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FATIN NOR ATIKAH BINTI OTHMAN PEGAWAI FARMASI UF 48 HOSPITAL SULTANAH NUR ZAHIRAH (HSNZ)

NORHAFIDAH BINTI OTHMAN PEGAWAI FARMASI UF52 HOSPITAL DUNGUN

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Therapy of chronic hepatitis C has evolved from interferon-alpha monotherapy in 1986 to the use of  Pegylated  Interferon-alpha ( pegIFN ), together with Ribavirin (RBV ). However both interferon and  Pegylated  Interferon-alpha cause severe side effects; Fever Depression flu-like illness Anaemia Anorexia lymphopenia These problems are exacerbated by Ribavirin. Many patients cannot complete their treatment course .

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Transformation of hepatitis C antiviral treatment in a national healthcare system is followed by the introduction of highly effective direct-acting antiviral.    With the availability of direct- acting antivirals (DAAs) curing at faster and higher rates, they set the scene for elimination of HCV as a major public health threat.  It  is estimated that 2.5% of population aged 15-64 years were living with HCV infection of which 59% (95% CI: 50%; 68%) acquired their infection through injecting drugs.  The  most common genotypes found are genotype 3 and 1 in  Malaysia.

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New DAAs combination appear safe and higher efficacious without the need of Peg-interferon or Ribavirin.  The cure rates is between 90% and 100% in most patients group. Combination treatment seems inevitable to prevent emergence of resistance in HCV. Clinical trials are ongoing to identify the ideal regimen which would be potent, well tolerated, with minimal drug-drug  interactions,once   daily,all   oral,and  for as short duration as possible.

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To eradicate Hepatitis C virus (HCV) & CURE the infection. To reduce all-cause mortality and liver-related complications including fibrosis, cirrhosis, end-stage liver disease and hepatocellular carcinoma(HCC). To prevent transmission of HCV infection. To  prevent or improve extra-hepatic manifestations like   cryoglobulinemic  vasculitis , diabetes and  etc. To  improve quality of life including physical, emotional, and social health.

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To achieve  S ustained  V irological  Response  (SVR) SVR12 :  Undectable  HCV RNA level (< 15IU/ml ) at 12 weeks after treatment completion .	 SVR is the surrogate marker for CURE in Hepatitis C infection. SVR is durable for at least 4 years after completion of therapy in more than  99 %  of patients and is independent of patient or treatment characteristics. It is considered as  “ CURED ”  from a  virologic  standpoint .

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MEDICATION
*Sofosbuvir
Sofosbuvir/
Ledipasvir
Pa ritaprevir/
Ombitasvir/
Ritonavir
Dasabuvir
*Daclatasvir
Elbasvir/
Grazoprevir
BRAND NAME
SOVALDI@
HARVONI@
EXVIERA@
DAKLINZA@
ZEPATIER@
DOSAGE FORM & STRENGTH
400 mg/ tab
400 mg of Sofosbuvir and 90 mg
of Ledipasvir/ tab
75 mg of Paritaprevir, 12.5 mg of
Ombitasvir and 50 mg of
Ritonavir/ tab
250 mg of Dasabuvir/ tab
30 or 60 mg/ tab
50 mg of Elbasvir and 100 mg of
Grazoprevir/ tab
DOSAGE
One tablet once daily
(morning)
One tablet once daily
(morning)
Two tablets once daily
(morning)
One tablet twice daily
(morning and evening)
One tablet once daily
(morning)
One tablet once daily
(morning)

Treatment duration depends on genotypes, treatment naive or experience, cirrhosis or
without cirrhosis & etc.
* Currently available in 18 MOH hospitals
13

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Combination regimen
Sofßbuvir + ribavirin
* Sofßbuvir/leåpasvir ± ribavirin
Sofßbuvirlvelpatasvir ± rudirin
* Ombitmrlpantaprevirlritonavir + dasabuvir ±
ribavirin
* Ombitasvir/paritaprevirlritonavir ± ribavirin
Grazoprevirlebasvir ± ribavirin
Sofßbuvir + daclatasvir ± ribavirin
Sof±vir + simeprevir ± ribavirin
* Available in Malaysia
Genotype 1
Yes
Yes
Yes
No
Yes
Yes
Sbptirnal
Genotyp2
Suboptimal
No
Yes
No
No
Yes
Genåyr 3
S#timal
No
Yes
No
No
Yes
Genotype 4
Yes
Yes
Yes
Yes
Yes
Genotyps 5 and 6
Yes
Yes
No
No
Yes

