Anthony WongCEATOX – Instituto da Criança

Hospital das Clinicas – FMUSPIBEMAX - Instituto Bras. de Estudos e Avaliação

Toxicológica

36º Congresso da SBMFHotel Maksoud Plaza – São Paulo

27 e 28 de outubro 2011

Paciente masculino de 34 anos, casado, raça branca Histórico: Antecedentes de gota há mais de 2½

anos, fora prescrito etoricoxibe 100mg durante 4 dias. A artralgia resolveu, porém no 3º dia notou uma ulceração de bordas irregulares no dorso da glande peniana, hiperemia local, com dor e prurido intenso, e secreção amarelada. Ele aplicou uma pomada com antifúngico-cortisona com melhora.

N.B.- Não estava outros medicamentos nem mudança de hábitos.

CASO CLÍNICO

Quatro meses mais tarde, apresentou novo episódio de dor articular e voltou ao reumatologista, que prescreveu novamente a mesma dose de etoricoxibe por 4 dias. Ele desenvolveu a mesma lesão, porém maior, afetando 60% da glande. Foram feitos exames para HIV, DST e infecções bacterianas e fúngicas, com todos os resultados negativos. O médico tratou como DST, com antibióticos e pomadas e as lesões resolveram após 15 dias.

Após mais 4 meses, as dores articulares recorreram e o mesmo profissional prescreveu novamente etoricoxibe. As lesões foram mais intensas com sangramento, secreção amarelada e dor intensa. Desta vez, ligou ao CEATOX e foi informado que poderia ser RAM. O médico não aceitou esta hipótese e repetiu todos os exames. Prescreveu todos os medicamentos para DST.

Duas semanas antes da reunião do OMS, telefonei-lhe para atualizar e confirmar suas informações. Disse-me que teve novo episódio de dor articular e recebeu etoricoxibe por 4 dias com as lesões recorrentes cobrindo quase 80% da glande.

Ele disse que agora estava convencido de que era um RAM e trocou de médico.

Caso Clínico Menina de 9 anos Há 2-3 meses, quadro progressivo de ataxia,

confusão mental, sonolência constante, hipotonia generalizada, impossibilidade de ficar de pé e de deambular, dificuldade de fixar a visão, incapacidade de articular palavras e anorexia.

Intolerância a alimentos, disfagia, vômitos e irritabilidade.

HD – neuropatia degenerativa, psicose aguda

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“Medicamento Natural”

Clorbenzorex anfetamina

hummm...não seria afrodisíaco?

Natu-DietMR

- PPA - diazepinico- T4

Fentanil Precautions

abuse potential, high risk of addiction, misuse or diversion concomitant cytochrome P450 3A4 inhibitors; may result in an increase in fentanyl plasma concentrations, and potentially fatal respiratory depression different bioavailabilities among products and manufacturers; converting patients from other oral fentanyl products, including oral transmucosal

fentanyl citrate (OTFC and Actiq(R)), to Fentora(TM) cannot be substituted on on a microgram per microgram basis hypoventilation; may occur at any dose abrupt discontinuation; may result in withdrawal symptoms bradyarrhythmias; potentiation of bradycardia chronic obstructive pulmonary disease; risk of further decreased respiratory function concomitant administration of opioid antagonists; may precipitate withdrawal symptoms concomitant use of alcohol, other opioids, or other respiratory depressants; increased central nervous system depressant effect concurrent consumption of grapefruit or grapefruit juice; risk of drug toxicity debilitated patients; higher risk of respiratory depression head injury, increased intracranial pressure, or impaired consciousness; carbon dioxide retention may exacerbate sedating effects of opioids and

increase risk of fatal overdose hepatic disease, severe; repeated dosing or high single doses may result in diminished clearance MAOI therapy within 14 days; severe and unpredictable potentiation of opioids by MAOI inhibitors renal disease, severe; repeated dosing or high single doses may result in diminished clearance respiratory depression; carbon dioxide retention may exacerbate sedating effects of opioids and increase risk of fatal overdose respiratory disorders, underlying; increased risk of respiratory depression

Adverse Effects COMMON

Cardiovascular: Peripheral edema (5% to 32% .) Endocrine metabolic: Dehydration (0% to 21% .), Weight loss (3% to 11% .) Gastrointestinal: Abdominal pain (3% to 15% .), Application site reaction (10% .), Constipation (8% to 26% .), Diarrhea (0% to 16% .), Loss of appetite (5% to 11% .), Nausea (9% to 42%

.), Vomiting (0% to 37% .) Musculoskeletal: Backache (0% to 11% .) Neurologic: Asthenia (5% to 16% .), Confusion (3% to 16% .), Dizziness (6% to 32% .), Headache (2% to 15% .), Sedated (0% to 15% .) Renal: Urinary retention Psychiatric: Fatigue (2% to 20% .), Insomnia (3% to 11% .) Respiratory: Cough (3% to 9% .)

