Trimbow - Chiesi USA, Inc.

• Administer TRIMBOW by oral inhalation.
  
• After inhalation, rinse the mouth with water without swallowing it to help reduce the risk of     oropharyngeal candidiasis [see Warnings and Precautions ( 5.4 )].

Priming Before Use

• Prime TRIMBOW by actuating 2 times prior to using the first dose from a new canister.
  
• Re-prime if the inhaler has not been used for 30 days or longer.

Dose Counter

TRIMBOW has a dose counter attached to the canister. The counter starts at 122 and counts down each time a spray is released. The correct amount of medication in each actuation cannot be assured after the counter reads 000, even though the canister is not completely empty and will continue to operate. The inhaler should be discarded when the counter reads 000 or if 2 months have passed since first use date, whichever comes first.

The recommended dosage of:

TRIMBOW is beclomethasone dipropionate 172 mcg, formoterol fumarate 9.8 mcg, and glycopyrrolate 21.2 mcg (administered as 2 actuations of TRIMBOW 86 mcg/4.9 mcg/10.6 mcg [beclomethasone dipropionate 86 mcg, formoterol fumarate 4.9 mcg, and glycopyrrolate 10.6 mcg]) twice daily (in the morning and evening) by oral inhalation.

or

TRIMBOW is beclomethasone dipropionate 344 mcg, formoterol fumarate 9.8 mcg, and glycopyrrolate 21.2 mcg (administered as 2 actuations of TRIMBOW 172 mcg/4.9 mcg/10.6 mcg [beclomethasone dipropionate 172 mcg, formoterol fumarate 4.9 mcg, glycopyrrolate 10.6 mcg]) twice daily (in the morning and evening) by oral inhalation

• The recommended starting dosage for TRIMBOW is based upon patients' asthma severity or level of control of asthma symptoms on current inhaled corticosteroids.
  
• For patients who do not respond adequately to a starting dose of TRIMBOW 172 mcg/9.8 mcg/21.2 mcg (2 actuations of TRIMBOW 86 mcg/4.9 mcg/10.6 mcg [beclomethasone dipropionate 86 mcg, formoterol fumarate 4.9 mcg, and glycopyrrolate 10.6 mcg]) twice daily, additional asthma control may be provided by replacement with a dose of TRIMBOW 344 mcg/9.8 mcg/21.2 mcg (2 actuations of TRIMBOW 172 mcg/4.9 mcg/10.6 mcg [beclomethasone dipropionate 344 mcg, formoterol fumarate 9.8 mcg, and glycopyrrolate 21.2 mcg]) twice daily. For patients who do not respond adequately to a dose of TRIMBOW 344 mcg/9.8 mcg/21.2 mcg twice daily, the therapeutic regimen should be re-evaluated and additional therapeutic options should be considered.  
  
• The maximum recommended dosage is TRIMBOW 344 mcg/9.8 mcg/21.2 mcg (2 actuations of TRIMBOW 172 mcg/4.9 mcg/10.6 mcg [beclomethasone dipropionate 344 mcg, formoterol fumarate 9.8 mcg, and glycopyrrolate 21.2 mcg]) twice daily by oral inhalation.
  
• Do not take more than two oral inhalations twice daily.

Use of long-acting beta₂-adrenergic agonists (LABA) 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 LABA as monotherapy increases the risk of asthma-related hospitalization in pediatric and adolescent patients (TRIMBOW is not indicated for pediatric patients). These findings are considered a class effect of LABA monotherapy. When LABA are used in fixed-dose combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared with ICS alone ( see Serious Asthma-Related Events with Inhaled Corticosteroid/Long-acting Beta2-adrenergic Agonists ).

Serious Asthma-Related Events with Inhaled Corticosteroid/Long-acting Beta₂-adrenergic Agonists

Four large, 26-week, randomized, double-blind, active-controlled clinical safety trials were conducted to evaluate the risk of serious asthma-related events when LABA were used in fixed-dose combination with ICS compared with ICS alone in patients with asthma. Three  trials included adult and adolescent patients aged 12 years and older: 1 trial compared budesonide/formoterol fumarate with budesonide, 1 trial compared fluticasone propionate/salmeterol inhalation powder with fluticasone propionate inhalation powder, and 1 trial compared mometasone furoate/formoterol fumarate with mometasone furoate. The fourth trial included pediatric subjects aged 4 to 11 years and compared fluticasone propionate/salmeterol inhalation powder with fluticasone propionate inhalation powder. The primary safety endpoint for all 4 trials was serious asthma-related events (hospitalizations, intubations, death). A blinded adjudication committee determined whether events were asthma related. While these trials included pediatric patients aged 4 years and older, and the analysis below includes pediatric patients aged 12 years and older, TRIMBOW is not indicated for pediatric patients.

