INFORMATION FOR THE PATIENT OR GUARDIAN
Information for the Patient or Guardian about PrFORADIL® inhalation powder capsules
Before using FORADIL, please read these instructions carefully. It contains information about FORADIL and itís use for the treatment of asthma and Chronic Obstructive Pulmonary Disease (COPD). Additional information specific to the treatment of asthma is presented separately in the section "USE IN ASTHMA"
This information may add to the specific advice from your doctor and pharmacist. If, after reading this material, you have further questions, ask your doctor or pharmacist.
USE IN ASTHMA AND COPD
What is FORADIL and how does it work?
FORADIL is the brand name for a medication called formoterol fumarate. FORADIL is a new type of drug known as a long-acting bronchodilator. FORADIL is used for the treatment of breathing problems in asthma and also other airway diseases such as chronic bronchitis and emphysema, which may also be referred to as chronic obstructive pulmonary disease (COPD). It makes breathing easier by opening the small air passages in the lungs, and helps them remain opened and relaxed for about 12 hours.
What is in FORADIL?
FORADIL comes as gelatin capsules containing a dry powder. The dry powder is INHALED into the lungs using the inhaler provided. Each capsule contains 12 micrograms of formoterol fumarate. The capsules also contain lactose. FORADIL comes in blister packs containing 60 capsules.
What should I tell my doctor before taking FORADIL?
Tell your doctor :
- about all the health problems you have now or have had in the past - especially heart disease, diabetes, overactive thyroid; - about other medications you take including ones you can buy without a prescription especially medications used to treat depression or sad mood (monoamine oxidase inhibitors and tricyclic antidepressants), sympathomimetic agents, antihistamines, water pills (diuretics), · -blockers for high blood pressure and certain eye drops for the treatment of glaucoma, drugs containing quinidine, disopyramide, procainamide, phenothiazine or xanthine derivatives (theophylline or aminophylline); - if you are severely allergic to milk or have ever had any unusual or allergic reaction to FORADIL; - if you are pregnant, plan to become pregnant, or are breast-feeding.
Are there any side effects?
Like any medication, FORADIL may cause unwanted side effects in some people. The side effects that do occur are usually mild and go away a short time after starting FORADIL.
FORADIL may occasionally cause mild side effects such as tremor, fast and irregular heart beat, headache, dizziness or irritation of the mouth or throat. Rarely, more serious side effects, such as muscle cramps and pain, agitation, feeling nervous or tired, difficulties in sleeping, and, very rarely, bronchospasm (an attack of asthma) can occur. In isolated cases allergic reactions with severe drop of blood pressure and swelling of the face, eyelids, lips have been reported. You should check with your doctor if:
- the mild side effects persist
- the more serious ones occur
- you notice any other effects not listed here.
What if you are pregnant, plan to become pregnant or are breast-feeding?
You should tell your doctor if you are pregnant, plan to become pregnant or are breast-feeding. Avoid using FORADIL during pregnancy. Mothers who are breast-feeding should not use FORADIL.
How do I take FORADIL properly?
Your doctor will have explained that you are to take this drug twice daily regularly. Follow your doctorís directions carefully. They may differ from the information outlined here.
ASTHMA: The regular dose for adults, (including elderly patients), and children 6 years of age and older is 1 or 2 capsules twice a day, once in the morning and again in the evening.
COPD: The regular dose for adults, including elderly patients, is 1 or 2 capsules twice a day, once in the morning and again in the evening.
FORADIL should not be taken more than twice daily. If you have difficulty breathing, tightness, wheezing or coughing and need relief, use the short-acting bronchodilator medication your doctor has prescribed for that purpose.
It is important that you take FORADIL correctly. The exact instructions for using FORADIL capsules with the inhaler are outlined in detail in this insert. If you have any questions or problems, ask your doctor or pharmacist.
The capsules are not to be swallowed; like most asthma and COPD medications, FORADIL is inhaled. Exact directions for using the inhaler are in this insert. Once your doctor and or your pharmacist has shown you how to use FORADIL, the diagrams and directions in this insert will serve as a reminder of the technique. It is suggested that you display it wherever you usually administer FORADIL.
Where should I keep FORADIL?
Keep this medication AT ROOM TEMPERATURE, IN A DRY PLACE. Your car or the bathroom are not good choices.
