1. ADR, pharmacovigilance

2. Philippus Aureolus Paracelsus
„Poison is in everything, and no thing is without poison. The dosage makes it either a poison or a remedy.“

3. Each pharmacotherapy means risk akceptation,
each drug can have potential
risk for patient
Risk of pharmacotherapy
should never exceed risks
of not treating particular
disease!!!
pharmacotherapy
benefit
risk

4. Pharmacovigilance EFFICACY SAFETY PRICE SUITABILITY
We take into consideration during drug selection:
EFFICACY
SAFETY
PRICE
SUITABILITY
pharmakon (Greek for drug)
vigilare (Latin for to keep watch)

5. Pharmacovigilance Includes all aspects of postmarketing development:
- monitoring of clinical safety
- identification of new threats
- estimation of risk and contribution
- action and communication
Goal: to prove product safety after registration of the drug

6. center for spontanneous ADR monitoring in Uppsala (Sweden)
Pharmacovigilance
 the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem
WHO established its Programme for International Drug Monitoring in response to the thalidomide disaster (1961)
center for spontanneous ADR monitoring in Uppsala (Sweden)

7. to the Uppsala Monitoring Centre
In European Union spontaneous reports of suspected ADRs are sent from national pharmacovigilance centers
to the Uppsala Monitoring Centre
where they are processed, evaluated and entered into the WHO International Database

8. THALIDOMID
: sedative, hypnotic drug for pregnant women (marketed in Germany, England, Canada..., never in USA)
Born were > children with phocomelia
Now: new indications – imunomodulatory, antiangiogenic and antiinflammatory properties:
skin lupus erythematodes
skin form of lepra
Kaposi´s sarcoma at AIDS ...

10. ADVERSE DRUG REACTION = ADR
Reaction to drug which is noxious and unintended and occurs at doses of drugs normally used for prophylaxis, diagnosis or treatment of disease or to modify physiologic functions
Detection of ADR at targeted monitoring 10-30%.
At spontanneous monitoring < than 1%.
Intoxications and mistakes in therapy don´t belong here

11. ADVERSE DRUG REACTION
From the point of view of drug =
ADVERSE EFFECT
From the point of view of patient

12. TOXIC EFFECT
Not common at normal doses
SIDE EFFECT
Is related to the pharmacological properties of drug, althought not the main aim of theray may be beneficial rather than harmful

13. SIDE EFFECT
Each unintend drug effect, occuring at normal doses used for patients, which is in relation to pharmacologic properties of drug.
(beta-blockers as antihypertensives + relieving the
symptoms of angina)
ADVERSE EVENT
Each noxious health event, which can occur during therapy, but doesn´t have to have relation with this therapy.
(patient takes ATB and breaks his leg)

14. UNEXPECTED ADVERSE REACTION
Adverse reaction whose character or intensity isn´t in concordance with domestic informations about drug or isn´t expected according to drug characteristic.
SIGNAL
Reported information about possible causal relationship between adverse event and, this relationship was yet unknown or incompletely documented. Usually more than 1 report is required for signal.

15. Risk factors of ADR Drug Prescription Pacient Number of drugs 0-5 6-10
nonselective and nonspecific
with narrow therapeutics range
lipophilic
Prescription
wrong selection of drug, drug combination, dose, route of administration, therapy length
Pacient
polymorbidity
diseases of organs of elimination
age, women
pharmacokinetic variability (etnic group, genetic polymorphism)
compliance
Number of drugs
0-5
6-10
11-15
> 16
ADR 4%
10%
28%
54%

16. Classification of ADRs
according to mechanism of origin
according to severity
according to frequency

17. I. ADR according to mechanism of origin
1.     Type A („Augmented“)
Dose-related
these ADR are expected
they can be predicted on the base of pharmacodynamic properties of drug
they depend on drug dose, they appear at higher doses
frequency is high > than 1%
mortality is low
therapy consists in dose adjustment
e.g.: cough after ACEI, bleeding from GIT after NSA, aspirin, corticoids ...

