Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/570
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rdf:type | |
rdfs:label |
Vesanoid (Capsule, Liquid Filled)
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dailymed-instance:dosage |
The recommended dose is 45 mg/m/day administered
as two evenly divided doses until complete remission is documented.
Therapy should be discontinued 30 days after achievement of complete
remission or after 90 days of treatment, whichever occurs first. If after initiation of treatment of VESANOID the presence
of the t(15;17) translocation is not confirmed by cytogenetics and/or
by polymerase chain reaction studies and the patient has not responded
to VESANOID, alternative therapy appropriate for acute myelogenous
leukemia should be considered. VESANOID is for the induction of remission only. Optimal consolidation or maintenance regimens have not been determined.
All patients should, therefore, receive a standard consolidation and/or
maintenance chemotherapy regimen for APL after induction therapy with
VESANOID, unless otherwise contraindicated.
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dailymed-instance:descripti... |
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:
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dailymed-instance:clinicalP... |
Mechanism of Action: Tretinoin is not a cytolytic agent but instead induces
cytodifferentiation and decreased proliferation of APL cells in culture
and in vivo. In APL patients, tretinoin treatment produces an initial
maturation of the primitive promyelocytes derived from the leukemic
clone, followed by a repopulation of the bone marrow and peripheral
blood by normal, polyclonalhematopoietic cells in patients achieving
complete remission (CR). The exact mechanism of action of tretinoin
in APL is unknown.<br/>Pharmacokinetics: Tretinoin activity is primarily due to the parent
drug. In human pharmacokinetics studies, orally administered drug
was well absorbed into the systemic circulation, with approximately
two-thirds of the administered radiolabel recovered in the urine.
The terminal elimination half-life of tretinoin following initial
dosing is 0.5 to 2 hours in patients with APL. There is evidence that
tretinoin induces its own metabolism. Plasma tretinoin concentrations
decrease on average to one-third of their day 1 values during 1 week
of continuous therapy. Mean��SD peak tretinoin concentrations
decreased from 394��89 to 138��139 ng/mL, while area under
the curve (AUC) values decreased from 537��191 ng���h/mL
to 249��185 ng���h/mL during 45 mg/mdaily
dosing in 7 APL patients. Increasing the dose to "correct" for this
change has not increased response.<br/>Absorption: A single 45 mg/m(~80 mg) oral dose to
APL patients resulted in a mean��SD peak tretinoin concentration
of 347��266 ng/mL. Time to reach peak concentration was between
1 and 2 hours.<br/>Distribution: The apparent volume of distribution of tretinoin
has not been determined. Tretinoin is greater than 95% bound in plasma,
predominately to albumin. Plasma protein binding remains constant
over the concentration range of 10 to 500 ng/mL.<br/>Metabolism: Tretinoin metabolites have been identified in plasma
and urine. Cytochrome P450 enzymes have been implicated in the oxidative
metabolism of tretinoin. Metabolites include 13-cis retinoic acid, 4-oxo trans retinoic acid, 4-oxo cis retinoic acid, and 4-oxo trans retinoic acid glucuronide. In
APL patients, daily administration of a 45 mg/mdose of
tretinoin resulted in an approximately tenfold increase in the urinary
excretion of 4-oxo trans retinoic
acid glucuronide after 2 to 6 weeks of continuous dosing, when compared
to baseline values.<br/>Excretion: Studies with radiolabeled drug have demonstrated
that after the oral administration of 2.75 and 50 mg doses of tretinoin,
greater than 90% of the radioactivity was recovered in the urine and
feces. Based upon data from 3 subjects, approximately 63% of radioactivity
was recovered in the urine within 72 hours and 31% appeared in the
feces within 6 days.<br/>Special Populations: The pharmacokinetics of tretinoin have not been separately
evaluated in women, in members of different ethnic groups, or in individuals
with renal or hepatic insufficiency.<br/>Drug-Drug Interactions: In 13 patients who had received daily doses of tretinoin
for 4 consecutive weeks, administration of ketoconazole (400 to 1200