The 3 adult and adolescent trials were designed to rule out a risk margin of 2.0, and the pediatric trial was designed to rule out a risk margin of 2.7. Each individual trial met its pre-specified objective and demonstrated non-inferiority of ICS/LABA to ICS alone. A meta-analysis of the 3 adult and adolescent trials did not show a significant increase in risk of a serious asthma-related event with ICS/LABA fixed-dose combination compared with ICS alone (Table 1). These trials were not designed to rule out all risk for serious asthma-related events with ICS/LABA compared with ICS.

ICS = Inhaled Corticosteroid, LABA = Long-acting Beta_2-adrenergic Agonist.

^a Randomized subjects who had taken at least 1 dose of study drug. Planned treatment used for analysis.

^b Estimated using a Cox proportional hazards model for time to first event with baseline hazards stratified by each of the 3 trials.

^c Number of subjects with event that occurred within 6 months after the first use of study drug or 7 days after the last date of study drug, whichever date was later. Subjects can have 1 or more events, but only the first event was counted for analysis. A single, blinded, independent adjudication committee determined whether events were asthma related.

The pediatric safety trial included 6,208 pediatric subjects aged 4 to 11 years who received ICS/LABA (fluticasone propionate/salmeterol inhalation powder) or ICS (fluticasone propionate inhalation powder). In this trial, 27/3,107 (0.9%) subjects randomized to ICS/LABA and 21/3,101 (0.7%) subjects randomized to ICS experienced a serious asthma-related event. There were no asthma-related deaths or intubations. ICS/LABA did not show a significantly increased risk of a serious asthma-related event compared with ICS based on the pre-specified risk margin (2.7), with an estimated hazard ratio of time to first event of 1.29 (95% CI: 0.73, 2.27). While the safety for pediatric patients is provided, TRIMBOW is not indicated for use in pediatric patients aged 17 years and younger.

Salmeterol Multicenter Asthma Research Trial (SMART)

A 28-week, placebo-controlled, U.S. trial that compared the safety of salmeterol with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in subjects receiving salmeterol (13/13,176 in subjects treated with salmeterol vs. 3/13,179 in subjects treated with placebo; relative risk: 4.37 [95% CI: 1.25, 15.34]). Use of background ICS was not required in SMART. The increased risk of asthma-related death is considered a class effect of LABA monotherapy.

TRIMBOW should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of asthma. TRIMBOW has not been studied in subjects with acutely deteriorating asthma. The use of TRIMBOW in this setting is not appropriate.

Increasing use of inhaled, short-acting beta₂-agonists is a marker of deteriorating asthma. In this situation, the patient requires immediate reevaluation with reassessment of the treatment regimen, giving special consideration to the need for additional therapeutic options. Patients should not use more than 2 inhalations twice daily of TRIMBOW.

TRIMBOW should not be used for the relief of acute symptoms (i.e., as rescue therapy for the treatment of acute episodes of bronchospasm). TRIMBOW 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.

When beginning treatment with TRIMBOW, patients who have been taking oral or inhaled, short-acting beta₂-agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs and to use them only for symptomatic relief of acute respiratory symptoms. When prescribing TRIMBOW, the healthcare provider should also prescribe an inhaled, short-acting beta₂-agonist/corticosteroid combination or an inhaled, short-acting beta₂-agonist and instruct the patient on how it should be used.

TRIMBOW should not be used more often than recommended, at higher doses than recommended, or in conjunction with other therapies 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 TRIMBOW should not use another therapy containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol, vilanterol, olodaterol or indacaterol) for any reason.  

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

Patients who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The safety and effectiveness of TRIMBOW have not been established in pediatric patients and TRIMBOW is not indicated for use in this population. 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 8 immune globulin (VZIG) may be indicated. If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective Prescribing Information for VZIG and IG.) 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; systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.

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 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 TRIMBOW may control asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticoid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies.

During periods of stress or a severe asthma 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 asthma exacerbation.

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

Inhaled beclomethasone dipropionate is absorbed into the circulation and can be systemically active. Effects of beclomethasone dipropionate on the HPA axis are not observed with the therapeutic doses of beclomethasone dipropionate in TRIMBOW. However, exceeding the recommended dosage or coadministration with a strong cytochrome P450 3A (CYP3A4 and CYP3A5) inhibitor may result in HPA dysfunction.

Because of the possibility of significant systemic absorption of ICS in sensitive patients, patients treated with TRIMBOW 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.

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

Hypersensitivity reactions have been reported after administration of beclomethasone dipropionate, formoterol fumarate or glycopyrrolate, the components of TRIMBOW. If signs suggesting allergic reactions occur, in particular, angioedema (including difficulties in breathing or swallowing, swelling of the tongue, lips and face), urticaria or skin rash, TRIMBOW should be discontinued immediately, and alternative therapy instituted [see Contraindications ( 4 )].

