Agencia Lei Va Hong
Full Prescribing Info
Salmeterol xinafoate.
Pressurised metered-dose inhaler delivering 25 micrograms salmeterol (as xinafoate) with each actuation.
Excipients/Inactive Ingredients: See Table 1.

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Pharmacology: Pharmacodynamics: Mechanism of Action: Salmeterol is a selective long-acting (12 hour) beta-2-adrenoceptor agonist with a long side chain which binds to the exo-site of the receptor.
Pharmacodynamic Effects: These pharmacological properties of salmeterol offer more effective protection against histamine-induced bronchoconstriction and produce a longer duration of bronchodilation, lasting for at least 12 hours, than recommended doses of conventional short-acting beta-2 agonists. In vitro tests have shown salmeterol is a potent and long-lasting inhibitor of the release from the human lung of mast cell mediators, such as histamine, leukotrienes and prostaglandin D2. In man salmeterol inhibits the early and late phase response to inhaled allergen; the latter persisting for over 30 hours after a single dose when the bronchodilator effect is no longer evident. Single dosing with salmeterol attenuates bronchial hyper-responsiveness. These properties indicate that salmeterol has additional non-bronchodilator activity, but the full clinical significance is not yet clear. The mechanism is different from the anti-inflammatory effect of corticosteroids which should not be stopped or reduced when salmeterol is prescribed.
Salmeterol has been studied in the treatment of conditions associated with COPD and has been shown to improve symptoms, pulmonary function and quality of life. In vitro salmeterol has also been shown to increase cilial beat frequency of human bronchial epithelial cells and also reduce a ciliotoxic effect of Pseudomonas toxin on the bronchial epithelium of patients with cystic fibrosis.
Clinical Studies: Asthma: The Salmeterol Multi-center Asthma Research Trial (SMART) was a large US study that compared the safety of SEREVENT or placebo added to usual therapy. There were no significant differences in the primary endpoint of the combined number of respiratory-related deaths and respiratory-related life-threatening experiences. The study showed a significant increase in asthma-related deaths in patients receiving SEREVENT (13 deaths out of 13,176 patients treated for 28 weeks on SEREVENT, versus, 3 deaths out of 13,179 patients on placebo). The study was not designed to assess the impact of concurrent inhaled corticosteroid use. However, post-hoc analyses showed there was no significant difference between treatment groups for asthma-related deaths for those patients using inhaled steroids at baseline (4/6127 on SEREVENT versus 3/6138 on placebo). The numbers of asthma-related deaths in the groups not using inhaled steroids were 9/7049 on SEREVENT versus 0/7041 on placebo. (See Tables 2 and 3.)

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Pharmacokinetics: Salmeterol acts locally in the lung therefore plasma levels are not an indication of therapeutic effects. In addition there are only limited data available on the pharmacokinetics of salmeterol because of the technical difficulty of assaying the drug in plasma due to the low plasma concentrations at therapeutic doses (approximately 200 picogram/ml or less) achieved after inhaled dosing.
In a placebo-controlled, crossover drug interaction study in 15 healthy subjects, coadministration of SEREVENT (50 micrograms twice daily inhaled) and the CYP3A4 inhibitor ketoconazole (400 mg once daily orally) for 7 days resulted in a significant increase in plasma salmeterol exposure (1.4-fold Cmax and 15-fold AUC). There was no increase in salmeterol accumulation with repeat dosing. Three subjects were withdrawn from SEREVENT and ketoconazole co-administration due to QTc prolongation or palpitations with sinus tachycardia. In the remaining 12 subjects, co-administration of SEREVENT and ketoconazole did not result in a clinically significant effect on heart rate, blood potassium or QTc duration (see Precautions and Interactions).
