Zenheyl

Treatment Of Asthma

Zenheyl is indicated for the treatment of asthma in patients 12 years of age and older.

Long-acting beta2-adrenergic agonists, such as formoterol, one of the active ingredients in Zenheyl, increase the risk of asthma-related death. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Therefore, when treating patients with asthma, Zenheyl should only be used for patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue Zenheyl) if possible without loss of asthma control, and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use Zenheyl for patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids.

Important Limitation Of Use

• Zenheyl is NOT indicated for the relief of acute bronchospasm.

Administration Information

Zenheyl should be administered as two inhalations twice daily every day (morning and evening) by the orally inhaled route (see Patient Instructions for Use in the Medication Guide). Shake well prior to each inhalation. After each dose, the patient should be advised to rinse his/her mouth with water without swallowing.

The cap from the mouthpiece of the actuator should be removed before using Zenheyl.

Zenheyl should be primed before using for the first time by releasing 4 test sprays into the air, away from the face, shaking well before each spray. In cases where the inhaler has not been used for more than 5 days, prime the inhaler again by releasing 4 test sprays into the air, away from the face, shaking well before each spray.

The Zenheyl canister should only be used with the Zenheyl actuator. The Zenheyl actuator should not be used with any other inhalation drug product. Actuators from other products should not be used with the Zenheyl canister.

Recommended Dosage

Adults And Adolescents 12 Years Of Age And Older

The dosage is either 2 inhalations twice daily of Zenheyl 100 mcg/5 mcg or Zenheyl 200 mcg/5 mcg. The maximum recommended dosage is two inhalations of Zenheyl 200 mcg/5 mcg twice daily (maximum daily dosage 800 mcg/20 mcg).

When choosing the starting dosage strength of Zenheyl, consider the patients' disease severity, based on their previous asthma therapy, including the inhaled corticosteroid dosage, as well as the patients' current control of asthma symptoms and risk of future exacerbation.

The maximum benefit may not be achieved for 1 week or longer after beginning treatment. Individual patients may experience a variable time to onset and degree of symptom relief. For patients who do not respond adequately after 2 weeks of therapy with two inhalations of Zenheyl 100 mcg/5 mcg twice daily (morning and evening), increasing the dosage to two inhalations of Zenheyl 200 mcg/5 mcg twice daily (morning and evening) may provide additional asthma control.

Do not use more than two inhalations twice daily of the prescribed strength of Zenheyl as some patients are more likely to experience adverse effects with higher doses of formoterol. If symptoms arise between doses, an inhaled short-acting beta2-agonist should be taken for immediate relief.

If a previously effective dosage regimen of Zenheyl fails to provide adequate control of asthma, the therapeutic regimen should be re-evaluated and additional therapeutic options, e.g., replacing the current strength of Zenheyl with a higher strength, adding additional inhaled corticosteroid, or initiating oral corticosteroids, should be considered.

Status Asthmaticus

Zenheyl is contraindicated in the primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required.

Hypersensitivity

Zenheyl is contraindicated in patients with known hypersensitivity to mometasone furoate, formoterol fumarate, or any of the ingredients in Zenheyl.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Asthma-Related Death

Long-acting beta₂-adrenergic agonists, such as formoterol, one of the active ingredients in Zenheyl, increase the risk of asthma-related death. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Therefore, when treating patients with asthma, physicians should only prescribe Zenheyl for patients with asthma not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue Zenheyl) if possible without loss of asthma control, and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use Zenheyl for patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids.

A 28-week, placebo-controlled US study comparing the safety of salmeterol with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in patients receiving salmeterol (13/13,176 in patients treated with salmeterol vs. 3/13,179 in patients treated with placebo; RR 4.37, 95% CI 1.25, 15.34). This finding with salmeterol is considered a class effect of the LABAs, including formoterol, one of the active ingredients in Zenheyl. No study adequate to determine whether the rate of asthma-related death is increased with Zenheyl has been conducted.

Clinical studies with formoterol suggested a higher incidence of serious asthma exacerbations in patients who received formoterol fumarate than in those who received placebo. The sizes of these studies were not adequate to precisely quantify the differences in serious asthma exacerbation rates between treatment groups.

Deterioration Of Disease And Acute Episodes

Zenheyl should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of asthma. Zenheyl has not been studied in patients with acutely deteriorating asthma. The initiation of Zenheyl 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 re-evaluation with reassessment of the treatment regimen, giving special consideration to the possible need for replacing the current strength of Zenheyl with a higher strength, adding additional inhaled corticosteroid, or initiating systemic corticosteroids. Patients should not use more than 2 inhalations twice daily (morning and evening) of Zenheyl.

Zenheyl is not indicated for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. An inhaled, short-acting beta₂-agonist, not Zenheyl, should be used to relieve acute symptoms such as shortness of breath. When prescribing Zenheyl, the physician must also provide the patient with an inhaled, short-acting beta₂-agonist (e.g., albuterol) for treatment of acute symptoms, despite regular twice-daily (morning and evening) use of Zenheyl.

When beginning treatment with Zenheyl, 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.

Excessive Use Of Zenheyl And Use With Other Long-Acting Beta₂-Agonists

As with other inhaled drugs containing beta₂-adrenergic agents, Zenheyl should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medications containing long-acting beta₂-agonists, 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 Zenheyl should not use an additional long-acting beta₂-agonist (e.g., salmeterol, formoterol fumarate, arformoterol tartrate) for any reason, including prevention of exercise-induced bronchospasm (EIB) or the treatment of asthma.

