Insulin Protaphane HM Penfill may be available in the countries listed below.
Insulin, Isophane human (a derivative of Insulin, Isophane) is reported as an ingredient of Insulin Protaphane HM Penfill in the following countries:
International Drug Name Search
Zyflo CR is indicated for the prophylaxis and chronic treatment of asthma in adults and children 12 years of age and older.
Zyflo CR is not indicated for use in the reversal of bronchospasm in acute asthma attacks. Therapy with Zyflo CR can be continued during acute exacerbations of asthma.
The recommended dosage of Zyflo CR for the treatment of patients with asthma is two 600 mg extended-release tablets twice daily, within one hour after morning and evening meals, for a total daily dose of 2400 mg. Tablets should not be chewed, cut or crushed. If a dose is missed, the patient should take the next dose at the scheduled time and not double the dose. Assess hepatic function enzymes prior to initiation of Zyflo CR and periodically during treatment [see Contraindications (4), Warnings and Precautions (5), and Use in Specific Populations (8.7)].
Extended-release tablets, 600 mg.
The use of Zyflo CR is contraindicated in patients with:
Elevations of one or more hepatic function enzymes and bilirubin may occur during Zyflo CR therapy. These laboratory abnormalities may progress to clinically significant liver injury, remain unchanged, or resolve with continued treatment, usually within three weeks. The ALT (SGPT) test is considered the most sensitive indicator of liver injury for Zyflo CR.
Assess hepatic function enzymes prior to initiation of, and during therapy with, Zyflo CR. Assess serum ALT before treatment begins, once a month for the first 3 months, every 2-3 months for the remainder of the first year, and periodically thereafter for patients receiving long-term Zyflo CR therapy. If clinical signs and/or symptoms of liver dysfunction develop (e.g., right upper quadrant pain, nausea, fatigue, lethargy, pruritus, jaundice, or "flu-like" symptoms) or transaminase elevations ≥5×ULN occur, discontinue Zyflo CR and follow hepatic function enzymes until normal.
In controlled and open-label clinical studies involving more than 5000 patients treated with zileuton immediate-release tablets, the overall rate of ALT elevation ≥3×ULN was 3.2%. In these trials, one patient developed symptomatic hepatitis with jaundice, which resolved upon discontinuation of therapy. An additional 3 patients with transaminase elevations developed mild hyperbilirubinemia that was less than 3×ULN. There was no evidence of hypersensitivity or other alternative etiologies for these findings.
Since treatment with Zyflo CR may result in increased hepatic function enzymes and liver injury, Zyflo CR should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease.
Neuropsychiatric events have been reported in adult and adolescent patients taking zileuton, the active ingredient in Zyflo CR and zileuton immediate-release tablets. Post-marketing reports with zileuton include sleep disorders and behavior changes. The clinical details of some post-marketing reports involving zileuton appear consistent with a drug-induced effect. Patients and prescribers should be alert for neuropsychiatric events. Patients should be instructed to notify their prescriber if these changes occur. Prescribers should carefully evaluate the risks and benefits of continuing treatment with Zyflo CR if such events occur [see Adverse Reactions (6.3)].
Hepatotoxicity: Elevations of one or more hepatic function enzymes and bilirubin may occur during Zyflo CR therapy [see Warnings and Precautions (5)].
The most commonly occurring adverse reactions (≥5%) with Zyflo CR are sinusitis, nausea, and pharyngolaryngeal pain.
The safety data described below reflect exposure to Zyflo CR in 199 patients for 12 weeks duration. In a 12-week, randomized, double-blind, placebo-controlled trial in adults and adolescents 12 years of age and older with asthma, patients received Zyflo CR two 600 mg tablets (n=199) or placebo (n=198) twice daily by mouth. Eighty-three percent of patients were white, 48% were male, and the mean age was 34 years.
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
The most commonly reported adverse reactions (occurring at a frequency of ≥5%) in Zyflo CR-treated patients and at a frequency greater than placebo-treated patients are reflected in Table 1.
Table 1.
Adverse Reactions with ≥5% Incidence in a 12‑Week Placebo-Controlled Trial in Patients with Asthma.
Adverse Reaction | Zyflo CR 600 mg Twice Daily N=199 n (%) | Placebo 2 Tablets Twice Daily N=198 n (%) |
Sinusitis | 13 (6.5) | 8 (4.0) |
Nausea | 10 (5.0) | 3 (1.5) |
Pharyngolaryngeal pain | 10 (5.0) | 8 (4.0) |
Less common adverse reactions occurring at a frequency ≥1% and more often in the Zyflo CR group than in the placebo group included gastrointestinal disorders (upper abdominal pain, diarrhea, dyspepsia, vomiting), rash, hypersensitivity, and hepatotoxicity.
There were no differences in the incidence of adverse reactions based upon gender. The clinical trials did not include sufficient numbers of patients <18 years of age or non-Caucasians to determine whether there is any difference in adverse reactions based upon age or race.
