For the use of a Registered Medical Practitioner only

QUALITATIVE AND QUANTITATIVE COMPOSITION

FORACORT-G Inhaler 

Each actuation delivers:

Budesonide IP………………………………. 200 mcg

Glycopyrronium (as Glycopyrrolate IP) ……12.5 mcg

Formoterol Fumarate Dihydrate IP ……….. 6 mcg

Suspended in propellant HFA134a………. q.s.

DOSAGE FORM(S) AND STRENGTH(S)

Aerosol for inhalation containing Budesonide 200 mcg, Glycopyrronium (as Glycopyrrolate IP) 12.5 mcg, and Formoterol Fumarate Dihydrate 6 mcg.

CLINICAL PARTICULARS

Therapeutic Indications

FORACORT-G Inhaler is indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD).

Posology and Method of Administration

Posology

The recommended dose of FORACORT-G Inhaler is budesonide 400 mcg, glycopyrronium 25 mcg and formoterol fumarate 12 mcg [administered as two inhalations from FORACORT-G Inhaler (budesonide/glycopyrronium/formoterol fumarate 200 mcg/12.5 mcg/6 mcg)] twice daily (in the morning and in the evening). Do not take more than two inhalations twice daily.

After inhalation, the patient should rinse the mouth with water, without swallowing.

Method of Administration

FORACORT-G Inhaler is for inhalation use only.

FORACORT-G Inhaler may be used with a Zerostat VT Spacer device or a Mini Zerostat Spacer device in patients who find it difficult to synchronise aerosol actuation with inspiration of breath.

Contraindications

The use of FORACORT-G Inhaler is contraindicated in patients who have demonstrated hypersensitivity to glycopyrronium, formoterol, budesonide or any of the excipients.

Special Warnings and Precautions for Use

Serious Asthma-Related Events: Hospitalisations, Intubations, Death

The safety and efficacy of budesonide/glycopyrronium/formoterol in patients with asthma have not been established. FORACORT-G Inhaler is not indicated for the treatment of asthma.

Use of long-acting beta₂-adrenergic agonists (LABAs) as monotherapy [without inhaled corticosteroid (ICS)] for asthma is associated with an increased risk of asthma-related death. Available data from controlled clinical trials also suggest that use of LABAs as monotherapy increases the risk of asthma-related hospitalisation in paediatric and adolescent patients. These findings are considered a class effect of LABA monotherapy. When a LABA is used in fixed-dose combination with an ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalisations, intubations, death) compared with ICS alone.

Available data do not suggest an increased risk of death with the use of LABAs in patients with COPD.

Deterioration of Disease and Acute Episodes

FORACORT-G Inhaler should not be initiated in patients with acutely deteriorating COPD, which may be a life-threatening condition. Budesonide/glycopyrronium/formoterol has not been studied in patients with acutely deteriorating COPD. The use of FORACORT-G Inhaler in this setting is not appropriate.

FORACORT-G Inhaler should not be used for the relief of acute symptoms, i.e. as rescue therapy for the treatment of acute episodes of bronchospasm. Budesonide/glycopyrronium/formoterol has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta₂-agonist (SABA).

When beginning treatment with FORACORT-G Inhaler, patients who have been taking inhaled SABAs 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 respiratory symptoms. When prescribing FORACORT-G Inhaler, the healthcare provider should also prescribe an inhaled SABA and instruct the patient on how it should be used. Increasing inhaled beta₂-agonist use is a signal of deteriorating disease for which prompt medical attention is indicated.

COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If FORACORT-G Inhaler no longer controls symptoms or the patient’s inhaled SABA becomes less effective or the patient needs more inhalations of a SABA than usual, these may be markers of deterioration of disease. In this setting, re-evaluate the patient and the COPD treatment regimen at once. The daily dosage of FORACORT-G Inhaler should not be increased beyond the recommended dose.

Avoid Excessive Use of Budesonide/Glycopyrronium/Formoterol and Avoid Use with other Long-acting Beta₂-Agonists 

As with other inhaled drugs containing beta₂-adrenergic agents, budesonide/glycopyrronium/formoterol 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 FORACORT-G Inhaler should not use another medicine containing a LABA (e.g. salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason [see Drug Interactions].

Oropharyngeal Candidiasis

FORACORT-G Inhaler contains budesonide, an ICS. Localised infections of the mouth and pharynx with Candida albicans have occurred in subjects treated with orally inhaled drug products containing budesonide. When such an infection develops, it should be treated with appropriate local or systemic (i.e. oral) antifungal therapy while treatment with FORACORT-G Inhaler continues. In some cases, therapy with FORACORT-G Inhaler may need to be interrupted. Advise the patient to rinse his/her mouth with water without swallowing following administration of budesonide/glycopyrronium/formoterol to help reduce the risk of oropharyngeal candidiasis.

Pneumonia

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

In a 52-week trial of subjects with COPD (n=8,529), the incidence of confirmed pneumonia was 4.2% for inhalation of budesonide/glycopyrrolate/formoterol fumarate through a pressurised metered dose inhaler [(pMDI); 320 mcg/18 mcg/9.6 mcg (n=2,144)], 3.5% for inhalation of budesonide,  glycopyrrolate and formoterol fumarate through pMDI [(BGF MDI); 160 mcg/18 mcg/9.6 mcg (n=2,124)], 2.3% for glycopyrrolate/formoterol fumarate pMDI [(GFF MDI); 18 mcg/9.6 mcg (n=2,125)] and 4.5% for a budesonide/formoterol fumarate pMDI [(BFF MDI); 320 mcg/9.6 mcg (n=2,136)].

Fatal cases of pneumonia occurred in 2 subjects receiving BGF MDI 160 mcg/18 mcg/9.6 mcg, 3 subjects receiving GFF MDI 18 mcg/9.6 mcg, and no subjects receiving budesonide/glycopyrrolate/formoterol fumarate 320 mcg/18 mcg/9.6 mcg.

In a 24-week trial of subjects with COPD (n=1,896), the incidence of confirmed pneumonia was 1.9% for budesonide/glycopyrrolate/formoterol fumarate 320 mcg/18 mcg/9.6 mcg (n=639), 1.6% for GFF MDI 18 mcg/9.6 mcg (n=625) and 1.9% for BFF MDI 320 mcg/9.6 mcg (n=320). There were no fatal cases of pneumonia in the study.

Immunosuppression and Risk of Infections

Patients who are using drugs that suppress the immune system are more susceptible to infection than healthy individuals. Chickenpox 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 immunised, particular care should be taken to avoid exposure to corticosteroids. 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 a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) 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 chickenpox develops, treatment with antiviral agents may be considered.

ICS 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

HPA Suppression/Adrenal Insufficiency

Particular care is needed for patients who have been transferred from systemically active corticosteroids to ICS because deaths due to adrenal insufficiency have occurred in patients during and after transfer from systemic corticosteroids to less systemically available ICS. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (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 budesonide/glycopyrronium/formoterol may provide control of COPD 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, 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 healthcare practitioner 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, or a severe COPD exacerbation.

Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to FORACORT-G Inhaler. Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with budesonide/glycopyrronium/formoterol. Lung function (forced expiratory volume in 1 second [FEV₁] or morning peak expiratory flow [PEF]), beta-agonist use, and 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.

Unmasking of Allergic Conditions Previously Suppressed by Systemic Corticosteroids

Transfer of patients from systemic corticosteroid therapy to budesonide/glycopyrronium/formoterol may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy (e.g. rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions).

