a pharmacovigilance case.... as adverse drug reaction

1. 1

2. CASE PRESENTATION
Dr. Pranesh Pawaskar
First Year Resident
Department Of Pharmacology
L.T.M.M.C. Sion Mumbai
400022
Date : 02/09/2016
2

3. MEROPENEM
INDUCED
NEUTROPENIA
3

4. CASE
• Male
• 13 years old
• h/o Road traffic accident ……..7 days back
• c/o Fever…… 5 days
• Admitted with…..Neck Stiffness and Altered Sensorium
4

5. COURSE OF REACTION
Patient suffered a road traffic accident on 20 July 2016.
Patient came to Sion Hospital casualty
On External Examination
Mild swelling, Abrasions and Bruising on Right thigh
On X-ray
No fracture seen
Apart from pain and some bleeding abrasions no other complaints.
20 July 2016
5

6. COURSE OF REACTION
Patient was given Tab. Diclofenac for pain reducing and ‘T-bact’ lotion for
local application on abrasions.
Patient allowed to go to home.
Swelling gradually increased and became painful.
Fever…..23 July……initially mild later high grade.
Vomiting and nausea
Altered sensorium…… 26 July
27 July 201620 July 2016
6

7. COURSE OF REACTION
Patient brought to Sion hospital casualty
Temperature: 101˚ 𝐹
Pulse : 96 per min.
Respiratory rate : 25 per min
BP : 110/80 mmHg
Unconscious , Altered sensorium, Neck stiffness
Big reddish Swelling on Rt. thigh
27 July 2016
On general
Examination
7

8. COURSE OF REACTION
Suspecting Meningitis patient was admitted to MICU
Patient work up started
Inj. Ceftriaxone (1 gm) i.v. OD
Inj. Pantoprazole (40 mg) i.v. BD
Inj. Ondansetron (4 mg) i.v. TDS
Inj. Paracetamol 5ml (100mg/ml) i.v. TDS
Inj. Mannitol (100cc) i.v. TDS
Treatment started at our
institute
8

9. COURSE OF REACTION
Based upon patients reports patient was diagnosed as having Pyomyositis With
Sepsis With Pyogenic Meningitis.
Treatment continued But Patient did not improved
Inj. Meropenem 1 gm TDS i.v. added to the regimen.
30 July 2016
28 July 2016
9

10. COURSE OF REACTION
Patients reports showed neutropenia.
when compared to CBC reports of previous days it was clearly pointing the
decrease in neutrophils after 30th July.
Suspecting Meropenem as causative agent it was stopped.
It was replaced with Inj. Levofloxacin 500mg i.v. BD
Following this replacement patient neutrophil count gradually recovered
And patient was discharged on 12 August 2016
3 August 2016
10

11. “
”
INVESTIGATIONS
Normal range 4000 – 10000 /microliter
11
Parameters 27
July
28
July
29
July
30
July
31
July
1
Aug
2
Aug
3
Aug
4
Aug
5
Aug
6
Aug
7 Aug
WBC 15000 17500 16000 14500 9800 7500 4800 2900 3500 4200 5300 8700

12. • SERIOUSNESS OF REACTION –
Reaction was serious as it prolonged the hospitalisation of patient.
• OUTCOME –
Patient recovered
• DIAGNOSIS –
Meropenem induced neutropenia.
12

13. 13
Gf11
2
1
0
-1
0
0
0
0
0

14. CAUSALITY ASSESSMENT
According to NARANJO CAUSALITY assessment scale …..
POSSIBLE
Because…
a) Reasonable drug-event temporal relation.
b) De-challenge response positive.
14

15. NEUTROPENIA
Definition:
• A reduction of the circulating WBC count to less than
4000/µl.
• Normal Range: 4000 - 10000/µl
• Neutropenia can be graded as mild, moderate, and
severe, corresponding respectively to ANC values
of 1000-1500 cells/mm3, 500-1000 cells/mm3, and
<500 cells/mm3.
• ANC = 15