In the 12-week placebo-controlled trial, the incidence of ALT elevations (≥3×ULN) was 2.5% (5 of 199) in the Zyflo CR group, compared to 0.5% (1 of 198) in the placebo group. In the Zyflo CR group, the majority of ALT elevations (60%) occurred in the first month of treatment, and in 2 of the 5 patients in the Zyflo CR group, ALT elevations were detected 14 days after completion of the 3-month study treatment. The levels returned to <2×ULN or normal within 9 and 12 days, respectively. The ALT elevations in the other 3 patients were observed to return to <2×ULN or normal within 15, 19, and 31 days after Zyflo CR discontinuation. There appeared to be no clinically relevant relationship between the time of onset and the magnitude of the first elevation or the magnitude of first elevation and time to resolution. The hepatic function enzyme elevations attributed to Zyflo CR did not result in any cases of jaundice, development of chronic liver disease, or death in this clinical trial.
The safety of Zyflo CR was evaluated in one 6-month, randomized, double-blind, placebo-controlled clinical trial in adults and adolescents 12 years of age and older with asthma. Patients received two 600 mg Zyflo CR tablets (n=619) or placebo (n=307) twice daily by mouth along with usual asthma care. Eighty-six percent of patients were white, 40% were male, and the overall mean age was 36.
The rate and type of adverse reactions observed in this study were comparable to the adverse reactions observed in the 12-week study. Other commonly reported adverse reactions (occurring at a frequency of ≥5%) in Zyflo CR-treated patients and at a frequency greater than placebo-treated patients included the following: headache (23%), upper respiratory tract infection (9%), myalgia (7%), and diarrhea (5%) compared to 21%, 7%, 5% and 2%, respectively, in the placebo-treated group.
ALT elevations (≥3×ULN) were observed in 1.8% of patients treated with Zyflo CR compared to 0.7% in patients treated with placebo. The majority of elevations (82%) were reported within the first 3 months of treatment and resolved within 21 days for most of these patients after discontinuation of the drug. The hepatic function enzyme elevations attributed to Zyflo CR did not result in any cases of jaundice, development of chronic liver disease, or death in this clinical trial.
Occurrences of low white blood cell (WBC) count (<3.0 × 109/L) were observed in 2.6% (15 of 619) of the Zyflo CR-treated patients and in 1.7% (5 of 307) of the placebo-treated patients. The WBC counts returned to normal or baseline following discontinuation of Zyflo CR. The clinical significance of these findings is not known.
The following adverse reactions have been identified during post-approval use of zileuton immediate-release tablets and may be applicable to Zyflo CR. 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.
Cases of severe hepatic injury have been reported in patients taking zileuton immediate-release tablets. These cases included death, life-threatening liver injury with recovery, symptomatic jaundice, hyperbilirubinemia, and elevations of ALT >8×ULN.
Cases of sleep disorders and behavior changes have also been reported [see Warnings and Precautions (5.2)].
The following study results were obtained using zileuton immediate-release tablets but the conclusions also apply to Zyflo CR.
In a drug-interaction study in 16 healthy subjects, co-administration of multiple doses of zileuton immediate-release tablets (800 mg every 12 hours) and theophylline (200 mg every 6 hours) for 5 days resulted in a significant decrease (approximately 50%) in steady-state clearance of theophylline, an approximate doubling of theophylline AUC, and an increase in theophylline Cmax (by 73%). The elimination half-life of theophylline was increased by 24%. Also, during co-administration, theophylline-related adverse reactions were observed more frequently than after theophylline alone. Upon initiation of Zyflo CR in patients receiving theophylline, the theophylline dosage should be reduced by approximately one-half and plasma theophylline concentrations monitored. Similarly, when initiating therapy with theophylline in a patient receiving Zyflo CR, the maintenance dose and/or dosing interval of theophylline should be adjusted accordingly and guided by serum theophylline determinations.
Concomitant administration of multiple doses of zileuton immediate-release tablets (600 mg every 6 hours) and warfarin (fixed daily dose obtained by titration in each subject) to 30 healthy male subjects resulted in a 15% decrease in R-warfarin clearance and an increase in AUC of 22%. The pharmacokinetics of S-warfarin were not affected. These pharmacokinetic changes were accompanied by a clinically significant increase in prothrombin times. Monitoring of prothrombin time, or other suitable coagulation tests, with the appropriate dose titration of warfarin is recommended in patients receiving concomitant Zyflo CR and warfarin therapy.
Co-administration of zileuton immediate-release tablets and propranolol results in a significant increase in propranolol concentrations. Administration of a single 80 mg dose of propranolol in 16 healthy male subjects who received zileuton immediate-release tablets 600 mg every 6 hours for 5 days resulted in a 42% decrease in propranolol clearance. This resulted in an increase in propranolol Cmax, AUC, and elimination half-life by 52%, 104%, and 25%, respectively. There was an increase in β-blockade as shown by a decrease in heart rate associated with the co-administration of these drugs. Patients concomitantly on Zyflo CR and propranolol should be closely monitored and the dose of propranolol reduced as necessary. No formal drug-drug interaction studies between zileuton and other beta-adrenergic blocking agents (i.e., β-blockers) have been conducted. It is reasonable to employ appropriate clinical monitoring when these drugs are co-administered with Zyflo CR.
