WIXELA™ INHUB™ (fluticasone propionate and salmeterol inhalation powder)

WIXELA INHUB(fluticasone propionate and salmeterol inhalation powder)

fluticasone propionate and salmeterol

Wixela™ Inhub™ 100/50, Wixela™ Inhub™ 250/50, and Wixela™ Inhub™ 500/50 are combinations of fluticasone propionate and salmeterol xinafoate.

One active component of Wixela™ Inhub™ is fluticasone propionate, a corticosteroid having the chemical name S-Fluoromethyl 6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-17β-carbothioate.

Fluticasone propionate, USP is a white to almost white powder with a molecular weight of 500.6, and the empirical formula is C25H31F3O5S. It is practically insoluble in water, freely soluble in dimethyl sulfoxide and dimethylformamide, and slightly soluble in methanol and 95% ethanol.

The other active component of Wixela™ Inhub™ is salmeterol xinafoate, a beta2-adrenergic bronchodilator.

Salmeterol xinafoate is the racemic form of the 1-hydroxy-2-naphthoic acid salt of salmeterol. It has the chemical name (±)-4-Hydroxy-α1-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-m-xylene-α,α′-diol 1-hydroxy-2-naphthoate (salt)

Salmeterol xinafoate, USP is a white to almost white powder with a molecular weight of 603.8, and the empirical formula is C25H37NO4•C11H8O3. It is freely soluble in methanol; slightly soluble in ethanol, chloroform, and isopropanol; and sparingly soluble in water.

INDICATIONS AND USAGE

Treatment of Asthma: Wixela Inhub is indicated for the twice-daily treatment of asthma in patients aged 4 years and older.

Wixela Inhub should be used for patients not adequately controlled on a long-term asthma control medication such as an inhaled corticosteroid (ICS) or whose disease warrants initiation of treatment with both an ICS and long-acting beta2-adrenergic agonist (LABA).

Important Limitation of Use: Wixela Inhub is NOT indicated for the relief of acute bronchospasm.

Maintenance Treatment of Chronic Obstructive Pulmonary Disease: Wixela™ Inhub™ 250/50 is indicated for the twice-daily maintenance treatment of airflow obstruction inpatients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.

Wixela Inhub 250/50 is also indicated to reduce exacerbations of COPD in patients with a history of exacerbations. Wixela Inhub 250/50 twice daily is the only approved dosage for the treatment of COPD because an efficacy advantage of the higher strength Wixela Inhub 500/50 over Wixela Inhub 250/50 has not been demonstrated.

Important Limitation of Use: Wixela Inhub is NOT indicated for the relief of acute bronchospasm.

Mechanism of Action

WIXELA™ INHUB™: Wixela™ Inhub™ contains both fluticasone propionate and salmeterol. The mechanisms of action described below for the individual components apply to Wixela™ Inhub™. These drugs represent 2 different classes of medications (a synthetic corticosteroid and a LABA) that have different effects on clinical, physiologic, and inflammatory indices.

Fluticasone Propionate: Fluticasone propionate is a synthetic trifluorinated corticosteroid with anti-inflammatory activity. Fluticasone propionate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor that is 18 times that of dexamethasone, almost twice that of beclomethasone-17-monopropionate (BMP), the active metabolite of beclomethasone dipropionate, and over 3 times that of budesonide. Data from the McKenzie vasoconstrictor assay in man are consistent with these results. The clinical significance of these findings is unknown.

Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have been shown to have a wide range of actions on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in inflammation. These anti-inflammatory actions of corticosteroids contribute to their efficacy in asthma.

Inflammation is also a component in the pathogenesis of COPD. In contrast to asthma, however, the predominant inflammatory cells in COPD include neutrophils, CD8+ T-lymphocytes, and macrophages. The effects of corticosteroids in the treatment of COPD are not well defined and ICS and fluticasone propionate when used apart from Wixela™ Inhub™ are not indicated for the treatment of COPD.

Salmeterol Xinafoate: Salmeterol is a selective LABA. In vitro studies show salmeterol to be at least 50 times more selective for beta2-adrenoceptors than albuterol. Although beta2-adrenoceptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-adrenoceptors are the predominant receptors in the heart, there are also beta2-adrenoceptors in the human heart comprising 10% to 50% of the total betaadrenoceptors.

