CURRICULUM VITAE. Name Dr. dr. Erwin Astha Triyono, SpPD, KPTI, FINASIM. Contact Address Taman Wisma Menanggal 17 Surabaya

CURRICULUM VITAE Name Dr. dr. Erwin Astha Triyono, SpPD, KPTI, FINASIM

Contact Address Taman Wisma Menanggal 17 Surabaya

Mobile Phone 08123259941 / Email erwintriyono@yahoo.com Education Dokter : FK Unair 1995 Spesialis Penyakit Dalam : FK Unair 2005 Konsultan Penyakit Tropik Infeksi : FK Unair 2011 Doktor : FK Unair 2016 Affiliated Associations Anggota IDI Cabang Surabaya Pengurus IDI Wilayah Jawa Timur Anggota PETRI Surabaya Wakil Ketua III PAPDI Surabaya Professional and Teaching Activities Dosen Divisi Penyakit Tropik Infeksi Departemen / SMF Ilmu Penyakit Dalam FK Unair – RSUD Dr. Soetomo Ketua Tim Medik AIDS FKUA - RSUD Dr. Soetomo Wakil Ketua Tim Penyusun DOEN dan Formularium Nasional Kementerian Kesehatan RI Kepala Bidang Pendidikan dan Pelatihan RSUD Dr. Soetomo Konsultan Medis RS Lapangan KOGABWILHAN II - COVID-19 Indrapura Provinsi Jawa Timur ₁

TERAPI RASIONAL PADA COVID-19

FOKUS: PENGGUNAAN TOCILIZUMAB DAN

MASALAH

•

Pandemi menjalar sangat cepat

•

Angka kematian sangat tinggi pada kasus berat (Komorbid?

COVID-19? Terapi lambat? Atau interaksi obat?)

•

Pilihan obat sudah banyak, tapi belum ada yang established

untuk berbukti ilmiah untuk Covid-19

•

Kebingungan di kalangan dokter

•

Tidak cukup waktu untuk mengembangkan obat/vaksin

baru

PENGGUNAAN OBAT YANG RASIONAL?

The rational use of drugs requires that patients receive

medications

appropriate to their clinical needs

, in

doses

that

meet their own individual requirements for an adequate

period

of time

, and at

the lowest cost

to them and their community.

CIRI PENGGUNAAN OBAT YANG RASIONAL

1. Efektif

2. Aman

3. Sesuai untuk pasien individual

4. Harga yang terjangkau

PILIHAN OBAT ANTI COVID-19

1. Klorokuin

2. Hidrosiklorokuin

3. Azitromisin

4. Favipiravir

5. Remdesivir

6. Lopinavir/ritonavir

7.

Oseltamivir

8.

Plasma konvalenses

9.

Interferon α-2b

10.

Levofloksasin

11.

Metisoprinol

12.

Anti Interleukin 6

13.

Immunoglobulin (IVIG)

7

BERBAGAI OBAT PENDAMPING LAINNYA

1. Asetilsistein

2. Bromheksin

3. Berbagai immune booster

dan imunomodulator

4. Analgetik/antipiretik

5. Berbagai sedativum

6. Loperamid

8.

Berbagai proton pump

inhibitors

9.

Berbagai vitamin dosis

tinggi

10.

Berbagai bronkodilator

11.

Berbagai antitusif

12.

Heparin

13.

Obat-obat herbal

BOLEHKAH KITA MENGGUNAKAN OBAT YANG BELUM

PUNYA BUKTI ILMIAH?

•

Pedoman dari Deklarasi Helsinki

– Penghormatan terhadap individu, hak menentukan nasib sendiri, dan hak untuk memberikan persetujuan setelah mendapatkan penjelasan tentang keterlibatannya dalam penelitian.

– keselamatan subjek harus selalu didahulukan di atas kepentingan sains dan masyarakat dan – pertimbangan etis harus selalu diutamakan di atas hukum dan peraturan.

•

Obat-obat yang belum mantap tapi menjadi favorit di Indonesia:

ü

Klorokuin

ü

Hidroksiklorokuin

ü

Azitromisin

ü

Favipiravir

ü

Lopinavir/ritonavir

ü

Tocilizumab (anti IL-6)

ü

Immunoglobulin (IVIG)

9

What are current evidence-based treatments

for individuals with COVID-19?

•

Supportive care

, including

supplemental oxygen

, is the

main treatment

for most patients.