SERIOUS Cardiovascular: Tachyarrhythmia (1% or greater .) Hematologic: Neutropenia (0% to 8% .) Respiratory: Apnea (3-10%), Dyspnea (0% to 19% .)

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Ciprofloxacina Adverse Effects

Ciprofloxacin is generally well tolerated. The range of adverse effects associated with ciprofloxacin and the other fluoroquinolones is broadly similar to that of earlier quinolones such as nalidixic acid. They most often involve the gastrointestinal tract, CNS, or skin.

Gastrointestinal disturbances include nausea, vomiting, diarrhoea, abdominal pain, and dyspepsia and are the most frequent adverse effects. Pseudomembranous colitis, pancreatitis, and dysphagia have been reported rarely.

Headache, dizziness, confusion, insomnia, and restlessness are among the commonest effects on the CNS. Others include tremor, drowsiness, nightmares, visual and other sensory disturbances, hallucinations, psychotic reactions, depression, convulsions, and intracranial hypertension. Paraesthesia and peripheral neuropathy have also been reported.

In addition to rash and pruritus, hypersensitivity-type reactions affecting the skin have included, rarely, vasculitis, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Photosensitivity has occurred, although it may be more frequent with some other fluoroquinolones such as lomefloxacin and sparfloxacin. Anaphylaxis has been associated with ciprofloxacin and some other quinolones. As with other quinolones, reversible arthralgia or myalgia has sometimes occurred and joint erosions have been documented in immature animals. Tendon damage has also been reported.

Other adverse effects reported with ciprofloxacin include crystalluria, transient increases in serum creatinineor blood urea nitrogen and, rarely, acute renal failure secondary to interstitial nephritis. Elevated liver enzyme values, jaundice, and hepatitis have occurred, as have haematological disturbances including eosinophilia, leucopenia, thrombocytopenia and, very rarely, pancytopenia, haemolytic anaemia or agranulocytosis. Cardiovascular adverse effects include tachycardia, hypotension, oedema, syncope, hot flushes, and sweating. Some fluoroquinolones may rarely cause prolongation of the QT interval and ventricular arrhythmias, including torsade de pointes.

As with other antibacterials, superinfection with organisms not very susceptible to ciprofloxacin is possible. Such organisms include Candida, Clostridium difficile, and Streptococcus pneumoniae. There is some evidence that fluoroquinolone use may be associated with an increased risk of colonisation by MRSA.

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Ciprofloxacina - InteraçõesFluoroquinolones, including ciprofloxacin, are known to inhibit the cytochrome P450 isoenzyme CYP1A2 and may increase plasma concentrations of drugs, such as

theophylline and tizanidine, that are metabolised by this isoenzyme. Use of ciprofloxacin with tizanidine is contra-indicated, although theophylline may be used providing its dose is reduced and concentrations monitored. Ciprofloxacin is reported to enhance the effect of oral anticoagulants such as warfarin and the oral antidiabetic glibenclamide. Severe hypoglycaemia, sometimes

fatal, has occurred in patients also taking glibenclamide. Renal tubular secretion of methotrexate may be inhibited by ciprofloxacin, potentially increasing its toxicity.

The excretion of ciprofloxacin or related drugs is reduced and plasma concentrations may be increased by probenecid. Cations such as aluminium, calcium, magnesium, or iron reduce the absorption of oral ciprofloxacin or related drugs when given together. Changes in the pharmacokinetics of fluoroquinolones have been reported when given with histamine H(2) antagonists, possibly due to changes in gastric pH, but do not seem to be of much clinical significance.

Transient increases in serum creatinine have occurred when ciprofloxacin is given with ciclosporin; monitoring of serum creatinine concentrations is recommended. Altered serum concentrations of phenytoin have been reported in patients also receiving ciprofloxacin.

Some fluoroquinolones have the potential to prolong the QT interval and should be avoided in patients also receiving class Ia antiarrhythmic drugs (such as quinidine and procainamide) or class III antiarrhythmics (such as amiodarone and sotalol). In addition, caution should be exercised when they are used with other drugs known to have this effect (such as the antihistamines astemizole and terfenadine, cisapride, erythromycin, pentamidine, phenothiazines, or tricyclicantidepressants). ..

