Source: Health Products and Food Branch (CA) Revision Year: 2021
ZENHALE contains both mometasone furoate and formoterol fumarate; therefore, the mechanisms of actions described below for the individual components apply to ZENHALE.
Mometasone furoate is a topical glucocorticosteriod with local anti-inflammatory properties.
Glucocorticoids, like mometasone furoate exert their anti-inflammatory effects through glucocorticoid receptors (GRs). On binding the glucocorticoid, the GR heterocomplex dissociates, and the ligand activated GR translocates from the cytoplasm to the nucleus. The activated GR may then upregulate the transcription of anti-inflammatory genes by binding to specific DNA sequences termed glucocorticoid response elements. However, it is more likely that the primary anti-inflammatory activity of glucocorticoids results from their ability to suppress the transcription of genes. In this case, the activated GR interacts with transcription factors apolipoproiein 1 (AP 1) or nuclear factor kappa B (NF-kB) to down regulate gene expression. In addition, glucocorticoids have been shown to upregulate the expression of an inhibitor of NF-kB.
Formoterol fumarate is a potent selective beta2-adrenergic stimulant. It exerts a bronchodilator effect in patients with reversible airway obstruction. The effect sets in rapidly and is still significant 12 hours after inhalation. In vitro, formoterol inhibits the release of histamine and leukotrienes from passively sensitized human lung. Some anti-inflammatory properties, such as inhibition of oedema and inflammatory cell accumulation, have been observed in animal experiments.
Affinity for binding to the GR corresponds to functional activity. Mometasone furoate binds with very high affinity to the human GR which in cells, results in potent inhibition of the synthesis and release of proinflammatory mediators and cytokines.
Mometasone furoate significantly inhibits the release of leukotrienes from leucocytes of allergic patients. In cell culture, mometasone furoate inhibits synthesis and release of IL-1, IL-5, IL-6, and TNF with high potency; it is also a potent inhibitor of the production of the TH2 cytokines, IL-4 and IL-5, from human CD4+ T-cells. In mixed leukocytes from atopic patients, mometasone furoate was a more potent inhibitor of leukotriene production than beclomethasone dipropionate.
In preclinical models, mometasone furoate has been shown to reduce the accumulation of inflammatory cells, including eosinophils, infiltrating into the upper and lower airways and improve lung function following allergen provocation. Additionally, mometasone furoate reduces the number of lymphocytes and the levels of messenger RNA for the proallergic cytokines IL-4 and IL-5.
In vitro studies on guinea pig trachea have indicated that racemic formoterol and its (R,R)- and (S,S)-enantiomers are highly selective beta2-adrenoceptor agonists. The (S,S)-enantiomer was 800 to 1,000 times less potent than the (R,R)enantiomer and did not affect the activity of the (R,R) enantiomer on tracheal smooth muscle. No pharmacological basis for the use of one of the two enantiomers in preference to the racemic mixture has been demonstrated.
In patients 12 years of age and older with asthma, there was no evidence of significant hypokalemia or hyperglycemia in response to formoterol treatment after doses of formoterol fumarate ranging from 10 mcg to 40 mcg from ZENHALE. No relevant changes in heart rate during the study were observed with ZENHALE. No patients had a QTcB (QTc corrected by Bazett’s formula) ≥500 msec during treatment. There were no other clinically significant abnormalities, including vital signs, or ECG data.
The effects of inhaled mometasone furoate administered via ZENHALE on adrenal function were evaluated in two clinical studies in patients with asthma. HPA-axis function was assessed by 24- hour plasma cortisol AUC. Dose related decreases in plasma cortisol were observed with ZENHALE but these effects are not considered to be clinically significant.
Among 91 children with asthma aged 5 to less than 12 years treated with ZENHALE for up to 24 weeks, there were no notable changes from baseline in heart rate or blood pressure. There were no reports of hypokalemia or hypoglycemia.
In a single-dose cross-over study, there was no evidence of a significant pharmacokine tic interaction between mometasone furoate and formoterol when given as ZENHALE.
