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A OBAT ANTI TUBERKULOSIS (OAT) . Obat yang dipakai: 1. Jenis obat utama (lini 1) yang digunakan adalah: 2.

2. INH Rifampisin Pirazinamid Streptomisin Etambutol Kanamisin Amikasin Kuinolon

Jenis obat tambahan lainnya (lini 2)

Obat lain masih dalam penelitian yaitu makrolid dan amoksilin + asam klavulanat Beberapa obat berikut ini belum tersedia di Indonesia antara lain :
o o o o o Kemasan - Obat tunggal, Obat disajikan secara terpisah, masing-masing INH, rifampisin, pirazinamid dan etambutol. - Obat kombinasi dosis tetap (Fixed Dose Combination FDC) Kombinasi dosis tetap ini terdiri dari 3 atau 4 obat dalam satu tablet Dosis OAT Tabel 2. Jenis dan dosis OAT O b at Dosi s (Mg/ Kg BB/H ari) 8-12 4-6 2030 1520 1518 Dosis yg dianjurkan Harian (mg/ kgBB / hari) Intermitten (mg/Kg /BB/kali) DosisM aks (mg) Dosis (mg) / berat badan (kg) < 40 40>60 60 Kapreomisin Sikloserino PAS (dulu tersedia) Derivat rifampisin dan INH Thioamides (ethionamide dan prothionamide)

R H Z E S

10 5 25 15 15

10 10 35 30 15

600 300

300 150 750 750

450 300 100 0 100 0 750

600 450 1500 1500 1000

1000

Sesuai BB

Pengembangan pengobatan TB paru yang efektif merupakan hal yang penting untuk menyembuhkan pasien dan menghindari MDR TB (multidrug resistant tuberculosis). Pengembangan strategi DOTS untuk mengontrol epidemi TB merupakan prioriti utama WHO. International Union Against Tuberculosis and Lung Disease (IUALTD) dan WHO menyarakan untuk menggantikan paduan obat tunggal dengan kombinasi dosis tetap dalam pengobatan TB primer pada tahun 1998. Dosis obat tuberkulosis kombinasi dosis tetap berdasarkan WHO seperti terlihat pada tabel 3. Keuntungan kombinasi dosis tetap antara lain: 1. Penatalaksanaan sederhana dengan kesalahan pembuatan resep minimal 2. Peningkatan kepatuhan dan penerimaan pasien dengan penurunan kesalahan pengobatan yang tidak disengaja 3. Peningkatan kepatuhan tenaga kesehatan terhadap penatalaksanaan yang benar dan standar

4. Perbaikan manajemen obat karena jenis obat lebih sedikit 5. Menurunkan risiko penyalahgunaan obat tunggal dan MDR akibat penurunan penggunaan monoterapi Tabel 3. Dosis obat antituberkulosis kombinasi dosis tetap Fase intensif Fase lanjutan 2 bulan 4 bulan BB Harian Harian 3x/minggu Harian 3x/minggu RHZE RHZ RHZ RH RH 150/75/400/ 150/75/400 150/150/500 150/75 150/150 275 30-37 2 2 2 2 2 38-54 3 3 3 3 3 55-70 4 4 4 4 4 >71 5 5 5 5 5 Penentuan dosis terapi kombinasi dosis tetap 4 obat berdasarkan rentang dosis yang telah ditentukan oleh WHO merupakan dosis yang efektif atau masih termasuk dalam batas dosis terapi dan non toksik. Pada kasus yang mendapat obat kombinasi dosis tetap tersebut, bila mengalami efek samping serius harus dirujuk ke rumah sakit / dokter spesialis paru / fasiliti yang mampu menanganinya. B PADUAN OBAT ANTI TUBERKULOSIS . Pengobatan tuberkulosis dibagi menjadi: TB paru (kasus baru), BTA positif atau pada foto toraks: lesi luas Paduan obat yang dianjurkan : 2 RHZE / 4 RH atau : 2 RHZE/ 6HE atau 2 RHZE / 4R3H3 Paduan ini dianjurkan untuk a. TB paru BTA (+), kasus baru b. TB paru BTA (-), dengan gambaran radiologi lesi luas (termasuk luluh paru) Bila ada fasiliti biakan dan uji resistensi, pengobatan disesuaikan dengan hasil uji resistensi TB Paru (kasus baru), BTA negatif, pada foto toraks: lesi minimal Paduan obat yang dianjurkan : 2 RHZE / 4 RH atau : 6 RHE atau 2 RHZE/ 4R3H3 TB paru kasus kambuh Sebelum ada hasil uji resistensi dapat diberikan 2 RHZES / 1 RHZE. Fase lanjutan sesuai dengan hasil uji resistensi. Bila tidak terdapat hasil uji resistensi dapat diberikan obat RHE selama 5 bulan. TB Paru kasus gagal pengobatan Sebelum ada hasil uji resistensi seharusnya diberikan obat lini 2 (contoh paduan: 3-6 bulan kanamisin, ofloksasin, etionamid, sikloserin dilanjutkan 15-18 bulan ofloksasin, etionamid, sikloserin). Dalam keadaan tidak memungkinkan pada fase awal dapat diberikan 2 RHZES / 1 RHZE. Fase lanjutan sesuai dengan hasil uji resistensi. Bila tidak terdapat hasil uji resistensi dapat diberikan obat RHE selama 5 bulan. Dapat pula dipertimbangkan tindakan bedah untuk mendapatkan hasil yang optimal Sebaiknya kasus gagal pengobatan dirujuk ke dokter spesialis paru TB Paru kasus putus berobat Pasien TB paru kasus lalai berobat, akan dimulai pengobatan kembali sesuai dengan kriteria sebagai berikut : a. Berobat > 4 bulan 1) BTA saat ini negatif Klinis dan radiologi tidak aktif atau ada perbaikan maka pengobatan OAT dihentikan. Bila gambaran radiologi aktif, lakukan analisis lebih lanjut untuk memastikan diagnosis TB dengan mempertimbangkan juga kemungkinan penyakit paru lain. Bila terbukti TB maka pengobatan dimulai dari awal dengan paduan obat yang lebih kuat dan jangka waktu pengobatan yang lebih lama.

