Quinobact may be available in the countries listed below.
Ciprofloxacin is reported as an ingredient of Quinobact in the following countries:
Ciprofloxacin lactate (a derivative of Ciprofloxacin) is reported as an ingredient of Quinobact in the following countries:
International Drug Name Search
Ampicin may be available in the countries listed below.
Ampicillin sodium salt (a derivative of Ampicillin) is reported as an ingredient of Ampicin in the following countries:
Ampicillin trihydrate (a derivative of Ampicillin) is reported as an ingredient of Ampicin in the following countries:
International Drug Name Search
Min-Ovral may be available in the countries listed below.
Ethinylestradiol is reported as an ingredient of Min-Ovral in the following countries:
Levonorgestrel is reported as an ingredient of Min-Ovral in the following countries:
International Drug Name Search
The active component of FLOVENT DISKUS is fluticasone propionate, a corticosteroid having the chemical name S-(fluoromethyl) 6α,9 - difluoro - 11β,17 - dihydroxy - 16α - methyl - 3 - oxoandrosta - 1,4 - diene - 17β - carbothioate, 17-propionate and the following chemical structure:
Fluticasone propionate is a 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.
FLOVENT DISKUS is a specially designed plastic inhalation delivery system containing a double-foil blister strip of a powder formulation of fluticasone propionate intended for oral inhalation only. The DISKUS® inhalation unit, which is the delivery component, is an integral part of the drug product. Each blister on the double-foil strip within the unit contains 50 mcg of microfine fluticasone propionate in 12.5 mg of formulation containing lactose (which contains milk proteins). After a blister containing medication is opened by activating the DISKUS, the medication is dispersed into the airstream created by the patient inhaling through the mouthpiece.
Under standardized in vitro test conditions, FLOVENT DISKUS 50 mcg delivers 46 mcg of fluticasone propionate when tested at a flow rate of 60 L/min for 2 seconds. In adult patients with obstructive lung disease and severely compromised lung function (mean forced expiratory volume in 1 second [FEV1] 20% to 30% of predicted), mean peak inspiratory flow (PIF) through a DISKUS® was 82.4 L/min (range, 46.1 to 115.3 L/min). In children with asthma 4 and 8 years old, mean PIF through FLOVENT DISKUS was 70 and 104 L/min, respectively (range, 48 to 123 L/min).
The actual amount of drug delivered to the lung may depend on patient factors, such as inspiratory flow profile.
Fluticasone propionate is a synthetic trifluorinated corticosteroid with potent anti-inflammatory activity. In vitro assays using human lung cytosol preparations have established fluticasone propionate as a human corticosteroid receptor agonist with an affinity 18 times greater than 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 inhibit multiple cell types (e.g., mast cells, eosinophils, basophils, lymphocytes, macrophages, neutrophils) and mediator production or secretion (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in the asthmatic response. These anti-inflammatory actions of corticosteroids contribute to their efficacy in asthma.
Though effective for the treatment of asthma, corticosteroids do not affect asthma symptoms immediately. Individual patients will experience a variable time to onset and degree of symptom relief. Maximum benefit may not be achieved for 1 to 2 weeks or longer after starting treatment. When corticosteroids are discontinued, asthma stability may persist for several days or longer.
Studies in patients with asthma have shown a favorable ratio between topical anti-inflammatory activity and systemic corticosteroid effects with recommended doses of orally inhaled fluticasone propionate. This is explained by a combination of a relatively high local anti-inflammatory effect, negligible oral systemic bioavailability (<1%), and the minimal pharmacological activity of the only metabolite detected in man.
Fluticasone propionate acts locally in the lung; therefore, plasma levels do not predict therapeutic effect. Studies using oral dosing of labeled and unlabeled drug have demonstrated that the oral systemic bioavailability of fluticasone propionate is negligible (<1%), primarily due to incomplete absorption and presystemic metabolism in the gut and liver. In contrast, the majority of the fluticasone propionate delivered to the lung is systemically absorbed. The systemic bioavailability of fluticasone propionate from the DISKUS device in healthy volunteers averages 18%.
Peak steady-state fluticasone propionate plasma concentrations in adult patients with asthma (N = 11) ranged from undetectable to 266 pg/mL after a 500-mcg twice-daily dosage of fluticasone propionate inhalation powder using the DISKUS device. The mean fluticasone propionate plasma concentration was 110 pg/mL.
Following intravenous administration, the initial disposition phase for fluticasone propionate was rapid and consistent with its high lipid solubility and tissue binding. The volume of distribution averaged 4.2 L/kg.
The percentage of fluticasone propionate bound to human plasma proteins averages 91%. Fluticasone propionate is weakly and reversibly bound to erythrocytes and is not significantly bound to human transcortin.