Drug-drug interaction studies conducted in healthy subjects between zileuton immediate-release tablets and prednisone and ethinyl estradiol (oral contraceptive), drugs known to be metabolized by the CYP3A4 isoenzyme, have shown no significant interaction. However, no formal drug-drug interaction studies between zileuton and CYP3A4 inhibitors, such as ketaconazole, have been conducted. It is reasonable to employ appropriate clinical monitoring when these drugs are co-administered with Zyflo CR.
Drug-drug interaction studies in healthy subjects have been conducted with zileuton immediate-release tablets and digoxin, phenytoin, sulfasalazine, and naproxen. There was no significant interaction between zileuton and any of these drugs.
Information on specific populations is based on studies conducted with zileuton immediate-release tablets and is applicable to Zyflo CR.
Pregnancy Category C:
Developmental studies indicated adverse effects (reduced body weight and increased skeletal variations) in rats at an oral dose of 300 mg/kg/day (providing greater than 10 times the systemic exposure [AUC] achieved at the maximum recommended human daily oral dose). Comparative systemic exposure [AUC] is based on measurements in nonpregnant female rats at a similar dosage. Zileuton and/or its metabolites cross the placental barrier of rats. Three of 118 (2.5%) rabbit fetuses had cleft palates at an oral dose of 150 mg/kg/day (equivalent to the maximum recommended human daily oral dose on a mg/m2 basis). There are no adequate and well-controlled studies in pregnant women. Zyflo CR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Zileuton and/or its metabolites are excreted in rat milk. It is not known if zileuton is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for tumorigenicity shown for zileuton in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
The safety and effectiveness of Zyflo CR in pediatric patients under 12 years of age have not been established. FDA has not required pediatric studies in patients under the age of 12 years due to the risk of hepatotoxicity. Zyflo CR is not appropriate for children less than 12 years of age.
Subgroup analysis of controlled and open-label clinical studies with zileuton immediate-release tablets suggests that females ≥65 years of age appear to be at increased risk of ALT elevations. In Zyflo CR placebo-controlled studies there were no discernable trends in ALT elevations noted in subset analyses for patients ≥65 years of age, although the database may not have been sufficiently large to detect a trend [see Pharmacokinetics (12.3)].
Dosing adjustment in patients with renal dysfunction or patients undergoing hemodialysis is not necessary [see Pharmacokinetics (12.3)].
Zyflo CR is contraindicated in patients with active liver disease or persistent ALT elevations ≥3×ULN [see Warnings and Precautions (5) and Pharmacokinetics (12.3)].
Human experience of acute overdose with zileuton is limited. A patient in a clinical study took between 6.6 and 9.0 grams of zileuton immediate-release tablets in a single dose. Vomiting was induced and the patient recovered without sequelae. Zileuton is not removed by dialysis. Should an overdose occur, the patient should be treated symptomatically and supportive measures instituted as required. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage; usual precautions should be observed to maintain the airway. A Certified Poison Control Center should be consulted for up-to-date information on management of overdose with Zyflo CR.
The oral minimum lethal doses in mice and rats were 500-4000 and 300-1000 mg/kg, respectively (providing greater than 3 and 9 times the systemic exposure [AUC] achieved at the maximum recommended human daily oral dose, respectively). In dogs, at an oral dose of 1000 mg/kg (providing in excess of 12 times the systemic exposure [AUC] achieved at the maximum recommended human daily oral dose) no deaths occurred but nephritis was reported.
Zileuton is an orally active inhibitor of 5-lipoxygenase, the enzyme that catalyzes the formation of leukotrienes from arachidonic acid. Zileuton has the chemical name (±)-1-(1-Benzo[b]thien-2-ylethyl)-1-hydroxyurea and the following chemical structure:
zileuton
Zyflo CR (zileuton) extended-release tablets for oral administration are triple-layer tablets comprised of an immediate-release layer, a middle (barrier) layer, and an extended-release layer. Zyflo CR tablets are oblong, film-coated tablets with one red layer between two white layers, debossed on one side with "CT2". Each tablet contains 600 mg of zileuton and the following inactive ingredients: crospovidone, ferric oxide, glyceryl behenate, hydroxypropyl cellulose, hypromellose, magnesium stearate, mannitol, microcrystalline cellulose, povidone, pregelatinized starch, propylene glycol, sodium starch glycolate, and talc.
