Bexarotene Capsules

Some medicines are not suitable for people with certain conditions, and sometimes a medicine may only be used if extra care is taken. For these reasons, before you start taking bexarotene it is important that your doctor knows:

• If you are pregnant or breast-feeding.
• If you have an infection or feel particularly unwell.
• If you have any problems with the way your liver works.
• If you have a lipid disorder (such as high cholesterol or triglycerides).
• If you have an underactive thyroid.
• If you have ever had inflammation of the pancreas (pancreatitis).
• If you have been told by a doctor that the level of vitamin A in your body is too high.
• If you have a rare inherited blood disorder called porphyria.
• If you have ever had an allergic reaction to a medicine.
• If you are taking or using any other medicines. This includes any medicines you are taking which are available to buy without a prescription, such as herbal and complementary medicines.

Bexarotene is a member of a subclass of retinoids that selectively activate retinoid X receptors (RXRs). These retinoid receptors have biologic activity distinct from that of retinoic acid receptors (RARs). Each soft gelatin capsule for oral administration contains 75 mg of bexarotene.

The chemical name is 4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) ethenyl] benzoic acid, and the structural formula is as follows:

Bexarotene is an off-white to white powder with a molecular weight of 348.48 and a molecular formula of C24H28O2. It is insoluble in water and slightly soluble in vegetable oils and ethanol, USP.

Each Bexarotene capsule also contains the following inactive ingredients: polyethyelene glycol 400, NF, polysorbate 20, NF, povidone, USP and butylated hydroxyanisole, NF. The capsule shell contains gelatin NF, water, sorbitol sorbitan solution, NF, glycerin, USP and titanium dioxide, USP.

Lipid abnormalities

Bexarotene Capsules induce major lipid abnormalities in most patients. These must be monitored and treated during long-term therapy. About 70% of patients with CTCL who received an initial dose of ≥ 300 mg/m2/day of Bexarotene Capsules had fasting triglyceride levels greater than 2.5 times the upper limit of normal. About 55% had values over 800 mg/dL with a median of about 1200 mg/dL in those patients. Cholesterol elevations above 300 mg/dL occurred in approximately 60% and 75% of patients with CTCL who received an initial dose of 300 mg/m2/day or greater than 300 mg/m2/day, respectively. Decreases in high density lipoprotein (HDL) cholesterol to less than 25 mg/dL were seen in about 55% and 90% of patients receiving an initial dose of 300 mg/m2/day or greater than 300 mg/m2/day, respectively, of Bexarotene Capsules. The effects on triglycerides, HDL cholesterol, and total cholesterol were reversible with cessation of therapy, and could generally be mitigated by dose reduction or concomitant antilipemic therapy.

Fasting blood lipid determinations should be performed before Bexarotene Capsules therapy is initiated and weekly until the lipid response to Bexarotene Capsules is established, which usually occurs within 2 to 4 weeks, and at 8 week intervals thereafter. Fasting triglycerides should be normal or normalized with appropriate intervention prior to initiating Bexarotene Capsules therapy. Attempts should be made to maintain triglyceride levels below 400 mg/dL to reduce the risk of clinical sequelae (see WARNINGS: Pancreatitis). If fasting triglycerides are elevated or become elevated during treatment, antilipemic therapy should be instituted, and if necessary, the dose of Bexarotene Capsules reduced or suspended. In the 300 mg/m2/day initial dose group, 60% of patients were given lipid lowering drugs. Atorvastatin was used in 48% (73/152) of patients with CTCL. Because of a potential drug-drug interaction (see PRECAUTIONS:Drug-Drug Interactions), gemfibrozil is not recommended for use with Bexarotene Capsules.

Pancreatitis

Acute pancreatitis has been reported in four patients with CTCL and in six patients with non-CTCL cancers treated with Bexarotene Capsules; the cases were associated with marked elevations of fasting serum triglycerides, the lowest being 770 mg/dL in one patient. One patient with advanced non-CTCL cancer died of pancreatitis. Patients with CTCL who have risk factors for pancreatitis (e.g., prior pancreatitis, uncontrolled hyperlipidemia, excessive alcohol consumption, uncontrolled diabetes mellitus, biliary tract disease, and medications known to increase triglyceride levels or to be associated with pancreatic toxicity) should generally not be treated with Bexarotene Capsules (see WARNINGS: Lipids abnormalities and PRECAUTIONS:Laboratory Tests).

