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Foradil Certihaler

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Foradil Certihaler

Warnings
Precautions

WARNINGS

Asthma Related Death

Long-acting beta2-adrenergic agonists, such as formoterol, the active ingredient in FORADIL CERTIHALER (formoterol fumarate inhalation powder) , increase the risk of asthma-related death. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA.

Because of this risk, use of FORADIL CERTIHALER (formoterol fumarate inhalation powder) for the treatment of asthma without concomitant use of a long-term asthma control medication, such as an inhaled corticosteroid, is contraindicated. Use FORADIL CERTIHALER (formoterol fumarate inhalation powder) only as additional therapy for patients with asthma who are currently taking but are inadequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g. discontinue FORADIL CERTIHALER (formoterol fumarate inhalation powder) ) if possible without loss of asthma control, and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use FORADIL CERTIHALER (formoterol fumarate inhalation powder) for patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids.

Pediatric and Adolescent Patients

Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. For pediatric and adolescent patients with asthma who require addition of a LABA to an inhaled corticosteroid, a fixed-dose combination product containing both an inhaled corticosteroid and LABA should ordinarily be considered to ensure adherence with both drugs. In cases where use of a separate long-term asthma control medication (e.g. inhaled corticosteroid) and LABA is clinically indicated, appropriate steps must be taken to ensure adherence with both treatment components. If adherence cannot be assured, a fixed-dose combination product containing both an inhaled corticosteroid and LABA is recommended.

A 28-week, placebo-controlled US study comparing the safety of salmeterol with placebo, each added to usual asthma therapy, showed an increase in asthma related deaths in patients receiving salmeterol (13/13,176 in patients treated with salmeterol vs. 3/13,179 in patients treated with placebo; RR 4.37, 95% CI 1.25, 15.34). The increased risk of asthma-related death is considered a class effect of the long-acting beta2-adrenergic agonists, including formoterol. No study adequate to determine whether the rate of asthma-related death is increased with FORADIL CERTIHALER (formoterol fumarate inhalation powder) has been conducted.

Clinical studies with FORADIL AEROLIZER suggested a higher incidence of serious asthma exacerbations in patients who received FORADIL AEROLIZER than in those who received placebo (See ADVERSE REACTIONS). The sizes of these studies were not adequate to precisely quantify the differences in serious asthma exacerbation rates between treatment groups.

The studies described above enrolled patients with asthma. No studies have been conducted that were adequate to determine whether the rate of death in patients with COPD is increased by long-acting beta2-adrenergic agonists.

  • FORADIL CERTIHALER (formoterol fumarate inhalation powder) should not be initiated in patients with significantly worsening or acutely deteriorating asthma, which may be a life-threatening condition. The use of FORADIL CERTIHALER (formoterol fumarate inhalation powder) in this setting is inappropriate.
  • FORADIL CERTIHALER (formoterol fumarate inhalation powder) should not be used in conjunction with an inhaled, long-acting beta2-agonist. FORADIL CERTIHALER (formoterol fumarate inhalation powder) should not be used with other medications containing long-acting beta2-agonists.
  • FORADIL CERTIHALER (formoterol fumarate inhalation powder) is not a substitute for inhaled or oral corticosteroids. Corticosteroids should not be stopped or reduced at the time FORADIL CERTIHALER (formoterol fumarate inhalation powder) is initiated.
  • When beginning treatment with FORADIL CERTIHALER (formoterol fumarate inhalation powder) , patients who have been taking inhaled, short-acting beta2-agonists on a regular basis (e.g., four times a day) should be instructed to discontinue the regular use of these drugs and use them only for symptomatic relief of acute asthma symptoms.
  • See PATIENT INFORMATION.

Paradoxical Bronchospasm

As with other inhaled beta2-agonists, formoterol can produce paradoxical bronchospasm, that may be life-threatening. If paradoxical bronchospasm occurs, FORADIL CERTIHALER (formoterol fumarate inhalation powder) should be discontinued immediately and alternative therapy instituted.