16. RISK FACTORS FOR NEUTROPENIA
• Drugs, such as Clozapine and Anti-thyroid medication
• Exposure to chemicals, such as the INSECTICIDES, DDT etc.
• Diseases that affect bone marrow, such as cancer.
• Serious infections
• Exposure to radiation
• Autoimmune diseases, such as Systemic Lupus Erythematosus.
• Nutritional deficiencies, including low levels of vitamin B-12 and
folate
• Bone marrow transplants.
• Chemotherapy.
16

17. DRUG INDUCED NEUTROPENIA
• DIN is associated with infectious complications and a mortality rate of
2.5-10%.
• The prevalence of DIN is 3-6/1,000,000 population.
• It occurs almost twice as frequently among women.
• Its incidence increases with age.
• More than 50% of cases occurring in patients over 60 years old.
17

18. DRUGS CAUSING NEUTROPENIA
• Anti thyroid drugs:
Methimazole, Carbimazole etc.
• Anticonvulsants :
Valproic acid, Phenytoin etc.
• Anti Microbial And Anti
Virals:
Penicillin, Gentamicin,
Acyclovir etc.
• Chemotherpeutic Agents:
Methotrexate, Cisplatin,
Busulfan etc.
• Cardiovascular Drugs:
Clopidogrel, Ticlopidine Etc.
• Analgesics:
Aminopyrrine, Indomethacin.
• Heavy metals:
Gold, Arsenic, Mercury
• Antihistaminic :
Cimetidine, Ranitidine etc.
18

19. MECHANISM
1. Immune mediated
Hapten (penicillin group)
Apoptosis (clozapine)
Immune complex
Complement Mediated mechanism (PTU)
2. Dose dependent inhibition of granulopoeisis
Beta lactams, Carbamazepine, Valproic Acid
3. Direct toxicity to Myeloid Precursors
Ticlopidine, Methimazole, Chemotherapeutic Agents
19

20. MECHANISM
• HAPTEN :-
1. Some drugs act as haptens to induce antibody formation against
neutrophils, leading to their destruction.
2. Continuous presence of the drug is required for the destruction of
neutrophils.
3. Drugs like Aminopyrine, Penicillin, and Gold compounds appear
to act as haptens
20

21. MECHANISM
• APOPTOSIS :-
1. Clozapine (0.8% risk )accelerates the process of apoptosis, as shown
by in vitro studies.
2. Clozapine undergoes bioactivation by P450 and peroxidase enzymes
to form the toxic and reactive Nitrenium ion. binds to cellular
proteins, depletes intracellular glutathione (GSH), and leads to
polymorphonuclear and mononuclear cell toxicity in vitro.
3. Concentrations of clozapine above 3 mM, in the presence of an
enzyme activating system, produced cell death.
21

22. MECHANISM
• IMMUNE COMPLEXES :-
1. Circulating immune complexes may be formed, which bind
to neutrophils and cause their destruction.
2. Complexes do not require the continuous presence of the
drug.
3. Drugs like Quinidine acts in this way..
22

23. MECHANISM
• COMPLEMENT MEDIATED MECHANISM:-
1. Drugs like …PROPYLTHIOURACIL
2. Cytotoxicity tests demonstrated that the anti-neutrophilic
antibodies lysed the neutrophils via a complement mediated
mechanism.
3. No antibody-dependent cell-mediated cytoxicity (ADCC).
23

24. MECHANISM
• DOSE DEPENDENT INHIBITION: -
1. This is seen by drugs such as BETA-LACTAM ANTIBIOTICS,
CARBAMAZEPINE, and VALPROIC ACID.
2. At high concentrations, these drugs induce inhibition of colony
forming units of granulocyte and macrophages in all bone marrow
samples.
24

25. MECHANISM
• DIRECT TOXICITY :-
1. Reversible direct cytotoxicity of TICLOPIDINE for pluripotent or
bipotent hemopoietic progenitor stem cells was noted by Symeonidis
et al.
2. BUSULFAN, factitiously ingested by a 34-yr-old woman, resulted in
life threatening bone marrow suppression.
3. Similar case reported for Methotrexate.
4. Other drugs acting in this way – Methimazole (4% risk) ,
Doxorubicin, Cyclophosphamide, clopidogrel.
25

