SMF Ilmu Penyakit Dalam

Drug Information Study

MEKANISME EFEK SAMPING DARI ARV DAN PENGATASANNYA

Ulfa Syafli Nosa 051815153001 Maria Ulfa 051815153012

Irsan Fahmi A. 051815153003 Indira Dayang Mahdayana 051815153015
Muhammad Yanuar Ahadi 051815153004 Ni Putu Ayu Deviana G . 051815153018
Hayu Intan Himawindy 051815153006 Riskilla Fauziyanda P. 051815153024
Bindaria Mutmaina 051815153008 Indira Dhany K. 051815153028
Lewi Tigor Simorangkir 051815153011 Dara Demi Sahayuna 051815153029

Program Studi Magister Farmasi Klinik

Fakultas Farmasi Universitas Airlangga Surabaya
1
2019
DAFTAR ISI

1. TENOFOVIR .....................................................................................3
2. NEVIRAPINE ....................................................................................9
3. LAMIVUDINE...................................................................................16
4. ZIDOVUDINE....................................................................................23
5. ABACAVIR .......................................................................................28
6. EFAVIRENZ ......................................................................................34
7. RIlPILVIRINE ………………....................................................................40
8. LOPINAVIR/RITONAVIR ………………………………………………………………..45

2
Tenofovir (TDF)
Side Effect Drug

3
 Tenofovir Cause Nephrotoxicity – Mechanisms

Is TDF nephrotoxic?
• Potential for nephrotoxicity
• Similar structure to
Adefovir  known
nephrotoxin
• Accumulation in renal
proximal tubule
• Vd = 0.8 L/kg
• Minimally protein
bound (<8%)
• Mainly excreted in
urine, unchanged pro-
drug form
• The Mitochondrial
Kondisi Normal Kondisi adanya defek pada OAT-1 dan/atau MRP-2/4
Cytopathy Hypothesis
4
Tenofovir Cause Nephrotoxicity – Drug Interaction

5
Tenofovir Cause Nephrotoxicity – Biochemical Features

6
Tenofovir Decrease Bone Mineral Density

1. preferential uptake by osteoclasts (altering gene

expression and resulting in increased bone resorption),
2. update by osteoblasts (altering gene expres-sion and
decreasing bone formation), and
3. uptake by both osteoclasts and osteoblasts (altering
gene expression of both cells types and ultimately the
balance between bone resorp-tion and bone formation
– resulting in bone loss)
Since tenofovir and TDF are both phosphonates, it is
conceivable that they could also have an association with
bone and be selectively taken up by osteoclasts by a
mechanism similar to that of bisphosphonates,
ultimately causing cellular stress

Following TDF uptake by osteoclasts, TDF can target the nucleus (1) and/or mitochondria (2), where it may directly or
indirectly perturb DNA synthesis by 1) incorporation and DNA chain termination, 2) DNA damage, 3) alteration of
deoxynucleotide transport, and/or 4) nucleotide pool imbalances. The impact of TDF on cellular DNA synthesis would
result in altered gene expression (3). 7
Tenofovir Side Effect Drug – Management Therapy
1. Penurunan Dosis (Micromedex, 2019)
CrCl (mL/min) * Dose and interval
50 or greater 300 mg every 24 hours
30 to 49 300 mg every 48 hours
10 to 29 300 mg every 72 to 96 hours
less than 10 (no hemodialysis) 300 mg every 7 days or after a total of approximately 12 hours of
hemodialysis. Give dose after a hemodialysis session
Key: * = CrCl using ideal (lean) body weight

2. Subtitusi dengan ARV lain (Permenkes 87 tahun 2014)

Kategori ARV Substitusi
Kategori Lini 1 AZT atau d4T
Kategori Lini 2 ABC atau ddI

8
Nevirapine (NVP)
Side Effect Drug

9
 Adverse Effect of Nevirapine (NVP)
Associated Not associated
Rash Mitochondrial toxicity
Hepatitis Bone marrow suppresion
Hypersensitivity reaction Gastrointestinal symptoms
Cytochrome p450 induction Pancreatitis
Lactic acidosis
Lipodystrophy