Local Effects

In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans have occurred in patients treated with Zenheyl. If oropharyngeal candidiasis develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while remaining on treatment with Zenheyl therapy, but at times therapy with Zenheyl may need to be interrupted. Advise patients to rinse the mouth after inhalation of Zenheyl.

Immunosuppression

Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals.

Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In such children or adults who have not had these diseases or who are not properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG) may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered.

Zenheyl should be used with caution, if at all, in patients with active or quiescent tuberculosis infection of the respiratory tract, untreated systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.

Transferring Patients From Systemic Corticosteroid Therapy

Particular care is needed for patients who are transferred from systemically active corticosteroids to Zenheyl because deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-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 Zenheyl may improve control of asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of corticosteroid systemically and does NOT provide the mineralocorticoid activity necessary for coping with these emergencies.

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

Patients requiring systemic corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to Zenheyl. Lung function (FEV₁ or PEF), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of systemic corticosteroids. In addition to monitoring asthma signs and symptoms, patients should be observed for signs and symptoms of adrenal insufficiency such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension.

Transfer of patients from systemic corticosteroid therapy to Zenheyl may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy, e.g., rhinitis, conjunctivitis, eczema, arthritis, and eosinophilic conditions.

During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal, e.g., joint and/or muscular pain, lassitude, and depression, despite maintenance or even improvement of respiratory function.

Hypercorticism And Adrenal Suppression

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

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

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

Drug Interactions With Strong Cytochrome P450 3A4 Inhibitors

Caution should be exercised when considering the coadministration of Zenheyl 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 mometasone furoate may occur.

Paradoxical Bronchospasm And Upper Airway Symptoms

Zenheyl may produce inhalation induced bronchospasm with an immediate increase in wheezing after dosing that may be life-threatening. If inhalation induced bronchospasm occurs, it should be treated immediately with an inhaled, short-acting bronchodilator. Zenheyl should be discontinued immediately and alternative therapy instituted.

Immediate Hypersensitivity Reactions

Immediate hypersensitivity reactions may occur after administration of Zenheyl, as demonstrated by cases of urticaria, flushing, allergic dermatitis, and bronchospasm.

Cardiovascular And Central Nervous System Effects

Excessive beta-adrenergic stimulation has been associated with seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, palpitation, nausea, dizziness, fatigue, malaise, and insomnia. Therefore, Zenheyl should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Formoterol fumarate, a component of Zenheyl, can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of Zenheyl at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce ECG changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.

Reduction In Bone Mineral Density

Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids, including mometasone furoate, one of the components of Zenheyl. The clinical significance of small changes in BMD with regard to long-term outcomes, such as fracture, is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants and corticosteroids) should be monitored and treated with established standards of care.

In a 2-year double-blind study in 103 male and female asthma patients 18 to 50 years of age previously maintained on bronchodilator therapy (Baseline FEV₁ 85%-88% predicted), treatment with mometasone furoate dry powder inhaler 200 mcg twice daily resulted in significant reductions in lumbar spine (LS) BMD at the end of the treatment period compared to placebo. The mean change from Baseline to Endpoint in the lumbar spine BMD was -0.015 (-1.43%) for the mometasone furoate group compared to 0.002 (0.25%) for the placebo group. In another 2-year double-blind study in 87 male and female asthma patients 18 to 50 years of age previously maintained on bronchodilator therapy (Baseline FEV₁ 82%-83% predicted), treatment with mometasone furoate 400 mcg twice daily demonstrated no statistically significant changes in lumbar spine BMD at the end of the treatment period compared to placebo. The mean change from Baseline to Endpoint in the lumbar spine BMD was -0.018 (-1.57%) for the mometasone furoate group compared to -0.006 (-0.43%) for the placebo group.

Effect On Growth

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

Glaucoma And Cataracts

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

Coexisting Conditions

Zenheyl, like other medications containing sympathomimetic amines, should be used with caution in patients with aneurysm, pheochromocytoma, convulsive disorders, or thyrotoxicosis; and in patients who are unusually responsive to sympathomimetic amines. Doses of the related beta₂-agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.

Hypokalemia And Hyperglycemia

Beta₂-agonist medications may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. Clinically significant changes in blood glucose and/or serum potassium were seen infrequently during clinical studies with Zenheyl at recommended doses.

Patient Counseling Information

See FDA-Approved Patient Labeling (Medication Guide).

Asthma-Related Death

Patients should be informed that formoterol, one of the active ingredients in Zenheyl, increases the risk of asthma-related death. In pediatric and adolescent patients, formoterol may increase the risk of asthma-related hospitalization. They should also be informed that data are not adequate to determine whether the concurrent use of inhaled corticosteroids, the other component of Zenheyl, or other long-term asthma-control therapy mitigates or eliminates this risk.

Not For Acute Symptoms

Zenheyl is not indicated to relieve acute asthma symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting, beta₂-agonist (the health care provider should prescribe the patient with such medication and instruct the patient in how it should be used).

Patients should be instructed to seek medical attention immediately if they experience any of the following:

• If their symptoms worsen
• Significant decrease in lung function as outlined by the physician
• If they need more inhalations of a short-acting beta₂-agonist than usual

Patients should be advised not to increase the dose or frequency of Zenheyl. The daily dosage of Zenheyl should not exceed two inhalations twice daily. If they miss a dose, they should be instructed to take their next dose at the same time they normally do. Zenheyl provides bronchodilation for up to 12 hours.