2) BTA saat ini positif Pengobatan dimulai dari awal dengan paduan obat yang lebih kuat dan jangka waktu pengobatan yang lebih lama b. Berobat < 4 bulan 1) Bila BTA positif, pengobatan dimulai dari awal dengan paduan obat yang lebih kuat dan jangka waktu pengobatan yang lebih lama 2) Bila BTA negatif, gambaran foto toraks positif TB aktif pengobatan diteruskan Jika memungkinkan seharusnya diperiksa uji resistensi terhadap OAT. TB Paru kasus kronik - Pengobatan TB paru kasus kronik, jika belum ada hasil uji resistensi, berikan RHZES. Jika telah ada hasil uji resistensi, sesuaikan dengan hasil uji resistensi (minimal terdapat 4 macam OAT yang masih sensitif) ditambah dengan obat lini 2 seperti kuinolon, betalaktam, makrolid dll. Pengobatan minimal 18 bulan. - Jika tidak mampu dapat diberikan INH seumur hidup - Pertimbangkan pembedahan untuk meningkatkan kemungkinan penyembuhan - Kasus TB paru kronik perlu dirujuk ke dokter spesialis paru Tabel 4. Ringkasan paduan obat Kate gori I Kasus - TB paru BTA +, BTA - , lesi luas Paduan obat yang diajurkan 2 RHZE / 4 RH atau 2 RHZE / 6 HE *2RHZE / 4R3H3 Keterangan

II

- Kambuh Gagal pengobatan

II

III

IV

IV

-RHZES / 1RHZE / sesuai hasil uji Bila resistensi atau 2RHZES / 1RHZE / 5 streptomisin RHE alergi, dapat -3-6 kanamisin, ofloksasin, etionamid, diganti sikloserin / 15-18 ofloksasin, etionamid, kanamisin sikloserin atau 2RHZES / 1RHZE / 5RHE - TB paru putus Sesuai lama pengobatan sebelumnya, berobat lama berhenti minum obat dan keadaan klinis, bakteriologi dan radiologi saat ini (lihat uraiannya) atau *2RHZES / 1RHZE / 5R3H3E3 -TB paru BTA neg. 2 RHZE / 4 RH atau lesi minimal 6 RHE atau *2RHZE /4 R3H3 - Kronik RHZES / sesuai hasil uji resistensi (minimal OAT yang sensitif) + obat lini 2 (pengobatan minimal 18 bulan) - MDR TB Sesuai uji resistensi + OAT lini 2 atau H seumur hidup Catatan : * Obat yang disediakan oleh Program Nasional TB

C EFEK SAMPING OAT . Sebagian besar pasien TB dapat menyelesaikan pengobatan tanpa efek samping. Namun sebagian kecil dapat mengalami efek samping, oleh karena itu pemantauan kemungkinan terjadinya efek samping sangat penting dilakukan selama pengobatan. Efek samping yang terjadi dapat ringan atau berat (terlihat pada tabel 4), bila efek samping ringan dan dapat diatasi dengan obat simptomatis maka pemberian OAT dapat dilanjutkan. 1. Isoniazid (INH) Sebagian besar pasien TB dapat menyelesaikan pengobatan tanpa efek samping. Namun sebagian