Zileuton is an inhibitor of 5-lipoxygenase and thus inhibits leukotriene (LTB4, LTC4, LTD4 and LTE4) formation. Both the R(+) and S(-) enantiomers are pharmacologically active as 5-lipoxygenase inhibitors in in vitro and in vivo systems. Leukotrienes are substances that induce numerous biological effects including augmentation of neutrophil and eosinophil migration, neutrophil and monocyte aggregation, leukocyte adhesion, increased capillary permeability, and smooth muscle contraction. These effects contribute to inflammation, edema, mucus secretion, and bronchoconstriction in the airways of asthmatic patients. LTB4, a chemoattractant for neutrophils and eosinophils, and cysteinyl leukotrienes (LTC4, LTD4, LTE4) can be measured in a number of biological fluids including bronchoalveolar lavage fluid (BALF), blood, urine and sputum from asthmatic patients.
Zileuton is an orally active inhibitor of ex vivo LTB4 formation in several species, including mice, rats, rabbits, dogs, sheep, and monkeys. Zileuton inhibits arachidonic acid-induced ear edema in mice, neutrophil migration in mice in response to polyacrylamide gel, and eosinophil migration into the lungs of antigen-challenged sheep. In a mouse model of allergic inflammation, zileuton inhibited neutrophil and eosinophil influx, reduced the levels of multiple cytokines in the BALF, and reduced serum IgE levels. Zileuton inhibits leukotriene-dependent smooth muscle contractions in vitro in guinea pig and human airways. The compound inhibits leukotriene-dependent bronchospasm in antigen and arachidonic acid-challenged guinea pigs. In antigen-challenged sheep, zileuton inhibits late-phase bronchoconstriction and airway hyperreactivity. The clinical relevance of these findings is unknown.
Zileuton is an orally active inhibitor of ex vivo LTB4 formation in humans. The inhibition of LTB4 formation in whole blood is directly related to zileuton plasma levels. In patients with asthma, the IC50 is estimated to be 0.46 µg/mL, and maximum inhibition ≥80% is reached at a zileuton concentration of 2 µg/mL. In patients with asthma receiving zileuton immediate-release tablets 600 mg four times daily, peak plasma levels averaging 5.9 µg/mL were associated with a mean LTB4 inhibition of 98%. Zileuton inhibits the synthesis of cysteinyl leukotrienes as demonstrated by reduced urinary LTE4 levels.
Information on the pharmacokinetics of zileuton following the administration of zileuton immediate-release tablets is available in healthy subjects. The results of two clinical pharmacology studies using Zyflo CR are described below.
Absorption
A three-way crossover study was conducted in healthy male and female subjects (n=23) with a mean age of 33 (range 20-55) following single dose of 1200 mg (2 × 600 mg) Zyflo CR tablets under fasted and fed conditions, and two doses of 600 mg zileuton immediate-release tablets every 6 hours under fasted conditions. Food increased the peak mean plasma concentrations (Cmax) and the mean extent of absorption (AUC) of Zyflo CR by 18 and 34%, respectively, and prolonged Tmax from 2.1 hours to 4.3 hours. The relative bioavailability of Zyflo CR to zileuton immediate-release tablets with respect to Cmax and AUC under fasted conditions were 0.39 (90% CI: 0.36, 0.43) and 0.57 (90% CI: 0.52, 0.62), respectively. Similarly, relative bioavailability of Zyflo CR to zileuton immediate-release tablets with respect to Cmax and AUC under fed conditions were 0.45 (90% CI: 0.41, 0.49) and 0.76 (90% CI: 0.70, 0.83), respectively.
A three-way crossover study was conducted in healthy male and female subjects (n=24) with a mean age of 35 (range 19-56) following multiple doses of 1200 mg (2 × 600 mg) Zyflo CR tablets administered every 12 hours under fasted and fed conditions, and 600 mg zileuton immediate-release tablets every 6 hours under fed conditions until steady state zileuton levels were achieved. Food increased AUC and Cmin of Zyflo CR by 43% and 170%, respectively, but had no effect on Cmax. Therefore, Zyflo CR is recommended to be administered with food [see Dosage and Administration (2)]. At steady state, relative bioavailability of Zyflo CR to zileuton immediate-release tablets with respect to Cmax, Cmin, and AUC were 0.65 (90% CI: 0.60, 0.71), 1.05 (90% CI: 0.88, 1.25) and 0.85 (90% CI: 0.78, 0.92) respectively. These data indicate that at steady state under fed conditions the Cmax of Zyflo CR is about 35% lower than that of zileuton immediate-release tablets but the Cmin and AUC are similar for both formulations.
Distribution
The apparent volume of distribution (V/F) of zileuton is approximately 1.2 L/kg. Zileuton is 93% bound to plasma proteins, primarily to albumin, with minor binding to α1‑acid glycoprotein.
Elimination
Elimination of zileuton is predominantly via metabolism with a mean terminal half-life of 3.2 hours. Apparent oral clearance (CL/F) of zileuton is 669 mL/min. Zileuton activity is primarily due to the parent drug. Studies with radiolabeled drug have demonstrated that orally administered zileuton is well absorbed into the systemic circulation with 94.5% and 2.2% of the radiolabeled dose recovered in urine and feces, respectively.
