Vesanoid® Tretinoin Capsules
SIZE: 100 Capsules
INDICATIONS: Indicated for the treatment of Acute Promyelocytic Leukemia (APL)
DIRECTIONS: The number of capsules you will take is based on your body surface area which your doctor will calculate for you. Take the dose which the doctor has prescribed twice daily.
ABOUT THE PRODUCT
Vesanoid® is a prescription medication. It belongs to the family of drugs called retinoids. Each capsule contains 10 mg of the active ingredient tretinoin. It also contains additional (non-medicinal or inactive) ingredients. These are: soybean oil, gelatin, partially hydrogenated soybean oil, glycerol, yellow beeswax, hydrogenated soybean oil, hydrogenated hydrolyzed starch, sorbitol, iron oxide, mannitol, titanium dioxide.
Vesanoid® is used to treat acute promyelocytic leukemia. Vesanoid® works to stop the growth of abnormal blood cells which occur in APL.
ACTIONS AND CLINICAL PHARMACOLOGY
All-trans retinoic acid is a natural metabolite of retinol and belongs to the class of compounds known as retinoids, which are structurally related to vitamin A and comprise natural and synthetic analogs. In vitro studies with all-trans retinoic acid have demonstrated induction of differentiation and inhibition of cell proliferation in transformed hemopoietic cell lines, including human myeloid leukemia cell lines.
Acute promyelocytic leukemia (APL) is associated with a non-random chromosomal abnormality characterized by balanced and reciprocal translocations between the long arms of chromosomes 15 and 17 [t(15;17)(q22;q21)]. The gene encoding the retinoic acid receptor-alpha (RAR-α) is located on chromosome 17. A previously unidentified gene, PML, that may act as a transcription factor, is located on chromosome 15. The 15;17 translocation fuses the genes for PML and RAR-α, resulting
in the synthesis of two reciprocal fusion transcripts, PML/RAR-α (found in all patients) and RAR-α/PML (found in about 2/3 of patients). PML/RAR-α may inhibit the differentiation of myeloid cells, resulting in carcinogenesis, an effect which may be overcome by the use of high doses of all-trans retinoic acid. Orally administered all-trans retinoic acid induces a high rate of complete remissions in patients with APL.
INDICATIONS AND CLINICAL USAGE
Vesanoid® (all-trans retinoic acid) may be used for the induction of remission in acute promyelocytic leukemia (APL; FAB classification AML-M3). Previously untreated patients, as well as patients who relapsed after, or were refractory to, standard chemotherapy (daunomycin and cytosine arabinoside or equivalent therapies) may be treated with all-trans retinoic acid. Upon achievement of complete remission, full-dose consolidation chemotherapy should be employed. Among patients maintained on all-trans retinoic acid, a loss of responsiveness to all-trans retinoic acid, has been reported, with a median time to relapse of 4-6 months.
Vesanoid® (all-trans retinoic acid) is highly teratogenic; therefore it is contraindicated during pregnancy and in nursing mothers. Vesanoid® must not be used by women of child-bearing potential unless effective contraception is practiced for at least one month before beginning therapy, during therapy and at least one month following discontinuation of therapy. Vesanoid® is contraindicated in patients with a known hypersensitivity to all-trans retinoic acid or related compounds.
The use of all-trans retinoic acid in combination with vitamin A is contraindicated.
All-trans retinoic acid should be administered to patients with APL only under the strict supervision of a physician who is experienced in the treatment of hematological / oncological diseases.
Symptoms of the “Retinoic Acid Syndrome” in APL have been frequently reported and may be lifethreatening unless treated (see WARNINGS).
The safety profile of Vesanoid® (all-trans retinoic acid) has been evaluated retrospectively in a small number of patients.
In persons treated with the recommended daily doses of Vesanoid®, the following adverse events were observed frequently (in about ¼ of the patients or more) signs and symptoms of the hypervitaminosis A syndrome (including xeroderma, lip and mouth dryness, cheilitis, rash, edema, nausea, vomiting and bone pain). Headache, fever, shivering, fatigue, back pain, chest pain, dyspnea, coughing, abdominal pain, dermal bleeding, and elevation in serum triglycerides, cholesterol and transaminases may also be observed.