Corticosteroid Withdrawal Symptoms

During withdrawal from oral corticosteroids, 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

Inhaled budesonide is absorbed into the circulation and can be systemically active. Effects of budesonide on the HPA axis are not observed with the therapeutic doses of budesonide in FORACORT-G Inhaler. However, exceeding the recommended dosage or co-administration with a strong cytochrome P450 3A4 (CYP3A4) inhibitor may result in HPA dysfunction.

Because of the possibility of systemic absorption of ICS, patients treated with budesonide/glycopyrronium/formoterol 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 who are sensitive to these effects. If such effects occur, appropriate therapy should be initiated as needed.

Drug Interactions with Strong CYP3A4 Inhibitors

Caution should be exercised when considering the co-administration of budesonide/glycopyrronium/formoterol 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 [see Drug Interactions].

Paradoxical Bronchospasm

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

Hypersensitivity Reactions, including Anaphylaxis

Immediate hypersensitivity reactions have been reported after administration of budesonide, glycopyrronium or formoterol fumarate, the components of FORACORT-G Inhaler. If signs suggesting allergic reactions occur, in particular, angio-oedema (including difficulties in breathing or swallowing, swelling of tongue, lips, and face), urticaria, or skin rash, FORACORT-G Inhaler should be stopped at once and alternative treatment should be considered.

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, systolic or diastolic blood pressure, and also cardiac arrhythmias, such as supraventricular tachycardia and extrasystoles. 

If such effects occur, FORACORT-G Inhaler may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiographic changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression, although the clinical significance of these findings is unknown. Therefore, FORACORT-G Inhaler should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Reduction in Bone Mineral Density

Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing ICS. 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 immobilisation, family history of osteoporosis, post-menopausal 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 FORACORT-G Inhaler and periodically thereafter. If significant reductions in BMD are seen and budesonide/glycopyrronium/formoterol is still considered medically important for that patient's COPD therapy, use of therapy to treat or prevent osteoporosis should be strongly considered.

In a subset of COPD patients in a 24-week trial with a 28-week safety extension that evaluated budesonide/glycopyrrolate/formoterol 320/18/9.6 mcg and a GFF MDI 18/9.6 mcg, the effects on BMD endpoints were evaluated. BMD evaluations were performed at baseline and 52-weeks using dual energy X-ray absorptiometry (DEXA) scans. Mean percent changes in BMD from baseline was –0.1% for budesonide/glycopyrrolate/formoterol 320/18/9.6 mcg and 0.4% for the GFF MDI(18/9.6 mcg.

Glaucoma and Cataracts: Worsening of Narrow-angle Glaucoma   

Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with COPD following the long-term administration of ICS or with use of inhaled anticholinergics. FORACORT-G Inhaler should be used with caution in patients with narrow-angle glaucoma. Prescribers and patients should be alert for signs and symptoms of acute narrow-angle glaucoma (e.g. eye pain or discomfort, blurred vision, visual halos or coloured images in association with red eyes from conjunctival congestion and corneal oedema). Instruct patients to consult a physician immediately should any of these signs or symptoms develop. Consider referral to an ophthalmologist in patients who develop ocular symptoms or use FORACORT-G Inhaler long term.

In a 52-week trial that evaluated budesonide/glycopyrrolate/formoterol 320/18/9.6 mcg, GFF MDI 18/9.6 mcg, and BFF MDI 320/9.6 mcg in subjects with COPD, the incidence of cataracts ranged from 0.7% to 1.0% across groups. 

Worsening of Urinary Retention

FORACORT-G Inhaler, like all therapies containing an anticholinergic, should be used with caution in patients with urinary retention. Prescribers and patients should be alert for signs and symptoms of prostatic hyperplasia or bladder-neck obstruction (e.g. difficulty passing urine, painful urination), especially in patients with prostatic hyperplasia or bladder neck obstruction. Instruct patients to consult a physician immediately should any of these signs or symptoms develop.

Coexisting Conditions

FORACORT-G Inhaler, like all therapies containing sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis and in those who are unusually responsive to sympathomimetic amines. Doses of the related beta₂-adrenoceptor agonist salbutamol, when administered intravenously, have been reported to aggravate pre-existing diabetes mellitus and ketoacidosis.

Hypokalaemia and Hyperglycaemia

Beta-adrenergic agonists may produce significant hypokalaemia 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. Beta₂-agonist therapies may produce transient hyperglycaemia in some patients. 

Drug Interactions

No formal drug interaction studies have been performed with the budesonide/glycopyrronium/formoterol combination.

Inhibitors of CYP3A4

The main route of metabolism of corticosteroids, including budesonide, a component of FORACORT-G Inhaler, is via isoenzyme 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 co-administration of FORACORT-G Inhaler with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g. ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) [see Special Warnings and Precautions for Use].

Adrenergic Drugs

If additional adrenergic drugs are to be administered by any route, they should be used with caution because the sympathetic effects of formoterol, a component of FORACORT-G Inhaler, may be potentiated.

Xanthine Derivatives, Steroids, or Diuretics

Concomitant treatment with xanthine derivatives, steroids or diuretics may potentiate any hypokalaemic effect of beta₂-adrenergic agonists such as formoterol, a component of FORACORT-G Inhaler.

Non-Potassium-sparing Diuretics

The electrocardiograph (ECG) changes and/or hypokalaemia that may result from the administration of non-potassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta₂-agonists, especially when the recommended dose of the beta₂-agonist is exceeded.

Monoamine Oxidase Inhibitors, Tricyclic Antidepressants, QTc-Prolonging Drugs

FORACORT-G Inhaler, as with other beta₂-agonists, should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants or other drugs known to prolong the QTc interval because the action of adrenergic agonists on the cardiovascular system may be potentiated by these agents. Drugs that are known to prolong the QTc interval may be associated with an increased risk of ventricular arrhythmias.

Beta-adrenergic Receptor-blocking Agents

Beta-adrenergic receptor antagonists (beta-blockers) and FORACORT-G Inhaler may interfere with the effect of each other when administered concurrently. Beta-blockers not only block the therapeutic effects of beta₂-agonists but may produce severe bronchospasm in COPD patients. Therefore, patients with COPD should not normally be treated with beta-blockers. However, under certain circumstances, e.g. as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-blockers in patients with COPD. In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution.

Anticholinergics

There is a potential for an additive interaction with concomitantly used anticholinergic medications. Therefore, avoid co-administration of FORACORT-G Inhaler with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects.

Use in Special Populations

Patients with Renal Impairment

Formal pharmacokinetic studies using budesonide/glycopyrronium/formoterol have not been conducted in patients with renal impairment. In patients with severe renal impairment (creatinine clearance of ≤30 mL/minute/1.73 m²) or end-stage renal disease requiring dialysis, FORACORT-G Inhaler should only be used if the expected benefit outweighs the potential risk.

Patients with Hepatic Impairment

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

Pregnant Women

Risk Summary

There are no adequate and well-controlled studies with budesonide/glycopyrronium/formoterol or with individual components, glycopyrronium or formoterol fumarate, in pregnant women to inform a drug-associated risk; however, studies are available for the other component, budesonide.

In animal reproduction studies, budesonide alone, administered by the subcutaneous route, caused structural abnormalities, was embryocidal, and reduced foetal weights in rats and rabbits at 0.3 and 0.75 times the maximum recommended human daily inhaled dose (MRHDID), respectively, but these effects were not seen in rats that received inhaled doses up to 4 times the MRHDID. Studies of pregnant women who received inhaled budesonide alone during pregnancy have not shown increased risk of abnormalities. 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 in rats and rabbits, caused structural abnormalities at 1,500 and 61,000 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 were seen following large multiples of the MRHDID when formoterol fumarate was administered by the oral route to achieve high systemic exposures. No structural abnormalities and embryocidal or developmental effects were seen in rats that received inhalation doses up to 350 times the MRHDID.