The precise function of these receptors has not been established, but their presence raises the

possibility that even selective beta2-agonists may have cardiac effects. The pharmacologic effects of beta2-adrenoceptor agonist drugs, including salmeterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3′,5′-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

In vitro tests show that salmeterol is a potent and long-lasting inhibitor of the release of mast cell mediators, such as histamine, leukotrienes, and prostaglandin D2, from human lung. Salmeterol inhibits histamine-induced plasma protein extravasation and inhibits platelet-activating factor-induced eosinophil accumulation in the lungs of guinea pigs when administered by the inhaled route. In humans, single doses of salmeterol administered via inhalation aerosol attenuate allergen-induced bronchial hyper-responsiveness.

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DOSAGE AND ADMINISTRATION

Wixela Inhub should be administered as 1 inhalation twice daily by the orally inhaled route only. After inhalation, the patient should rinse his/her mouth with water without swallowing to help reduce the risk of oropharyngeal candidiasis.

More frequent administration or a greater number of inhalations (more than 1 inhalation twice daily) of the prescribed strength of Wixela Inhub is not recommended as some patients are more likely to experience adverse effects with higher doses of salmeterol. Patients using Wixela Inhub should not use additional LABA for any reason.

Asthma: If asthma symptoms arise in the period between doses, an inhaled, short-acting beta2-agonist should betaken for immediate relief.

Adult and Adolescent Patients Aged 12 Years and Older: For patients aged 12 years and older, the dosage is 1 inhalation twice daily, approximately 12 hours apart.

When choosing the starting dosage strength of Wixela Inhub, consider the patients’ disease severity, based on their previous asthma therapy, including the ICS dosage, as well as the patients’ current control of asthma symptoms and risk of future exacerbation.

The maximum recommended dosage is Wixela Inhub 500/50 twice daily.

Improvement in asthma control following inhaled administration of Wixela Inhub can occur within 30 minutes of beginning treatment, although maximum benefit may not be achieved for 1 week or longer after starting treatment. Individual patients will experience a variable time to onset and degree of symptom relief.

For patients who do not respond adequately to the starting dosage after 2 weeks of therapy, replacing the current strength of Wixela Inhub with a higher strength may provide additional improvement in asthma control.

If a previously effective dosage regimen fails to provide adequate improvement in asthma control, the therapeutic regimen should be reevaluated and additional therapeutic options (e.g., replacing the current strength of Wixela Inhub with a higher strength, adding additional ICS, initiating oral corticosteroids)  should be considered.

Pediatric Patients Aged 4 to 11 Years: For patients with asthma aged 4 to 11 years who are not controlled on an ICS, the dosage is 1 inhalation of Wixela Inhub 100/50 twice daily, approximately 12 hours apart.

Chronic Obstructive Pulmonary Disease: The recommended dosage for patients with COPD is 1 inhalation of Wixela Inhub 250/50 twice daily,approximately 12 hours apart.

If shortness of breath occurs in the period between doses, an inhaled, short-acting beta2-agonist should be taken for immediate relief.

CONTRAINDICATIONS

The use of Wixela Inhub is contraindicated in the following conditions:

  • Primary treatment of status asthmaticus or other acute episodes of asthma or COPD where intensive measures are required.
  • Severe hypersensitivity to milk proteins or demonstrated hypersensitivity to fluticasone propionate, salmeterol, or any of the excipients

WARNINGS AND PRECAUTIONS

Serious Asthma-Related Events – Hospitalizations, Intubations, Death

Use of LABA as monotherapy (without ICS) for asthma is associated with an increased risk of asthma-related death [see Salmeterol Multicenter Asthma Research Trial (SMART)]. Available data from controlled clinical trials also suggest that use of LABA as monotherapy increases the risk of asthma-related hospitalization in pediatric and adolescent patients. These findings are considered a class effect of LABA monotherapy. When LABA are used in fixed-dose combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared with ICS alone.

Deterioration of Disease and Acute Episodes

Wixela Inhub should not be initiated in patients during rapidly deteriorating or potentially lifethreatening episodes of asthma or COPD. Wixela Inhub has not been studied in subjects with acutely deteriorating asthma or COPD. The initiation of Wixela Inhub in this setting is not appropriate.

Excessive Use of Wixela™ Inhub™ and Use with Other Long-acting Beta2-agonists

Wixela™ Inhub™ should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines containing LABA, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using Wixela™ Inhub™ should not use another medicine containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason.

