Zenheyl

Лечение астмы

Зенхейл показан для лечения астмы у пациентов в возрасте 12 лет и старше.

Бета2-адренергические агонисты длительного действия, такие как формотерол, один из активных ингредиентов в Зенхейле, повышают риск смерти от астмы. Имеющиеся данные контролируемых клинических испытаний позволяют предположить, что LABA увеличивает риск госпитализации, связанной с астмой, у педиатрических и подростковых пациентов. Поэтому, при лечении пациентов с астмой, Zenheyl следует использовать только для пациентов, которые не контролируются адекватно при длительном лечении астмы, такой как ингаляционный кортикостероид или тяжесть заболевания которого явно требует начала лечения ингаляционным кортикостероидом и LABA. Как только контроль астмы достигнут и поддерживается, оценивать пациента через регулярные промежутки времени и прекратить терапию (например., прекратить Zenheyl), если это возможно, без потери контроля над астмой, и поддерживать пациента на длительном лекарстве для контроля астмы, таком как ингаляционный кортикостероид. Не используйте Zenheyl для пациентов, чья астма адекватно контролируется при низких или средних дозах ингаляционных кортикостероидов.

Важное ограничение использования

• Зенхейл НЕ показан для облегчения острого бронхоспазма.

Информация об администрировании

Зенхейл следует вводить в виде двух ингаляций два раза в день (утром и вечером) перорально вдыхаемым путем (см Инструкции для пациентов в Руководстве по лекарствам). Хорошо встряхивайте перед каждым вдыханием. После каждой дозы пациенту следует рекомендовать промыть рот водой, не глотая.

Крышка из мундштука привода должна быть снята перед использованием Zenheyl.

Zenheyl следует грунтовать перед использованием в первый раз, выпуская 4 тестовых спрея в воздух, вдали от лица, хорошо встряхивая перед каждым спреем. В тех случаях, когда ингалятор не использовался более 5 дней, снова заправляйте ингалятор, выпуская 4 пробных спрея в воздух, вдали от лица, хорошо встряхивая перед каждым спреем.

Цистерна Zenheyl должна использоваться только с приводом Zenheyl. Привод Zenheyl не следует использовать с любым другим продуктом ингаляционного препарата. Приводы из других продуктов не должны использоваться с канистрой Zenheyl.

Рекомендуемая дозировка

Взрослые и подростки 12 лет и старше

Дозировка составляет 2 ингаляции два раза в день Zenheyl 100 мкг / 5 мкг или Zenheyl 200 мкг / 5 мкг. Максимальная рекомендуемая доза составляет две ингаляции Zenheyl 200 мкг / 5 мкг два раза в день (максимальная суточная доза 800 мкг / 20 мкг).

При выборе начальной лекарственной силы Zenheyl учитывайте тяжесть заболевания пациентов на основе их предыдущей терапии астмой, включая вдыхаемую дозировку кортикостероидов, а также текущий контроль пациентов над симптомами астмы и риском дальнейшего обострения.

Максимальная выгода не может быть достигнута в течение 1 недели или дольше после начала лечения. Отдельные пациенты могут испытывать переменное время до начала и степень облегчения симптомов. Для пациентов, которые не реагируют адекватно после 2 недель терапии двумя ингаляциями Zenheyl 100 мкг / 5 мкг два раза в день (утром и вечером), увеличивая дозировку до двух ингаляций Zenheyl 200 мкг / 5 мкг два раза в день (утром и вечером) ) может обеспечить дополнительный контроль астмы.

Не используйте более двух ингаляций два раза в день от предписанной силы Зенхейла, так как некоторые пациенты с большей вероятностью испытывают побочные эффекты при более высоких дозах формотерола. Если между дозами возникают симптомы, для немедленного облегчения следует принять вдыхаемый бета2-агонист короткого действия.

Если ранее эффективный режим дозировки Зенхейла не обеспечивает адекватного контроля над астмой, следует пересмотреть режим лечения и дополнительные варианты лечения, например,.следует рассмотреть возможность замены текущей силы Зенхейла на более высокую прочность, добавления дополнительного ингаляционного кортикостероида или начала пероральных кортикостероидов.

Статус Астматик

Зенхейл противопоказан при первичном лечении астматического статуса или других острых эпизодов астмы, где требуются интенсивные меры.

Гиперчувствительность

Зенхейл противопоказан пациентам с известной гиперчувствительностью к фуроату мометазона, фумарату формотерола или любому из ингредиентов в Зенхейле.