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 [see Clinical Pharmacology ( 12.2 )]. If such effects occur, TRIMBOW may need to be discontinued.

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 [see Clinical Pharmacology ( 12.2 )]. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. TRIMBOW, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. 

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, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care.

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

TRIMBOW, 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 urinary retention (e.g., difficulty passing urine, painful urination), especially in patients with prostatic hyperplasia or bladder-neck obstruction. Instruct patients to consult a healthcare provider immediately if any of these signs or symptoms develop.

TRIMBOW, 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 albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.

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

Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to

pediatric patients. TRIMBOW is not indicated for use in this population [ s ee Use in Specific Populations ( 8.4 ) ].

The safety of TRIMBOW in asthma is based on the safety data from two randomized, double-blind, parallel-group, active-controlled trials of 52 weeks’ duration (TRIMARAN and TRIGGER) that included 2,294 adult patients with asthma who received TRIMBOW or BDP/FF comparator [ see Clinical Studies ( 14 ) ]. The incidence of adverse reactions occurring in ≥1% of the patients treated with a dose of TRIMBOW 172 mcg/9.8 mcg/21.2 mcg or a dose of TRIMBOW 344 mcg/9.8 mcg/21.2 mcg, both doses at twice daily by oral inhalation, is shown in Table 2.

Abbreviations: BDP, beclomethasone dipropionate; FF, formoterol fumarate; N, number of patients

If additional adrenergic drugs are to be administered by any route, they should be used with caution because the sympathetic effects of formoterol fumarate, a component of TRIMBOW, may be potentiated [see Warnings and Precautions ( 5.3 )].

Concomitant treatment with xanthine derivatives, steroids, or diuretics may potentiate the hypokalemic effect of beta₂-adrenergic agonists such as formoterol fumarate, a component of TRIMBOW. 

Formoterol, as with other beta₂-agonists, should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, macrolides or 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 have an increased risk of ventricular arrhythmias.

Beta-adrenergic receptor antagonists (beta-blockers) and formoterol may inhibit the effect of each other when administered concurrently. Beta-blockers not only block the therapeutic effects of beta2-agonists, such as formoterol, but may produce severe bronchospasm in asthmatic patients. Therefore, patients with asthma 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 asthma. In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution.

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

There is potential for an additive interaction with concomitantly used anticholinergic medicines. Therefore, avoid coadministration of TRIMBOW with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects [see Warnings and Precautions ( 5.12 , 5.13 )].

Risk Summary 

There are no adequate and well-controlled studies with TRIMBOW or its individual components, beclomethasone dipropionate, formoterol fumarate, and glycopyrrolate in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes (See Clinical Considerations ).

In animal reproduction studies, beclomethasone dipropionate (BDP) resulted in adverse developmental effects in mice and rabbits at subcutaneous doses equal to or greater than approximately 0.6 times the maximum recommended human daily inhalation dose (MRHDID) in adults (800 mcg/day) [see Data ]. In rats exposed to beclomethasone dipropionate by inhalation, dose-related gross injury to the fetal adrenal glands was observed at doses greater than 140 times the MRHDID, but there was no evidence of external or skeletal malformations or embryolethality at inhalation doses of up to 350 times the MRHDID.

In animal reproduction studies, formoterol fumarate (FF) produced malformations that included umbilical hernia and brachygnathia (a skeletal malformation) in rats at oral doses 1,200 and 6,100 times the MRHDID in adults, respectively. In rabbits, formoterol fumarate produced subcapsular cysts on the liver at oral doses 49,000 times the MRHDID in adults. In rats exposed to formoterol fumarate by inhalation, no teratogenic effects were observed at 500 times the MRHDID in adults.  

Glycopyrrolate (G) administered by the oral route in rats and rabbits did not cause structural abnormalities or affect fetal survival at exposures approximately 179 and 50 times MRHDID, respectively.

TRIMBOW administered by the oral route in rats caused reduction in fetal weights and increased incidence of visceral variations at doses 83 and 0.8 times the MRHDID and higher for BDP (metabolite- B17MP) and FF, respectively. TRIMBOW also caused decreased pup survival, increase in post-implantation loss and reduced mean litter size in rats at 1.9, 3.7, and 7.7 times the MRHDID (based on a mg/m²) for BDP, FF, and G, respectively.

The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations 

Disease-Associated Maternal and/or Embryofetal Risk:  

In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal outcomes such as pre-eclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women should be closely monitored, and medication adjusted as necessary to maintain optimal control of asthma. 

