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00110136/CLB-P-263-750-12545.qxd:Layout 1 20/12/2011 10:32 Page 1 Tretinoin Capsules
decreased from 537 ± 191 ng·h/mL to 249 ± 185 ng·h/mL during 45 mg/m2 There are no adequate and wel -control ed studies in pregnant women.
Carcinogenesis, Mutagenesis and Impairment of Fertility
daily dosing in 7 APL patients. Increasing the dose to “correct” for this Although experience with humans administered tretinoin capsules is extremely limited, increased spontaneous abortions and major human fetal No long-term carcinogenicity studies with tretinoin have been conducted. In PATIENT INFORMATION:
WARNINGS
short-term carcinogenicity studies, tretinoin at a dose of 30 mg/kg/day abnormalities related to the use of other retinoids have been documented in (about 2 times the human dose on a mg/m2 basis) was shown to increase Experienced Physician and Institution
humans. Reported defects include abnormalities of the CNS, musculoskele- the rate of diethylnitrosamine (DEN)-induced mouse liver adenomas and WARNING TO FEMALE PATIENTS
Patients with acute promyelocytic leukemia (APL) are at high risk in gen- A single 45 mg/m2 (~80 mg) oral dose to APL patients resulted in a mean ± tal system, external ear, eye, thymus and great vessels; and facial dysmor- carcinomas. Tretinoin was negative when tested in the Ames and Chinese eral and can have severe adverse reactions to tretinoin capsules.
SD peak tretinoin concentration of 347 ± 266 ng/mL. Time to reach peak phia, cleft palate, and parathyroid hormone deficiency. Some of these hamster V79 cel HGPRT assays for mutagenicity. A twofold increase in the Tretinoin capsules should therefore be administered only to patients with concentration was between 1 and 2 hours.
abnormalities were fatal. Cases of IQ scores less than 85, with or without sister chromatid exchange (SCE) has been demonstrated in human diploid APL under the strict supervision of a physician who is experienced in the obvious CNS abnormalities, have also been reported. Al fetuses exposed fibroblasts, but other chromosome aberration assays, including an in vitro management of patients with acute leukemia and in a facility with labora- The apparent volume of distribution of tretinoin has not been determined.
during pregnancy can be af ected and at the present time there is no assay in human peripheral lymphocytes and an in vivo mouse micronucle- tory and supportive services suf icient to monitor drug tolerance and pro- Tretinoin is greater than 95% bound in plasma, predominately to albumin.
antepartum means of determining which fetuses are and are not af ected.
us assay, did not show a clastogenic or aneuploidogenic ef ect. Adverse tect and maintain a patient compromised by drug toxicity, including respi- Plasma protein binding remains constant over the concentration range of 10 to Ef ective contraception must be used by al females during tretinoin cap- ef ects on fertility and reproductive performance were not observed in stud- There is an extremely high risk that a deformed ratory compromise. Use of tretinoin capsules requires that the physician sules therapy and for 1 month fol owing discontinuation of therapy.
ies conducted in rats at doses up to 5 mg/kg/day (about 2/3 the human dose baby wil result if you become pregnant while taking concludes that the possible benefit to the patient outweighs the fol owing Contraception must be used even when there is a history of infertility or on a mg/m2 basis). In a 6-week toxicology study in dogs, minimal to marked known adverse ef ects of the therapy.
menopause, unless a hysterectomy has been performed. Whenever contra- testicular degeneration, with increased numbers of immature spermatozoa, tretinoin capsules, in any amount, for even short Tretinoin metabolites have been identified in plasma and urine. Cytochrome ception is required, it is recommended that two reliable forms of contracep- were observed at 10 mg/kg/day (about 4 times the equivalent human dose periods of time. Potential y any exposed fetuses can Retinoic Acid-APL Syndrome
P450 enzymes have been implicated in the oxidative metabolism of tion be used simultaneously, unless abstinence is the chosen method. If About 25% of patients with APL treated with tretinoin capsules have expe- be af ected. There is also an increased risk of mis- cis retinoic acid, 4-oxo trans retinoic acid, pregnancy does occur during treatment, the physician and patient should rienced a syndrome cal ed the retinoic acid-APL (RA-APL) syndrome Nursing Mothers
cis retinoic acid, and 4-oxo trans retinoic acid glucuronide. In APL discuss the desirability of continuing or terminating the pregnancy.
