For the use of Registered Medical Practitioner only

Budesonide/Glycopyrronium/Formoterol powder for inhalation

FORACORT G 400 Rotacaps

QUALITATIVE AND QUANTITATIVE COMPOSITION

FORACORT G 400 Rotacaps

Each capsule contains:

Budesonide IP………………………….400 mcg

Glycopyrronium ………………………25 mcg

(As Glycopyrrolate IP)

Formoterol Fumarate ……………...…...12 mcg

(As Formoterol Fumarate Dihydrate IP)

Excipients………………………………………… q.s.

DOSAGE FORM(S) AND STRENGTH(S)

Each rotacap contains Budesonide/Glycopyrronium/Formoterol (400/25/12 mcg) dry powder for inhalation.

CLINICAL PARTICULARS

Therapeutic Indications

FORACORT G 400 Rotacaps is indicated as maintenance treatment for patients with chronic obstructive pulmonary disease (COPD).

Posology and Method of Administration

Posology

The recommended dose is the inhalation of the contents of one capsule of FORACORT G 400 Rotacaps twice daily using the Cipla Rotahaler or Revolizer device.

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

Method of Administration

FORACORT G 400 Rotacaps is for inhalation only. The rotacaps must not be swallowed.

FORACORT G 400 Rotacaps must be administered using a Cipla Rotahaler or Revolizer device. It is recommended to use new Rotahaler or Revolizer every 6 months. 

Contraindications

The use of FORACORT G 400 Rotacaps is contraindicated in patients who have demonstrated hypersensitivity to glycopyrronium, formoterol, budesonide lactose or any other component of the product.

Special Warnings and Precautions for Use

Serious Asthma-Related Events: Hospitalizations, Intubations, Death

The safety and efficacy of budesonide/glycopyrronium/formoterol in patients with asthma have not been established. FORACORT G 400 Rotacaps 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 hospitalization 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 (hospitalizations, 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 400 Rotacaps 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 400 Rotacaps in this setting is not appropriate.

FORACORT G 400 Rotacaps 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 400 Rotacaps, 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 400 Rotacaps, 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 400 Rotacaps 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 400 Rotacaps 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 400 Rotacaps 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 400 Rotacaps contains budesonide, an ICS. Localized 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 400 Rotacaps continues. In some cases, therapy with FORACORT G 400 Rotacaps 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 pressurized metered dose inhaler (pMDI) (320 mcg/18 mcg/9.6 mcg) (n = 2144), 3.5% for inhalation of budesonide,  glycopyrrolate and formoterol fumarate through pMDI (BGF MDI) (160 mcg/18 mcg/9.6 mcg) (n = 2124), 2.3% for glycopyrrolate/formoterol fumarate pMDI (GFF MDI) (18 mcg/9.6 mcg) (n = 2125) and 4.5% for a budesonide/formoterol fumarate pMDI (BFF MDI) 320 mcg/9.6 mcg (n = 2136).

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. 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 to corticosteroids. How the dose, route and duration of corticosteroid administration affects 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 chicken-pox 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 400 Rotacaps. 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 400 Rotacaps. 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 Cytochrome P450 3A4 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 which 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 400 Rotacaps. 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 400 Rotacaps should be stopped at once and alternative treatment should be considered.

FORACORT G 400 Rotacaps should be used with caution in patients with severe hypersensitivity to lactose.

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 400 Rotacaps 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 400 Rotacaps 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 immobilization, 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 400 Rotacaps 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/glycopyrronium/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/glycopyrronium/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 400 Rotacaps 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 400 Rotacaps long term.

In a 52-week trial that evaluated budesonide/glycopyrronium/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 400 Rotacaps, 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 400 Rotacaps, 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 Budesonide/Glycopyrronium/Formoterol.

Inhibitors of Cytochrome P450 3A4

The main route of metabolism of corticosteroids, including budesonide, a component of FORACORT G 400 Rotacaps, is via the 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 co-administration of FORACORT G 400 Rotacaps 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 400 Rotacaps, 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 400 Rotacaps.