Deterioration of Asthma

Asthma may deteriorate acutely over a period of hours or chronically over several days or longer. It is important to watch for signs of worsening asthma, such as increasing use of inhaled, short-acting beta2-adrenergic agonists or a significant decrease in peak expiratory flow (PEF) or lung function. Such findings require immediate evaluation. Patients should be advised to seek immediate attention should their condition deteriorate. Increasing the daily dosage of FORADIL CERTIHALER (formoterol fumarate inhalation powder) beyond the recommended dose in this situation is not appropriate. FORADIL CERTIHALER (formoterol fumarate inhalation powder) should not be used more frequently than twice daily (morning and evening) at the recommended dose.

Use of Anti-inflammatory Agents

There are no data demonstrating that FORADIL has any clinical antiinflammatory effect and therefore it cannot be expected to take the place of corticosteroids. Patients who require oral or inhaled corticosteroids for treatment of asthma should be continued on this type of treatment even if they feel better as a result of initiating FORADIL CERTIHALER (formoterol fumarate inhalation powder) . Any change in corticosteroid dosage, in particular a reduction, should be made ONLY after clinical evaluation (see PATIENT INFORMATION).

Cardiovascular Effects

Formoterol fumarate, like other beta2-agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of FORADIL CERTIHALER (formoterol fumarate inhalation powder) at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce ECG changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Therefore, formoterol fumarate, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension (see PRECAUTIONS, General).

Immediate Hypersensitivity Reactions

Immediate hypersensitivity reactions may occur after administration of FORADIL CERTIHALER, as demonstrated by cases of anaphylactic reactions, urticaria, angioedema, rash, and bronchospasm.

Do Not Exceed Recommended Dose

Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs in patients with asthma. The exact cause of death is unknown, but cardiac arrest following an unexpected development of a severe acute asthmatic crisis and subsequent hypoxia is suspected. In addition, data from clinical trials with FORADIL AEROLIZER suggest that the use of doses higher than recommended is associated with an increased risk of serious asthma exacerbations (see ADVERSE REACTIONS).

PRECAUTIONS

General

FORADIL CERTIHALER (formoterol fumarate inhalation powder) should not be used to treat acute symptoms of asthma. FORADIL CERTIHALER has not been studied in the relief of acute asthma symptoms and extra doses should not be used for that purpose. When prescribing FORADIL CERTIHALER (formoterol fumarate inhalation powder) , the physician should also provide the patient with an inhaled, short-acting beta2-agonist for treatment of symptoms that occur acutely, despite regular twice-daily (morning and evening) use of FORADIL CERTIHALER (formoterol fumarate inhalation powder) . Patients should also be cautioned that increasing inhaled beta2 agonist use is a signal of deteriorating asthma. (See PATIENT INFORMATION.)

Formoterol fumarate, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension; in patients with convulsive disorders or thyrotoxicosis; and in patients who are unusually responsive to sympathomimetic amines. Clinically significant changes in systolic and/or diastolic blood pressure, pulse rate and electrocardiograms have been seen infrequently in individual patients in controlled clinical studies with formoterol. Doses of the related beta2-agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.

Beta-agonist medications may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation.

Clinically significant changes in blood glucose and/or serum potassium were infrequent during clinical studies with administration of FORADIL CERTIHALER (formoterol fumarate inhalation powder) at the recommended dose.

FORADIL CERTIHALER (formoterol fumarate inhalation powder) contains lactose, which contains trace levels of milk protein. Allergic reactions to products containing milk proteins may occur in patients with severe milk protein allergy.