carriage. Premature births may also occur.
characterized by fever, dyspnea, acute respiratory distress, weight gain, patients, daily administration of a 45 mg/m2 dose of tretinoin resulted in an It is not known whether this drug is excreted in human milk. Because many radiographic pulmonary infiltrates, pleural and pericardial ef usions, approximately tenfold increase in the urinary excretion of 4-oxo Patients Without the t(15;17) Translocation
drugs are excreted in human milk, and because of the potential for serious edema, and hepatic, renal, and multi-organ failure. This syndrome has retinoic acid glucuronide after 2 to 6 weeks of continuous dosing, when Initiation of therapy with tretinoin capsules may be based on the morpholog- adverse reactions from tretinoin capsules in nursing infants, mothers should Ef ective contraception (birth control) should be dis- occasional y been accompanied by impaired myocardial contractility and ical diagnosis of acute promyelocytic leukemia. Confirmation of the diagno- discontinue nursing prior to taking this drug.
cussed with your doctor. Two forms of reliable con- episodic hypotension. It has been observed with or without concomitant sis of APL should be sought by detection of the t(15;17) genetic marker by leukocytosis. Endotracheal intubation and mechanical ventilation have cytogenetic studies. If these are negative, PML/RARα fusion should be Pediatric Use
traception must be used during therapy, and must been required in some cases due to progressive hypoxemia, and several Studies with radiolabeled drug have demonstrated that after the oral admin- sought using molecular diagnostic techniques. The response rate of other There are limited clinical data on the pediatric use of tretinoin capsules. Of be continued for one month after tretinoin treatment patients have expired with multi-organ failure. The syndrome general y istration of 2.75 and 50 mg doses of tretinoin, greater than 90% of the AML subtypes to tretinoin capsules has not been demonstrated; therefore, 15 pediatric patients (age range: 1 to 16 years) treated with tretinoin cap- has stopped. If directed by your doctor, two forms of occurs during the first month of treatment, with some cases reported fol- radioactivity was recovered in the urine and feces. Based upon data from patients who lack the genetic marker should be considered for alternative sules, the incidence of complete remission was 67%. Safety and ef ective- lowing the first dose of tretinoin capsules.
3 subjects, approximately 63% of radioactivity was recovered in the urine ness in pediatric patients below the age of 1 year have not been estab- reliable contraception must also be used simultane- The management of the syndrome has not been defined rigorously, but within 72 hours and 31% appeared in the feces within 6 days.
lished. Some pediatric patients experience severe headache and pseudotu- ously for at least one month before beginning thera- Retinoic Acid-APL (RA-APL) Syndrome
high-dose steroids given at the first suspicion of the RA-APL syndrome mor cerebri, requiring analgesic treatment and lumbar puncture for relief.
py. It is recommended that you either abstain from appear to reduce morbidity and mortality. At the first signs suggestive of In up to 25% of patients with APL treated with tretinoin capsules, a syn- Increased caution is recommended in the treatment of pediatric patients.
The pharmacokinetics of tretinoin have not been separately evaluated in the syndrome (unexplained fever, dyspnea and/or weight gain, abnormal drome occurs which can be fatal (see boxed WARNINGS and ADVERSE
Dose reduction may be considered for pediatric patients experiencing seri- sexual intercourse or use two reliable kinds of birth women, in members of dif erent ethnic groups, or in individuals with renal or chest auscultatory findings or radiographic abnormalities), high-dose REACTIONS).
ous and/or intolerable toxicity; however, the ef icacy and safety of tretinoin control at the same time. Birth control must be used steroids (dexamethasone 10 mg intravenously administered every 12 hours Leukocytosis at Presentation and Rapidly Evolving Leukocytosis
capsules at doses lower than 45 mg/m2/day have not been evaluated in the even if you think you cannot become pregnant, for 3 days or until the resolution of symptoms) should be immediately ini- During Tretinoin Capsules Treatment
tiated, irrespective of the leukocyte count. The majority of patients do not In 13 patients who had received daily doses of tretinoin for 4 consecutive boxed WARNINGS.