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 400 Rotacaps, 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 400 Rotacaps 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 400 Rotacaps 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 Glycopyrronium/Budesonide/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 400 Rotacaps should only be used if the expected benefit outweighs the potential risk.

Patients with Hepatic Impairment

Formal pharmacokinetic studies using Glycopyrronium/Budesonide/Formoterol have not been conducted in patients with hepatic impairment. However, since both budesonide and formoterol fumarate, components of FORACORT G 400 Rotacaps, 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, glycopyrrolate 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 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 1500 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 occurred at large multiples of the MRHDID when formoterol fumarate was administered by the oral route to achieve high systemic exposures. No structural abnormalities, embryocidal, or developmental effects were seen in rats that received inhalation doses up to 350 times the MRHDID.

Glycopyrrolate alone, administered by the subcutaneous route in rats and rabbits, did not cause structural abnormalities or affect foetal survival at exposures approximately 2700 and 5400 times from MRHDID, respectively. Glycopyrrolate had no effects on the physical, functional, and behavioural development of rat pups with exposures up to 2700 times the MRHDID.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized 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 1995-1997 (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 2014 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 utilized 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 a 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 a 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 to 18, budesonide produced foetal loss, decreased foetal weight, and skeletal abnormalities at a dose 0.75 times the MRHDID (on a 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 a 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 a 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 a 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 a 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 a 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 a 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 a 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 to 15, no structural abnormalities, embryocidal effects, or developmental effects were seen at doses up to 350 times the MRHDID (on a 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 to 18, subcapsular cysts on the liver were observed in the foetuses at a dose 61,000 times the MRHDID (on a 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 a 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 a 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.

Glycopyrrolate

In an embryo-foetal development study in pregnant rats dosed during the period of organogenesis from gestation days 6 to 17, glycopyrrolate produced no structural abnormalities or effects on foetal survival; however, slight reductions of foetal body weight in the presence of maternal toxicity at the highest tested dose that was 2,700 times the MRHDID (on a 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 a 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 a 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 to 18, glycopyrrolate produced no structural abnormalities or effects on foetal survival; however, slight reductions of foetal body weight in the presence of maternal toxicity at the highest tested dose that was 5,400 times the MRHDID (on a 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 a 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 a 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 a 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 a mcg/m² basis with maternal subcutaneous doses up to 10,000 mcg/kg/day). Maternal toxicity was observed from gestation days 6 to 18 with doses 270 times the MRHDID and higher (on a 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, glycopyrrolate or formoterol fumarate on the breastfed child or on milk production. Budesonide, like other ICS, is present in human milk [see Data]. There are no available data on the presence of glycopyrrolate or formoterol fumarate in human milk. Formoterol fumarate and glycopyrrolate have been detected in the plasma of undosed rat pups suckling from exposed dams [see Data]. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for FORACORT G 400 Rotacaps and any potential adverse effects on the breast-fed child from FORACORT G 400 Rotacaps 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% to 1% of the dose inhaled by the mother. For FORACORT G 400 Rotacaps, 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 glycopyrrolate.

Animal Data

In the fertility and reproduction study in rats, plasma levels of formoterol were measured in pups on postnatal 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 400 Rotacaps 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 400 Rotacaps in geriatric patients is necessary, but greater sensitivity in some older individuals cannot be ruled out.

In Trials 1 and 2, 1,100 subjects and 343 subjects, respectively, aged 65 years and older were administered budesonide/glycopyrronium/formoterol 320 mcg/18 mcg/9.6 mcg 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 sections.

• Serious asthma-related events – hospitalizations, intubations, death
• Candida albicans infection
• Increased risk of pneumonia in COPD
• Immunosuppression and risk of infections
• Hypercorticism and adrenal suppression
• Paradoxical bronchospasm
• Hypersensitivity reactions including anaphylaxis
• Cardiovascular effects
• Reduction in bone mineral density
• Worsening of narrow-angle glaucoma and cataracts
• Worsening of urinary retention

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/glycopyrronium/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 2783 subjects have received at least one dose of budesonide/glycopyrronium/formoterol 320/18/9.6 mcg.