Liver function test abnormalities

For patients with CTCL receiving an initial dose of 300 mg/m2/day of Bexarotene Capsules, elevations in liver function tests (LFTs) have been observed in 5% (SGOT/AST), 2% (SGPT/ALT), and 0% (bilirubin). In contrast, with an initial dose greater than 300 mg/m2/day of Bexarotene Capsules, the incidence of LFT elevations was higher at 7% (SGOT/AST), 9% (SGPT/ALT), and 6% (bilirubin). Two patients developed cholestasis, including one patient who died of liver failure.

In clinical trials, elevation of LFTs resolved within one month in 80% of patients following a decrease in dose or discontinuation of therapy. Baseline LFTs should be obtained, and LFTs should be carefully monitored after 1, 2 and 4 weeks of treatment initiation, and if stable, at least every 8 weeks thereafter during treatment. Consideration should be given to a suspension or discontinuation of Bexarotene Capsules if test results reach greater than three times the upper limit of normal values for SGOT/AST, SGPT/ALT, or bilirubin.

Hepatic insufficiency

No specific studies have been conducted with Bexarotene Capsules in patients with hepatic insufficiency. Because less than 1% of the dose is excreted in the urine unchanged and there is in vitro evidence of extensive hepatic contribution to bexarotene elimination, hepatic impairment would be expected to lead to greatly decreased clearance. Bexarotene Capsules should be used only with great caution in this population.

Thyroid axis alterations

Bexarotene Capsules induce biochemical evidence of or clinical hypothyroidism in about half of all patients treated, causing a reversible reduction in thyroid hormone (total thyroxine [total T4]) and thyroid-stimulating hormone (TSH) levels. The incidence of decreases in TSH and total T4 were about 60% and 45%, respectively, in patients with CTCL receiving an initial dose of 300 mg/m2/day. Hypothyroidism was reported as an adverse event in 29% of patients. Treatment with thyroid hormone supplements should be considered in patients with laboratory evidence of hypothyroidism. In the 300 mg/m2/day initial dose group, 37% of patients were treated with thyroid hormone replacement. Baseline thyroid function tests should be obtained and patients monitored during treatment.

Leukopenia

A total of 18% of patients with CTCL receiving an initial dose of 300 mg/m2/day of Bexarotene Capsules had reversible leukopenia in the range of 1000 to < 3000 WBC/mm3. Patients receiving an initial dose greater than 300 mg/m2/day of Bexarotene Capsules had an incidence of leukopenia of 43%. No patient with CTCL treated with Bexarotene Capsules developed leukopenia of less than 1000 WBC/mm3. The time to onset of leukopenia was generally four to eight weeks. The leukopenia observed in most patients was explained by neutropenia. In the 300 mg/m2/day initial dose group, the incidence of NCI Grade 3 and Grade 4 neutropenia, respectively, was 12% and 4%. The leukopenia and neutropenia experienced during Bexarotene Capsules therapy resolved after dose reduction or discontinuation of treatment, on average within 30 days in 93% of the patients with CTCL and 82% of patients with non-CTCL cancers. Leukopenia and neutropenia were rarely associated with severe sequelae or serious adverse events. Determination of WBC with differential should be obtained at baseline and periodically during treatment.

Cataracts

Posterior subcapsular cataracts were observed in preclinical toxicity studies in rats and dogs administered bexarotene daily for 6 months. In 15 of 79 patients who had serial slit lamp examinations, new cataracts or worsening of previous cataracts were found. Because of the high prevalence and rate of cataract formation in older patient populations, the relationship of Bexarotene Capsules and cataracts cannot be determined in the absence of an appropriate control group. Patients treated with Bexarotene Capsules who experience visual difficulties should have an appropriate ophthalmologic evaluation.

Pregnancy

See CONTRAINDICATIONS.

General

Bexarotene Capsules should be used with caution in patients with a known hypersensitivity to retinoids. Clinical instances of crossreactivity have not been noted.

In clinical studies, patients were advised to limit vitamin A intake to ≤ 15,000 IU/day. Because of the relationship of bexarotene to vitamin A, patients should be advised to limit vitamin A supplements to avoid potential additive toxic effects.