Geriatric Use
require termination of tretinoin capsules therapy during treatment of the weeks, administration of ketoconazole (400 to 1200 mg oral dose) 1 hour Of the total number of subjects in clinical studies of tretinoin capsules, RA-APL syndrome. However, in cases of moderate and severe RA-APL prior to the administration of the tretinoin dose on day 29 led to a 72% Pseudotumor Cerebri
21.4% were 60 and over. No overal dif erences in safety or ef ectiveness If you are pregnant or become pregnant while on syndrome, temporary interruption of tretinoin capsules therapy should be increase (218 ± 224 vs 375 ± 285 ng·h/mL) in tretinoin mean plasma AUC.
Retinoids, including tretinoin capsules, have been associated with pseudo- were observed between these subjects and younger subjects, and other The precise cytochrome P450 enzymes involved in these interactions have tumor cerebri (benign intracranial hypertension), especial y in pediatric reported clinical experience has not identified dif erences in responses tretinoin therapy or during the month after treatment not been specified; CYP 3A4, 2C8 and 2E have been implicated in various patients. The concomitant use of other agents known to cause pseudotumor has stopped, immediately contact your doctor to dis- Leukocytosis at Presentation and Rapidly Evolving Leukocytosis
between the elderly and younger patients, but greater sensitivity of some cerebri/intracranial hypertension, such as tetracyclines, might increase the During Tretinoin Capsules Treatment
older individuals cannot be ruled out.
cuss the desirability of continuing the pregnancy.
PRECAUTIONS: Drug Interactions). [2] Early
During tretinoin capsules treatment about 40% of patients wil develop Clinical Studies
signs and symptoms of pseudotumor cerebri include papil edema, rapidly evolving leukocytosis. Patients who present with high WBC at Tretinoin capsules have been investigated in 114 previously treated APL headache, nausea and vomiting, and visual disturbances. Patients with ADVERSE REACTIONS
diagnosis (>5x109/L) have an increased risk of a further rapid increase in patients and in 67 previously untreated (“de novo”) patients in one open- these symptoms should be evaluated for pseudo - tumor cerebri, and, if WBC counts. Rapidly evolving leukocytosis is associated with a higher label, uncontrol ed single investigator clinical study (Memorial Sloan- present, appropriate care should be instituted in concert with neurological Virtual y al patients experience some drug-related toxicity, especial y head risk of life-threatening complications.
Ket ering Cancer Center [MSKCC]) and in two cohorts of compassionate ache, fever, weakness, and fatigue. These adverse ef ects are seldom per- manent or irreversible nor do they usual y require interruption of therapy.
If signs and symptoms of the RA-APL syndrome are present together with cases treated by multiple investigators under the auspices of the National Some of the adverse events are common in patients with APL, including Tretinoin capsules should not be taken by nursing leukocytosis, treatment with high-dose steroids should be initiated imme- Cancer Institute (NCI). Al patients received 45 mg/m2/day as a divided oral hemorrhage, infections, gastrointestinal hemorrhage, disseminated diately. Some investigators routinely add chemotherapy to tretinoin cap- dose for up to 90 days or 30 days beyond the day that CR was reached.
Up to 60% of patients experienced hypercholesterolemia and/or hypertriglyc- intravascular coagulation, pneumonia, septicemia, and cerebral hemor- mothers since it is not known whether it is excreted sules treatment in the case of patients presenting with a WBC count of Results are shown in the fol owing table: eridemia, which were reversible upon completion of treatment. The clinical rhage. The fol owing describes the adverse events, regardless of drug rela- in human milk. Since many drugs are excreted in >5x109/L or in the case of a rapid increase in WBC count for patients consequences of temporary elevation of triglycerides and cholesterol are tionship, that were observed in patients treated with tretinoin capsules.
human milk and because of the potential for serious leukopenic at start of treatment, and have reported a lower incidence of NCI Cohort 1
NCI Cohort 2
unknown, but venous thrombosis and myocardial infarction have been the RA-APL syndrome. Consideration could be given to adding ful -dose reported in patients who ordinarily are at low risk for such complications.