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

Использование LABA может привести к следующему:

• Серьезные события, связанные с астмой - госпитализации, интубации и смерть.
• Сердечно-сосудистые эффекты и эффекты центральной нервной системы.

Системное и местное использование кортикостероидов может привести к следующему:

• Кандида альбиканцы инфекция
• Иммуносупрессия
• Гиперкортицизм и подавление надпочечников
• Влияние роста в педиатрии
• Глаукома и катаракта

Поскольку клинические испытания проводятся в широко варьирующихся условиях, частота побочных реакций, наблюдаемая в клинических испытаниях лекарственного средства, не может быть напрямую сопоставлена с частотой клинических испытаний другого лекарственного средства и может не отражать показатели, наблюдаемые на практике.

Опыт клинических испытаний

Данные по безопасности, описанные ниже, основаны на 3 клинических испытаниях, которые рандомизировали 1913 пациентов в возрасте 12 лет и старше с астмой, в том числе 679 пациентов, подвергшихся воздействию Зенхейла в течение 12-26 недель, и 271 пациент, подвергшийся воздействию в течение 1 года. Zenheyl был изучен в двух плацебо- и активно контролируемых исследованиях (n = 781 и n = 728 соответственно) и в длительном 52-недельном испытании безопасности (n = 404). В клинических испытаниях от 12 до 26 недель население составляло от 12 до 84 лет, 41% мужчин и 59% женщин, 73% кавказцев, 27% некавказцев. Пациенты получали две ингаляции два раза в день Zenheyl (100 мкг / 5 мкг или 200 мкг / 5 мкг), MDI фуроата мометазона (100 мкг или 200 мкг), MDI формотерола (5 мкг) или плацебо. В длительном 52-недельном исследовании безопасности активных компараторов население было от 12 до 75 лет с астмой, 37% мужчин и 63% женщин, 47% кавказцев, 53% некавказцев и получало два ингаляции два раза в день. Zenheyl 100 мкг / 5 мкг или 200 мкг активного вещества,.

Частота возникновения возникающих побочных реакций, связанных с Зенхейлом, в Таблице 2 ниже основана на объединенных данных из 2 клинических испытаний продолжительностью от 12 до 26 недель у пациентов в возрасте 12 лет и старше, получавших два ингаляции дзенхейла два раза в день (100 мкг / 5 мкг или 200 мкг / 5 мкг) мометазон фуроат MDI (100 мкг или 200 мкг) формотерол МДИ (5mcg) или плацебо.

Таблица 2: Неблагоприятные реакции на лечение в группах дзенхейлов, возникающие при частоте ≥3% и чаще, чем плацебо

Оральный кандидоз был зарегистрирован в клинических испытаниях с частотой 0,7% у пациентов, использующих Zenheyl 100 мкг / 5 мкг, 0,8% у пациентов, использующих Zenheyl 200 мкг / 5 мкг, и 0,5% в группе плацебо.

Долгосрочный опыт клинических испытаний

В длительном исследовании безопасности у пациентов в возрасте 12 лет и старше, получавших в течение 52 недель Zenheyl 100 мкг / 5 мкг (n = 141), Zenheyl 200 мкг / 5 мкг (n = 130) или активный компаратор (n = 133) результаты безопасности в целом были аналогичны тем, которые наблюдались в более коротких 12 контролируемых испытаний. Случаев астмы не наблюдалось. Дисфония наблюдалась с более высокой частотой в более длительном исследовании лечения при зарегистрированной частоте 7/141 (5%) пациентов, получавших Zenheyl 100 мкг / 5 мкг, и 5/130 (3,8%) пациентов, получавших Zenheyl 200 мкг / 5 мкг. Клинически значимых изменений в химии крови, гематологии или ЭКГ не наблюдалось.

Опыт постмаркетинга

Следующие побочные реакции были зарегистрированы во время использования Zenheyl или после одобрения с вдыхаемым фуроатом мометазона или вдыхаемым фумаратом формотерола. Поскольку об этих реакциях сообщается добровольно от населения неопределенного размера, не всегда возможно надежно оценить их частоту или установить причинную связь с воздействием наркотиков.

