In some countries, this medicine may only be approved for veterinary use.
In the US, ACTH is a member of the drug class corticotropin and is used to treat Allergies, Eye Conditions, Multiple Sclerosis, Psoriasis, Rheumatoid Arthritis, Systemic Lupus Erythematosus and Ulcerative Colitis.
Corticotropin is reported as an ingredient of ACTH in the following countries:
International Drug Name Search
Fendibina may be available in the countries listed below.
Ranitidine hydrochloride (a derivative of Ranitidine) is reported as an ingredient of Fendibina in the following countries:
International Drug Name Search
Long-acting beta2-adrenergic agonists (LABA), such as formoterol, one of the active ingredients in Dulera, increase the risk of asthma-related death. Data from a large placebo-controlled U.S. study that compared the safety of another long-acting beta2-adrenergic agonist (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol. This finding with salmeterol is considered a class effect of the LABA, including formoterol. 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, Dulera 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 Dulera) 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 Dulera for patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids. [See Warnings and Precautions (5.1).]
Dulera 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 Dulera, 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 [see Warnings and Precautions (5.1)]. Therefore, when treating patients with asthma, Dulera 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 Dulera) 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 Dulera for patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids.
Important Limitation of Use
Dulera should be administered only by the orally inhaled route (see Instructions for Using Dulera in the Medication Guide). After each dose, the patient should be advised to rinse his/her mouth with water without swallowing.
Dulera 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 Dulera canister should only be used with the Dulera actuator. The Dulera actuator should not be used with any other inhalation drug product. Actuators from other products should not be used with the Dulera canister.
Dulera should be administered as two inhalations twice daily every day (morning and evening) by the orally inhaled route.
Shake well prior to each inhalation.
The recommended starting dosages for Dulera treatment are based on prior asthma therapy.
| Previous Therapy | Recommended Dose | Maximum Recommended Daily Dose |
|---|---|---|
| Inhaled medium dose corticosteroids | Dulera 100 mcg/5 mcg, 2 inhalations twice daily | 400 mcg/20 mcg |
| Inhaled high dose corticosteroids | Dulera 200 mcg/5 mcg, 2 inhalations twice daily | 800 mcg/20 mcg |
The maximum daily recommended dose is two inhalations of Dulera 200 mcg/5 mcg twice daily. Do not use more than two inhalations twice daily of the prescribed strength of Dulera 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 Dulera fails to provide adequate control of asthma, the therapeutic regimen should be reevaluated and additional therapeutic options, e.g., replacing the current strength of Dulera with a higher strength, adding additional inhaled corticosteroid, or initiating oral corticosteroids, should be considered.
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 ≥12 years of age who do not respond adequately after 2 weeks of therapy, higher strength may provide additional asthma control.
Dulera is a pressurized metered dose inhaler that is available in 2 strengths.
Dulera 100 mcg/5 mcg delivers 100 mcg of mometasone furoate and 5 mcg of formoterol fumarate dihydrate per actuation.
Dulera 200 mcg/5 mcg delivers 200 mcg of mometasone furoate and 5 mcg of formoterol fumarate dihydrate per actuation.
Dulera is contraindicated in the primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required.
Dulera is contraindicated in patients with known hypersensitivity to mometasone furoate, formoterol fumarate, or any of the ingredients in Dulera [see Warnings and Precautions (5.10)].
Long-acting beta2-adrenergic agonists, such as formoterol, one of the active ingredients in Dulera, 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 Dulera 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 Dulera) 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 Dulera 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 Dulera. No study adequate to determine whether the rate of asthma-related death is increased with Dulera 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.
Dulera should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of asthma. Dulera has not been studied in patients with acutely deteriorating asthma. The initiation of Dulera 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 Dulera 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 Dulera.
Dulera 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 Dulera, should be used to relieve acute symptoms such as shortness of breath. When prescribing Dulera, 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 Dulera.
When beginning treatment with Dulera, 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.
As with other inhaled drugs containing beta2-adrenergic agents, Dulera 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 Dulera 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.
In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans have occurred in patients treated with Dulera. If oropharyngeal candidiasis develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while remaining on treatment with Dulera therapy, but at times therapy with Dulera may need to be interrupted. Advise patients to rinse the mouth after inhalation of Dulera.
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.
Dulera 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.
Particular care is needed for patients who are transferred from systemically active corticosteroids to Dulera 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 Dulera 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 Dulera. 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 Dulera 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.