mg oral dose) 1 hour prior to the administration of the tretinoin
dose on day 29 led to a 72% increase (218��224 vs 375��285 ng���h/mL) in tretinoin mean plasma AUC. The precise cytochrome
P450 enzymes involved in these interactions have not been specified; CYP 3A4, 2C8 and 2E have been implicated
in various preliminary reports.<br/>Clinical Studies: VESANOID has been investigated in 114 previously
treated APL patients and in 67 previously untreated ("de novo") patients
in one open-label, uncontrolled single investigator clinical study
(Memorial Sloan-Kettering Cancer Center [MSKCC]) and in two cohorts
of compassionate cases treated by multiple investigators under the
auspices of the National Cancer Institute (NCI). All patients received
45 mg/m/day as a divided oral dose for up to 90 days or
30 days beyond the day that CR was reached. Results are shown in the
following table: The median time to CR was between 40 and 50 days
(range: 2 to 120 days). Most patients in these studies received cytotoxic
chemotherapy during the remission phase. These results compare to
the 30% to 50% CR rate and���6 month median survival reported
for cytotoxic chemotherapy of APL in the treatment of relapse. Ten of 15 pediatric cases achieved CR (8 of 10 males and
2 of 5 females). There were insufficient patients of black, Hispanic
or Asian derivation to estimate relative response rates in these groups,
but responses were seen in each category. Responses
were seen in 3 of 4 patients for whom cytogenetic analysis failed
to detect the t(15;17) translocation typically seen in APL. The t(15;17)
translocation results in the PML/RAR��gene, which appears necessary
for this disease. Molecular genetic studies were not conducted in
these cases, but it is likely they represent cases with a masked translocation
giving rise to PML/RAR��. Responses to tretinoin have not been
observed in cases in which PML/RAR��fusion has been shown to
be absent.
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dailymed-instance:activeIng... | |
dailymed-instance:contraind... |
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.
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dailymed-instance:supply |
VESANOID is supplied as 10 mg capsules, two-tone
(lengthwise), orange-yellow and reddish-brown and imprinted VESANOID
10 ROCHE. Supplied in high-density polyethylene, opaque bottles of
100 capsules with child-resistant closure (NDC 0004-0250-01). Store at 15��to 30��C (59��to 86��F).
Protect from light.
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dailymed-instance:genericDr... | |
dailymed-instance:boxedWarn... |
WARNINGS:<br/>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 followingknown adverse effects of the therapy.<br/>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 radiographicabnormalities), 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.<br/>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��10/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��10/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��10/L,
or immediately, for patients presenting with a WBC count of<5��10/L, if the WBC count reaches���6��10/L by day 5, or���10��10/L by day 10, or���15��10/L by day 28.<br/>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.
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dailymed-instance:activeMoi... | |
dailymed-instance:inactiveI... |
dailymed-ingredient:beeswax,
dailymed-ingredient:butylated_hydroxyanisole,
dailymed-ingredient:edetate_disodium,
dailymed-ingredient:gelatin,
dailymed-ingredient:glycerin,
dailymed-ingredient:hydrogenated_soybean_oil_flakes,
dailymed-ingredient:hydrogenated_vegetable_oils,
dailymed-ingredient:methylparaben,
dailymed-ingredient:propylparaben,
dailymed-ingredient:red_iron_oxide,
dailymed-ingredient:soybean_oil,
dailymed-ingredient:titanium_dioxide,
dailymed-ingredient:yellow_iron_oxide
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dailymed-instance:possibleD... | |
dailymed-instance:precautio... |
General: VESANOID has potentially significant toxic side effects
in APL patients. Patients undergoing therapy should be closely observed
for signs of respiratory compromise and/or leukocytosis . Supportive care appropriate for APL patients, eg, prophylaxis
for bleeding, prompt therapy for infection, should be maintained during
therapy with VESANOID. There is a risk of thrombosis
(both venous and arterial) which may involve any organ system, during
the first month of treatment .