•

_{Recent trials indicate that dexamethasone decreases mortality}

(subgroup analysis suggests benefit is limited to patients who require

supplemental oxygen and who have symptoms for >7 d) and

Treatment

•

Supportive Care and Respiratory Support

•

Targeting the Virus and the Host Response

11

JAMA | Review

Pathophysiology, Transmission, Diagnosis, and Treatment of

Coronavirus Disease 2019 (COVID-19)

A Review

W. Joost Wiersinga, MD, PhD; Andrew Rhodes, MD, PhD; Allen C. Cheng, MD, PhD; Sharon J. Peacock, PhD; Hallie C. Prescott, MD, MSc

Supportive Care and Respiratory Support

• Currently, best practices for supportive management of acute hypoxic respiratory failure and ARDS

should be followed.

• Evidence based guideline initiatives have been established by many countries and professional societies

• More than 75% of patients hospitalized with COVID-19 require supplemental oxygen therapy. • For patients who are unresponsive to conventional oxygen therapy, heated high-flow nasal canula

oxygen may be administered.

• For patients requiring invasive mechanical ventilation, lung-protective ventilation with low tidal volumes (4-8 mL/kg, predicted body weight) and plateau pressure less than 30 mg Hg is

recommended.

• Additionally, prone positioning, a higher positive end-expiratory pressure strategy, and short term neuromuscular blockade with cisatracurium or other muscle relaxants may facilitate oxygenation.

Targeting the Virus and the Host Response

•

The following classes of drugs are being evaluated or developed for the

management of COVID-19:

antivirals

(eg, remdesivir, favipiravir),

antibodies

(eg,

convalescent plasma, hyperimmune immuno- globulins),

anti-inflammatory agents

(dexamethasone, statins),

targeted immunomodulatory therapies

(eg, tocilizumab,

sarilumab, anakinra, ruxolitinib),

anticoagulants

(eg, heparin), and

antifibrotics

(eg,

tyrosine kinase inhibitors).

•

It is likely that

different treatment modalities

might have

different efficacies

at

different stages of illness

and in

different manifestations of disease

.

•

Viral inhibition

would be expected to be

most effective early in infection

, while, in

hospitalized patients, immunomodulatory agents

may be useful to

prevent disease

progression

and

anticoagulants

may be useful to prevent

thromboembolic

complications.

•

Alternative therapeutic strategies consist of

modulating the inflammatory response

in patients with COVID-19.

•

Monoclonal antibodies

directed against key inflammatory mediators, such as

interferon gamma, interleukin 1, interleukin 6, and complement factor 5a, all target

the overwhelming inflammatory response following SARS-CoV-2 infection with the

goal of preventing organ damage.

•

Of these, the

interleukin 6 inhibitors tocilizumab and sarilumab

are best studied,

with more than a dozen randomized clinical trials underway.

•

Tyrosine kinase inhibitors

, such as

imatinib

, are studied for their potential to

TOCILIZUMAB

(ANTI IL - 6)

Tocilizumab merupakan antibodi monoklonal penghambat IL-6 yang dapat secara spesifik berikatan dengan mIL-6R dan sIL-6R.

Zhang S, Li L, Shen A, Chen Y, Qi Z. Rational Use of Tocilizumab in the Treatment of Novel Coronavirus Pneumonia. Clin Drug Investig. 2020;40(6):511-518.

TOSILIZUMAB

•

Injeksi 162 mg/0,9 ml (sc) dan Infus 20 mg/ml (iv)

•

Terdaftar sebagai indikasi utama di Indonesia

– Rheumatoid Arthritis (RA) (injeksi iv dan subkutan) – Polyarticular Juvenile Idiopathic Arthritis (pJIA) (Injeksi iv) – Systemic Juvenile Idiopathic Arthritis (sJIA) (Injeksi iv)

•

Sebagai obat Uji untuk COVID-19

– Kecurigaan hiperinflamasi untuk pasien COVID-19 (iv atau sc)

INTRAVENOUS IMMUNOGLOBULIN (IVIG)

• Produk Derivatif plasma pendonor yang dapat memberikan proteksi imun secara

pasif terhadap berbagai macam patogen

•

Terdaftar sebagai indikasi utama di Indonesia

– Imunodefisiensi humoral primer – Purpura Trombositopenik Idiopatik (ITP) – Pasien anak dengan gejala Kawasaki

•

Sebagai obat Uji untuk COVID-19

– Pasien COVID-19 kondisi berat dan kritis – Dosis 0,3 – 0,4 g/KgBB perhari selama 5 hari