Analgesics. Use of fenbufen with fluoroquinolones may increase the incidence of fluoroquinolone CNS adverse effects. Adverse neurological effects have also been reported in a

patient receiving naproxen and chloroquine when ciprofloxacin was given, which abated when the antirheumatic drugs were stopped. (4) Ciprofloxacin also interacts with opioid analgesics; peak serum concentrations of ciprofloxacin given by mouth pre-operatively were significantly reduced when

intramuscular papaveretum was injected. Antacids and metal ions. . Antibacterials. The simultaneous use of parenteral ciprofloxacin and azlocillin has resulted in higher and more prolonged serum concentrations of

ciprofloxacin. (1) Anticoagulants. Antidiabetics. Antiepileptics. phenytoin.. Antifungals. Both fluconazole and levofloxacin can prolong the QT interval. The simultaneous use of intravenous levofloxacin and fluconazole resulted in an

episode of torsade de pointes in a patient on haemodialysis. Antimigraine drugs.

Antineoplastics. Absorption of oral ciprofloxacin appears to be reduced after cytotoxic chemotherapy. (1)

Antivirals. Both ciprofloxacin and foscarnet can cause convulsions and 2 patients developed generalised tonic-clonic seizures while receiving the drugs together.

Immunosuppressants. Muscle relaxants.

Xanthines. Ciprofloxacin and other fluoroquinolones (to a greater or lesser extent) decrease the clearance of theophylline (Ref.) and caffeine (Ref.) from the body. Seizures have occurred in patients given ciprofloxacin and theophylline and in one such report (1) serum-theophylline concentrations were normal.

A Wong - IBET/CEATOX A Wong - IBET-CEATOX

Hidrato de Cloral

Precautions history of gastritis, esophagitis, or gastric or duodenal ulcers mentally depressed patients or those with suicidal tendencies severe cardiac disease

Adverse Effects COMMON

Cardiovascular: Lightheadedness Gastrointestinal: Abdominal pain, Diarrhea, Nausea, Vomiting Neurologic: Clumsiness, Dizziness, Hangover, Somnolence,

Unsteadiness present SERIOUS

Dermatologic: Cutaneous hypersensitivity (rare) Neurologic: Confusion, Excitement, Unusual (rare) Psychiatric: Hallucinations

A Wong - IBET/CEATOX A Wong - IBET-CEATOX

Hidrato de Cloral – InteraçõesAcecainide (major, theoretical) Adinazolam (major, theoretical) Ajmaline (major, theoretical) Alfentanil (major, theoretical) Alprazolam (major, theoretical) Amiodarone (major, theoretical) Amisulpride (major, theoretical) Amitriptyline (major, theoretical) Amobarbital (major, theoretical) Amoxapine (major, theoretical) Anileridine (major, theoretical) Aprindine (major, theoretical) Aprobarbital (major, theoretical) Arsenic Trioxide (major, theoretical) Astemizole (major, theoretical) Azimilide (major, theoretical) Bepridil (contraindicated, theoretical) Bretylium (major, theoretical) Bromazepam (major, theoretical) Brotizolam (major, theoretical) Butabarbital (major, theoretical) Butalbital (major, theoretical) Carisoprodol (major, theoretical) Chlordiazepoxide (major, theoretical) Chloroquine (major, theoretical) Chlorpromazine (major, theoretical) Chlorzoxazone (major, theoretical) Cisapride (contraindicated, theoretical) Clarithromycin (major, theoretical) Clobazam (major, theoretical) Clonazepam (major, theoretical)

Clorazepate (major, theoretical) Codeine (major, theoretical) Dantrolene (major, theoretical) Desipramine (major, theoretical) Diazepam (major, theoretical) Dibenzepin (major, theoretical) Disopyramide (major, theoretical) Dofetilide (major, theoretical) Dolasetron (major, theoretical) Droperidol (major, theoretical) Enflurane (major, theoretical) Erythromycin (major, theoretical) Estazolam (major, theoretical) Fentanyl (major, theoretical) Flecainide (major, theoretical) Fluconazole (major, theoretical) Flunitrazepam (major, theoretical) Fluoxetine (major, theoretical) Flurazepam (major, theoretical) Foscarnet (major, theoretical) Gemifloxacin (major, probable) Halazepam (major, theoretical) Halofantrine (major, theoretical) Haloperidol (major, theoretical) Halothane (major, theoretical) Hydrocodone (major, theoretical) Hydromorphone (major, theoretical) Hydroquinidine (major, theoretical) Ibutilide (major, theoretical) Imipramine (major, theoretical) Isoflurane (major, theoretical)

Isradipine (major, theoretical) Ketazolam (major, theoretical) Levomethadyl (contraindicated, theoretical) Levorphanol (major, theoretical) Lidoflazine (major, theoretical) Lorazepam (major, theoretical) Lorcainide (major, theoretical) Lormetazepam (major, theoretical) Medazepam (major, theoretical) Mefloquine (major, theoretical) Meperidine (major, theoretical) Mephenesin (major, theoretical) Mephobarbital (major, theoretical) Meprobamate (major, theoretical) Mesoridazine (contraindicated, theoretical) Metaxalone (major, theoretical) Methocarbamol (major, theoretical) Methohexital (major, theoretical) Midazolam (major, theoretical) Morphine (major, theoretical) Morphine Sulfate Liposome (major, theoretical) Nitrazepam (major, theoretical) Nordazepam (major, theoretical) Nortriptyline (major, theoretical) Octreotide (major, theoretical) Oxazepam (major, theoretical) Oxycodone (major, theoretical) Oxymorphone (major, theoretical) Pentamidine (major, theoretical) Pentobarbital (major, theoretical) Phenobarbital (major, theoretical) Pimozide (contraindicated, theoretical) Pirmenol (major, theoretical) Prajmaline (major, theoretical) Prazepam (major, theoretical) Primidone (major, theoretical)