Patients should not stop or reduce Zenheyl therapy without physician/provider guidance since symptoms may recur after discontinuation.

Do Not Use Additional Long-Acting Beta₂-Agonists

When patients are prescribed Zenheyl, other long-acting beta₂-agonists should not be used.

Risks Associated With Corticosteroid Therapy

Local Effects: Patients should be advised that localized infections with Candida albicans occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while still continuing with Zenheyl therapy, but at times therapy with Zenheyl may need to be temporarily interrupted under close medical supervision. Rinsing the mouth after inhalation is advised.

Immunosuppression: Patients who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles and, if exposed, to consult their physician without delay. Patients should be informed of potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex.

Hypercorticism and Adrenal Suppression: Patients should be advised that Zenheyl may cause systemic corticosteroid effects of hypercorticism and adrenal suppression. Additionally, patients should be instructed that deaths due to adrenal insufficiency have occurred during and after transfer from systemic corticosteroids. Patients should taper slowly from systemic corticosteroids if transferring to Zenheyl.

Reduction in Bone Mineral Density: Patients who are at an increased risk for decreased BMD should be advised that the use of corticosteroids may pose an additional risk and should be monitored and, where appropriate, be treated for this condition.

Reduced Growth Velocity: Patients should be informed that orally inhaled corticosteroids, a component of Zenheyl, may cause a reduction in growth velocity when administered to pediatric patients. Physicians should closely follow the growth of pediatric patients taking corticosteroids by any route.

Glaucoma and Cataracts: Long-term use of inhaled corticosteroids may increase the risk of some eye problems (glaucoma or cataracts); regular eye examinations should be considered.

Risks Associated With Beta-Agonist Therapy

Patients should be informed that treatment with beta₂-agonists may lead to adverse events which include palpitations, chest pain, rapid heart rate, tremor or nervousness.

Instructions For Use

Patients should be instructed regarding the following:

• Read the Medication Guide before use and follow the Instructions for Use carefully.
• Patients should be reminded to:
  • Remove the cap from the mouthpiece of the actuator before use.
  • Not remove the canister from the actuator.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Mometasone furoate: In a 2-year carcinogenicity study in Sprague Dawley® rats, mometasone furoate demonstrated no statistically significant increase in the incidence of tumors at inhalation doses up to 67 mcg/kg (approximately 14 times the MRHD on an AUC basis). In a 19-month carcinogenicity study in Swiss CD-1 mice, mometasone furoate demonstrated no statistically significant increase in the incidence of tumors at inhalation doses up to 160 mcg/kg (approximately 9 times the MRHD on an AUC basis).

Mometasone furoate increased chromosomal aberrations in an in vitro Chinese hamster ovary cell assay, but did not have this effect in an in vitro Chinese hamster lung cell assay. Mometasone furoate was not mutagenic in the Ames test or mouse lymphoma assay, and was not clastogenic in an in vivo mouse micronucleus assay, a rat bone marrow chromosomal aberration assay, or a mouse male germ-cell chromosomal aberration assay. Mometasone furoate also did not induce unscheduled DNA synthesis in vivo in rat hepatocytes.

In reproductive studies in rats, impairment of fertility was not produced by subcutaneous doses up to 15 mcg/kg (approximately 8 times the MRHD on an AUC basis).

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 265 times human exposure at the MRHD). 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 27 times human exposure at the MRHD). 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 350 times human exposure at the MRHD) 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 35 times human exposure at the MRHD). 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 14 times human exposure at the MRHD). 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.

Reproduction studies in rats revealed no impairment of fertility at oral doses up to 3 mg/kg (approximately 1200 times the MRHD on a mcg/m² basis).

Use In Specific Populations

Pregnancy

Zenheyl: Teratogenic Effects

Pregnancy Category C

There are no adequate and well-controlled studies of Zenheyl, mometasone furoate only or formoterol fumarate only in pregnant women. Animal reproduction studies of mometasone furoate and formoterol in mice, rats, and/or rabbits revealed evidence of  teratogenicity as well as other developmental toxic effects. Because animal reproduction studies are not always predictive of human response, Zenheyl should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Mometasone Furoate: Teratogenic Effects

When administered to pregnant mice, rats, and rabbits, mometasone furoate increased fetal malformations and decreased fetal growth (measured by lower fetal weights and/or delayed ossification). Dystocia and related complications were also observed when mometasone furoate was administered to rats late in gestation. However, experience with oral corticosteroids suggests that rodents are more prone to teratogenic effects from corticosteroid exposure than humans.

In a mouse reproduction study, subcutaneous mometasone furoate produced cleft palate at approximately one-third of the maximum recommended daily human dose (MRHD) on a mcg/m² basis and decreased fetal survival at approximately 1 time the MRHD. No toxicity was observed at approximately one-tenth of the MRHD on a mcg/m² basis.

In a rat reproduction study, mometasone furoate produced umbilical hernia at topical dermal doses approximately 6 times the MRHD on a mcg/m² basis and delays in ossification at approximately 3 times the MRHD on a mcg/m² basis.

In another study, rats received subcutaneous doses of mometasone furoate throughout pregnancy or late in gestation. Treated animals had prolonged and difficult labor, fewer live births, lower birth weight, and reduced early pup survival at a dose that was approximately 8 times the MRHD on an area under the curve (AUC) basis. Similar effects were not observed at approximately 4 times MRHD on an AUC basis.