Сердечные расстройства: стенокардия, сердечные аритмии, например,.мерцательная аритмия, желудочковая экстрасистолия, тахиаритмия Расстройства иммунной системы: немедленные и отсроченные реакции гиперчувствительности, включая анафилактическую реакцию, ангионевротический отек, тяжелую гипотензию, сыпь, зуд

Исследования: электрокардиограмма QT продлена, артериальное давление повышено (включая гипертонию)

Нарушения обмена веществ и питания: гипокалиемия, гипергликемия

Респираторные, грудной и средостения расстройства: обострение астмы, которое может включать кашель, одышку, одышку и бронхоспазм

Signs And Symptoms

Zenheyl: Zenheyl contains both mometasone furoate and formoterol fumarate; therefore, the risks associated with overdosage for the individual components described below apply to Zenheyl.

Mometasone Furoate: Chronic overdosage may result in signs/symptoms of hypercorticism. Single oral doses up to 8000 mcg of mometasone furoate have been studied on human volunteers with no adverse reactions reported.

Formoterol Fumarate: The expected signs and symptoms with overdosage of formoterol are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the following signs and symptoms: angina, hypertension or hypotension, tachycardia, with rates up to 200 beats/min., arrhythmias, nervousness, headache, tremor, seizures, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, hypokalemia, hyperglycemia, and insomnia. Metabolic acidosis may also occur. Cardiac arrest and even death may be associated with an overdose of formoterol.

The minimum acute lethal inhalation dose of formoterol fumarate in rats is 156 mg/kg (approximately 63,000 times the MRHD on a mcg/m² basis). The median lethal oral doses in Chinese hamsters, rats, and mice provide even higher multiples of the MRHD.

Treatment

Zenheyl: Treatment of overdosage consists of discontinuation of Zenheyl together with institution of appropriate symptomatic and/or supportive therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of Zenheyl. Cardiac monitoring is recommended in cases of overdosage.

Cardiovascular Effects

Zenheyl: In a single-dose, double-blind placebo-controlled crossover trial in 25 patients with asthma, single-dose treatment of 10 mcg formoterol fumarate in combination with 400 mcg of mometasone furoate delivered via Zenheyl 200 mcg/5 mcg 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 Zenheyl 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. There was no evidence of significant hypokalemia or hyperglycemia in response to formoterol treatment.

No relevant changes in heart rate or changes in ECG data were observed with Zenheyl in the trial. No patients had a QTcB (QTc corrected by Bazett's formula) ≥ 500 msec during treatment.

In a single-dose crossover trial involving 24 healthy subjects, single dose of formoterol fumarate 10, 20, or 40 mcg in combination with 400 mcg of mometasone furoate delivered via Zenheyl 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 clinically significant increases in mean blood glucose values or heart rate were observed. No subjects had a QTcB > 500 msec during treatment.

Three active-and placebo-controlled trials (study duration ranging from 12, 26, and 52 weeks) evaluated 1913 patients 12 years of age and older with asthma. No clinically meaningful changes were observed in potassium and glucose values, vital signs, or ECG parameters in patients receiving Zenheyl.

HPA Axis Effects

The effects of inhaled mometasone furoate administered via Zenheyl on adrenal function were evaluated in two clinical trials 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 small number of subjects per treatment arm, results from these trials taken together demonstrated suppression of 24-hour plasma cortisol AUC for Zenheyl 200 mcg/5 mcg compared to placebo consistent with the known systemic effects of inhaled corticosteroid.

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: Zenheyl 100 mcg/5 mcg, Zenheyl 200 mcg/5 mcg, fluticasone propionate/salmeterol xinafoate 230 mcg/21 mcg, or placebo. At Day 42, the mean change from baseline plasma cortisol AUC(0-24 hr) was 8%, 22% and 34% lower compared to placebo for the Zenheyl 100 mcg/5 mcg (n=13), Zenheyl 200 mcg/5 mcg (n=15) and fluticasone propionate/salmeterol xinafoate 230 mcg/21 mcg (n=16) treatment groups, respectively.

In a 52-week, open-label 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 Zenheyl 100 mcg/5 mcg, Zenheyl 200 mcg/5 mcg, fluticasone propionate/salmeterol xinafoate 125/25 mcg, or fluticasone propionate/salmeterol xinafoate 250/25 mcg. At Week 52, the mean plasma cortisol AUC(0-24 hr) was 2.2%, 29.6%, 16.7%, and 32.2% lower from baseline for the Zenheyl 100 mcg/5 mcg (n=18), Zenheyl 200 mcg/5 mcg (n=20), fluticasone propionate/salmeterol xinafoate 125/25 mcg (n=8), and fluticasone propionate/salmeterol xinafoate 250/25 mcg (n=11) treatment groups, respectively.