COMBINATION  TREATMENT REGIMEN FOR EACH HCV GENOTYPE

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DAAs  are molecules that  target specific  non-structural  proteins  of the virus and results in  disruption of viral replication  and infection.  4   classes  of  DAAs (Defined  by their mechanism of action and therapeutic  target ) N onstructural  proteins 3/4A ( NS3/4A) protease  inhibitors ( PIs) NS5B  nucleoside polymerase inhibitors ( NPIs) NS5B  non-nucleoside polymerase inhibitors ( NNPIs) NS5A inhibitors

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Classes of DAAs
NS3/4A Protease Inhibitors
NS5B nucleoside polymerase inhibitors
NS5B non-nucleoside polymerase inhibitors
NS5A inhibitors
Drugs
Simeprevir
Glecaprevir
Grazoprevir
Paritaprevir
Voxilaprevir
Sofobuvir
Dasabuvir
Daclatasvir
Elbasvir
Ledispasvir
Ombitavir
Pibrentasvir
Velpatasvir

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TREATMENT REGIMEN
[8]
Sofosbuvir + Ribavirin
Sofosbuvir +
Peg-interferon Alpha +
Ribavirin [8]
Daclatasvir + Sofosbuvir [91
Daclatasvir + Sofosbuvir +
Ribavirin
SIDE EFFECTS
Fatigue and Headache
Fatigue, Headache, Nausea,
Insomnia, Anemia
Flu-like Illness, Decrease
Appetite, Rash, Chills
Headache And Fatigue
Fatigue, Nausea, Anemia And
Headache
PERCENTAGE (0/0)
>200/0
< I OYO

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TREATMENT REGIMEN
Ledipasvir + Sofosbuvir[ll]
Viekirax+ Dasabuvir [121
Viekirax+ Dasabuvir +
Ribavirin [121
SIDE EFFECTS
Fatigue and headache
Cough, myalgia, dizziness,
dyspnea
depression, BUN elevation,
Lipase elevation
Itching
Swelling or angioedema
Fatigue, nausea, asthenia,
itching, insomnia, anemia
Swelling or angioedema
PERCENTAGE (0/0)
<10%
5%

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DRUG
Ledipasvir/Sofosbuvir
Daclatasvir
Sofosbuvir
Ombitasvir/Paritaprevir/
Ritonavir — Dasabuvir
•
•
CONTRAINDICATION/ WARNING
Amiodarone co-administration
P-glycoprotein (gp) inducers
Renal failure (eGFR<30 mL/min/1.73 rn2)
Drugs inducing or inhibiting CYP3A
Amiodarone co-administration (caution also with beta-
blockers)
Renal failure (eGFR<30 mL/min/1.73 m2)
Child—Pugh Class B and C cirrhosis
Drugs inducing or inhibiting CYP3A or CYP2C8
Use of ethinylestradiol-containing medicinal products
Untreated HIV-I infection because Ritonavir can lead to
antiretroviral drug resistance

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It is strongly recommended that prescribers consult the University of Liverpool webpage on hepatitis drug  interactions http://www.hep-druginteractions.org/ It  includes details of interactions with prescribed and non-prescribed drugs.

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Renal
Impairment
eGFR
(mL/min)
Ribavirin
ofosbuvir
Ombitasvir
Dasabuvir
Parita revir
Mild
(50-80)
PEG-IFN (2a)
180 ug;
PEG-IFN (2b)
1.5pg/kg
Standard
Standard
Standard
Standard
Standard
Standard
Standard
Moderate
(30-50)
PEG-IFN (2a)
180 ug;
PEG_IFN (2b)
1 pg/kg
(25% reduction)
Alternating doses
200mg and
400mg every
other day
Standard
Standard
Standard
Standard
Standard
Standard
Severe
PEG-IFN (2a)
135 ug;
PEG_IFN (2b)
1 ug/kg
(50% reduction)
200 mg/d
Limited data
available
No Data
Limited data
available
Limited data
available
Limited data
available
Limited data
available
ESRD with HD
PEG-IFN (2a)
135pg/wk or
PEG-IFN(2b)
1 ug/kg/wk or
standard IFN 3
mU3x./wk
200 mg/d
Limited data
available
Limited data
available
Limited data
available
Limited data
available
Limited data
available
Limited data
available