In Trials 1 and 2, subjects received one of the following treatments: budesonide/glycopyrronium/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, randomized, double-blind clinical trial, a total of 2144 subjects with COPD received at least one dose of budesonide/glycopyrronium/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, randomized, 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/glycopyrronium/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/glycopyrronium/formoterol 320/18/9.6 mcg, GFF MDI 18 mcg/9.6 mcg, or BFF MDI 320 mcg/9.6 mcg.

Table 1: Adverse reactions occurring at an incidence of ≥ 2% of subjects and more common in budesonide/glycopyrronium/formoterol compared with GFF MDI and BFF MDI (Trial 1).

Adverse Reaction	budesonide/glycopyrronium/formoterol 320/18/9.6 mcg N=2144 (%)	GFF MDI 18/9.6 mcg N=2125 (%)	BFF MDI 320/9.6 mcg N=2136 (%)
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)
Diarrheal	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/glycopyrronium/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 400 Rotacaps include: 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. FORACORT G 400 Rotacaps contain glycopyrronium, formoterol and budesonide; therefore, the risks associated with overdosage for the individual components described below apply to FORACORT G 400 Rotacaps. 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 400 Rotacaps, 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 eye), 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: 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 400 Rotacaps contains budesonide, glycopyrronium, and formoterol fumarate. The mechanism of action described below for the individual components apply to Budesonide/Glycopyrronium/Formoterol. 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/glycopyrronium/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 QTcI 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.

Chronic Obstructive Pulmonary Disease

The effects of budesonide/glycopyrronium/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/glycopyrronium/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/glycopyrronium/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/glycopyrronium/formoterol group 320/18/9.6mcg and GFF MDI 18 mcg/9.6 mcg, respectively.

Pharmacokinetic Properties

Linear pharmacokinetics were demonstrated for budesonide (80 to 320 mcg), glycopyrrolate (18 to 144 mcg), and formoterol fumarate (2.4 to 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 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 budesonide/glycopyrronium/formoterol are presented below.

Absorption

Budesonide

Following inhaled administration of budesonide/glycopyrronium/formoterol in subjects with COPD, C_max occurred within 20 to 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 to 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 to 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 1200 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%.

Glycopyrrolate

The estimated glycopyrronium apparent volume of distribution at steady state in subjects with COPD is approximately 5500 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 2400 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.

Glycopyrrolate

After intravenous (IV) administration of a 0.2 mg radiolabelled glycopyrronium, 85% of dose recovered was recovered in urine 48 hours post-dose and some of radioactivity 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 six 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 metabolized. Two major metabolites formed via CYP3A4 catalysed biotransformation have been isolated and identified as 16α-hydroxy prednisolone and 6ß-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.

Glycopyrrolate

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

Specific 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 a doubled systemic availability after oral ingestion. The intravenous budesonide pharmacokinetics was, however, similar in cirrhotic patients and in healthy subjects.

As budesonide and formoterol are primarily eliminated via hepatic metabolism, an 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 31-192 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 was found not to 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 a 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 a 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 a 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 a 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 a 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 a 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 bodyweight gain, at subcutaneous doses of 20 mcg/kg and above (0.3 times the MRHDID on a mcg/m2 basis). No such effects were noted at 5 mcg/kg (0.08 times the MRHDID on a 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 tumourigenicity 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 a mcg/m² basis, respectively).

In a 24-month carcinogenicity study in rats, glycopyrrolate produced no evidence of tumorigenicity 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 a mcg/m² basis).

Glycopyrrolate 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 maximum recommended human

daily inhalation dose (MRHDID) on a 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 a mcg/m² basis). No tumours were seen at 22 mcg/kg (approximately 10 times the MRHDID on a 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 2600 times the MRHDID on an AUC basis). No such effect was seen at 3000 mcg/kg (approximately 1,500 times the MRHDID on a mcg/m² 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/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 1400 times the MRHDID on an AUC basis).