Caution should be used when administering Bexarotene Capsules in patients using insulin, agents enhancing insulin secretion (e.g., sulfonylureas), or insulin-sensitizers (e.g., thiazolidinedione class). Based on the mechanism of action, Bexarotene Capsules could enhance the action of these agents, resulting in hypoglycemia. Hypoglycemia has not been associated with the use of Bexarotene Capsules as monotherapy.

Retinoids as a class have been associated with photosensitivity. In vitro assays indicate that bexarotene is a potential photosensitizing agent. Mild phototoxicity manifested as sunburn and skin sensitivity to sunlight was observed in patients who were exposed to direct sunlight while receiving Bexarotene Capsules. Patients should be advised to minimize exposure to sunlight and artificial ultraviolet light while receiving Bexarotene Capsules.

Information for Patients

Please see accompanying "Patient's Instructions for Use"

Laboratory Tests

Blood lipid determinations should be performed before Bexarotene Capsules are given. Fasting triglycerides should be normal or normalized with appropriate intervention prior to therapy. Hyperlipidemia usually occurs within the initial two to four weeks. Therefore, weekly lipid determinations are recommended during this interval. Subsequently, in patients not hyperlipidemic, determinations can be performed less frequently (see WARNINGS:Lipid abnormalities).

A white blood cell count with differential should be obtained at baseline and periodically during treatment. Baseline liver function tests should be obtained and should be carefully monitored after 1, 2 and 4 weeks of treatment initiation, and if stable, periodically thereafter during treatment. Baseline thyroid function tests should be obtained and then monitored during treatment as indicated (see WARNINGS: Leukopenia, Liver function test abnormalities, and Thyroid axis alterations).

Drug-Food Interaction

In all clinical trials, patients were instructed to take Bexarotene Capsules with or immediately following a meal. In one clinical study, plasma bexarotene AUC and Cmax values were substantially higher following a fat-containing meal versus those following the administration of a glucose solution. Because safety and efficacy data are based upon administration with food, it is recommended that Bexarotene Capsules be administered with food (see CLINICAL PHARMACOLOGY: Pharmacokinetics and DOSAGE AND ADMINISTRATION).

Drug-Drug Interactions

Concomitant administration of Bexarotene Capsules and gemfibrozil resulted in substantial increases in plasma concentrations of bexarotene. Concomitant administration of gemfibrozil with Bexarotene Capsules is not recommended (see CLINICAL PHARMACOLOGY: Drug-Drug Interactions).

Coadministration of paclitaxel plus carboplatin with Bexarotene Capsules increased bexarotene AUC by 2-fold. Caution should be exercised when Bexarotene Capsules are concomitantly administered with paclitaxel plus carboplatin (see CLINICAL PHARMACOLOGY: Drug-Drug Interactions).

Concomitant administration of Bexarotene Capsules and tamoxifen resulted in approximately a 35% decrease in plasma concentrations of tamoxifen.

The exposure (AUC) to atorvastatin decreased by half when atorvastatin was coadministered with Bexarotene Capsules. This suggest that Bexarotene Capsules is an inducer for the CYP3A4 enzymes, and that it may reduce plasma concentrations of other substrates metabolized by CYP3A4, including oral or other systemic hormonal contraceptives (see CLINICAL PHARMACOLOGY: Drug-Drug Interactions and CONTRAINDICATIONS: Pregnancy: Category X). Thus, if treatment with Bexarotene Capsules is intended in a woman with child-bearing potential, it is strongly recommended that two reliable forms of contraception be used concurrently, one of which should be non-hormonal.

Protein Binding

Bexarotene is highly bound (> 99%) to plasma proteins. The plasma proteins to which bexarotene binds have not been elucidated, and the ability of bexarotene to displace drugs bound to plasma proteins and the ability of drugs to displace bexarotene binding have not been studied.

Renal Insufficiency

No formal studies have been conducted with Bexarotene Capsules in patients with renal insufficiency. Urinary elimination of bexarotene and its known metabolites is a minor excretory pathway for bexarotene (< 1% of administered dose), but because renal insufficiency can result in significant protein binding changes, and bexarotene is > 99% protein bound, pharmacokinetics may be altered in patients with renal insufficiency.