Glycopyrronium alone, administered by the subcutaneous route in rats and rabbits, did not cause structural abnormalities or affect foetal survival at exposures approximately 2,700 and 5,400 times from MRHDID, respectively. Glycopyrronium had no effects on the physical, functional, and behavioural development of rat pups with exposures up to 2,700 times the MRHDID.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognised pregnancies is 2–4% and 15–20%, respectively.

Clinical Considerations

LABOUR OR DELIVERY

There are no well-controlled human trials that have investigated the effects of budesonide/glycopyrronium/formoterol on preterm labour or labour at term. Because of the potential for beta-agonist interference with uterine contractility, use of budesonide/glycopyrronium/formoterol during labour should be restricted to those patients in whom the benefits clearly outweigh the risks.

Data

HUMAN DATA

Studies of pregnant women have shown that inhaled budesonide does not increase the risk of abnormalities when administered during pregnancy. The results from a large population-based prospective cohort epidemiological study reviewing data from three Swedish registries covering approximately 99% of the pregnancies from 1995 to 1997 (i.e. Swedish Medical Birth Registry; Registry of Congenital Malformations; Child Cardiology Registry) indicate no increased risk for congenital malformations from the use of inhaled budesonide during early pregnancy. Congenital malformations were studied in 2,014 infants born to mothers reporting the use of inhaled budesonide for asthma in early pregnancy (usually 10–12 weeks after the last menstrual period), the period when most major organ malformations occur. The rate of recorded congenital malformations was similar compared with the general population rate (3.8% vs 3.5%, respectively). In addition, after exposure to inhaled budesonide, the number of infants born with orofacial clefts was similar to the expected number in the normal population (4 children vs 3.3, respectively).

These same data were utilised in a second study bringing the total to 2,534 infants whose mothers were exposed to inhaled budesonide. In this study, the rate of congenital malformations among infants whose mothers were exposed to inhaled budesonide during early pregnancy was not different from the rate for all new-born babies during the same period (3.6%).

ANIMAL DATA

BUDESONIDE

In a fertility and reproduction study, male rats were subcutaneously dosed for 9 weeks and females for 2 weeks prior to pairing and throughout the mating period. Females were dosed up until weaning of their offspring. Budesonide caused a decrease in prenatal viability and viability of the offspring at birth and during lactation, along with a decrease in maternal body weight gain, at a dose 0.3 times the MRHDID (on an mcg/m² basis at maternal subcutaneous doses of 20 mcg/kg/day and above). No such effects were noted at a dose 0.08 times the MRHDID (on an mcg/m² basis at a maternal subcutaneous dose of 5 mcg/kg/day).

In an embryo-foetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 6–18, budesonide produced foetal loss, decreased foetal weight, and skeletal abnormalities at a dose 0.75 times the MRHDID (on an mcg/m² basis at a maternal subcutaneous dose of 25 mcg/kg/day).

In an embryo-foetal development study in pregnant rats dosed during the period of organogenesis from gestation days 6–15, budesonide produced similar adverse foetal effects at doses approximately 8 times the MRHDID (on an mcg/m² basis at a maternal subcutaneous dose of 500 mcg/kg/day). In another embryo-foetal development study in pregnant rats, no structural abnormalities or embryocidal effects were seen at doses up to 4 times the MRHDID (on an mcg/m² basis at maternal inhalation doses up to 250 mcg/kg/day).

In a peri- and post-natal development study, rats dosed from gestation day 15 to postpartum day 21, budesonide had no effects on delivery, but did affect growth and development of offspring. Offspring survival was reduced and surviving offspring had decreased mean body weights at birth and during lactation at doses 0.3 times the MRHDID and higher (on an mcg/m² basis at maternal subcutaneous doses of 20 mcg/kg/day and higher). These findings occurred in the presence of maternal toxicity.

FORMOTEROL FUMARATE

In a fertility and reproduction study, male rats were orally dosed for at least 9 weeks and females for 2 weeks prior to pairing and throughout the mating period. Females were either dosed up to gestation day 19 or up until weaning of their offspring. Males were dosed up to 25 weeks. Umbilical hernia was observed in rat foetuses at oral doses 1,500 times the MRHDID (on an mcg/m² basis at maternal oral doses of 3,000 mcg/kg/day and higher). Brachygnathia was observed in rat foetuses at a dose 8,000 times the MRHDID (on an mcg/m² basis at a maternal oral dose of 15,000 mcg/kg/day). Pregnancy was prolonged at a dose 8,000 times the MRHDID (on an mcg/m² basis at a maternal oral dose of 15,000 mcg/kg/day). Foetal and pup deaths occurred at doses approximately 1,500 times the MRHDID and higher (on an mcg/m² basis at oral doses of 3,000 mcg/kg/day and higher) during gestation.

In an embryo-foetal development study in pregnant rats dosed during the period of organogenesis from gestation days 6–15, no structural abnormalities, embryocidal effects, or developmental effects were seen at doses up to 350 times the MRHDID (on an mcg/m² basis with maternal inhalation doses up to 690 mcg/kg/day).

In an embryo-foetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 6–18, subcapsular cysts on the liver were observed in the foetuses at a dose 61,000 times the MRHDID (on an mcg/m² basis with a maternal oral dose of 60,000 mcg/kg/day). No teratogenic effects were observed at doses up to 3,500 times the MRHDID (on an mcg/m² basis at maternal oral doses up to 3,500 mcg/kg/day).

In a pre- and post-natal development study, pregnant female rats received formoterol at oral doses of 0, 210, 840 and 3,400 mcg/kg/day from gestation day 6 (completion of implantation) through the lactation period. Pup survival was decreased from birth to postpartum day 26 at doses 110 times the MRHDID and higher (on an mcg/m² basis at maternal oral doses of 210 mcg/kg/day and higher), although there was no evidence of a dose-response relationship. There were no treatment-related effects on the physical, functional, and behavioural development of rat pups.

GLYCOPYRRONIUM

In an embryo-foetal development study in pregnant rats dosed during the period of organogenesis from gestation days 6–17, glycopyrronium produced no structural abnormalities or effects on foetal survival; however, slight reductions in foetal body weight were seen in the presence of maternal toxicity at the highest tested dose that was 2,700 times the MRHDID (on an mcg/m² basis at a maternal subcutaneous dose of 10,000 mcg/kg/day). Foetal body weights were unaffected with doses up to 270 times the MRHDID (on an mcg/m² basis with maternal subcutaneous doses up to 1,000 mcg/kg/day). Maternal toxicity was observed with doses 270 times the MRHDID and higher (on an mcg/m² basis with maternal subcutaneous doses of 1,000 mcg/kg/day and higher).

In an embryo-foetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 6–18, glycopyrrolate produced no structural abnormalities or effects on foetal survival; however, slight reductions in foetal body weight were seen in the presence of maternal toxicity at the highest tested dose that was 5,400 times the MRHDID (on an mcg/m² basis at a maternal subcutaneous dose of 10,000 mcg/kg/day). Foetal body weights were unaffected with doses up to 540 times the MRHDID (on an mcg/m² basis with maternal subcutaneous doses up to 1,000 mcg/kg/day). Maternal toxicity was observed with doses 540 times the MRHDID and higher (on an mcg/m² basis with maternal subcutaneous doses of 1,000 mcg/kg/day and higher).