kecil dapat mengalami efek samping, oleh karena itu pemantauan kemungkinan terjadinya efek samping sangat penting dilakukan selama pengobatan. Efek samping yang terjadi dapat ringan atau berat (terlihat pada tabel 4), bila efek samping ringan dan dapat diatasi dengan obat simptomatis maka pemberian OAT dapat dilanjutkan. 2. Rifampisin Efek samping ringan yang dapat terjadi dan hanya memerlukan pengobatan simptomatis ialah : - Sindrom flu berupa demam, menggigil dan nyeri tulang - Sindrom perut berupa sakit perut, mual, tidak nafsu makan, muntah kadang-kadang diare - Sindrom kulit seperti gatal-gatal kemerahan Efek samping yang berat tetapi jarang terjadi ialah : - Hepatitis imbas obat atau ikterik, bila terjadi hal tersebut OAT harus distop dulu dan penatalaksanaan sesuai pedoman TB pada keadaan khusus - Purpura, anemia hemolitik yang akut, syok dan gagal ginjal. Bila salah satu dari gejala ini terjadi, rifampisin harus segera dihentikan dan jangan diberikan lagi walaupun gejalanya telah menghilang - Sindrom respirasi yang ditandai dengan sesak napas Rifampisin dapat menyebabkan warna merah pada air seni, keringat, air mata dan air liur. Warna merah tersebut terjadi karena proses metabolisme obat dan tidak berbahaya. Hal ini harus diberitahukan kepada pasien agar mereka mengerti dan tidak perlu khawatir. 3. Pirazinamid Efek samping utama ialah hepatitis imbas obat (penatalaksanaan sesuai pedoman TB pada keadaan khusus). Nyeri sendi juga dapat terjadi (beri aspirin) dan kadang-kadang dapat menyebabkan serangan arthritis Gout, hal ini kemungkinan disebabkan berkurangnya ekskresi dan penimbunan asam urat. Kadang-kadang terjadi reaksi demam, mual, kemerahan dan reaksi kulit yang lain. 4. Etambutol Etambutol dapat menyebabkan gangguan penglihatan berupa berkurangnya ketajaman, buta warna untuk warna merah dan hijau. Meskipun demikian keracunan okuler tersebut tergantung pada dosis yang dipakai, jarang sekali terjadi bila dosisnya 15-25 mg/kg BB perhari atau 30 mg/kg BB yang diberikan 3 kali seminggu. Gangguan penglihatan akan kembali normal dalam beberapa minggu setelah obat dihentikan. Sebaiknya etambutol tidak diberikan pada anak karena risiko kerusakan okuler sulit untuk dideteksi 5. Streptomisin Efek samping utama adalah kerusakan syaraf kedelapan yang berkaitan dengan keseimbangan dan pendengaran. Risiko efek samping tersebut akan meningkat seiring dengan peningkatan dosis yang digunakan dan umur pasien. Risiko tersebut akan meningkat pada pasien dengan gangguan fungsi ekskresi ginjal. Gejala efek samping yang terlihat ialah telinga mendenging (tinitus), pusing dan kehilangan keseimbangan. Keadaan ini dapat dipulihkan bila obat segera dihentikan atau dosisnya dikurangi 0,25gr. Jika pengobatan diteruskan maka kerusakan alat keseimbangan makin parah dan menetap (kehilangan keseimbangan dan tuli). Reaksi hipersensitiviti kadang terjadi berupa demam yang timbul tiba-tiba disertai sakit kepala, muntah dan eritema pada kulit. Efek samping sementara dan ringan (jarang terjadi) seperti kesemutan sekitar mulut dan telinga yang mendenging dapat terjadi segera setelah suntikan. Bila reaksi ini mengganggu maka dosis dapat dikurangi 0,25gr Streptomisin dapat menembus sawar plasenta sehingga tidak boleh diberikan pada perempuan hamil sebab dapat merusak syaraf pendengaran janin. Tabel 5. Efek samping OAT dan Penatalaksanaannya Efek samping Minor Tidak nafsu makan, mual, sakit perut Nyeri sendi Kesemutan s/d rasa terbakar di kaki Warna kemerahan pada air seni Rifampisin Pyrazinamid INH Rifampisin Kemungkinan Penyebab Tatalaksana OAT diteruskan Obat diminum malam sebelum tidur Beri aspirin /allopurinol Beri vitamin B6 (piridoksin) 1 x 100 mg perhari Beri penjelasan, tidak perlu diberi

Mayor Gatal dan kemerahan pada kulit Tuli Gangguan keseimbangan (vertigo dan nistagmus) Ikterik / Hepatitis Imbas Obat (penyebab lain disingkirkan) Muntah dan confusion (suspected drug-induced pre-icteric hepatitis) Gangguan penglihatan Kelainan sistemik, termasuk syok dan purpura Semua jenis OAT Streptomisin Streptomisin Sebagian besar OAT

apa-apa Hentikan obat Beri antihistamin dan dievaluasi ketat Streptomisin dihentikan Streptomisin dihentikan Hentikan semua OAT sampai ikterik menghilang dan boleh diberikan hepatoprotektor Hentikan semua OAT dan lakukan uji fungsi hati Hentikan etambutol Hentikan rifampisin