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MEDICATION
PEG-IFN + Ribavirin
Sofosbuvir
[11]
Ledipasvir
Daclatasvir
Ombitasvir/Paritaprevir
[12
Ritonavir+Dasabuvir
CHILD-PUGH A
Suitable
candidate
CHILD-PUGH B
Not entirely
contraindicated
CHILD-PUGH C
Not a good
candidate
No dose adjustment. Safety and efficacy of Sofosbuvir
have not been established in patients with
decompensate cirrhosis
No dose adjustment
No dose adjustment
No dose
adjustment
Not
recommended
Contraindicated

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No adequate human data  are available for all direct acting  antivirals. However , any regimen is administered with Ribavirin or  Pegylated  Interferon  is  contraindicated.

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KAUNSELING PESAKIT YANG MENERIMA RAWATAN HEPATITIS C

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Dianggarkan  1  dari  3   pesakit  yang  dijangkiti  virus hepatitis C  progres   ke   arah   cirrhosis  hati,kurang   dari  20  tahun . kadar   progres   ini   akan  di  cepatkan   lagi   dengan   penuaan,pengalkoholan   dan   jangkitan  HIV Ketercepatan   kepada  cirrhosis  dengan  HCV/HIV 3 kali  ganda   lebih   tinggi   berbanding   pesakit  HCV  tanpa  HIV

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The INF era
The HCV Identification
IFN
The "DAA revolution"era
The Early era of DAA's
SOF/ LOV
OBV PTV r
Peg-IFN + RBV
The pangenotypic era
EBR / GZR
984 1989 1998
anon-A, non-B" hepatitis
2001 2011
BOC
NS3/NS4A
Protease inhibitors
2013
SMV
SOF
2014
2015 20162017..
SOF / VEL
Elimination?
SOF / VEL / VOX
NSSA (replication
Polymerase inhibitors
complex) inhibitors
NSS8
HCV polyprotein

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Range Rover SVR 5.0 V8- Unreg-SUPER H...
RM 990 999
Penang - Juru
30 Mar 1 0:44
Abadi Motor Penang
Cornpany ID Verified

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Sustaine   virologic  response Indikasi   kejayaan   rawatan   untuk   jangkitan  Hepatitis C Ketidakhadiran  detectable HCV  R na   dalam  serum Setelah  3  bulan   tamat   rawatan

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PROSES KERJA PENDISPENSAN DAN KAUNSEUNG PESAKJT HEPATITIS C
YANG MENERIMA UBAT DIRECT ACT'NG ANTIVIRALS (DAAs)
(Bagi Hospital Yang Tiada Perkhidmatan MTAC Hepatitis)
Hubungi preskrib«
Tervn.a yang
OAAs
preskricxi
Ada masatah?
TIDAK
Labe' dan isi ubat
Sernak •saang.
Ada masalah?
TIOAK
ubat
Kaunse&ng 2
Rekod dan
etan
TAMAT
p-F'ppF
rppF
pnppF

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Sesi   pertama Mulakan   rawatan : Sejarah   ubat-ubatan,matlamat   rawatan,kesan   sampingan   biasa,pengesanan   interaksi   ubat-ubatan,cara   pengambilan   dan   penyimpanan Sesi   kedua / seterusnya Penilaian   komplian   dan   dokumentasi   kesan   advers

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HEPATITIS MTAC WORKFLOW ONrTIAL
LOCATION: Clinic' Outpatient pharrnacy
Doctor/
—•arrnacist
Nurse
dr.«-dr•.«
Pro.4de to
drug—drug
with
aq•ßtrnent
Schedule tor next