In a pre- and post-natal development study, pregnant female rats received glycopyrrolate at doses of 100, 1,000, and 10,000 mcg/kg/day from gestation day 6 through the lactation period. Pup body weight gain was slightly reduced from birth through the lactation period at a dose 2,700 times the MRHDID (on an mcg/m² basis with a maternal subcutaneous dose of 10,000 mcg/kg/day); however, pup body weight gain was unaffected after weaning. There were no treatment-related effects on the physical, functional, and behavioural development of pups with doses up to 2,700 times the MRHDID (on an mcg/m² basis with maternal subcutaneous doses up to 10,000 mcg/kg/day). Maternal toxicity was observed from gestation days 6–18 with doses 270 times the MRHDID and higher (on an mcg/m² basis with maternal subcutaneous doses of 1,000 mcg/kg/day and higher).

Lactating Women  

Risk Summary

There are no available data on the effects of budesonide/glycopyrronium/formoterol, budesonide, glycopyrronium or formoterol fumarate on the breastfed child or on milk production. Budesonide, like other ICS, is present in human milk . There are no available data on the presence of glycopyrronium or formoterol fumarate in human milk. Formoterol fumarate and glycopyrronium have been detected in the plasma of undosed rat pups suckling from exposed dams. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for FORACORT-G Inhaler and any potential adverse effects on the breastfed child from FORACORT-G Inhaler or from the underlying maternal condition.

Data

HUMAN DATA

Human data with budesonide delivered via a dry powder inhaler indicates that the total daily oral dose of budesonide available in breast milk to the infant is approximately 0.3–1% of the dose inhaled by the mother. For FORACORT-G Inhaler, the dose of budesonide available to the infant in breast milk, as a percentage of the maternal dose, would be expected to be similar.

There is no available human data for formoterol or glycopyrronium.

ANIMAL DATA

In the fertility and reproduction study in rats, plasma levels of formoterol were measured in pups on post-natal day 15. It was estimated that the maximum plasma concentration that the pups received from the maternal animal, at the highest dose of 15 mg/kg, after nursing was 4.4% (0.24 nmol/L for a litter vs 5.5 nmol/L for the mother).

In the reproductive/developmental toxicity study in rats, plasma levels of glycopyrrolate were measured in pups on post-natal day 4. The maximum concentration in the pups was 6% of the maternal dose of 10 mg/kg/day (pup plasma concentration of 96 ng/mL at 1 hour after dosing corresponded with 1,610 ng/mL in the dam at 0.5 hours after dosing).

Paediatric Patients  

FORACORT-G Inhaler is not indicated for use in children. The safety and efficacy of budesonide/glycopyrronium/formoterol in paediatric patients have not been established.

Geriatric Patients  

Based on available data, no adjustment of the dosage of FORACORT-G Inhaler in geriatric patients is necessary, but greater sensitivity in some older individuals cannot be ruled out.

In trials in 1,100 subjects (Trial 1) and 343 subjects (Trial 2) aged 65 years and older, budesonide/glycopyrrolate/formoterol 320 mcg/18 mcg/9.6 mcg were administered twice daily. In both trials, no overall differences in safety or effectiveness were observed between these subjects and younger subjects.

Effects on Ability to Drive and Use Machines

Glycopyrronium, formoterol and budesonide have no or negligible influence on the ability to drive and use machines.

Undesirable Effects

The following adverse reactions are discussed in greater detail in the Special Warnings and Precautions for Use section:

• Serious Asthma-related Events: Hospitalisations, Intubations, Death
• Deterioration of Disease and Acute Episodes
• Avoid Excessive Use of Budesonide/Glycopyrronium/Formoterol and Avoid Use with other Long-acting Beta₂-Agonists
• Oropharyngeal Candidiasis
• Pneumonia
• Immunosuppression and Risk of Infections
• Transferring Patients from Systemic Corticosteroid Therapy
• Hypercorticism and Adrenal Suppression
• Drug Interactions with Strong CYP3A4 Inhibitors
• Paradoxical Bronchospasm
• Hypersensitivity Reactions, including Anaphylaxis
• Cardiovascular Effects
• Reduction in Bone Mineral Density
• Glaucoma and Cataracts: Worsening of Narrow-angle Glaucoma
• Worsening of Urinary Retention
• Coexisting Conditions
• Hypokalaemia and Hyperglycaemia

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of budesonide/glycopyrrolate/formoterol is based on the safety data from one 52-week exacerbation trial (Trial 1) and one 24-week lung function trial with a 28-week safety extension study, resulting in up to 52 weeks of treatment (Trial 2). In Trials 1 and 2, a total of 2,783 subjects have received at least one dose of budesonide/glycopyrrolate/formoterol 320/18/9.6 mcg.

In Trials 1 and 2, subjects received one of the following treatments: budesonide/glycopyrrolate/formoterol 320/18/9.6 mcg, glycopyrrolate and formoterol fumarate [GFF MDI 18/9.6 mcg], or budesonide and formoterol fumarate [BFF MDI 320/9.6 mcg]. Each treatment was administered twice daily.

In Trial 1, a 52-week, randomised, double-blind clinical trial, a total of 2,144 subjects with COPD received at least one dose of budesonide/glycopyrrolate/formoterol 320/18/9.6 mcg (mean age: 64.7 years, 84.9% Caucasian, 59.7% male across all treatments).

In Trial 2, a 24-week, randomised, double-blind clinical trial, with a 28-week long-term safety extension resulting in up to 52 weeks of treatment, a total of 639 subjects received at least one dose of budesonide/glycopyrrolate/formoterol 320/18/9.6 mcg (mean age: 65.2 years, 50.1% Caucasian, 71.2% male across all treatments).

The incidence of adverse reactions from the 52-week trial (Trial 1) is presented in Table 1 for subjects treated with budesonide/glycopyrrolate/formoterol 320/18/9.6 mcg, GFF MDI 18 mcg/9.6 mcg, or BFF MDI 320 mcg/9.6 mcg.

Adverse Reactions Occurring in ≥2% of Subjects and More Common in Budesonide/Glycopyrrolate/Formoterol Compared with GFF MDI and BFF MDI (Trial 1)

Adverse Reaction	Budesonide/ Glycopyrrolate/ Formoterol 320/18/9.6 mcg N=2,144 (%)	GFF MDI 18/9.6 mcg N=2,125 (%)	BFF MDI 320/9.6 mcg   N=2,136 (%)
Upper respiratory tract infection	123 (5.7)	102 (4.8)	115 (5.4)
Pneumonia	98 (4.6)	61 (2.9)	107 (5.0)
Back pain	67 (3.1)	55 (2.6)	64 (3.0)
Oral candidiasis	65 (3.0)	24 (1.1)	57 (2.7)
Influenza	63 (2.9)	42 (2.0)	61 (2.9)
Muscle spasms	60 (2.8)	19 (0.9)	53 (2.5)
Urinary tract infection	58 (2.7)	60 (2.8)	41 (1.9)
Cough	58 (2.7)	50 (2.4)	51 (2.4)
Sinusitis	56 (2.6)	47 (2.2)	55 (2.6)
Diarrhoea	44 (2.1)	37 (1.7)	38 (1.8)

GFF MDI = glycopyrrolate/formoterol fumarate 18/9.6 mcg; BFF MDI = budesonide/formoterol fumarate 320 mcg/9.6 mcg. All treatments were administered twice daily.

In 24-week data from Trial 2, adverse reactions that occurred in subjects treated with budesonide/glycopyrrolate/formoterol 320/18/9.6 mcg (n=639) at an incidence of

≥2% included dysphonia (3.3%) and muscle spasms (3.3%).

Additional Adverse Reactions

Other adverse reactions that have been associated with one or more of the individual components of FORACORT-G Inhaler include the following: hyperglycaemia, anxiety, insomnia, headache, palpitations, nausea, hypersensitivity, depression, agitation, restlessness, nervousness, tremor, dizziness, angina pectoris, tachycardia, cardiac arrhythmias (e.g. atrial fibrillation, supraventricular tachycardia, and extrasystoles), throat irritation, bronchospasm, dry mouth, bruising, urinary retention, chest pain, sign or symptoms of systemic glucocorticoid steroid effects (e.g. hypofunctional adrenal gland), and abnormal behaviour.