Labor or Delivery:

There are no well-controlled human trials that have investigated the effects of TRIMBOW on preterm labor or labor at term. TRIMBOW should be used during late gestation and labor only if the potential benefit justifies the potential for risks related to beta-agonists interfering with uterine contractility.

Infants and neonates born to mothers receiving substantial doses should be observed for adrenal suppression. If treatment during pregnancy is necessary, the lowest effective dose should be used. 

Data 

Animal Data

Beclomethasone dipropionate (BDP)

In an embryofetal development study in pregnant rats, beclomethasone dipropionate administration during organogenesis from gestation days 6 to 15 at inhaled doses 140 times the MRHDID in adults and higher (on a mg/m² basis at maternal doses of 11,500 and 28,300 mcg/kg/day) produced dose-dependent gross injury (characterized by red foci) of the adrenal glands in fetuses. There were no findings in the adrenal glands of rat fetuses at an inhaled dose that was 30 times the MRHDID in adults (on a mg/m² basis at a maternal dose of 2,400 mcg/kg/day). There was no evidence of external or skeletal malformations or embryolethality in rat at inhaled doses up to 350 times the MRHDID (on a mg/m² basis at maternal doses up to 28,300 mcg/kg/day).

In an embryofetal development study in pregnant mice, beclomethasone dipropionate administration from gestation days 1 to 18 at subcutaneous doses equal to and greater than 0.6 times the MRHDID in adults (on a mg/m² basis at maternal doses of 100 mcg/kg/day and higher) produced adverse developmental effects (increased incidence of cleft palate). A no-effect dose in mice was not identified. In a second embryofetal development study in pregnant mice, beclomethasone dipropionate administration from gestation days 1 to 13 at subcutaneous doses equal to and greater than 2.0 times the MRHDID in adults (on a mg/m² basis at a maternal dose of 300 mcg/kg/day) produced embryolethal effects (increased fetal resorptions) and decreased pup survival.

In an embryofetal development study in pregnant rabbits, beclomethasone dipropionate administration during organogenesis from gestation days 7 to 16 at subcutaneous doses equal to and greater than 0.6 times the MRHDID in adults (on a mg/m² basis at maternal doses of 25 mcg/kg/day and higher) produced external and skeletal malformations and embryolethal effects (increased fetal resorptions). There were no effects in fetuses of pregnant rabbits administered a subcutaneous dose 0.15 times the MRHDID in adults (on a mg/m² basis at a maternal dose of 6 mcg/kg/day).

Formoterol fumarate (FF)

Formoterol fumarate administered throughout organogenesis did not cause malformations in rats or rabbits following oral administration. When given to rats throughout organogenesis, oral doses equal to or greater than 80 times the MRHDID for adults (on a mcg/m² basis for maternal doses of 200 mcg/kg/day and above) delayed ossification of the fetus and doses equal to or greater than 2,400 times the MRHDID for adults (on a mcg/m² basis for maternal doses of 6,000 mcg/kg/day and above) decreased fetal weight. Formoterol fumarate has been shown to cause stillbirth and neonatal mortality at oral doses equal to or greater than 2,400 times the MRHDID for adults (on a mcg/m² basis for maternal doses of 6,000 mcg/kg/day and above) in rats receiving the drug during the late stage of pregnancy. These effects, however, were not produced at a dose equal to 80 times the MRHDID for adults (on a mcg/m² basis for a maternal dose of 200 mcg/kg/day).

In another testing laboratory, formoterol fumarate was shown to be teratogenic in rats and rabbits. Umbilical hernia, a malformation, was observed in rat fetuses at oral doses equal to or greater than 1,200 times the MRHDID for adults (on a mcg/m² basis for maternal doses of 3,000 mcg/kg/day and above). Brachygnathia, a skeletal malformation, was observed for rat fetuses at an oral dose equal to 6,100 times the MRHD for adults (on a mcg/m² basis for a maternal dose of 15,000 mcg/kg/day. In another study in rats, no teratogenic effects were seen at inhalation doses up to 500 times the MRHD for adults (on a mcg/m² basis for maternal doses up to 1,200 mcg/kg/day). Subcapsular cysts on the liver were observed for rabbit fetuses at an oral dose equal to 49,000 times the MRHD for adults (on a mcg/m² basis for a maternal dose of 60,000 mcg/kg). No teratogenic effects were observed at oral doses up to 3,000 times the MRHD for adults (on a mcg/m² basis for maternal doses up to 3,500 mcg/kg/day).

Glycopyrrolate (G)

In an embryo-fetal development study in pregnant rats, orally dosed during the period of organogenesis from gestation days 6 to 17, glycopyrrolate administration produced no structural abnormalities or effects on fetal survival at the highest tested dose that was 179 times the MRHDID. Maternal toxicity was characterized by significant reduction in maternal body weight observed at doses 26 times the MRHDID and higher.