In rabbits, mometasone furoate caused multiple malformations (e.g., flexed front paws, gallbladder agenesis, umbilical hernia, hydrocephaly) at topical dermal doses approximately 3 times the MRHD on a mcg/m² basis. In an oral study, mometasone furoate increased resorptions and caused cleft palate and/or head malformations (hydrocephaly and domed head) at a dose less than the MRHD based on AUC. At a dose approximately 2 times the MRHD based on AUC, most litters were aborted or resorbed.

Nonteratogenic Effects

Hypoadrenalism may occur in infants born to women receiving corticosteroids during pregnancy. Infants born to mothers taking substantial corticosteroid doses during pregnancy should be monitored for signs of hypoadrenalism.

Formoterol Fumarate: Teratogenic Effects

Formoterol fumarate administered throughout organogenesis did not cause malformations in rats or rabbits following oral administration. When given to rats throughout organogenesis, oral doses of approximately 80 times the MRHD on a mcg/m² basis and above delayed ossification of the fetus, and doses of approximately 2400 times the MRHD on a mcg/m² basis and above decreased fetal weight. Formoterol fumarate has been shown to cause stillbirth and neonatal mortality at oral doses of approximately 2400 times the MRHD on a mcg/m² basis and above in rats receiving the drug during the late stage of pregnancy. These effects, however, were not produced at a dose of approximately 80 times the MRHD on a mcg/m² basis.

In another testing laboratory, formoterol was shown to be teratogenic in rats and rabbits. Umbilical hernia, a malformation, was observed in rat fetuses at oral doses approximately 1200 times and greater than the MRHD on a mcg/m² basis. Brachygnathia, a skeletal malformation, was observed in rat fetuses at an oral dose approximately 6100 times the MRHD on a mcg/m² basis. In another study in rats, no teratogenic effects were seen at inhalation doses up to approximately 500 times the MRHD on a mcg/m² basis. Subcapsular cysts on the liver were observed in rabbit fetuses at an oral dose approximately 49,000 times the MRHD on a mcg/m² basis. No teratogenic effects were observed at oral doses up to approximately 3000 times the MRHD on a mcg/m² basis.

Labor And Delivery

There are no adequate and well-controlled human studies that have studied the effects of Zenheyl during labor and delivery.

Because beta-agonists may potentially interfere with uterine contractility, Zenheyl should be used during labor only if the potential benefit justifies the potential risk.

Nursing Mothers

Zenheyl: It is not known whether Zenheyl is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Zenheyl is administered to a nursing woman.

Since there are no data from well-controlled human studies on the use of Zenheyl on nursing mothers, based on data for the individual components, a decision should be made whether to discontinue nursing or to discontinue Zenheyl, taking into account the importance of Zenheyl to the mother. 

Mometasone Furoate: It is not known if mometasone furoate is excreted in human milk. However, other corticosteroids are excreted in human milk.

Formoterol Fumarate: In reproductive studies in rats, formoterol was excreted in the milk. It is not known whether formoterol is excreted in human milk.

Pediatric Use

The safety and effectiveness of Zenheyl have been established in patients 12 years of age and older in 3 clinical trials up to 52 weeks in duration. In the 3 clinical trials, 101 patients 12 to 17 years of age were treated with Zenheyl. Patients in this age-group demonstrated efficacy results similar to those observed in patients 18 years of age and older. There were no obvious differences in the type or frequency of adverse drug reactions reported in this age group compared to patients 18 years of age and older. Similar efficacy and safety results were observed in an additional 22 patients 12 to 17 years of age who were treated with Zenheyl in another clinical trial. The safety and efficacy of Zenheyl have not been established in children less than 12 years of age.

Controlled clinical studies have shown that inhaled corticosteroids may cause a reduction in growth velocity in pediatric patients. In these studies, the mean reduction in growth velocity was approximately 1 cm per year (range 0.3 to 1.8 per year) and appears to depend upon dose and duration of exposure. This effect was observed in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The long-term effects of this reduction in growth velocity associated with orally inhaled corticosteroids, including the impact on final adult height, are unknown. The potential for “catch up” growth following discontinuation of treatment with orally inhaled corticosteroids has not been adequately studied.

The growth of children and adolescents receiving orally inhaled corticosteroids, including Zenheyl, should be monitored routinely (e.g., v

LABA kullanımı aşağıdakilerle sonuçlanabilir:

• Astımla ilgili ciddi olaylar - hastaneye yatışlar, entübasyonlar ve ölüm.
• Kardiyovasküler ve merkezi sinir sistemi etkileri.

Sistemik ve lokal kortikosteroid kullanımı aşağıdakilerle sonuçlanabilir:

• Candida albicans enfeksiyon
• İmmünsüpresyon
• Hiperkortikizm ve adrenal baskılama
• Pediatride büyüme etkileri
• Glokom ve katarakt

Klinik araştırmalar çok çeşitli koşullar altında yapıldığından, bir ilacın klinik çalışmalarında gözlenen advers reaksiyon oranları, başka bir ilacın klinik çalışmalarındaki oranlarla doğrudan karşılaştırılamaz ve uygulamada gözlemlenen oranları yansıtmayabilir.