Reporting of Side Effects

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 Programme of India by calling on 1800 180 3024 or you can report to Cipla Ltd on 1800 267 7779. By reporting side effects, you can help provide more information on the safety of this product.

Overdose

No cases of overdose have been reported with budesonide/glycopyrronium/formoterol combination. FORACORT-G Inhaler contains budesonide, glycopyrronium and formoterol; therefore, the risks associated with overdosage for the individual components, as described below, apply to FORACORT-G Inhaler.

Treatment of overdosage consists of discontinuation of budesonide/glycopyrronium/formoterol together with institution of appropriate symptomatic and/or supportive therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. Cardiac monitoring is recommended in case of overdosage.

Budesonide

If used at excessive doses for prolonged periods, systemic corticosteroid effects such as hypercorticism may occur.

Glycopyrronium

High doses of glycopyrronium, a component of FORACORT-G Inhaler, may lead to anticholinergic signs and symptoms such as nausea, vomiting, dizziness, light-headedness, blurred vision, increased intraocular pressure (causing pain, vision disturbances or reddening of the eyes), obstipation or difficulties in voiding.

Formoterol Fumarate

An overdose of formoterol fumarate would likely lead to an exaggeration of effects that are typical for beta₂-agonists, viz. seizures, angina, hypertension, hypotension, tachycardia, atrial and ventricular tachyarrhythmias, nervousness, headache, tremor, palpitations, muscle cramps, nausea, dizziness, sleep disturbances, metabolic acidosis, hyperglycaemia, hypokalaemia. As with all sympathomimetic medications, cardiac arrest, and even death may be associated with overdosage of formoterol fumarate.  

PHARMACOLOGICAL PROPERTIES

Mechanism of Action

FORACORT-G Inhaler contains budesonide, glycopyrronium and formoterol fumarate. The mechanism of action described below for the individual components apply to FORACORT-G Inhaler. These drugs represent three different classes of medications (a synthetic corticosteroid, an anticholinergic and a long-acting, selective beta₂-adrenoceptor agonist) that have different effects on the clinical physiology and inflammatory indices of COPD.

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 1,000-fold higher topical anti-inflammatory potency than cortisol (rat croton oil ear oedema assay). As a measure of systemic activity, budesonide is 40 times more potent than cortisol when administered subcutaneously and 25 times more potent when administered orally in the rat thymus involution assay.

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. 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.

Glycopyrronium

Glycopyrronium is a long-acting antimuscarinic that is often referred to as an anticholinergic. It has similar affinity to the subtypes of muscarinic receptors M1 to M5. In the airways, glycopyrronium exhibits pharmacological effects through inhibition of M3 receptor at the smooth muscle leading to bronchodilation. The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations. In preclinical in vitro as well as in vivo studies, prevention of methylcholine and acetylcholine-induced bronchoconstrictive effects was dose-dependent and lasted longer than 12 hours. The clinical relevance of these findings is unknown. The bronchodilation following inhalation of glycopyrrolate is predominantly a site-specific effect.

Formoterol Fumarate

Formoterol fumarate is a long-acting, selective beta₂-adrenergic agonist (beta₂-agonist) with a rapid onset of action. Inhaled formoterol fumarate acts locally in the lungs as a bronchodilator. In vitro studies have shown that formoterol has more than 200-fold greater agonist activity at beta₂-receptors than at beta₁-receptors. The in vitro binding selectivity to beta₂- 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.

Pharmacodynamic Properties

Cardiac Electrophysiology

A TQT study was not performed with budesonide/glycopyrrolate/formoterol as budesonide is not known to affect the QT interval. However, the potential for QTc interval prolongation with glycopyrrolate/formoterol fumarate was assessed in a double-blind, single-dose, placebo- and positive-controlled crossover trial in 69 healthy subjects. The largest mean (90% upper confidence bound) differences from placebo in baseline-corrected QTc for two inhalations of glycopyrrolate/formoterol fumarate 9/4.8 mcg and glycopyrrolate/formoterol fumarate 72/19.2 mcg, were 3.1 (4.7) ms and 7.6 (9.2) ms, respectively, and excluded the clinically relevant threshold of 10 ms. A dose-dependent increase in heart rate was also observed. The largest mean (90% upper confidence bound) differences from placebo in baseline-corrected heart rate were 3.3 (4.9) beats/minute and 7.6 (9.5) beats/minute seen within 10 minutes of dosing with two inhalations of glycopyrrolate/formoterol fumarate 9/4.8 mcg and glycopyrrolate/formoterol fumarate 72/19.2 mcg, respectively.

COPD

The effect of budesonide/glycopyrrolate/formoterol on cardiac rhythm in subjects with COPD was assessed using 24-hour Holter monitoring at week 16 in a 52-week trial (Trial 1).

The Holter monitoring population in Trial 1 included 180 subjects on budesonide/glycopyrrolate/formoterol 320/18/9.6 mcg, 160 subjects on glycopyrrolate and formoterol fumarate [GFF MDI 18/9.6 mcg], and 183 subjects on budesonide/formoterol fumarate [BFF MDI 320/9.6 mcg]. No clinically meaningful effects on cardiac rhythm were observed.

HPA Axis Effects

Effects of budesonide/glycopyrrolate/formoterol on the HPA axis were assessed by measurement of 24-hour serum cortisol at baseline and week 24 in subjects with COPD. The geometric mean ratio (week 24/baseline) was 0.86 [co-efficient of variation (CV) = 39%] and 0.94 (CV=36.6%) for budesonide/glycopyrrolate/formoterol group 320/18/9.6 mcg and GFF MDI 18 mcg/9.6 mcg, respectively.

Pharmacokinetic Properties

Linear pharmacokinetics were demonstrated for budesonide (80–320 mcg), glycopyrrolate (18–144 mcg), and formoterol fumarate (2.4–38.4 mcg). Pharmacokinetic information for glycopyrrolate and formoterol fumarate is for the active moieties, glycopyrronium and formoterol, respectively. The pharmacokinetics of budesonide, glycopyrronium and formoterol from the budesonide/glycopyrronium/formoterol combination are comparable with the pharmacokinetics of budesonide, glycopyrronium and formoterol when administered as budesonide/formoterol or glycopyrrolate/formoterol in studies of healthy subjects (single dose) and subjects with COPD (repeated dose).

The pharmacokinetics of the individual components of inhaled FORACORT-G Inhaler are presented below.

Absorption

Budesonide

Following inhaled administration of budesonide/glycopyrronium/formoterol in subjects with COPD, C_max occurred within 20–40 minutes. Steady state is estimated to be achieved after approximately 1 day of repeated dosing of budesonide/glycopyrronium/formoterol via population pharmacokinetic analysis and the AUC_0-12 is approximately 1.3 times higher than after the first dose.

Glycopyrrolate

Following inhaled administration of budesonide/glycopyrronium/formoterol in subjects with COPD, C_max occurred within 2–6 minutes. Steady state is estimated to be achieved after approximately 3 days of repeated dosing of budesonide/glycopyrronium/formoterol via population pharmacokinetic analysis and the AUC_0-12 is approximately 1.8 times higher than after the first dose.

Formoterol Fumarate

Following inhaled administration of budesonide/glycopyrronium/formoterol in subjects with COPD, C_max occurred within 20–60 minutes. Steady state is estimated to be achieved after approximately 2 days of repeated dosing with budesonide/glycopyrronium/formoterol combination via population pharmacokinetic analysis and the AUC_0-12 is approximately 1.4 times higher than after the first dose.