Drug/Laboratory Test Interactions

CA125 assay values in patients with ovarian cancer may be increased by Bexarotene capsule therapy.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals to assess the carcinogenic potential of bexarotene have not been conducted. Bexarotene is not mutagenic to bacteria (Ames assay) or mammalian cells (mouse lymphoma assay). Bexarotene was not clastogenic in vivo (micronucleus test in mice). No formal fertility studies were conducted with bexarotene. Bexarotene caused testicular degeneration when oral doses of 1.5 mg/kg/day were given to dogs for 91 days (producing an AUC of approximately one fifth the AUC at the recommended human

daily dose).

Use in Nursing Mothers

It is not known whether bexarotene is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from bexarotene, 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.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Of the total patients with CTCL in clinical studies of Bexarotene Capsules, 64% were 60 years or older, while 33% were 70 years or older. No overall differences in safety were observed between patients 70 years or older and younger patients, but greater sensitivity of some older individuals to Bexarotene Capsules cannot be ruled out. Responses to Bexarotene Capsules were observed across all age group decades, without preference for any individual age group decade.

The safety of Bexarotene Capsules has been evaluated in clinical studies of 152 patients with CTCL who received Bexarotene Capsules for up to 97 weeks and in 352 patients in other studies. The mean duration of therapy for the 152 patients with CTCL was 166 days. The most common adverse events reported with an incidence of at least 10% in patients with CTCL treated at an initial dose of 300 mg/m2/day of Bexarotene Capsules are shown in Table 1. The events at least possibly related to treatment are lipid abnormalities (elevated triglycerides, elevated total and LDL cholesterol and decreased HDL cholesterol), hypothyroidism, headache, asthenia, rash, leukopenia, anemia, nausea, infection, peripheral edema, abdominal pain, and dry skin. Most adverse events occurred at a higher incidence in patients treated at starting doses of greater than 300 mg/m2/day (see Table 1).

Adverse events leading to dose reduction or study drug discontinuation in at least two patients were hyperlipemia, neutropenia/leukopenia, diarrhea, fatigue/lethargy, hypothyroidism, headache, liver function test abnormalities, rash, pancreatitis, nausea, anemia, allergic reaction, muscle spasm, pneumonia, and confusion.

The moderately severe (NCI Grade 3) and severe (NCI Grade 4) adverse events reported in two or more patients with CTCL treated at an initial dose of 300 mg/m2/day of Bexarotene Capsules (see Table 2) were hypertriglyceridemia, pruritus, headache, peripheral edema, leukopenia, rash, and hypercholesteremia. Most of these moderately severe or severe adverse events occurred at a higher rate in patients treated at starting doses of greater than 300 mg/m2/day than in patients treated at a starting dose of 300 mg/m2/day.

As shown in Table 3, in patients with CTCL receiving an initial dose of 300 mg/m2/day, the incidence of NCI Grade 3 or 4 elevations in triglycerides and total cholesterol was 28% and 25%, respectively. In contrast, in patients with CTCL receiving greater than 300 mg/m2/day, the incidence of NCI Grade 3 or 4 elevated triglycerides and total cholesterol was 45% and 45%, respectively. Other Grade 3 and 4 laboratory abnormalities are shown in Table 3.

In addition to the 152 patients enrolled in the two CTCL studies, 352 patients received Bexarotene Capsules as monotherapy for various advanced malignancies at doses from 5 mg/m2/day to 1000 mg/m2/day. The common adverse events (incidence greater than 10%) were similar to those seen in patients with CTCL.

In the 504 patients (CTCL and non-CTCL) who received Bexarotene Capsules as monotherapy, drug-related serious adverse events that were fatal, in one patient each, were acute pancreatitis, subdural hematoma, and liver failure.

In the patients with CTCL receiving an initial dose of 300 mg/m2/day of Bexarotene Capsules, adverse events reported at an incidence of less than 10% and not included in Tables 1-3 or discussed in other parts of labeling and possibly related to treatment were as follows:

Body as a Whole: chills, cellulitis, chest pain, sepsis, and monilia.

Cardiovascular: hemorrhage, hypertension, angina pectoris, right heart failure, syncope, and tachycardia.

Digestive: constipation, dry mouth, flatulence, colitis, dyspepsia, cheilitis, gastroenteritis, gingivitis, liver failure, and melena.

Hemic and Lymphatic: eosinophilia, thrombocythemia, coagulation time increased, lymphocytosis, and thrombocytopenia.

Metabolic and Nutritional: LDH increased, creatinine increased, hypoproteinemia, hyperglycemia, weight decreased, weight increased, and amylase increased.