Following inhalation of single and multiple doses of ZENHALE, mometasone furoate (200 to 800 mcg) was rapidly absorbed with a prolonged absorption phase. Median Tmax values ranged from 0.50 to 4 hours. Exposure to mometasone furoate increased with increasing inhaled dose. Absorbed mometasone furoate is rapidly cleared from plasma at a rate of approximately 12.5 mL/min/kg, independent of dose. The effective t½ for mometasone furoate following inhalation with ZENHALE was 25 hours. Using the steady-state exposure to mometasone furoate when administered by inhalation from ZENHALE and after a single IV dose from different studies, estimates of the absolute bioavailability were approximately 14% in healthy subjects and ranged from 5% to 7% in asthmatic patients.
Following ZENHALE administration formoterol was rapidly absorbed with median Tmax values ranging from 0.17 to 1.97 hours. Over the dose range of 10 to 40 mcg for formoterol from ZENHALE, the exposure to formoterol was dose proportional. The mean t½ for formoterol in plasma was 9.1 hours.
After intravenous bolus administration, the mean steady-state volume of distribution (Vd) was 152 liters. The in vitro protein binding for mometasone furoate was reported to be 98 to 99% (in a concentration range of 5 to 500 ng/mL).
The plasma protein binding of formoterol was 61% to 64% and binding to human serum albumin was 34%.
Mometasone furoate is extensively metabolized in all species investigated. No major metabolites have been identified. The portion of an inhaled mometasone furoate dose that is swallowed and absorbed from the gastrointestinal tract undergoes extensive metabolism to multiple metabolites. In human liver microsomes, mometasone furoate is metabolized to many metabolites, including 6-beta hydroxy mometasone furoate, which is formed by cytochrome P450 3A4.
Formoterol is eliminated primarily by metabolism, with direct glucuronidation being the major pathway of biotransformation. O-demethylation followed by glucuronidation is another pathway. Minor pathways involve sulphate conjugation of formoterol and deformylation followed by sulphate conjugation. Multiple isozymes catalyse the glucuronidation (UGT1A1, 1A3, 1A6, 1A7, 1A8, 1A9, 1A10, 2B7 and 2B15) and O-demethylation (CYP2D6, 2C19, 2C9 and 2A6) of formoterol, suggesting a low potential for drug-drug interactions through inhibition of a specific isozyme involved in formoterol metabolism. Formoterol did not inhibit cytochrome P450 isozymes at therapeutically relevant concentrations.
A radiolabeled, orally inhaled dose is excreted mainly in the feces (74%) and to a lesser extent in the urine (8%).
Following oral administration of 80 mcg of radiolabeled formoterol fumarate to 2 healthy subjects, 59% to 62% of the radioactivity was eliminated in the urine and 32% to 34% in the feces over a period of 104 hours. In an oral inhalation study with ZENHALE, renal clearance of formoterol from the blood was 217 mL/min. Following single inhaled doses of formoterol ranging from 10 to 40 mcg from ZENHALE, 6.2% to 6.8% of the formoterol dose was excreted in urine unchanged.
Pediatrics: The pharmacokinetics of ZENHALE has not been specifically studied in children below 5 years of age.
Geriatrics: The pharmacokinetics of ZENHALE has not been specifically studied in the elderly population.
Gender: Studies to examine the effects of gender on the pharmacokinetics of ZENHALE have not been specifically conducted.
Based on analysis of single and multiple dose pharmacokinetics studies, no effect of gender on mometasone furoate and formoterol exposure was observed.
Race: Studies to examine the effects of race on the pharmacokinetics of ZENHALE have not been specifically conducted.
Hepatic Insufficiency: The pharmacokinetics of ZENHALE has not been specifically studied in patients with hepatic impairment. Concentrations of mometasone furoate appear to increase with severity of hepatic impairment. These increases are not considered to be clinically significant.
