RESPOCORT 100 MCG/ACTUATION PRESSURISED INHALATION SOLUTION AUTOHALER - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Respocort 100 microgram­s/actuation pressurised inhalation solution Autohaler™

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each actuation of Respocort Autohaler delivers Beclometasone Dipropionate 100 micrograms ex-valve into the mouthpiece of the actuator.

(The dose delivered from the mouthpiece is on average 75 micrograms)

For the full list of excipients see 6.1.

3 PHARMACEUTICAL FORM

Pressurised inhalation solution for use through a breath actuated actuator.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Prophylactic management of mild, moderate or severe asthma.

4.2 Posology and method of administration

Posology

NOTE: The recommended total daily dose of Respocort is lower than that for current beclometasone dipropionate CFC containing products and should be adjusted to the needs of the individual patient.

ADULT STARTING AND MAINTENANCE DOSE:

It is important to gain control of asthma symptoms and optimise pulmonary function as soon as possible. When patients’ symptoms remain under satisfactory control, the dose should be titrated to the lowest dose at which effective control of asthma is maintained.

To be effective inhaled Respocort must be used on a regular basis even when patients are asymptomatic.

THERAPY IN NEW PATIENTS SHOULD BE INITIATED AT THE

FOLLOWING DOSAGES

Mild asthma:     100 to 200 micrograms per day in two divided doses.

Moderate asthma: 200 to 400 micrograms per day in two divided doses. Severe asthma: 400 to 800 micrograms per day in two divided doses.

TRANSFERRING PATIENTS TO RESPOCORT FROM A CFC-CONTAINING INHALER

The general approach to switching patients to Respocort involves two steps as detailed below. Specific guidance on switching well-controlled and poorly-controlled (symptomatic) patients is given below the table.

Step 1 : Consider the dose of CFC containing beclometasone dipropionate product appropriate to the patient’s current condition.

Step 2 : Convert the CFC containing beclometasone dipropionate dose to the Respocort dose according to the table below.

1. Dosing in well-controlled patients with asthma

Patients with well-controlled asthma using beclometasone dipropionate CFC containing product should be switched to Respocort at a dose in accordance with the table above.

For example:

Patients on 2 puffs twice daily of CFC beclometasone dipropionate 200 micrograms would change to 2 puffs twice daily of Respocort 100 micrograms.

2. Dosing in poorly-controlled (symptomatic) patients with asthma

Patients with poorly-controlled asthma may be switched from CFC containing beclometasone dipropionate products to Respocort at the same microgram for microgram dose, since comparative clinical studies have demonstrated that asthma patients achieve equivalent pulmonary function and control of symptoms with Respocort at lower total daily doses than with CFC containing beclometasone dipropionate products.

Alternatively the patient’s current CFC containing beclometasone dipropionate dose can be doubled and this dose can be converted to the Respocort dose according to the table above.

Once transferred to Respocort the dose should be adjusted to meet the needs of the individual patient.

The maximum recommended dose is 800 micrograms per day in divided doses.

The same total daily dose in micrograms from either Respocort 50 (a lower strength) or Respocort 100 Autohaler provides the same clinical effect.

Paediatric population

The safety and efficacy of Respocort in children under 12 years of age have not yet been established.

Special patient groups

No special dosage recommendations are made for elderly or patients with hepatic or renal impairment.

Method of administration

Respocort is for oral inhalation use only

Patients should be instructed in the proper use of their inhaler, including rinsing out their mouth with water after use. Patients should be advised that Respocort may have a different taste and feel than a CFC inhaler.

Respocort Autohaler is a breath-actuated inhaler which automatically releases the metered dose of medication during a patient’s inha­lation through the mouthpiece and overcomes the need for patients to have good manual coordination.

The patient should read the instruction leaflet before use.

Respocort delivers a consistent dose

– whether or not the canister is shaken by the patient

– without the need for the patient to wait between individual actuations

– regardless of storage orientation or periods without use of up to 14 days

– at temperatures as low as –10°C.