Metabolism
In vitro studies utilizing human liver microsomes have shown that zileuton and its N-dehydroxylated metabolite can be oxidatively metabolized by CYP1A2, CYP2C9 and CYP3A4.
Several zileuton metabolites have been identified in human plasma and urine. These include two diastereomeric O-glucuronide conjugates (major metabolites) and an N-dehydroxylated metabolite (A-66193) of zileuton. The urinary excretion of the inactive A-66193 metabolite and unchanged zileuton each accounted for less than 0.5% of the single radiolabeled dose. Multiple doses of 1200 mg Zyflo CR twice daily resulted in peak plasma levels of 4.9 µg/mL of the inactive metabolite A-66193 with an AUC of 93 µg∙hr/mL, showing large inter-subject variability. This inactive metabolite has been shown to be formed by the gastrointestinal microflora prior to the absorption of zileuton and its formation increases with delayed absorption of zileuton.
Renal Impairment
The pharmacokinetics of zileuton immediate-release tablets were similar in healthy subjects and in subjects with mild, moderate, and severe renal insufficiency. In subjects with renal failure requiring hemodialysis, zileuton pharmacokinetics were not altered by hemodialysis and a very small percentage of the administered zileuton dose (<0.5%) was removed by hemodialysis. Hence, dosing adjustment in patients with renal dysfunction or undergoing hemodialysis is not necessary.
Hepatic Impairment
The pharmacokinetics of zileuton immediate-release tablets were compared between subjects with mild and moderate chronic hepatic insufficiency. The mean apparent plasma clearance of total zileuton in subjects with hepatic impairment was approximately half the value of the healthy subjects. The percent binding of zileuton to plasma proteins after multiple dosing was significantly reduced in patients with moderate hepatic impairment. Zyflo CR is contraindicated in patients with active liver disease or persistent ALT elevations ≥3×ULN [see Warnings and Precautions (5)].
Geriatric Use
The pharmacokinetics of zileuton immediate-release tablets were investigated in healthy elderly subjects (ages 65 to 81 years, 9 males, 9 females) and healthy young subjects (ages 20 to 40 years, 5 males, 4 females) after single and multiple oral doses of 600 mg zileuton every 6 hours. Zileuton pharmacokinetics were similar in healthy elderly subjects (≥65 years) compared to healthy younger adults (20 to 40 years).
In 2-year carcinogenicity studies, increases in the incidence of liver, kidney, and vascular tumors in female mice and a trend toward an increase in the incidence of liver tumors in male mice were observed at 450 mg/kg/day (providing approximately 5 times [females] or 8 times [males] the systemic exposure [AUC=64 µg∙hr/mL] achieved at the maximum recommended human daily oral dose). No increase in the incidence of tumors was observed at 150 mg/kg/day (providing approximately 2-3 times the systemic exposure [AUC] achieved at the maximum recommended human daily oral dose). In rats, an increase in the incidence of kidney tumors was observed in both sexes at 170 mg/kg/day (providing approximately 8 times [males] or 16 times [females] the systemic exposure [AUC] achieved at the maximum recommended human daily oral dose). No increased incidence of kidney tumors was seen at 80 mg/kg/day (providing approximately 4 times [males] or 7 times [females] the systemic exposure [AUC] achieved at the maximum recommended human daily oral dose). Although a dose-related increased incidence of benign Leydig cell tumors was observed, Leydig cell tumorigenesis was prevented by supplementing male rats with testosterone.
Zileuton was negative in genotoxicity studies including bacterial reverse mutation (Ames) using S. typhimurium and E. coli, chromosome aberration in human lymphocytes, in vitro unscheduled DNA synthesis (UDS), in rat hepatocytes with or without zileuton pretreatment and in mouse and rat kidney cells with zileuton pretreatment, and mouse micronucleus assays. However, a dose-related increase in DNA adduct formation was reported in kidneys and livers of female mice treated with zileuton. Although some evidence of DNA damage was observed in a UDS assay in hepatocytes isolated from Aroclor-1254-treated rats, no such finding was noticed in hepatocytes isolated from monkeys, where the metabolic profile of zileuton is more similar to that of humans.
In reproductive performance/fertility studies, zileuton produced no effects on fertility in rats at oral doses up to 300 mg/kg/day (providing approximately 12 times [male rats] and greater than 10 times [female rats] the systemic exposure [AUC] achieved at the maximum recommended human daily oral dose). Comparative systemic exposure (AUC) is based on measurements in male rats or nonpregnant female rats at similar dosages. However, reduction in fetal implants was observed at oral doses of 150 mg/kg/day and higher (providing approximately 10 times the systemic exposure [AUC] achieved at the maximum recommended human daily oral dose). These effects were not seen at an estimated 4 times clinical exposure. Increases in gestation length, prolongation of estrus cycle, and increases in stillbirths were observed at oral doses of 70 mg/kg/day and higher (providing approximately 3 times the systemic exposure [AUC] achieved at the maximum recommended human daily oral dose). In a perinatal/postnatal study in rats, reduced pup survival and growth were noted at an oral dose of 300 mg/kg/day (providing approximately greater than 10 times the systemic exposure [AUC] achieved at the maximum recommended human daily oral dose).