Klinik Araştırmalar Deneyimi

Aşağıda açıklanan güvenlik verileri, 12 ila 26 hafta boyunca Zenheyl'e maruz kalan 679 hasta ve 1 yıl maruz kalan 271 hasta dahil olmak üzere 12 yaş ve üstü astımı olan 1913 hastayı randomize eden 3 klinik çalışmaya dayanmaktadır. Zenheyl iki plasebo ve aktif kontrollü çalışmada (sırasıyla n = 781 ve n = 728) ve uzun süreli 52 haftalık güvenlik çalışmasında (n = 404) çalışıldı. 12 ila 26 haftalık klinik çalışmalarda, popülasyon 12 ila 84 yaş,% 41 erkek ve% 59 kadın,% 73 Kafkasyalı,% 27 Kafkasyalı değildi. Hastalara günde iki kez Zenheyl (100 mcg / 5 mcg veya 200 mcg / 5 mcg), mometazon furoat MDI (100 mcg veya 200 mcg), formoterol MDI (5 mcg) veya plasebo verildi. Uzun süreli 52 haftalık aktif karşılaştırıcı güvenlik çalışmasında, nüfus astım,% 37 erkek ve% 63 kadın,% 47 Kafkasyalı,% 53 Kafkasyalı olmayan ve günde iki kez iki inhalasyon alan 12 ila 75 yaş arasındaydı. Zenheyl 100 mcg / 5 mcg veya 200 mcg / 5 mc.

Aşağıdaki Tablo 2'de Zenheyl ile ilişkili ortaya çıkan advers reaksiyonların görülme sıklığı, günde iki kez Zenheyl ile iki inhalasyon ile tedavi edilen 12 yaş ve üstü hastalarda 12 ila 26 hafta süren 2 klinik çalışmadan toplanan verilere dayanmaktadır (100 mcg / 5 mcg veya 200 mcg / 5 mcg) mometazon furoat MDI (100 mcg veya 200 mcg) formoterol MDI (5mcg) veya plasebo.

Tablo 2: Zenheyl Gruplarında Plasebodan% ≥3 ve Daha Yaygın Bir İnsidansta Meydana Gelen Tedaviye Bağlı Olumsuz Reaksiyonlar

Klinik çalışmalarda, Zenheyl 100 mcg / 5 mcg kullanan hastalarda% 0.7, Zenheyl 200 mcg / 5 mcg kullanan hastalarda% 0.8 ve plasebo grubunda% 0.5 oranında oral kandidiyaz bildirilmiştir.

Uzun Süreli Klinik Araştırma Deneyimi

Zenheyl 100 mcg / 5 mcg (n = 141), Zenheyl 200 mcg / 5 mcg (n = 130) veya aktif karşılaştırıcı (n = 133) ile 52 hafta tedavi edilen 12 yaş ve üstü hastalarda yapılan uzun süreli bir güvenlik çalışmasında genel olarak güvenlik sonuçları, daha kısa 12 ila 2 arasında gözlenenlere benzerdi. Astıma bağlı ölüm gözlenmedi. Zenheyl 100 mcg / 5 mcg alan 7/141 (% 5) hasta ve Zenheyl 200 mcg / 5 mcg alan 5/130 (% 3.8) hasta insidansında bildirilen uzun süreli tedavi çalışmasında disfoni daha yüksek sıklıkta gözlenmiştir. Kan kimyası, hematoloji veya EKG'de klinik olarak anlamlı bir değişiklik gözlenmedi.

Pazarlama Sonrası Deneyim

Zenheyl'in onay sonrası kullanımı veya inhale mometazon furoat veya inhale formoterol fumarat ile onay sonrası kullanım sırasında aşağıdaki advers reaksiyonlar bildirilmiştir. Bu reaksiyonlar, belirsiz büyüklükteki bir popülasyondan gönüllü olarak bildirildiğinden, sıklıklarını güvenilir bir şekilde tahmin etmek veya ilaca maruz kalma ile nedensel bir ilişki kurmak her zaman mümkün değildir.

Kardiyak bozukluklar: anjina pektoris, kardiyak aritmiler, ör.atriyal fibrilasyon, ventriküler ekstrasistoller, taşiaritmi Bağışıklık sistemi bozuklukları: anafilaktik reaksiyon, anjiyoödem, şiddetli hipotansiyon, döküntü, kaşıntı dahil olmak üzere acil ve gecikmiş aşırı duyarlılık reaksiyonları

Araştırmalar: elektrokardiyogram QT uzamış, kan basıncı artmıştır (hipertansiyon dahil)

Metabolizma ve beslenme bozuklukları: hipokalemi, hiperglisemi

Solunum, göğüs bozuklukları ve mediastinal hastalıklar: öksürük, nefes darlığı, hırıltı ve bronkospazmı içerebilen astım alevlenmesi

İşaretler ve Belirtiler

Zenheyl: Zenheyl hem mometazon furoat hem de formoterol fumarat içerir; bu nedenle, aşağıda açıklanan münferit bileşenler için doz aşımı ile ilişkili riskler Zenheyl için geçerlidir.

Mometazon Furoat: Kronik aşırı doz, hiperkortizmin belirtilerine / semptomlarına neden olabilir. İnsan gönüllüleri üzerinde 8000 mcg'ye kadar mometazon furoat tekli oral dozlar, hiçbir advers reaksiyon bildirilmemiştir.