Sebagian besar OAT

Etambutol Rifampisin

Penggunaan Obat Anti Tuberkulosis (OAT) merupakan hal penting pada terapi tuberkulosis, paling sedikit dua obat, umumnya tiga atau lebih obat dimana mikroorganisme penginfeksi tersebut sensitif harus diberikan secara terus menerus paling tidak selama enam bulan dan ditingkatkan 2 -3 tahun untuk beberapa kasus resisten multi obat. Program Nasional Penanggulangan Tuberkulosis di Indonesia, menetapkan panduan penggunaan obat anti tuberkulosis, yaitu Kategori 1 : 2(HRZE)/4(HR)3 dan Kategori : 2(HRZE)S/(HRZE)/5(HR)3E3. Disamping kedua kategori tersebut, disediakan juga paduan obat Sisipan (HRZE) dan Kategori Anak : 2RHZ/4RH. Kombinasi kemoterapi dimaksudkan untuk mencegah atau memperlambat timbulnya resitensi organisme, dan ini sangatlah penting pada terapi infeksi tuberkulosis. Paling sedikit dua macam obat yang sensitif terhadap M. tuberculosis harus diberikan. Obat Antituberkulosis Obat anti tuberkulosis adalah antibiotik dan anti infeksi sintetik yang digunakan untuk pengobatan tuberkulosis dan penyakit lain yang disebabkan oleh organisme genus Mycobacterium. Isoniazid, Rifampisin, Pirazinamid, Ethambutol, dan Streptomisin adalah obat yang paling sering digunakan untuk pengobatan tuberkulosis dan disebut sebagai obat anti tuberkulosis lini pertama. Rifapentin, Rifabutin, seperti juga Rifampisin, adalah derivat Rifamisin : obat tersebut digunakan sebagai alternatif dari Rifampisin. Obat antituberkulosis lainnya adalah Asam aminosalisilik, Kapreomisin, Etionamid, Sikloserin, dan Kanamisin. Umumnya obat tersebut lebih toksik dan kurang efektif daripada obat lini pertama dan hanya digunakan apabila obat lini pertama dikontraindikasikan atau telah resisten. Streptomisin, Kanamisin, dan Kapreomisin mempunyai efek toksik yang mirip, oleh karena itu tidak boleh ada lebih dari satu obat tersebut dalam rejimen antituberkulosis. Isoniazid 300 mg per oral sehari adalah bakterisidal untuk Mycobacterium tuberkulosis, M. kansasii, dan M. bovis.Isoniazid diabsorpsi sangat baik secara oral dan didistribusikan ke seluruh tubuh , termasuk ke dalam cairan otak (CSF). Efek samping Hepatotoksik. Peningkatan serum transaminase terjadi pada lebih dari 20% pasien setelah beberapa bulan pertama pemberian Isoniazid, tetapi biasanya membaik meski pengobatan dilanjutkan. Hepatitis merupakan toksisitas yang dapat terjadi pada pemakaian Isoniazid, kejadian Isoniazid-induced hepatitis meningkat dengan meningkatnya usia, 0,3 % pada pasien usia 24-30 tahun sampai 2,3 % untk pasien 50 tahun keatas. Konsumsi minuman beralkohol, dan penyakit hati alkoholik meningkatkan risiko Isoniazid-induced hepatitis. Isoniazid-induced hepatitis biasanya reversible, membaik setelah penggunaan obat dihentikan. Peripheral neuropathy sering terjadi pada pasien dengan Isoniazid, hal ini mungkin disebabkan karena meningkatnya ekskresi piridoxin. Pasien dengan gizi buruk, dan pasien berisiko neuropathy karena diabetes, uremia, atau alcoholism sebaiknya mendapatkan piridoxine 50 mg peroral sehari. Pasien yang mendapatkan Isonazid

dosis tinggi, wanita hamil, dan pasien dengan penyakit kejang juga mendapatkan piridoxin.

harus

Rifampisin 10 mg/kg/hari maksimum 600 mg peroral sekali sehari, merupakan bakterisidal untuk gram-positif cocci, beberapa gram negatif bacilli dan hampir semua species Mycobacterium. Absorpsi dan distribusi, termasuk penetrasi kedalam SSP, sangat baik. Pasien perlu diberitahu terjadinya pewarnaan oranye kemerahan pada sekresi air mata, urin dan keringat karena penggunaan rifampisin, tetapi ini tidak membahayakan. Toksisitas seperti kulit kemerahan, efek samping terhadap SSP, gangguan pencernaan, dan hepatitis dapat diperberat dengan adanya penyakit hati. Rifampisin dimetabolisme oleh hati , menginduksi enzim miksosomal hati dan mempengaruhi metabolism banyak obat lainnya. Interaksi Rifampisin dengan banyak obat lain ini perlu diwaspadaai karena dapat membahayakan pasien. Rifampisin berinteraksi dengan obat antiretroviral golongan protease Inhibitor : saquinavir, idinavir, ritonavir dan nelfinavir ; serta golongan nonnucleosid reverse transcriptase Inhibitors = NNRTIs : nevirapine, delavirdine, dan efavirenz, interaksi tersebut dapat mempengaruhi konsentrasi obat dalam plasma. Oleh karena interaksi tersebut dapat membahayakan pasien maka penggunaan bersama harus dihindari. Adanya makanan dapat menurunkan absorpsi Rifampisin, konsentrasi Rifampisin dapat turun jika digunakan bersama makanan. Oleh karena itu Rifampisin dianjurkan untuk diminum saat lambung kosong yaitu satu jam sebelum makan atau dua jam sesudah makan, untuk meningkatkan absorpsi total obat. Pirazinamid 15-30 mg/kg/hari per oral ; maksimum 2 g/hari merupakan bakterisidal untuk micobakteri intraselular. Pirazinamid diabsorpsi dengan baik dari saluran pencernaan dan didistribusikan ke jaringan dan cairan tubuh termasuk CSF. Obat diekskresikan melalui ginjal. Efek samping utama adalah hepatotoksik. Ethambutol dosis lazim 15 mg/kg sehari, dosis awal 25 mg/kg/hari dapat digunakan pada infeksi yang lebih berat. Obat diekskresikan terutama melalui ginjal, dan dosis sebaiknya dikurangi pada pasien dengan kerusakan ginjal. Toksisitas yang signifikan adalah optic neuritis, yang dapat terjadi pada kurang dari 1% pasien yang menggunakan ethambutol 15 mg/kg/hari dan lebih banyak lagi terjadi pada dosis yang lebih tinggi. Penurunan ketajaman penglihatan, persepsi warna hijau, atau gangguan visual dapat terjadi kemudian. Pemeriksaan mata secara rutin sebaiknya dilakukan, komplikasi ophtahalmologic tersebut dapat hilang seiring dengan penghentian obat. Streptomisin Dosis 15 mg/kg/hari IM, maksimum 1 g merupakan aminoglikosida tuberkulosidal. Dosis 25-30 mg/kg IM dua kali seminggu atau tiga kali seminggu, maksimum 1,5 g juga dapat diberikan dengan pengawasan (DOTS). Dosis perlu disesuaikan pada pasien dengan kerusakan fungsi ginjal. Risiko Ototoksisitas menyebabkan pasien perlu mendapatkan pemeriksaan pada pendengarannya. Evaluasi dan monitoring perlu dilakukan untuk mengetahui respon pasien terhadap pengobatan. Keberhasilan terapi ataupun kegagalan terapi dapat diketahui dengan