The total clearance of fluticasone propionate is high (average, 1,093 mL/min), with renal clearance accounting for less than 0.02% of the total. The only circulating metabolite detected in man is the 17β-carboxylic acid derivative of fluticasone propionate, which is formed through the cytochrome P450 3A4 pathway. This metabolite had less affinity (approximately 1/2,000) than the parent drug for the corticosteroid receptor of human lung cytosol in vitro and negligible pharmacological activity in animal studies. Other metabolites detected in vitro using cultured human hepatoma cells have not been detected in man.
Following intravenous dosing, fluticasone propionate showed polyexponential kinetics and had a terminal elimination half-life of approximately 7.8 hours. Less than 5% of a radiolabeled oral dose was excreted in the urine as metabolites, with the remainder excreted in the feces as parent drug and metabolites.
Since fluticasone propionate is predominantly cleared by hepatic metabolism, impairment of liver function may lead to accumulation of fluticasone propionate in plasma. Therefore, patients with hepatic disease should be closely monitored.
Full pharmacokinetic profiles were obtained from 9 female and 16 male patients given 500 mcg twice daily. No overall differences in fluticasone propionate pharmacokinetics were observed.
In a clinical study conducted in patients 4 to 11 years of age with mild to moderate asthma, fluticasone propionate concentrations were obtained in 61 patients at 20 and 40 minutes after dosing with 50 and 100 mcg twice daily of fluticasone propionate inhalation powder using the DISKUS. Plasma concentrations were low and ranged from undetectable (about 80% of the plasma samples) to 88 pg/mL. Mean peak fluticasone propionate plasma concentrations at the 50- and 100-mcg dose levels were 5 and 8 pg/mL, respectively.
Formal pharmacokinetic studies using fluticasone propionate have not been conducted in other special populations.
Fluticasone propionate is a substrate of cytochrome P450 3A4. Coadministration of fluticasone propionate and the highly potent cytochrome P450 3A4 inhibitor ritonavir is not recommended based upon a multiple-dose, crossover drug interaction study in 18 healthy subjects. Fluticasone propionate aqueous nasal spray (200 mcg once daily) was coadministered for 7 days with ritonavir (100 mg twice daily). Plasma fluticasone propionate concentrations following fluticasone propionate aqueous nasal spray alone were undetectable (<10 pg/mL) in most subjects, and when concentrations were detectable, peak levels (Cmax) averaged 11.9 pg/mL (range, 10.8 to 14.1 pg/mL) and AUC(0-τ) averaged 8.43 pg•hr/mL (range, 4.2 to 18.8 pg•hr/mL). Fluticasone propionate Cmax and AUC(0-τ) increased to 318 pg/mL (range, 110 to 648 pg/mL) and 3,102.6 pg•hr/mL (range, 1,207.1 to 5,662.0 pg•hr/mL), respectively, after coadministration of ritonavir with fluticasone propionate aqueous nasal spray. This significant increase in plasma fluticasone propionate concentration resulted in a significant decrease (86%) in plasma cortisol area under the plasma concentration versus time curve (AUC).
Caution should be exercised when other potent cytochrome P450 3A4 inhibitors are coadministered with fluticasone propionate. In a drug interaction study, coadministration of orally inhaled fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily) resulted in increased plasma fluticasone propionate concentration and reduced plasma cortisol AUC, but had no effect on urinary excretion of cortisol.
In another multiple-dose drug interaction study, coadministration of orally inhaled fluticasone propionate (500 mcg twice daily) and erythromycin (333 mg 3 times daily) did not affect fluticasone propionate pharmacokinetics.
In clinical trials with fluticasone propionate inhalation powder using dosages up to and including 250 mcg twice daily, occasional abnormal short cosyntropin tests (peak serum cortisol <18 mcg/dL assessed by radioimmunoassay) were noted both in patients receiving fluticasone propionate and in patients receiving placebo. The incidence of abnormal tests at 500 mcg twice daily was greater than placebo. In a 2-year study carried out with the DISKHALER® inhalation device in 64 patients with mild, persistent asthma (mean FEV1 91% of predicted) randomized to fluticasone propionate 500 mcg twice daily or placebo, no patient receiving fluticasone propionate had an abnormal response to 6-hour cosyntropin infusion (peak serum cortisol<18 mcg/dL). With a peak cortisol threshold <35 mcg/dL, 1 patient receiving fluticasone propionate (4%) had an abnormal response at 1 year; repeat testing at 18 months and 2 years was normal. Another patient receiving fluticasone propionate (5%) had an abnormal response at 2 years. No patient on placebo had an abnormal response at 1 or 2 years.
