FORACORT Inhaler

Formoterol fumarate dihydrate + Budesonide

Prescribing information

For the use of a registered medical practitioner or a hospital or a laboratory only

FORACORT Inhaler

Formoterol fumarate dihydrate and Budesonide Inhaler

Qualitative and Quantitative Composition

FORACORT-100 Inhaler

Each actuation delivers:

Formoterol fumarate dihydrate IP .……6 mcg

Budesonide IP ………100 mcg

Suspended in propellant HFA 134a.………………….....q.s.

FORACORT-200 Inhaler

Each actuation delivers:

Formoterol fumarate dihydrate IP……....6 mcg

Budesonide IP…………200 mcg

Suspended in propellant HFA 134a………………….........q.s.

FORACORT-400 Inhaler

Each actuation delivers:

Formoterol fumarate dihydrate IP…….....6 mcg

Budesonide IP………….400 mcg

Suspended in propellant HFA 134a…………………..........q.s.

Dosage Form and Strength

FORACORT-100 Inhaler

Formoterol fumarate dihydrate 6mcg and budesonide 100mcg aerosol for inhalation

FORACORT-200 Inhaler

Formoterol fumarate dihydrate 6mcg and budesonide 200mcg aerosol for inhalation

FORACORT-400 Inhaler

Formoterol fumarate dihydrate 6mcg and budesonide 400mcg aerosol for inhalation

Clinical Particulars

Therapeutic Indications

Asthma

FORACORT Inhaler is indicated in the regular treatment of asthma, where the use of a combination (long-acting, beta₂-agonist and inhaled corticosteroid) has been found to be appropriate.

FORACORT Inhaler is also indicated in regular treatment of patients with moderate to severe COPD with frequent symptoms and a history of exacerbations

Posology and Method of Administration

Asthma

FORACORT Inhaler can be used according to different treatment approaches:

Dosage is individual and should be adjusted according to disease severity. When control has been achieved, the dose should be titrated to the lowest effective dose, which could include FORACORT Inhaler used once daily.

For FORACORT there are two treatment approaches:

Maintenance Therapy: FORACORT Inhaleris taken as regular maintenance treatment with a separate rapid acting bronchodilator as rescue.
Single maintenance and reliever therapy: FORACORT Inhaleris taken as regular maintenance and as needed in response to symptoms.
Maintenance Therapy:Patients should be advised to have their separate rapid acting bronchodilator available for rescue use at all times.

Recommended Dosage

Adults (18 Years and Older)

FORACORT-100 Inhaler

1–2 inhalations, twice daily

Maximum dose is 4 inhalations, twice daily

FORACORT-200 Inhaler

1–2 inhalations, twice daily

Maximum dose is 4 inhalations, twice daily

FORACORT- 400 Inhaler

1 inhalation, twice daily

Maximum dose is 2 inhalations, twice daily

Adolescents (12-17 Years)

FORACORT-100 Inhaler

1–2 inhalations, twice daily

FORACORT-200 Inhaler

1–2 inhalations, twice daily

FORACORT- 400 Inhaler

1 inhalation, twice daily

Children (6-11 Years)

FORACORT-100 Inhaler

2 inhalations, twice daily

Single Maintenance and Reliever Therapy (For FORACORT -100 and 200 only)

Patients take a daily maintenance dose of FORACORT INHALER and in combination take FORACORT INHALER as needed in response to symptoms. Patients should be advised to always have FORACORT INHALER available for use.

Adults (18 years and older)

The recommended maintenance dosage is 2 inhalations per day as maintenance therapy (either one inhalation twice daily, or two inhalations in either the morning or the evening), although some patients may require two inhalations twice daily.

Patients should take 1 additional inhalation as needed in response to symptoms. If symptoms persist after a few minutes, an additional inhalation should be taken. Not more than 6 inhalations should be taken on any single occasion.

A total daily dose of more than 8 inhalations is not normally needed; however, a total daily dose of up of 12 inhalations could be used for a limited period. Patients using more than 8 inhalations daily should be strongly recommended to seek medical advice. They should be reassessed and their maintenance therapy should be reconsidered.

Single inhaler as maintenance and reliever therapy is not recommended in children and adolescents.

FORACORT- 400 Inhaler should not be used for single maintenance and reliever therapy.

COPD (Chronic Obstructive Pulmonary Disease)

FORACORT 200 Inhaler

2 inhalations, twice daily

Contraindications

FORACORT Inhaler are contraindicated in patients with a history of hypersensitivity to any of the components of the drug product.

Primary treatment of status asthmaticus or other acute episodes of asthma or COPD where intensive measures are required.
Relief from acute bronchospasm

Special Warnings and Precautions for Use

General

If patients find the treatment ineffective, or exceed the highest recommended dose of FORACORT Inhaler, medical attention must be sought. Sudden and progressive deterioration in control of asthma is potentially life threatening and the patient should undergo urgent medical assessment. In this situation consideration should be given to the need for increased therapy with corticosteroids e.g. a course of oral corticosteroids, or antibiotic treatment if an infection is present.

Patients should be advised to have their rescue inhaler available at all times, either FORACORT Inhaler (for patients using FORACORT Inhaler as maintenance and reliever therapy) or a separate rapid-acting bronchodilator (for patients using FORACORT Inhaler as maintenance therapy only).

Patients should be reminded to take their FORACORT Inhaler maintenance dose as prescribed, even when asymptomatic. The prophylactic use of FORACORT Inhaler, e.g. before exercise, has not been studied. The reliever inhalations of FORACORT Inhaler should be taken in response to asthma symptoms but are not intended for regular prophylactic use, e.g. before exercise. For such use, a separate rapid-acting bronchodilator should be considered.

Once asthma symptoms are controlled, consideration may be given to gradually reducing the dose of FORACORT Inhaler. Regular review of patients as treatment is stepped down is important. The lowest effective dose of FORACORT Inhaler should be used.

Patients should not be initiated on FORACORT Inhaler during an exacerbation, or if they have significantly worsening or acutely deteriorating asthma.

Patients should be regularly reassessed by their health care provider, so that the dosage of formoterol/budesonide combination remains optimal. The dose should be titrated to the lowest dose at which effective control of symptoms is maintained. When control of symptoms is maintained with the lowest recommended dosage, then the next step could include a test of inhaled corticosteroid alone.

Increasing use of a separate rapid-acting bronchodilator indicates a worsening of the underlying condition and warrants a reassessment of the asthma therapy.

In usual practice when control of symptoms is achieved with the twice daily regimen, titration to the lowest effective dose could include formoterol/budesonide combination given once daily, when in the opinion of the prescriber, a long-acting bronchodilator would be required to maintain control.

It is recommended that the dose is tapered when the treatment is discontinued and should not be stopped abruptly.

Serious asthma-related adverse events and exacerbations may occur during treatment with FORACORT Inhaler. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation with FORACORT Inhaler.