In an embryofetal development study in pregnant rabbits, orally dosed during the period of organogenesis from gestation days 6 to 18, glycopyrrolate administration produced no structural abnormalities or effects on fetal survival at the highest tested dose that was 50 times the MRHDID . Maternal toxicity was characterized by abortions at doses 18 times the MRHDID and higher.  

TRIMBOW

In an embryofetal development study in pregnant rats orally dosed during organogenesis from gestation days 6 to 17, TRIMBOW (BDP/FF/GB ratio 100/6/25 mg/kg/day) produced reduction in fetal weights and increased incidence of visceral variations at doses 83 and 0.8 times the MRHDID and higher for BDP (metabolite- B17MP) and FF, respectively.

In a pre- and post-natal development study, pregnant female rats received TRIMBOW (BDP/FF/GB ratio 100/6/25 mg/kg/day) from gestation day 6 through prenatal day 21. Maternal toxicity included mortalities in females during gestation. Increased post-implantation loss, reduced litter sizes and decreased pup survival were observed at doses 1.9, 3.7, and 7.7 times the MRHDID (based on mcg/m²) for beclomethasone, formoterol fumarate, and glycopyrrolate, respectively. F1 generation pups showed reduction in corpora lutea leading to increase in post-implantation loss and reduced mean litter size at 1.9, 3.7, and 7.7 times the MRHDID (based on mg/m²) for beclomethasone, formoterol fumarate, and glycopyrrolate, respectively.

Risk Summary  

There are no data available on the presence of beclomethasone dipropionate, formoterol fumarate or glycopyrrolate in human milk; the effects on the breastfed child; or the effects on milk production. Glucocorticoids are excreted in human milk. It is reasonable to assume that beclomethasone dipropionate and its metabolites are also excreted in human milk. Formoterol is present in animal milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Anticholinergics like glycopyrrolate could suppress lactation. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for TRIMBOW and any potential adverse effects on the breast-fed child from TRIMBOW or from the underlying maternal condition. 

Beclomethasone Dipropionate

Impairment of fertility was observed in rats and dogs at oral doses of beclomethasone dipropionate corresponding to 250 and 25 times the MRHDID for adults on a mg/m² basis, respectively [see Nonclinical Toxicology ( 13.1 )].

TRIMBOW

A reduction of conception rate, fertility index, slight increase in mean precoital time, significant reduction in corpora lutea, and increased pre-implantation loss were identified in female rats treated with TRIMBOW at an oral dose 187, 367, 767 times the MRHDID for BDP, FF, and G components, respectively, based on mg/m². No effects on male fertility were noted [see Nonclinical Toxicology ( 13.1 )].

The safety and effectiveness of TRIMBOW have not been established in pediatric patients.

Of the total number of TRIMBOW-treated patients in clinical studies for asthma, 204 (18%) were 65 years of age and older [see Clinical Studies ( 14 )]. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between elderly and younger patients.

Formal pharmacokinetic studies using TRIMBOW have not been conducted in patients with hepatic impairment. However, since formoterol fumarate is predominantly cleared by hepatic metabolism, impairment of liver function may lead to accumulation of formoterol fumarate in plasma. Therefore, patients with severe hepatic disease should be closely monitored. 

Glycopyrronium systemic exposure is increased in patients with severe renal impairment (eGFR <15 mL/min/1.73 m²) [ see  Clinical Pharmacology ( 12.3 ) ]. In patients with severe renal impairment or end-stage renal disease (eGFR <15 mL/min/1.73 m²) requiring dialysis, TRIMBOW should only be used if the expected benefit outweighs the potential risk.

TRIMBOW contains beclomethasone dipropionate, formoterol fumarate and glycopyrrolate. The mechanism of action described below for the individual components applies to TRIMBOW. These drugs represent three different classes of medications (an inhaled corticosteroid, a long-acting beta₂-adrenergic agonist and an anticholinergic) that have different effects on clinical physiology.

Beclomethasone Dipropionate

Beclomethasone dipropionate is a corticosteroid demonstrating potent anti-inflammatory activity. The precise mechanism through which beclomethasone dipropionate effects asthma symptoms is not known. Corticosteroids have been shown to have multiple anti-inflammatory effects, inhibiting both inflammatory cells (e.g., mast cells, eosinophils, basophils, lymphocytes, macrophages, and neutrophils) and release of inflammatory mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines). These anti-inflammatory actions of corticosteroids contribute to their efficacy in asthma.

Beclomethasone dipropionate is a prodrug that is rapidly activated by hydrolysis to the active monoester, 17-monopropionate (17-BMP). Beclomethasone 17-monopropionate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor, which is approximately 13 times that of dexamethasone, 6 times that of triamcinolone acetonide, 1.5 times that of budesonide and 25 times that of beclomethasone dipropionate. The clinical relevance of these findings is unknown.