The efficacy of Zyflo CR was evaluated in a randomized, double-blind, parallel-group, placebo-controlled, multicenter trial of 12 weeks duration in patients 12 years of age and older with asthma. The 12-week trial included 199 patients randomized to Zyflo CR (two 600 mg tablets twice daily) and 198 to placebo. Eighty-three percent of patients were white, 48% were male, and the mean age was 34 years. The mean baseline FEV1 percent predicted was 58.5%.
Assessment of efficacy was based upon forced expiratory volume in one second (FEV1) at 12 weeks. Zyflo CR demonstrated a significantly greater improvement in mean change from baseline trough FEV1 at 12 weeks compared to placebo (0.39 L vs. 0.27 L; p=0.021). The mean change from baseline FEV1 over the course of the 12-week study is shown in Figure 1. Secondary endpoints (PEFR and rescue beta-agonist use) were supportive of efficacy.
Examination of gender subgroups did not identify differences in response between men and women. The database was not large enough to assess whether there were differences in response in age or racial subgroups.
Figure 1.
Mean Change from Baseline in Trough FEV1 in
12-Week Clinical Trial in Patients with Asthma.
Mean Change from Baseline in Trough Forced Expiratory Volume After 1 Second in 12-Week Clinical Trial in Patients With Asthma.
Zyflo CR (zileuton) extended-release tablets are debossed on one side with "CT2"; they are available in bottles of 120 tablets (NDC 10122-902-12) and as samples in bottles of 20 tablets (NDC 10122-902-20).
Store between 20 and 25°C (68-77ºF); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Protect from light.
Patients should be told that:
ZYFLO (zy"-flō) CR (zileuton) extended-release tablets
Read the Patient Information that comes with Zyflo CR carefully before you start taking it and read it each time you get a refill. There may be new information. This leaflet does not take the place of talking with your health care provider about your medical condition or your treatment.
What is Zyflo CR?
Zyflo CR is a medicine that is used to prevent asthma attacks and for long-term management of asthma in adults and children 12 years of age and older. Zyflo CR blocks the production of leukotrienes. Leukotrienes are substances that may contribute to your asthma.
Zyflo CR is not a rescue medicine (it is not a bronchodilator) and should not be used if you need relief right away for an asthma attack.
Who should not take Zyflo CR?
Do not take Zyflo CR if you have:
What should I tell my health care provider before taking Zyflo CR?
Zyflo CR may not be right for you. Tell your health care provider if you:
Tell your health care provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Zyflo CR and other medicines may affect each other causing side effects. Your health care provider may need to adjust the doses of certain medicines while you are taking Zyflo CR. Talk with your health care provider before starting or stopping any prescription or nonprescription medicine.
Know the medicines you take. Keep a list of your medicines and show it to your health care provider and pharmacist when you get a new medicine.
How should I take Zyflo CR?
What are the possible side effects of Zyflo CR?
Zyflo CR can cause serious side effects.
Liver problems. Liver function enzymes and bilirubin can increase while taking Zyflo CR, and severe liver injury can occur.
Sleep disorders and changes in your behavior can happen while you take Zyflo CR. Tell your healthcare provider if you have any sleep problems or changes in behavior.
Allergic reactions can happen while taking Zyflo CR. Tell your health care provider right away if you get any of the following signs or symptoms: rash or hives.
Tell your health care provider if you have any new or unusual symptoms that bother you or do not go away while taking Zyflo CR.
These are not all of the possible side effects of Zyflo CR. For more information, ask your health care provider or pharmacist.
How should I store Zyflo CR?
Keep Zyflo CR and all medicines out of the reach of children.
General Information about Zyflo CR:
Medicines are sometimes prescribed for conditions that are not mentioned in the patient leaflet. Do not use Zyflo CR for a condition for which it was not prescribed. Do not give Zyflo CR to other people, even if they have the same symptoms you have. It may harm them.
This patient information leaflet summarizes the most important information about Zyflo CR. If you would like more information about Zyflo CR, talk with your health care provider or pharmacist. You can ask your health care provider or pharmacist for information about Zyflo CR that is written for health professionals.
For more information go to www.ZYFLOCR.com or call 1-888-661-9260.
What are the ingredients in Zyflo CR?
Active ingredient: zileuton
Inactive ingredients: crospovidone, ferric oxide, glyceryl behenate, hydroxypropyl cellulose, hypromellose, magnesium stearate, mannitol, microcrystalline cellulose, povidone, pregelatinized starch, propylene glycol, sodium starch glycolate, and talc.