Other Mometasone Products

HPA Axis Effects

The potential effect of mometasone furoate via a dry powder inhaler (DPI) on the HPA axis was assessed in a 29-day study. A total of 64 adult patients with mild to moderate asthma were randomized to one of 4 treatment groups: mometasone furoate DPI 440 mcg twice daily, mometasone furoate DPI 880 mcg twice daily, oral prednisone 10 mg once daily, or placebo. The 30-minute post-Cosyntropin stimulation serum cortisol concentration on Day 29 was 23.2 mcg/dl for the mometasone furoate DPI 440 mcg twice daily group and 20.8 mcg/dl for the mometasone furoate DPI 880 mcg twice daily group, compared to 14.5 mcg/dl for the oral prednisone 10 mg group and 25 mcg/dl for the placebo group. The difference between mometasone furoate DPI 880 mcg twice daily (twice the maximum recommended dose) and placebo was statistically significant.

Поглощение

Фуроат мометазона: здоровые предметы: Сравнивались системные воздействия фуроата мометазона из Зенхейла в сравнении с фуроатом мометазона, доставляемым через DPI. После перорального вдыхания однократных и многократных доз Зенхейла мометазон фуроат абсорбировался у здоровых субъектов со средними значениями Tmax в диапазоне от 0,50 до 4 часов. После однократного введения более высокой, чем рекомендуемая доза Зенхейла (4 ингаляции Zenheyl 200 мкг / 5 мкг) у здоровых людей, среднее арифметическое (CV%) Cmax и AUC(0-12 часов) значения для MF были 67,8 (49) пг / мл и 650 (51) pg • ч / мл, соответственно, в то время как соответствующие оценки после 5 дней дозирования BID Zenheyl 800 мкг / 20 мкг составляли 241 (36) пг / мл и 2200 (35) пг • ч / мл. Воздействие фуроата мометазона увеличивается с увеличением вдыхаемой дозы Zenheyl от 100 мкг / 5 мкг до 200 мкг / 5 мкг. Исследования с использованием перорального дозирования меченного и немеченыго лекарственного средства показали, что оральная системная биодоступность фуроата мометазона незначительна (<1%).

Вышеупомянутое исследование показало, что системное воздействие фуроата мометазона (на основе AUC) было приблизительно на 52% и 25% ниже в день 1 и день 5, соответственно, после введения Зенхейла по сравнению с фуроатом мометазона через DPI

Пациенты с астмой: После перорального вдыхания однократных и многократных доз Зенхейла мометазон фуроат абсорбировался у пациентов с астмой со средними значениями Tmax в диапазоне от 1 до 2 часов. После однократного введения Zenheyl 400 мкг / 10 мкг, среднее арифметическое (CV%) Cmax и AUC(0-12 часов) значения для MF были 20 (88) пг / мл и 170 (94) pg • ч / мл, соответственно, в то время как соответствующие оценки после дозировки BID Zenheyl 400 мкг / 10 мкг в стационарном состоянии составляли 60 (36) пг / мл и 577 (40) pg • ч / мл .

Формотерол фумарат: здоровые предметы: Когда Зенхейл вводили здоровым субъектам, формотерол всасывался со средними значениями Tmax в диапазоне от 0,167 до 0,5 часа. В исследовании с однократной дозой Zenheyl 400 мкг / 10 мкг у здоровых субъектов среднее арифметическое (CV%) Cmax и AUC для формотерола составляли 15 (50) пмоль / л и 81 (51) пмоль * ч / л соответственно. В диапазоне доз от 10 до 40 мкг для формотерола из Зенхейла воздействие формотерола было пропорциональным дозе.

Пациенты с астмой: Когда Zenheyl вводили пациентам с астмой, формотерол всасывался со средними значениями Tmax в диапазоне от 0,58 до 1,97 часа. В исследовании с однократной дозой Zenheyl 400 мкг / 10 мкг у пациентов с астмой среднее арифметическое (CV%) Cmax и AUC (0-12 ч) для формотерола составляли 22 (29) пмоль / л и 125 (42) пмоль * ч / л соответственно. После введения нескольких доз Zenheyl 400 мкг / 10 мкг среднее арифметическое в стационарном состоянии (CV%) Cmax и AUC (0-12 ч) для формотерола составляло 41 (59) пмоль / л и 226 (54) пмоль * час / л .