Formoterol Fumarat: Formoterolün aşırı dozuyla beklenen belirti ve semptomlar, aşırı beta-adrenerjik stimülasyon ve / veya aşağıdaki belirti ve semptomlardan herhangi birinin ortaya çıkması veya abartılmasıdır: anjina, hipertansiyon veya hipotansiyon, taşikardi, 200 atım / dakikaya kadar oranlarda.aritmiler, sinirlilik, baş ağrısı, titreme, nöbetler, kas krampları, ağız kuruluğu, çarpıntı, bulantı, baş dönmesi, yorgunluk, halsizlik, hipokalemi, hiperglisemi ve uykusuzluk. Metabolik asidoz da ortaya çıkabilir. Kardiyak arrest ve hatta ölüm, aşırı dozda formoterol ile ilişkili olabilir.

Sıçanlarda formoterol fumaratın minimum akut ölümcül inhalasyon dozu 156 mg / kg'dır (mcg / m² bazında MRHD'nin yaklaşık 63.000 katı). Çin hamsterleri, sıçanları ve farelerindeki ortanca ölümcül oral dozlar, MRHD'nin daha da yüksek katlarını sağlar

Tedavi

Zenheyl: Doz aşımı tedavisi, uygun semptomatik ve / veya destekleyici tedavi kurumu ile birlikte Zenheyl'in kesilmesinden oluşur. Kardiyoselektif bir beta-reseptör blokerinin mantıklı kullanımı, bu tür ilaçların bronkospazm üretebileceğini akılda tutarak düşünülebilir. Diyalizin Zenheyl doz aşımı için yararlı olup olmadığını belirlemek için yeterli kanıt yoktur. Doz aşımı durumunda kardiyak izleme önerilir.

Kardiyovasküler Etkiler

Zenheyl: Tek dozda, astımı olan 25 hastada çift kör plasebo kontrollü çapraz çalışma, Zenheyl 200 mcg / 5 mcg yoluyla verilen 400 mcg mometazon furoat ile kombinasyon halinde 10 mcg formoterol fumaratın tek doz tedavisi, formoterol fumarat 10 mcg MDI ile karşılaştırıldı, formoterol fumarat 12 mcg kuru toz inhaleri (DPI; 10 mcg verilen formoterol fumaratın nominal dozu) veya plasebo. Zenheyl ile dozlamadan 12 saat sonra bronkodilasyon derecesi, MDI veya DPI yoluyla tek başına verilen formoterol fumarat ile benzerdi

Dozlamadan ve dozdan önce glikoz ve potasyum için EKG'ler ve kan örnekleri elde edildi. Serum potasyumunda düşüş eğilimi gözlenmedi ve değerler normal aralıkta idi ve 12 saatlik süre boyunca tüm tedavilerde benzer görünüyordu. Ortalama kan şekeri her zaman noktası için tüm gruplarda benzer görünüyordu. Formoterol tedavisine yanıt olarak anlamlı hipokalemi veya hiperglisemi kanıtı yoktu.

Denemede Zenheyl ile kalp atış hızında herhangi bir değişiklik veya EKG verilerinde değişiklik gözlenmedi. Hiçbir hastada tedavi sırasında QTcB (Bazett'in formülü ile düzeltilmiş QTc) ≥ 500 msn idi.

24 sağlıklı kişiyi içeren tek dozluk bir çapraz çalışmada, Zenheyl yoluyla verilen 400 mcg mometazon furoat ile kombinasyon halinde tek doz formoterol fumarat 10, 20 veya 40 mcg güvenlik açısından değerlendirildi (EKG, kan potasyum ve glikoz değişiklikleri). Başlangıçta ve doz sonrası glikoz ve potasyum için EKG'ler ve kan örnekleri elde edildi. Ortalama serum potasyumundaki azalma her üç tedavi grubunda da (yaklaşık 0.3 mmol / L) benzerdi ve değerler normal aralıktaydı. Ortalama kan şekeri değerlerinde veya kalp atış hızında klinik olarak anlamlı bir artış gözlenmemiştir. Hiçbir deneğin tedavi sırasında QTcB> 500 msn idi.

Üç aktif ve plasebo kontrollü çalışma (12, 26 ve 52 hafta arasında değişen çalışma süresi) 12 yaş ve üstü astımı olan 1913 hastayı değerlendirmiştir. Zenheyl alan hastalarda potasyum ve glikoz değerlerinde, hayati belirtilerde veya EKG parametrelerinde klinik olarak anlamlı bir değişiklik gözlenmemiştir.

HPA Eksen Etkileri

Zenheyl yoluyla uygulanan inhale mometazon furoatın adrenal fonksiyon üzerindeki etkileri astımı olan hastalarda yapılan iki klinik çalışmada değerlendirilmiştir. HPA ekseni fonksiyonu 24 saatlik plazma kortizol EAA ile değerlendirildi. Her iki çalışma da açık etiketli tasarıma sahip olmasına ve tedavi kolu başına az sayıda denek içermesine rağmen, birlikte yapılan bu çalışmaların sonuçları, inhale kortikosteroidin bilinen sistemik etkileri ile tutarlı plaseboya kıyasla Zenheyl 200 mcg / 5 mcg için 24 saatlik plazma kortizol EAA'nın baskılandığını göstermiştir.

42 günlük, açık etiketli, plasebo ve aktif kontrollü bir çalışmada, 18 yaş ve üstü astımı olan 60 hasta, aşağıdaki tedavilerin 1'inden günde iki kez iki inhalasyon alacak şekilde randomize edildi: Zenheyl 100 mcg / 5 mcg, flutikazon propionat / salmeterol ksinafoat. 42. günde, başlangıç plazma kortizol EAA (0-24 saat) ortalama değişimi, Zenheyl 100 mcg / 5 mcg (n = 13), Zenheyl 200 mcg / 5 mcg (n = 15) ve flutikazon propionat / salat.