Issued 11/2011
CTZC-001-0611-00-SPL
Manufactured for:
Cornerstone Therapeutics Inc.
Cary, NC 27518
Zyflo CR 120 Count Label
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| Marketing Information | |||
| Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date |
| NDA | NDA022052 | 05/30/2007 | |
| Labeler - Cornerstone Therapeutics Inc. (088084228) |
| Registrant - Cornerstone Therapeutics Inc. (088084228) |
Generic Name: sodium chloride (Injection route)
SOE-dee-um KLOR-ide
In the U.S.
Available Dosage Forms:
Therapeutic Class: Parenteral Electrolyte, Sodium
Sodium chloride as a 20% solution is given by injection into the uterus to cause abortion. It is to be administered only by or under the immediate care of your doctor.
In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:
Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.
| Pregnancy Category | Explanation | |
|---|---|---|
| All Trimesters | C | Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women. |
Studies in women suggest that this medication poses minimal risk to the infant when used during breastfeeding.
Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.
Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.
The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:
This section provides information on the proper use of a number of products that contain sodium chloride. It may not be specific to Syrex. Please read with care.
During the procedure, you will be awake and asked questions about how you are doing by the health care team. This helps them to react quickly to any problems you might have and to keep side effects to a minimum.
The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.
The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.
Do not have sexual intercourse and avoid using tampons or douches for 2 to 3 weeks after the abortion to allow your body time to heal. This will also help protect you from getting an infection of the vagina or uterus.
Spotting (or slight bleeding from the uterus) is normal after the abortion. This may continue for 2 weeks. Heavier spotting or uterine bleeding should be reported to your health care professional.
Contraception should be considered for the near future because you may ovulate before your first menstrual period. Your first menstrual period will occur 4 to 6 weeks after the abortion.
Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.
Check with your doctor immediately if any of the following side effects occur:
After the procedure is completed, some side effects may occur that need medical attention. Check with your doctor if you notice any of the following side effects:
Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.
Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.
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Treating athlete's foot, jock itch, and ringworm. It may also be used for other conditions as determined by your doctor.
Clotrimazole Cream is an antifungal agent. It kills sensitive fungi by binding to the fungal cell membrane and weakening it. This allows the cell contents to leak out and results in the death of the fungus.
Contact your doctor or health care provider right away if any of these apply to you.
Some medical conditions may interact with Clotrimazole Cream. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:
Some MEDICINES MAY INTERACT with Clotrimazole Cream. Because little, if any, of Clotrimazole Cream is absorbed into the blood, the risk of it interacting with another medicine is low.
Ask your health care provider if Clotrimazole Cream may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.
Use Clotrimazole Cream as directed by your doctor. Check the label on the medicine for exact dosing instructions.
Ask your health care provider any questions you may have about how to use Clotrimazole Cream.
All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:
Mild stinging.
Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); reddening, blistering, peeling, itching, or burning of the skin.
This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.
Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Clotrimazole Cream may be harmful if swallowed.
Store Clotrimazole Cream at room temperature, 59 to 86 degrees F (15 to 30 degrees C), in a tightly closed container. Store away from heat, moisture, and light. Do not store in the bathroom. Keep Clotrimazole Cream out of the reach of children and away from pets.
This information is a summary only. It does not contain all information about Clotrimazole Cream. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.
Generic Name: sulfacetamide sodium and sulfur topical (SUL fa SEET a mide SOE dee um and SUL fur TOP i kal)
Brand Names: Avar Cleanser, Avar Gel, Avar LS Cleanser, Avar-E, Avar-E Emollient, Avar-E Green, Avar-e LS, BP 10-Wash, Clarifoam EF, Clenia Emollient Cream, Clenia Foaming Wash, Plexion , Plexion Cleanser, Plexion Cleansing Cloths, Plexion SCT, Prascion, Prascion Cleanser, Prascion FC Cloths, Prascion RA, Rosac, Rosac Wash, Rosaderm Cleanser, Rosanil Cleanser, Rosula, SE 10-5 SS, Sulfacet-R, Sulfatol C, Sulfatol SS, SulZee Wash, Sumaxin, Sumaxin TS, Sumaxin Wash, Suphera, Topisulf, Zencia Wash, Zetacet
Sulfacetamide sodium and sulfur are antibiotic that fight bacteria.
The combination of sulfacetamide sodium and sulfur topical (for the skin) is used to treat acne, rosacea, and seborrheic dermatitis (a red, flaking skin rash).
Sulfacetamide sodium and sulfur topical may also be used for purposes not listed in this medication guide.
Do not cover the treated skin area unless your doctor has told you to.
To make sure you can safely use this medication, tell your doctor about all of your medical conditions.
Use exactly as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.
Do not cover the treated skin area unless your doctor has told you to.
Use this medication regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely.
Use the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not use extra medicine to make up the missed dose.
Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.