The following adverse events, considered remotely, possibly or probably related to drug treatment have been reported in less than ¼ of all APL patients treated with Vesanoid® in the clinical trials:
Autonomic Nervous System: tachycardia, hypertension, hypotension, flushing, pallor, red extremeties.
Body as a Whole: generalized pain, abdominal distension, post traumatic pain, chest discomfort, hypothermia.
Cardiovascular System: cardiac failure, cyanosis, heart enlarged, arrhythmias. Cases of thrombosis (both venous and arterial) involving various sites (e.g. cerebrovascular accident, myocardial infarctions, renal infarct) have been reported uncommonly.
Central and Peripheral Nervous System: dizziness, confusion, intracranial hypertension, light headed feeling, flank pain, numbness of extremeties, abnormal gait, leg weakness, neurologic reaction, inguinal pain, visual field defects, hyporeflexia, paresthesia.
Dermatological: pruritus, increased sweating, alopecia, dry scalp, nasal dryness, nail disorder, photosensitivity reaction, xerophthalmia, erythemia.
Gastrointestinal: abdominal pain, diarrhea, constipation, blisters in the mouth, stomach upset, dysphagia, buccal mucosa ulceration, stomatitis, flatulence, ulcer, pancreatitis, diminished appetite.
Metabolic and Nutritional Disorders: weight changes, edema of extremities, acidosis, gout, dehydration, fluid overload, moonface, elevation in serum creatinine.
Musculoskeletal: musculoskeletal pain.
Platelet, Bleeding & Clotting: disseminated intravascular coagulation (DIC), nosebleed and other bleeding disorders, thrombosis.
Psychiatric: generalized weakness, anxiety, lethargy, depression, malaise, insomnia, anorexia, agitation, forgetfulness.
Resistance Mechanism Disorders: infection, septicemia, moniliasis.
Respiratory System: pleural effusion, nasal congestion, pharyngitis, rale, respiratory insufficiency, asthma-like syndrome, pneumonia, respiratory distress, tachypnea, pharynx irritation, pulmonary infiltration, hypoxia, sinusitis, bronchial asthma.
Special Senses: blurred vision, visual disturbance, photophobia, conjunctivitis, decreased vision, changes in visual acuity, ear fullness, earache, ear buzzing.
Urinary System: dysuria, kidney failure, urinary tract infection, micturition frequency, renal insufficiency, cystitis.
The decision to interrupt or continue therapy should be based on an evaluation of the benefit of the treatment versus the severity of the side effects.
Metabolic and Nutritional Disorders: Occasional cases of hypercalcemia have been reported.
Dermatological: Sweet’s syndrome has been reported uncommonly. Erythema nodosum has been reported rarely.
Hematologic: Thrombocytosis has been reported rarely. Marked basophilia with or without symptomatic hyperhistaminemia has been reported rarely, mainly in patients with the rare APL variant associated with basophilic differentiation.
Musculoskeletal: Myositis has been reported rarely.
Others: Vasculitis, predominantly involving the skin has been reported rarely.
There is limited safety information on the use of all-trans retinoic acid in children. There have been some reports of increased toxicity in children treated with tretinoin, particularly increased pseudotumor cerebri.
DOSAGE AND ADMINISTRATION
A total daily dose of 45 mg/m2 body surface divided in two equal doses is recommended for oral administration to APL patients, including pediatric and geriatric patients.
This is approximately 8 capsules per adult dose. It is recommended that pediatric patients be treated with 45mg/m2 unless severe toxicity becomes apparent. Dose reduction should be particularly considered for children with intractable headache.
Treatment should be continued for 30 to 90 days until complete remission has been achieved.
After completion of remission, a course of consolidation chemotherapy including anthracycline and cytosine arabinoside should be initiated immediately; for example, three courses in 5 to 6 week intervals.
If there has been a remission with ATRA alone, it is not necessary to modify doses of ATRA if ATRA is used with chemotherapy.
The effect of food on the bioavailability of all-trans retinoic acid has not been characterized. Since the bioavailability of retinoids, as a class, is known to increase in the presence of food, it is recommended that all-trans retinoic acid be administered with a meal or shortly thereafter.