Typical Retinoid Toxicity
adverse reactions in nursing infants from tretinoin, chemotherapy (including an anthracycline if not contraindicated) to the Relapsed De Novo Relapsed* De Novo Relapsed De Novo†
Elevated Liver Function Test Results
The most frequently reported adverse events were similar to those described mothers should discontinue nursing prior to taking tretinoin capsules therapy on day 1 or 2 for patients presenting with a Elevated liver function test results occur in 50% to 60% of patients during in patients taking high doses of vitamin A and included headache (86%), WBC count of >5x109/L, or immediately, for patients presenting with a treatment. Liver function test results should be careful y monitored during fever (83%), skin/mucous membrane dryness (77%), bone pain (77%), nau- WBC count of <5x109/L, if the WBC count reaches >6x109/L by day 5, or Remission 16 (80%) 11 (73%) 24 (50%) 5 (36%) 24 (52%) 26 (68%) treatment and consideration be given to a temporary withdrawal of tretinoin sea/vomiting (57%), rash (54%), mucositis (26%), pruritus (20%), increased >10x109/L by day 10, or >15x109/L by day 28.
capsules if test results reach >5 times the upper limit of normal values.
sweating (20%), visual disturbances (17%), ocular disorders (17%), alope- cia (14%), skin changes (14%), changed visual acuity (6%), bone inflamma- General guidelines for taking your medication.
Teratogenic Effects. Pregnancy Category D–see WARNINGS
However, the majority of these abnormalities resolve without interruption of tion (3%), visual field defects (3%).
There is a high risk that a severely deformed infant wil result if tretinoin tretinoin capsules or after completion of treatment.
• Cal your doctor if you have any questions or capsules are administered during pregnancy. If, nonetheless, it is deter- RA-APL Syndrome
mined that tretinoin capsules represent the best available treatment for a experience any severe or troubling symptoms.
PRECAUTIONS
APL patients treated with tretinoin capsules have experienced a potential y pregnant woman or a woman of childbearing potential, it must be assured fatal syndrome characterized by fever, dyspnea, acute respiratory distress, that the patient has received ful information and warnings of the risk to the weight gain, radiographic pulmonary infiltrates, pleural and pericardial ef u- • Tretinoin capsules do not need to be refrigerat- fetus if she were to be pregnant and of the risk of possible contraception Tretinoin capsules have potential y significant toxic side ef ects in APL sions, edema, and hepatic, renal, and multi-organ failure. This syndrome failure and has been instructed in the need to use two reliable forms of patients. Patients undergoing therapy should be closely observed for signs has occasional y been accompanied by impaired myocardial contractility ed. However, do not expose the capsules to contraception simultaneously during therapy and for 1 month fol owing of respiratory compromise and/or leukocytosis (see boxed WARNINGS).
and episodic hypotension and has been observed with or without concomi- discontinuation of therapy, and has acknowledged her understanding of Supportive care appropriate for APL patients, eg, prophylaxis for bleeding, tant leukocytosis. Some patients have expired due to progressive hypox- the need for using dual contraception, unless abstinence is the chosen prompt therapy for infection, should be maintained during therapy with emia and multi-organ failure. The syndrome general y occurs during the first month of treatment, with some cases reported fol owing the first dose of • Be sure to take your medication as prescribed Within 1 week prior to the institution of tretinoin capsules therapy, the There is a risk of thrombosis (both venous and arterial) which may involve tretinoin capsules. The management of the syndrome has not been defined by your doctor. Read the prescription label on patient should have blood or urine col ected for a serum or urine pregnan- † Including 8 patients who received chemotherapy but failed to enter remission any organ system, during the first month of treatment (see rigorously, but high-dose steroids given at the first signs of the syndrome the package careful y. If there is anything you cy test with a sensitivity of at least 50 mIU/mL. When possible, tretinoin appear to reduce morbidity and mortality. Treatment with dexamethasone, REACTIONS). Therefore, caution should be exercised when treating
capsules therapy should be delayed until a negative result from this test is The median time to CR was between 40 and 50 days (range: 2 to 120 patients with the combination of tretinoin capsules and anti-fibrinolytic 10 mg intravenously administered every 12 hours for 3 days or until resolu- donʼt understand, ask your doctor or pharmacist obtained. When a delay is not possible, the patient should be placed on days). Most patients in these studies received cytotoxic chemotherapy dur- agents, such as tranexamic acid, aminocaproic acid or aprotinin (see tion of symptoms, should be initiated without delay at the first suspicion of two reliable forms of contraception. Pregnancy testing and contraception ing the remission phase. These results compare to the 30% to 50% CR symptoms (one or more of the fol owing: fever, dyspnea, weight gain, abnor- Interactions). [3,4]
counseling should be repeated monthly throughout the period of tretinoin rate and <6 month median survival reported for cytotoxic chemotherapy of mal chest auscultatory findings or radiographic abnormalities). Sixty percent The ability to drive or operate machinery might be impaired in patients treat- or more of patients treated with tretinoin capsules may require high-dose ed with tretinoin capsules, particularly if they are experiencing dizziness or steroids because of these symptoms. The majority of patients do not require • Keep tretinoin capsules and al medications out Ten of 15 pediatric cases achieved CR (8 of 10 males and 2 of 5 females).
termination of tretinoin capsules therapy during treatment of the syndrome.