A study evaluating the administration of a single inhaled dose of 400 mcg mometasone furoate by a dry powder inhaler to subjects with mild (n=4), moderate (n=4), and severe (n=4) hepatic impairment resulted in only 1 or 2 subjects in each group having detectable peak plasma concentrations of mometasone furoate (ranging from 50-105 pg/mL). The observed peak plasma concentrations appear to increase with severity of hepatic impairment; however, the numbers of detectable levels were few.
Renal Insufficiency: The pharmacokinetics of ZENHALE has not been specifically studied in patients with renal impairment.
Non-clinical pharmacology studies were conducted for both individual active products. The results of the nonclinical studies did not identify any unique toxicities with the ZENHALE combination or any indication of pharmacodynamic interactions. The findings were consistent with the individual components.
Clinical Pharmacokinetic and Pharmacodynamic studies for the mometasone furoate/formoterol metered dose inhaler indicate the data for the monocomponent dry powder inhaler formulations are relevant to the understanding of the performance of the combination product, and thus to its safety and efficacy. ZENHALE when administered from the metered dose inhaler (MDI) was safe and well tolerated with no new safety issues or adverse events identified when compared to the monocomponents.
A single-dose, cross over study in healthy subjects (P03658) confirmed that no significant pharmacokinetic interaction occurs between mometasone furoate and formoterol when coadministered via the metered dose inhaler. See ACTION AND CLINICAL PHARMACOLOGY for more detailed information.
Systemic Safety: In a single dose, double blind placebo controlled crossover study in 25 patients with asthma, single dose treatment of 10 mcg formoterol fumarate in combination with 100 mcg or 400 mcg of mometasone furoate delivered via ZENHALE 50/5 or 200/5 were compared to formoterol fumarate 10 mcg MDI, formoterol fumarate 12 mcg dry powder inhaler (DPI; nominal dose of formoterol fumarate delivered 10 mcg), or placebo. The degree of bronchodilation at 12 hours after dosing with ZENHALE was similar to formoterol fumarate delivered alone via MDI or DPI.
ECGs and blood samples for glucose and potassium were obtained prior to dosing and post dose. No downward trend in serum potassium was observed and values were within the normal range and appeared to be similar across all treatments over the 12 hour period. Mean blood glucose appeared similar across all groups for each time point and no changes were of clinical concern. There was no evidence of significant hypokalemia or hyperglycemia in response to formoterol treatment.
No relevant changes in heart rate during the study were observed with ZENHALE. No patients had a QTcB (QTc corrected by Bazett’s formula) ≥500 msec during treatment. There were no other clinically significant abnormalities or changes in ECG data.
In a single dose crossover study involving 24 healthy subjects, single dose of formoterol fumarate 10, 20, or 40 mcg in combination with 400 mcg of mometasone furoate delivered via ZENHALE were evaluated for safety (ECG, blood potassium and glucose changes). ECGs and blood samples for glucose and potassium were obtained at baseline and post dose. Decrease in mean serum potassium was similar across all three treatment groups (approximately 0.3 mmol/L) and values were within the normal range. No relevant trends towards an increase in mean blood glucose values were observed. No relevant changes in heart rate during the study were observed with ZENHALE. No subjects had a QTcB >500 msec during treatment.
Five active- and placebo-controlled studies (study duration ranging from 12, 26, and 52 weeks) evaluated 3381 patients 12 years of age and older with asthma. No clinically meaningful changes were observed in potassium and glucose values in patients receiving ZENHALE. The effects of ZENHALE on heart/pulse rate and blood pressure was comparable to that of the individua l component mometasone furoate and formoterol fumarate. No changes in vital signs and ECG parameters suggesting a treatment effect were observed and no clinically significant ECG abnormalities were reported in patients receiving ZENHALE.
HPA-axis effects (Adults): The effects of inhaled mometasone furoate administered via ZENHALE on adrenal function were evaluated in two clinical studies in patients with asthma. HPA-axis function was assessed by 24-hour plasma cortisol AUC. Although both these trials have open-label design and contain a small number of subjects per treatment arm, results from these trials taken together demonstrated suppression of 24-hour plasma cortisol AUC for ZENHALE 200 mcg/5 mcg compared to placebo consistent with the known systemic effects of inhaled corticosteroids.