The capsules should be removed from the blister pack just before use. Keep this medicine out of the reach of children because it may harm them. Do not use FORADIL after the expiry date marked on the carton.
USE IN ASTHMA:
Your doctor will have explained that this drug is to be taken twice daily regularly, in addition to the drug which reduces the inflammation of the lungs due to asthma (also known as a preventive medication). A short-acting bronchodilator (also known as a quick reliever) should also be used when you are aware of the shortness of breath, tightness, coughing and wheezing of your asthma.
Can my child take FORADIL for the treatment of breathing problems in asthma?
FORADIL inhalation powder is suitable for children aged 6 years or more. Children should only use FORADIL if they are able to handle the inhaler correctly,. They should only use the inhaler with the help of an adult.
The severity of asthma changes with age. Your child should therefore be periodically re-examined by a physician. It is important to make sure that your child also understands and properly follows the asthma therapies prescribed to him/her. These will include in addition to FORADIL, a drug which reduces the inflammation in the lung due to asthma (also known as a preventive medication) and a short-acting bronchodilator (also known as a quick reliever).
You must continue to regularly take the anti-inflammatory medications (e.g., inhaled steroids) your doctor has prescribed. Your anti-inflammatory medications and FORADIL are designed to act together to best treat your asthmatic condition. Even though you feel better, DO NOT STOP or reduce your doses of FORADIL or your anti-inflammatory medications.
It is very important that you take FORADIL exactly as your doctor tells you. If the relief of your asthma is not as good as usual or does not last as long as usual, TELL YOUR DOCTOR RIGHT AWAY. A change from "usual" includes more wheezing, coughing, tightness or shortness of breath.
If you are using more of your short-acting bronchodilating medication or if you feel that it is less effective TELL YOUR DOCTOR RIGHT AWAY. Your doctor may adjust your treatment.
If your symptoms are waking you up at night TELL YOUR DOCTOR RIGHT AWAY. Your doctor may adjust your treatment.
If you have taken all your medication and an hour at rest has not relieved your symptoms, YOU MAY NEED EMERGENCY TREATMENT.
Nothing in this material should stop you from calling your doctor or pharmacist with any questions or concerns you may have about using FORADIL.
Information for the Patient/Guardian about Administering FORADIL® inhalation powder capsules
Before using FORADIL, please read these instructions carefully. They contain information about FORADIL which may add to the specific advice from your doctor and pharmacist. If, after reading this material, you have further questions, ask your doctor or pharmacist.
Your doctor will have explained that you are to take this drug regularly, as well as the drug which reduces the inflammation of the lungs due to your asthma or COPD. You will also probably have a short-acting bronchodilator to use when you are aware of the tightening, coughing and wheezing of your asthma.
How do I use the FORADIL inhaler and capsules?
1. Pull off cap
2. To open, hold base of the inhaler firmly and turn the mouthpiece in the direction of the arrow.
3. Remove the capsule from the blister pack. It is important to keep the capsule in the blister pack until you are ready to use it. Place the capsule in the capsule shaped compartment in the base of the inhaler.
4. Return the mouthpiece to the closed position.
5. Keeping the inhaler upright, firmly squeeze the two blue buttons fully ONLY ONCE. This will pierce the capsule. Release the buttons. Although the capsule is now pierced, the powder will not be released until you inhale it.
Please note that the capsule might splinter at this step and small fragments of gelatin might reach your mouth and throat. This gelatin is edible and is therefore not harmful. You can minimize the tendency of the capsule splintering by:
- piercing the capsule only once
- keeping the capsules stored in a dry place at room temperature
- keeping the capsule in the blister pack until you are ready to use it.
6. Breathe out fully.
7. Place the mouthpiece in your mouth and tilt your head slightly backward. Close your lips around the mouthpiece and breathe in steadily as deeply as you can. As you breathe in, you will inhale the medication into your lungs.
You should hear a whirring noise as you breathe in because inhalation causes the capsule to spin around in the inhaler. Please note if you do not hear the whirring noise, the capsule may be stuck in the capsule-shaped compartment. If this occurs, re-open the inhaler carefully and pry the capsule out. You cannot loosen the capsule by repeatedly pressing the buttons.