Musculoskeletal: arthralgia, myalgia, bone pain, myasthenia, and arthrosis.

Nervous: depression, agitation, ataxia, cerebrovascular accident, confusion, dizziness, hyperesthesia, hypesthesia, and neuropathy.

Respiratory: pharyngitis, rhinitis, dyspnea, pleural effusion, bronchitis, cough increased, lung edema, hemoptysis, and hypoxia.

Skin and Appendages: skin ulcer, acne, alopecia, skin nodule, macular papular rash, pustular rash, serous drainage, and vesicular bullous rash.

Special Senses: dry eyes, conjunctivitis, ear pain, blepharitis, corneal lesion, keratitis, otitis externa, and visual field defect.

Urogenital: albuminuria, hematuria, urinary incontinence, urinary tract infection, urinary urgency, dysuria, kidney function abnormal, and breast pain.

BEXAROTENE (beks-AIR-oh-teen) CAPSULES, 75 MG

To help you get the full benefits from this medicine, you should read this leaflet carefully and ask your doctor to explain anything you do not understand.

What are the most important things I should know about Bexarotene (beks-AIR-oh-teen) capsules?

• Bexarotene (beks-AIR-oh-teen) capsules can cause major damage to a fetus. Pregnancy must be avoided in patients receiving Bexarotene (beks-AIR-oh-teen) capsules.

• Bexarotene (beks-AIR-oh-teen) capsules can greatly increase blood levels of lipids (triglycerides and cholesterol) and these levels must be monitored and, if elevated, treated.

• Bexarotene (beks-AIR-oh-teen) capsules can cause an underactive thyroid and periodic blood tests will be needed to detect this. Medication to control the condition may be necessary.

What are Bexarotene (beks-AIR-oh-teen) capsules?

Bexarotene (beks-AIR-oh-teen) capsules contain bexarotene (beks-AIR-oh-teen). Bexarotene (beks-AIR-oh-teen) capsules belong to a class of medicines known as retinoids. Each white to off-white, oblong soft gelatin Bexarotene capsule (beks-AIR-oh-teen) contains 75 mg of bexarotene (beks-AIR-oh-teen). Each capsule is printed with “B75” in black ink.

What are the uses for Bexarotene (beks-AIR-oh-teen)capsules?

This medicine is used to treat the skin problems arising from a disease called cutaneous T-cell lymphoma, or CTCL. Your doctor must supervise the use of Bexarotene (beks-AIR-oh-teen) capsules.

Do not take Bexarotene (beks-AIR-oh-teen) capsules if you are allergic to this medicine.

If you have any of the following conditions, make sure you have discussed them with your doctor before you start to take this medicine.

• You are pregnant or think you may be pregnant.

• You have or previously had an inflamed pancreas (pancreatitis).

• You are breastfeeding.

• You are taking gemfibrozil (Lopid®)*, a medication to reduce high triglyceride cholesterol (fats) levels in the blood.

• You are taking tamoxifen (Nolvadex®)+,paclitaxel (Taxol®)***, and atorvastatin (Lipitor®)**

• You are taking oral or systemic hormonal contraceptives.

Medical conditions you should tell your doctor about.

• If you are allergic to retinoid medications (for example: Accutane® [isotretinoin], Soriatane® [acitretin], Tegison® [etretinate], Vesanoid® [tretinoin])++

• If you have or ever had high triglyceride (a fatty substance) levels in your blood.

• If you have diabetes mellitus (sugar diabetes).

• If you have a history of or currently have gall bladder disease.

• If you have or have had any liver disease.

• If you regularly drink more than a small amount of alcohol.

• If you are currently taking any prescription medication especially for fungal infections, bacterial infections, or seizures.

• If you eat a lot of grapefruit or drink a lot of grapefruit juice.

When should you be extra careful while taking Bexarotene (beks-AIR-oh-teen) capsules?

• Because vitamin A in large doses may cause some side effects which are similar to those seen in patients taking Bexarotene (beks-AIR-oh-teen) capsules, do not take more than the recommended daily dietary allowance of vitamin A (4000 to 5000 International Units). If you take vitamins, check the label to see how much vitamin A they contain. If you are not sure, ask your doctor or pharmacist.

• Your skin may become more sensitive to sunlight while taking this medicine. Minimize exposure to sunlight and do not use a sunlamp.

How should Bexarotene (beks-AIR-oh-teen) capsules be taken?