Local Effects of Inhaled Corticosteroids

In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in subjects treated with fluticasone propionate and salmeterol inhalation powder. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while treatment with Wixela™ Inhub™ continues, but at times therapy with Wixela™ Inhub™ may need to be interrupted. Advise the patient to rinse his/her mouth with water without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis.

Pneumonia

Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of pneumonia and exacerbations frequently overlap.

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 been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated.

If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered.

Transferring Patients from Systemic Corticosteroid Therapy

Particular care is needed for patients who have been transferred from systemically active corticosteroids to ICS because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available ICS. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function.

Hypercorticism and Adrenal Suppression

Fluticasone propionate, a component of Wixela™ Inhub™, will often help control asthma symptoms with less suppression of HPA function than therapeutically equivalent oral doses of prednisone. Since fluticasone propionate is absorbed into the circulation and can be systemically active at higher doses, the beneficial effects of Wixela™ Inhub™ in minimizing HPA dysfunction may be expected only when recommended dosages are not exceeded and individual patients are titrated to the lowest effective dose. A relationship between plasma levels of fluticasone propionate and inhibitory effects on stimulated cortisol production has been shown after 4 weeks of treatment with fluticasone propionate inhalation aerosol. Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing Wixela™ Inhub™.

Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors

The use of strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with Wixela™ Inhub™ is not recommended because increased systemic corticosteroid and increased cardiovascular adverse effects may occur.

As with other inhaled medicines, Wixela™ Inhub™ can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with Wixela™ Inhub™, it should be treated immediately with an inhaled, short-acting bronchodilator; Wixela™ Inhub™ should be discontinued immediately; and alternative therapy should be instituted. Upper airway symptoms of laryngeal spasm, irritation, or swelling, such as stridor and choking, have been reported in patients receiving fluticasone propionate and salmeterol inhalation powder.

Immediate Hypersensitivity Reactions

Immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur after administration of Wixela™ Inhub™. There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of powder products containing lactose; therefore, patients with severe milk protein allergy should not use Wixela™ Inhub™

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, Wixela™ Inhub™, like all products containing sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Reduction in Bone Mineral Density

Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing ICS. The clinical significance of small changes in BMD with regard to long-term consequences such as fracture is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids), should be monitored and treated with established standards of care. Since patients with COPD often have multiple risk

factors for reduced BMD, assessment of BMD is recommended prior to initiating Wixela™ Inhub™ and periodically thereafter. If significant reductions in BMD are seen and Wixela™ Inhub™ is still considered medically important for that patient’s COPD therapy, use of medicine to treat or prevent osteoporosis should be strongly considered.

Effect on Growth

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

Glaucoma and Cataracts

Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with asthma and COPD following the long-term administration of ICS, including fluticasone propionate, a component of Wixela™ Inhub™. Consider referral to an ophthalmologist in patients who develop ocular symptoms or use Wixela™ Inhub™ long term.

Eosinophilic Conditions and Churg-Strauss Syndrome

In rare cases, patients on inhaled fluticasone propionate, a component of Wixela™ Inhub™, may present with systemic eosinophilic conditions. Some of these patients have clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition that is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of fluticasone propionate. Cases of serious eosinophilic conditions have also been reported with other ICS in this clinical setting. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal relationship between fluticasone propionate and these underlying conditions has not been established.

Coexisting Conditions

Wixela™ Inhub™, like all medicines containing sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis and in those who are unusually responsive to sympathomimetic amines. Doses of the related beta2-adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.

Hypokalemia and Hyperglycemia

Beta-adrenergic agonist medicines 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 trials with fluticasone propionate and salmeterol inhalation powder at recommended doses.

DRUG INTERACTIONS

Ritonavir: Fluticasone Propionate: A drug interaction trial with fluticasone propionate aqueous nasal spray in healthy subjects has shown that ritonavir (a strong CYP3A4 inhibitor) can significantly increase plasma fluticasone propionate exposure, resulting in significantly reduced serum cortisol concentrations. During postmarketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression.

Ketoconazole: Fluticasone Propionate: Coadministration of orally inhaled fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily) resulted in a 1.9-fold increase in plasma fluticasone propionate exposure and a 45% decrease in plasma cortisol area under the curve (AUC), but had no effect on urinary excretion of cortisol.