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 lung as a bronchodilator. In vitro studies have shown that formoterol fumarate has more than 200-fold greater agonist activity at beta₂-receptors than at beta₁-receptors.

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 comprising 10% to 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 pharmacologic effects of beta₂-adrenoceptor agonist drugs, including formoterol fumarate, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes 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 inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

Glycopyrrolate 

Glycopyrrolate is a long-acting antimuscarinic agent which is often referred to as an anticholinergic. It has similar affinity to the subtypes of muscarinic receptors M1 to M5. In the airways, it exhibits pharmacological effects through inhibition of the M3 receptor at the smooth muscle leading to bronchodilation. In preclinical in vitro as well as in vivo studies, prevention of acetylcholine, ovalbumin, acetaldehyde and histamine-induced bronchoconstrictive effects was dose-dependent. The clinical relevance of these findings is unknown. The bronchodilation following inhalation of glycopyrrolate is predominantly a site-specific effect.

Cardiac Electrophysiology

A randomized, double-blind, placebo controlled, single dose study in 95 healthy volunteers assessed the effect of beclomethasone dipropionate, formoterol fumarate, and glycopyrrolate (BDP/FF/G) on the heart rate corrected QT interval based on the Fridericia's correction (QTcF) using electrocardiographic monitoring. 

The maximum mean (90% two-sided upper confidence bound) difference in QTcF from placebo after baseline correction was 4.4 (5.9) milliseconds and 11.8 (13.4) milliseconds for BDP/FF/G with 172 mcg/9.8 mcg/21.2 mcg of BDP/FF/G and 4 times the dose of 172 mcg/9.8 mcg/ 21.2 mcg of BDP/FF/G, respectively.

A dose-dependent increase in heart rate was also observed. The maximum mean (90% two-sided CI) difference in heart rate between BDP/FF/G and placebo after baseline-correction was 3.8 (2.3; 5.4) beats/min observed 10 min post-dose at 172 mcg/9.8 mcg/21.2 mcg of BDP/FF/G and 10.3 (9.3; 11.3) beats/min observed 2 h post-dose at 4 times the dose of 172 mcg/9.8 mcg/ 21.2 mcg of BDP/FF/G.

HPA Axis Effects

The potential systemic effects of TRIMBOW on the HPA axis have not been evaluated.

The systemic effects of inhaled corticosteroids are related to the systemic exposure to such drugs.

Pharmacokinetic studies have demonstrated that the systemic exposure to BDP/17-BMP at a single BDP/FF/G dose of 344 mcg/9.8 mcg/21.2 mcg was lower compared with the highest dose of a BDP MDI product (640 mcg administered as a single dose). Therefore, the systemic effects on HPA-axis of BDP/17-BMP delivered from TRIMBOW would be expected to be no greater than that of a BDP MDI product. 

The systemic exposure of beclomethasone dipropionate and 17-BMP approximately doubles following a single dose (4 inhalations) of TRIMBOW 172 mcg/4.9 mcg/10.6 mcg compared to a single dose (4 inhalations) of TRIMBOW 86 mcg/4.9 mcg/10.6 mcg in healthy subjects. Meanwhile, the systemic exposure of formoterol and glycopyrrolate was generally similar between TRIMBOW 172 mcg/4.9 mcg/10.6 mcg and TRIMBOW 86 mcg/4.9 mcg/10.6 mcg after inhalation.

Absorption

Beclomethasone dipropionate

Following inhaled administration of TRIMBOW 86 mcg/4.9 mcg/10.6 mcg in healthy subjects the median time to reach C_max was 5 minutes for beclomethasone dipropionate and 30 minutes for 17-BMP.

Formoterol fumarate

Following inhaled administration of TRIMBOW 86 mcg/4.9 mcg/10.6 mcg in healthy subjects the median time to reach C_max was 5 minutes. As with drug products for oral inhalation, it is likely that the majority of the inhaled formoterol fumarate is swallowed and then absorbed from the gastrointestinal tract.  

Glycopyrrolate 

Following inhaled administration of TRIMBOW 86/4.9 mcg/10.6 mcg in healthy subjects the median time to reach C_max was 5 minutes. Following glycopyrrolate inhalation, the absolute bioavailability was 9.6% and 11.9% with or without oral ingestion of charcoal block, respectively, when compared to intravenous infusion. 

