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Only physicians experienced in immunosuppressive therapy and management of organ
transplant patients should prescribe ZENAPAX® (Daclizumab). The physician responsible for
ZENAPAX administration should have complete information requisite for the follow-up of the
patient. ZENAPAX should only be administered by healthcare personnel trained in the
administration of the drug who have available adequate laboratory and supportive medical

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 under the 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, weight gain, radiographic pulmonary infiltrates and pleural or
pericardial effusions. 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 multiorgan
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 toreduce morbidity and mortality. At the first signs suggestive of the syndrome(unexplained fever, dyspnea and/or weight gain, abnormal chest auscultatoryfindings or radiographic abnormalities), high-dose steroids (dexamethasone10 mg intravenously administered every 12 hours for 3 days or until theresolution of symptoms) should be immediately initiated, irrespective of theleukocyte count. The majority of patients do not require termination ofVESANOID therapy during treatment of the RA-APL syndrome.
3. Leukocytosis at Presentation and Rapidly Evolving
Leukocytosis During VESANOID Treatment
During VESANOID treatment about 40% of patients will develop rapidlyevolving leukocytosis. Patients who present with high WBC at diagnosis (>5x109/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 withleukocytosis, treatment with high-dose steroids should be initiatedimmediately. Some investigators routinely add chemotherapy to VESANOIDtreatment in the case of patients presenting with a WBC count of >5x109/L orin the case of a rapid increase in WBC count for patients leukopenic at start oftreatment, and have reported a lower incidence of the RA-APL syndrome.
Consideration could be given to adding full-dose chemotherapy (including ananthracycline if not contraindicated) to the VESANOID therapy on day 1 or 2for patients presenting with a WBC count of >5x109/L, or immediately, forpatients presenting with a WBC count of <5x109/L, if the WBC count reaches³6x109/L by day 5, or ³10x109/L by day 10, or ³15x109/L by day 28.
4. Teratogenic Effects. Pregnancy Category D – see
There is a high risk that a severely deformed infant will result if VESANOIDis administered during pregnancy. If, nonetheless, it is determined thatVESANOID represents the best available treatment for a pregnant woman or awoman of childbearing potential, it must be assured that the patient hasreceived full information and warnings of the risk to the fetus if she were to bepregnant and of the risk of possible contraception failure and has beeninstructed in the need to use two reliable forms of contraceptionsimultaneously during therapy and for 1 month following discontinuation oftherapy, and has acknowledged her understanding of the need for using dualcontraception, unless abstinence is the chosen method.
Within 1 week prior to the institution of VESANOID therapy, the patientshould have blood or urine collected for a serum or urine pregnancy test witha sensitivity of at least 50 mIU/mL. When possible, VESANOID therapyshould be delayed until a negative result from this test is obtained. When adelay is not possible, the patient should be placed on two reliable forms ofcontraception. Pregnancy testing and contraception counseling should berepeated 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 molecularweight of 300.44.
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, polyclonal hematopoietic
cells in patients achieving complete remission (CR). The exact mechanism of
action of tretinoin in APL is unknown.
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/m2 daily dosing in 7 APL patients. Increasing the dose to
“correct” for this change has not increased response.
AbsorptionA single 45 mg/m2 (~80 mg) oral dose to APL patients resulted in a mean ±SD peak tretinoin concentration of 347 ± 266 ng/mL. Time to reach peakconcentration was between 1 and 2 hours.
DistributionThe 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 to500 ng/mL.
MetabolismTretinoin metabolites have been identified in plasma and urine. CytochromeP450 enzymes have been implicated in the oxidative metabolism of tretinoin.
Metabolites include 13-cis retinoic acid, 4-oxo trans retinoic acid, 4-oxo cisretinoic acid, and 4-oxo trans retinoic acid glucuronide. In APL patients, dailyadministration of a 45 mg/m2 dose of tretinoin resulted in an approximatelytenfold increase in the urinary excretion of 4-oxo trans retinoic acidglucuronide after 2 to 6 weeks of continuous dosing, when compared tobaseline values.