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

To be effective, Respocort must be used by patients on a regular basis, even when patients do not have asthma symptoms. When symptoms are controlled, maintenance Respocort therapy should be reduced in a stepwise manner to the minimum effective dose. Inhaled steroid treatment should not be stopped abruptly.

Patients with asthma are at risk of acute attacks and should have regular assessments of their asthma control including pulmonary function tests.

Respocort is not indicated for the immediate relief of asthma attacks. Patients therefore need to have relief medication (inhaled short-acting bronchodilator) available for such circumstances.

Respocort is not indicated in the management of status asthmaticus.

Severe asthma exacerbations should be managed in the usual way. Subsequently, it may be necessary to increase the dose of Respocort up to the maximum daily dose. Systemic steroid treatment may be needed and/or an antibiotic, if there is an infection.

Patients should be advised to seek medical attention for review of maintenance Respocort therapy if peak flow falls, symptoms worsen or if the short-acting bronchodilator becomes less effective and increased inhalations are required. This may indicate worsening asthma.

Patients who have received systemic steroids for long periods of time or at high doses, or both, need special care and subsequent management when being transferred to inhaled steroid therapy. Patients should have stable asthma before being given inhaled steroids in addition to the usual maintenance dose of systemic steroid. Withdrawal of systemic steroids should be gradual, starting about seven days after the introduction of Respocort therapy. For daily oral doses of prednisolone of 10mg or less, dose reduction in 1mg steps, at intervals of not less than one week is recommended. For patients on daily maintenance doses of oral prednisolone greater than 10mg, larger weekly reductions in the dose might be acceptable. The dose reduction scheme should be chosen to correlate with the magnitude of the maintenance systemic steroid dose.

Most patients can be successfully transferred to inhaled steroids with maintenance of good respiratory function, but special care is necessary for the first few months after the transfer, until the hypothalamic-pituitary-adrenal (HPA) system has sufficiently recovered to enable the patient to cope with stressful emergencies such as trauma, surgery or serious infections. Patients should, therefore, carry a steroid warning card to indicate the possible need to re-instate systemic steroid therapy rapidly during periods of stress or where airways obstruction or mucus significantly compromises the inhaled route of administration. In addition, it may be advisable to provide such patients with a supply of corticosteroid tablets to use in these circumstances. The dose of inhaled steroids should be increased at this time and then gradually reduced to the maintenance level after the systemic steroid has been discontinued. As recovery from impaired adrenocortical function, caused by prolonged systemic steroid therapy is slow, adrenocortical function should be monitored regularly.

Patients should be advised that they may feel unwell in a non-specific way during systemic steroid withdrawal despite maintenance of, or even improved respiratory function. Patients should be advised to persevere with their inhaled product and to continue withdrawal of systemic steroids, even if feeling unwell, unless there is evidence of HPA axis suppression.

Discontinuation of systemic steroids may also cause exacerbation of allergic diseases such as atopic eczema and rhinitis. These should be treated as required with topical therapy, including corticosteroids and/or antihistamines.

Beclometasone dipropionate, like other inhaled steroids, is absorbed into the systemic circulation from the lungs. Beclometasone dipropionate and its metabolites may exert detectable suppression of adrenal function. Within the dose range 100–800 micrograms daily, clinical studies with Respocort have demonstrated mean values for adrenal function and responsiveness within the normal range. However, 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 adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children).

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.

It is important, therefore, that the dose of inhaled corticosteroid is titrated to the lowest dose at which effective control of asthma is maintained.

It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroids is regularly monitored. If growth is slowed, therapy should be reviewed with the aim of reducing the dose of inhaled corticosteroid, if possible, to the lowest dose at which effective control of asthma is maintained. In addition, consideration should be given to referring the patient to a paediatric respiratory specialist.