Distribution

Beclomethasone dipropionate

Apparent volume of distribution at steady state for 17-BMP in subjects with asthma following inhaled administration of TRIMBOW 86 mcg/4.9 mcg/10.6 mcg was estimated to be approximately 135 L, via population PK analysis.  The in vitro protein binding for 17-BMP was reported to be 94% to 96% over the concentration range of 1000 to 5000 pg/mL. Protein binding was constant over the concentration range evaluated. There is no evidence of tissue storage of beclomethasone dipropionate or its metabolites.

Formoterol fumarate

Apparent volume of distribution at steady state in subjects with asthma following inhaled administration of TRIMBOW 86 mcg/4.9 mcg/10.6 mcg was estimated to be approximately 1560 L, via population PK analysis. Plasma protein binding of formoterol fumarate is 61-64% at concentrations from 0.1 to 100 ng/mL. Binding to human serum albumin in vitro was 31% to 38% over a range of 5 to 500 ng/mL.

Glycopyrrolate 

Apparent volume of distribution at steady state in subjects with asthma following inhaled administration of TRIMBOW 86 mcg/4.9 mcg/10.6 mcg was estimated to be approximately 3895 L, via population PK analysis. Glycopyrronium binding to plasma proteins was 71 ± 4% over the range of 50-250 pg/mL.

Elimination

Beclomethasone dipropionate

Beclomethasone dipropionate is excreted in feces in the form of metabolites. Only negligible amounts of unchanged beclomethasone dipropionate and its metabolites have been detected in urine. The mean elimination half-life of beclomethasone dipropionate and 17-BMP in subjects with asthma following inhaled administration of TRIMBOW 172 mcg/4.9 mcg/10.6 mcg was 0.3 hours and 5 hours, respectively.  

Formoterol fumarate 

The excretion of formoterol in urine was studied in seventeen healthy subjects, as part of the investigation of the effect of renal impairment on the pharmacokinetics of inhaled TRIMBOW. In that study, 4.7% of the administered formoterol dose was excreted in urine as unchanged formoterol. The mean elimination half-life of formoterol in subjects with asthma following inhaled administration of TRIMBOW 172 mcg/4.9 mcg/10.6 mcg was 6.7 hours.

Glycopyrrolate 

The excretion of glycopyrrolate in urine was studied in seventeen healthy subjects, as part of the investigation of the effect of renal impairment on the pharmacokinetics of inhaled TRIMBOW. In that study, 7% of the inhaled dose was excreted in urine as unchanged glycopyrronium.

Metabolism

Beclomethasone dipropionate

Beclomethasone dipropionate is cleared very rapidly from the systemic circulation by metabolism mediated via esterases found in most tissues, with limited involvement of CYP450 enzymes. The main product of metabolism of beclomethasone dipropionate is the active metabolite 17-BMP. Minor inactive metabolites, beclomethasone 21-monopropionate and beclomethasone, are also formed. 

Formoterol fumarate

Formoterol is metabolized primarily by direct glucuronidation at either the phenolic or aliphatic hydroxyl group and O-demethylation followed by glucuronide conjugation at either phenolic hydroxyl groups. Minor pathways involve sulfate conjugation of formoterol and deformylation followed by sulfate conjugation. The most prominent pathway involves direct conjugation at the phenolic hydroxyl group. Cytochrome P450 isoenzymes CYP2D6, CYP2C19 and CYP2C9 are involved in the O-demethylation of formoterol. The liver appears to be the primary site of metabolism.

Glycopyrrolate

Metabolism plays a minor role in the overall elimination of glycopyrronium. The in vitro metabolic pattern of glycopyrrolate in human liver microsomes and hepatocytes demonstrates the main metabolic reaction was the hydroxylation on the phenyl or cyclopentyl rings. CYP2D6 was found to be the primary enzyme responsible for glycopyrrolate metabolism. 

Specific Populations

Population pharmacokinetic analysis showed no evidence of a clinically significant effect of age, sex, or body weight on the pharmacokinetics of beclomethasone 17-monopropionate, formoterol fumarate or glycopyrronium.

Patients with Hepatic Impairment

Dedicated studies of TRIMBOW evaluating effect of hepatic impairment on the pharmacokinetics of beclomethasone dipropionate, formoterol fumarate and glycopyrrolate were not conducted.

As formoterol fumarate is primarily eliminated via hepatic metabolism, an increased exposure can be expected in patients with severe hepatic impairment.

Patients with Renal Impairment

The effect of renal impairment on the exposure to beclomethasone dipropionate, formoterol and glycopyrronium was evaluated after single administration of inhaled TRIMBOW in subjects with mild, moderate and severe renal impairment (9, 7 and 9 subjects, respectively) in comparison with demographically matching healthy volunteers. Renal impairment did not result in clinically significant increases in systemic exposure to beclomethasone dipropionate, 17-BMP, or formoterol fumarate. For glycopyrronium, there was no clinically significant increases in systemic exposure in subjects with mild and moderate renal impairment. However, an increase in total systemic exposure of up to 2.5-fold was observed in subjects with severe renal impairment (glomerular filtration rate < 30 mL/min/1.73 m²).