Distribution

Budesonide

The estimated budesonide apparent volume of distribution at steady state in subjects with COPD is approximately 1,200 L, via population pharmacokinetic analysis. Over the concentration range of 1–100 nmol/L, mean plasma protein-binding of budesonide ranged from 86% to 87%.

Glycopyrronium

The estimated glycopyrronium apparent volume of distribution at steady state in subjects with COPD is approximately 5,500 L, via population pharmacokinetic analysis. Over the concentration range of 2–500 nmol/L, plasma protein-binding of glycopyrronium ranged from 43% to 54%.

Formoterol Fumarate

The estimated formoterol apparent volume of distribution at steady state in subjects with COPD is approximately 2,400 L, via population pharmacokinetic analysis. Over the concentration range of 10–500 nmol/L, plasma protein-binding of formoterol ranged from 46% to 58%.

Elimination

Budesonide

Budesonide was excreted in urine and faeces in the form of metabolites. Only negligible amounts of unchanged budesonide have been detected in the urine. The effective half-life of budesonide in subjects with COPD derived via population pharmacokinetic analysis was approximately 5 hours.

Glycopyrronium

After intravenous (IV) administration of 0.2 mg radiolabelled glycopyrronium, 85% of the dose recovered was recovered in urine 48 hours post-dose and some part was also recovered in bile. The effective half-life of glycopyrronium in subjects with COPD derived via population pharmacokinetics analysis was approximately 15 hours.

Formoterol Fumarate

The excretion of formoterol was studied in 6 healthy subjects following simultaneous administration of radiolabelled formoterol via the oral and IV routes. In that study, 62% of the drug related radioactivity of formoterol was excreted in the urine while 24% was eliminated in the faeces. The effective half-life of formoterol in subjects with COPD derived via population pharmacokinetics analysis was approximately 10 hours.

Metabolism

Budesonide

In vitro studies with human liver homogenates have shown that budesonide was rapidly and extensively metabolised. Two major metabolites formed via CYP3A4 catalysed biotransformation have been isolated and identified as 16alpha-hydroxy prednisolone and 6beta-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 lungs and serum preparations.

Glycopyrronium

Based on information from the published literature and an in vitro human hepatocyte study, metabolism plays a minor role in the overall elimination of glycopyrronium. CYP2D6 was found to be the predominant enzyme involved in the metabolism of glycopyrronium.

Formoterol Fumarate

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 sulphate conjugation. CYP2D6 and CYP2C have been identified as being primarily responsible for O-demethylation.

Special Populations

Population pharmacokinetic analysis showed no evidence of a clinically significant effect of age, sex, race/ethnicity or body weight on the pharmacokinetics of budesonide, glycopyrronium or formoterol.

Patients with Hepatic Impairment

Dedicated studies of budesonide/glycopyrronium/formoterol evaluating the effect of hepatic impairment on the pharmacokinetics of budesonide, glycopyrronium, and formoterol were not conducted.

Reduced liver function may affect the elimination of corticosteroids. Budesonide pharmacokinetics was affected by compromised liver function as evidenced by doubled systemic availability after oral ingestion. IV budesonide pharmacokinetics was, however, similar in cirrhotic patients and in healthy subjects.

As budesonide and formoterol are primarily eliminated via hepatic metabolism, increased exposure can be expected in patients with severe hepatic impairment.

Patients with Renal Impairment

Studies with budesonide/glycopyrronium/formoterol evaluating the effect of renal impairment on the pharmacokinetics of budesonide, glycopyrronium and formoterol were not conducted.

The effect of renal impairment on the exposure to budesonide, glycopyrronium and formoterol for up to 24 weeks was evaluated in a population pharmacokinetic analysis. Estimated glomerular filtration rate (eGFR) varied from 31 to 192 mL/minute, representing a range of moderate to no renal impairment. Simulation of the systemic exposure (AUC_0-12) in subjects with COPD with moderate renal impairment (eGFR of 45 mL/minute) indicates an approximate 68% increase for glycopyrronium compared with subjects with COPD with normal renal function (eGFR of >90 mL/minute). Renal function did not significantly affect exposure to budesonide or formoterol after drug clearance adjusted by age or body weight in a population pharmacokinetic analysis.

Drug Interactions

No pharmacokinetic interaction has been observed between budesonide, glycopyrrolate and formoterol fumarate when administered in combination by the inhaled route. Specific drug interaction studies of budesonide/glycopyrronium/formoterol with other co-administered drugs have not been performed.

Ketoconazole and Itraconazole

Ketoconazole and itraconazole, strong inhibitors of CYP3A4, the main metabolic enzyme for corticosteroids, increased plasma levels of orally ingested budesonide and orally inhaled budesonide, respectively.

Cimetidine

At recommended doses, cimetidine, a non-specific inhibitor of CYP enzymes, had a slight but clinically insignificant effect on the pharmacokinetics of oral budesonide.

NONCLINICAL PROPERTIES

Animal Toxicology or Pharmacology

Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies of carcinogenicity, mutagenicity, or impairment of fertility were conducted with budesonide/glycopyrronium/formoterol; however, separate studies of budesonide, glycopyrrolate and formoterol fumarate are described below.

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 an mcg/m² 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 an mcg/m² 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 an mcg/m² basis). However, in the male Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of hepatocellular tumours at an oral dose of 50 mcg/kg (approximately equivalent to the MRHDID in adults and children on an mcg/m² 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 an mcg/m² basis).

Budesonide was not mutagenic or clastogenic in the 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 an mcg/m² 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 body weight gain, at subcutaneous doses of 20 mcg/kg and above (0.3 times the MRHDID on an mcg/m² basis). No such effects were noted at 5 mcg/kg (0.08 times the MRHDID on an mcg/m² basis).  

Glycopyrronium

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

In a 24-month inhalation carcinogenicity study in B6C3F1 mice, glycopyrrolate produced no evidence of tumorigenicity when administered to males or females at doses up to 705 and 335 mcg/kg/day, respectively (approximately 95 and 45 times the MRHDID of glycopyrrolate on an mcg/m² basis, respectively).

In a 24-month carcinogenicity study in rats, glycopyrrolate produced no evidence of tumourigenicity when administered to males or females by oral gavage at dosages up to 40,000 mcg/kg/day (approximately 11,000 times the MRHDID of glycopyrrolate on an mcg/m² basis).

Glycopyrronium was not mutagenic or clastogenic in the Ames Salmonella/microsome plate test, in vitro mammalian cell micronucleus assay in TK6 cells, or in vivo micronucleus assay in rats.

Fertility and reproductive performance indices were unaffected in male and female rats that received glycopyrrolate by the subcutaneous route at doses up to 10,000 μg/kg/day (approximately 2,700 times the MRHDID on a mcg/m² basis).

Formoterol Fumarate

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 fumarate at oral doses

of 0.1 mg/kg and above (approximately 25 times the MRHDID on an mg/m² 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 mesovarian leiomyoma and uterine leiomyosarcoma were observed at the inhaled dose of 130 mcg/kg (approximately 65 times the MRHDID on an mcg/m² basis). No tumours were seen at 22 mcg/kg (approximately 10 times the MRHDID on an mcg/m² 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 fumarate 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 2,600 times the MRHDID on an AUC basis). No such effect was seen at 3,000 mcg/kg (approximately 1,500 times the MRHDID on an mcg/m² basis). In a separate study with male rats treated with an oral dose of 15,000 mcg/kg (approximately 8,000 times the MRHDID on an mcg/m² 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 1,400 times the MRHDID on an AUC basis).