Prolonged treatment with high doses of inhaled corticosteroids, particularly higher than the recommended doses, may result in clinically significant adrenal suppression. Additional systemic corticosteroid cover should be considered during periods of stress or elective surgery.

Like other corticosteroids, caution is necessary in patients with active or latent pulmonary tuberculosis.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

Beclomethasone is less dependent on CYP3A metabolism than some other corticosteroids, and in general interactions are unlikely; however the possibility of systemic effects with concomitant use of strong CYP3A inhibitors (e.g. ritonavir, cobicistat) cannot be excluded, and therefore caution and appropriate monitoring is advised with the use of such agents.

4.6 Fertility, Pregnancy and lactation

Pregnancy

There are no adequate data from the use of Respocort in pregnant women.

An inhalation reproductive study with Respocort in rats did not exhibit any teratogenic effects.

Studies of propellant HFA-134a administered to pregnant and lactating rats and rabbits have not revealed any special hazard.

In animals, systemic administration of relatively high doses of beclometasone dipropionate can cause abnormalities of foetal development including growth retardation and cleft palate. There may therefore be a very small risk of such effects in the human foetus. However, inhalation of beclometasone dipropionate into the lungs avoids the high level of exposure that occurs with administration by systemic routes.

The potential risk for humans is unknown. However, the drug has been in widespread use for many years without apparent ill consequence.

Respocort should not be used during pregnancy unless clearly necessary (the expected benefits to the mother must be thought to outweigh any potential risk to the fetus or neonate).

Breast-feeding

It is probable that beclometasone dipropionate is excreted in milk However, given the relatively low doses used by the inhalation route, the levels are likely to be low. Respocort should not be used during lactation unless clearly necessary (the therapeutic benefits of the drug should be weighed against the potential hazards to mother and baby).

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

When taking Respocort an occasional incidence of hoarseness may occur. Candidiasis of the mouth and throat (thrush) occurs in some patients; the incidence of which is increased with increasing doses of corticosteroid. Patients with high blood levels of Candida precipitins, indicating a previous infection, are more likely to develop this complication. Patients may find it helpful to rinse out their mouth with water after using their inhaler to reduce the risk of candidiasis and hoarseness. Topical anti-fungal therapy can be used for the treatment of candidiasis while continuing treatment with Respocort.

As with other inhaled therapy, paradoxical bronchospasm with wheezing may occur immediately after dosing. Immediate treatment with an inhaled short acting bronchodilator is required. Respocort should be discontinued immediately and alternate prophylactic therapy introduced.

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

Systemic effects of inhaled corticosteroids may occur, particularly at high doses prescribed for prolonged periods. These may include adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma (see Section 4.4).

Common (>1/100 to <1/10):   Mouth/throat: hoarseness,

pharyngitis, taste

Uncommon (>1/1000 to      Respiratory organs: coughing, increased asthma

symptoms <1/100):           Central nervous system: headache, vertigo

Gastro-intestinal system: nausea Muscle-skeleton system: tremor Skin: urticaria, erythema, purpura

Not Known Psychiatric Disorders; Psychomotor hyperactivity, sleep disorders, anxiety, depression, aggression, behavioural changes (predominantly in children)

Eye disorders: Vision, blurred (see 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 at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Acute overdosage is unlikely to cause problems. The only harmful effect that follows inhalation of large amounts of the drug over a short time period is suppression of HPA function. Specific emergency action need not be taken. Treatment with Respocort should be continued at the recommended dose to control the asthma; HPA function recovers in a day or two.

If excessive doses of beclometasone dipropionate were taken over a prolonged period a degree of atrophy of the adrenal cortex could occur in addition to HPA suppression. In this event the patient should be treated as steroid dependent and transferred to a suitable maintenance dose of a systemic steroid such as prednisolone. Once the condition is stabilised, the patient should be returned to Respocort by the method described above in Section 4.4.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Glucocorticoid for inhalation/an­tiasthmatic agent, ATC-Code: R03BA01

Respocort contains beclometasone dipropionate in solution in propellant HFA-134a resulting in an extrafine aerosol. The aerosol droplets are on average much smaller than the beclometasone dipropionate particles delivered by CFC-suspension formulations or dry powder formulations of beclometasone dipropionate. The extrafine particle fraction will be 60% ± 20% of the drug particles < 3.3 microns per shot, ex-actuator.