There were insuf icient patients of black, Hispanic or Asian derivation to Microdosed progesterone preparations (“minipil ”) may be an inadequate DESCRIPTION
estimate relative response rates in these groups, but responses were seen Body as a Whole
Tretinoin Capsules
method of contraception during treatment with tretinoin capsules. [5] Tretinoin Capsules are a retinoid that induces maturation of acute promye- General disorders related to tretinoin capsules administration and/or associ- Store at 20° to 25°C (68° to 77°F) [see USP con-
locytic leukemia (APL) cel s in culture. It is available in a 10 mg soft gelatin Responses were seen in 3 of 4 patients for whom cytogenetic analysis Laboratory Tests
ated with APL included malaise (66%), shivering (63%), hemorrhage (60%), trolled room temperature].
capsule for oral administration. Each capsule also contains butylated failed to detect the t(15;17) translocation typical y seen in APL. The t(15;17) The patientʼs hematologic profile, coagulation profile, liver function test infections (58%), peripheral edema (52%), pain (37%), chest discomfort (32%), hydroxyanisole, edetate disodium, ethanol, soybean oil, hydrogenated veg- translocation results in the PML/RARα gene, which appears necessary for results, and triglyceride and cholesterol levels should be monitored fre- edema (29%), disseminated intravascular coagulation (26%), weight etable oils, medium chain triglycerides, soya lecithin, and yel ow beeswax.
this disease. Molecular genetic studies were not conducted in these cases, increase (23%), injection site reactions (17%), anorexia (17%), Protect from light.
The gelatin capsule shel contains gelatin, glycerin, yel ow iron oxide, red but it is likely they represent cases with a masked translocation giving rise weight decrease (17%), myalgia (14%), flank pain (9%), cel ulitis (8%), face Drug Interactions
to PML/RARα. Responses to tretinoin have not been observed in cases in edema (6%), fluid imbalance (6%), pal or (6%), lymph disorders (6%), aci- Limited clinical data on potential drug interactions are available.
dosis (3%), hypothermia (3%), ascites (3%).
trans retinoic acid and is related to retinol which PML/RARα fusion has been shown to be absent.
(Vitamin A). It is a yel ow to light orange crystal ine powder with a molecu- Drugs Metabolized By the Hepatic P450 System Respiratory System Disorders
As tretinoin capsules are metabolized by the hepatic P450 system, there is Respiratory system disorders were commonly reported in APL patients INDICATIONS AND USAGE
a potential for alteration of pharmacokinetics parameters in patients admin- administered tretinoin capsules. The majority of these events are symptoms Tretinoin capsules are indicated for the induction of remission in patients istered concomitant medications that are also inducers or inhibitors of this with acute promyelocytic leukemia (APL), French-American-British (FAB) boxed WARNINGS). Respiratory system
system. Medications that general y induce hepatic P450 enzymes include adverse events included upper respiratory tract disorders (63%), dysp- classification M3 (including the M3 variant), characterized by the presence rifampicin, glucocorticoids, phenobarbital and pentobarbital. Medications nea (60%), respiratory insuf iciency (26%), pleural ef usion (20%), pneu- of the t(15;17) translocation and/or the presence of the PML/RARα gene that general y inhibit hepatic P450 enzymes include ketoconazole, cimeti- monia (14%), rales (14%), expiratory wheezing (14%), lower respiratory who are refractory to, or who have relapsed from, anthracycline chemother- dine, erythromycin, verapamil, diltiazem and cyclosporine. To date there are tract disorders (9%), pulmonary infiltration (6%), bronchial asthma (3%), apy, or for whom anthracycline-based chemotherapy is contraindicated.
no data to suggest that co-use with these medications increases or pulmonary edema (3%), larynx edema (3%), unspecified pulmonary dis- Tretinoin capsules are for the induction of remission only. The optimal con- decreases either ef icacy or toxicity of tretinoin capsules.