As with other inhalation therapy, paradoxical bronchospasm may occur, with an immediate increase in wheezing after dosing. FORACORT Inhaler should then be discontinued; treatment should be re-assessed and alternative therapy instituted if necessary. Paradoxical bronchospasm responds to a rapid-acting inhaled bronchodilator and should be treated straightaway.

Serious Asthma-Related Events – Hospitalizations, Intubations and Death

Use of long-acting beta -adrenergic agonist (LABA) as monotherapy (without inhaled corticosteroids [ICS]) for asthma is associated with an increased risk of asthma related death. Available data from controlled clinical trials also suggest that use of LABA as monotherapy increases the risk of asthma related hospitalization in pediatric and adolescent patients. These findings are considered a class effect of LABA. When LABA are used in fixed-dose combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared to ICS alone.

Deterioration of Disease and Acute Episodes

Formoterol/budesonide combination should not be initiated in patients during rapidly deteriorating or potentially life threatening episodes of asthma or COPD. The fixed dose combination of budesonide and formoterol fumarate dihydrate has not been studied in patients with acutely deteriorating asthma or COPD. The initiation of formoterol/budesonide combination in this setting is not appropriate.

Increasing use of inhaled, short-acting beta -agonists is a marker of deteriorating asthma. In this situation, the patient requires immediate re-evaluation with reassessment of the treatment regimen, giving special consideration to the possible need for replacing the current strength of formoterol/budesonide combination with a higher strength, adding additional inhaled corticosteroid, or initiating systemic corticosteroids.

Patients should not use more than 2 inhalations twice daily (morning and evening) of formoterol/budesonide combination. Formoterol/budesonide combination should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. An inhaled, short-acting beta -agonist, not formoterol/budesonide combination, should be used to relieve acute symptoms such as shortness of breath.

When beginning treatment with formoterol/budesonide combination, patients who have been taking oral or inhaled, short-acting beta -agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs.

Excessive Use of Formoterol/Budesonide Combination and Use with Other Long-Acting Beta-Agonists

As with other inhaled drugs containing beta -adrenergic agents, formoterol/budesonide combination should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medications containing LABA, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using formoterol/budesonide combination should not use an additional LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate) for any reason, including prevention of exercise-induced bronchospasm (EIB) or the treatment of asthma or COPD.

Local Effects

In clinical studies, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in patients treated with formoterol/budesonide combination. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral antifungal) therapy while treatment with formoterol/budesonide combination continues, but at times therapy with formoterol/budesonide combination may need to be interrupted. Advise the patient to rinse his/her mouth with water without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis.

Pneumonia and Other Lower Respiratory Tract Infections

Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of pneumonia and exacerbations frequently overlap. Lower respiratory tract infections, including pneumonia, have been reported following the inhaled administration of corticosteroids.

Immunosuppression

Patients who are on drugs that suppress the immune system are more susceptible to infection than healthy individuals. Chicken pox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated (see the respective package inserts for complete VZIG and IG prescribing information). If chicken pox develops, treatment with antiviral agents may be considered. The immune responsiveness to varicella vaccine was evaluated in pediatric patients with asthma ages 12 months to 8 years with budesonide inhalation suspension. Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; untreated systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.

Transferring Patients from Systemic Corticosteroid Therapy

Particular care is needed for patients who have been transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma 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 adrenocortical (HPA) function.

Patients who have been previously maintained on 20 mg or more per day of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although formoterol/ budesonide combination may provide control of asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticoid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies.

During periods of stress, a severe asthma attack or a severe COPD exacerbation, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction. These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic corticosteroids during periods of stress, a severe asthma attack, or a severe COPD exacerbation.

Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to formoterol/ budesonide combination. Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with formoterol/ budesonide combination. Lung function (mean forced expiratory volume in 1 second [FEV] or morning peak expiratory flow [PEF]), beta-agonist use, and asthma or COPD symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition, patients should be observed for signs and symptoms of adrenal insufficiency, such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension.

Transfer of patients from systemic corticosteroid therapy to inhaled corticosteroids or formoterol/ budesonide combination may unmask conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions). Some patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, depression) despite maintenance or even improvement of respiratory function.

Hypercorticism and Adrenal Suppression

Budesonide, a component of formoterol/budesonide combination, will often help control asthma and COPD symptoms with less suppression of HPA function than therapeutically equivalent oral doses of prednisone. Since budesonide is absorbed into the circulation and can be systemically active at higher doses, the beneficial effects of formoterol/budesonide combination in minimizing HPA dysfunction may be expected only when recommended dosages are not exceeded and individual patients are titrated to the lowest effective dose.

Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with formoterol/budesonide combination should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response.

It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients, particularly when budesonide is administered at higher than recommended doses over prolonged periods of time. If such effects occur, the dosage of formoterol/budesonide combination should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids and for management of asthma symptoms.

If there is any reason to suppose that adrenal function is impaired from previous systemic steroid therapy, care should be taken when transferring patients to formoterol/budesonide combination therapy.

Drug Interactions With Strong Cytochrome P450 3A4 Inhibitors

Caution should be exercised when considering the co-administration of Budesonide/formoterol inhaler with ketoconazole, and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) because adverse effects related to increased systemic exposure to budesonide may occur.

Paradoxical Bronchospasm and Upper Airway Symptoms

As with other inhaled medications, formoterol/ budesonide combination can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with formoterol/ budesonide combination, it should be treated immediately with an inhaled, short-acting bronchodilator, formoterol/ budesonide combination should be discontinued immediately, and alternative therapy should be instituted.

Immediate Hypersensitivity Reactions

Immediate hypersensitivity reactions may occur after administration of formoterol/ budesonide combination, as demonstrated by cases of urticaria, angioedema, rash, and bronchospasm.

Cardiovascular and Central Nervous System Effects

Excessive beta-adrenergic stimulation has been associated with seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, palpitation, nausea, dizziness, fatigue, malaise, and insomnia. Therefore, formoterol/budesonide combination, like all products containing sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension, hypertrophic obstructive cardiomyopathy, idiopathic subvalvular aortic stenosis, severe hypertension, aneurysm or other severe cardiovascular disorders, such as ischemic heart disease, tachyarrhythmias or severe heart failure.

Formoterol, a component of formoterol/budesonide combination, can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of formoterol 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. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.

Reduction in Bone Mineral Density

Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. The clinical significance of small changes in BMD with regard to long-term consequences such as fracture is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care. Since patients with COPD often have multiple risk factors for reduced BMD, assessment of BMD is recommended prior to initiating Formoterol/Budesonide inhaler and periodically thereafter. If significant reductions in BMD are seen and Formoterol/Budesonide inhaler is still considered medically important for that patient's COPD therapy, use of medication to treat or prevent osteoporosis should be strongly considered.