• RCT di China • Masih berlangsung • Intervensi : IVIG 0,5 g/kg/hari selama 5 hari • Hasil ? Kriteria Eksklusi • Alergi IVIG • IgA defisiensi

• Hamil atau menyusui

Antivirals, immunomodulators and other

adjunctive therapies for COVID-19

We recommend that

the following drugs not be administered as treatment or

prophylaxis for COVID-19

, outside of the context of clinical trials:

•

Chloroquine and hydroxychloroquine (+/- azithromycin)

•Antivirals, including but not limited to:

– Lopinavir/ritonavir – Remdesivir – Umifenovir – Favipiravir

•

Immunomodulators, including but not limited to:

– Tocilizumab – Interferon-β-1a

•

Plasma therapy

25

Remark 1:

Existing published literature on these agents is mostly observational in nature, with few clinical trials; and does not provide high-quality evidence in favour of any of these agents. In addition, important

side-effects have been described. •Chloroquine and hydroxychloroquine +/- azithromycin: each can cause QT prolongation and taken together can increase the risk of cardiotoxicity. •Lopinavir/ritonavir: the most common adverse effects are gastrointestinal. •Remdesivir: elevation of hepatic enzymes, GI complications, rash, renal impairment and hypotension. •Umifenovir: diarrhoea, nausea. •Favipiravir: QT interval prolongation. •Interferon-β-1a: pyrexia, rhabdomyolysis. •Tocilizumab: URT infections, nasopharyngitis, headache, hypertension, increased alanine

Remark 2:

•

This recommendation is consistent with other international

grade-based guidelines

Blood-Derived Products Under Evaluation

for the Treatment of COVID-19

• Panel para ahli tidak memiliki data yang cukup dalam merekomendasikan atau menentang penggunaan blood-derived products berikut dalam pengobatan COVID-19:

– COVID-19 convalescent plasma

– Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulins

• Panel para ahli tidak merekomendasikan penggunaan blood-derived products berikut untuk

pengobatan COVID-19, kecuali dalam uji klinis:

– Mesenchymal stem cells (AII)

– Non-SARS-CoV-2-specific intravenous immunoglobulins (IVIG) (AIII).

• Rekomendasi ini tidak menghalangi penggunaan IVIG jika sebaiknya diindikasikan untuk pengobatan pada komplikasi yang terjadi selama perjalanan penyakit COVID-19.

Immunomodulators Under Evaluation for the

Treatment of COVID-19

• Dexamethasone dan Kortikosteroid lainnya

– Rekomendasi penggunaan dexamethasone (atau kortikosteroid yang lain) dengan atau tanpa remdesivir berdasarkan keparahan penyakit

• Immunomodulator lainnya: Panel tidak memiliki cukup data untuk merekomendasikan atau menentang penggunaan immunomodulator berikut untuk pengobatan COVID-19:

– Interleukin (IL)-1 inhibitors (e.g., anakinra).

– Interferon beta for the treatment of early (i.e., <7 days from symptom onset) mild and moderate COVID-19.

• Panel tidak merekomendasikan penggunaan immunomodulator berikut untuk pengobatan COVID-19, kecuali dalam uji klinis:

– Anti-IL-6 receptor monoclonal antibodies (e.g., sarilumab, tocilizumab) or anti-IL-6 monoclonal

antibody (siltuximab) (BI).

– Interferons (alfa or beta) for the treatment of severely or critically ill patients with COVID-19 (AIII).

Ringkasan Obat yang Saat Ini Tersedia yang Berpotensi Digunakan untuk Pengobatan COVID-19: Opsi Berikut Tidak Berlisensi untuk Digunakan dalam Perawatan COVID-19

Terapi COVID-19 Berdasarkan

PPK RSUD Dr. Soetomo

• Kasus ringan / mild / poliklinis: oseltamivir (IIB)

• Kasus moderate / severe / critical diberikan pilihan obat sebagai

berikut (sesuai kondisi klinis dan ketersediaan obat):

a. Lopinavir/Ritonavir (IIB)

b. Oseltamivir (IIB)

c. Favipiravir (kondisional) (IIB)

d. Remsdesivir (kondisional) (IIB)

e. Interferon β-1α (kondisional) (IIC)

• Pemberian tocilizumab dipertimbangkan apabila ada tandatanda perburukan klinis terkait hiperinflamasi seperti dyspnea, takipnea, demam, penurunan saturasi oksigen (SpO2 atau PaO2), peningkatan kebutuhan suplemen oksigen, dan penambahan infiltrat > 50% dari total paru pada foto polos dada, disertai dengan

peningkatan kadar IL-6 secara bermakna (> 80 pg/dL) dan/atau 2 dari 3 tanda-tanda berikut yaitu:

– CRP tinggi (5 kali nilai baseline) atau > 100 ng/ml – Ferritin tinggi (> 1000 ng/ml)

– D-dimer > 1000 ng/ml

• Kontra indikasi pemberian tocilizumab meliputi:

– Ada dugaan atau terkonfirmasi infeksi bakterial/ fungal

– Trombosit <100.000/mm3 – Neutrofil <2000/mm3

– SGOT/ SGPT lebih dari 5 kali batas nilai maksimal (40 U/L untuk SGOT dan 50 U/L untuk SGPT)

– HBSAg reaktif

Tocilizumab: Grade Rekomendasi IIC

Stem Cell dan Intravenous Immunoglobulin (IVIG): Grade

Rekomendasi IIC

• Pengobatan stem cell dan IVIG sampai saat ini

masih merupakan pengobatan yang

membutuhkan studi lebih lanjut. Penggunaan

dapat dipertimbangkan berdasarkan

pengalaman klinis dengan persetujuan dari

Komite Medik dan Komite Etik Rumah Sakit.

POLIFARMASI DAN RISIKONYA

PENYEBAB TERJADINYA KECENDERUNGAN

POLIFARMASI PADA TERAPI COVID-19

1. Hingga sekarang tidak diketahui obat anti Covid-19 yang efektif dan aman à

berikan saja banyak obat, mungkin “ada yang kena”

2. Tidak diketahui penyebab kematian

pada kasus berat infeksi Covid-19 (Badai

sitokin? Disseminated intra vascular coagulation? Penyakit komorbid? Usia lanjut?

Daya tahan lemah? Kurang vitamin? Interaksi obat?)

3. Banyaknya keluhan pasien

: sesak, demam, diare, sakit kepala, sulit tidur, tidak

nafsu makan, mual/muntah, gelisah, palpitasi, dll à memicu

pengobatan “per

gejala”

APA BAHAYA PENGOBATAN BERLEBIHAN?

1. Frekuensi dan intensitas efek samping meningkat

2. Kemungkinan interaksi obat meningkat

3. Fenomena prescribing cascade

4. Beban tambahan bagi organ ekskresi

5. Biaya meningkat

6. Kepatuhan (compliance) pasien bisa menurun

45

“LESSON LEARNED”

TATALAKSANA ANTI COVID-19 YANG RASIONAL

1. Pilih salah satu

(AGRESIF” ?)

yang dipertimbangakan paling aman,

efektif, tersedia, dan terjangkau atau

(“WAIT AND SEE”? - MONITORING)

2. Perhatikan

posologinya

dengan teliti

3. Hindarkan

polifarmasi

sedapat mungkin

4. Hindari

pengobatan “per gejala”

Which patients are most at risk of medication error?

•

patients on multiple medications

•

patients with another condition, e.g. renal impairment,

pregnancy

•

patients who cannot communicate well

•

patients who have more than one doctor

•

patients who do not take an active role in their own

medication use

•

children and babies (dose calculations required)

47

7. Betapapun bagusnya teori mekanisme kerja, data in vitro, data

pada hewan coba dll dari suatu obat, sebelum itu terbukti dengan

EBM, maka bukti itu belum memadai

8. Hindari

penggunaan berbagai obat yang belum terbukti

manfaatnya:

vitamin-vitamin dosis tinggi, pendongkrak sistem

imun, kortikosteroid, mukolitik, obat herbal

, dll

Prevention of complications in hospitalized and

critically ill patients with COVID-19 (WHO)

Adverse effects of medications

•

Careful consideration should be given to the numerous, clinically

significant

side-effects

of medications that may be used in the context

of COVID-19, as well as

drug-drug interactions

between medications,

both of which may

affect COVID-19 symptomatology

(including effects

on

respiratory, cardiac, immune and mental and neurological

function

).

•

Both

pharmacokinetic and pharmacodynamic

effects should be

considered.

Conclusions

•

Many aspects of

transmission, infection, and treatment remain

unclear.

•

_{Advances in}

_prevention

_{and effective}

_{management of COVID-19}

_will

require basic and clinical investigation and public health and clinical

interventions.

•

In therapy for

severe infections

there is always a

tendency to use

excessive drugs

•

_{The principle of the use of}

_{rational medicine}

_{must be applied in the}

conduct of Covid-19