18. 2. Type B („Bizzare“) Non-dose-related
immunologic and idiosyncratic reactions
these ADR are not expected
they can be hardly predicted
doesn´t depend on dose
frequency is low < than 0,1%
mortality is high
treatment consists in stopping drug administration
e.g.: haemolytic anaemia after metyldopa, hepatitis induced by isoniazid, allergic reaction after PNC ...

19. rash

20. stopping administration
TYPE A
TYPE B
Predictability + –
Dosage dependence
Occurrence
high
low
Mortality
Treatment
dose adjustment
stopping administration

21. 1 drug – different types of ADR
Type A reaction
Type B reaction
Ampicillin
Pseudomembr. colitis
Intersticial nephritis, allergy
Chlorpropamid
Sedation
Hepatotoxicity
Naproxen
GIT haemorrhage
Agranulocytosis
Warfarin
Bleeding
Breast necrosis

22. 3. Type C („Continuous“) Dose-related and time-related
this type of ADR increases number of “spontanneous“ diseases
they occur usually after long-lasting administration
they are often serious and persistant
mechanism of genesis is unclear
they are unexpected, not predictable
they can´t be verified experimentally
e.g.: oral contraceptives and increased occurrence of thromboembolia, analgetic nephropaty, ...

23. 4. Type D („Delayed“) Time-related late ADR (years resp. generations)
teratogenity
carcinogenity
mutagenity
Carcinogenity e.g.:
ca. of vagina at daughters of mothers treated with dietylstilbestrol
cytotoxic and immunosuppressant drugs

24. Some known teratogens
Warfarin (saddle nose, retarded growth, defects of limbs, eyes and CNS)
Phenytoin (cleft of lip and palate, microcephaly, mental retardation)
Valproate (neural tube defects)
Ethanol (fetal alcohol syndrome)
ACEI (oligohydramnion, renal failure)

25. Fetal development and drugs
0-16 days (blastocyst formation; cytotoxic drugs)
17-60 days (organogenesis; teratogens)
60-term (histogenesis and functional maturation; alcohol, nicotine, steroids, ...)

26. 5. Type E („End of Use“) End of use
after therapy ending (syndrom from omitting)
rebound phenomenon
e.g.: beta blockers, opioids, corticosteroids,
nitrates ...

27. II. ADR according to intensity
mild – don´t require to stop or to change treatment
moderate – require to change therapy, but don´t threat life of the patient
serious – death, hospitalization, invalidization, teratogenity

28. III. ADR according to frequency
Very common (>10%) > 1/10 = (more than 1 in 10 people are affected)
Common (frequent) (1-10%) > 1/100 and < 1/10
Uncommon (infrequent) (0,1 - 1 %) > 1/1000 and < 1/100
Rare (0,001-0,1%) > 1/10000 and < 1/1000
Very rare (< 0,001 %) < 1/10000

29. The most frequent drugs causing ADRs
DIGOXIN
ANTIBIOTICS, PNC
DIURETICS
POTASSIUM
ANALGESICS
NSAIDs, ASPIRIN
SEDATIVES, PSYCHOPHARMACONS
INSULIN
GLUCOCORTICOIDS
WARFARIN

30. 1. Digoxin Digitalis glycoside Originally isolated from foxglove
(Digitalis purpura)
Binds to energy dependent Na+ pump
Useful for treating certain arrhythmias
ADRs:
arrhytmogenic
nausea, vomitting, anorexia
Gynaecomastia
TDM (extremely low dose)

31. 2. Antibiotics PNC (allergy)
Aminoglycosides (ototoxicity, nefrotoxicity)
Tetracyclines (avoid in children and pregnant women)

32. 3. Diuretics
osmotic, loop, thiazide and thiazide related diuretics, potassium-sparing
Indications: hypertension, heart failure, nephrotic syndrome, hepatic cirrhosis
ADRs: hypokalaemia, hypotension, hypomagnesaemia, hyperuricaemia

33. 4. Potassium ADRs: arrhythmias
Drugs with potential to cause hypokalaemia:
diuretics, corticosteroids, ...
Drugs with potential to cause hyperkalaemia:
amilorid, spironolactone, ACEI, ...

