Vesanoid

Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

Tretinoin is a cancer medicine that interferes with the growth of cancer cells and slows their growth and spread in the body.

Tretinoin is used to treat acute promyelocytic leukemia (a type of blood cancer).

Tretinoin may also be used for other purposes not listed in this medication guide.

Do not use if you are pregnant. You may need to have a pregnancy test every month during treatment.

You should not use this medicine if you are allergic to tretinoin or to other retinoids (such as Accutane, Retin-A, Renova).

This medicine can cause birth defects, miscarriage, premature birth, or death of a baby. Do not use tretinoin if you are pregnant. Tell your doctor right away if you miss a period or become pregnant during treatment. You may need to have a negative pregnancy test before starting this treatment, and every month while taking tretinoin.

Tretinoin can make certain birth control pills less effective. Ask your doctor about the best method of birth control to prevent pregnancy while taking tretinoin. You must use effective birth control while you are taking tretinoin unless you have had a hysterectomy and no longer have a uterus. Use birth control even if you have been infertile (unable to have children) in the past, or if you have gone through menopause.

To make sure tretinoin is safe for you, tell your doctor if you have:

• high cholesterol;
• liver disease; or
• a history of blood clot or stroke.

It is not known whether tretinoin passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Do not use Vesanoid if:

• you are pregnant or plan to become pregnant
• you are sunburned or your skin is irritated
• you are highly sensitive to sunlight
• have eczema or other skin conditions
• you are allergic to any of the ingredients in Vesanoid

Vesanoid may cause severe side effects.

• Vesanoid may increase the levels of cholesterol and other fats in your blood and may stop your liver from working normally. Your doctor will monitor you carefully to see whether you are experiencing either of these side effects.
• Vesanoid should be given only under the supervision of a doctor who has experience in treating people who have leukemia (cancer of the white blood cells) and in a hospital where patients can be monitored for severe side effects and treated if these side effects occur.
• Vesanoid may cause a serious or life-threatening group of symptoms called retinoic acid-APL (RA-APL) syndrome. Your doctor will monitor you carefully to see whether you are developing this syndrome. If you experience any of the following symptoms, call your doctor immediately: fever; weight gain; swelling of the arms, hands, feet, ankles, or lower legs; shortness of breath; labored breathing; wheezing; chest pain; or cough. At the first sign that you are developing RA-APL syndrome, your doctor will prescribe one or more medications to treat the syndrome.
• Vesanoid may cause a rapid increase in the number of white blood cells in the body. This is associated with a higher risk of life-threatening side effects. If you have a very high number of white blood cells before you begin Vesanoid treatment, or if you have an increase in the number of white blood cells during your treatment with Vesanoid, especially if you experience any of the symptoms of RA-APL syndrome, your doctor may prescribe one or more medications to treat or prevent the increase in white blood cells.
• For female patients:
  • Vesanoid must not be taken by patients who are pregnant or who may become pregnant. There is a high risk that Vesanoid will cause the baby to be born with birth defects (physical problems that are present at birth).
  • If you can become pregnant, you will need to avoid pregnancy during your treatment with Vesanoid. You must use two acceptable forms of birth control during your treatment and for 1 month after your treatment, even if you have infertility (difficulty becoming pregnant) or have experienced menopause ('change of life'; end of monthly menstrual periods). You must use these two forms of birth control at all times unless you can promise that you will not have any sexual contact with a male for 1 month after your treatment. Your doctor will tell you which forms of birth control are acceptable, and will give you full information about birth control.
  • If you plan to use oral contraceptives (birth control pills) while taking Vesanoid, tell your doctor the name of the pill you will use. Microdosed progestin ('minipill') oral contraceptives (Ovrette, Micronor, Nor-D) may not be an effective form of birth control for people who are taking Vesanoid.
  • You must have a negative pregnancy test within 1 week before you begin to take Vesanoid. You will also need to be tested for pregnancy in a laboratory each month during your treatment.
• Do not drive or operate heavy machinery until you know how this medication affects you.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

This medication falls into category D.

• YOU MUST NOT BECOME PREGNANT DURING TREATMENT. There is an extremely high risk that a deformed baby will result if you become pregnant while taking Vesanoid, in any amount, for even short periods of time. Potentially any exposed fetus (unborn baby) can be affected. There is also an increased risk of miscarriage. Premature births may also occur.
• Effective contraception (birth control) should be discussed with your doctor. Two forms of reliable contraception must be used during therapy, and must be continued for one month after Vesanoid treatment has stopped. If directed by your doctor, two forms of reliable contraception must also be used simultaneously for at least one month before beginning therapy. It is recommended that you either abstain from sexual intercourse or use two reliable kinds of birth control at the same time. Birth control must be used even if you think you cannot become pregnant, unless you have had a hysterectomy.
• If you are pregnant or become pregnant while on Vesanoid therapy or during the month after treatment has stopped, immediately contact your doctor to discuss the desirability of continuing the pregnancy.