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Probucol (major, theoretical) Procainamide (major, theoretical) Prochlorperazine (major, theoretical) Propafenone (major, theoretical) Propoxyphene (major, theoretical) Quazepam (major, theoretical) Quetiapine (major, theoretical) Quinidine (major, theoretical) Remifentanil (major, theoretical) Risperidone (major, theoretical) Secobarbital (major, theoretical) Sematilide (major, theoretical) Sertindole (major, theoretical) Sotalol (major, theoretical) Spiramycin (major, theoretical) Sufentanil (major, theoretical) Sulfamethoxazole (major, theoretical) Sultopride (major, theoretical) Tedisamil (major, theoretical) Telithromycin (major, theoretical) Temazepam (major, theoretical) Terfenadine (major, theoretical) Thiopental (major, theoretical) Thioridazine (contraindicated, theoretical) Triazolam (major, theoretical) Trifluoperazine (major, theoretical) Trimethoprim (major, theoretical) Trimipramine (major, theoretical) Vasopressin (major, theoretical) Warfarin (moderate, probable) Ziprasidone (contraindicated, theoretical) Zotepine (major, theoretical)

Problemas Preveníveis – Efeitos Adversos porMedicamentos

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Riscos e Benefícios

Doença

Benefício do Tratamento

Risco doTratamento

Segurança ao Paciente!

Detectar e antecipar o impacto de vários produtos na segurança dos pacientes

Produtos avaliados

FarmacovigilanciaProdutos para a Saúde:

FarmacosVacinasFitoterápicos

TeratovigilanciaErros de MedicaçãoCosmetovigilanciaVigilancia de materiais médicos

Centros de IntoxicaçãoProdutos para a SaúdePlantas tóxicasSubstancias químicas Metais Animais em geralContaminação de alimentos e água ….

17

Pharmacovigilance Terminology Evento Adverso

Reação Adversa ao Medicamento

Avaliação de Causalidade

NÃO

RAM não prevenívelSIM

RAM prevenívelErros de

Medicação9 March 2011

Metodos/avaliação de prevenção?

Efeito deletério não intencional resultante do uso autorizado do produto em doses ou condições recomendadas, mas tambem de erros de medicação e do uso for a da indicação e autorização oficial, incluindo abuso e mal uso do produto.

Qualquer evento médico não-esperado temporalmente associado ao uso do produto medicinal, mas não necessariamente tendo relação causal

DECLARAÇÃO DE ERICE 2008

Background Coletar os dados de erros de medicação faz parte da rotina dos Centros de Farmacovigilância (CFs);

Nem todos os Centros de Farmacovigilância estão cientes de que as Reações Adversas ao Medicamento (RAMs) podem estar relacionadas ao Erro de Medicação;

Os Centros de Farmacovigilância estão permanentemente comprometidos no sentido de minimizar Reações Adversas ao Medicamento e os Erros de Medicação, aumentando a Segurança do Paciente (Patient Safety).

Vantagens de se vincular um Centro Toxicológico a um Centro de Farmacovigilância

Compartilhar recursos físicos e humanos;

Competência dos profissionais são coincidentes;

Desenvolvimento e fluxo de atividades semelhantes;

Ambos são centros de referência para a avaliação do impacto dos produtos comerciais na saúde e no ambiente.

Reporting of Adverse Drug Reactions by PoisonControl Centers in the US- Pete A. Chyka e Steven W. McCommon (Drug Safety 2000) Em 1996, MedWatch tabulou

159.504 casos de EAM, sendo 91% da industria

De 2.241082 relatos aos PCC’s 32.601 eram de EAM

Dos 65 PCC americanos: 56 responderam ao questionario

30 não reportaram EAM 22 reportaram < 10/ano 4 reportaram total de 47/ano

Porque não relatam?

CONCLUSÕES As bases de uma Farmacovigilância está no

preparo do profissional médico e farmacêutico na identificação e no diagnóstico de EAs.

O universo de “notificadores” deve ser ampliado, preparado e estimulado.

A notificação de um Evento Adverso deve merecer a mesma importância de uma doença de notificação compulsória.

É necessário investir na cultura do “uso seguro” no lugar de “indicações terapêuticas”.