Zileuton (Page 4 of 5)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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 MRHD). 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 MRHD). 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 MRHD). 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 MRHD). 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 at least 10 times [male rats] and greater than 20 times [female rats] the systemic exposure [AUC] achieved at the MRHD). However, reduction in fetal implants was observed at oral doses of 150 mg/kg/day and higher (providing approximately 20 times the systemic exposure [AUC] achieved at the MRHD). Comparative systemic exposure (AUC) is based on measurements in male rats or nonpregnant female rats obtained from the comparable doses of 3-month or 1-year general toxicity study at similar dosages. Increases in gestation length, prolongation of estrus cycle, and increases in stillbirths were observed at oral doses of 75 mg/kg/day and higher (providing approximately 7 times the systemic exposure [AUC] achieved at MRHD on an AUC basis with data obtained from the comparable doses of 2-year dietary carcinogenicity study). No adverse effects were observed at 15 mg/kg/day in the study at estimated exposure similar to that at the MRHD.

14 CLINICAL STUDIES

The efficacy of Zileuton Extended-Release Tablets 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 Zileuton Extended-Release Tablets (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. Zileuton Extended-Release Tablets 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.
(click image for full-size original)

*p ≤0.050. Endpoint analysis based on last-observation-carried-forward (LOCF) methodology.

16 HOW SUPPLIED/STORAGE AND HANDLING

Zileuton Extended-Release Tablets are debossed on one side with “CT2”; they are available in bottles of 120 tablets (NDC 66993-485-32).

Store between 20 and 25°C (68 — 77ºF); excursions permitted to 15 — 30°C (59 — 86ºF). [see USP Controlled Room Temperature]. Protect from light.

17 PATIENT COUNSELING INFORMATION

17.1 Information for Patients

Patients should be told that:

· Zileuton Extended-Release Tablets is indicated for the chronic treatment of asthma and should be taken regularly as prescribed, even during symptom-free periods.

· Zileuton Extended-Release Tablets is a leukotriene synthesis inhibitor which works by inhibiting the formation of leukotrienes.

· Zileuton Extended-Release Tablets should be taken within one hour after morning and evening meals.

· Zileuton Extended-Release Tablets should not be cut, chewed or crushed.

· Zileuton Extended-Release Tablets is not a bronchodilator and should not be used to treat acute episodes of asthma.

· When taking Zileuton Extended-Release Tablets, they should not decrease the dose or stop taking any other antiasthma medications unless instructed by a health care provider. If a dose is missed, they should take the next dose at the scheduled time and not double the dose.

· While using Zileuton Extended-Release Tablets, 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 Zileuton Extended-Release Tablets is potential elevation of liver enzymes (in 2% of patients) and that, while taking Zileuton Extended-Release Tablets, they must return for liver enzyme test monitoring on a regular basis.

· If they 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 health care provider immediately.

· Patients should be instructed to notify their healthcare provider if neuropsychiatric events occur while using Zileuton Extended-Release Tablets.

· Zileuton Extended-Release Tablets can interact with other drugs and that, while taking Zileuton Extended-Release Tablets, they should consult their health care provider before starting or stopping any prescription or non-prescription medicines.

· A patient leaflet is included with the tablets.

CTZC-009-0119-02-SPL-1

Manufactured for:

Prasco Laboratories
Mason, OH 45040

17.2 FDA-Approved Patient Labeling

Zileuton Extended-Release Tablets

Read the Patient Information that comes with Zileuton Extended-Release Tablets 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 are Zileuton Extended-Release Tablets?

Zileuton Extended-Release Tablets 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. Zileuton Extended-Release Tablets blocks the production of leukotrienes. Leukotrienes are substances that may contribute to your asthma.

Zileuton Extended-Release Tablets 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 Zileuton Extended-Release Tablets?

Do not take Zileuton Extended-Release Tablets if you have:

• active liver disease or repeated blood tests showing elevated liver enzymes (substances released by the liver).

• ever had an allergic reaction to Zileuton Extended-Release Tablets or any of the ingredients in Zileuton Extended-Release Tablets.

What should I tell my health care provider before taking Zileuton Extended-Release Tablets?

Zileuton Extended-Release Tablets may not be right for you. Tell your health care provider if you:

• have ever had liver problems, including hepatitis, jaundice (yellow eyes or skin), or dark urine.