Long-term studies with inhaled budesonide in children at mean daily doses of 400 mcg (metered dose) or in adults at daily doses of 800 mcg (metered dose) have not shown any significant effects on bone mineral density. No information regarding the effect of formoterol/budesonide at higher doses is available.

Effect on Growth

Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. Monitor the growth of pediatric patients receiving formoterol/budesonide combination routinely (e.g., via stadiometry). To minimize the systemic effects of orally inhaled corticosteroids, including formoterol/budesonide combination, titrate each patient's dose to the lowest dosage that effectively controls his/her Symptoms.

It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroids is regularly monitored. If growth is slowed, therapy should be re-evaluated with the aim of reducing the dose of inhaled corticosteroid. The benefits of the corticosteroid therapy and the possible risks of growth suppression must be carefully weighed. In addition consideration should be given to referring the patient to a pediatric respiratory specialist.

Limited data from long-term studies suggest that most children and adolescents treated with inhaled budesonide will ultimately achieve their adult target height. However, an initial small but transient reduction in growth (approximately 1 cm) has been observed. This generally occurs within the first year of treatment.

Visual Disturbance

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.

Glaucoma and Cataracts

Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with asthma and COPD following the long-term administration of inhaled corticosteroids, including budesonide, a component of formoterol/ budesonide combination. Therefore, close monitoring is warranted in patients with a change in vision or with history of increased intraocular pressure, glaucoma, and/or cataracts.

Eosinophilic Conditions and Churg-Strauss Syndrome

In rare cases, patients on inhaled corticosteroids may present with systemic eosinophilic conditions. Some of these patients have clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition that is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of inhaled corticosteroids. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal relationship between budesonide and these underlying conditions has not been established.

Coexisting Conditions

Formoterol/budesonide combination, like all medications containing sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis, pheochromocytoma, diabetes mellitus, and in those who are unusually responsive to sympathomimetic amines. Doses of the related beta -adrenoceptor agonist albuterol, When administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.

The need for, and dose of inhaled corticosteroids should be re-evaluated in patients with active or quiescent pulmonary tuberculosis, fungal and viral infections in the airways.

Hypokalemia and Hyperglycemia

Beta-adrenergic 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 seen infrequently during clinical studies with formoterol/budesonide combination at recommended doses.

As for all beta₂-agonists, additional blood glucose controls should be considered in diabetic patients.

The benefits of inhaled budesonide therapy would normally minimize the need for oral steroids, but patients transferring from oral steroids may remain at risk of impaired adrenal reserve for a considerable time. Patients, who have required high dose emergency corticosteroid therapy in the past or prolonged treatment with high doses of inhaled corticosteroids, may also be at risk. Additional systemic corticosteroid cover should be considered during periods of stress or elective surgery.

Drug Interactions

In clinical studies, concurrent administration of Formoterol/Budesonide combination and other drugs, such as short-acting beta2 agonists, intranasal corticosteroids, and antihistamines/ decongestants has not resulted in an increased frequency of adverse reactions. No formal drug interaction studies have been performed with Formoterol/Budesonide combination.

Potent Cytochrome P450 3A4 Inhibitors

The main route of metabolism of corticosteroids, including budesonide, a component of Formoterol/Budesonide combination, is via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4). After oral administration of ketoconazole, a strong inhibitor of CYP3A4, the mean plasma concentration of orally administered budesonide increased. Concomitant administration of CYP3A4 may inhibit the metabolism of, and increase the systemic exposure to, budesonide. Caution should be exercised when considering the coadministration of Formoterol/Budesonide combination with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin).

Monoamine Oxidase Inhibitors and Tricyclic Antidepressants

Formoterol/Budesonide combination should be administered with caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of formoterol, a component of Formoterol/budesonide combination, on the vascular system may be potentiated by these agents. In clinical trials with Formoterol/Budesonide combination, a limited number of COPD and asthma patients received tricyclic antidepressants, and, therefore, no clinically meaningful conclusions on adverse events can be made.

Beta-Adrenergic Receptor Blocking Agents

Beta-blockers (including eye drops) may not only block the pulmonary effect of beta-agonists, such as formoterol, a component of Formoterol/Budesonide combination, but may produce severe bronchospasm in patients with asthma. Therefore, patients with asthma should not normally be treated with beta-blockers. However, under certain circumstances, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents in patients with asthma. In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution.

Diuretics

The ECG changes and/or hypokalemia that may result from the administration of non-potassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of Formoterol/Budesonide combination with non-potassium-sparing diuretics.

Use in Special Population

Patients with Renal Impairment

There are no data regarding the specific use of the budesonide/formoterol combination in patients with renal impairment.

Patients with Hepatic Impairment

Formal pharmacokinetic studies using budesonide/formoterol combination have not been conducted in patients with hepatic impairment. However, since both budesonide and formoterol fumarate dihydrate are predominantly cleared by hepatic metabolism, impairment of liver function may lead to accumulation of budesonide and formoterol fumarate dihydrate in plasma. Therefore, patients with hepatic disease should be closely monitored.

Pregnant Women

For formoterol/budesonide combination or the concomitant treatment with formoterol and budesonide, no clinical data on exposed pregnancies are available. In animal reproduction studies, Formoterol/Budesonide combination, administered by the inhalation route, was teratogenic, embryocidal, and reduced fetal weights in rats at less than the maximum recommended human daily inhalation dose (MRHDID) on a mcg/m2 basis. Budesonide alone, administered by the subcutaneous route, was teratogenic, embryocidal, and reduced fetal weights in rats and rabbits at less than the MRHDID, but these effects were not seen in rats that received inhaled doses up to 4 times the MRHDID. Studies of pregnant women have not shown that inhaled budesonide alone increases the risk of abnormalities when administered during pregnancy. Experience with oral corticosteroids suggests that rodents are more prone to teratogenic effects from corticosteroid exposure than humans. Formoterol fumarate alone, administered by the oral route, was teratogenic in rats and rabbits at 1600 and 65,000 times the MRHDID, respectively. Formoterol fumarate was also embryocidal, increased pup loss at birth and during lactation, and decreased pup weight in rats at 110 times the MRHDID. These adverse effects generally occurred at large multiples of the MRHDID when formoterol fumarate was administered by the oral route to achieve high systemic exposures. No teratogenic, embryocidal, or developmental effects were seen in rats that received inhalation doses up to 375 times the MRHDID. During pregnancy, FORACORT Inhaler should only be used when the benefits outweigh the potential risks. The lowest effective dose of budesonide needed to maintain adequate asthma control should be used. In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal adverse outcomes such as preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women with asthma should be closely monitored and medication adjusted as necessary to maintain optimal asthma control.

Labor or Delivery

There are no well-controlled human studies that have investigated the effects of formoterol/budesonide during labor and delivery. Because of the potential for beta-agonist interference with uterine contractility, use of formoterol/budesonide during labor should be restricted to those patients in whom the benefits clearly outweigh the risk.