In a 42-day, open-label, placebo and active-controlled study 60 patients with asthma 18 years of age and older were randomized to receive two inhalations twice daily of 1 of the following treatments: ZENHALE 100/5, ZENHALE 200/5, fluticasone propionate/salmeterol xinafoate 250 mcg/25 mcg, or placebo. At Day 42, the mean change from baseline plasma cortisol AUC was 8%, 22% and 34% lower compared to placebo for the ZENHALE 100/5 (n=13), ZENHALE 200/5 (n=15) and fluticasone propionate/salmeterol xinafoate 250 mcg/25 mcg (n=16) treatment groups, respectively.
In a 52-week safety study, primary analysis of the plasma cortisol 24-hour AUC was performed on 57 patients with asthma who received 2 inhalations twice daily of ZENHALE 100/5, ZENHALE 200/5, fluticasone propionate/salmeterol 125/25, or fluticasone propionate/salmeterol 250/25. At Week 52, the mean plasma cortisol AUC was 2.2%, 29.6%, 16.7%, and 32.2% lower from baseline for the ZENHALE 100/5 (n=18), ZENHALE 200/5 (n=20), fluticasone propionate/salmeterol 125/25 (n=8), and fluticasone propionate/salmeterol 250/25 (n=11) treatment groups, respectively.
HPA-axis effects (Pediatrics): The effects of mometasone furoate via a DPI on adrenal function in the pediatric population were assessed in one randomized, double-blind, placebo-controlled, parallel-group clinical trial with mometasone furoate via a DPI administered at doses of 100 mcg twice daily, 200 mcg twice daily, 400 mcg twice daily over 29 days to 50 pediatric patients with asthma aged 6 to 11 years of age. HPA-axis function was assessed by 12-hour plasma cortisol AUC and 24-hour urinary-free cortisol concentrations. The mean differences from placebo (n=7) in the groups treated with mometasone furoate via a DPI 100 mcg twice daily (n=12), 200 mcg twice daily (n=12) and 400 mcg twice daily (n=11) were 3.4 mcg mcg•hr/dL, -16.0 mcg•hr/dL, and -17.9 mcg•hr/dL, respectively.
The toxicity observed in animal studies with mometasone furoate and formoterol fumarate, given in combination as ZENHALE or separately, were effects associated with exaggerated pharmacological activity.
Toxicity Studies:
| Species | Route of Administration | ZENHALE Dose Ratio | Duration |
|---|---|---|---|
| Rats | Inhalation | 50:5 and 200:5 | 2 weeks and 13 weeks |
| Dogs | Inhalation | 50:5 and 200:5 | 2 weeks and 13 weeks |
In 2- and 13-week inhalation toxicity studies conducted in rats and dogs using formulations containing ratios of 50:5 and 200:5 mometasone furoate:formoterol fumarate dihydrate, all findings were consistent with toxicities that would be expected with the individual active drugs. No new or additive toxicities were observed. No pharmacokinetic interactions were observed after co-administration of mometasone furoate and formoterol fumarate.
ZENHALE contains both mometasone furoate and formoterol fumarate; therefore, the mutagenicity, carcinogenicity and reproductive toxicity information of the individual components described below apply to ZENHALE.
Specific mutagenicity, carcinogenicity, and reproduction toxicity studies have not been conducted with ZENHALE.