Avoid using other medications on the areas you treat with sulfacetamide sodium and sulfur topical unless you doctor tells you to.
new or worsening skin rash;
joint pain;
fever; or
mouth sores.
Less serious side effects may include redness, warmth, swelling, itching, stinging, burning, or irritation of treated skin.
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
It is not likely that other drugs you take orally or inject will have an effect on topically applied sulfacetamide sodium and sulfur. But many drugs can interact with each other. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.
See also: Plexion TS side effects (in more detail)
Neutrexin must be used with another medicine called leucovorin to protect against potentially serious or life-threatening reactions, such as kidney or liver problems; infected stomach, intestinal or mouth sores; or a decreased ability to fight infections.
Treating moderate to severe Pneumocystis carinii pneumonia (PCP) in patients with weak immune systems, including those with AIDS, who are not able to take the standard treatment. Neutrexin is used in combination with leucovorin.
Neutrexin is an anti-infective agent. It works by inhibiting DNA, RNA, and protein synthesis, leading to cell death.
Contact your doctor or health care provider right away if any of these apply to you.
Some medical conditions may interact with Neutrexin. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:
Some MEDICINES MAY INTERACT with Neutrexin. Tell your health care provider if you are taking any other medicines, especially any of the following:
This may not be a complete list of all interactions that may occur. Ask your health care provider if Neutrexin may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.
Use Neutrexin as directed by your doctor. Check the label on the medicine for exact dosing instructions.
Ask your health care provider any questions you may have about how to use Neutrexin.
All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:
Confusion; fatigue.
Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); chills; drops in counts of blood cells; fever; itching; nausea; sores in mouth; symptoms of a new infection; unusual bruising or bleeding; unusual tiredness or weakness; vomiting; yellow discoloration of skin or eyes.
This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.
See also: Neutrexin side effects (in more detail)
Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include blood disorders.
Store Neutrexin at room temperature, between 68 to 77 degrees F (20 to 25 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Neutrexin out of the reach of children and away from pets.
This information is a summary only. It does not contain all information about Neutrexin. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.
Generic Name: sulfacetamide and phenylephrine ophthalmic (sul fa SET a mide/ fen ill EFF rin)
Brand Names: Vasosulf
Sulfacetamide is an antibiotic. It is used to treat bacterial infections.
Phenylephrine is a vasoconstrictor. It makes the blood vessels in your eyes smaller to reduce redness and congestion, and to keep the sulfacetamide in your eye for a longer period of time.
Sulfacetamide and phenylephrine ophthalmic may also be used for purposes other than those listed in this medication guide.
Contact your doctor if your symptoms begin to get worse or if you do not see any improvement in your condition after a few days.
Apply light pressure to the inside corner of your eye (near your nose) after each drop to prevent the fluid from draining down your tear ducts.
Do not use sulfacetamide and phenylephrine ophthalmic if you have ever had an allergic reaction to a "sulfa"-based drug.
Use sulfacetamide and phenylephrine ophthalmic eyedrops exactly as directed by your doctor. If you do not understand these directions, ask your pharmacist, nurse, or doctor to explain them to you.
To apply the eyedrops:
Shake the drops gently to be sure the medicine is well mixed. Tilt your head back slightly and pull down on your lower eyelid. Position the dropper above your eye. Look up and away from the dropper. Squeeze out a drop and close your eye. Apply gentle pressure to the inside corner of your eye (near your nose) for about 1 minute to prevent the liquid from draining down your tear duct. If you are using more than one drop in the same eye or drops in both eyes, repeat the process with about 5 minutes between drops.
Apply the missed dose as soon as you remember. However, if it is almost time for your next regularly scheduled dose, skip the missed dose and apply the next one as directed. Do not use a double dose of this medication.
An overdose of this medication is unlikely to occur. If you do suspect an overdose, wash the eye with water and call an emergency room or poison control center near you. If the drops have been ingested, drink plenty of fluid and call an emergency center for advice.
Use caution with contact lenses. Wear them only if your doctor approves. After applying this medication, wait at least 15 minutes before inserting contact lenses.
Avoid other eye medications unless your doctor approves.
Serious side effects are not expected with this medication.
Commonly, some burning, stinging, irritation, itching, redness, blurred vision, eyelid itching, eyelid swelling, or sensitivity to light may occur. Continue to use sulfacetamide and phenylephrine ophthalmic and talk to your doctor about any side effects you experience.
Do not use this medication with other eye drops containing nitrates (e.g., silver nitrate).
Avoid using other eyedrops or medications unless they are approved by your doctor.
Drugs other than those listed here may also interact with sulfacetamide and phenylephrine ophthalmic. Talk to your doctor and pharmacist before taking any prescription or over-the-counter medicines.
Sulfacetamide and phenylephrine ophthalmic is available with a prescription under the brand name Vasosulf in a 15% solution. Other brand and generic formulations may also be available. Ask your pharmacist any questions you have about this medication, especially if it is new to you.