8. If you have heard the whirring noise, HOLD YOUR BREATH for as long as you comfortably can while removing the inhaler from your mouth. Then breathe out.
9. After use, open the inhaler. Check that the capsule is empty. If it is not close the inhaler and re-inhale following steps 6, 7 and 8. Remove the empty capsule. Close the mouthpiece. Replace the cap.
What if I miss a dose?
FORADIL should not be used more often than twice a day. If you forget to take a dose, take it as soon as possible. However, if it is almost time for your next dose, do not take the missed one, just go back to your regular dosing schedule. Never take a double dose.
What if you have taken an overdose?
If you accidentally used a lot more FORADIL than your doctor has prescribed, tell your doctor immediately or go to your nearest Poison Control Centre or hospital. If you develop nausea and/or vomiting, shakiness, headache, fast or irregular heartbeat, or sleepiness, your dose of FORADIL may be too high. Tell your doctor immediately.
How do I clean the inhaler?
To remove any powder residues, wipe the mouthpiece and capsule compartment with a DRY cloth or a small, soft, clean brush.
The principal therapeutic effect of formoterol is to relieve and prevent bronchoconstriction by relaxing airway smooth muscle via specific interaction with ß2-adrenoreceptors. Numerous studies have confirmed that formoterol is highly potent and possesses high intrinsic activity and very high affinity at the ß2-adrenoreceptor.
As reported for other inhaled drugs, it is likely that about 90% of formoterol administered from an inhaler will be swallowed and then absorbed from the gastrointestinal tract. This means that the pharmacokinetic characteristics of the oral formulation largely apply also to the inhalation powder.
Oral doses of up to 300 m g formoterol fumarate are readily absorbed from the gastrointestinal tract. Peak plasma concentrations of the unchanged substance are reached 0.5 to 1 hour after administration. The absorption of an oral 80m g dose is 65% or more.
The pharmacokinetics of formoterol appear linear in the range of oral doses investigated, i.e. 20 to 300m g. Repeated oral administration of 40 to 160m g daily does not lead to significant accumulation of the drug.
Following inhalation of therapeutic doses, formoterol cannot be detected in the plasma using earlier analytical methods. However, analysis of urinary excretion rates suggests that inhaled formoterol is rapidly absorbed. The maximum excretion rate after administration of 12 to 96m g is reached within 1 to 2 hours of inhalation.
Cumulative urinary excretion of formoterol after administration of the inhalation powder (12 to 24m g) and two different aerosol formulations (12 to 96m g) showed the amount of formoterol available in the circulation to increase in proportion to the dose.
The plasma protein binding of formoterol is 61 to 64% (34% to albumin). There is no saturation of binding sites in the concentration range reached with therapeutic doses.
Foradil is eliminated primarily by metabolism, direct fold glucuronidation being the major pathway of biotransformation. O-demethylation followed by glucuronidation is another pathway.
Elimination of formoterol from the circulation seems to be polyphasic; the apparent half-life depends on the time interval considered. On the basis of plasma or blood concentrations up to 6, 8 or 12 hours after oral administration, an elimination half-life of about 2 to 3 hours was determined. From urinary excretion rates between 3 and 16 hours after inhalation, a half-life of about 5 hours was calculated.
The drug and its metabolites are completely eliminated from the body; about two-thirds of an oral dose appear in the urine and one-third in the feces. After inhalation about 6 to 9% of the dose on average is excreted unchanged in the urine. Renal clearance of formoterol is 150 mL/min.
PHARMACODYNAMICS AND CLINICAL TRIALS
ASTHMA: The efficacy of formoterol dry powder was evaluated in controlled cli nical studies using 12m g and 24m g b.i.d. in adults and children. Foradil sh owed superior efficacy compared to salbutamol dry powder (400m g b.i.d.). Foradil significantly improved lung function, reduced nocturnal and daytime asthma symptoms and reduced the need for additional short-acting relief bronchodilators.