Therefore, caution should be exercised when treating patients with
the combination of VESANOID and anti-fibrinolytic agents, such as
tranexamic acid, aminocaproic acid or aprotinin (see Drug Interactions). The ability to drive or operate
machinery might be impaired in patients treated with VESANOID, particularly
if they are experiencing dizziness or severe headache. Microdosed progesterone preparations ("minipill") may
be an inadequate method of contraception during treatment with VESANOID.<br/>Laboratory Tests: The patient's hematologic profile, coagulation profile,
liver function test results, and triglyceride and cholesterol levels
should be monitored frequently.<br/>Drug Interactions: Limited clinical data on potential drug interactions
are available.<br/>Drugs Metabolized By the Hepatic
P450 System: As VESANOID is metabolized by the hepatic P450 system,
there is a potential for alteration of pharmacokinetics parameters
in patients administered concomitant medications that are also inducers
or inhibitors of this system. Medications that generally induce hepatic
P450 enzymes include rifampicin, glucocorticoids, phenobarbital and
pentobarbital. Medications thatgenerally inhibit hepatic P450 enzymes
include ketoconazole, cimetidine, erythromycin, verapamil, diltiazem
and cyclosporine. To date there are no data to suggest that co-use
with these medications increases or decreases either efficacy or toxicity
of VESANOID.<br/>Agents Known to Cause Pseudotumor
Cerebri/Intracranial Hypertension (Such as Tetracyclines): VESANOID may cause pseudotumor cerebri/intracranial
hypertension. Concomitant administration of VESANOID and agents known
to cause pseudotumor cerebri/intracranial hypertension as well might
increase the risk of this condition .<br/>Vitamin A: As with other retinoids, VESANOID must not be administered
in combination with vitamin A because symptoms of hypervitaminosis
A could be aggravated.<br/>Anti-fibrinolytic Agents (Such
as Tranexamic Acid, Aminocaproic Acid, or Aprotinin): Cases of fatal thrombotic complications have been
reported rarely in patients concomitantly treated with VESANOID and
anti-fibrinolytic agents. Therefore, caution should be exercised when
administering VESANOID concomitantly with these agents .<br/>Effect of Food: No data on the effect of food on the absorption of
VESANOID are available. The absorption of retinoids as a class has
been shown to be enhanced when taken together with food.<br/>Carcinogenesis, Mutagenesis
and Impairment Of Fertility: No long-term carcinogenicity studies with tretinoin
have been conducted. In short-term carcinogenicity studies, tretinoin
at a dose of 30 mg/kg/day (about 2 times the human dose on a mg/mbasis) was shown to increase the rate of diethylnitrosamine
(DEN)-induced mouse liver adenomas and carcinomas. Tretinoin was negative
when tested in the Ames and Chinese hamster V79 cell HGPRT assays
for mutagenicity. A twofold increase in the sister chromatid exchange
(SCE) has been demonstrated in human diploid fibroblasts, but other
chromosome aberration assays, including an in vitro assay in human
peripheral lymphocytesand an in vivo mouse micronucleus assay, did
not show a clastogenic or aneuploidogenic effect. Adverse effects
on fertility and reproductive performance were not observed in studies
conducted in rats at doses up to 5 mg/kg/day (about 2/3 the human
dose on a mg/mbasis). In a 6-week toxicology study in
dogs, minimal to marked testicular degeneration, with increased numbers
of immature spermatozoa, were observed at 10 mg/kg/day (about 4 times
the equivalent human dose in mg/m).<br/>Nursing Mothers: It is not known whether this drug is excreted in
human milk. Because many drugs are excreted in human milk, and because
of the potential for serious adverse reactions from VESANOID in nursing
infants, mothers should discontinue nursing prior to taking this drug.<br/>Pediatric Use: There are limited clinical data on the pediatric
use of VESANOID. Of 15 pediatric patients (age range: 1 to 16 years)
treated with VESANOID, the incidence of complete remission was 67%.