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HEPATITIS MTAC WORKFLOW (SUBSEQUENT VISITS)
Location: Clinic/ Outpatient pharmacy
Pharmacist
Pharmacist
Pharmacist
Pharmacist
Pharmacist
Pharrnacist
Pharrnacst
Pharmacist
Registratbn
Trace record of follow-up patient
Pharmacist's and monitoring:
Adherence (Pill count)
Drug—drug
Adverse drug reaction (report if
any found)
Detected drug-drug
if any added
prescribed medications
Refer back to for
interactions
Medication dispensing
Schedule for ræxt visit/
Docu.menta oon

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1.Pengenalan 2.Adherence  dan   cara   pengambilan   ubat 3.Diari  ubat   pesakit 4.Penyimpanan  ubat 5.Kemungkinan  interaksi   ubat   dan   kesan   sampingan 6.Maklumat  tambahan

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• Education on disease & treatment goals
What is Hepatitis?
Hepatitis Viruses
Disease Progression*
1
Chronic hepatitis (20%)
Several types of viruses:
Liver fibrosis (Early scarrin
Inflammation of liver &
general health affected
Liver cirrhosis
2
(Hardening of liver, 20%)
Hepatitis C virus:
-many formc (genotypes): 1
-affect treatment length
Ascites, variceal bleed,
hepatic encephalopathy,
hepatocellular carcinoma
No vaccine is available
to prevent hepatitis C
'Porson-to-porson variability
Patient Module: Hepatitis C

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DAA  untuk   rawatan   Hep  C DAA(direct acting antiviral)  ialah   ubat  yang  bertindak   secara   gangguan   terus   pada   replikasi  viral HCV yang  secara   dramatiknya   menambahbaik   efikasi   terapi Contoh  DAA:  Sofosfuvir  400mg,Daclatasvir 60mg  dan  30 mg  Kadar  keberkesanan   rawatan   antara  90-100%

Scene 40

• Education on disease
Transmission of Hepatitis
PRETREATMENT COUNSELLING CHECKLIST
pa•errs Narre:-
Done
Fur-coms •ver
Hepatos C
Dsease euraænst»cs
Dsease essm
Trmsmtsuon ot repays
Preventve precautÜ1
e-trearnent
nvest
Done
trr•.
•
•
•
•
•
•
•
•
Truths
Blood transfusion
Organ transplant
Body piercing, tattooing,
acupuncture by needles
Sharing sharp instruments
e.g. toothbrush, razor etc.
Sharing unsterilised needles/
dental equipment
Unprotected sex/high risk
sexual practices
(may cause bleeding)
Mother-to-child
Long-term haemodialysis
F actors
wal cea
Patent sed
Hepatos C treat'W%
Best to e
Mtssea
Common sde effects
reatnvt boas pa
pajent
PÜnrs regarü-g C treat'Mt (18M):

Scene 41

• Counseling on importance of review & monitoring
Lab. Tests
Before Starting Treatment
• Physical examination
• Screening test:
- Anti-HCV antibody
• Confirmation test:
- Presence of RNA (HCV RNA)
- Viral load
- Genotyping
• Other baseline tests (e.g. presence of other
hepatitis, liver function test, thyroid function
test, autoimmune disease test, renal
profile etc.)
• Liver biopsy, ultrasound, fibrosis scan etc.
H.aot•s C
fi¯r

Scene 42

Tekankan   kepentingan   rawatan -Masa yang  tetap  ( pandulah   pesakit   kearah  masa yang  benar ) - Galakan   pesakit   untuk   guna   alat   bantuan   ingatan Sofosbuvir   dan   daclatasvir   sebaiknya   diambil   pagi * Pesakit   ketinggalan (  petua  18) Ubatan   hendaklah   ditelan   kesemuanya   dengan  air

Scene 43

Kesemua   pesakit   hendaklah   dibekalkan   dengan   diari   ubat  DAA( pandulah   mereka ) 4.  Penyimpanan   Simpan   ditempat  yang  bersesuaian -  pada   suhu   bilik  normal (<30c)