Mometasone furoate was non-mutagenic in the mouse-lymphoma assay and the Salmonella/E. coli/mammalian microsome mutagenicity bioassay. At cytotoxic doses only, mometasone furoate produced an increase in chromosome aberrations in vitro in Chinese hamster ovary cell (CHO) cultures in the non-activation phase, but not in the presence of rat liver S9 fraction. However, mometasone furoate did not induce chromosomal aberrations in vitro in a Chinese hamster lung cell (CHL) chromosomal-aberrations assay, or in vivo in the mouse bone marrow erythrocyte-micronucleus assay, in the rat bone-marrow clastogenicity assay, and the mouse male germ-cell clastogenicity assay. Mometasone furoate also did not induce unscheduled DNA synthesis in vivo in rat hepatocytes. The finding of simple chromosomal aberrations in the non-activation phase of the CHO assay is considered to be related to cytotoxicity and is not considered to be of significance in the risk assessment of mometasone furoate because of the negative results in the S9 phase of this assay, the negative results in a second in vitro chromal aberrations assay (CHL assay), and the negative results in three in vivo chromosomal aberrations assays.
Mutagenicity tests covering a broad range of experimental endpoints have been conducted. No genotoxic effects were found in any of the in vitro or in vivo tests performed.
In a 2-year carcinogenicity study in Sprague Dawley rats, mometasone furoate demonstrated no statistically significant increase in the incidence of tumours at inhalation doses up to 67 mcg/kg (approximately 8 times the maximum recommended daily inhalation dose in adults on an AUC basis and 2 times the maximum recommended daily inhalation dose in pediatric patients based on a mcg/m² bases). In a 19-month carcinogenicity study in Swiss CD-1 mice, mometasone furoate demonstrated no statistically significant increase in the incidence of tumours at inhalation doses up to 160 mcg/kg (approximately 10 times the maximum recommended daily inhalation dose in adults on an AUC basis and 2 times the maximum recommended daily inhalation dose in pediatrics patients base on a mcg/m² bases).
On the basis of these findings and the absence of a mutagenic potential, it is concluded that use of mometasone furoate at therapeutic doses does not present a carcinogenic risk.
Two-year studies in rats and mice did not show any carcinogenic potential.
Male mice treated at very high dose levels showed a slightly higher incidence of benign adrenal subcapsular cell tumours. However, this finding was not seen in a second mouse feeding study, in which pathological changes at high doses consisted of an increased incidence both of benign smooth muscle tumours in the female genital tract, and of liver tumours in both sexes. Smooth muscle tumours are a known effect of beta-agonists given at high doses in rodents.
Two studies in rats, covering different dose ranges, showed an increase in mesovarial leiomyomas. These benign neoplasms are typically associated with long-term treatment of rats at high doses of beta2-adrenergic drugs. Increased incidences of ovarian cysts and benign granulosa/theca cell tumours were also seen; beta-agonists are known to have effects on the ovary in rats which are very likely specific to rodents. A few other tumour types noted in the first study using the higher doses were within the incidences of the historical control population, and were not seen in the lower-dose experiment.
None of the tumor incidences were increased to a statistically significant extent at the lowest dose of the second rat study, a dose leading to a systemic exposure 10 times higher than that expected from the maximum recommended dose of formoterol in humans.
In studies of reproductive function, subcutaneous mometasone furoate was well tolerated at doses up to 7.5 mcg/kg. At 15 mcg/kg, mometasone furoate caused prolonged gestation and prolonged and difficult labor occurred with a reduction in offspring survival and body weight or body weight gain. There was no effect on fertility.
Reproduction studies in rats revealed no impairment of fertility at oral doses up to 3 mg/kg (approximately 1000 times the maximum recommended daily inhalation dose in humans on a mg/m² basis).
Like other glucocorticoids, mometasone furoate is a teratogen in rodents and rabbits. Teratology studies were conducted in rats, mice and rabbits by the oral, topical, and/or subcutaneous routes. Effects noted were umbilical hernia in rats, cleft palate in mice, and gall bladder agenesis, umbilical hernia, and flexed front paws in rabbits. There were also reductions in maternal body weight gains, effects on fetal growth (lower fetal body weight and/or delayed ossification) in rats, rabbits and mice, and reduced offspring survival in mice.
In an oral teratology study in rabbits, at 700 mcg/kg, increased incidences of resorption and malformation, including cleft palate and/or malformation (hydrocephaly or domed head) were observed. Pregnancy failure was observed in most rabbits at 2800 mcg /kg.
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