mengevaluai hasil terapi yang diinginkan dan monitoring efek toksik yang perlu diwaspadai. Daftar Pustaka American Society of Health-System Pharmacists : American Hospital Formulary Service Drug Information, 2004 Departemen Kesehatan Republik Indonesia, Pedoman Nasional Penanggulangan Tuberkulosis, Edisi 2, 2007 Dipiro Joseph T, et.al : Pharmacotherapy Handbook 5th Edition, McGraw-Hill, 2003 Ewald Gregory A., McKenzie Clark R : The Washington Manual, Manual of Medical Therapeutics 28thEdition, Little Brown, USA, 1995. Semla Todd P, Beizer Judith L, Higbee Martin D : Geriatric Dosage Handbook 14th Edition, Lexi-Comp, Ohio, 2009 Taketomo Carol H, Hodding Jane H, Kraus Dona M : Pediatric Dosage Handbook 13th Edition, Lexi Comp, Ohio, 2006 Therapeutic Guideline : Antibiotic 10th Edition, Therapeutic Guideline Limited, North Melbourne Australia, 1998

ISONIAZID SIDE EFFECTS The most frequent reactions are those affecting the nervous system and theliver. Nervous System Reactions: Peripheral neuropathy is the most common toxic effect. It is dose-related, occurs most often in the malnourished and in those predisposed to neuritis (e.g., alcoholics and diabetics), and is usually preceded by paresthesias of the feet and hands. The incidence is higher in "slow inactivators". Other neurotoxic effects, which are uncommon with conventional doses, are convulsions, toxic encephalopathy, optic neuritis and atrophy, memoryimpairment, and toxic psychosis. Hepatic Reactions: Elevated serum transaminase (SGOT; SGPT), bilirubinemia, bilirubinuria, jaundice, and occasionally severe and sometimes fatal hepatitis. The common prodromal symptoms of hepatitis are anorexia, nausea, vomiting, fatigue, malaise, and weakness. Mild hepatic dysfunction, evidenced by mild and transient elevation of serum transaminase levels occurs in 10 to 20 percent of patients taking isoniazid. This abnormality usually appears in the first 1 to 3 months of treatment but can occur at any time during therapy. In most instances, enzyme levels return to normal, and generally, there is no necessity to discontinue medication during the period of mild serum transaminase elevation. In occasional instances, progressive liver damage occurs, with accompanying symptoms. If the SGOT value exceeds three to five times the upper limit of normal, discontinuation of the isoniazid should be strongly considered. The frequency of progressive liver damage increases with age. It is rare in persons under 20, but occurs in up to 2.3 percent of those over 50 years of age. Gastrointestinal Reactions: Nausea, vomiting, and epigastric distress. Hematologic Reactions: Agranulocytosis; hemolytic, sideroblastic, oraplastic anemia, thrombocytopenia; and eosinophilia. Hypersensitivity Reactions: Fever, skin eruptions (morbilliform, maculopapular, purpuric, or exfoliative), lymphadenopathy, and vasculitis. Metabolic And Endocrine Reactions: Pyridoxine deficiency, pellagra,hyperglycemia, metabolic acidosis, and gynecomastia. Miscellaneous Reactions: Rheumatic syndrome and systemic lupuserythematosus-like syndrome. Read the Isoniazid Tablets (isoniazid) Side Effects Center for a complete guide to possible side effects DRUG INTERACTIONS Food: Isoniazid should not be administered with food. Studies have shown that the bioavailability of isoniazid is reduced significantly when administered with food. Tyramineand histamine-containing foods should be avoided in patients receiving isoniazid. Because isoniazid has some monoamine oxidase inhibiting activity, an interaction with tyraminecontaining foods (cheese, red wine) may occur. Diamine oxidase may also be inhibited, causing exaggerated response (e.g., headache, sweating, palpitations, flushing,hypotension) to foods containing histamine (e.g., skipjack, tuna, other tropical fish). Acetaminophen: a report of severe acetaminophen toxicity was reported in a patient receiving Isoniazid It is believed that the toxicity may have resulted from a previously unrecognized interaction between isoniazid and acetaminophen and a molecular basis for this interaction has been proposed. However current evidence suggests that isoniazid does induce P-450IIE1, a mixed-function oxidase enzyme that appears to generate the toxic metabolites, in the liver.