DESCRIPTION

FORACORT G 400 Rotacaps is a dry powder for inhalation that contains a combination of budesonide (an inhaled corticosteroid), glycopyrronium (an anticholinergic), and formoterol fumarate (a long acting beta₂-agonist).

Budesonide is a corticosteroid with the following chemical name: (RS)-11β, 16α, 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 centers 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] α-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 has the chemical name N-[2-Hydroxy-5-[(1RS)-1-hydroxy-2-[[(1RS)- 2-(4-methoxyphenyl)-1- methylethyl]-amino] ethyl]phenyl] formamide, (E)-2-butenedioate dihydrate. Formoterol fumarate 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 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 400 Rotacaps is supplied as dry powder for inhalation filled in size 3 HPMC capsules with -

Cap: pantone shade 2429c, spin imprinted with “Cipla” in white ink

Body: clear spin imprinted with “Cipla” in black Ink.

The capsules are packed in blister strips.

Each carton of FORACORT G 400 Rotacaps contains 3 blisters of 10 capsules each and prescribing information.

Storage and Handling Instructions

FORACORT G 400 Rotacaps should be stored away from moisture at a temperature of 25 °C.

Keep out of reach of children.

FORACORT G 400 Rotacaps should be used only with a Cipla Revolizer or Rotahaler device.

Do not swallow FORACORT G 400 Rotacaps.  

PATIENT COUNSELLING INFORMATION

What is FORACORT G 400 Rotacaps?

FORACORT G 400 Rotacaps combines 3 medicines, an inhaled corticosteroid (ICS) medicine (budesonide), an anticholinergic medicine (glycopyrrolate), and a long-acting beta2-adrenergic agonist (LABA) medicine (formoterol fumarate) in 1 capsule, delivered as dry powder for inhalation.  

• 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 400 Rotacaps 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.
• FORACORT G 400 Rotacaps is used long term as one capsule, two times each day with a Revolizer or Rotahaler device, to improve symptoms of COPD for better breathing.
• FORACORT G 400 Rotacaps is not for the treatment of asthma. It is not known if FORACORT G 400 Rotacaps is safe and effective in people with asthma. FORACORT G 400 Rotacaps contains formoterol fumarate. LABA medicines such as formoterol fumarate when used alone increase the risk of hospitalizations and death from asthma problems. FORACORT G 400 Rotacaps contains an ICS, an anticholinergic, and a LABA. When an ICS and LABA are used together, there is not a significant risk in hospitalizations and deaths from asthma problems.
• FORACORT G 400 Rotacaps 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 400 Rotacaps should not be used in children. It is not known if FORACORT G 400 Rotacaps is safe and effective in children.

Do not use FORACORT G 400 Rotacaps if you:

are allergic to budesonide, glycopyrrolate, formoterol, lactose or any of the ingredients in FORACORT G 400 Rotacaps.

Before using FORACORT G 400 Rotacaps, tell your healthcare provider about all of your medical conditions, including if you:

• have heart problems
• have high blood pressure
• have seizures
• have thyroid problems
• have diabetes
• have liver problems
• have kidney problems
• have weak bones (osteoporosis)
• have an immune system problem
• have eye problems such as glaucoma. Budesonide/Glycopyrronium/Formoterol may make your glaucoma worse.
• have prostate or bladder problems, or problems in passing urine. Budesonide/Glycopyrronium/Formoterol may make these problems worse.
• have any type of viral, bacterial, parasitic, or fungal infection
• are exposed to chicken pox 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 400 Rotacaps while breastfeeding.

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

Especially tell your healthcare provider if you take:

• 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.

How should I use FORACORT G 400 Rotacaps?