Salmeterol: In a drug interaction trial in 20 healthy subjects, coadministration of inhaled salmeterol (50 mcg twice daily) and oral ketoconazole (400 mg once daily) for 7 days resulted in greater systemic exposure to salmeterol (AUC increased 16-fold and Cmax increased 1.4-fold). Three (3) subjects were withdrawn due to beta2-agonist side effects (2 with prolonged QTc and 1 with palpitations and sinus tachycardia). Although there was no statistical effect on the mean QTc, coadministration of salmeterol and ketoconazole was associated with more frequent increases in QTc duration compared with salmeterol and placebo administration.

Monoamine Oxidase Inhibitors and Tricyclic Antidepressants

Wixela™ Inhub™ should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of salmeterol, a component of Wixela™ Inhub™, on the vascular system may be potentiated by these agents.

Beta-adrenergic Receptor Blocking Agents

Beta-blockers not only block the pulmonary effect of beta-agonists, such as salmeterol, a component of Wixela™ Inhub™, but may also produce severe bronchospasm in patients with asthma or COPD. Therefore, patients with asthma or COPD should not normally be treated with beta-blockers. However, under certain circumstances, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents for these patients; cardioselective beta-blockers could be considered, although they should be administered with caution.

Non–Potassium-Sparing Diuretics

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, such as salmeterol, a component of Wixela™ Inhub™, especially when the recommended dose of the beta-agonist is exceeded.

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USE IN SPECIFIC POPULATIONS

Pregnancy: There are insufficient data on the use of fluticasone propionate and salmeterol inhalationpowder or individual monoproducts, fluticasone propionate and salmeterol xinafoate, in pregnant women. Thereare clinical considerations with the use of fluticasone propionate and salmeterol inhalation powder in pregnantwomen.

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

There are no human studies evaluating the effects of fluticasone propionate and salmeterol

inhalation powder during labor and delivery. Because of the potential for beta-agonist interference with uterine contractility, use of Wixela™ Inhub™ during labor should be restricted to those patients in whom the benefits clearly outweigh the risks.

Lactation: There are no available data on the presence of fluticasone propionate or salmeterol in human milk, the effects on the breastfed child, or the effects on milk production. Other corticosteroids have been detected in human milk. However, fluticasone propionate and salmeterol concentrations in plasma after inhaled therapeutic doses are low and therefore concentrations in human breast milk are likely to be correspondingly low. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Wixela™ Inhub™ and any potential adverse effects on the breastfed child from Wixela™ Inhub™ or from the underlying maternal condition.

Hepatic Impairment

Formal pharmacokinetic studies using fluticasone propionate and salmeterol inhalation powder have not been conducted in patients with hepatic impairment. However, since both fluticasone propionate and salmeterol are predominantly cleared by hepatic metabolism, impairment of liver function may lead to accumulation of fluticasone propionate and salmeterol in plasma. Therefore, patients with hepatic disease should be closely monitored.

Renal Impairment

Formal pharmacokinetic studies using fluticasone propionate and salmeterol inhalation powder have not been conducted in patients with renal impairment.

OVERDOSAGE

No human overdosage data has been reported for fluticasone propionate and salmeterol inhalation powder.

Wixela™ Inhub™ contains both fluticasone propionate and salmeterol; therefore, the risks associated with overdosage for the individual components described below apply to Wixela™ Inhub™. Treatment of overdosage consists of discontinuation of Wixela™ Inhub™ 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. Cardiac monitoring is recommended in cases of overdosage.

Fluticasone Propionate

Chronic overdosage of fluticasone propionate may result in signs/symptoms of hypercorticism. Inhalation by healthy volunteers of a single dose of 4,000 mcg of fluticasonepropionate inhalation powder or single doses of 1,760 or 3,520 mcg of fluticasone propionate CFC inhalationaerosol was well tolerated. Fluticasone propionate given by inhalation aerosol at dosages of 1,320 mcg twicedaily for 7 to 15 days to healthy human volunteers was also well tolerated. Repeat oral doses up to 80 mg dailyfor 10 days in healthy volunteers and repeat oral doses up to 20 mg daily for 42 days in subjects were welltolerated. Adverse reactions were of mild or moderate severity, and incidences were similar in active andplacebo treatment groups.

Salmeterol

The expected signs and symptoms with overdosage of salmeterol are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the signs and symptoms of beta-adrenergic stimulation (e.g., seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, insomnia, hyperglycemia, hypokalemia, metabolic acidosis). Overdosage with salmeterol can lead to clinically significant prolongation of the QTc interval, which can produce ventricular arrhythmias.

As with all inhaled sympathomimetic medicines, cardiac arrest and even death may be associated with an overdose of salmeterol.

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