ExcretionStudies with radiolabeled drug have demonstrated that after the oraladministration of 2.75 and 50 mg doses of tretinoin, greater than 90% of theradioactivity was recovered in the urine and feces. Based upon data from 3subjects, approximately 63% of radioactivity was recovered in the urinewithin 72 hours and 31% appeared in the feces within 6 days.
Special PopulationsThe pharmacokinetics of tretinoin have not been separately evaluated inwomen, in members of different ethnic groups, or in individuals with renal orhepatic insufficiency.
Drug-Drug InteractionsIn 13 patients who had received daily doses of tretinoin for 4 consecutiveweeks, administration of ketoconazole (400 to 1200 mg oral dose) 1 hourprior 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 notbeen specified; CYP 3A4, 2C8 and 2E have been implicated in variouspreliminary reports.
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/m2/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:
NCI Cohort 1
NCI Cohort 2
De Novo†
NR = Not ReachedNA = Not Available*Including 9 chemorefractory patients†Including 8 patients who received chemotherapy but failed to enter remission 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 theremission phase. These results compare to the 30% to 50% CR rate and £6month median survival reported for cytotoxic chemotherapy of APL in thetreatment 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 toestimate relative response rates in these groups, but responses were seen ineach category.
Responses were seen in 3 of 4 patients for whom cytogenetic analysis failed todetect the t(15;17) translocation typically seen in APL. The t(15;17)translocation results in the PML/RARa gene, which appears necessary for thisdisease. Molecular genetic studies were not conducted in these cases, but it islikely they represent cases with a masked translocation giving rise toPML/RARa. Responses to tretinoin have not been observed in cases in whichPML/RARa fusion has been shown to be absent.
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/RARa 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 is contraindicated in patients with a known hypersensitivity to
retinoids. VESANOID should not be given to patients who are sensitive to
parabens, which are used as preservatives in the gelatin capsule.
Pregnancy Category D – See Boxed WARNINGS
Tretinoin has teratogenic and embryotoxic effects in mice, rats, hamsters,
rabbits and pigtail monkeys, and may be expected to cause fetal harm when
administered to a pregnant woman. Tretinoin causes fetal resorptions and a
decrease in live fetuses in all animals studied. Gross external, soft tissue and
skeletal alterations occurred at doses higher than 0.7 mg/kg/day in mice, 2
mg/kg/day in rats, 7 mg/kg/day in hamsters, and at a dose of 10 mg/kg/day,
the only dose tested, in pigtail monkeys (about 1/20, 1/4, and 1/2 and 4 times
the human dose, respectively, on a mg/m2 basis).
There are no adequate and well-controlled studies in pregnant women.
Although experience with humans administered VESANOID is extremelylimited, increased spontaneous abortions and major human fetal abnormalitiesrelated to the use of other retinoids have been documented in humans.
Reported defects include abnormalities of the CNS, musculoskeletal system,external ear, eye, thymus and great vessels; and facial dysmorphia, cleftpalate, and parathyroid hormone deficiency. Some of these abnormalities werefatal. Cases of IQ scores less than 85, with or without obvious CNSabnormalities, have also been reported. All fetuses exposed during pregnancycan be affected and at the present time there is no antepartum means ofdetermining which fetuses are and are not affected.
Effective contraception must be used by all females during VESANOIDtherapy and for 1 month following discontinuation of therapy. Contraceptionmust be used even when there is a history of infertility or menopause, unless ahysterectomy has been performed. Whenever contraception is required, it isrecommended that two reliable forms of contraception be usedsimultaneously, unless abstinence is the chosen method. If pregnancy doesoccur during treatment, the physician and patient should discuss thedesirability of continuing or terminating the pregnancy.