solidation or maintenance regimens have not been defined, but al patients should receive an accepted form of remission consolidation and/or mainte- Agents Known to Cause Pseudotumor Cerebri/Intracranial Hypertension Ear Disorders
nance therapy for APL after completion of induction therapy with tretinoin Ear disorders were consistently reported, with earache or feeling of ful ness Tretinoin capsules may cause pseudotumor cerebri/intracranial hyperten- in the ears reported by 23% of the patients. Hearing loss and other unspec- CLINICAL PHARMACOLOGY
sion. Concomitant administration of tretinoin capsules and agents known to ified auricular disorders were observed in 6% of patients, with infrequent Mechanism of Action
cause pseudotumor cerebri/intracranial hypertension as wel might increase (<1%) reports of irreversible hearing loss.
Tretinoin is not a cytolytic agent but instead induces cytodif erentiation and CONTRAINDICATIONS
the risk of this condition (see WARNINGS).
Gastrointestinal Disorders
decreased proliferation of APL cel s in culture and in vivo. In APL patients, Tretinoin capsules are contraindicated in patients with a known hypersensi- tretinoin treatment produces an initial maturation of the primitive promyelo- tivity to tretinoin capsules, any of its components, or other retinoids.
GI disorders included GI hemorrhage (34%), abdominal pain (31%), other cytes derived from the leukemic clone, fol owed by a repopulation of the Tretinoin capsules should not be given to patients who are sensitive to As with other retinoids, tretinoin capsules must not be administered in com- gastrointestinal disorders (26%), diarrhea (23%), constipation (17%), dys- bone marrow and peripheral blood by normal, polyclonal hematopoietic parabens, which are used as preservatives in the gelatin capsule.
bination with vitamin A because symptoms of hypervitaminosis A could be pepsia (14%), abdominal distention (11%), hepatosplenomegaly (9%), hep- cel s in patients achieving complete remission (CR). The exact mechanism atitis (3%), ulcer (3%), unspecified liver disorder (3%).
of action of tretinoin in APL is unknown.
Anti-fibrinolytic Agents (Such as Tranexamic Acid, Aminocaproic Acid, or Cardiovascular and Heart Rate and Rhythm Disorders
WARNINGS
Pharmacokinetics
Arrhythmias (23%), flushing (23%), hypotension (14%), hypertension (11%), Tretinoin activity is primarily due to the parent drug. In human pharmacoki- Pregnancy Category D – See Boxed WARNINGS
Cases of fatal thrombotic complications have been reported rarely in phlebitis (11%), cardiac failure (6%) and for 3% of patients: cardiac arrest, netics studies, oral y administered drug was wel absorbed into the systemic Tretinoin has teratogenic and embryotoxic ef ects in mice, rats, hamsters, patients concomitantly treated with tretinoin capsules and anti-fibrinolytic myocardial infarction, enlarged heart, heart murmur, ischemia, stroke, circulation, with approximately two-thirds of the administered radiolabel rabbits and pigtail monkeys, and may be expected to cause fetal harm when agents. Therefore, caution should be exercised when administering myocarditis, pericarditis, pulmonary hypertension, secondary cardiomyopathy.
recovered in the urine. The terminal elimination half-life of tretinoin fol owing administered to a pregnant woman. Tretinoin causes fetal resorptions and tretinoin capsules concomitantly with these agents (see PRECAUTIONS:
Central and Peripheral Nervous System Disorders and Psychiatric
initial dosing is 0.5 to 2 hours in patients with APL. There is evidence that a decrease in live fetuses in al animals studied. Gross external, soft tissue General).
tretinoin induces its own metabolism. Plasma tretinoin concentrations and skeletal alterations occurred at doses higher than 0.7 mg/kg/day in Dizziness (20%), paresthesias (17%), anxiety (17%), insomnia (14%), Effect of Food
decrease on average to one-third of their day 1 values during 1 week of con- mice, 2 mg/kg/day in rats, 7 mg/kg/day in hamsters, and at a dose of depression (14%), confusion (11%), cerebral hemorrhage (9%), intracranial tinuous therapy. Mean ± SD peak tretinoin concentrations decreased from 10 mg/kg/day, the only dose tested, in pigtail monkeys (about 1/20, 1/4, and No data on the ef ect of food on the absorption of tretinoin capsules are hypertension (9%), agitation (9%), hal ucination (6%) and for 3% of patients: 394 ± 89 to 138 ± 139 ng/mL, while area under the curve (AUC) values 1/2 and 4 times the human dose, respectively, on a mg/m2 basis).
available. The absorption of retinoids as a class has been shown to be abnormal gait, agnosia, aphasia, asterixis, cerebel ar edema, cerebel ar dis- enhanced when taken together with food.