Mometasone furoate, a component of Dulera, 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 Dulera 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 Dulera 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 Dulera should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids and for management of asthma symptoms.
Caution should be exercised when considering the coadministration of Dulera 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 [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].
Dulera 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 inhaled bronchodilator. Dulera should be discontinued immediately and alternative therapy instituted.
Immediate hypersensitivity reactions may occur after administration of Dulera, as demonstrated by cases of urticaria, flushing, allergic dermatitis, and bronchospasm.
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, Dulera should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.
Formoterol fumarate, a component of Dulera, 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 Dulera 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.
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 Dulera. 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.
Orally inhaled corticosteroids, including Dulera, may cause a reduction in growth velocity when administered to pediatric patients. Monitor the growth of pediatric patients receiving Dulera routinely (e.g., via stadiometry). To minimize the systemic effects of orally inhaled corticosteroids, including Dulera, titrate each patient's dose to the lowest dosage that effectively controls his/her symptoms [see Use in Specific Populations (8.4)].
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 Dulera. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts [see Adverse Reactions (6)].
Dulera, like other medications containing sympathomimetic amines, should be used with caution in patients with 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.
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 Dulera at recommended doses.
Long-acting beta2-adrenergic agonists, such as formoterol, one of the active ingredients in Dulera, 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. Data from a large placebo-controlled US trial that compared the safety of another long-acting beta2-adrenergic agonist (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol [see Warnings and Precautions (5.1)].
Systemic and local corticosteroid use may result in the following:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety data described below is based on 3 clinical trials which randomized 1913 patients 12 years of age and older with asthma, including 679 patients exposed to Dulera for 12 to 26 weeks and 271 patients exposed for 1 year. Dulera was studied in two placebo- and active-controlled trials (n=781 and n=728, respectively) and in a long term 52-week safety trial (n=404). In the 12 to 26-week clinical trials, the population was 12 to 84 years of age, 41% male and 59% female, 73% Caucasians, 27% non-Caucasians. Patients received two inhalations twice daily of Dulera (100 mcg/5 mcg or 200 mcg/5 mcg), mometasone furoate MDI (100 mcg or 200 mcg), formoterol MDI (5 mcg) or placebo. In the long term 52-week active-comparator safety trial, the population was 12 years to 75 years of age with asthma, 37% male and 63% female, 47% Caucasians, 53% non-Caucasians and received two inhalations twice daily of Dulera 100 mcg/5 mcg or 200 mcg/5 mcg, or an active comparator.
The incidence of treatment emergent adverse reactions associated with Dulera in Table 2 below is based upon pooled data from 2 clinical trials 12 to 26-week in duration in patients 12 years and older treated with two inhalations twice daily of Dulera (100 mcg/5 mcg or 200 mcg/5 mcg), mometasone furoate MDI (100 mcg or 200 mcg), formoterol MDI (5mcg) or placebo.
| Adverse Reactions | Dulera* | Mometasone Furoate* | Formoterol* | Placebo* | ||
|---|---|---|---|---|---|---|
| 100 mcg/5 mcg n=424 n (%) | 200 mcg/5 mcg n=255 n (%) | 100 mcg n=192 n (%) | 200 mcg n=240 n (%) | 5 mcg n=202 n (%) | n=196 n (%) | |
| ||||||
| Nasopharyngitis | 20 (4.7) | 12 (4.7) | 15 (7.8) | 13 (5.4) | 13 (6.4) | 7 (3.6) |
| Sinusitis | 14 (3.3) | 5 (2.0) | 6 (3.1) | 4 (1.7) | 7 (3.5) | 2 (1.0) |
| Headache | 19 (4.5) | 5 (2.0) | 10 (5.2) | 8 (3.3) | 6 (3.0) | 7 (3.6) |
| Average Duration of Exposure (days) | 116 | 81 | 165 | 79 | 131 | 138 |
Oral candidiasis has been reported in clinical trials at an incidence of 0.7% in patients using Dulera 100 mcg/5 mcg, 0.8 % in patients using Dulera 200 mcg/5 mcg and 0.5 % in the placebo group.
Long Term Clinical Trial Experience
In a long term safety trial in patients 12 years and older treated for 52 weeks with Dulera 100 mcg/5 mcg (n=141), Dulera 200 mcg/5 mcg (n=130) or an active comparator (n=133), safety outcomes in general were similar to those observed in the shorter 12 to 26 week controlled trials. No asthma-related deaths were observed. Dysphonia was observed at a higher frequency in the longer term treatment trial at a reported incidence of 7/141 (5%) patients receiving Dulera 100 mcg/5 mcg and 5/130 (3.8%) patients receiving Dulera 200 mcg/5 mcg. No clinically significant changes in blood chemistry, hematology, or ECG were observed.