Radio-labelled deposition studies in patients with mild asthma have demonstrated that the majority of drug (>55% ex-actuator) is deposited in the lung and a small amount (< 35% ex-actuator) is deposited in the oropharynx. These delivery characteristics result in equivalent therapeutic effects at lower total daily doses of Respocort, compared with CFC beclometasone dipropionate formulations.

Inhaled beclometasone dipropionate is now well established in the management of asthma. It is a synthetic glucocorticoid and exerts a topical, anti-inflammatory effect on the lungs, with fewer systemic effects than oral corticosteroids.

Comparative clinical studies have demonstrated that asthma patients achieve equivalent pulmonary function and control of symptoms with Respocort at lower total daily doses than CFC containing beclometasone dipropionate aerosol inhalers.

Pharmacodynamic studies in patients with mild asthma given Respocort for 14 days. have shown that there is a linear correlation among urinary free cortisol suppression, dose administered, and serum total-BOH levels obtained. At a daily dose of 800 micrograms Respocort, suppression of urinary free cortisol was comparable with that observed with the same daily dose of CFC containing beclometasone dipropionate, indicating a wider safety margin, as Respocort is administered at lower doses than the CFC product.

5.2 Pharmacokinetic properties

The pharmacokinetic profile of Respocort shows that the peak serum concentration for total- beclometasone (BOH) (total of any beclometasone OH and beclometasone dipropionate or monopropionate hydrolysed to beclometasone OH) after single and multiple doses is achieved after 30 minutes. The value at the peak is approximately 2 nanograms/mi­llilitre after a total daily dose of 800 micrograms and the serum levels after 100, 200 and 400 micrograms are proportional. The principal route of elimination of beclometasone dipropionate and its several metabolites is in the faeces.

Between 10% and 15% of an orally administered dose is excreted in the urine, as both conjugated and free metabolites of the drug.

In both single dose and multiple dose pharmacokinetic studies, a dose of 200 micrograms of Respocort achieved comparable total-BOH levels, as a dose of 400 micrograms of CFC containing beclometasone dipropionate aerosol.

Pharmacokinetic studies with Respocort have not been carried out in any special populations.

5.3 Preclinical safety data

Safety studies with this product in rat and dog showed few, if any, adverse effects other than those normally associated with general steroid exposure, including lymphoid tissue alterations such as reduction in thymus, adrenal and spleen weights.

In animal studies, propellant HFA-134a has been shown to have no significant pharmacological effects other than at very high exposure concentrations, then narcosis and a relatively weak cardiac sensitising effect were found. The potency of the cardiac sensitisation was less than that of CFC-11 (trichloroflu­oromethane).

In studies to detect toxicity, repeated high dose levels of propellant HFA-134a indicated that safety margins based on systemic exposure would be of the order 2200, 1314 and 381 for mouse, rat and dog with respect to humans.

There are no reasons to consider propellant HFA-134a as a potential mutagen, clastogen or carcinogen judged from in vitro and in vivo studies including long-term administration by inhalation in rodents.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Propellant HFA-134a (Norflurane) Ethanol.

Respocort contains a new propellant and does not contain any chlorofluorocarbons (CFCs).

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

Do not store above 25oC.Storage in direct sunlight or heat should be avoided. Protect from frost.

6.5 Nature and contents of container

Pressurised canister closed with a metering valve containing either 100 or 200 actuations. Each actuation of Respocort Autohaler delivers a nominal 50p.l of solution.

6.6 Special precautions for disposal

As the canister is pressurised, no attempt should be made to puncture or dispose of it by burning.