Safety and effectiveness in pediatric patients below the age of 1
year have not been established. Some pediatric patients experience
severe headache and pseudotumor cerebri, requiring analgesic treatment
and lumbar puncture for relief. Increased caution is recommended in
the treatment of pediatric patients. Dose reduction may be considered
for pediatric patients experiencing serious and/or intolerable toxicity;
however, the efficacy and safety of VESANOID at doses lower than 45
mg/m/day have not been evaluated in the pediatric population.<br/>Geriatric Use: Of the total number of subjects in clinical studies
of VESANOID, 21.4% were 60 and over. No overall differences in safety
or effectiveness were observed between these subjects and younger
subjects, and other reported clinical experience has not identified
differences in responses between the elderly and younger patients,
but greater sensitivity of some older individuals cannot be ruled
out.
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dailymed-instance:overdosag... |
In case of overdose with VESANOID, reversible signs
of hypervitaminosis A (headache, nausea, vomiting, mucocutaneous symptoms)
can appear. The maximal tolerated dose in patients with myelodysplastic
syndrome or solid tumors was 195 mg/m/day. The maximal
tolerated dose in pediatric patients was lower at 60 mg/m/day. Overdosage with other retinoids has been associated with transient
headache, facial flushing, cheilosis, abdominal pain, dizziness and
ataxia. These symptoms have quickly resolved without apparent residual
effects. There is no specific treatment in the
case of an overdose; however, it is important that the patient be
treated in a special hematological unit.
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dailymed-instance:genericMe... |
tretinoin
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dailymed-instance:fullName |
Vesanoid (Capsule, Liquid Filled)
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dailymed-instance:adverseRe... |
Virtually all patients experience some drug-related
toxicity, especially headache, fever, weakness, and fatigue. These
adverse effects are seldom permanent or irreversible nor do they usually
require interruption of therapy. Some of the adverse events are common
in patients with APL, including hemorrhage, infections,gastrointestinal
hemorrhage, disseminated intravascular coagulation, pneumonia, septicemia,
and cerebral hemorrhage. The following describes the adverse events,
regardless of drug relationship, that were observed in patients treated
with VESANOID.<br/>Typical Retinoid Toxicity: The most frequently reported adverse events were
similar to those described in patients taking high doses of vitamin
A and included headache (86%), fever (83%), skin/mucous membrane dryness
(77%), bone pain (77%), nausea/vomiting (57%), rash (54%), mucositis
(26%), pruritus (20%), increased sweating (20%), visual disturbances
(17%), ocular disorders (17%), alopecia (14%), skin changes (14%),
changed visual acuity (6%), bone inflammation (3%), visual fielddefects
(3%).<br/>RA-APL Syndrome: APL patients treated with VESANOID have experienced
a potentially fatal 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 and
has been observed with or without concomitant leukocytosis. Some patients
have expired due to progressive hypoxemia and 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 ofthe syndrome has not been defined rigorously, but high-dose
steroids given at the first signs of the syndrome appear to reduce
morbidity and mortality. Treatment with dexamethasone, 10 mg intravenously
administered every 12 hours for 3 days or until resolution of symptoms,
should be initiated without delay at the first suspicion of symptoms
(one or more of the following: fever, dyspnea, weight gain, abnormal
chest auscultatory findings or radiographic abnormalities). Sixty
percent or more of patients treated with VESANOID may require high-dose
steroids because of these symptoms. The majority of patients do not
require termination of VESANOID therapy during treatment of the syndrome.<br/>Body as a Whole: General disorders related to VESANOID administration
and/or associated with APL included malaise (66%), shivering (63%),
hemorrhage (60%), infections (58%), peripheral edema (52%), pain (37%),
chest discomfort (32%), edema (29%), disseminated intravascular coagulation
(26%), weight increase (23%), injection site reactions (17%), anorexia
(17%), weight decrease (17%), myalgia (14%), flank pain (9%), cellulitis
(8%), face edema (6%), fluid imbalance (6%), pallor (6%), lymph disorders
(6%), acidosis (3%), hypothermia (3%), ascites (3%).<br/>Respiratory System Disorders: Respiratory system disorders were commonly reported
in APL patients administered VESANOID. The majority of these events
are symptoms of the RA-APL syndrome . Respiratory system adverse events included upper respiratory tract
disorders (63%), dyspnea (60%), respiratory insufficiency (26%), pleural
effusion (20%), pneumonia (14%), rales (14%), expiratory wheezing
(14%), lower respiratory tract disorders (9%), pulmonary infiltration
(6%), bronchial asthma (3%), pulmonary edema (3%), larynx edema (3%),
unspecified pulmonary disease (3%).<br/>Ear Disorders: Ear disorders were consistently reported, with earache
or feeling of fullness in the ears reported by 23% of the patients.