In a placebo-controlled clinical study conducted in patients 4 to 11 years of age, a 30-minute cosyntropin stimulation test was performed in 41 patients after 12 weeks of dosing with 50 or 100 mcg twice daily of fluticasone propionate via the DISKUS device. One patient receiving fluticasone propionate via DISKUS had a prestimulation plasma cortisol concentration <5 mcg/dL, and 2 patients had a rise in cortisol of <7 mcg/dL. However, all poststimulation values were >18 mcg/dL.
The potential systemic effects of inhaled fluticasone propionate on the hypothalamic-pituitaryadrenal (HPA) axis were also studied in patients with asthma. Fluticasone propionate given by inhalation aerosol at dosages of 220, 440, 660, or 880 mcg twice daily was compared with placebo or oral prednisone 10 mg given once daily for 4 weeks. For most patients, the ability to increase cortisol production in response to stress, as assessed by 6-hour cosyntropin stimulation, remained intact with inhaled fluticasone propionate treatment. No patient had an abnormal response (peak serum cortisol <18 mcg/dL) after dosing with placebo or fluticasone propionate 220 mcg twice daily. For patients treated with 440, 660, and 880 mcg twice daily, 10%, 16%, and 12%, respectively, had an abnormal response as compared to 29% of patients treated with prednisone.
To confirm that systemic absorption does not play a role in the clinical response to inhaled fluticasone propionate, a double-blind clinical study comparing inhaled fluticasone propionate powder and oral fluticasone propionate was conducted. Inhaled fluticasone propionate powder in dosages of 100 and 500 mcg twice daily was compared to oral fluticasone propionate 20,000 mcg once daily and placebo for 6 weeks. Plasma levels of fluticasone propionate were detectable in all 3 active groups, but the mean values were highest in the oral group. Both doses of inhaled fluticasone propionate were effective in maintaining asthma stability and improving lung function, while oral fluticasone propionate and placebo were ineffective. This demonstrates that the clinical effectiveness of inhaled fluticasone propionate is due to its direct local effect and not to an indirect effect through systemic absorption.
Four randomized, double-blind, parallel-group, placebo-controlled, US clinical trials were conducted in 1,036 adolescent and adult patients (≥12 years of age) with asthma to assess the efficacy and safety of fluticasone propionate inhalation powder in the treatment of asthma. Fixed dosages of 100, 250, and 500 mcg twice daily were compared with placebo to provide information about appropriate dosing to cover a range of asthma severity. Patients in these studies included those not adequately controlled with bronchodilators alone and those already maintained on daily inhaled corticosteroids. All doses were delivered by inhalation of the contents of 1 or 2 blisters from the DISKUS twice daily.
Figures 1 through 4 display results of pulmonary function tests (mean percent change from baseline in FEV1 prior to AM dose) for 3 recommended dosages of fluticasone propionate inhalation powder (100, 250, and 500 mcg twice daily) and placebo from the four 12-week trials in adolescents and adults. These trials used predetermined criteria for lack of efficacy (indicators of worsening asthma), resulting in withdrawal of more patients in the placebo group. Therefore, pulmonary function results at Endpoint (the last evaluable FEV1 result, including most patients’ lung function data) are also displayed. Pulmonary function at recommended dosages of fluticasone propionate improved significantly compared with placebo by the first week of treatment, and improvement was maintained for up to 1 year or more.
Figure 1. A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 100 mcg Twice Daily in Adolescents and Adults Receiving Bronchodilators Alone
Figure 2. A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 100 mcg Twice Daily in Adolescents and Adults Receiving Inhaled Corticosteroids
Figure 3. A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 250 mcg Twice Daily in Adolescents and Adults Receiving Inhaled Corticosteroids or Bronchodilators Alone
Figure 4. A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 500 mcg Twice Daily in Adolescents and Adults Receiving Inhaled Corticosteroids or Bronchodilators Alone
In all 4 efficacy trials, measures of pulmonary function (FEV1) were statistically significantly improved as compared with placebo at all twice-daily doses. Patients on all dosages of FLOVENT DISKUS were also less likely to discontinue study participation due to asthma deterioration (as defined by predetermined criteria for lack of efficacy including lung function and patient-recorded variables such as AM PEF, albuterol use, and nighttime awakenings due to asthma) compared with placebo.
In a clinical trial of 111 patients with severe asthma requiring chronic oral prednisone therapy (average baseline daily prednisone dose was 14 mg), fluticasone propionate given by inhalation powder at doses of 500 and 1,000 mcg twice daily was evaluated. Both doses enabled a statistically significantly larger percentage of patients to wean successfully from oral prednisone as compared with placebo (75% of the patients on 500 mcg twice daily and 89% of the patients on 1,000 mcg twice daily as compared with 9% of patients on placebo). Accompanying the reduction in oral corticosteroid use, patients treated with fluticasone propionate had significantly improved lung function and fewer asthma symptoms as compared with the placebo group.