Drug Interaction Studies

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

Cimetidine: At recommended doses, cimetidine, a non-specific inhibitor of CYP enzymes and an inhibitor of organic cation transport, had no clinically significant interactions with TRIMBOW.

No studies of carcinogenicity or mutagenicity were conducted with TRIMBOW; however, separate studies of beclomethasone dipropionate, formoterol fumarate and glycopyrrolate are described below. 

Beclomethasone dipropionate

The carcinogenicity of beclomethasone dipropionate was evaluated in rats which were exposed for a total of 95 weeks, 13 weeks at inhalation doses up to 0.4 mg/kg/day and the remaining 82 weeks at combined oral and inhalation doses up to 2.4 mg/kg/day. There was no evidence of treatment-related increases in the incidence of tumors in this study at the highest dose, which is approximately 30 times the MRHDID in adults on a mg/m² basis.

Beclomethasone dipropionate did not induce gene mutation in bacterial cells or mammalian Chinese hamster ovary (CHO) cells in vitro. No significant clastogenic effect was seen in cultured CHO cells in vitro or in the mouse micronucleus test in vivo.

Formoterol fumarate

The carcinogenic potential of formoterol fumarate has been evaluated in 2-year drinking water and dietary studies in both rats and mice. In rats, the incidence of ovarian leiomyomas was increased at doses of 15 mg/kg and above in the drinking water study and at 20 mg/kg in the dietary study, but not at dietary doses up to 5 mg/kg (AUC exposure approximately 450 times human exposure at the maximum recommended daily inhalation dose). In the dietary study, the incidence of benign ovarian theca-cell tumors was increased at doses of 0.5 mg/kg and above (AUC exposure at the low dose of 0.5 mg/kg was approximately 45 times human exposure at the maximum recommended daily inhalation dose). This finding was not observed in the drinking water study, nor was it seen in mice (see below).

In mice, the incidence of adrenal subcapsular adenomas and carcinomas was increased in males at doses of 69 mg/kg and above in the drinking water study, but not at doses up to 50 mg/kg (AUC exposure approximately 590 times human exposure at the maximum recommended daily inhalation dose) in the dietary study. The incidence of hepatocarcinomas was increased in the dietary study at doses of 20 and 50 mg/kg in females and 50 mg/kg in males, but not at doses up to 5 mg/kg in either males or females (AUC exposure approximately 60 times human exposure at the maximum recommended daily inhalation dose). Also in the dietary study, the incidence of uterine leiomyomas and leiomyosarcomas was increased at doses of 2 mg/kg and above (AUC exposure at the low dose of 2 mg/kg was approximately 25 times human exposure at the maximum recommended daily inhalation dose). Increases in leiomyomas of the rodent female genital tract have been similarly demonstrated with other beta-agonist drugs.

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

Glycopyrrolate

There was no evidence of treatment-related increases in the incidence of tumors in an oral 26-week carcinogenicity study in transgenic Tg-rasH2 mice and in a 2-year inhalation study in rats at up to 81 times the MRHDID in adults on a mg/m² basis.

Glycopyrrolate was not mutagenic or clastogenic in the following tests: Ames assay in bacterial and mammalian cells, chromosomal aberrations in mammalian cells, and micronucleus tests in mice and rats.

Impairment of Fertility

Beclomethasone Dipropionate

In rats, beclomethasone dipropionate caused decreased conception rates at an oral dose of 16 mg/kg/day (approximately 250 times the MRHDID in adults on a mg/m ² basis). Impairment of fertility, as evidenced by inhibition of the estrous cycle in dogs, was observed following treatment by the oral route at a dose of 0.5 mg/kg/day (approximately 25 times the MRHDID in adults on a mg/m ² basis). No inhibition of the estrous cycle in dogs was seen following 12 months of exposure to beclomethasone dipropionate by the inhalation route at an estimated daily dose of 0.33 mg/kg (approximately 17 times the MRHDID in adults on a mg/m² basis).

TRIMBOW

In a fertility and reproduction study, male rats were orally dosed for at least 6 weeks and females for 2 weeks prior to pairing, throughout the mating period, and up to gestation day 7. TRIMBOW BDP/FF/GB ratio 100/6/25 mg/kg/day) caused reduction of conception rate and fertility index, a slight increase in mean precoital time, reduction in the number of corpora lutea, increased pre- and post-implantation loss, and reduction in the number of live embryos at doses 19, 37, and 77 times the MRHDID for BDP, FF, and G components, respectively (based on mg/m² at oral dose of 2,000 mcg/kg or higher). No effects on male fertility were noted.