Scene 44

5.Kemungkinan  interaksi   ubatan   dan   kesan   sampingan   biasa

Mana-mana  m akanan   tambahan / herba  yang  tidak   dipreskrib   oleh  prescriber  adalah   di  haramkan Terdapat   beberapa   ubatan  yang  mengakibatkan   interaksi 	 - CCB  :  elakkan   pengambilan   sekali 	 - Statin   : withhold  sehingga   tamat   rawatab 	 - NNRTI  :  tingkatkan  dos  Daclatasvir Kesan   sampingan   biasa : ~10% lethargic(anemia), ringan   sakit   kepala,symptom   berkaitan   perut Segera   laporkan   kepada   pengamal   perubatan   jika   terdapat   kesan   luar   jangka

Scene 45

1 IVI RIVxm
Liverpool HEP iChart
O Ths is comc.etible With cf your '*vices
Add to WisHist
HEP
interaction O•arts
HEP
Ledipasvir /Sofosbuvir
o
OBVfPTV/r + OSV
LIVERPOOL
Apps v
C-cntact us
o
o
CEO
Co-rnedkations
Acarbose
Drug Intermtions
No f
OSV
Abacavir

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• Medication history taking & reconciliation
• Drug- related problem assessment & intervention
Drug- drug interaction checkers:
https://wow.hep-druginteractions.org/
https://reference.medscape.com/drug-interactionchecker
IBM Micromedex Complete Drug Interactions
Lexicomp@ Drug Interactions

Scene 47

DOSAGE ADJUSTMENT TABLE
Lab. Pegytated IFN
Pegytated IFN a-2b
Result
a-2a
Haemoglobin (gldL)
Appendix IX
Ribavirin
No cardiac
disease
cardiac
disease
Sep 1:
< 10.0
No cardiac
disease
to
00 mg,fday
Dixontinue
Stable
cardiac
disease
St•p I:
4 wæks
to
600
r«luction)
4 —sin
r«iuced
Dosage/ toxicity
adjustment
Sofosbuvir is licensed for
use only in patients CKD
stage 1-3 (>30ml/min)
Ribavirin:
by
No chanæ
dL despite
Dixontjnue
4 in
c»rmanently
re&ed dose:
White blood cell ccnant (x 10'/mm')
Step 1 (first redætön):
to 1 pg/kg/wk
Step 2 (sæmd reoctm:
doæ OS ÆtWwk
p«rnmendy
•
Decompensated
cirrhosis, start at the
dose of 600 mg daily and
the dose subsequently
adjusted depending on
tolerance.
Daily
weight-based
(1000mg:
1200mg: 275
divided doses)
<75kg;
kg, in

Scene 48

Senantiasa   bawa   semua   botol   termasuk   botol   kosong   dan   diari   setiap  kali  lawatan Jangan   simpan  mana-mana  ubat  yang  tak   digunakan   dirumah Jangan   kongsi   ubatan Setiap   kaunseling   berbeza   antara   pesakit   ke   pesakit

Scene 49

Patient's Drug Diary
MTAC Hepatitis C
Patient's Name:
MRN:
Contact Number:
Genotype:
60 W
Baseline Viral Load HCV DNA:
Liver Status: -a mg
Non Cirrhotic / Cirrhotic (Child:
Tr ment Experience:
N iv / Experience (Year :
): Failed due to Intolerance Side
E Null Responder/ Relapses
Treatment
Regimen: 00 A.
b . Weeks
Duration:
Started Date:
Ended Date:
.00
Treating Physician:

Scene 50

initiation:
Oate
Sofosbuvir " t
O a clatasvir
Days S
Sofosbuvir
18
32
46
60
74
26
OacJata Svir
Week 4
Date
Sofosbuvir
Daclatasvir
week 6
Date
Sofosbuvir
Daclatasvir
Date
Sofosbuvir
Daclatasvir
week 10
Date
Daclatasvir
43
31
45
47
61
62
36
78
37
65
52
66
80
67
81
55
82
Please remember to brine this card with you on every visit-

DIRECT ACTING ANTIVIRALS (DAAs)

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 It is strongly recommended that prescribers consult the University of Liverpool webpage on hepatitis drug  interactions http://www.hep-druginteractions.org/ It  includes details of interactions with prescribed and non-prescribed drugs.

DIRECT ACTING ANTIVIRALS (DAAs)

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