Increased LDL, Cholesterol plasma levels

Mood disorders
Fetal abnormalities
Neuropathy
Murphy, 2003
10
Metabolic pathways of NVP

11
Metabolic pathways of NVP

12
 Manajemen Adverse Effect of NVP
No Adverse effect Management
1 Acute hepatitis Jika mungkin, monitor serum tranaminases, bilirubin

Stop pemberian NVP selamanya

2 Hypersensitivity reaction Stop pemberian NVP sampai gejala menghilang

Berikan suportive terapi

3 Severe Rash / SJS
Jika gejala HS menghilang ganti dengan ARV berbasis PI atau
NRTI
Stop pemberian NVP selamany, bila gejala SR/SJS
menghilangmaka ganti regimen dengan ARV 3 NRTI atau 2
NRTI dan PI

Jika Rash katagori moderate dan tanpa gejala mukosa atau

sistemik maka ganti dengan EFV

4 Gastrointestinal symptoms terapi simptomatis. Penghentian NVP jarang dilakukan

selain diare

Fact Sheet on Antiretroviral Drugs, WHO, 2002 13

Lamivudine (3TC)
Side effect

16
17
18
Asidosis laktat

• FDA, 2017 ema.europe.eu

19
Cecilia Shikuma, MD, University of Hawaii and ACTG Lipodystrophy researcher

20
21
Dosis dan farmakokinetik lamivudine pada ESRD

22
Zidovudine (ZDV)
Side effect drugs
Zidovudine-Induced Neutropenia and
Anemia Megaloblastic

23
Adverse Effects of Zidovudine

24
 Incidence and Timing
• Anemia (1% Adult) may present as early as 2-4 weeks but can occur after years on
treatment
• Neutropenia (2% Adult) usually occurs after 6 to 8 weeks

Mechanism
• Direct bone marrow toxicity → inhibition of production of blood cell progenitor
cells
• Mitochondrial dysfunction → haematological disorders

Risk Factor
• Pre-existing anemia or neutropenia
• Advance HIV disease
• Opportunistic infections associated with anemia such as Mycobacterium
Tuberculosis
• Concominant use of bone marrow suppressants (cotrimoxazole, antituberculosis
therapy) or drugs that cause haemolytic anemia (ribavirin)
25
• Significant anaemia (haemoglobin of <7.5 g/dL or reduction of >25% of baseline) and/or
significant granulocytopenia (granulocyte count of <750/mm3 or reduction of >50% from
baseline) require a dose interruption until evidence of marrow recovery is observed
(usually observed within 2 weeks after dose interruption)
• For less severe anaemia (Hb 7.5-9 g/dl) or granulocytopenia (neutrophil count 750-
1000/mm3), a reduction in daily dose may be adequate.
• If marrow recovery occurs following dose modification, gradual increases in dose may be
appropriate depending on haematologic indices and patient tolerance.
• Blood transfusion fro grade 4 anemia or as clinically indicated (such as if the patient is
symptomatic with shortness of breath, cardiac decomposition, severe lethargy) in
26
addition to interruption of Zidovudine
Prevention
• Avoid Zidovudine use in patients at risk
• Check haemoglobin prior to initiation of Zidovudine therapy whenever
possible
• Avoid concominant use of bone marrow suppressants if possible

Monitoring
• Monitor complete blood count or Hb or haematocrit at least every two weeks
for first three months of therapy and at least monthly thereafter (Depending
on the overall patient condition.