Furthermore it has been proposed that isoniazid resulted in induction of P-450IIE1 in the patients liver which, in turn, resulted in a greater proportion of the ingested acetaminophen being converted to the toxic metabolites. Studies have demonstrated that pretreatment with isoniazid potentiates acetaminophen hepatotoxicity in rats1,2. Carbamazepine: Isoniazid is known to slow the metabolism of carbamazepine and increase its serum levels. Carbamazepine levels should be determined prior to concurrent administration with isoniazid signs and symptoms of carbamazepine toxicity should be monitored closely, and appropriate dosage adjustment of the anticonvulsant should be made3. Ketoconazole: Potential interaction of Ketoconazole and Isoniazid may exist. When Ketoconazole is given in combination with isoniazid and rifampin the AUC of ketoconazole is decreased by as much as 88% after 5 months of concurrent Isoniazid and Rifampin therapy4. Phenytoin: Isoniazid may increase serum levels of phenytoin. To avoid phenytoin intoxication appropriate adjustment of the anticonvulsant should be made5,6. Theophylline: A recent study has shown that concomitant administration of isoniazid and theophylline may cause elevated plasma levels of theophylline, and in some instances a slight decrease in the elimination of isoniazid. Since the therapeutic range of theophylline is narrow, theophylline serum levels should be monitored closely, and appropriate dosage adjustments of theophylline should be made7. Valproate: A recent case study has shown a possible increase in the plasma level of valproate when co-administered with isoniazid. Plasma valproate concentration should be monitored when isoniazid and valproate are co-administered, and appropriate dosage adjustments of valproate should be made5 References 1. Murphy, R., et al: Annuals of Internal Medicine; 1990: November 15; volume 113: 799800 2. Burke, R.F., et al: Res Commun Chem Pathol Pharmacol; 1990: July; vol. 69: 115-118 3. Fleenor, M. F., et al: Chest (United States) Letter; 1991; June; 99 (6): 1554 4. Baciewicz, A.M. and Baciewicz, Jr. F.A.: Arch Int Med 1993: September; volume 153: 1970-1971 5. Jonviller, A.P, et al:European Journal of Clinical Pharmacol (Germany), 1991: 40 (2) p198 6. American Thoracic Society/Centers for Disease Control: Treatment of Tuberculosis and Tuberculosis Infection in Adults and Children. Amer. J. Respir Crit Care Med.1994;149: p1359-1374 7. Hoglund P., et al: European Journal of Respir Dis (Denmark) 1987: February; 70 (2) p110116.

RIFAMPIN SIDE EFFECTS Gastrointestinal Heartburn, epigastric distress, anorexia, nausea, vomiting, jaundice,flatulence, cramps, and diarrhea have been noted in some patients. Although Clostridium difficile has been shown in vitro to be sensitive to rifampin, pseudomembranous colitis has been reported with the use of rifampin (and other broad spectrum antibiotics). Therefore, it is important to consider this diagnosis in patients who develop diarrhea in association withantibiotic use. Hepatic Transient abnormalities in liver function tests (e.g., elevations in serumbilirubin, alkaline phosphatase, serum transaminases) have been observed. Rarely, hepatitis or a shock-like syndrome with hepatic involvement and abnormal liver function tests has been reported. Hematologic Thrombocytopenia has occurred primarily with high dose intermittent therapy, but has also been noted after resumption of interrupted treatment. It rarely occurs during well supervised daily therapy. This effect is reversible if the drug is discontinued as soon as purpura occurs. Cerebral hemorrhageand fatalities have been reported when rifampin administration has been continued or resumed after the appearance of purpura. Rare reports of disseminated intravascular coagulation have been observed. Leukopenia, hemolytic anemia, and decreased hemoglobin have been observed. Agranulocytosis has been reported very rarely. Central Nervous System Headache, fever, drowsiness, fatigue, ataxia, dizziness, inability to concentrate, mental confusion, behavioral changes, muscular weakness, pains in extremities, and generalized numbness have been observed. Psychoses have been rarely reported. Rare reports of myopathy have also been observed. Ocular Visual disturbances have been observed. Endocrine Menstrual disturbances have been observed. Rare reports of adrenal insufficiency in patients with compromised adrenal function have been observed. Renal Elevations in BUN and serum uric acid have been reported. Rarely,hemolysis, hemoglobinuria, hematuria, interstitial nephritis, acute tubularnecrosis, renal insufficiency, and acute renal failure have been noted. These are generally considered to be hypersensitivity reactions. They usually occur during intermittent therapy or when