**The information above is an excerpt from pages 2-8 in the product monograph
ABOUT THE DISEASE
Acute promyclocytic leukemia, also known as APL, is a form of cancer in the blood where there is uncontrolled growth of certain types of abnormal white blood cells. Symptoms of the disease include weakness, tiredness and weight loss.
Treatment for APL can include chemical therapy (known as chemotherapy), blood transfusions, and antibiotics to control infection. Acute promyclocytic leukemia (APL) is associated with a non-random chromosomal abnormality characterized by balanced and reciprocal translocations between the long arms of chromosomes 15 and 17 [t(15;17)(q22;q21)]
Early diagnosis and treatment of acute promyelocytic leukemia (APL), the M3 subtype of acute myeloid leukemia (AML), is important because patients with APL can develop serious blood-clotting or bleeding problems. This is less often a problem now that treatment includes differentiating drugs like all-trans-retinoic acid (ATRA). Other treatments might include chemotherapy and transfusions of platelets or other blood products.
Treatment of most cases of APL is done differently from usual Acute myelocytic leukemia (AML) treatment. Initially, treatment begins with the administration of the non-chemotherapy drug all-trans-retinoic acid (ATRA), which is most often combined with an anthracycline chemotherapy (chemo) drug (either daunorubicin or idarubicin), which may also be used in combination with the chemo drug cytarabine (ara-c). For patients who cannot tolerate an anthracycline drug, another possibility would be to give ATRA plus another differentiating drug called arsenic trioxide (Trisenox). The aim of this phase of treatment is to clear the blood of leukemia cells (called blasts) and reduce the blast number in the bone marrow to normal levels.
After recovering from the initial induction treatment, Patients with APL then receive post-remission treatment. What drugs are used depends on what was given for induction, and are administrated several times over a given number of weeks in cycles. Some of the options include:
- An anthracycline along with ATRA for a few cycles (sometimes different anthracyclines are used in different cycles)
- An anthracycline plus cytarabine for at least 2 cycles
- Arsenic trioxide for 2 cycles (over about 2½ months), then ATRA plus an anthracycline for 2 cycles
- ATRA plus arsenic trioxide for several cycles
The aim here is to kill whatever few leukemia cells remain that cannot be seen due to their low number.
Consolidation may be followed by maintenance therapy with ATRA for at least a year. Sometimes low doses of the chemo drugs 6-mercaptopurine (6-MP) and methotrexate are given as well. This is common for APL, but rare in other types of AML.
FREQUENTLY ASKED QUESTIONS
Acute promyclocytic leukemia, also known as APL, is a form of cancer in the blood where there is uncontrolled growth of certain types of abnormal white blood cells.
Symptoms of the disease include weakness, tiredness and weight loss. Treatment for APL can include chemical therapy (known as chemotherapy), blood transfusions, and antibiotics to control infection.
Before beginning treatment with Vesanoid®, make sure your doctor knows if:
- You have ever had a bad reaction to all-trans retinoic acid (tretinoin) or any of the inactive ingredients of Vesanoid®.
- You are allergic to other medicines, food and dyes
- You have any other illnesses/diseases, such as kidney or liver disease
- You are pregnant, plan on becoming pregnant, or are breast-feeding a child
- You are taking any vitamin preparations or health food supplements that contain vitamin A. Vitamin A in high doses has many of the same side-effects as Vesanoid®. Taking both together may increase your chance of getting side-effects.
- You are taking any other medicines, particularly: Those used to treat fibrin disorders such as tranexamic acid (Cyklokapron®†), aminocaproic acid (Amicar®†) and aprotinin (Trasylol®†), birth control pills as Vesanoid® may reduce the effectiveness of some low dose products, antibiotics, particularly tetracyclines, as these products when taken withVesanoid® may increase pressure in the brain.
This information will help your doctor and you decide whether you should use Vesanoid® and what extra care may need to be taken while you are on the medication.
Unwanted effects are possible with all medicines. Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Vesanoid®.
The most common possible unwanted effects are:
- dry skin
- dry mouth and lips
- swelling of the mouth and lips
- bone pain.
Less common possible unwanted effects are:
- back pain
- chest pain
- stomach pain
Should you develop depression or your depression worsens, consult your doctor. Signs of depression include feelings of sadness, irritability, unusual tiredness, trouble concentrating, change in normal sleep patterns and loss of appetite.
**The information above is an excerpt from the product monograph