27
Abacavir (ABC)
Side Effect Drug

28
 Abacavir – Hypersensitivity Mechanisms

Symptoms

Epidemiologi

29
 Abacavir –
Hypersensitivity
Mechanisms

30
Abacavir – Hypersensitivity Mechanisms
HLA-B*57:01 in Role

31
Managing HSR

32
Efavirenz (EFV)
Side Effect Drug

33
EFAVIRENZ

34
 Adverse Event of Efavirenz
>10%:
• Central nervous system: Dizziness (2% to 28%), depression (≤19%; severe: 2%), insomnia (≤16%), anxiety
(2% to 13%), pain (1% to 13%), headache (2% to 8%)
• Dermatologic: Skin rash (5% to 32%)
• Endocrine & metabolic: Increased serum cholesterol (20% to 40%), increased HDL cholesterol (25% to
35%), increased serum triglycerides (≥751 mg/dL: 6% to 11%)
• Gastrointestinal: Diarrhea (3% to 14%), nausea (2% to 10%), vomiting (3% to 6%)
1% to 10%:
• Central nervous system: Fatigue (≤8%), lack of concentration (≤8%), drowsiness (≤7%), nervousness
(≤7%), abnormal dreams (1% to 6%), hallucination (1%)

• Warnings/Precautions
Concerns related to adverse effects:
• CNS effects: May cause CNS effects (eg, abnormal dreams, insomnia, impaired concentration,
hallucinations, dizziness or drowsiness); symptoms usually begin within 1 to 2 days after starting
efavirenz, and generally resolve within 2 to 4 weeks of continued therapy; dosing at bedtime may
improve tolerability
• Psychiatric effects: Serious psychiatric side effects have been associated with use, including aggressive
behavior, delusions, severe depression, suicidal ideation, fatal and nonfatal suicide attempts, paranoid,
psychosis-like behavior, and mania; use with caution in patients with a history of mental illness 35
 CNS Side effect
• EFV has a high rate of CNS side effects (up to 55%) including :
more frequently dizziness, insomnia, impaired concentration, agitation,
amnesia, somnolence, abnormal dreams and hallucinations.
- These symptoms usually begin during the first days of therapy and
generally resolve after 2–4 weeks with up to 10% of patients with
persistent complaints discontinuing the drug.
- CNS toxicity has been reported more frequently in adult and pediatric
patients with high EFV trough plasma concentrations > 4 mcg/ml.
- Other CNS manifestations include depression, anxiety, and nervousness,
and occasional post-marketing reports of death by suicide or psychosis-like
behavior in patients taking EFV have been made

36
Rakhmanina et al, 2011
 CNS
Adverse
Event of
EFV

37
Apostolova et al, 2015
Efavirenz Induced Neurotoxicity

38
Dalwadi et al, 2018
Penatalaksanaan Adverse Event

Permenkes, 2014

39
Rilpivirine (RLP)
Side Effect Drug

40
Second generation of NNRTI

Rilpivirine was associated with fewer neurological and

psychiatric adverse effect than another NNRTI (Efavirens)

Rilpivirin in renal and liver impairment

41
Mills, A., Antinori, A., Clotet, B., Fourie, J., Herrera, G., Hicks, C., Madruga, J., Vanveggel, S., Stevens, M., Boven, K. 2013.
Neurological and Psychiatric Tolerability of Rilpivirine (TMC278) vs Efavirenz in Treatment-naïve, HIV-1 Infected
Patients at 48 weeks. 42
Sharma, 2012
43
 25 mg per oral qDay with meal
Rilpivirin in pregnancy

Rilpivirin in liver impairment

Rilpivirin in renal impairment

Sharma, 2012 44
LOPINAVIR/RITONAVIR
Side effect

45
ESO Lopinavir/Ritonavir
Grade ESO
>10% Dermatologic: Skin rash (children 12%; adults ≤5%)
Endocrine & metabolic : hypercholesterolemia (3% - 39%)
Gastrointestinal : diarrhea (7% - 28%), vomiting (children 21%; adults
2% - 7%), nausea (5% - 16%), abdominal pain (1% - 11%)

2-10% Endocrine & metabolic: hypertriglyceridemia (6%), hyperglycemia

(≤5%)

46
Mekanisme ESO Lopinavir/Ritonavir

47
(Flint, et al., 2009)
Efek Metabolik Protease Inhibitor

(Flint, et al., 2009)

48
 Lopinavir:
- Triglycerides & Cholesterol (sebelum terapi dimulai
dan selama terapi diberikan) , LFT’s, Basic HIV
monitoring, Viral load, CD4 count, Glucose.