A 12-week, placebo-controlled clinical trial was conducted in 437 patients (177 on fluticasone propionate via DISKUS) aged 4 to 11 years, approximately half of whom were receiving inhaled corticosteroids at baseline. In this study, doses of fluticasone propionate inhalation powder 50 and 100 mcg twice daily significantly improved FEV1 (15% and 18% change from baseline at Endpoint, respectively) compared to placebo (7% change). Morning peak expiratory flow rate was also significantly improved with doses of fluticasone propionate 50 and 100 mcg twice daily (26% and 27% change from baseline at Endpoint, respectively) compared to placebo (14% change). In this study, patients on active treatment were significantly less likely to discontinue treatment due to asthma deterioration (as defined by predetermined criteria for lack of efficacy including lung function and patient recorded variables such as AM PEFR, albuterol use, and nighttime awakenings due to asthma).
Two other 12-week placebo-controlled clinical trials were conducted in 504 pediatric patients with asthma, approximately half of whom were receiving inhaled corticosteroids at baseline. In these studies, fluticasone propionate inhalation powder was efficacious at doses of 50 and 100 mcg twice daily when compared to placebo on major endpoints including lung function and symptom scores. Pulmonary function improved significantly compared with placebo by the first week of treatment, and patients treated with fluticasone propionate were also less likely to discontinue study participation due to asthma deterioration. One hundred ninety-two (192) patients received fluticasone propionate for up to 1 year during an open-label extension. Data from this open-label extension suggested that lung function improvements could be maintained up to 1 year.
FLOVENT DISKUS is indicated for the maintenance treatment of asthma as prophylactic therapy in adult and pediatric patients 4 years of age and older. It is also indicated for patients requiring oral corticosteroid therapy for asthma. Many of these patients may be able to reduce or eliminate their requirement for oral corticosteroids over time.
FLOVENT DISKUS is NOT indicated for the relief of acute bronchospasm.
FLOVENT DISKUS is contraindicated in the primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required.
Hypersensitivity to any of the ingredients of these preparations contraindicates their use (see DESCRIPTION and ADVERSE REACTIONS: Observed During Clinical Practice: Non-Site Specific).
Particular care is needed for patients who are transferred from systemically active corticosteroids to FLOVENT DISKUS because deaths due to adrenal insufficiency have occurred in patients with asthma 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 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 fluticasone propionate inhalation powder may provide 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 that is necessary for coping with these emergencies.
During periods of stress or a 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 warning card indicating that they may need supplementary systemic corticosteroids during periods of stress or a severe asthma attack.
A drug interaction study in healthy subjects has shown that ritonavir (a highly potent cytochrome P450 3A4 inhibitor) can significantly increase plasma fluticasone propionate concentration, resulting in significantly reduced serum cortisol concentrations (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Drug Interactions and PRECAUTIONS: Drug Interactions: Inhibitors of Cytochrome P450). 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 syndrome and adrenal suppression. Therefore, coadministration of fluticasone propionate and ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to fluticasone propionate inhalation powder. In a clinical trial of 111 patients, prednisone reduction was successfully accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during transfer to inhaled fluticasone propionate. Successive reduction of prednisone dose was allowed only when lung function; symptoms; and as-needed, short-acting beta-agonist use were better than or comparable to that seen before initiation of prednisone dose reduction. Lung function (FEV1 or AM PEF), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral 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 FLOVENT DISKUS may unmask conditions previously suppressed by the systemic corticosteroid therapy, e.g., rhinitis, conjunctivitis, eczema, arthritis, and eosinophilic conditions.
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 exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) 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.
FLOVENT DISKUS is not to be regarded as a bronchodilator and is not indicated for rapid relief of bronchospasm.
As with other inhaled medications, bronchospasm may occur with an immediate increase in wheezing after dosing. If bronchospasm occurs following dosing with FLOVENT DISKUS, it should be treated immediately with a fast-acting inhaled bronchodilator. Treatment with FLOVENT DISKUS should be discontinued and alternative therapy instituted.
Patients should be instructed to contact their physicians immediately when episodes of asthma that are not responsive to bronchodilators occur during the course of treatment with FLOVENT DISKUS. During such episodes, patients may require therapy with oral corticosteroids.
Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients (see PRECAUTIONS: Pediatric Use.)
During withdrawal from systemically active corticosteroids, some patients may experience symptoms of corticosteroid withdrawal, e.g., joint and/or muscular pain, lassitude, and depression, despite maintenance or even improvement of respiratory function.
