Leukotrienes are important mediators in the pathogenesis of asthma, causing inflammation, bronchoconstriction, edema and mucus secretions.¹ There are two types of Leukotrienes: Cysteinyl and Non-Cysteinyl. The Cysteinyl Leukotrienes are C₄, D₄ and E₄, and the Non-Cysteinyl Leukotriene is B₄. In addition to Leukotrienes, other mediators also play a role in asthma.

Leukotrienes induce numerous biological effects, including:¹

• Augmentation of neutrophils
• Eosinophil migration
• Neutrophil and monocyte aggregation
• Leukocyte adhesion
• Increased capillary permeability
• Smooth muscle contraction

Additionally, LTB₄ is a chemoattractant for neutrophils and eosinophils.

The United States Pharmacopeia (USP) model formulary guidelines for Medicare recognize Leukotriene Synthesis Inhibitors (LTSIs) as a unique drug type.² ZYFLO CR is the only FDA-Approved Leukotriene Synthesis Inhibitor.

ZYFLO CR is NOT a steroid.

*In vitro data do not necessarily correlate with clinical efficacy.

ZYFLO CR is an inhibitor of Cysteinyl and Non-Cysteinyl Leukotrienes. By inhibiting the catalytic activity of 5-lipoxygenase, ZYFLO CR inhibits the formation of the leukotrienes that are biologically active in asthma-LTB₄, LTC₄, LTD₄, and LTE₄. These four leukotrienes have been implicated in the inflammation associated with asthma.¹ ZYFLO CR is the first and only Leukotriene Synthesis Inhibitor approved by the FDA.²

Learn more about the mechanism of action of ZYFLO CR.

Learn more about the efficacy of ZYFLO CR in relieving asthma symptoms and providing asthma control.

ZYFLO CR Provided Greater Improvements in FEV₁ Than Placebo¹

These results are from a 3-month, Phase III randomized, double-blind, parallel-group, placebo-controlled, multicenter trial of ZYFLO CR 1200 mg twice daily (N=192) compared to placebo (N=187) in patients 12 years of age and older with asthma. The mean baseline FEV₁ percent predicted was 58.5. Assessment of efficacy was based upon FEV₁ at 12 weeks.

• On the final day (Study Day 85), ZYFLO CR demonstrated a significantly greater improvement in the mean percent change from baseline in FEV₁ compared to placebo (21% vs 12%; P<.050)
• Secondary endpoints (PEFR, beta-agonist use) were supportive of efficacy¹

Dosing and Administration
The recommended dosage of ZYFLO CR for the treatment of patients with asthma is two 600-mg extended release tablets two times a day within one hour after the morning and evening meals for a total daily dose of 2400 mg. Tablets should not be chewed, cut or crushed. ZYFLO CR should be taken regularly, even during symptom-free periods. Hepatic transaminases should be evaluated prior to initiation of ZYFLO CR and periodically during treatment (see PRECAUTIONS, Hepatotoxicity in the full Prescribing Information).

How Supplied
ZYFLO CR tablets are available as one dosage strength: 600-mg tablets debossed on one side with "CT 2." Each bottle contains 120 tablets. The NDC # 68734-0710-10.

Recommended storage: Store tablets at controlled room temperature between 20°-25°C (68°-77°F). See USP. Protect from light.

Hepatotoxicity¹

• Co-administration of ZYFLO CR with theophylline, warfarin and/or propranolol warrants close monitoring and dosage adjustments of the co-administered drug
• Elevations of one or more hepatic function enzymes and bilirubin may occur during therapy with ZYFLO CR
• In a 12-week placebo-controlled study, the incidence of ALT elevations (≥3X ULN) was 2.5% (5 of 199) in the ZYFLO CR group vs 0.5% (1 of 198) in the placebo group (P=NS)


• In the ZYFLO CR-treated group, the majority of ALT elevations (60%) occurred within the first month of treatment


• In a 6-month placebo-controlled study, ALT elevations were observed in 1.8% of patients treated with ZYFLO CR vs 0.7% treated with placebo (P=NS)


• 82% of elevations were reported during the first 3 months of treatment and resolved within 21 days for most of these patients after discontinuation of the drug
• Elevations of one or more hepatic function enzymes and bilirubin may occur during therapy with ZYFLO CR

Other Safety Considerations¹

• ZYFLO CR is contraindicated in patients with active liver disease or transaminase elevations ≥3X ULN
• Liver function monitoring is recommended at baseline, once a month for the first 3 months, every 2 to 3 months for the remainder of the first year and periodically thereafter
• 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 ≥5X ULN occur, discontinue ZYFLO CR and follow hepatic function enzymes until normal
• Use with caution in patients who consume substantial quantities of alcohol and/or have past history of liver disease

Patients taking ZYFLO CR should be told that:

• ZYFLO CR is indicated for the prophylaxis and chronic treatment of asthma and should be taken regularly as prescribed, even during symptom-free periods
• ZYFLO CR is not a bronchodilator and should not be used to treat acute episodes of asthma, but it may be continued during acute, or sudden, asthma attacks
• When taking ZYFLO CR, patients should not decrease the dose or stop taking any other anti-asthma medications, unless instructed by a physician
• While using ZYFLO CR, medical attention should be sought if short-acting bronchodilators are needed more often than usual, or if more than the maximum number of inhalations of short-acting bronchodilator treatment prescribed for a 24-hour period are needed
• The most serious side effect of ZYFLO CR is elevation of liver enzymes and while taking ZYFLO CR, patients must return for liver enzyme test monitoring on a regular basis
• If patients experience signs and/or symptoms of liver dysfunction (e.g., right upper quadrant pain, nausea, fatigue, lethargy, pruritus, jaundice, or "flu-like" symptoms), they should contact their physician immediately
• Co-administration of ZYFLO CR with theophylline, warfarin and/or propranolol warrants close monitoring and dosage adjustments of the co-administered drug. Upon initiation of ZYFLO CR in patients receiving theophylline, the theophylline dosage should be reduced by approximately one-half and plasma theophylline concentrations monitored.
• A patient leaflet is included with the tablets when picked up from the pharmacy or delivered by mail

1. Prescribing Information for ZYFLO CR. Lexington, MA: Critical Therapeutics, Inc.; May 2007.
   
2. Revisions to the USP Medicare Model Guidelines. U.S. Pharmacopeia.
   Available at: www.usp.org/pdf/en/mmg/drugListTablev3.0.pdf
   Accessed 6/1/07.