26. MECHANISM
• IDIOSYNCRATIC :-
1. Indomethacin.
2. Ethanol.
3. Tamoxifen.
4. Colchicine.
26

27. MEROPENEM
• BETA LACTAM group of antibiotic drug under subgroup
CARBAPENEMS.
• Share a common structure and mechanism of action: inhibition of
synthesis of the bacterial peptidoglycan cell wall.
• Carbapenems are B-lactams that contain a fused -lactam ring and a
five-member ring system that differs from the penicillins because it is
unsaturated and contains a carbon atom instead of the sulfur atom.
• Carbapenems, including IMIPENEM, DORIPENEM, ERTAPENEM
AND MEROPENEM, have the broadest antimicrobial spectrum of any
antibiotic.
27

28. MEROPENEM
• Meropenem is bactericidal except against listeria monocytogenes,
where it is bacteriostatic.
• It is highly resistant to degradation by β-lactamases or
Cephalosporinases.
• Resistance is due to mutation in PBP.
• The spectrum of action includes many gram-positive and gram-
negative bacteria (including pseudomonas) and anaerobic bacteria.
• Meropenem is frequently given in the treatment of Febrile
Neutropenia. 28

29. MEROPENEM
• Meropenem- administered intravenously.
• Supplied as a white crystalline powder to be dissolved in 5%
monobasic potassium phosphate solution.
• Dosing must be adjusted for altered kidney function.
• It does not require co-administration with Cilastatin because it is
not sensitive to renal dipeptidase.
• The most common adverse effects are :- Diarrhea (4.8%), Nausea
And Vomiting (3.6%), Injection-site Inflammation (2.4%), Headache
(2.3%), Rash (1.9%), And Thrombophlebitis (0.9%). 29

30. MEROPENEM
• Activity against some Imipenem-resistant P. Aeruginosa but less
activity against gram-positive cocci.
• Clinical experience with MEROPENEM demonstrates therapeutic
equivalence with IMIPENEM.
30

31. MANAGEMENT
• Discontinuation of offending drugs or presumably offending drugs.
• Maintainance of good oral hygiene, preventing trauma to perirectal area
by using stool softners and cleanliness of skin.
• Recombinant human granulocyte colony stimulating factor (rG-CSF) is
the major cytokine that stimulates the growth and development of
neutrophils in the bone marrow.
• A recombinant form of G-CSF (Filgrastim; r-metHuGCSF) is
commercially available. 31

32. MANAGEMENT
32
• FILGRASTIM increases the activation, proliferation, and
differentiation of neutrophil progenitor cells and enhances the
function of mature neutrophils.
• Pegylated G-CSF (PEGFILGRASTIM) provides patients similar
benefits as Filgrastim, but with a simpler (once/chemotherapy cycle)
dosing regimen that is efficient and cost-effective.
• British anti-lewisite (BAL) or Penicillamine therapy, if the
neutropenia is associated with gold or arsenic exposure.

33. CONCLUSION
• A case on possible drug-related adverse reaction was presented.
Involves multiple drugs of probable haematological toxicity
Concomitant / Follow-by multiple drugs administration results in
difficulties in identifying responsible drug
• Possible drugs responsible for leukopenia
Meropenem
• Complicated by underlying disease…. Pyomyositis, Sepsis, Pyogenic
Meningitis 33

34. CONCLUSION
• Antibiotics clearly saves the life.
• Poorly prescribing put patient into unnecessary risk, adverse
reactions and development of resistance to organisms Every time
antibiotic is prescribed make sure indication , dose and duration is
proper.
• Adjust or stop antibiotic if necessary.
• Be specific to use of antibiotics.
• ADR cases should be highlighted to provide better information and
precaution to other healthcare providers.
34

35. REFERENCES
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Meropenem (Rx) - (Merrem IV). Drug Information [cited 2012 Jan 7 ]. available from:
http://reference.medscape.com/ drug/merrem-iv-meropenem-342565#0.
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36. REFERENCES
6. Manning L, et al. Continuous infusions of meropenem in ambulatory care: Clinical
efficacy, safety and stability. 2014. PLoS One 9. Avaliable from: URL:
http://doi.org/10.1371/journal.pone.0102023
7. Anonymous. Imipenem/meropenem: Neutropenia: a case report. Reactions weekly.
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37. REFERENCES
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