Fluticasone propionate 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 FLOVENT DISKUS 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. Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing FLOVENT DISKUS.
Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with FLOVENT DISKUS 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 FLOVENT DISKUS is administered at higher than recommended doses over prolonged periods of time. If such effects occur, the dosage of FLOVENT DISKUS should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids and for management of asthma.
The long-term effects of fluticasone propionate in human subjects are not fully known. In particular, the effects resulting from chronic use of fluticasone propionate on developmental or immunologic processes in the mouth, pharynx, trachea, and lung are unknown. Some patients have received inhaled fluticasone propionate on a continuous basis for periods of 3 years or longer. In clinical studies with patients treated for 2 years with inhaled fluticasone propionate, no apparent differences in the type or severity of adverse reactions were observed after long- versus short-term treatment.
Rare instances of glaucoma, increased intraocular pressure, and cataracts have been reported in patients following the long term administration of inhaled corticosteroids, including fluticasone propionate.
In clinical studies with inhaled fluticasone propionate, the development of localized infections of the pharynx with Candida albicans has occurred. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral antifungal) therapy while remaining on treatment with FLOVENT DISKUS, but at times therapy with FLOVENT DISKUS may need to be interrupted.
Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; untreated systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.
In rare cases, patients on inhaled fluticasone propionate may present with systemic eosinophilic conditions, with some patients presenting with 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 inhaled corticosteroids 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 (see ADVERSE REACTIONS: Observed During Clinical Practice: Eosinophilic Conditions).
Patients being treated with FLOVENT DISKUS should receive the following information and instructions. This information is intended to aid them in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects.
It is important that patients understand how to use the DISKUS inhalation device appropriately and how it should be used in relation to other asthma medications they are taking. Patients should be given the following information:
Fluticasone propionate is a substrate of cytochrome P450 3A4. A drug interaction study with fluticasone propionate aqueous nasal spray in healthy subjects has shown that ritonavir (a highly potent cytochrome P450 3A4 inhibitor) can significantly increase plasma fluticasone propionate concentration, resulting in significantly reduced serum cortisol concentrations (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Drug Interactions). 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 syndrome and adrenal suppression. Therefore, coadministration of fluticasone propionate and ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
In a placebo-controlled crossover study in 8 healthy volunteers, coadministration of a single dose of orally inhaled fluticasone propionate (1,000 mcg) with multiple doses of ketoconazole (200 mg) to steady state resulted in increased plasma fluticasone propionate concentrations, a reduction in plasma cortisol AUC, and no effect on urinary excretion of cortisol. Caution should be exercised when FLOVENT DISKUS is coadministered with ketoconazole and other known potent cytochrome P450 3A4 inhibitors.
Fluticasone propionate demonstrated no tumorigenic potential in mice at oral doses up to 1,000 mcg/kg (approximately 2 times the maximum recommended daily inhalation dose in adults and approximately 10 times the maximum recommended daily inhalation dose in children on a mcg/m2 basis) for 78 weeks or in rats at inhalation doses up to 57 mcg/kg (less than the maximum recommended daily inhalation dose in adults and approximately equal to the maximum recommended daily inhalation dose in children on a mcg/m2 basis) for 104 weeks.
Fluticasone propionate did not induce gene mutation in prokaryotic or eukaryotic cells in vitro. No significant clastogenic effect was seen in cultured human peripheral lymphocytes in vitro or in the mouse micronucleus test.
No evidence of impairment of fertility was observed in reproductive studies conducted in male and female rats at subcutaneous doses up to 50 mcg/kg (less than the maximum recommended daily inhalation dose in adults on a mcg/m2 basis). Prostate weight was significantly reduced at a subcutaneous dose of 50 mcg/kg.
Pregnancy Category C. Subcutaneous studies in the mouse and rat at 45 and 100 mcg/kg, respectively (less than the maximum recommended daily inhalation dose in adults on a mcg/m2 basis), revealed fetal toxicity characteristic of potent corticosteroid compounds, including embryonic growth retardation, omphalocele, cleft palate, and retarded cranial ossification. No teratogenicity was seen in the rat at inhalation doses up to 68.7 mcg/kg (less than the maximum recommended daily inhalation dose in adults on a mcg/m2 basis).
In the rabbit, fetal weight reduction and cleft palate were observed at a subcutaneous dose of 4 mcg/kg (less than the maximum recommended daily inhalation dose in adults on a mcg/m2 basis). However, no teratogenic effects were reported at oral doses up to 300 mcg/kg (approximately 3 times the maximum recommended daily inhalation dose in adults on a mcg/m2 basis) of fluticasone propionate. No fluticasone propionate was detected in the plasma in this study, consistent with the established low bioavailability following oral administration (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Absorption).