Information for Patients

Patients should be instructed to read the accompanying Medication Guide with each new prescription and refill. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be given the following information:

  1. Patients should be informed that long-acting beta2-adrenergic agonists (LABA), including formoterol, the active ingredient in FORADIL CERTIHALER (formoterol fumarate inhalation powder) , increase the risk of asthma-related death and may increase the risk of asthma-related hospitalizations in pediatric and adolescent patients. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Patients should be informed that FORADIL CERTIHALER (formoterol fumarate inhalation powder) should not be the only therapy for the treatment of asthma and must only be used as additional therapy when other long-term asthma control medications (e.g., inhaled corticosteroids) do not adequately control asthma symptoms. Patients should be informed that when FORADIL CERTIHALER (formoterol fumarate inhalation powder) is added to their treatment regimen they must continue to use their long-term asthma control medication.
  2. FORADIL CERTIHALER (formoterol fumarate inhalation powder) is not indicated to relieve acute asthma symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting, beta2-agonist (the health-care provider should prescribe the patient with such medication and instruct the patient in how it should be used). Patients should be instructed to seek medical attention if their symptoms worsen, if FORADIL CERTIHALER (formoterol fumarate inhalation powder) treatment becomes less effective, or if they need more inhalations of a short-acting beta2-agonist than usual. Patients should not inhale more than one dose at any one time. The daily dosage of FORADIL CERTIHALER (formoterol fumarate inhalation powder) should not exceed one inhalation twice daily (20 mcg total daily dose).
  3. FORADIL CERTIHALER (formoterol fumarate inhalation powder) should not be used as a substitute for oral or inhaled corticosteroids. The dosage of these medications should not be changed and they should not be stopped without consulting the physician, even if the patient feels better after initiating treatment with FORADIL CERTIHALER.
  4. The active ingredient of FORADIL (formoterol fumarate) is a long-acting, bronchodilator used for the treatment of asthma. FORADIL CERTIHALER (formoterol fumarate inhalation powder) provides bronchodilation for up to 12 hours. Patients should be advised not to increase the dose or frequency of FORADIL CERTIHALER (formoterol fumarate inhalation powder) without consulting the prescribing physician. Patients should be warned not to stop or reduce concomitant asthma therapy without medical advice.
  5. Patients should be informed that treatment with beta2-agonists may lead to adverse events which include palpitations, chest pain, rapid heart rate, tremor or nervousness.
  6. Patients should be informed never to use FORADIL CERTIHALER (formoterol fumarate inhalation powder) with a spacer and never to exhale into the device.
  7. The CERTIHALER Inhaler should never be washed and should be kept dry.
  8. Women should be advised to contact their physician if they become pregnant or if they are nursing.
  9. It is important that patients understand how to use the CERTIHALER Inhaler appropriately and how it should be used in relation to other asthma medications they are taking (see the accompanying Medication Guide).

Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of formoterol fumarate has been evaluated in 2-year drinking water and dietary studies in both rats and mice. In rats, the incidence of ovarian leiomyomas was increased at doses of 15 mg/kg and above in the drinking water study and at 20 mg/kg in the dietary study (AUC exposure approximately 1000 times human exposure at the maximum recommended daily inhalation dose), but not at dietary doses up to 5 mg/kg (AUC exposure approximately 250 times human exposure at the maximum recommended daily inhalation dose). In the dietary study, the incidence of benign ovarian theca-cell tumors was increased at doses of 0.5 mg/kg and above (AUC exposure was approximately 25 times human exposure at the maximum recommended daily inhalation dose). This finding was not observed in the drinking water study.

In mice, the incidence of adrenal subcapsular adenomas and carcinomas was increased in males at doses of 69 mg/kg (AUC exposure approximately 460 times human exposure at the maximum recommended daily inhalation dose) and above in the drinking water study, but not at doses up to 50 mg/kg (AUC exposure approximately 330 times human exposure at the maximum recommended daily inhalation dose) in the dietary study. The incidence of hepatocarcinomas was increased in the dietary study at doses of 20 and 50 mg/kg in females (AUC exposure approximately 130 and 330 times human exposure at the maximum recommended daily inhalation dose, respectively) and 50 mg/kg in males, but not at doses up to 5 mg/kg (AUC exposure approximately 33 times human exposure at the maximum recommended daily inhalation dose). Also in the dietary study, the incidence of uterine leiomyomas and leiomyosarcomas was increased at doses of 2 mg/kg and above (AUC exposure was approximately 15 times human exposure at the maximum recommended daily inhalation dose). Increases in leiomyomas of the rodent female genital tract have been similarly demonstrated with other beta-agonist drugs.