DESCRIPTION

FORACORT-G Inhaler is a pressurised metered dose inhaler that delivers a combination of micronized budesonide (an inhaled corticosteroid), micronized glycopyrronium (an anticholinergic), and micronized formoterol fumarate (a long-acting beta₂-agonist) for oral inhalation.

Budesonide is a corticosteroid with the following chemical name: (RS)-11beta, 16alpha,17,21Tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with butyraldehyde. Budesonide is a white to off-white, powder that is practically insoluble in water. The molecular formula is C₂₅H₃₄O₆ and the molecular weight is 430.54. The structural formula is as follows:

 

Budesonide contains nine chiral centres and is a mixture of the two epimers (22R and 22S).

Glycopyrrolate is a quaternary ammonium salt with the following chemical name: (RS)-[3-(SR)-Hydroxy-1,1-dimethylpyrrolidinium bromide] alpha-cyclopentylmandelate. Glycopyrrolate is a powder that is freely soluble in water. The molecular formula is C₁₉H₂₈BrNO₃, and the molecular weight is 398.33 g/mol. The structural formula is as follows:

 

Glycopyrrolate contains two chiral centres and is a racemate of a 1:1 mixture of the R,S and S,R diastereomers. The active moiety, glycopyrronium, is the positively charged ion of glycopyrrolate.

Formoterol fumarate dihydrate has the chemical name of N-[2-Hydroxy-5-[(1RS)-1-hydroxy-2-[[(1RS)-2-(4-methoxyphenyl)-1-methylethyl]-amino]ethyl]phenyl] formamide, (E)-2-butenedioate dihydrate. Formoterol fumarate dihydrate is a powder that is slightly soluble in water. The molecular formula is (C₁₉H₂₄N₂O₄)₂.C₄H₄O₄.2H₂O and the molecular weight is 840.91 g/mol. The structural formula is as follows:

 

Formoterol fumarate dihydrate contains two chiral centres, and consists of a single enantiomeric pair (a racemate of R,R and S,S).

PHARMACEUTICAL PARTICULARS

Incompatibilities

Not applicable.

Shelf-Life

As on the pack.

Packaging Information

FORACORT-G Inhaler is supplied as a pressurised aluminium canister for inhalation use with an attached dose indicator, a white plastic actuator and mouthpiece, and a red dust cap.

Contains 120 inhalations per canister.

Each 120 inhalation canister has a net fill weight of 7.2 grams.

Storage and Handling Instructions

Store below 30°C. Do not freeze.

• The canister is pressurised and should be kept away from direct sunlight.
• The canister must not be punctured, broken or incinerated even when apparently empty.
• Keep away from contact with the eyes.
• Shake well before using.
• Keep out of the reach of children.

Prime FORACORT-G Inhaler before using for the first time by releasing two sprays into the air, away from the face, shaking well for 5 seconds before each spray. In cases where the inhaler has not been used for more than 1 week or when it has been dropped, prime the inhaler again by releasing two sprays into the air away from the face, shaking well for 5 seconds before each spray. Shake FORACORT-G Inhaler well before each use.

PATIENT COUNSELLING INFORMATION

1. What is FORACORT-G Inhaler?

FORACORT-G Inhaler combines three medicines – budesonide (an inhaled corticosteroid [ICS]), glycopyrronium (an anticholinergic, in the form of glycopyrrolate), and formoterol fumarate dihydrate (a long-acting beta₂-adrenergic agonist [LABA]) in one inhaler and is delivered as a spray.   

• ICS medicines such as budesonide help to decrease inflammation in the lungs. Inflammation in the lungs can lead to breathing problems.
• Anticholinergic medicines such as glycopyrronium and LABA medicines, such as formoterol help the muscles around the airways in your lungs stay relaxed to prevent symptoms such as wheezing, cough, chest tightness, and shortness of breath. These symptoms can happen when the muscles around the airways tighten. This makes it hard to breathe.
• FORACORT-G Inhaler is a prescription medicine used as a maintenance bronchodilator treatment for patients with chronic obstructive pulmonary disease (COPD). COPD is a chronic lung disease that includes chronic bronchitis, emphysema, or both.
• For long-term use, the recommendation is two puffs from FORACORT-G Inhaler two times each day (two puffs in the morning and two puffs in the evening), to improve symptoms of COPD for better breathing and to reduce the number of flare-ups (the worsening of COPD symptoms for several days).
• FORACORT-G Inhaler is not for the treatment of asthma. It is not known if FORACORT-G Inhaler is safe and effective in people with asthma. FORACORT-G Inhaler contains formoterol fumarate dihydrate (referred to hereon as formoterol). LABA medicines such as formoterol, when used alone, increase the risk of hospitalisations and death from asthma problems. FORACORT-G Inhaler contains an ICS, an anticholinergic, and a LABA. When an ICS and LABA are used together, there is no significant risk of hospitalisations and deaths from asthma problems.
• FORACORT-G Inhaler is not to be used to relieve sudden breathing problems and should not replace a rescue inhaler. Always have a rescue inhaler (an inhaled, short-acting bronchodilator) with you to treat sudden breathing problems. If you do not have a rescue inhaler, contact your healthcare provider to have one prescribed for you.
• FORACORT-G Inhaler should not be used in children. It is not known if FORACORT-G Inhaler is safe and effective in children.

Do not use FORACORT-G Inhaler if you are allergic to budesonide, glycopyrronium (glycopyrrolate), formoterol, lactose or any of the ingredients in FORACORT-G Inhaler.

Before using FORACORT-G Inhaler, tell your healthcare provider about all of your medical conditions, including any of the following:

• Heart problems
• High blood pressure
• Seizures
• Thyroid problems
• Diabetes
• Liver problems
• Kidney problems
• Weak bones (osteoporosis)
• An immune system problem
• Eye problems such as glaucoma. Budesonide/glycopyrronium/formoterol may make your glaucoma worse.
• Prostate or bladder problems, or problems in passing urine. Budesonide/glycopyrronium/formoterol may make these problems worse.
• Any type of viral, bacterial, parasitic, or fungal infection
• Are exposed to chickenpox or measles
• Are pregnant or plan to become pregnant. It is not known if budesonide/glycopyrronium/formoterol may harm your unborn baby.
• Are breastfeeding. It is not known if the medicines in budesonide/glycopyrronium/formoterol pass into your breast milk and if they can harm your baby. You and your healthcare provider should decide if you will take FORACORT-G Inhaler while breastfeeding.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. FORACORT-G Inhaler and certain other medicines may interact with each other. This may cause serious side effects.

Especially tell your healthcare provider if you take the following:

• Anticholinergics (including tiotropium, ipratropium, aclidinium, and umeclidinium)
• Other LABAs (including salmeterol, formoterol fumarate, arformoterol tartrate, vilanterol, olodaterol, and indacaterol)
• Atropine
• Antifungal or anti-HIV medicines

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist each time you get a new medicine.

2. How should I use FORACORT-G Inhaler?

• It is important for you to understand how to correctly use FORACORT-G Inhaler. Do not use FORACORT-G Inhaler unless your healthcare provider has taught you how to use the inhaler and you understand how to use it correctly.
• Use FORACORT-G Inhaler exactly as prescribed. Do not use FORACORT-G Inhaler more often than prescribed.
• Take two puffs from FORACORT-G Inhaler two times each day (two puffs in the morning and two puffs in the evening), 12 hours apart.
• Do not take more than two puffs from FORACORT-G Inhaler two times each day.
• If a dose (two puffs) of FORACORT-G Inhaler is missed, it should be taken as soon as possible and the next dose should be taken at the usual time. Do not take more than one dose to make up for the forgotten dose.
• The metal canister holds the medicine and has a counter to show how many sprays of medicine you have left. Do not try to change the numbers or remove the counter from the metal canister. The counter cannot be reset.
• Before you use FORACORT-G Inhalerfor the first time, you must prime the inhaler two times so that you will get the right amount of medicine when you use it.
• To prime the inhaler, take the cap off the mouthpiece and shake the inhaler well for 5 seconds and spray the inhaler into the air away from your face. Repeat this procedure one more time.
• You must prime your inhaler again if you have not used it in more than 1 week or if you drop it.