Fluticasone propionate crossed the placenta following administration of a subcutaneous dose of 100 mcg/kg to mice (less than the maximum recommended daily inhalation dose in adults on a mcg/m2 basis), a subcutaneous or an oral dose of 100 mcg/kg to rats (less than the maximum recommended daily inhalation dose in adults on a mcg/m2 basis), and an oral dose of 300 mcg/kg to rabbits (approximately 3 times the maximum recommended daily inhalation dose in adults on a mcg/m2 basis).
There are no adequate and well-controlled studies in pregnant women. FLOVENT DISKUS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Experience with oral corticosteroids since their introduction in pharmacologic, as opposed to physiologic, doses suggests that rodents are more prone to teratogenic effects from corticosteroids than humans. In addition, because there is a natural increase in corticosteroid production during pregnancy, most women will require a lower exogenous corticosteroid dose and many will not need corticosteroid treatment during pregnancy.
It is not known whether fluticasone propionate is excreted in human breast milk. However, other corticosteroids have been detected in human milk. Subcutaneous administration to lactating rats of 10 mcg/kg of tritiated fluticasone propionate (less than the maximum recommended daily inhalation dose in adults on a mcg/m2 basis) resulted in measurable radioactivity in the milk.Since there are no data from controlled trials on the use of FLOVENT DISKUS by nursing mothers, a decision should be made whether to discontinue nursing or to discontinue FLOVENT DISKUS, taking into account the importance of FLOVENT DISKUS to the mother.
Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. A reduction of growth velocity in children or teenagers may occur as a result of poorly controlled asthma or from use of corticosteroids including inhaled corticosteroids. The effects of long-term treatment of children and adolescents with inhaled corticosteroids, including fluticasone propionate, on final adult height are not known.
Controlled clinical studies have shown that inhaled corticosteroids may cause a reduction in growth in pediatric patients. In these studies, the mean reduction in growth velocity was approximately 1 cm/year (range, 0.3 to 1.8 cm/year) and appears to depend upon dose and duration of exposure. This effect was observed in the absence of laboratory evidence of 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 effects on growth velocity of treatment with orally inhaled corticosteroids for over 1 year, including the impact on final adult height, are unknown. The growth of children and adolescents receiving orally inhaled corticosteroids, including FLOVENT DISKUS, should be monitored routinely (e.g., via stadiometry). The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained and the risks associated with alternative therapies. To minimize the systemic effects of orally inhaled corticosteroids, including FLOVENT DISKUS, each patient should be titrated to the lowest dose that effectively controls his/her symptoms.
A 52-week, placebo-controlled study to assess the potential growth effects of fluticasone propionate inhalation powder (FLOVENT® ROTADISK®) at 50 and 100 mcg twice daily was conducted in the US in 325 prepubescent children (244 males and 81 females) aged 4 to 11 years. The mean growth velocities at 52 weeks observed in the intent-to-treat population were 6.32 cm/year in the placebo group (n = 76), 6.07 cm/year in the 50-mcg group (n = 98), and 5.66 cm/year in the 100-mcg group (n = 89). An imbalance in the proportion of children entering puberty between groups and a higher dropout rate in the placebo group due to poorly controlled asthma may be confounding factors in interpreting these data. A separate subset analysis of children who remained prepubertal during the study revealed growth rates at 52 weeks of 6.10 cm/year in the placebo group (n = 57), 5.91 cm/year in the 50-mcg group (n = 74), and 5.67 cm/year in the 100-mcg group (n = 79). In children 8.5 years of age, the mean age of children in this study, the range for expected growth velocity is: boys − 3rd percentile = 3.8 cm/year, 50th percentile = 5.4 cm/year, and 97th percentile = 7.0 cm/year; girls − 3rd percentile = 4.2 cm/year, 50th percentile =5.7 cm/year, and 97th percentile = 7.3 cm/year.
The clinical significance of these growth data is not certain. Physicians should closely follow the growth of children and adolescents taking corticosteroids by any route, and weigh the benefits of corticosteroid therapy against the possibility of growth suppression if growth appears slowed. Patients should be maintained on the lowest dose of inhaled corticosteroid that effectively controls their asthma.
The safety and effectiveness of FLOVENT DISKUS in children below 4 years of age have not been established.
Safety data have been collected on 280 patients (FLOVENT DISKUS n = 83, Flovent Rotadisk n = 197) 65 years of age or older and 33 patients (FLOVENT DISKUS n = 14, Flovent Rotadisk n = 19) 75 years of age or older who have been treated with fluticasone propionate inhalation powder in US and non-US clinical trials. There were no differences in adverse reactions compared to those reported by younger patients. In addition, there were no apparent differences in efficacy between patients 65 years of age or older and younger patients. Fifteen patients 65 years of age or older and 1 patient 75 years of age or older were included in the efficacy evaluation of US clinical studies.