Lactating Women

There are no available data on the effects of Formoterol/Budesonide combination, budesonide or formoterol fumarate on the breastfed child or on milk production. Budesonide, like other inhaled corticosteroids, is present in human breast milk. However, at therapeutic doses no effects on the suckling child are anticipated. It is not known whether formoterol passes into human breast milk. In rats, small amounts of formoterol have been detected in maternal milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for FORACORT Inhaler and any potential adverse effects on the breastfed infant from FORACORT Inhaler or from the underlying maternal condition.

Fertility

There is no data available on the potential effect of budesonide on fertility. Animal reproduction studies with formoterol have shown a somewhat reduced fertility in male rats at high systemic exposure.

Paediatric Patients

Safety and effectiveness of formoterol/budesonide combination in asthma patients 12 years of age and older have been established in studies up to 12 months. Efficacy results in this age group were similar to those observed in patients 18 years and older. The safety and effectiveness of Formoterol/Budesonide combination 80/4.5 in asthma patients 6 to less than 12 years of age have been established in studies of up to 12-week duration. The safety profile in these patients was consistent to that observed in patients 12 years of age and older who also received Formoterol/Budesonide combination. The safety and effectiveness of formoterol/budesonide combination in asthma patients less than 6 years of age have not been established.

The growth of pediatric patients receiving orally inhaled corticosteroids, including FORACORT Inhaler, should be monitored. If a child or adolescent on any corticosteroid appears to have growth suppression, the possibility that he/she is particularly sensitive to this effect should be considered. The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained. To minimize the systemic effects of orally inhaled corticosteroids, including FORACORT Inhaler, each patient should be titrated to the lowest strength that effectively controls his/her asthma.

Geriatric Patients

No overall differences in safety were observed between these patients and younger patients. As with other products containing beta₂-agonists, special caution should be observed when using FORACORT Inhaler in geriatric patients who have concomitant cardiovascular disease that could be adversely affected by beta₂-agonists. Based on available data for formoterol and budesonide or its active components, no adjustment of dosage for formoterol/budesonide combination in geriatric patients is warranted.

Effects on Ability to Drive and Use Machines

Formoterol/budesonide combination has no or negligible influence on the ability to drive and use machines.

Undesirable Effects

Since FORACORT Inhaler contains both budesonide and formoterol, the same pattern of undesirable effects as reported for these substances may occur. No increased incidence of adverse reactions has been seen following concurrent administration of the two compounds. The most common drug related adverse reactions are pharmacologically predictable side-effects of beta₂-agonist therapy, such as tremor and palpitations. These tend to be mild and usually disappear within a few days of treatment.

Clinical trials experience

Long-term safety studies in adolescent and adult patients 12 years of age and older, treated for up to 1 year at doses up to 1280/36 mcg/day (640/18 mcg twice daily), revealed neither clinically important changes in the incidence nor new types of adverse events emerging after longer periods of treatment.

Similarly, no significant or unexpected patterns of abnormalities were observed for up to 1 year in safety measures including chemistry, hematology, ECG, Holter monitor, and HPA-axis assessments.

The common undesirable effects seen in >/= 3% in clinical trials with asthmatic patients 12 years and older are: nasopharyngitis, headache, upper respiratory tract infection, pharyngolaryngeal pain, sinusitis, influenza, back pain, nasal congestion, stomach discomfort, vomiting and oral candidiasis.

The common undesirable effects with an incidence of 3% or more in clinical trials with duration of 12 weeks in adult COPD patients are: nasopharyngitis, oral candidiasis, bronchitis, sinusitis, viral upper respiratory tract infections.

Other adverse reactions, which have been associated with budesonide or formoterol are as follows frequencies are defined as: very common [≥1/10], common [≥ 1/100 <1/10], uncommon (≥1/1,000, < 1/100), rare (≥1/10,000, < 1/1,000), very rare [<1/10,000] and not known [cannot be estimated from the available data]:

Infections and Infestations (common): Candida infections in the oropharynx, pneumonia or lower respiratory tract infections (in COPD patients)

Immune system disorders (Rare): Immunosuppression, Immediate and delayed hypersensitivity reactions, e.g. exanthema, urticaria, pruritus, dermatitis, angioedema and anaphylactic reaction.

Pneumonia and lower respiratory tract infections in patients with COPD

Glaucoma and cataracts

Serious asthma-related events, hospitalizations, death (due to LABA)

Cardiovascular and central nervous system effects (due to LABA)

Endocrine disorders: (very rare): Cushing

(Rare): Hypercorticism, adrenal suppression, growth retardation, growth effects in pediatric patients, decrease in bone mineral density

Metabolic and nutrition disorders: Hypokalemia, hyperglycemia.

Psychiatric disorders: (uncommon); Aggression, psychomotor hyperactivity, anxiety, sleep disorders (Very rare); Depression, behavioral changes (predominantly in children)

Nervous system disorders: Headache, tremors (common), dizziness (uncommon), taste disturbances (very rare).

Cardiac disorders: (Common); Palpitations

(Uncommon); Tachycardia

(Rare); Cardiac arrhythmias, e.g. atrial fibrillation, supraventricular tachycardia, extrasystoles (Very rare); Angina pectoris. Prolongation of QTc-interval

Eye Disorders: Cataract and glaucoma (very rare), Vision, blurred (uncommon)

Cardiac disorders: Palpitations (common), Tachycardia (uncommon), Cardiac arrhythmias, e.g. atrial fibrillation, supraventricular tachycardia, extrasystoles (rare), Angina pectoris. Prolongation of QTc-interval (very rare)

Vascular Disorders (very rare): Variations in blood pressure

Respiratory, thoracic and mediastinal disorders: Mild irritation in the throat, coughing, hoarseness (common), Bronchospasm (rare), Paradoxical bronchospasm (very rare)

Gastrointestinal Disorders (Uncommon): Nausea

Skin and subcutaneous tissue disorders: Bruises.

Musculoskeletal and Connective Tissue Disorders: (Uncommon); Muscle cramps

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of formoterol/budesonide combination.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Some of these adverse reactions may also have been observed in clinical studies with formoterol/budesonide combination.

Cardiac disorders: angina pectoris, tachycardia, atrial and ventricular tachyarrhythmias, atrial fibrillation, extrasystoles, palpitations

Endocrine disorders: hypercorticism, growth velocity reduction in pediatric patients

Eye disorders: cataract, glaucoma, increased intraocular pressure

Gastrointestinal disorders: oropharyngeal candidiasis, nausea

Immune system disorders: immediate and delayed hypersensitivity reactions, such as anaphylactic reaction, angioedema, bronchospasm, urticaria, exanthema, dermatitis, pruritus

Metabolic and nutrition disorders: hyperglycemia, hypokalemia

Musculoskeletal, connective tissue, and bone disorders: muscle cramps

Nervous system disorders: tremor, dizziness

Psychiatric disorders: behavior disturbances, sleep disturbances, nervousness, agitation, depression, restlessness

Respiratory, thoracic, and mediastinal disorders: dysphonia, cough, throat irritation

Skin and subcutaneous tissue disorders: skin bruising

Vascular disorders: hypotension, hypertension

If you experience any side-effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024 or you can report to Cipla Ltd on 18002677779. By reporting side-effects, you can help provide more information on the safety of this product.