treatment is resumed following intentional or accidental interruption of a daily dosage regimen, and are reversible when rifampin is discontinued and appropriate therapy instituted. Dermatologic Cutaneous reactions are mild and self-limiting and do not appear to be hypersensitivity reactions. Typically, they consist of flushing and itching with or without a rash. More serious cutaneous reactions which may be due to hypersensitivity occur but are uncommon. Hypersensitivity Reactions Occasionally, pruritus, urticaria, rash, pemphigoid reaction, erythema multiforme including Stevens-Johnson Syndrome, toxic epidermal necrolysis,vasculitis, eosinophilia, sore mouth, sore tongue, and conjunctivitis have been observed. Anaphylaxis has been reported rarely. Miscellaneous Edema of the face and extremities have been reported. Other reactions which have occurred with intermittent dosage regimens include &lduqo;flu syndrome&rduqo; (such as episodes of fever, chills, headache, dizziness, and bone pain), shortness of breath, wheezing, decrease in blood pressure and shock. The &lduqo;flu syndrome&rduqo; may also appear if rifampin is taken irregularly by the patient or if daily administration is resumed after a drug free interval. Read the Rifadin (rifampin) Side Effects Center for a complete guide to possible side effects DRUG INTERACTIONS Healthy subjects who received rifampin 600 mg once daily concomitantly with saquinavir 1000 mg/ritonavir 100 mg twice daily (ritonavir-boosted saquinavir) developed severe hepatocellular toxicity. Therefore, concomitant use of these medications is contraindicated. Enzyme Induction Rifampin is known to induce certain cytochrome P-450 enzymes. Administration of rifampin with drugs that undergo biotransformation through these metabolic pathways may accelerate elimination of coadministered drugs. To maintain optimum therapeutic blood levels, dosages of drugs metabolized by these enzymes may require adjustment when starting or stopping concomitantly administered rifampin. Rifampin has been reported to substantially decrease the plasma concentrations of the following antiviral drugs: atazanavir, darunavir, fosamprenavir, saquinavir, and tipranavir. These antiviral drugs must not be co-administered with rifampin. Rifampin has been reported to accelerate the metabolism of the following drugs: anticonvulsants (e.g., phenytoin), digitoxin, antiarrhythmics (e.g., disopyramide, mexiletine, quinidine, tocainide), oral anticoagulants, antifungals (e.g., fluconazole, itraconazole, ketoconazole), barbiturates, beta-blockers, calcium channel blockers (e.g., diltiazem, nifedipine, verapamil), chloramphenicol, clarithromycin, corticosteroids, cyclosporine, cardiac glycoside preparations, clofibrate, oral or other systemic hormonal contraceptives, dapsone, diazepam, doxycycline, fluoroquinolones (e.g., ciprofloxacin), haloperidol, oral hypoglycemic agents (sulfonylureas),levothyroxine, methadone, narcotic analgesics, progestins, quinine, tacrolimus, theophylline, tricyclic antidepressants (e.g., amitriptyline,

nortriptyline) and zidovudine. It may be necessary to adjust the dosages of these drugs if they are given concurrently with rifampin. Patients using oral or other systemic hormonal contraceptives should be advised to change to nonhormonal methods of birth control during rifampin therapy. Rifampin has been observed to increase the requirements for anticoagulantdrugs of the coumarin type. In patients receiving anticoagulants and rifampin concurrently, it is recommended that the prothrombin time be performed daily or as frequently as necessary to establish and maintain the required dose of anticoagulant. Other Interactions: When the two drugs were taken concomitantly, decreased concentrations of atovaquone and increased concentrations of rifampin were observed. Concurrent use of ketoconazole and rifampin has resulted in decreased serum concentrations of both drugs. Concurrent use of rifampin and enalapril has resulted in decreased concentrations of enalaprilat, the active metabolite of enalapril. Dosage adjustments should be made if indicated by the patient's clinical condition. Concomitant antacid administration may reduce the absorption of rifampin. Daily doses of rifampin should be given at least 1 hour before the ingestion of antacids. Probenecid and cotrimoxazole have been reported to increase the blood level of rifampin. When rifampin is given concomitantly with either halothane or isoniazid, the potential for hepatotoxicity is increased. The concomitant use of rifampin and halothane should be avoided. Patients receiving both rifampin and isoniazid should be monitored close for hepatotoxicity. Plasma concentrations of sulfapyridine may be reduced following the concomitant administration of sulfasalazine and rifampin. This finding may be the result of alteration in the colonic bacteria responsible for the reduction of sulfasalazine to sulfapyridine and mesalamine. Drug/Laboratory Interactions Cross-reactivity and false-positive urine screening tests for opiates have been reported in patients receiving rifampin when using the KIMS (KineticInteraction of Microparticles in Solution) method (e.g., Abuscreen OnLine opiates assay; Roche Diagnostic Systems). Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish rifampin from opiates. Therapeutic levels of rifampin have been shown to inhibit standard microbiological assays for serum folate and vitamin B12. Thus, alternate assay methods should be considered. Transient abnormalities in liver function tests (e.g., elevation in serum bilirubin, alkaline phosphatase, and serum transaminases) and reduced biliary excretion of contrast media used for visualization of the gallbladder have also been observed. Therefore, these tests should be performed before the morning dose of rifampin.

PYRAZINAMIDE SIDE EFFECTS General: Fever, porphyria and dysuria have rarely been reported. Gout