The incidence of common adverse events in Table 1 is based upon 7 placebo-controlled US clinical trials in which 1,176 pediatric, adolescent, and adult patients (466 females and 710 males) previously treated with as-needed bronchodilators and/or inhaled corticosteroids were treated with FLOVENT DISKUS (doses of 50 to 500 mcg twice daily for up to 12 weeks) or placebo.
| Adverse Event | Placebo (n = 543) % | FLOVENT DISKUS 50 mcg Twice Daily (n = 178) % | FLOVENT DISKUS 100 mcg Twice Daily (n = 305) % | FLOVENT DISKUS 250 mcg Twice Daily (n = 86) % | FLOVENT DISKUS 500 mcg Twice Daily (n = 64) % |
| Ear, nose, and throat | |||||
| Upper respiratory tract infection | 16 | 20 | 18 | 21 | 14 |
| Throat irritation | 8 | 13 | 13 | 3 | 22 |
| Sinusitis/sinus infection | 6 | 9 | 10 | 6 | 6 |
| Upper respiratory inflammation | 3 | 5 | 5 | 0 | 5 |
| Rhinitis | 2 | 4 | 3 | 1 | 2 |
| Oral candidiasis | 7 | <1 | 9 | 6 | 5 |
| Gastrointestinal | |||||
| Nausea and vomiting | 4 | 8 | 4 | 1 | 2 |
In some countries, this medicine may only be approved for veterinary use.
BAN
0035575-96-3
C9-H10-Cl-N2-O5-P-S
324
Insecticide
S-[(6-Chloro-2,3-dihydro-2-oxo-1,3-oxazolo[4,5-b]pyridin-3-yl)methyl]-O,O-dimethylphosphorothioate
International Drug Name Search
Glossary
| BAN | British Approved Name |
| IS | Inofficial Synonym |
| OS | Official Synonym |
Each capsule contains
Oxytetracycline hydrochloride equivalent to. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250 mg
oxytetracycline
Sulfamethizole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250 mg
Phenazopyridine hydrochloride . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 mg
Inert ingredients in the formulation are: hard gelatin capsules (which may contain Green 3, Yellow 6, Yellow 10 and other inert ingredients); magnesium stearate; sodium lauryl sulfate; starch.
Urobiotic-250 is a product designed for use specifically in urinary tract infections.
Terramycin® (oxytetracycline HCl) is a widely used antibiotic with clinically proved activity against gram-positive and gram-negative bacteria, rickettsiae, spirochetes, large viruses, and certain protozoa. Terramycin is well tolerated and well absorbed after oral administration. It diffuses readily through the placenta and is present in the fetal circulation. It diffuses into the pleural fluid, and under some circumstances, into the cerebrospinal fluid. Oxytetracycline HCl appears to be concentrated in the hepatic system and is excreted in the bile. It is excreted in the urine and in the feces, in high concentrations, in a biologically active form.
Sulfamethizole is a chemotherapeutic agent active against a number of important gram-positive and gram-negative bacteria. This sulfonamide is well absorbed, has a low degree of acetylation, and is extremely soluble. Because of these features and its rapid renal excretion, sulfamethizole has a low order of toxicity and provides prompt and high concentrations of the active drug in the urinary tract.
Phenazopyridine is an orally absorbed agent which produces prompt and effective local analgesia and relief of urinary symptoms by virtue of its rapid excretion in the urinary tract. These effects are confined to the genitourinary system and are not accompanied by generalized sedation or narcosis.
Based on a review of this drug by the National Academy of Sciences-National Research Council and/or other information, FDA has classified the indications as follows:
"Lacking substantial evidence of effectiveness as a fixed combination":
Urobiotic-250 is indicated in the therapy of a number of genitourinary infections caused by susceptible organisms. These infections include the following: pyelonephritis, pyelitis, ureteritis, cystitis, prostatitis, and urethritis.
Since both Terramycin and sulfamethizole provide effective levels in blood, tissue, and urine, Urobiotic-250 provides a multiple antimicrobial approach at the site of infection. Both antibacterial components are active against the most common urinary pathogens, including Escherichia coli, Pseudomonas aeruginosa, Aerobacter aerogenes, Streptococcus faecalis, Streptococcus hemolyticus, and Micrococcus pyogenes. Urobiotic-250 is particularly useful in the treatment of infections caused by bacteria more sensitive to the combination than to either component alone. The combination is also of value in those cases with mixed infections, and in those instances where the causative organism is unknown pending laboratory isolation.