Overdosage

An overdose of formoterol would likely lead to effects that are typical for beta₂-adrenergic agonists: tremor, headache, palpitations. Symptoms reported from isolated cases are tachycardia, hyperglycemia, hypokalemia, prolonged QTc-interval, arrhythmia, nausea and vomiting. Supportive and symptomatic treatment may be indicated. A dose of 90 mcg administered during three hours in patients with acute bronchial obstruction raised no safety concerns.

Acute overdosage with budesonide, even in excessive doses, is not expected to be a clinical problem. When used chronically in excessive doses, systemic glucocorticosteroid effects, such as hypercorticism and adrenal suppression, may appear.

If FORACORT Inhaler therapy has to be withdrawn due to overdose of the formoterol component of the drug, provision of appropriate inhaled corticosteroid therapy must be considered.

Pharmacological Properties

Mechanism of Action

FORACORT Inhaler are a combination of budesonide, a potent glucocorticoid, and formoterol fumarate dihydrate, a selective, long-acting beta₂-agonist, which have different modes of action and show additive effects in terms of reduction of asthma exacerbations.

Budesonide is a potent glucocorticoid that binds with high affinity to the glucocorticoid receptor. It has a high ratio of topical to systemic activity.

Formoterol is a very potent, long-acting, beta₂adrenoceptor-agonist with a high intrinsic activity and a rapid onset of action.

Pharmacodynamics

FORACORT Inhaler contain both budesonide and formoterol; therefore, the mechanisms of action described below for the individual components apply to FORACORT Inhaler. These drugs represent two classes of medications (a synthetic corticosteroid and a long-acting, selective beta₂-adrenoceptor agonist) that have different effects on the clinical, physiological, and inflammatory indices of Chronic Obstructive Pulmonary Disease (COPD) and asthma.

Budesonide

Budesonide is an anti-inflammatory corticosteroid that exhibits potent glucocorticoid activity and weak mineralocorticoid activity. In standard in vitro and animal models, budesonide has approximately a 200-fold higher affinity for the glucocorticoid receptor and a 1000-fold higher topical anti-inflammatory potency than cortisol.

In glucocorticoid receptor affinity studies, the 22R form of budesonide was two times as active as the 22S epimer. In vitro studies indicated that the two forms of budesonide do not interconvert.

Inflammation is an important component in the pathogenesis of COPD and asthma. Corticosteroids have a wide range of inhibitory activities against multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in allergic and non-allergic-mediated inflammation. These anti-inflammatory actions of corticosteroids may contribute to their efficacy in COPD and asthma.

Studies in asthmatic patients have shown a favorable ratio between topical anti-inflammatory activity and systemic corticosteroid effects over a wide range of doses of budesonide. This is explained by a combination of a relatively high local anti-inflammatory effect, extensive first pass hepatic degradation of orally absorbed drug (85-95%), and the low potency of formed metabolites.

Formoterol

Formoterol fumarate dihydrate is a long-acting, selective beta₂-adrenergic agonist with a rapid onset of action. Inhaled formoterol fumarate dihydrate acts locally in the lungs as a bronchodilator. In vitro studies have shown that formoterol has over 200-fold greater agonist activity at beta₂-receptors than at beta₁-receptors. The in vitro binding selectivity to beta₂-adrenoceptors over beta₁-adrenoceptors is higher for formoterol than for salbutamol (5 times), whereas salmeterol has a higher (3 times) beta₂-selectivity ratio than formoterol.

Although beta₂-receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta₁-receptors are the predominant receptors in the heart, there are also beta₂-receptors in the human heart, which comprise 10–50% of the total beta-adrenergic receptors. The precise function of these receptors has not been established, but they raise the possibility that even highly selective beta₂-agonists may have cardiac effects.

The pharmacological effects of beta₂-adrenoceptor agonist drugs, including formoterol, are, at least in part, attributable to the stimulation of intracellular adenyl cyclase, the enzyme that catalyses the conversion of adenosine triphosphate (ATP) to cyclic-3′, 5′-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibit the release of mediators of immediate hypersensitivity from the cells, especially from mast cells.

Pharmacokinetics

Budesonide

Absorption:

Orally inhaled budesonide is rapidly absorbed in the lungs and peak concentration is typically reached within 20 minutes. After oral administration of budesonide, peak plasma concentration was achieved in about 1-2 hours and the absolute systemic availability was 6–13%, due to extensive first pass metabolism. In contrast, most of the budesonide delivered to the lungs was systemically absorbed. In healthy subjects, 34% of the metered dose was deposited in the lungs (as assessed by the plasma concentration method, and using a budesonide-containing DPI) with an absolute systemic availability of 39% of the metered dose.

Following administration of formoterol/budesonide combination 160/4.5 mcg, (two or four inhalations twice daily) for 5 days in healthy subjects, plasma concentration of budesonide generally increased in proportion to dose. The accumulation index for the group that received two inhalations twice daily was 1.32 for budesonide.

Asthma Patients: In a single-dose study, higher than recommended doses of formoterol/budesonide combination (12 inhalations of formoterol/budesonide combination 160/4.5 mcg) were administered to patients with moderate asthma. Peak budesonide plasma concentration of 4.5 nmol/L occurred at 20 minutes following dosing.

In a repeat dose study, the highest recommended dose of formoterol/budesonide combination (160/4.5 mcg, two inhalations twice daily) was administered to patients with moderate asthma and healthy subjects for 1 week. Peak budesonide plasma concentration of 1.2 nmol/L occurred at 21 minutes in asthma patients. Peak budesonide plasma concentration was 27% lower in asthma patients compared to that in healthy subjects. However, the total systemic exposure of budesonide was comparable to that in asthma patients.

Peak steady-state plasma concentrations of budesonide administered by DPI in adults with asthma averaged 0.6 and 1.6 nmol/L at doses of 180 mcg and 360 mcg twice daily, respectively. In asthmatic patients, budesonide showed a linear increase in AUC and C_max with increasing dose after both single and repeated dosing of inhaled budesonide.

COPD Patients: In a single-dose study, 12 inhalations of formoterol/budesonide combination 80/4.5 mcg (total dose 960/54 mcg) were administered to patients with COPD. Mean budesonide peak plasma concentration of 3.3 nmol/L occurred at 30 minutes following dosing. In the same study, an open-label group of moderate asthma patients also received the same higher dose of formoterol/budesonide combination. For budesonide, COPD patients exhibited 12% greater AUC and 10% lower C_max compared to asthma patients.