Adults: sustained bronchodilator and bronchoprotective effect of formoterol inhaled twice daily for six months in moderate asthma
A 6-month randomized double-blind trial was conducted in 271 patients with moderate asthma to compare the effect on bronchial hyperresponsiveness (as measured by the methacholine challenge) of three treatments; twice daily
formoterol dry powder capsules (12m g b.i.d.), four times daily salbutamol dry powder capsules (200m g q.i.d.), or salbutamol MDI on-demand. All patients were taking inhaled corticosteroids (400 to 1200m g beclomethasone or equivalent). Mean baseline FEV1 was 2.73 L (80% of predicted). Mean age was 36. Geometric means of PC20 were comparable between treatment groups, at baseline (0.7 to 0.8 mg/mL), but increased during double-blind period to values between 4.1 and 5.1 in the formoterol group, 2.6 and 3.6 in the regular salbutamol group, and 1.3 and 1.7 in the on-demand salbutamol group. Foradil achieved significantly better protection against methacholine-induced bronchial hyperreactivity at the beginning of treatment, at 3 months, at 6 months, and achieved significantly better control of the disease as measured by spirometry, peak flow, symptom scores, and rescue medication compared to on-demand salbutamol. In all treatment groups there was no rebound effect measured 2 days after cessation of treatment: (PC20 between 2.0 and 2.2 mg/mL). Foradil treated patients experienced fewer exacerbation days compared to patients treated with on-demand salbutamol. A similar trend between Foradil and regular salbutamol did not reach statistical significance.
Children: sustained bronchodilator and bronchoprotective effect of formoterol inhaled twice daily for twelve months in asthma
A 12-month, double-blind, placebo-controlled trial was conducted in 518 children (aged 5 - 12 years) with asthma to determine if 12m g or 24m g of formoterol dry powder capsules for inhalation delivered by a single-dose breath actuated inhaler (AerolizerTM) administered b.i.d. were superior to placebo with respect to lung function measurements over a 12-month period.
Patients had baseline FEV1 of 50 - 85% of normal and 15% increase in FEV 1 within 30 mins after inhaling 200m g salbutamol.
The area under the FEV1 curve measured over 12 hours was significantly greater than placebo for both formoterol 12m g b.i.d. and 24m g b.i.d after twelve weeks of treatment. No difference was seen between the doses. Similar results were seen after the first dose and after 12 months treatment, for FEF 25-75%, FVC for the 24m g dose and for morning and evening premedication PEFR. Symptom scores were significantly lower than placebo in the 12m g b.i.d.group but not in the 24m g b.i.d group at the three month efficacy time point, but were no longer significant at 12 months for either dose. Rescue medication was used significantly less at night-time for both formoterol doses, but was only significantly less for the lower dose during the night-time over the twelve month period.
Potentially serious ECG changes (such as increased QTc interval) and hypokalemia may result from ß2-agonist therapy. Although clinically not significant, a small increase in QTc interval and/or decrease in serum potassium has been reported at therapeutic doses of formoterol. The effects of single doses of formoterol at 12 to 96µg were studied in 22 adult asthmatics, all of whom were receiving inhaled cor ticosteroids and an inhaled short-acting ß2- agonist prior to entering the trial. The number of patients whose longest measured QTc in this trial was >440 msec was greater for placebo (3 patients) than it was for formoterol 12 µg (no patient), 24 µg (2 patients), and 48 µg (2 patients). Five patients treated with formoterol 96µg showed QTc prolongations >440 msec. Six patients had clinically meaningful ([K+] <3.2 mmol/L) hypokalemia at 96 µg, compared with one each at 12 and 48 µg.
CHRONIC OBSTRUCTIVE PULMONARY DISEASE:
The efficacy of formoterol dry powder was evaluated in two placebo-controlled and comparator-controlled clinical studies.
A12-week randomized double-blind trial was conducted in 780 patients with COPD to assess the efficacy of inhaled formoterol fumarate dry powder capsules (12µg b.i.d. and 24µg b.i.d.) compared with placebo or ipratropium bromide MDI (40µg q.i.d.). Patients were male or female out-patients over or equal to 40 years old. Their FEV1 was expected to be less than 70% of the predicted value and at least 0.75 litres, with the FEV1 /VC being less than 88% for men and less than 89% for women. Fomoterol at both 24 µg and 12 µg b.i.d. produced statistically and clinically significant improvements in lung function, as measured by FEV1 area under the curve, when compared to placebo after 12 weeks of treatment. The estima ted improvement was 194 mL and 223 mL for 24 µg and 12 µg b.i.d., respectively.Foradil was also statistically significant when compared to ipratropium bromide.