YOU MUST NOT TAKE  VESANOID IF YOU ARE A NURSING MOTHER.

Vesanoid should not be taken by nursing mothers since it is not known whether it is excreted in human milk. Since many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Vesanoid, mothers should discontinue nursing prior to taking this drug.

Do not use if you are pregnant. You may need to have a pregnancy test every month during treatment.

Do not use vitamin A supplements or multivitamins that contain vitamin A while you are taking tretinoin.

This medicine may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

This medicine can pass into body fluids (urine, feces, vomit). Caregivers should wear rubber gloves while cleaning up a patient's body fluids, handling contaminated trash or laundry or changing diapers. Wash hands before and after removing gloves. Wash soiled clothing and linens separately from other laundry.

Acute Promyelocytic Leukemia

Used to induce remission in acute promyelocytic leukemia (APL), French-American-British classification M3 including the M3 variant, characterized by the presence of certain genetic markers (i.e., 15;17 chromosomal translocation and/or PML/RAR-α gene) in patients with relapsed or refractory disease following anthracycline-based chemotherapy or in patients for whom anthracycline therapy is contraindicated.1 16

Most clinicians recommend addition of tretinoin to induction combination chemotherapy (anthracycline-based)39 40 41 c as initial† treatment for APL in patients with previously untreated disease.6 7 8 13 15 16 41

May initiate tretinoin therapy based on the morphologic diagnosis of APL, but perform cytogenetic evaluation to confirm presence of the 15;17 translocation, and if absent, perform molecular diagnostic testing for the PML/RAR-α fusion protein.1

May be ineffective when these genetic markers are absent; consider alternative therapy.1 2 19 41 c

Metabolized by CYP isoenzymes.1

Drugs Affecting Hepatic Microsomal Enzymes

Concomitant use of drugs that affect CYP isoenzymes (e.g., CYP3A4, CYP2C8, CYP2E) may alter metabolism of tretinoin; not known whether concomitant use of drugs affecting the CYP enzyme system alters the efficacy or toxicity of tretinoin.1 1

Inducers of CYP isoenzymes: Potential pharmacokinetic interaction (decreased plasma tretinoin concentrations).1

Inhibitors of CYP isoenzymes: Potential pharmacokinetic interaction (increased plasma tretinoin concentrations).1

Specific Drugs

• Not a cytolytic agent; precise mechanism(s) of action not fully elucidated.1 10

• PML/RAR-α fusion protein resulting from 15;17 chromosomal translocation apparently blocks myeloid differentiation at the promyelocyte stage;2 induces cellular differentiation and decreases proliferation of APL cells.1 10

• Causes initial maturation of primitive promyelocytes (derived from the cellular leukemic clone) followed by normal, polyclonal hematopoietic cell repopulation of bone marrow and peripheral blood.1

• Apoptosis (programmed cell death) may be a mechanism for eliminating malignant cells.9

• Tretinoin alone does not eradicate the leukemic clone because PML/RAR-α fusion protein usually can be detected following induction.2

• High initial complete response rate, but remissions induced and maintained by tretinoin alone are short (median: 3.5 months).11

• Clinical resistance occurs with prolonged administration; increased tretinoin metabolism and clearance with resultant, reduction in plasma concentrations, may contribute to resistance.4 5

• Importance of advising patients of adverse effects and associated manifestations.1

• Importance of advising patients that their ability to drive or operate machinery might be impaired, especially if experiencing dizziness or severe headache.1

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

• Importance of women using effective contraception (i.e., 2 reliable forms of contraception simultaneously unless abstinence is the chosen method) during tretinoin therapy and for 1 month following discontinuance, unless a hysterectomy has been performed.1 Importance of informing women that progestin-only preparations (i.e., minipill) may be an inadequate method of contraception during tretinoin therapy and for 1 month following discontinuance.1

• Importance of fully informing women of high risk of fetal harm and risks of contraceptive failure, discussing desirability of continuing or terminating pregnancy when administered during pregnancy or when woman becomes pregnant while receiving the drug.1

• Importance of performing pregnancy testing before initiation of tretinoin, and repeating pregnancy testing and contraception counseling monthly during tretinoin therapy.1

• Importance of informing patients of other important precautionary information.1 (See Cautions.)

In the U.S.

• Vesanoid

Available Dosage Forms:

• Capsule, Liquid Filled

Therapeutic Class: Antineoplastic Agent

Chemical Class: Retinoid

It is very important that you take tretinoin only as directed by your doctor . Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. To do so may increase the chance of side effects.

Dosing

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.

• For oral dosage form (capsules):
  • For acute promyelocytic leukemia (APL):
    • Adults—Dose is based on body size and must be determined by your doctor. The usual dose is 45 milligrams (mg) for each square meter of body surface area a day, given in two equally divided doses.
    • Children—The dose will be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

If it is almost time for your next dose, check with your health care professional to find out how much medicine to take for the next dose.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

1. Experienced Physician and Institution

Patients with acute promyelocytic leukemia (APL) are at high risk in general and can have severe adverse reactions to Vesanoid (tretinoin). Vesanoid should therefore be administered only to patients with APL under the strict supervision of a physician who is experienced in the management of patients with acute leukemia and in a facility with laboratory and supportive services sufficient to monitor drug tolerance and protect and maintain a patient compromised by drug toxicity, including respiratory compromise. Use of Vesanoid requires that the physician concludes that the possible benefit to the patient outweighs the following known adverse effects of the therapy.