Hearing loss and other unspecified auricular disorders were observed
in 6% of patients, with infrequent (<1%) reports of irreversible
hearing loss.<br/>Gastrointestinal Disorders: GI disorders included GI hemorrhage (34%), abdominal
pain (31%), other gastrointestinal disorders (26%), diarrhea (23%),
constipation (17%), dyspepsia (14%), abdominal distention (11%), hepatosplenomegaly
(9%), hepatitis (3%), ulcer (3%), unspecified liver disorder (3%).<br/>Cardiovascular and Heart Rate
and Rhythm Disorders: Arrhythmias (23%), flushing (23%), hypotension (14%),
hypertension (11%), phlebitis (11%), cardiac failure (6%) and for
3% of patients: cardiac arrest, myocardial infarction, enlarged heart,
heart murmur, ischemia, stroke, myocarditis, pericarditis, pulmonary
hypertension, secondary cardiomyopathy.<br/>Central and Peripheral Nervous
System Disorders and Psychiatric: Dizziness (20%), paresthesias (17%), anxiety (17%),
insomnia (14%), depression (14%), confusion (11%), cerebral hemorrhage
(9%), intracranial hypertension (9%), agitation (9%), hallucination
(6%) and for 3% of patients: abnormal gait, agnosia, aphasia, asterixis,
cerebellar edema, cerebellar disorders, convulsions, coma, CNS depression,
dysarthria, encephalopathy, facial paralysis, hemiplegia, hyporeflexia,
hypotaxia, no light reflex, neurologic reaction, spinal cord disorder,
tremor, leg weakness, unconsciousness, dementia, forgetfulness, somnolence,
slow speech.<br/>Urinary System Disorders: Renal insufficiency (11%), dysuria (9%), acute renal
failure (3%), micturition frequency (3%), renal tubular necrosis (3%),
enlarged prostate (3%).<br/>Miscellaneous Adverse Events: Isolated cases of erythema nodosum, basophilia and
hyperhistaminemia, Sweet's syndrome, organomegaly, hypercalcemia,
pancreatitis and myositis have been reported.<br/>Additional Adverse Reactions
Reported With VESANOID:<br/>Cardiovascular: Cases of thrombosis (both venous and arterial) involving
various sites (eg, cerebrovascular accident, myocardial infarction,
renal infarct) have been reported rarely .<br/>Hematologic: Rare cases of thrombocytosis have been reported.<br/>Skin: Genital ulceration<br/>Miscellaneous Adverse Events: Rare cases of vasculitis, predominantly involving
the skin, have been reported.
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dailymed-instance:warning |
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 followingknown adverse effects of the therapy.<br/>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 radiographicabnormalities), 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.<br/>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��10/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��10/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��10/L,
or immediately, for patients presenting with a WBC count of<5��10/L, if the WBC count reaches���6��10/L by day 5, or���10��10/L by day 10, or���15��10/L by day 28.<br/>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.
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dailymed-instance:indicatio... |
VESANOID (tretinoin) capsules are indicated for the
induction of remission in patients with acute promyelocytic leukemia
(APL), French-American-British (FAB) classification M3 (including
the M3 variant), characterized by the presence of the t(15;17) translocation
and/or the presence of the PML/RAR��gene who are refractory
to, or who have relapsed from, anthracycline chemotherapy, or for
whom anthracycline-based chemotherapy is contraindicated. VESANOID
is for the induction of remission only. The optimal consolidation
or maintenance regimens have not been defined, but all patients should
receive an accepted form of remission consolidation and/or maintenance
therapy for APL after completion of induction therapy with VESANOID.
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dailymed-instance:represent... | |
dailymed-instance:routeOfAd... | |
dailymed-instance:name |
Vesanoid
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