52 haftalık açık etiketli bir güvenlik çalışmasında, günde iki kez 2 inhalasyon alan 57 astımı olan 57 hastada 100 mcg / 5 mcg, Zenheyl 200 mcg / 5 mcg, flutikazon propionat / salmeterol ksinafoat 12. 52. haftada, Zenheyl 100 mcg / 5 mcg (n = 18), Zenheyl 200 mcg / 5 mcg (n = 18), Zenheyl 200 mcg / 5 mcg (n = 20) için ortalama plazma kortaz 1 =% 2.

Diğer Mometazon Ürünleri

HPA Eksen Etkileri

Kuru toz inhaleri (DPI) yoluyla mometazon furoatın HPA ekseni üzerindeki potansiyel etkisi 29 günlük bir çalışmada değerlendirilmiştir. Hafif ila orta derecede astımı olan toplam 64 yetişkin hasta 4 tedavi grubundan birine randomize edildi: günde iki kez mometazon furoat DPI 440 mcg, günde iki kez mometazon furoat DPI 880 mcg, günde bir kez oral prednizon 10 mg veya plasebo. 29. günde 30 dakikalık Cosyntropin stimülasyon serum kortizol konsantrasyonu, günde iki kez mometazon furoat DPI 440 mcg ve günde iki kez mometazon furoat DPI 880 mcg için 23.2 mcg / dl idi, oral prednizon 10 mg grubu için 14.5 mcg / dl ve plasebo grubu için 25 mcg / dl ile karşılaştırılmıştır. Mometazon furoat DPI 880 mcg günde iki kez (önerilen maksimum dozun iki katı) ve plasebo arasındaki fark istatistiksel olarak anlamlıydı.

Emilim

Mometazon furoat: Sağlıklı Konular: DPI yoluyla verilen mometazon furoata karşı Zenheyl'den mometazon furoata sistemik maruziyetler karşılaştırıldı. Tek ve çoklu dozlarda Zenheyl'in oral solunmasının ardından, medyan Tmax değerleri 0.50 ila 4 saat arasında değişen sağlıklı kişilerde mometazon furoat emildi. Tek dozun önerilenden daha yüksek dozda Zenheyl uygulanmasını takiben (4 Zenheyl solunması 200 mcg / 5 mcg) sağlıklı kişilerde, aritmetik ortalama (CV%) Cmax ve AUC(0-12 saat) MF değerleri 67.8 idi (49) pg / mL ve 650 (51) pg • saat / mL, sırasıyla Zenheyl 800 mcg / 20 mcg'nin 5 günlük BID dozunu takiben karşılık gelen tahminler 241 idi (36) pg / mL ve 2200 (35) pg • saat / mL. İnhale edilen 100 mcg / 5 mcg dozunun 200 mcg / 5 mcg'ye çıkarılmasıyla mometazon furoata maruz kalma artmıştır. Etiketli ve etiketsiz ilacın oral dozunu kullanan çalışmalar, mometazon furoatın oral sistemik biyoyararlanımının ihmal edilebilir olduğunu göstermiştir (<% 1).

Yukarıdaki çalışma, bir DPI yoluyla mometazon furoata kıyasla Zenheyl uygulamasını takiben, 1. ve 5. günde mometazon furoata göre sırasıyla 1. ve 5. günde sistemik maruziyetin yaklaşık% 52 ve% 25 daha düşük olduğunu göstermiştir

Astım Hastaları: Tek ve çoklu dozlarda Zenheyl'in oral solunmasının ardından, medyan Tmax değerleri 1 ila 2 saat arasında değişen astım hastalarında mometazon furoat emildi. Zenheyl'in tek doz uygulanmasını takiben 400 mcg / 10 mcg, aritmetik ortalama (CV%) Cmax ve AUC(0-12 saat) MF değerleri 20 idi (88) pg / mL ve 170 (94) pg • saat / mL, sabit durumda Zenheyl 400 mcg / 10 mcg'nin BID dozunu takiben karşılık gelen tahminler 60 idi (36) pg / mL ve 577 (40) pg • saat / mL .

Formoterol fumarat: Sağlıklı Konular: Zenheyl sağlıklı deneklere uygulandığında, formoterol 0.167 ila 0.5 saat arasında değişen medyan Tmax değerleri ile emildi. Sağlıklı kişilerde Zenheyl 400 mcg / 10 mcg ile yapılan tek dozlu bir çalışmada, formoterol için aritmetik ortalama (% CV) Cmax ve AUC sırasıyla 15 (50) pmol / L ve 81 (51) pmol * h / L idi. Zenheyl'den formoterol için 10 ila 40 mcg doz aralığında, formoterole maruz kalma dozla orantılıydı.

Astım Hastaları: Astımı olan hastalara Zenheyl uygulandığında, formoterol 0.58 ila 1.97 saat arasında değişen medyan Tmax değerleri ile emildi. Astımı olan hastalarda Zenheyl 400 mcg / 10 mcg ile yapılan tek dozlu bir çalışmada, formoterol için aritmetik ortalama (CV%) Cmax ve AUC (0-12 saat) 22 (29) pmol / L ve 125 (42) pmol * h / L, sırasıyla. Zenheyl 400 mcg / 10 mcg'nin çoklu doz uygulamasını takiben, formoterol için kararlı durum aritmetik ortalaması (% CV) Cmax ve AUC (0-12 saat) 41 (59) pmol / L ve 226 (54) pmol * saat idi. / L .