The following adverse reactions have been reported during post-approval use of Dulera. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Immune system disorders: anaphylactic reaction
In clinical trials, concurrent administration of Dulera and other drugs, such as short-acting beta2-agonist and intranasal corticosteroids have not resulted in an increased frequency of adverse drug reactions. No formal drug interaction studies have been performed with Dulera. The drug interactions of the combination are expected to reflect those of the individual components.
The main route of metabolism of corticosteroids, including mometasone furoate, a component of Dulera, is via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4). After oral administration of ketoconazole, a strong inhibitor of CYP3A4, the mean plasma concentration of orally inhaled mometasone furoate increased. Concomitant administration of CYP3A4 inhibitors may inhibit the metabolism of, and increase the systemic exposure to, mometasone furoate. Caution should be exercised when considering the coadministration of Dulera with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) [see Warnings and Precautions (5.8) and Clinical Pharmacology (12.3)].
If additional adrenergic drugs are to be administered by any route, they should be used with caution because the pharmacologically predictable sympathetic effects of formoterol, a component of Dulera, may be potentiated.
Concomitant treatment with xanthine derivatives may potentiate any hypokalemic effect of formoterol, a component of Dulera.
Concomitant treatment with diuretics may potentiate the possible hypokalemic effect of adrenergic agonists. The ECG changes and/or hypokalemia that may result from the administration of non-potassium sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of Dulera with non-potassium sparing diuretics.
Dulera should be administered with caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or drugs known to prolong the QTc interval or within 2 weeks of discontinuation of such agents, because the action of formoterol, a component of Dulera, on the cardiovascular system may be potentiated by these agents. Drugs that are known to prolong the QTc interval have an increased risk of ventricular arrhythmias.
Beta-adrenergic receptor antagonists (beta-blockers) and formoterol may inhibit the effect of each other when administered concurrently. Beta-blockers not only block the therapeutic effects of beta2-agonists, such as formoterol, a component of Dulera, but may produce severe bronchospasm in patients with asthma. Therefore, patients with asthma should not normally be treated with beta-blockers. However, under certain circumstances, e.g., as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-blockers in patients with asthma. In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution.
Dulera: Teratogenic Effects: Pregnancy Category C
There are no adequate and well-controlled studies of Dulera, 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, Dulera 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 [see Nonclinical Toxicology (13.2)].
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 2,400 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 2,400 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 1,200 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 6,100 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 3,000 times the MRHD on a mcg/m2 basis [see Nonclinical Toxicology (13.2)].
There are no adequate and well-controlled human studies that have studied the effects of Dulera during labor and delivery.
Because beta-agonists may potentially interfere with uterine contractility, Dulera should be used during labor only if the potential benefit justifies the potential risk [see Nonclinical Toxicology (13.2)].
Dulera: It is not known whether Dulera is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Dulera is administered to a nursing woman.
Since there are no data from well-controlled human studies on the use of Dulera on nursing mothers, based on data for the individual components, a decision should be made whether to discontinue nursing or to discontinue Dulera, taking into account the importance of Dulera 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.
The safety and effectiveness of Dulera 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 Dulera. 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 Dulera in another clinical trial. The safety and efficacy of Dulera 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 Dulera, should be monitored routinely (e.g., via stadiometry). If a child or adolescent on any corticosteroid appears to have growth suppression, the possibility that he/she is particularly sensitive to this effect should be considered. The potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the risks associated with alternative therapies. To minimize the systemic effects of orally inhaled corticosteroids, including Dulera, each patient should be titrated to his/her lowest effective dose [see Dosage and Administration (2.2)].
A total of 77 patients 65 years of age and older (of which 11 were 75 years and older) have been treated with Dulera in 3 clinical trials up to 52 weeks in duration. Similar efficacy and safety results were observed in an additional 28 patients 65 years of age and older who were treated with Dulera in another clinical trial. No overall differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. As with other products containing beta2-agonists, special caution should be observed when using Dulera in geriatric patients who have concomitant cardiovascular disease that could be adversely affected by beta2-agonists. Based on available data for Dulera or its active components, no adjustment of dosage of Dulera in geriatric patients is warranted.
Concentrations of mometasone furoate appear to increase with severity of hepatic impairment [see Clinical Pharmacology (12.3)].