2. Retinoic Acid-APL Syndrome

About 25% of patients with APL treated with Vesanoid have experienced a syndrome called the retinoic acid-APL (RA-APL) syndrome characterized by fever, dyspnea, acute respiratory distress, weight gain, radiographic pulmonary infiltrates, pleural and pericardial effusions, edema, and hepatic, renal, and multi-organ failure. This syndrome has occasionally been accompanied by impaired myocardial contractility and episodic hypotension. It has been observed with or without concomitant leukocytosis. Endotracheal intubation and mechanical ventilation have been required in some cases due to progressive hypoxemia, and several patients have expired with multi-organ failure. The syndrome generally occurs during the first month of treatment, with some cases reported following the first dose of Vesanoid.

The management of the syndrome has not been defined rigorously, but high-dose steroids given at the first suspicion of the RA-APL syndrome appear to reduce morbidity and mortality. At the first signs suggestive of the syndrome (unexplained fever, dyspnea and/or weight gain, abnormal chest auscultatory findings or radiographic abnormalities), high-dose steroids (dexamethasone 10 mg intravenously administered every 12 hours for 3 days or until the resolution of symptoms) should be immediately initiated, irrespective of the leukocyte count. The majority of patients do not require termination of Vesanoid therapy during treatment of the RA-APL syndrome. However, in cases of moderate and severe RA-APL syndrome, temporary interruption of Vesanoid therapy should be considered.

3. Leukocytosis at Presentation and Rapidly Evolving Leukocytosis During Vesanoid Treatment

During Vesanoid treatment about 40% of patients will develop rapidly evolving leukocytosis. Patients who present with high WBC at diagnosis (>5×109/L) have an increased risk of a further rapid increase in WBC counts. Rapidly evolving leukocytosis is associated with a higher risk of life-threatening complications.

If signs and symptoms of the RA-APL syndrome are present together with leukocytosis, treatment with high-dose steroids should be initiated immediately. Some investigators routinely add chemotherapy to Vesanoid treatment in the case of patients presenting with a WBC count of >5×109/L or in the case of a rapid increase in WBC count for patients leukopenic at start of treatment, and have reported a lower incidence of the RA-APL syndrome. Consideration could be given to adding full-dose chemotherapy (including an anthracycline if not contraindicated) to the Vesanoid therapy on day 1 or 2 for patients presenting with a WBC count of >5×109/L, or immediately, for patients presenting with a WBC count of <5×109/L, if the WBC count reaches ≥6×109/L by day 5, or ≥10×109/L by day 10, or ≥15×109/L by day 28.

4. Teratogenic Effects.

Pregnancy Category D – see WARNINGS

There is a high risk that a severely deformed infant will result if Vesanoid is administered during pregnancy. If, nonetheless, it is determined that Vesanoid represents the best available treatment for a pregnant woman or a woman of childbearing potential, it must be assured that the patient has received full information and warnings of the risk to the fetus if she were to be pregnant and of the risk of possible contraception failure and has been instructed in the need to use two reliable forms of contraception simultaneously during therapy and for 1 month following discontinuation of therapy, and has acknowledged her understanding of the need for using dual contraception, unless abstinence is the chosen method

Within 1 week prior to the institution of Vesanoid therapy, the patient should have blood or urine collected for a serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL. When possible, Vesanoid therapy should be delayed until a negative result from this test is obtained. When a delay is not possible, the patient should be placed on two reliable forms of contraception. Pregnancy testing and contraception counseling should be repeated monthly throughout the period of Vesanoid treatment.

Vesanoid (tretinoin) is a retinoid that induces maturation of acute promyelocytic leukemia (APL) cells in culture. It is available in a 10 mg soft gelatin capsule for oral administration. Each capsule also contains beeswax, butylated hydroxyanisole, edetate disodium, hydrogenated soybean oil flakes, hydrogenated vegetable oils and soybean oil. The gelatin capsule shell contains glycerin, yellow iron oxide,red iron oxide, titanium dioxide, methylparaben and propylparaben.

Chemically, tretinoin is all-trans retinoic acid and is related to retinol (Vitamin A). It is a yellow to light orange crystalline powder with a molecular weight of 300.44.

The structural formula is as follows:

Vesanoid is contraindicated in patients with a known hypersensitivity to Vesanoid, any of its components, or other retinoids. Vesanoid should not be given to patients who are sensitive to parabens, which are used as preservatives in the gelatin capsule.

NDC 0004-0250-01

Roche

Vesanoid®
(tretinoin) Capsules

10 mg

AVOID
PREGNANCY

Rx only

100 Capsules