Final classification of the less than effective indications requires further investigation. Clinical studies to substantiate the efficacy of Urobiotic 250 are ongoing. Completion of these ongoing studies will provide data for final classification of these indications.
This drug is contraindicated in individuals who have shown hypersensitivity to any of its components.
This drug, because of the sulfonamide component, should not be used in patients with a history of sulfonamide sensitivities, and in pregnant females at term.
If renal impairment exists, even usual oral or parenteral doses may lead to excessive systemic accumulation of the drug and possible liver toxicity. Under such conditions, lower than usual doses are indicated and if therapy is prolonged, tetracycline serum level determinations may be advisable.
Oxytetracycline HCl, which is one of the ingredients of Urobiotic-250, may form a stable calcium complex in any bone-forming tissue with no serious harmful effects reported thus far in humans. However, use of oxytetracycline during tooth development (last trimester of pregnancy, neonatal period and early childhood) may cause discoloration of the teeth (yellow-grey-brownish). This effect occurs mostly during long term use of the drug but it also has been observed in usual short treatment courses.
Because of its sulfonamide content, this drug should be used only after critical appraisal in patients with liver damage, renal damage, urinary obstruction, or blood dyscrasias. Deaths have been reported from hypersensitivity reactions, agranulocytosis, aplastic anemia, and other blood dyscrasias associated with sulfonamide administration. When used intermittently, or for a prolonged period, blood counts and liver and kidney function tests should be performed.
Certain hypersensitive individuals may develop a photodynamic reaction precipitated by exposure to direct sunlight during the use of this drug. This reaction is usually of the photoallergic type which may also be produced by other tetracycline derivatives. Individuals with a history of photosensitivity reactions should be instructed to avoid exposure to direct sunlight while under treatment with this or other tetracycline drugs, and treatment should be discontinued at first evidence of skin discomfort.
NOTE: Reactions of a photoallergic nature are exceedingly rare with Terramycin (oxytetracycline HCl). Phototoxic reactions are not believed to occur with Terramycin.
As with all antibiotic preparations, use of this drug may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, the antibiotic should be discontinued and appropriate specific therapy should be instituted. This drug should be used with caution in persons having histories of significant allergies and/or asthma.
Glossitis, stomatitis, proctitis, nausea, diarrhea, vaginitis, and dermatitis, as well as reactions of an allergic nature, may occur during oxytetracycline HCl therapy, but are rare. If adverse reactions, individual idiosyncrasy, or allergy occur, discontinue medication. Rare instances of esophagitis and esophageal ulcerations have been reported in patients receiving capsule forms of drugs in the tetracycline class. Most of these patients took medications immediately before going to bed. (See Dosage and Administration.)
With oxytetracycline therapy bulging fontanels in infants and benign intracranial hypertension in adults have been reported in individuals receiving full therapeutic dosages. These conditions disappeared rapidly when the drug was discontinued.
As in all sulfonamide therapy, the following reactions may occur: nausea, vomiting, diarrhea, hepatitis, pancreatitis, blood dyscrasias, neuropathy, drug fever, skin rash, injection of the conjunctiva and sclera, petechiae, purpura, hematuria and crystalluria. The dosage should be decreased or the drug withdrawn, depending upon the severity of the reaction.
Urobiotic-250 is recommended in adults only. A dose of 1 capsule four times daily is suggested. In refractory cases 2 capsules four times a day may be used.
Therapy should be continued for a minimum of seven days or until bacteriologic cure in acute urinary tract infections.
Administration of adequate amounts of fluid along with capsule forms of drugs in the tetracycline class is recommended to wash down the drugs and reduce the risk of esophageal irritation and ulceration. (SeeAdverse Reactions.)
To aid absorption of the drug, it should be given at least one hour before or two hours after eating. Aluminum hydroxide gel given with antibiotics has been shown to decrease their absorption and is contraindicated.
Urobiotic-250 capsules: bottles of 50 (NDC 0049-0920-50), and unit dose packages of 100 (10 × 10's) (NDC 0049-0920-41).
Rx only
70-1636-00-9
December 1986
| Urobiotic oxytetracycline hydrochloride, sulfamethizole and phenazopyridine hydrochloride capsule | ||||||||||||||||||||||||||||||||||||
| ||||||||||||||||||||||||||||||||||||
| ||||||||||||||||||||||||||||||||||||
| ||||||||||||||||||||||||||||||||||||
| ||||||||||||||||||||||||||||||||||||
Citalopram Heumann may be available in the countries listed below.
Citalopram hydrobromide (a derivative of Citalopram) is reported as an ingredient of Citalopram Heumann in the following countries:
International Drug Name Search