Gastrointestinal: The principal adverse effect is a hepatic reaction Hepatotoxicity appears to be dose related, and may appear at any time during therapy. Gl disturbances including nausea, vomiting andanorexia have also been reported. Hematologic and Lymphatic: Thrombocytopenia and sideroblastic anemiawith erythroid hyperplasia, vacuolation of erythrocytes and increased serum iron concentration have occurred rarely with this drug. Adverse effects on blood clotting mechanisms have also been rarely reported. Other: Mild arthralgia and myalgia have been reported frequently. Hypersensitivity reactions including rashes, urticaria, and pruritis have been reported. Fever, acne, photosensitivity, porphyria, dysuria and interstitial nephritis have been reported rarely. Read the Pyrazinamide (pyrazinamide) Side Effects Center for a complete guide to possible side effects DRUG INTERACTIONS Drug/Laboratory Test Interactions: Pyrazinamide has been reported to interfere with ACETEST and KETOSTIX urine tests to produce a pink-brown color.5 Last reviewed on RxList: 12/3/2008 This monograph has been modified to include the generic and brand name in many instances. ETHAMBUTOL SIDE EFFECTS MYAMBUTOL may produce decreases in visual acuity, including irreversible blindness, which appear to be due to optic neuritis. Optic neuropathyincluding optic neuritis or retrobulbar neuritis occurring in association with ethambutol therapy may be characterized by one or more of the following events: decreased visual acuity, scotoma, color blindness, and/or visual defect. These events have also been reported in the absence of a diagnosis of optic or retrobulbar neuritis. Patients should be advised to report promptly to their physician any change of visual acuity. The change in visual acuity may be unilateral or bilateral and hence each eye must be tested separately and both eyes tested together. Testing of visual acuity should be performed before beginning MYAMBUTOL therapy and periodically during drug administration, except that it should be done monthly when a patient is on a dosage of more than 15 mg per kilogram per day. Snellen eye charts are recommended for testing of visual acuity. Studies have shown that there are definite fluctuations of one or two lines of the Snellen chart in the visual acuity of many tuberculous patients not receiving MYAMBUTOL. The following table may be useful in interpreting possible changes in visual acuity attributable to MYAMBUTOL. READING INDICATING SIGNIFICANT SIGNIFICANT NUMBER OF DECREASE LINES 20/25 20/25 20/30 3 2 2

INITIAL SNELLEN READING 20/13 20/15 20/20

DECREASE NUMBER OF POINTS 12 10 10

20/25 20/30 20/40 20/50

20/40 20/50 20/70 20/70

2 2 2 1

15 20 30 20

In general, changes in visual acuity less than those indicated under Significant Number of Lines and Decrease Number of Points may be due to chance variation, limitations of the testing method, or physiologicvariability. Conversely, changes in visual acuity equaling or exceeding those under Significant Number of Lines and Decrease Number of Points indicate need for retesting and careful evaluation of the patient's visual status. If careful evaluation confirms the magnitude of visual change and fails to reveal another cause, MYAMBUTOL should be discontinued and the patient reevaluated at frequent intervals. Progressive decreases in visual acuity during therapy must be considered to be due to MYAMBUTOL. If corrective glasses are used prior to treatment, these must be worn during visual acuity testing. During 1 to 2 years of therapy, a refractive error may develop which must be corrected in order to obtain accurate test results. Testing the visual acuity through a pinhole eliminates refractive error. Patients developing visual abnormality during MYAMBUTOL treatment may show subjective visual symptoms before, or simultaneously with, the demonstration of decreases in visual acuity, and all patients receiving MYAMBUTOL should be questioned periodically about blurred vision and other subjective eye symptoms. Recovery of visual acuity generally occurs over a period of weeks to months after the drug has been discontinued. Some patients have received MYAMBUTOL (ethambutol hydrochloride) again after such recovery without recurrence of loss of visual acuity. Other adverse reactions reported include: hypersensitivity, anaphylactic/anaphylactoid reaction, dermatitis, erythema multiforme, pruritus, and joint pain; anorexia, nausea, vomiting,gastrointestinal upset, and abdominal pain; fever, malaise, headache, and dizziness; mental confusion, disorientation, and possible hallucinations;thrombocytopenia, leukopenia, and neutropenia. Numbness and tingling of the extremities due to peripheral neuritis have been reported. Elevated serum uric acid levels occur and precipitation of acute gout has been reported. Pulmonary infiltrates, with or without eosinophilia, also have been reported during MYAMBUTOL therapy. Liver toxicities, including fatalities, have been reported. Since MYAMBUTOL is recommended for therapy in conjunction with one or more other antituberculous drugs, these changes may be related to the concurrent therapy. Hypersensitivity syndrome consisting of cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, and one or more of the following: hepatitis, pneumonitis, nephritis, myocarditis, pericarditis. Fever and lymphadenopathy may be present. Read the Myambutol (ethambutol) Side Effects Center for a complete guide to possible side effects DRUG INTERACTIONS The results of a study of coadministration of MYAMBUTOL (50mg/kg) with an aluminum hydroxide containing antacid to 13 patients with tuberculosisshowed a reduction of mean serum concentrations and urinary excretion of ethambutol of approximately 20% and 13%, respectively, suggesting that the oral absorption of ethambutol may be reduced by these antacid products. It is recommended to avoid concurrent administration of ethambutol with

aluminum hydroxide containing antacids for at least 4 hours following ethambutol administration.

References 1. Murphy, R., et al: Annuals of Internal Medicine; 1990: November 15; volume 113: 799800 2. Burke, R.F., et al: Res Commun Chem Pathol Pharmacol; 1990: July; vol. 69: 115-118 3. Fleenor, M. F., et al: Chest (United States) Letter; 1991; June; 99 (6): 1554 4. Baciewicz, A.M. and Baciewicz, Jr. F.A.: Arch Int Med 1993: September; volume 153: 1970-1971 5. Jonviller, A.P, et al:European Journal of Clinical Pharmacol (Germany), 1991: 40 (2) p198 6. American Thoracic Society/Centers for Disease Control: Treatment of Tuberculosis and Tuberculosis Infection in Adults and Children. Amer. J. Respir Crit Care Med.1994;149: p1359-1374 7. Hoglund P., et al: European Journal of Respir Dis (Denmark) 1987: February; 70 (2) p110116.