Dulera: Dulera contains both mometasone furoate and formoterol fumarate; therefore, the risks associated with overdosage for the individual components described below apply to Dulera.
Mometasone Furoate: Chronic overdosage may result in signs/symptoms of hypercorticism [see Warnings and Precautions (5.7)]. 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.
Dulera: Treatment of overdosage consists of discontinuation of Dulera 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 Dulera. Cardiac monitoring is recommended in cases of overdosage.
Dulera 100 mcg/5 mcg and Dulera 200 mcg/5 mcg, are combinations of mometasone furoate and formoterol fumarate dihydrate for oral inhalation only.
One active component of Dulera is mometasone furoate, a corticosteroid having the chemical name 9,21-dichloro-11(Beta),17-dihydroxy-16 (alpha)-methylpregna-1,4-diene-3,20-dione 17-(2-furoate) with the following chemical structure:
Mometasone furoate is a white powder with an empirical formula of C27H30Cl2O6, and molecular weight 521.44. It is practically insoluble in water; slightly soluble in methanol, ethanol, and isopropanol; soluble in acetone.
One active component of Dulera is formoterol fumarate dihydrate, a racemate. Formoterol fumarate dihydrate is a selective beta2-adrenergic bronchodilator having the chemical name of (±) - 2 - hydroxy - 5 - [(1RS) - 1 - hydroxy - 2 - [[(1RS) - 2 - (4 - methoxyphenyl) - 1 - methylethyl] - amino]ethyl]formanilide fumarate dihydrate with the following chemical structure:
Formoterol fumarate dihydrate has a molecular weight of 840.9, and its empirical formula is (C19H24N2O4)2•C4H4O4•2H2O. Formoterol fumarate dihydrate is a white to yellowish powder, which is freely soluble in glacial acetic acid, soluble in methanol, sparingly soluble in ethanol and isopropanol, slightly soluble in water, and practically insoluble in acetone, ethyl acetate, and diethyl ether.
Each Dulera 100 mcg/5 mcg and 200 mcg/5 mcg is a hydrofluoroalkane (HFA-227) propelled pressurized metered dose inhaler containing sufficient amount of drug for 60 or 120 inhalations [see How Supplied/Storage and Handling (16)]. After priming, each actuation of the inhaler delivers 115 or 225 mcg of mometasone furoate and 5.5 mcg of formoterol fumarate dihydrate in 69.6 mg of suspension from the valve and delivers 100 or 200 mcg of mometasone furoate and 5 mcg of formoterol fumarate dihydrate from the actuator. The actual amount of drug delivered to the lung may depend on patient factors, such as the coordination between actuation of the device and inspiration through the delivery system. Dulera also contains anhydrous alcohol as a cosolvent and oleic acid as a surfactant.
Duler
Dawnex may be available in the countries listed below.
Fluoxetine is reported as an ingredient of Dawnex in the following countries:
Fluoxetine hydrochloride (a derivative of Fluoxetine) is reported as an ingredient of Dawnex in the following countries:
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Lofostin may be available in the countries listed below.
Levocarnitine is reported as an ingredient of Lofostin in the following countries:
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Triazolam NM Pharma may be available in the countries listed below.
Triazolam is reported as an ingredient of Triazolam NM Pharma in the following countries:
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Gemcitabine Mayne may be available in the countries listed below.
Gemcitabine is reported as an ingredient of Gemcitabine Mayne in the following countries:
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Levodopa-Benserazide may be available in the countries listed below.
Benserazide is reported as an ingredient of Levodopa-Benserazide in the following countries:
Levodopa is reported as an ingredient of Levodopa-Benserazide in the following countries:
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Olmec may be available in the countries listed below.
Olmesartan Medoxomil is reported as an ingredient of Olmec in the following countries:
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Beclorex may be available in the countries listed below.
Beclometasone 17α,21-dipropionate (a derivative of Beclometasone) is reported as an ingredient of Beclorex in the following countries:
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Paroxetine Merck may be available in the countries listed below.
Paroxetine hydrochloride (a derivative of Paroxetine) is reported as an ingredient of Paroxetine Merck in the following countries:
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Urgocor may be available in the countries listed below.
Salicylic Acid is reported as an ingredient of Urgocor in the following countries:
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Isoptina SR may be available in the countries listed below.
Verapamil is reported as an ingredient of Isoptina SR in the following countries:
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Nanotiv may be available in the countries listed below.
Coagulation Factor IX, Human is reported as an ingredient of Nanotiv in the following countries:
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