• Always take Bexarotene (beks-AIR-oh-teen) capsules the way your doctor tells you.

• Your doctor will tell you how many Bexarotene (beks-AIR-oh-teen) capsules to take each day. You should take your daily dose of Bexarotene (beks-AIR-oh-teen) capsules all at once. It is best to take them once each day with or immediately following a meal. For example, you might always take your daily amount of Bexarotene (beks-AIR-oh-teen) capsules with your evening meal.

• Always swallow each capsule whole; do not chew them or dissolve them in liquid or in your mouth. Depending on your health and condition, your doctor may change your daily dose (the number of capsules you are taking) during your treatment.

• If you miss a dose, take it as soon as possible, with food. However, if it is nearly time for your next dose, skip the missed dose and continue your dose schedule as before. Do not take a double dose.

• If you take too many Bexarotene (beks-AIR-oh-teen) capsules or someone else accidentally takes your medicine, contact your doctor, emergency room or the nearest hospital immediately.

How long before you can expect your CTCL to improve on Bexarotene (beks-AIR-oh-teen) capsule treatment?

• Although some patients saw improvement within the first several weeks of Bexarotene (beks-AIR-oh-teen) capsule treatment, most patients required several months or more of treatment to improve.

• Your doctor should determine how long you should be taking Bexarotene (beks-AIR-oh-teen) capsules, and when treatment may be stopped.

What side effects do Bexarotene (beks-AIR-oh-teen) capsules have?

The most common side effect is an increase in blood lipids (fats in the blood). Periodic blood tests will be needed to determine blood levels of lipids, including triglycerides and cholesterol. Medication may be needed to control high fat levels in the blood.

Another common side effect is underactive thyroid. The symptoms of underactive thyroid may be difficult to detect because they may develop very gradually and may be very mild. For example, you may begin to feel always tired, low on energy, or feeling unusually cold all the time. A thyroid hormone medication is readily available to fully control these temporary symptoms, so contact your doctor early if you feel you are beginning to experience any of these symptoms. Periodic blood tests will be needed to detect this.

When should you call your doctor about possible complications of Bexarotene (beks-AIR-oh-teen) capsule treatment?

As an infrequent side effect of Bexarotene (beks-AIR-oh-teen) capsule treatment, pancreatitis (inflamed pancreas) may occur. Symptoms of pancreatitis include persistent nausea, vomiting, and abdominal or back pain. If you develop any of these symptoms while taking Bexarotene (beks-AIR-oh-teen) capsules, contact your doctor immediately.

All medications have side effects. You should call your physician regarding any questions or concerns you may have when taking Bexarotene (beks-AIR-oh-teen)capsules. You can get more information by calling Mylan Pharmaceuticals Inc. at the following toll free number 1-877-446-3679 (1-877-4-INFO-RX).

How should Bexarotene (beks-AIR-oh-teen) capsules be stored?

• The capsules should be stored in a dry place in a closed container, away from light and heat. Store at 2°-25°C (36°-77°F).

• The capsules should not be used after the expiration date printed on the bottle.

• Keep this medicine out of the reach and sight of children.

If Bexarotene (beks-AIR-oh-teen) capsules are broken or leaking, do not touch the capsules or the contents and notify your pharmacist immediately. Should the contents of a broken capsule get on your skin, immediately wash the area with soap and water and notify your physician.

Further Information

• You can get more information on Bexarotene (beks-AIR-oh-teen) capsules from your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at

1-800-FDA-1088.

* Lopid® (gemfibrozil tablets, USP) is a registered trademark of Parke-Davis, Division of Warner-Lambert Co.

+ Nolvadex® (tamoxifen citrate) is a registered trademark of AstraZeneca LP.

++ Accutane® (isotretinoin) is a registered trademark of Roche Pharmaceuticals, Roche Laboratories Inc.

++ Soriatane® (acitretin) is a registered trademark of Roche Pharmaceuticals, Roche Laboratories Inc.

++ Tegison® (etretinate) is a registered trademark of Roche Pharmaceuticals, Roche Laboratories, Inc.

++ Vesanoid® (tretinoin) is a registered trademark of Roche Pharmaceuticals, Roche Laboratories Inc.

** Lipitor® (atorvastatin calcium) is a registered trademark of Pfizer Inc.

***Taxol (paclitaxel) is a registered trademark of Bristol Myers Squib Company