Absorption: After regular dosing with salmeterol xinafoate, hydroxynaphthoic acid can be detected in the systemic circulation, reaching steady state concentrations of approximately 100 nanograms/ml. These concentrations are up to 1000 fold lower than steady state levels observed in toxicity studies and in long term regular dosing (more than 12 months) in patients with airways obstruction, have been shown to produce no ill effects.
Metabolism: An in vitro study showed that salmeterol is extensively metabolised to α-hydroxysalmeterol (aliphatic oxidation) by cytochrome P450 3A4 (CYP3A4). A repeat dose study with salmeterol and erythromycin in healthy volunteers showed no clinically significant changes in pharmacodynamic effects at 500 mg three times daily doses of erythromycin. However, a salmeterol-ketoconazole interaction study resulted in a significant increase in plasma salmeterol exposure. (See Precautions and Interactions).
Salmeterol is a selective long-acting bronchodilator indicated for the regular symptomatic treatment of reversible airways obstruction in patients with asthma, including those with nocturnal asthma or chronic obstructive pulmonary disease (COPD). SEREVENT Inhaler may also be used for the prevention of exercise-induced asthma.
For patients with asthma, it is indicated for those treated with inhaled corticosteroids who require a long-acting beta-agonist.
SEREVENT Inhaler is not a replacement for inhaled or oral corticosteroids which should be continued at the same dose, and not stopped or reduced, when treatment with SEREVENT Inhaler is initiated.
Dosage/Direction for Use
SEREVENT Inhaler is for inhalation use only.
SEREVENT Inhaler should be used regularly. The full benefits of treatment will be apparent after several doses of the drug. As there may be adverse effects associated with excessive dosing with this class of drug, the dosage or frequency of administration should only be increased on medical advice.
Recommended Doses: Asthma: Adults and adolescents 12 years and older: Two actuations of 25 micrograms salmeterol twice daily.
In asthma patients with more severe airways obstruction up to four inhalations of 25 micrograms of salmeterol twice daily may be of benefit.
Children aged 4 years and older: Two actuations of 25 micrograms salmeterol twice daily.
There are insufficient data available currently to support use of SEREVENT Inhaler in children under four years of age.
COPD: Adults: Two actuations of 25 micrograms salmeterol twice daily.
Children: Not appropriate.
Special patient groups: There is no need to adjust the dose in elderly patients or in those with renal impairment. There are no data available on the use of SEREVENT Inhaler in patients with hepatic impairment.
Symptoms and Signs: The expected symptoms and signs of SEREVENT overdosage are those typical of excessive beta-2-adrenergic stimulation, including tremor, headache, tachycardia, increases in systolic blood pressure and hypokalaemia.
Treatment: If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary. Further management should be as clinically indicated or as recommended by the national poisons centre, where available.
Hypersensitivity to any ingredient of the preparation.
Special Precautions
SEREVENT should be used only as an adjunct to corticosteroids in the management of asthma.
SEREVENT should not be initiated in patients with significantly worsening or acutely deteriorating asthma. Sudden and progressive deterioration in control of asthma is potentially life-threatening and consideration should be given to increasing corticosteroid therapy. In patients at risk, daily peak flow monitoring may be instituted. For maintenance treatment of asthma salmeterol should be given in combination with inhaled or oral corticosteroids.
Increasing use of bronchodilators, in particular short-acting inhaled beta-2 agonists, to relieve symptoms indicates deterioration of asthma control.
Patients must be warned not to stop steroid therapy and not to reduce it without medical advice even if they feel better on SEREVENT.
As with other inhalation therapy paradoxical bronchospasm may occur with an immediate increase in wheezing after dosing. This should be treated immediately with a fast and short-acting inhaled bronchodilator. Salmeterol should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary (see Adverse Reactions).
The pharmacological side-effects of beta-2 agonist treatment, such as tremor, subjective palpitations and headache have been reported, but tend to be transient and to reduce with regular therapy (see Adverse Reactions).