Monitoring Parameter
Laboratorium

Ritonavir:
- Triglycerides, Cholesterol, Complete Blood Count,
LFT’s, CPK, Uric Acid, Basic HIV monitoring, Viral
load, CD4 count, Glucose, Serum amylase & lipase

(American Pharmacists Association, 2016) 49

 Manajemen ESO
Lopinavir/ritonavir

(Kementerian Kesehatan Republik Indonesia, 2014)

51
52
Manajemen Dislipidemia

53
Manajemen Dislipidemia

Rekomendasi NCEP terkait monitoring ESO Dislipidemia: Monitoring lipid

parameters (TC, HDL, LDL, TG) pada bulan ketiga saat memulai terapi dan
sebelum memulai terapi
54
Pankreatitis Akut

Balani & Grendell, 2008

Dragovic, 2013
Greffrath, et.al. 2018

55
Kaitan Pankreatitis dengan
Hipertrigliseridemia

56
Pretis & Frulloni, 2018
Kaitan Pankreatitis dengan Hipertrigliseridemia cont’d

Dixit, et.al., 2016 57

Manajemen Pankreatitis Akut

Jika gejala klinis dan laboratorium muncul pada pasien

dan pasien diduga kuat mengalami pankreatitis akut
maka,
1. Hentikan terapi segera
2. Hidrasi pasien (aggressive IV fluid replacement) 
terkait diare
3. Relief abdominal pain  analgesik

Balani & Grendell, 2008

58
 PUSTAKA
• American Pharmacists Association, 2016. Drug Information Handbook with International Trade
Names Index. 25 ed. United States: Wolters Kluwer.

• Balani, A.R., James, H.G. 2008. Drug-Induced Pancreatitis Incidence, Management and
Prevention. Drug Safety 2008; 31 (10). P 823-837

• Calza L., Manfredi, R., Farneti, B., Chiodo, F. 2003. Incidence of hyperlipidaemia in a cohort of
212 HIV-infected patients receiving a protease inhibitor-based antiretroviral therapy. International
Journal of Antimicrobial Agents 22 (2003) 54-59

• Estrada, V., Portilla, J. 2011. Dyslipidemia Related to Antiretroviral Therapy. AIDS Rev.2010;
Volume 12. P 49-56

• Flint, O. P. et al., 2009. The Role of Protease Inhibitors in the Pathogenesis of HIV-Associated
Lipodystrophy: Cellular Mechanisms and Clinical Implications. Toxicologic Pathology, Volume 37,
pp. 65-77 59
• Greffrath, W. P., Plessis, J.M., Viljoen, M., Cockeran, M. 2016. Hypertriglyceridaemia and the risk
of pancreatitis six months post lopinavir/ritonavir initiation. S Afr J HIV Med. 2018;19(1), a766.

• Kementerian Kesehatan Republik Indonesia, 2014. PERATURAN MENTERI KESEHATAN

REPUBLIK INDONESIA NOMOR 87 TAHUN 2014 TENTANG PEDOMAN PENGOBATAN
ANTIRETROVIRAL. Jakarta: s.n.

• LV, Z., Chu, Y. & Wang, Y., 2015. HIV protease inhibitors: a review of molecular selectivity and
toxicity. HIV/AIDS-Research and Palliative Care, Volume 7, pp. 95-104.

• Pretis, N.D., Amodio, Frulloni, A. 2018. Hypertriglyceridemic pancreatitis: Epidemiology,

pathophysiology and clinical management. United European Gastroenterology Journal 2018, Vol.
6(5) 649–655

• Oh, J., Hegele, R.A. 2007. HIV-associated dyslipidaemia: pathogenesis and treatment. Lancet
Infect Dis 2007; 7: 787–96

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