34. 5. Analgesics (opiates, NSAIDs)
frequent causes of ADRs
NSAIDs (many of them OTC)

35. 6. Sedatives, psychopharmacons
many ADRs; many of them addictive

36. 7. Insulin
the most feared ADR: hyoglycaemia

37. 8. Glucocorticoids locally at asthma: no systemic ADR
systemic administration: avoid for longer time if not neccessary (adrenal and/or pituitary suppression); many systemic adverse effects

38. 9. Warfarin
the most feared ADR: bleeding
need to monitor INR

39. Determination of causality
Basic categories:
High probability of causality
No sufficient proof of causality
0. Isn´t possible to evaluate causality

40. Diagnosis and determination of causality
is patient taking OTC, herbal or traditional remedies, recreational drugs, drugs of abuse, long-term treatments (e.g. oral contracetive)
Timing
the time relation between the use of the drug and the reaction
Pattern recognition
the pattern may fit the known pharmacology or allergy pattern of one of the suspected medicine
frequency of the event and how often it is associated with drug (headache – common even without taking drugs, aplastic anaemia – more likely to be ADR)

41. Diagnosis and determination of causality
Investigations
Plasma concentration measurements, biopsies, allergy tests
Sometimes is needed to establish baseline functions at the start of therapy (e.g. amiodarone – thyroid function)
Dechallenge the stopping of the drug:
Positive dechallenge: ADR disappearing after the stopping of the drug.
A negative dechallenge: ADR not disappearing after the stopping of the drug.
Rechallenge restarting of the same drug after having stopped it, usually for an ADR. 
Can be possitive/negative 

42. Diagnosis and determination of causality
Investigations
Challenge is giving of the drug to the patient during the ADR or treatment in question. 
Prechallenge is use of the same drug at some point in the past. 

43. ACTIONS AT PROOF OF CAUSALITY
         warning
         methodic direction
         limitation of indication
         change of dose
         deregistration of the drug

44. Troglitazon (p.o. antidiabetic; drug-induced hepatotoxicity)
Deregistered drugs
Troglitazon (p.o. antidiabetic; drug-induced hepatotoxicity)
Benaxoprofen (NSAIDs; liver and kidney failure, gastrointestinal bleeding, ulcers)
Terfenadin (antihistamine; prolonged QT interval, ventricular tachycardia)
Mibefradil (CCB; fatal arrhythmia, drug interactions)
Cerivastatin – (risk of rhabdomyolysis)
Rofekoxib, Vadekoxib –
(risk of myocardial infarction and stroke)
group with the highest risk NSAIDs
(> 30% of deregistrations)

45. % of ADR reported
at active monitoring: 10-30% (mostly done by pharmaceutical companies during clinical trials)
at pasive monitoring: < 1%
Type A ADR: - 80%
Treatment of ADR represents 13-15% of therapy costs
ADR occurs mostly between 1-10 day from beginning of therapy

46. ADVANTAGES of pharmacovigilance at worldwide cooperation
Large number of treated patients
Detection of possible race variations
Detection of rare ADR
Possibility of soon warning of particular drug risk all over the world

47. Safety of drugs in children
Off-label drug use remains an important public
health issue, especially for infants, young children, and children with rare diseases
Clinical trials in children
(special considerations)

48. Safety of drugs in pregnancy
Former pregnancy medication categories:
Category A:  Controlled studies show no risk or find no evidence of harm.
Category B:  Animal studies show no risks, but there are no controlled studies on pregnant women.
Category C:  Animal studies have shown risk to the fetus, there are no controlled studies in women, or studies in women and animals are not available.
Category D:  There is positive evidence of potential fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (i.e. life threatening condition to mother).
Category X:  Studies in animals or human beings have demonstrated fetal abnormalities, or there is evidence of fetal risk. The drug is contraindicated in women who are or may become pregnant.
Category C (confusing category). A medication gets this classification if there is insufficient data on its use during pregnancy. It could be safe or probably safe, or it could be potentially harmful.