In the 6 month pivotal clinical study, steady-state pharmacokinetic data of budesonide was obtained in a subset of COPD patients with treatment arms of formoterol/budesonide combination pMDI 160/4.5 mcg, formoterol/budesonide combination pMDI 80/4.5 mcg, budesonide 160 mcg, budesonide 160 mcg and formoterol 4.5 mcg given together, all administered as two inhalations twice daily. Budesonide systemic exposure (AUC and C_max) increased proportionally with doses from 80 mcg to 160 mcg and was generally similar between the 3 treatment groups receiving the same dose of budesonide (formoterol/budesonide combination pMDI 160/4.5 mcg, budesonide 160 mcg, budesonide 160 mcg and formoterol 4.5 mcg administered together).

Distribution

The volume of distribution of budesonide was approximately 3 L/kg. It was 85-90% bound to plasma proteins. Protein binding was constant over the concentration range (1-100 nmol/L) achieved with, and exceeding, recommended inhaled doses. Budesonide showed little or no binding to corticosteroid binding globulin. Budesonide rapidly equilibrated with red blood cells in a concentration independent manner with a blood plasma ratio of about 0.8.

Metabolism

In vitro studies with human liver homogenates have shown that budesonide was rapidly and extensively metabolized. Two major metabolites formed via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4) catalyzed biotransformation have been isolated and identified as 16-alpha-hydroxyprednisolone and 6-beta-hydroxybudesonide. The corticosteroid activity of each of these two metabolites was less than 1% of that of the parent compound. No qualitative differences between the in vitro and in vivo metabolic patterns were detected. Negligible metabolic inactivation was observed in human lung and serum preparations.

Excretion/Elimination

Budesonide was excreted in urine and feces in the form of metabolites. Approximately 60% of an intravenous radiolabeled dose was recovered in the urine.

No unchanged budesonide was detected in the urine. The 22R form of budesonide was preferentially cleared by the liver with systemic clearance vs. 1.0 L/min for the 22S form. The terminal half- 2 to 3 hours was the same for both epimers and was independent of dose.

Formoterol

Absorption:

For formoterol, maximal plasma concentration was similar after administration of the fixed combination.

Inhaled formoterol is rapidly absorbed; peak plasma concentrations are typically reached at the first plasma sampling time, within 5-10 minutes after dosing. As with many drug products for oral inhalation, it is likely that the majority of the inhaled formoterol delivered is swallowed and then absorbed from the gastrointestinal tract.

Healthy Subjects: Following administration of formoterol/budesonide combination (160/4.5 mcg, two or four inhalations twice daily) for 5 days in healthy subjects, plasma concentration of formoterol generally increased in proportion to dose. The accumulation index for the group that received two inhalations twice daily was 1.77 for formoterol.

Asthma patients: In a single-dose study, higher than recommended doses of formoterol/budesonide combination (12 inhalations of formoterol/budesonide combination160/4.5 mcg) were administered to patients with moderate asthma. Peak plasma concentration for formoterol of 136 pmol/L occurred at 10 minutes following dosing. Approximately 8% of the delivered dose of formoterol was recovered in the urine as unchanged drug.

In a repeat dose study, the highest recommended dose of formoterol/budesonide combination (160/4.5 mcg, two inhalations twice daily) was administered to patients with moderate asthma and healthy subjects for 1 week. Peak formoterol plasma concentration of 28 pmol/L occurred at 10 minutes in asthma patients. Peak formoterol plasma concentration was about 42% lower in asthma patients compared to that in healthy subjects. However, the total systemic exposure of formoterol was comparable to that in asthma patients.

COPD patients: Following single-dose administration of 12 inhalations of formoterol/budesonide combination 80/4.5 mcg, mean peak formoterol plasma concentration of 167 pmol/L was rapidly achieved at 15 minutes after dosing. In the same study, an open label group of moderate asthma patients received the same dose of formoterol/budesonide combination. COPD patients exhibited 12-15% greater AUC and C_max for formoterol compared to asthma patients.

In a 6 month pivotal clinical study, steady-state pharmacokinetic data of formoterol was obtained in a subset of COPD patients with treatment arms of formoterol/budesonide combination pMDI 160/4.5 mcg, formoterol/budesonide combination pMDI 80/4.5 mcg, formoterol 4.5 mcg, budesonide 160 mcg and formoterol 4.5 mcg given together, all administered as two inhalations twice daily. The systemic exposure of formoterol as evidenced by AUC, was about 30% and 16% higher from formoterol/budesonide combination pMDI compared to formoterol alone treatment arm and coadministration of individual components of budesonide and formoterol treatment arm, respectively.

Distribution

Over the concentration range of 10-500 nmol/L, plasma protein binding for the RR and SS enantiomers of formoterol was 46% and 58%, respectively. The concentrations of formoterol used to assess the plasma protein binding were higher than those achieved in plasma following inhalation of a single 54 mcg dose.

Metabolism

The primary metabolism of formoterol is by direct glucuronidation and by O-demethylation followed by conjugation to inactive metabolites. Secondary metabolic pathways include deformylation and sulfate conjugation. CYP2D6 and CYP2C have been identified as being primarily responsible for O-demethylation

Elimination

The excretion of formoterol was studied in four healthy subjects following simultaneous administration of radiolabeled formoterol via the oral and IV routes. In that study, 62% of the radiolabeled formoterol was excreted in the urine while 24% was eliminated in the feces.

Nonclinical Properties

Carcinogenesis, Mutagenesis, Impairment of Fertility

Budesonide

Long-term studies were conducted in rats and mice using oral administration to evaluate the carcinogenic potential of budesonide. In a 2-year study in Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of gliomas in male rats at an oral dose of 50 mcg/kg (approximately equivalent to the MRHDID in adults and children on a mcg/m basis). No tumorigenicity was seen in male and female rats at respective oral doses up to 25 and 50 mcg/kg (approximately equivalent to the MRHDID in adults and children on a mcg/m basis). In two additional 2-year studies in male Fischer and Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (approximately equivalent to the MRHDID in adults and children on a mcg/m basis). However, in the male Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (approximately equivalent to the MRHDID in adults and children on a mcg/m basis). The concurrent reference corticosteroids (prednisolone and triamcinolone acetonide) in these two studies showed similar findings. In a 91-week study in mice, budesonide caused no treatment-related carcinogenicity at oral doses up to 200 mcg/kg (approximately 2 times the MRHDID in adults and children on a mcg/m basis). Budesonide was not mutagenic or clastogenic in six different test systems: Ames Salmonella/microsome plate test, mouse micronucleus test, mouse lymphoma test, chromosome aberration test in human lymphocytes, sex-linked recessive lethal test in Drosophila melanogaster, and DNA repair analysis in rat hepatocyte culture. Fertility and reproductive performance were unaffected in rats at subcutaneous doses up to 80 mcg/kg (approximately equal to the MRHDID on a mcg/m basis). However, it caused a decrease in prenatal viability and viability in the pups at birth and during lactation, along with a decrease in maternal bodyweight gain, at subcutaneous doses of 20 mcg/kg and above (less than the MRHDID on a mcg/m basis). No such effects were noted at 5 mcg/kg (less than the MRHDID on a mcg/m basis).