1. Shake the inhaler well for 5 seconds before every use. Take the cap off the mouthpiece, and hold the inhaler with the mouthpiece facing downwards. Breathe out through your mouth and push as much air out of your lungs as possible. Put the mouthpiece into your mouth and close your lips firmly around it.
2. Push the top of the metal canister all the way down while you breathe in deeply and slowly through your mouth.
3. Hold your breath for about 10 seconds, or for as long as comfortable. Breathe out slowly as long as you can.

Repeat steps 1–3 once again to take your second inhalation.

• Rinse your mouth with water after breathing in the medicine. Spit out the water. Do not swallow it.
• Put the cap back on the mouthpiece after every use. Make sure it snaps firmly into place.
• Wipe the inside & the outside of the mouthpiece with a clean, dry cloth. Replace the mouthpiece cap. DO NOT wash or soak any part of the inhaler in water.
• When the dose counter reads ‘20’, ask your healthcare professional for another prescription of FORACORT-G Inhaler
• When the counter reads ‘0’, throw the inhaler away.
• Do not use the inhaler after the expiration date, which is mentioned on the packaging.
• If you take too many puffs from the FORACORT-G Inhaler, call your healthcare provider or go to the nearest hospital emergency room right away if you have any unusual symptoms, such as worsening shortness of breath, chest pain, increased heart rate, or shakiness.
• Do not use other medicines that contain an ICS, LABA and an anticholinergic for any reason. Ask your healthcare provider or pharmacist if any of your other medicines are ICS or a LABA or anticholinergic.
• Do not stop using FORACORT-G Inhaler, even if you are feeling better, unless your healthcare provider tells you to.
• FORACORT-G Inhalerdoes not relieve sudden breathing problems. Always have a rescue inhaler with you to treat sudden symptoms. If you do not have a rescue inhaler, call your healthcare provider to have one prescribed for you.
• Rinse your mouth with water, without swallowing, after each dose of the FORACORT-G Inhaler medicine. This will help lessen the chance of getting a yeast infection (thrush) in your mouth and throat.

3. What are the possible side effects with FORACORT-G Inhaler?

FORACORT-G Inhaler can cause serious side effects, including the following:

• Fungal infection in your mouth or throat (thrush). Rinse your mouth with water without swallowing after using FORACORT-G Inhaler to help reduce your chance of getting thrush.
• Pneumonia. People with COPD have a higher chance of getting pneumonia. FORACORT-G Inhaler may increase your chance of getting pneumonia. Call your healthcare provider if you notice any of the following symptoms:
• increase in mucus (sputum) production
• change in mucus colour
• fever
• chills
• increased cough
• increased breathing problems
• Weakened immune system and increased chance of getting infections (immunosuppression).
• Reduced adrenal function (adrenal insufficiency). Adrenal insufficiency is a condition where the adrenal glands do not make enough steroid hormones. This can happen when you stop taking oral corticosteroid medicines (such as prednisone) and start taking a medicine containing an ICS (such as budesonide, one of the ingredients in this inhaler). During this transition period, when your body is under stress from fever, trauma (such as a car accident), infection, surgery, or worse COPD symptoms, adrenal insufficiency can get worse and may cause death. Symptoms of adrenal insufficiency include the following:
• feeling tired
• lack of energy
• weakness
• nausea and vomiting
• low blood pressure (hypotension)
• Sudden breathing problems immediately after inhaling your medicine. If you have sudden breathing problems immediately after inhaling your medicine, stop taking FORACORT-G Inhaler and call your healthcare provider right away.
• Serious allergic reactions. Call your healthcare provider or get emergency medical care if you get any of the following symptoms of a serious allergic reaction:
• rash
• hives
• swelling of your face, mouth, and tongue
• breathing problems
• Effects on your heart:
• increase in blood pressure
• chest pain
• a fast or irregular heartbeat
• Effects on your nervous system:
• tremor
• nervousness
• Bone thinning or weakness (osteoporosis)
• New or worsened eye problems, including acute narrow-angle glaucoma and cataracts. Acute narrow-angle glaucoma can cause permanent loss of vision if not treated. Symptoms of acute narrow-angle glaucoma may include the following:
• eye pain or discomfort
• nausea or vomiting
• blurred vision
• seeing halos or bright colours around lights
• red eyes

If you have these symptoms, call your healthcare provider right away before taking another dose.

• Urinary retention. People who take budesonide/glycopyrronium/formoterol may develop new or worsening urinary retention. Symptoms of urinary retention may include the following:
• difficulty urinating
• urinating frequently
• painful urination
• urination in a weak stream or drips

    If you have these symptoms of urinary retention, stop using FORACORT-G Inhaler and call your healthcare provider right away before taking another dose.

• Changes in laboratory blood values, including high levels of blood sugar (hyperglycaemia) and low levels of potassium (hypokalaemia). Low levels of potassium may cause symptoms of muscle spasm, muscle weakness, or abnormal heart rhythm.

Common side effects of the budesonide/glycopyrronium/formoterol combination include the following:

 

• upper respiratory tract infection
• pneumonia
• back pain
• thrush in your mouth and throat

(To help prevent this, rinse your mouth with water, without swallowing, after inhaler use)

• joint pain
• flu
• headache
• high blood sugar levels
• muscle spasms
• cough
• inflammation of the sinuses
• diarrhoea
• hoarseness
• painful and frequent urination

(Signs of a urinary tract infection)

• nausea
• difficulty sleeping
• feeling anxious
• awareness of your heart beating

(palpitations)

 

Tell your healthcare provider about any side effect that bothers you or that does not go away.

These are not all the possible side effects of budesonide/glycopyrronium/formoterol. Ask your healthcare provider for more information

Reporting of side effects

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 Programme of India by calling on 1800 180 3024 or you can report to Cipla Ltd on 1800 267 7779. By reporting side effects, you can help provide more information on the safety of this product.

4. How should I store FORACORT-G Inhaler?

• FORACORT-G Inhaler should be stored at a temperature below 30°C. Do not freeze.
• Keep FORACORT-G Inhaler and all medicines out of the reach of children.
• The canister is pressurised and must be kept away from direct sunlight.
• Do not throw the canister into a fire or an incinerator.
• Safely throw away FORACORT-G Inhalerinto the trash when the counter reads ‘0’.
• Keep away from contact with the eyes.

5. General Information about the safe and effective use of FORACORT-G Inhaler

• Do not use FORACORT-G Inhaler for a condition for which it was not prescribed. Do not give your FORACORT-G Inhaler to other people, even if they have the same condition that you have. It may harm them.
• You can ask your healthcare provider for information about FORACORT-G Inhaler that is written for healthcare professionals.

6. What are the ingredients in FORACORT-G Inhaler?

Active ingredients: Micronized budesonide, micronized glycopyrronium (in the form of glycopyrrolate), and micronized formoterol fumarate dihydrate.

Inactive ingredients:  Propellant HFA134a

DETAILS OF THE MANUFACTURER

Cipla Ltd

Regd. Office: Peninsula Business Park, Ganapatrao Kadam Marg,

Lower Parel West, Mumbai – 400013, India

DETAILS OF PERMISSION OR LICENCE NUMBER WITH DATE

MNB/05/109 dated 04-04-20

DATE OF REVISION

05-10-2023