Patients Without the t(15;17) Translocation
Initiation of therapy with VESANOID may be based on the morphological
diagnosis of acute promyelocytic leukemia. Confirmation of the diagnosis of
APL should be sought by detection of the t(15;17) genetic marker by
cytogenetic studies. If these are negative, PML/RARa fusion should be
sought using molecular diagnostic techniques. The response rate of other
AML subtypes to VESANOID has not been demonstrated; therefore, patients
who lack the genetic marker should be considered for alternative treatment.
Retinoic Acid-APL (RA-APL) Syndrome
In up to 25% of patients with APL treated with VESANOID, a syndrome
occurs which can be fatal (see boxed WARNINGS and ADVERSE
Leukocytosis at Presentation and Rapidly Evolving
Leukocytosis During VESANOID Treatment

See boxed WARNINGS.
Pseudotumor Cerebri
Retinoids, including VESANOID, have been associated with pseudotumor
cerebri (benign intracranial hypertension), especially in pediatric patients.
Early signs and symptoms of pseudotumor cerebri include papilledema,
headache, nausea and vomiting, and visual disturbances. Patients with these
symptoms should be evaluated for pseudotumor cerebri, and, if present,
appropriate care should be instituted in concert with neurological assessment.
Up to 60% of patients experienced hypercholesterolemia and/or
hypertriglyceridemia, which were reversible upon completion of treatment.
The clinical consequences of temporary elevation of triglycerides and
cholesterol are unknown, but venous thrombosis and myocardial infarction
have been reported in patients who ordinarily are at low risk for such
Elevated Liver Function Test Results
Elevated liver function test results occur in 50% to 60% of patients during
treatment. Liver function test results should be carefully monitored during
treatment and consideration be given to a temporary withdrawal of
VESANOID if test results reach >5 times the upper limit of normal values.
However, the majority of these abnormalities resolve without interruption of
VESANOID or after completion of treatment.
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 (see boxed WARNINGS).
Supportive care appropriate for APL patients, eg, prophylaxis for bleeding,
prompt therapy for infection, should be maintained during therapy with
Laboratory Tests
The patient’s hematologic profile, coagulation profile, liver function test
results, and triglyceride and cholesterol levels should be monitored frequently.
Drug Interactions
Limited clinical data on potential drug interactions are available. 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 that generally
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.
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.
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/m2 basis) 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 lymphocytes and 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/m2 basis). 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
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.
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/m2/day have not been evaluated in the pediatric population.
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.
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.
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 field defects (3%).
RA-APL Syndrome
APL patients treated with VESANOID have experienced a syndrome
characterized by fever, dyspnea, weight gain, radiographic pulmonary
infiltrates and pleural or pericardial effusions. 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 multiorganfailure. The syndrome generally occurs during the first month of treatment,with some cases reported following the first dose of VESANOID. Themanagement of the syndrome has not been defined rigorously, but high-dosesteroids given at the first signs of the syndrome appear to reduce morbidityand mortality. Treatment with dexamethasone, 10 mg intravenouslyadministered every 12 hours for 3 days or until resolution of symptoms,should be initiated without delay at the first suspicion of symptoms (one ormore of the following: fever, dyspnea, weight gain, abnormal chestauscultatory findings or radiographic abnormalities). Sixty percent or more ofpatients treated with VESANOID may require high-dose steroids because ofthese symptoms. The majority of patients do not require termination ofVESANOID therapy during treatment of the syndrome.
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%).
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 (see boxed WARNINGS). 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%).
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.
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%).
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
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.
Urinary System Disorders
Renal insufficiency (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,
Sweet’s syndrome, organomegaly, hypercalcemia, pancreatitis and myositis
have been reported.
There has been no experience with acute overdosage in humans. 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, abdominal pain, dizziness and
ataxia. These symptoms have quickly resolved without apparent residual
The recommended dose is 45 mg/m2/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 chainreaction studies and the patient has not responded to VESANOID, alternativetherapy 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
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.
Copyright 1998-2003 by Roche Laboratories Inc. All rights reserved.

Source: http://patient.cancerconsultants.com/druginserts/Tretinoin.pdf


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