with Asmanex Twisthaler 400 micrograms Inhalation Powder is then discontinued immediately and alternative therapy instituted.

Asmanex Twisthaler 400 micrograms Inhalation Powder is not to be regarded as a bronchodilator and is not indicated for rapid relief of bronchospasm or asthma attacks; thus, patients should be instructed to keep an appropriate short-acting beta2-agonist-containing bronchodilator inhaler on hand for use when needed. Patients must also be informed of the need to seek medical treatment immediately if their asthma deteriorates suddenly.

Asthma exacerbations

Instruct patients to contact their physician immediately when asthmatic episodes are not responsive to bronchodilators during treatment with this product or if peak-flow falls. This may indicate worsening asthma. During such episodes, patients may require systemic corticosteroid therapy. In these patients, dose titration to the maximum recommended maintenance dose of inhaled mometasone furoate may be considered.

Immunosuppression

Use Asmanex Twisthaler 400 micrograms Inhalation Powder with caution, if at all, in patients with untreated active or quiescent tuberculous infections of the respiratory tract, or in untreated fungal, bacterial, systemic viral infections or ocular herpes simplex.

Advise patients who are receiving corticosteroids or other immunosuppressant medicines of the risk of exposure to certain infections (e.g., chickenpox, measles) and of the importance of obtaining medical advice if such exposure occurs. This is of particular importance in children.

Effects on growth

A reduction of growth velocity in children or adolescents may occur as a result of inadequate control of chronic diseases such as asthma or from use of corticosteroids for treatment. Physicians are advised to closely follow the growth of adolescents taking corticosteroids by any route and weigh the benefits of corticosteroid therapy and asthma control against the possibility of growth suppression if an adolescent's growth appears slowed.

If growth is slowed, review therapy with the aim of reducing the dose of inhaled corticosteroids if possible, to the lowest dose at which effective control of symptoms is achieved. In addition, consideration should be given to referring the patient to a paediatric respiratory specialist.

Adrenal suppression

When using inhaled corticosteroids, the possibility for clinically significant adrenal suppression may occur, especially after prolonged treatment with high doses and particularly with higher than recommended doses. This is to be considered during periods of stress or elective surgery, when additional systemic corticosteroids may be needed. However, during clinical trials there was no evidence of HPA axis suppression after prolonged treatment with Asmanex Twisthaler 400 micrograms Inhalation Powder at doses of ≤ 800 micrograms per day.

Dosing considerations

Lack of response or severe exacerbations of asthma should be treated by increasing the maintenance dose of inhaled mometasone furoate, and if necessary, by giving a systemic corticosteroid and/or an antibiotic if infection is suspected, and by use of beta-agonist therapy.

The patient should be advised against abrupt discontinuation of therapy with Asmanex Twisthaler 400 micrograms Inhalation Powder.

There is no evidence that the administration of this product in amounts greater than recommended doses increases efficacy.

Patients with lactose intolerance

The maximum recommended daily dose contains lactose 4.64 mg per day. This amount does not normally cause problems in lactose intolerant people.

4.5. Interaction with other medicinal products and other forms of interaction

Due to the very low plasma concentration achieved after inhaled dosing, clinically significant drug interactions are unlikely. However, there may be a potential for increased systemic exposure to mometasone furoate when strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, nelfinavir, ritonavir, cobicistat) are co-administered. Co-administration of inhaled mometasone furoate with the potent CYP3A4 enzyme inhibitor ketoconazole causes small but marginally significant (p= 0.09) decreases in serum cortisol AUC (0-24) and resulted in approximately a 2-fold increase in plasma concentration of mometasone furoate.

Interaction studies have only been performed in adults.

Co-treatment with CYP3A inhibitors, including cobicistat-containing products, is expected to increase the risk of systemic side-effects of corticosteroids. The combination 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.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of mometasone furoate in pregnant women. Studies in animals with mometasone furoate, like other glucocorticoids, have shown reproductive toxicity (see section 5.3).

As with other inhaled corticosteroid preparations, mometasone furoate is not to be used during pregnancy unless the potential benefit to the mother justifies the potential risk to the mother, fetus or infant. Infants born of mothers who received corticosteroids during pregnancy are to be observed carefully for hypoadrenalism.

Breast-feeding

It is unknown whether mometasone furoate/metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of mometasone furoate in milk (see section 5.3). A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from mometasone furoate therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

In reproductive studies in rats, there was no effect on fertility (see section 5.3).

4.7. Effects on ability to drive and use machines

Asmanex Twisthaler 400 micrograms Inhalation Powder has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

Summary of safety profile

In placebo-controlled clinical trials, oral candidiasis was very common (> 10 %) in the 400 micrograms twice daily treatment group; other common (1-10 %), treatment-related undesirable effects were pharyngitis, headache and dysphonia. Treatment related undesirable effects seen in the clinical trials and post-marketing reporting with Asmanex Twisthaler Inhalation Powder use are listed below.

Tabulated list of adverse reactions

The adverse reactions reported during clinical trials and the post-marketing period are listed in the following table by treatment regimen, severity, System Organ Class and Preferred Term. 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) and not known (cannot be estimated from the available data).

System Organ Class

QD (Once Daily Dosing)

BID (Twice Daily Dosing)

200 mcg

400 mcg

200 mcg

400 mcg

Infections and infestations

Candidiasis

common

common

common

very common

Immune system disorders

Hypersensitivity reactions including rash, pruritus, angioedema and anaphylactic reaction

not known

not known

not known

not known

Psychiatric disorders

Psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression

not known

not known

not known

not known

Respiratory, thoracic and mediastinal disorders

Pharyngitis

Dysphonia

common

uncommon

common

common

common

common

common

common

Asthma aggravation including cough, dyspnea, wheezing and bronchospasm

not known

not known

not known

not known

General disorders and administration site conditions

Headache

common

common

common

common

Eye disorder

Vision blurred (see also section 4.4)

not known

not known

not known

not known

In patients dependent on oral corticosteroids, who were treated with Asmanex Twisthaler 400 micrograms twice daily for 12 weeks, oral candidiasis occurred in 20 %, and dysphonia in 7 %. These effects were considered treatment-related.

Uncommonly reported adverse events were dry mouth and throat, dyspepsia, weight increase and palpitations.

As with other inhalation therapy, bronchospasm may occur (see section 4.4 Special warnings and precautions for use). This should be treated immediately with a fast-acting inhaled bronchodilator. Asmanex should be discontinued immediately, the patient assessed, and if necessary alternative therapy instituted.

Systemic effects of inhaled corticosteroids may occur, particularly when prescribed at high doses for prolonged periods. These may include adrenal suppression, growth retardation in children and adolescents, and decrease in bone mineral density.

As with other inhaled corticosteroids, rare cases of glaucoma, increased intraocular pressure and/or cataracts have been reported.

As with other glucocorticoid products, the potential for hypersensitivity reactions including rashes, urticaria, pruritus and erythema and oedema of the eyes, face, lips and throat should be considered.

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 at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Because of the low systemic bioavailability of this product, overdose is unlikely to require any therapy other than observation, followed by initiation of the appropriate prescribed dosage. Inhalation or oral administration of excessive doses of corticosteroids may lead to suppression of HPA axis function.

Management

Management of the inhalation of mometasone furoate in doses in excess of the recommended dose regimens should include monitoring of adrenal function. Mometasone furoate therapy in a dose sufficient to control asthma can be continued.