• It is important for you to understand how to correctly use FORACORT G 400 Rotacaps. Do not use FORACORT G 400 Rotacaps unless your healthcare provider has taught you how to use the inhaler and you understand how to use it correctly.
• Use FORACORT G 400 Rotacaps exactly as prescribed. Do not use FORACORT G 400 Rotacaps more often than prescribed.
• Use one capsule of FORACORT G 400 Rotacaps twice daily only using Rotahaler or Revolizer device. Do not swallow FORACORT G 400 Rotacaps.
• Read the Instructions for Use provided with Revolizer and Rotahaler for details on how to use the device.
• FORACORT G 400 Rotacaps should not be pushed through the foil. The blister should be peeled to expose the capsule.
• Place the FORACORT G 400 Rotacaps in the Revolizer or Rotahaler device and breathe out fully before placing the mouthpiece inside your mouth. Do not blow into the mouthpiece.
• To breathe the medicine deeply into the airways, place the mouthpiece in your mouth and close the lips firmly around it, followed by rapid and steady deep breathing.
• Hold breath for at least 5-10 seconds or as long as comfortably possible after inhalation, while taking the inhaler out of the mouth.
• Open the inhaler and check if any powder is remaining after the inhalation, If there is powder left in the capsule, close the inhaler and repeat the inhalation procedure.
• Rinse your mouth with water and spit the water out after each dose of FORACORT G 400 Rotacaps. Do not swallow the water. This will help to lessen the chance of getting a fungus infection (thrush) in the mouth and throat.
• After finishing inhalation of FORACORT G 400 Rotacaps, open the mouthpiece and remove the empty capsule by tipping it out of the capsule chamber and dispose the empty capsule in the household waste.
• If you miss a dose of FORACORT G 400 Rotacaps, take your next dose at the same time you normally do. Do not take more than your prescribed dose of FORACORT G 400 Rotacaps.
• If you use too much FORACORT G 400 Rotacaps, 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 G 400 Rotacaps unless told to do so by your healthcare provider because your symptoms might come back. Your healthcare provider will change your medicines as needed.
• Do not use other medicines that contain a LABA or an anticholinergic for any reason. Ask your healthcare provider or pharmacist if any of your other medicines are LABA or anticholinergic containing medicines.
• FORACORT G 400 Rotacaps 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.
• your rescue inhaler does not work as well to relieve your symptoms.

What are the possible side effects with FORACORT G 400 Rotacaps?

Budesonide/Glycopyrronium/Formoterol can cause serious side effects, including:

• fungal infection in your mouth or throat (thrush). Rinse your mouth with water without swallowing after using Budesonide/Glycopyrronium/Formoterol to help reduce your chance of getting thrush.
• pneumonia. People with COPD have a higher chance of getting pneumonia. FORACORT G 400 Rotacaps 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/Glycopyrronium/Formoterol). 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:

• 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 400 Rotacaps 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:
• 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:
• difficulty urinating
• urinating frequently
• painful urination
• urination in a weak stream or drips

If you have these symptoms of urinary retention, stop taking FORACORT G 400 Rotacaps 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 Budesonide/Glycopyrronium/Formoterol include

 

• upper respiratory tract infection
• pneumonia
• back pain
• thrush in your mouth and throat. Rinse your mouth with water without swallowing after use to help prevent this.
• 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

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.

How should I store FORACORT G 400 Rotacaps?

• Budesonide/Glycopyrronium/Formoterol Rotacaps should be stored away from moisture at a temperature of 25 °C and should be taken out of the blister immediately before use.
• Keep Budesonide/Glycopyrronium/Formoterol Rotacaps and all medicines out of the reach of children.

General Information about the safe and effective use of FORACORT G 400 Rotacaps

Do not use FORACORT G 400 Rotacaps for a condition for which it was not prescribed. Do not give your FORACORT G 400 Rotacaps 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 400 Rotacaps that is written for healthcare professionals.

What are the ingredients in FORACORT G 400 Rotacaps?

Active ingredients: budesonide, glycopyrronium, and formoterol fumarate

Inactive ingredients:  Magnesium stearate and lactose monohydrate

DETAILS OF MANUFACTURER

Mfd. by CIPLA LTD.

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 dated 30.07.2020

DATE OF REVISION

18-09-2023