Cardiovascular effects, such as increases in systolic blood pressure and heart rate, may occasionally be seen with all sympathomimetic drugs, especially at higher than therapeutic doses. For this reason, salmeterol should be used with caution in patients with pre-existing cardiovascular disease.
There have been very rare reports of increases in blood glucose levels (see Adverse Reactions) and this should be considered when prescribing to patients with a history of diabetes mellitus.
Salmeterol should be administered with caution in patients with thyrotoxicosis.
A transient decrease in serum potassium may occur with all sympathomimetic drugs at higher than therapeutic doses. Therefore, SEREVENT should be used with caution in patients predisposed to low levels of serum potassium.
Data from a large US study (SMART) comparing the safety of SEREVENT or placebo added to usual therapy showed an increase in asthma-related deaths in patients receiving SEREVENT. Data from this study suggested that African-American patients may be at greater risk of serious respiratory-related events or deaths when using SEREVENT compared to placebo. It is not known if this was due to pharmacogenetic or other factors. Long-acting beta2-agonists, such as SEREVENT, should be prescribed with corticosteroids. (See Indications/Uses and Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
It was observed in a drug interaction study that concomitant use of systemic ketoconazole increases exposure to SEREVENT. This may lead to prolongation in the QTc interval. Caution should be exercised when strong CYP3A4 inhibitors (e.g. ketoconazole) are co-administered with SEREVENT. (See Interactions and Pharmacology: Pharmacokinetics under Actions).
Patients should be instructed in the proper use of their inhaler and their technique checked to ensure optimum delivery of the inhaled drug to the lungs.
This medicine should be used for the shortest duration of time required to achieve control of asthma symptoms and discontinue, if possible, once asthma control is achieved. This medicine should only be used long-term in patients whose asthma cannot be adequately controlled on asthma controller medications.
Effects on Ability to Drive and Use Machines: None reported.
Use In Pregnancy & Lactation
Pregnancy: In animal studies, some effects on the foetus, typical for a beta-2 agonist, occurred at exposure levels substantially higher than those that occur with therapeutic use. Extensive experience with other beta-2 agonists has provided no evidence that such effects are relevant for women receiving clinical doses.
There are no adequate and well-controlled studies of salmeterol in pregnant women. The effect of salmeterol on human pregnancy is unknown.
As with any medicine, use during pregnancy should be considered only if the expected benefit to the mother is greater than any possible risk to the foetus.
Lactation: Plasma levels of salmeterol after inhaled therapeutic doses are negligible and therefore levels in milk should be correspondingly low. Nevertheless, as there is limited experience of the use of salmeterol in nursing mothers, its use in such circumstances should only be considered if the expected benefit to the mother is greater than any possible risk to the infant.
Studies in lactating animals support the view that salmeterol is likely to be secreted in only very small amounts into breast milk.
Adverse Reactions
Adverse events are listed as follows by system organ class and frequency. Frequencies are defined as: very common (≥ 1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000) and very rare (<1/10,000) including isolated reports. Common and uncommon events were generally determined from clinical trial data. The incidence of placebo was not taken into account. Very rare events were generally determined from post-marketing spontaneous data.
The following frequencies are estimated at the standard dose of 50 micrograms twice daily. Frequencies at the higher dose of 100 micrograms twice daily have also been taken to account where appropriate.
Immune system disorders: Hypersensitivity reactions: Uncommon: Rash.
Very rare: Anaphylactic reactions including oedema and angioedema, bronchospasm and anaphylactic shock.
Metabolism and nutrition disorders: Very rare: Hyperglycaemia.
Nervous system disorders: Common: Tremor and headache (see Precautions).
The pharmacological side-effects of beta-2 agonist treatment, such as tremor and headache have been reported, but tend to be transient and to reduce with regular therapy. Tremor occurs more commonly when administered at doses higher than 50mcg twice daily.
Cardiac disorders: Common: Palpitations (see Precautions).
Uncommon: Tachycardia.