Formoterol

Long-term studies were conducted in mice using oral administration and rats using inhalation administration to evaluate the carcinogenic potential of formoterol fumarate.

In a 24-month carcinogenicity study in CD-1 mice, formoterol at oral doses of 100 mcg/kg and above (approximately 30 and 15 times the MRHDID in adults and children, respectively, on a mcg/m basis) caused a dose-related increase in the incidence of uterine leiomyomas. In a 24-month carcinogenicity study in Sprague-Dawley rats, an increased incidence of mesovarianleiomyoma and uterine leiomyosarcoma were observed at the inhaled dose of 130 mcg/kg (approximately 70 and 35 times the MRHDID in adults and children, respectively, on a mcg/m basis). No tumors were seen at 22 mcg/kg (approximately 12 and 6 times the MRHDID in adults and children, respectively, on a mcg/m basis). Other beta-agonist drugs have similarly demonstrated increases in leiomyomas of the genital tract in female rodents. The relevance of these findings to human use is unknown. Formoterol was not mutagenic or clastogenic in Ames Salmonella/microsome plate test, mouse lymphoma test, chromosome aberration test in human lymphocytes, and rat micronucleus test. A reduction in fertility and/or reproductive performance was identified in male rats treated with formoterol at an oral dose of 15,000 mcg/kg (approximately 2200 times the MRHDID on an AUC basis). No such effect was seen at 3000 mcg/kg (approximately 1600 times the MRHDID on a mcg/m basis). In a separate study with male rats treated with an oral dose of 15,000 mcg/kg (approximately 8000 times the MRHDID on a mcg/m basis), there were findings of testicular tubular atrophy and spermatic debris in the testes and oligospermia in the epididymides. No effect on fertility was detected in female rats at doses up to 15,000 mcg/kg (approximately 1100 times the MRHDID on an AUC basis).

Animal Toxicology and/or Pharmacology

Preclinical: Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta-agonists and methylxanthines are administered concurrently. The clinical significance of these findings is unknown.

Description

FORACORT Inhaler is a combination of budesonide, a potent glucocorticoid, and formoterol fumarate dihydrate, a selective, long-acting beta₂-agonist, which have different modes of action and show additive effects in terms of reduction of asthma exacerbations. Budesonide is a potent glucocorticoid that binds with high affinity to the glucocorticoid receptor. It has a high ratio of topical to systemic activity. Formoterol is a very potent, long-acting, beta₂adrenoceptor-agonist with a high intrinsic activity and a rapid onset of action.

Budesonide:

budesonide, a corticosteroid designated chemically as (RS)11β, 16α, 17,21-Tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with butyraldehyde. Budesonide is provided as a mixture of two epimers (22R and 22S). The empirical formula of budesonide is C25H34O6 and its molecular weight is 430.5. Its structural formula is:

Foracort_inhaler_1

Figure: 1. Structural formula of Budesonide

Budesonide is a white to off-white, tasteless, odorless powder which is practically insoluble in water and in heptane, sparingly soluble in ethanol, and freely soluble in chloroform. Its partition coefficient between octanol and water at pH 7.4 is 1.6 x 103.

Formoterol fumarate:

Formoterol fumarate dihydrate, a selective beta2-agonist designated chemically as (R*,R*)-(±)-N-[2-hydroxy-5-[1-hydroxy-2-[[2-(4-methoxyphenyl)-1methylethyl]amino]ethyl]phenyl]formamide, (E)-2-butendioate(2:1), dihydrate. The empirical formula of formoterol is C42H56N4O14 and its molecular weight is 840.9. Its structural formula is:

Foracort_inhaler_2

Figure: 2.Structural formula of Formoterol fumarate

Formoterol fumarate dihydrate is a powder which is slightly soluble in water. Its octanol-water partition coefficient at pH 7.4 is 2.6. The pKa of formoterol fumarate dihydrate at 25°C is 7.9 for the phenolic group and 9.2 for the amino group.

Pharmaceutical Particulars

Incompatibilities

Not Applicable

Shelf-Life

See on the pack

Packaging Information

FORACORT-100 Inhaler

FORACORT-200 Inhaler
FORACORT-400 Inhaler

Each sales pack contains 30 Inhaler

Storage and Handling Instructions

Patient Counselling Information

What is FORACORT Inhaler used for?

FORACORT Inhaler is indicated in the regular treatment of asthma, where the use of a combination (long-acting, beta₂-agonist and inhaled corticosteroid) has been found to be appropriate for instance:

FORACORT Inhaler is also indicated in regular treatment of patients with moderate to severe COPD with frequent symptoms and a history of exacerbations

It can be prescribed for asthma in two different ways.

Asthma

FORACORT Inhaler can be used according to different treatment approaches:

Asthma

For FORACORT there are two treatment approaches:

Maintenance Therapy: FORACORT Inhaleris taken as regular maintenance treatment with a separate rapid acting bronchodilator as rescue.
Single maintenance and reliever therapy: FORACORT Inhaleris taken as regular maintenance and as needed in response to symptoms.

Maintenance Therapy:Patients should be advised to have their separate rapid acting bronchodilator available for rescue use at all times.

Recommended Dosage

Adults (18 Years and Older)

FORACORT-100 Inhaler

1–2 inhalations, twice daily

Maximum dose is 4 inhalations, twice daily

FORACORT-200 Inhaler

1–2 inhalations, twice daily

Maximum dose is 4 inhalations, twice daily

FORACORT- 400 Inhaler

1 inhalation, twice daily

Maximum dose is 2 inhalations, twice daily

Adolescents (12-17 Years)

FORACORT-100 Inhaler

1–2 inhalations, twice daily

FORACORT-200 Inhaler

1–2 inhalations, twice daily

FORACORT- 400 Inhaler

1 inhalation, twice daily

Children (6-11 Years)

FORACORT-100 Inhaler

2 inhalations, twice daily

Single Maintenance and Reliever Therapy (For FORACORT -100 and 200 only)

Adults (18 years and older)

Single inhaler as maintenance and reliever therapy is not recommended in children and adolescents.

FORACORT- 400 Inhaler should not be used for single maintenance and reliever therapy.