• drink alcohol. Tell your health care provider how much and how often you drink alcohol.

• have difficulty swallowing pills.

• are pregnant or planning to become pregnant. It is not known if Zileuton Extended-Release Tablets will harm your unborn baby. Do not take Zileuton Extended-Release Tablets during pregnancy unless you and your health care provider decide that taking the medicine is more important than the possible risk to your unborn baby.

• are breastfeeding. It is not known if Zileuton Extended-Release Tablets passes into your breast milk. You and your health care provider should decide if you will take Zileuton Extended-Release Tablets or breastfeed. You should not do both.

Tell your health care provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Zileuton Extended-Release Tablets 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 Zileuton Extended-Release Tablets. 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 Zileuton Extended-Release Tablets?

• Take Zileuton Extended-Release Tablets exactly as prescribed by your health care provider. Do not decrease the dose of Zileuton Extended-Release Tablets or stop taking the medicine without talking to your health care provider first, even if you have no asthma symptoms.

• Take two Zileuton Extended-Release Tablets two times each day within one hour after your morning and evening meals.

• Swallow Zileuton Extended-Release Tablets whole. Do not chew, cut or crush Zileuton Extended-Release Tablets. Tell your health care provider if you cannot swallow the tablets whole.

• Follow your health care provider’s instructions for what to do if you get sudden symptoms of an asthma attack. You can continue taking Zileuton Extended-Release Tablets during asthma attacks.

• Get medical help right away if you need to use your rescue medicine more often than usual or if you use the highest number of “puffs” prescribed for one 24-hour period. These could be signs that your asthma is getting worse. This means that your asthma therapy may need to be changed.

• Keep taking your other asthma medicines as directed while taking Zileuton Extended-Release Tablets.

• If you miss a dose, just take your next scheduled dose when it is due. Do not double the dose.

• If you take too much Zileuton Extended-Release Tablets, call your health care provider or a Poison Control Center right away.

What are the possible side effects of Zileuton Extended-Release Tablets?

Zileuton Extended-Release Tablets can cause serious side effects.

Liver problems. Liver function enzymes and bilirubin can increase while taking Zileuton Extended-Release Tablets, and severe liver injury can occur.

Sleep disorders and changes in your behavior can happen while you take Zileuton Extended-Release Tablets. Tell your healthcare provider if you have any sleep problems or changes in behavior.

• Keep all of your health care provider’s appointments and be sure to follow all of your health care provider’s instructions. Have your blood tests done as ordered to check your liver enzymes.

• Tell your health care provider right away if you get any of the following signs or symptoms: pain on the right side of your abdomen (stomach area), nausea, tiredness, lack of energy, itching, yellow skin or yellow color in the whites of your eyes, dark urine, or “flu-like” symptoms.

Some of the most common side effects are:

• nose and throat irritation

• sinusitis

• upper respiratory infection

• throat pain

• headache

• muscle aches

• nausea

• diarrhea

Allergic reactions can happen while taking Zileuton Extended-Release Tablets. 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 Zileuton Extended-Release Tablets.

These are not all of the possible side effects of Zileuton Extended-Release Tablets. For more information, ask your health care provider or pharmacist.

How should I store Zileuton Extended-Release Tablets?

• Store Zileuton Extended-Release Tablets between 68°F and 77°F (20ºC — 25ºC).

• Protect Zileuton Extended-Release Tablets from light and replace the cap each time after use.

Keep Zileuton Extended-Release Tablets and all medicines out of the reach of children.

General Information about Zileuton Extended-Release Tablets:

Medicines are sometimes prescribed for conditions that are not mentioned in the patient leaflet. Do not use Zileuton Extended-Release Tablets for a condition for which it was not prescribed. Do not give Zileuton Extended-Release Tablets 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 Zileuton Extended-Release Tablets. If you would like more information about Zileuton Extended-Release Tablets, talk with your health care provider or pharmacist. You can ask your health care provider or pharmacist for information about Zileuton Extended-Release Tablets that is written for health professionals.

For more information call 1-866-525-0688.

What are the ingredients in Zileuton Extended-Release Tablets?

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 03/2019

CTZC-009-0119-02-SPL-1

Manufactured for:

Prasco Laboratories
Mason, OH 45040 USA

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