Dağıtım

Mometazon furoat: İnsanlarda 1000 mcg inhale doz tritiated mometazon furoat inhalasyon tozu kullanan çalışmaya dayanarak, kırmızı kan hücrelerinde kayda değer bir mometazon furoat birikimi bulunamamıştır. İntravenöz 400 mcg'lik bir mometazon furoat dozunu takiben, plazma konsantrasyonları, ortalama kararlı durum hacmi 152 litre olan iki fazlı bir düşüş gösterdi. in vitro mometazon furoat için protein bağlanmasının% 98 ila% 99 olduğu bildirilmiştir (5 ila 500 ng / mL konsantrasyon aralığında).

Formoterol fumarat: Formoterolün insan plazma proteinlerine bağlanması in vitro 0.1 ila 100 ng / mL konsantrasyonlarında% 61 ila% 64 idi. İnsan serum albüminine bağlanma in vitro 5 ila 500 ng / mL aralığında% 31 ila% 38 idi. Plazma protein bağlanmasını değerlendirmek için kullanılan formoterol konsantrasyonları, tek bir 120 mcg dozun solunmasının ardından plazmada elde edilenlerden daha yüksekti.

Metabolizma

Mometazon furoat: Çalışmalar, mometazon furoatın, araştırılan tüm türlerin karaciğerinde öncelikle ve yaygın olarak metabolize olduğunu ve çoklu metabolitlere kapsamlı metabolizmaya maruz kaldığını göstermiştir. İn vitro çalışmalar, insan karaciğer sitokrom P-450 3A4'ün (CYP3A4) bu bileşiğin metabolizmasındaki birincil rolünü doğrulamıştır, ancak hiçbir büyük metabolit tanımlanmamıştır. İnsan karaciğeri CYP3A4, mometazon furoatını 6-beta hidroksi mometazon furoata metabolize eder.

Formoterol fumarat: Formoterol öncelikle fenolik veya alifatik hidroksil grubunda doğrudan glukuronidasyon ve O-demetilasyon ve ardından her iki fenolik hidroksil grubunda glukuronid konjugasyonu ile metabolize edilir. Küçük yollar, formoterolün sülfat konjugasyonunu ve deformilasyonu ve ardından sülfat konjugasyonunu içerir. En belirgin yol fenolik hidroksil grubunda doğrudan konjugasyonu içerir. İkinci ana yol O-demetilasyonu ve ardından fenolik 2'-hidroksil grubunda konjugasyonu içerir. Formoterolün Odemetilasyonunda dört sitokrom P450 izozimi (CYP2D6, CYP2C19, CYP2C9 ve CYP2A6) yer alır. Formoterol, terapötik olarak ilgili konsantrasyonlarda CYP450 enzimlerini inhibe etmedi. Bazı hastalar CYP2D6 veya 2C19 veya her ikisinde eksik olabilir. Bu izozimlerin birinde veya her ikisinde bir eksikliğin formoterole veya sistemik yan etkilere yüksek sistemik maruziyetle sonuçlanıp sonuçlanmadığı yeterince araştırılmamıştır.

Boşaltım

Mometazon furoat: İntravenöz dozlamanın ardından terminal yarılanma ömrünün yaklaşık 5 saat olduğu bildirilmiştir. İnhale edilen 1000 mcg mometazon furoat dozunu takiben, radyoaktivite esas olarak dışkıda (ortalama% 74) ve az miktarda idrarda (ortalama% 8) 7 güne kadar atılır. İdrarda değişmemiş mometazon furoat ile hiçbir radyoaktivite ilişkili değildi. Emilen mometazon furoat, dozdan bağımsız olarak yaklaşık 12.5 mL / dak / kg oranında plazmadan temizlenir. Zenheyl ile inhalasyondan sonra mometazon furoat için etkili t½ sağlıklı kişilerde ve astımı olan hastalarda 25 saattir.

Formoterol fumarat: 2 sağlıklı kişiye 80 mcg radyoaktif işaretli formoterol fumaratın oral yoldan verilmesinden sonra, radyoaktivitenin% 59 ila 62'si idrarda ve dışkıda% 32 ila% 34'ü 104 saatlik bir süre boyunca elimine edildi. Zenheyl ile yapılan oral inhalasyon çalışmasında, formoterolün kandan renal klerensi 217 mL / dak idi. Tek dozlu çalışmalarda, plazmada formoterol için ortalama t½ değerleri, idrar atılım verilerinden 9.1 saat ve 10.8 saat idi. Çoklu doz uygulamasından sonra plazmada formoterol birikimi, terminal t½ değeri 9 ila 11 saat olan bir ilaçla beklenen artışla tutarlıydı.

MFF MDI'dan sağlıklı deneklere 10 ila 40 mcg arasında değişen tek inhale dozların ardından, formoterol dozunun% 6.2 ila% 6.8'i değişmeden idrarla atılmıştır. (R, R) ve (S, S) -enantiyomerleri, idrarda geri kazanılan formoterolün sırasıyla% 37 ve% 63'ünü oluşturmuştur. Sağlıklı kişilerde ölçülen idrar atılım oranlarından, (R, R) ve (S, S) -enantiyomerleri için ortalama terminal eliminasyon yarılanma ömürlerinin sırasıyla 13 ve 9.5 saat olduğu belirlenmiştir. İki enantiyomerin nispi oranı, incelenen doz aralığı üzerinde sabit kaldı.