COPD (Chronic Obstructive Pulmonary Disease)

FORACORT 200 Inhaler

2 inhalations, twice daily

Always keep your FORACORT Inhaler with you, so you can use it when you need it. A total daily dose of more than 8 inhalations is not normally needed. However, your doctor may allow you to take up to 12 inhalations a day for a limited period. If you regularly need to use 8 or more inhalations a day, make an appointment to see your doctor. They may need to change your treatment. Do not use more than 12 inhalations in total in 24 hours. If you are doing exercise and you get asthma symptoms, use FORACORT Inhaler as described here. However, do not use FORACORT Inhaler just before exercise to stop asthma symptoms from happening.

What you need to know before you use FORACORT Inhaler?

Do not use FORACORT Inhaler if you are allergic to budesonide, formoterol or the other ingredient of this medicine

Warnings and Precautions

Talk to your doctor before using FORACORT Inhaler if:

You are diabetic.
You have a lung infection.
You have high blood pressure or you have ever had a heart problem (including an uneven heart beat, a very fast pulse, narrowing of the arteries or heart failure).
You have problems with your thyroid or adrenal glands.
You have low levels of potassium in your blood.
You have severe liver problems. Contact your doctor if you experience blurred vision or other visual disturbances. Other medicines and FORACORT Inhaler .Tell your doctor if you are using, have recently used or might use any other medicines. In particular, tell your doctor if you are using any of the following medicines:
Beta-blocker medicines (such as atenolol or propranolol for high blood pressure), including eyedrops (such as timolol for glaucoma).
Medicines for a fast or uneven heart beat (such as quinidine).
Medicines like digoxin, often used to treat heart failure.
Diuretics, also known as ‘water tablets’ (such as furosemide). These are used to treat high blood pressure.
Steroid medicines that you take by mouth (such as prednisolone).
Xanthine medicines (such as theophylline or aminophylline). These are often used to treat asthma.
Other bronchodilators (such as salbutamol).
Tricyclic anti-depressants (such as amitriptyline) and the anti-depressant nefazodone.
Phenothiazine medicines (such as chlorpromazine and prochlorperazine).
Medicines called ‘HIV-protease inhibitors’ (such as ritonavir) to treat HIV infection.
Medicines to treat infections (such as ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin and telithromycin).
Medicines for Parkinson’s disease (such as leva-dopa).
Medicines for thyroid problems (such as levo-thyroxine). If any of the above applies to you, or if you are not sure, talk to your doctor or pharmacist before using FORACORT Inhaler

Also tell your doctor if you are going to have a general anaesthetic for an operation or for dental work. Pregnancy, breast-feeding and fertility

If you are pregnant, or planning to get pregnant, talk to your doctor before using FORACORT Inhaler - do not use your inhaler unless your doctor tells you to.
If you get pregnant while using FORACORT Inhaler, do not stop using your inhaler but talk to your doctor immediately.
If you are breast-feeding, talk to your doctor before using FORACORT Inhaler.
Driving and using machines FORACORT Inhaler has no or negligible effect on your ability to drive or to use tools or machines.

How to use FORACORT Inhaler?

Always use this medicine exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.
It is important to use FORACORT Inhaler every day, even if you have no asthma symptoms at the time.
Your doctor will want to regularly check your asthma symptoms. If you have been taking steroid tablets for your asthma or COPD, your doctor may reduce the number of tablets that you take, once you start to use FORACORT Inhaler. If you have been taking oral steroid tablets for a long time, your doctor may want you to have blood tests from time to time. When reducing oral steroid tablets, you may feel generally unwell even though your chest symptoms may be improving. You might experience symptoms such as a stuffy or runny nose, weakness or joint or muscle pain and rash (eczema). If any of these symptoms bother you, or if symptoms such as headache, tiredness, nausea (feeling sick) or vomiting (being sick) occur, please contact your doctor immediately. You may need to take other medication if you develop allergic or arthritic symptoms. You should speak to your doctor if you are concerned as to whether you should continue to use FORACORT Inhaler. Your doctor may consider adding steroid tablets to your usual treatment during periods of stress (for example, when you have a chest infection or before an operation).

Important information about your asthma symptoms :

If you feel you are getting breathless or wheezy while using FORACORT Inhaler, you should continue to use FORACORT Inhaler but go to see your doctor as soon as possible, as you may need additional treatment.

Contact your doctor immediately if:

Your breathing is getting worse or you often wake up at night with asthma.
Your chest starts to feel tight in the morning or your chest tightness lasts longer than usual. These signs could mean that your asthma is not being properly controlled and you may need different or additional treatment immediately.

How to take an inhalation?

It is important for you to understand how to correctly use FORACORT Inhaler. Do not use FORACORT Inhaler unless your healthcare provider has taught you how to use the inhaler and you understand how to use it correctly.
Please refer to the Patient Information Leaflet given in the carton to read the full steps of how to use FORACORT Inhaler.
Use FORACORT Inhaler exactly as prescribed. Do not use FORACORT Inhaler more often than prescribed.
If you miss a dose of FORACORT Inhaler, take your next dose at the same time you normally do. Do not take more than your prescribed dose of FORACORT Inhaler If you take too much FORACORT Inhaler, call your healthcare provider or go to the nearest hospital emergency room right away if you have unusual symptoms, such as worsening shortness of breath, chest pain, increased heart rate, or shakiness.
Do not stop using FORACORT Inhaler unless told to do so by your healthcare provider because your symptoms might come back. Your healthcare provider will change your medicines as needed.
FORACORT Inhaler does not relieve sudden symptoms of COPD. Always have a rescue inhaler with you to treat sudden If you do not have a rescue inhaler, call your healthcare provider to have one prescribed for you.
Call your healthcare provider or get medical care right away if your breathing problems get worse; you need to use your rescue inhaler more often than usual, or your rescue inhaler does not work as well to relieve your symptoms.

How should I store FORACORT Inhaler?

FORACORT Inhaler should be stored away from moisture below a temperature of 30 °C and should be taken out of the blister immediately before use.
Keep FORACORT Inhaler and all medicines out of reach of children.

General Information About the Safe and Effective use of FORACORT Inhaler

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use FORACORT Inhaler for a condition for which it was not prescribed. Do not give your FORACORT Inhaler to other people, even if they have the same symptoms that you have. It may harm them.

You can ask your healthcare provider or pharmacist for information about FORACORT Inhaler that is written for health professionals.

Details of the Manufacturer

Manufactured by:

Cipla Ltd., Village Malpur,

Baddi, Dist. Solan (H.P.)- 173205

Cipla Ltd., Unit II, TAZA Block,

Rorathang, East Sikkim-737133

Registered Office:

Cipla House, Peninsula Business Park,

Ganpatrao Kadam Marg

Lower Parel

Mumbai – 400 013, India

Details of Permission or Licence Number with Date

MNB/05/109; Date: 04.04.2020
M/719/2016, Date: 22.12.2020

Date of Revision

21.06.2023