Both doses of formoterol, when compared to placebo, produced statistically and clinically significant improvement or this variable in both reversible and irreversible sub-groups of patients. (Reversibility is defined as 15% increase in forced expiratory volume in one second (FEV1) 30 minutes after inhalation of 200 µg salbutamol). For reversible patients the improvement seen was 244 mL and 241 mL for fo rmoterol 24 µg and 12 µg b.i.d., respectively. For irreversible patients the improvement seen was 137 mL and 213 mL for formoterol 24 µg and 12µg b.i.d., respectively.
Foradil (24 µg and 12 µg b.i.d.) when compared to placebo showed statistically significant improvements in all the lung function measurements: FEV1 AUC on day 1 of treatment, FEV1 at each time-point over 12 hours, IVC, FVC AUC and morning pre-medication PEF. Statistically significant improvements were also seen in clinical measures: total score on the patient diary, number of puffs of rescue medication and the percentage of bad days. Quality of Life, as measured by the St. Georgeís Respiratory Questionaire (SGRQ), was both statistically and clinically signficantly improved in all areas (total, symptoms, activity and impacts) for formoterol (12 µg b.i.d.) when compared to placebo with statistically improvements for the 24 µg b.i.d. dose for the total, symptoms and activity scores.
The primary objective of the 12-month randomized between patient trial was to assess the efficacy of inhaled formoterol fumarate dry powder capsules (12 µg b.i.d. and 24 µg b.i.d.) compared with placebo with respect to FEV1 AUC (after 12 weeks). The secondary objective was to compare formoterol with placebo (with respect to FEV1 AUC at 6 and 12 months) and with oral SR theophylline after 3, 6 and 12 months (FEV1 pre-dose at all visits and post-dose after 3, 6 and 12 months). The two formoterol and the placebo groups were compared in a double-blind mode, while the theophylline group was open-label. A total of 854 male or female out-patients over or equal to 40 years old patients with COPD were randomized. Their FEV1 was expected to be less than 70% of the predicted value and at least 0.75 litres, with the FEV1/VC being less than 88% for men and less than 89% for women.
Foradil at both 24 µg and 12 µg b.i.d. produced statistically and clinically significant improvements in lung funation, as measured by FEV1 area under the curve, when compared to placebo after 12 weeks of treatment. The estimated improvement was 208 mL and 200 mL for 24 µg and 12 µg b.i.d., respectively. Foradil was also statistically significant when compared to theophylline. Both doses of formoterol, when compared to placebo, produced statistically and clinically significant improvement or this variable in both reversible and irreversible sub-groups of patients. (Reversibility is defined as 15% increase in forced expiratory volume in one second (FEV1) 30 minutes after inhalation of 200 µg salbutamol). For reversible patients the improvement seen was 271 mL and 331 mL for formoterol 24 µg and 12 µg b.i.d., respectively. For irreversible patients the improvement seen was 166 mL and 109 mL for formoterol 24 µg and 12µg b.i.d., respectively.
Foradil (24 µg and 12 µg b.i.d.) when compared to placebo showed statistically significant improvements in the other lung function measurements: FEV1 AUC after 6 and 12 months of treatment, FEV1 at each time-point over 12 hours, FVC AUC and morning pre-medication PEF after 3, 6 and 12 months of treatment. Statistically significant improvements between both doses of formoterol when compared with placebo were also seen in the number of puffs of rescue medication taken. Quality of Life, as measured by the St. Georgeís Respiratory Questionaire (SGRQ), was statistically signficantly improved in all areas (total, symptoms, activity and impacts) for formoterol (12 µg b.i.d.) when compared to placebo after 6 months of treatment, and for both impact and total scores for 24 µg b.i.d. Clinically relevant improvement in the symptoms scores were seen in the formoterol 12 µg b.i.d. treatment group at both 6 and 12 months and in the impacts score for the formoterol 24 µg b.i.d. treatment group at 12 months.
In conclusion, FORADIL administered by the AerolizerTM at doses of 12 µg b.i.d. and 24 µ g b.i.d. provides rapid onset of bronchodilation in patients with stable COPD that was maintained over at least 12 hours.
Since the bronchodilator effect of Foradil is still significant 12 hours after inhalation, twice-daily maintenace therapy controls bronchoconstriction associated with chronic conditions both during the day and at night.
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