49. Safety of drugs in pregnancy
In 2015 the FDA replaced the former pregnancy risk letter categories on prescription and biological drug labeling with new information to make them more meaningful to both patients and healthcare providers.
While the new labeling improves the old format, it still does not provide a definitive “yes” or “no” answer in most cases.

50. Safety of drugs in pregnancy
The A, B, C, D and X risk categories, in use since 1979, are now replaced with narrative sections and subsections to include:
Pregnancy (includes Labor and Delivery):
Pregnancy Exposure Registry
Risk Summary
Clinical Considerations
Data
Lactation (includes Nursing Mothers)
Females and Males of Reproductive Potential
Pregnancy Testing
Contraception
Infertility

51. DRUG TOXICITY
Pharmacological (predictable extension of the known pharmacology of drug)
Biochemical (tissue damage or toxicity caused by interaction of the drug or its metabolite with cell components such as structural proteins or enzymes)
Immunological (allergic reactions)

52. Pharmacological drug toxicity
ADRs related to primary use
e.g. warfarin (risk of ischaemia/bleeding)
ADRs unrelated to primary use
e.g. opioid analgesics (respiratory depression)
the most frequent toxicities
If needed to take drugs, might be prescribed
drugs to reduce side effects
(e.g. chemotherapeutics + antiemetics)

53. Biochemical drug toxicity
Methaemoglobinaemia, haemolysis (e.g. primaquine)
Hepatotoxicity (e.g. acetaminophen, isoniazid)
Nephrotoxicity (e.g. cyclophosphamide)
Cardiotoxicity (e.g. doxorubicin)

54. Immunological drug toxicity
Types of allergic reactions:
Immediate/anaphylactic reactions (via IgE; minutes to hours after drug exposure; e.g. penicillins, peptide drugs)
Cytotoxic reactions (specific IgG or IgM antibodies directed at drug-hapten coated cells; variable timing; e.g. thrombocytopenia, neutropenia, haemolytic anaemia)
Immune-complex reactions (tissue deposition of drug- antibody complexes with complement activation and inflammation; 1-3 weeks after drug exposure; e.g. serum sickness, lupus-erythematosus-like syndrome)
Cell-mediated/delayed reactions (major histocompatibility complex presentation of drug molecules to T-cells with the release of cytokines and inflammatory mediators; e.g. contact dermatitis)

55. Anaphylaxis According to: Food Allergy and Research Education
a severe, potentially fatal allergic reaction 
allergic symptoms can affect several areas of the body and may threaten breathing and blood circulation (low blood pressure)
food allergy is the most common cause of anaphylaxis (e.g. peanuts, tree nuts, milk, egg, soy, wheat, fish, shellfish); strict avoidance of problem foods
other causes: insect stings, medications, latex
epinephrine auto-injector (i.m.) in known severe allergy should be carried and used if needed  (it must be administered promptly to be most effective)
epinephrine expires after a certain period (usually around one year)
even if epinephrine is administered promptly and symptoms seem to subside completely, the individual who was treated with epinephrine should always be taken to the emergency room for further evaluation and treatment
According to: Food Allergy and Research Education

56. Anaphylactic shock stop administration (e.g. penicillin i.v.)
an episode of anaphylaxis where the person goes into a state of shock due to poor blood circulation that deprives the body of oxygen and nutrients
shock does not happen with most cases of anaphylaxis
stop administration (e.g. penicillin i.v.)
A, B, C, D, E (airway, breathing, circulation, disability, exposure)
feet raised, give oxygen, establish venous acces, monitor BP
According to: Kumar and Clark, 2017

57. Anaphylactic shock epinephrine other medicaments administered:
antihistaminic drug
hydrocortisone i.v.
if hypotension persists (i.v. fluids)
if hypoxia (assisted ventilation)
take blood for tryptase levels (diagnosis)
According to: Kumar and Clark, 2017