Tachycardia occurs more commonly when administered at doses higher than 50 mcg twice daily.
Very rare: Cardiac arrhythmias including atrial fibrillation, supraventricular tachycardia and extrasystoles.
Respiratory, thoracic and mediastinal disorders: Very rare: Oropharyngeal irritation and paradoxical bronchospasm (see Precautions).
Musculoskeletal and connective tissue disorders: Common: Muscle cramps.
Very rare: Arthralgia.
Drug Interactions
Both non-selective and selective beta-blockers should be avoided in patients with reversible obstructive airways disease, unless there are compelling reasons for their use.
Co-administration of ketoconazole and SEREVENT resulted in a significant increase in plasma salmeterol exposure (1.4-fold Cmax and 15-fold AUC) and this may cause a prolongation of the QTc interval. (See Precautions and Pharmacology: Pharmacokinetics under Actions).
Caution For Usage
Instructions for Use/Handling: Testing the inhaler: Before using for the first time or if the inhaler has not been used for a week or more remove the mouthpiece cover by gently squeezing the sides of the cover, shake the inhaler well, and release one puff into the air to make sure that it works.
Using the inhaler: 1. Remove the mouthpiece cover by gently squeezing the sides of the cover.
2. Check inside and outside of the inhaler including the mouthpiece for the presence of loose objects.
3. Shake the inhaler well to ensure that any loose objects are removed and that the contents of the inhaler are evenly mixed.
4. Hold the inhaler upright between fingers and thumb with the thumb on the base, below the mouthpiece.
5. Breathe out as far as is comfortable and then place the mouthpiece in the mouth between the teeth and close the lips around it but do not bite it.
6. Just after starting to breathe in through the mouth press down on the top of the inhaler to release SEREVENT while still breathing in steadily and deeply.
7. While holding the breath, take the inhaler from the mouth and take the finger from the top of the inhaler. Continue holding the breath for as long as is comfortable.
8. To take further puffs, keep the inhaler upright and wait about half a minute before repeating steps 3 to 7.
9. Replace the mouthpiece cover by firmly pushing and snapping the cap into position.
Important: Do not rush steps 5, 6 and 7. It is important to start breathing in as slowly as possible just before operating the inhaler. Practice in front of a mirror for the first few times. If "mist" can be seen coming from the top of the inhaler or the sides of the mouth, start again from step 2.
If the doctor has given different instructions for using the inhaler, please follow them carefully. Tell the doctor if the patient has any difficulties.
Children: Young children may need help and an adult may need to operate the inhaler for them. Encourage the child to breathe out and operate the inhaler just after the child starts to breathe in. Practice the technique together. Older children or people with weak hands should hold the inhaler with both hands. Put the two forefingers on the top of the inhaler and both thumbs on the base below the mouthpiece.
Caution: The metal canister is pressurised. Do not attempt to puncture it or burn even when empty.
If the inhaler becomes very cold, remove the metal canister and warm in hand a few minutes before use. Never use other forms of heat.
Cleaning: The inhaler should be cleaned at least once a week.
1. Remove the mouthpiece cover.
2. Do not remove the canister from the plastic casing.
3. Wipe the inside and outside of the mouthpiece and the plastic casing with a dry cloth or tissue.
4. Replace the mouthpiece cover.
Do not put the metal canister into water.
Replace the mouthpiece cover firmly and snap it into position.
Protect from frost and direct sunlight.
As with most inhaled medications in pressurised metered-dose inhalers, the therapeutic effect of this medication may decrease when the canister is cold.
The canister should not be broken, punctured or burnt, even when apparently empty.
ATC Classification
R03AC12 - salmeterol ; Belongs to the class of adrenergic inhalants, selective beta-2-adrenoreceptor agonists. Used in the treatment of obstructive airway diseases.
Inhaler 25 mcg/actuation (pressurised metered-dose) x 120 actuations.
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