Formoterol fumarate was not mutagenic or clastogenic in the following tests: mutagenicity tests in bacterial and mammalian cells, chromosomal analyses in mammalian cells, unscheduled DNA synthesis repair tests in rat hepatocytes and human fibroblasts, transformation assay in mammalian fibroblasts and micronucleus tests in mice and rats.

Reproduction studies in rats revealed no impairment of fertility at oral doses up to 3 mg/kg (approximately 1200 times the maximum recommended daily inhalation dose in adults on a mg/m² basis).

Pregnancy

Teratogenic Effects

Pregnancy Category C

Formoterol fumarate administered throughout organogenesis did not cause malformations in rats or rabbits following oral administration. When given to rats throughout organogenesis, oral doses of 0.2 mg/kg (approximately 80 times the maximum recommended daily inhalation dose in humans on a mg/m² basis) and above delayed ossification of the fetus, and doses of 6 mg/kg (approximately 2400 times the maximum recommended daily inhalation dose in adults on a mg/m² basis) and above decreased fetal weight. Formoterol fumarate has been shown to cause stillbirth and neonatal mortality at oral doses of 6 mg/kg and above in rats receiving the drug during the late stage of pregnancy. These effects, however, were not produced at a dose of 0.2 mg/kg. Because there are no adequate and well-controlled studies in pregnant women, FORADIL

CERTIHALER should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Use in Labor and Delivery

Because beta-agonists may potentially interfere with uterine contractility, FORADIL CERTIHALER (formoterol fumarate inhalation powder) should be used during labor only if the potential benefit justifies the potential risk.

Nursing Mothers

In reproductive studies in rats, formoterol was excreted in the milk. It is not known whether formoterol is excreted in human milk, but because many drugs are excreted in human milk, caution should be exercised if FORADIL CERTIHALER (formoterol fumarate inhalation powder) is administered to nursing women.

Pediatric Use

Asthma

Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. For pediatric and adolescent patients with asthma who require addition of a LABA to an inhaled corticosteroid, a fixed-dose combination product containing both an inhaled corticosteroid and LABA should ordinarily be used to ensure adherence with both drugs (see INDICATIONS AND USAGE and WARNINGS).

A total of 326 children 5 years of age and older with asthma were studied in two multiple-dose controlled clinical trials. Of the 204 children who received FORADIL CERTIHALER (formoterol fumarate inhalation powder) , all were 5-12 years of age, and 69, approximately one third, were 5-8 years of age.

The safety and effectiveness of FORADIL CERTIHALER (formoterol fumarate inhalation powder) in pediatric patients below 5 years of age has not been established. (See Clinical Trials, Pediatric Asthma Trial, and ADVERSE REACTIONS, Experience in Pediatric, Adolescent and Adult Patients.)

Geriatric Use

Of the total number of patients who received FORADIL CERTIHALER (formoterol fumarate inhalation powder) in adolescent and adult chronic dosing asthma clinical trials, 30 (5.4%) were 65 years of age or older and 2 (0.4%) were 75 years of age and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. However, the number of elderly patients studied with FORADIL CERTIHALER (formoterol fumarate inhalation powder) is low. Additionally, there is experience with FORADIL AEROLIZER (FORADIL AEROLIZER consists of a single-dose dry powder inhaler and capsules containing formoterol fumarate and lactose) and of the total number of patients who received FORADIL AEROLIZER in adolescent and adult chronic dosing asthma clinical trials, 318 were 65 years of age or older and 39 were 75 years of age and older. Of the 811 patients who received FORADIL AEROLIZER in two pivotal multiple-dose controlled clinical studies in patients with COPD, 395 (48.7%) were 65 years of age or older while 62 (7.6%) were 75 years of age or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. A slightly higher frequency of chest infection was reported in the 39 asthma patients 75 years of age and older, although a causal relationship with FORADIL has not been established. Other reported clinical experience has not identified differences in responses between the elderly and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out. (See PRECAUTIONS: DRUG INTERACTIONS.)

Last reviewed on RxList: 6/29/2010
This monograph has been modified to include the generic and brand name in many instances.

Warnings
Precautions
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