00110136/CLB-P-263-750-12545.qxd:Layout 1 20/12/2011 10:32 Page 2 orders, convulsions, coma, CNS depression, dysarthria, encephalopathy, facial paralysis, hemiplegia, hyporeflexia, hypotaxia, no light reflex, neuro- logic reaction, spinal cord disorder, tremor, leg weakness, unconscious- ness, dementia, forgetfulness, somnolence, slow speech.
Urinary System Disorders
Renal insuf iciency (11%), dysuria (9%), acute renal failure (3%), micturition
frequency (3%), renal tubular necrosis (3%), enlarged prostate (3%).
Miscellaneous Adverse Events
Isolated cases of erythema nodosum, basophilia and hyperhistaminemia,
Sweetʼs syndrome, organomegaly, hypercalcemia, pancreatitis and myosi- tis have been reported.
Additional Adverse Reactions Reported With Tretinoin Capsules
Cardiovascular
Cases of thrombosis (both venous and arterial) involving various sites (eg, cerebrovascular accident, myocardial infarction, renal infarct) have been reported rarely (see PRECAUTIONS: General).
Rare cases of thrombocytosis have been reported. [6]Skin Genital ulceration [7]Miscel aneous Adverse Events Rare cases of vasculitis, predominantly involving the skin, have been OVERDOSAGE
In case of overdose with Tretinoin, 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/m2/day. The maximal tolerated dose in pediatric patients was lower at 60 mg/m2/day. Overdosage with other retinoids has been associated with transient headache, facial flushing, cheilosis, abdom- inal pain, dizziness and ataxia. These symptoms have quickly resolved 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.
DOSAGE AND ADMINISTRATION
The recommended dose is 45 mg/m2/day administered as two evenly divid- ed doses until complete remission is documented. Therapy should be dis- continued 30 days after achievement of complete remission or after 90 days of treatment, whichever occurs first.
If after initiation of treatment of Tretinoin Capsules the presence of the t(15;17) translocation is not confirmed by cytogenetics and/or by poly- merase chain reaction studies and the patient has not responded to tretinoin capsules, alternative therapy appropriate for acute myelogenous leukemia should be considered.
Tretinoin Capsules are for the induction of remission only. Optimal con-
solidation or maintenance regimens have not been determined. Al patients should, therefore, receive a standard consolidation and/or maintenance chemotherapy regimen for APL after induction therapy with tretinoin cap- sules, unless otherwise contraindicated.
HOW SUPPLIED
Tretinoin Capsules are supplied as 10 mg capsules, two-tone (lengthwise) with reddish-brown opaque and yel ow gelatin shel , imprinted with “TR” with black ink on the yel ow side. Supplied in high-density polyethylene, opaque bot les of 100 capsules with child-resistant closure.
Store at 20° to 25°C (68° to 77°F) [see USP control ed room temperature].
Par Pharmaceutical Companies, Inc.
ANNOTATIONS
1. Tal man MS, et al. Clinical description of 44 patients with acute promye- locytic leukemia who developed retinoic acid syndrome. Blood. 2000; 2. Longauer M. Drug Safety Report No. 1007960: Concomitant use of 3. Longauer M. Drug Safety Report No. 1008342: Thromboses involving 4. Longauer M. Issue Work-Up: Safety of concomitant administration of Vesanoid® and anti-fibrinolytic agents. May 4, 2001.
5. Longauer M. Drug Safety Report No. 1007959: Interaction with low- dose progestogens (“minipil ”). March 27, 2002.
6. Longauer M. Issue Work-Up: Thrombocytosis. December 18, 2000.
7. Longauer M. Safety Evaluation Update: Genital Ulcerations. Provided in Periodic Safety Update Report on Tretinoin Oral (Vesanoid®) Period: April 1, 1998-March 31, 1991 (Research Report No. B-170ʼ967, 8. Longauer M. Issue Work-Up: Vasculitis. September 26, 2000.

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