Распределение

Мометазон фуроат: На основании исследования, в котором использовалась вдыхаемая доза тритированного порошка фуроата мометазона в дозе 1000 мкг у людей, заметного накопления фуроата мометазона в эритроцитах обнаружено не было. После внутривенной дозы 400 мкг фуроата мометазона концентрации в плазме показали двухфазное снижение со средним стационарным объемом распределения 152 литра. in vitro сообщалось, что связывание белка с фуроатом мометазона составляет от 98% до 99% (в диапазоне концентраций от 5 до 500 нг / мл).

Формотерол фумарат: Связывание формотерола с белками плазмы человека in vitro было от 61% до 64% в концентрациях от 0,1 до 100 нг / мл. Связывание с человеческим сывороточным альбумином in vitro было от 31% до 38% в диапазоне от 5 до 500 нг / мл. Концентрации формотерола, используемые для оценки связывания с белками плазмы, были выше, чем концентрации, достигнутые в плазме после вдыхания одной дозы 120 мкг.

Метаболизм

Мометазон фуроат: Исследования показали, что фуроат мометазона в основном и широко метаболизируется в печени всех исследованных видов и подвергается обширному метаболизму до нескольких метаболитов. Исследования in vitro подтвердили основную роль цитохрома печени человека P-450 3A4 (CYP3A4) в метаболизме этого соединения, однако основных метаболитов выявлено не было. Печень человека CYP3A4 метаболизирует фуроат мометазона до 6-бета фуроата гидроксимометазона.

Формотерол фумарат: Формотерол метаболизируется главным образом путем прямой глюкуронидации в фенольной или алифатической гидроксильной группе и O-деметилирования с последующим конъюгацией глюкуронида в любой фенольной гидроксильной группе. Незначительные пути включают сульфатное конъюгацию формотерола и деформилирование с последующим сульфатным конъюгацией. Наиболее заметный путь включает прямое конъюгацию в фенольной гидроксильной группе. Второй основной путь включает O-деметилирование с последующим конъюгацией в фенольной 2'-гидроксильной группе. Четыре изозима цитохрома P450 (CYP2D6, CYP2C19, CYP2C9 и CYP2A6) участвуют в одеметилировании формотерола. Формотерол не ингибировал ферменты CYP450 в терапевтически значимых концентрациях. У некоторых пациентов может быть дефицит CYP2D6 или 2C19 или обоих. Не было адекватно изучено, приводит ли дефицит одного или обоих из этих изозимов к повышенному системному воздействию формотерола или системным побочным эффектам.

Экскреция

Мометазон фуроат: После внутривенного введения конечный период полувыведения составил около 5 часов. После вдыхаемой дозы тритированного фуроата мометазона 1000 мкг радиоактивность выводится в основном с калом (в среднем 74%) и в небольшой степени с мочой (в среднем 8%) до 7 дней. Никакой радиоактивности не было связано с неизменным фуроатом мометазона в моче. Поглощенный фуроат мометазона очищается от плазмы со скоростью приблизительно 12,5 мл / мин / кг, независимо от дозы. Эффективный t½ для фуроата мометазона после ингаляции Зенхейлом составлял 25 часов у здоровых людей и у пациентов с астмой.

Формотерол фумарат: После перорального введения 80 мкг радиоактивно меченного формотеролфумарата двум здоровым субъектам от 59% до 62% радиоактивности было выведено с мочой и от 32% до 34% с калом в течение 104 часов. В исследовании перорального вдыхания с Zenheyl почечный клиренс формотерола из крови составлял 217 мл / мин. В исследованиях с однократной дозой средние значения t½ для формотерола в плазме составляли 9,1 часа и 10,8 часа по данным экскреции с мочой. Накопление формотерола в плазме после многократного введения дозы соответствовало ожидаемому увеличению при приеме препарата с терминальным t½ от 9 до 11 часов.

После однократного вдыхания в диапазоне от 10 до 40 мкг здоровым субъектам из MFF MDI от 6,2% до 6,8% дозы формотерола выводилось с мочой без изменений. (R, R) и (S, S) -энантиомеры составляли, соответственно, 37% и 63% формотерола, выделенного в моче. Из показателей экскреции с мочой, измеренных у здоровых субъектов, средний конечный период полувыведения для (R, R) и (S, S) -энантиомеров был определен как 13 и 9,5 часов соответственно. Относительная доля двух энантиомеров оставалась постоянной в исследуемом диапазоне доз.