Adverse Effects Comments

Admin.: Consists pi vesicisaf Way.* li|>isuriK- with ampiiri H mtoicalatod within the membrane Dosage 3-5 ma per kg per day iVas smijl" d w .iitused ver a period crt approx 120mm II well tolerated. lnlu9ion time can bo reduced lo 60 min (sou lootnoto 3. page BJ) 1 mg por kg per day was as effective as 4 ---------■ ----■ ■-— — ---'—---------'-------■—-'—---------n transplant and/or neutropenia

Amphotericin B cholesteryl complex

£imphotericin B colloidal dispersion, BCD, Amphotec): j 4 mg |>ei kg pel day as single inlusion 100 mg $160

25.6%, i Mg 20 4% vs 25 6% Aculo iniusion-felaled reactions ate common with liposomal ampho B. 20-10% 86% occulted within 5 min ol infusion, Including chest pain, dyspnea & hypoxia ot severe abdominal, (lank ot leg pam. 14% developed Hushing & urticaria neai the end of 4-hr inlusion All losponded to diphenhydramine (I mg per kg) & Interruption ol L-AmB infusion Theso reactions may be due to complement activation by the liposomo/CfD 36 1213. 20031

Admin.: Consists ot ampho B deoxycholale stabilized Willi cholesteryl sullnle lesulting in a disc-shaped colloidal complex Compared lo standard ampho B, larger volume ol distNliulion. tapid blood clearance high tissue concentrations Dosage Initial dose tor adults & children 3-4 mg per kg per day II mvessary

. T to 6 mg pet kg day Dilute m D5W & inluse at 1 mg pel kg pel hr Do NOT use in-line Wter Toxicity: dulls 50% fever 33% 1 serum creatinine 12-20% 1 Ca 6% -1 K 17% Hepaloloxicity more lhan ampho Btinc 0 78/100 pt days) (CIO 41 301, 2005/& T Willi ccntinuinq tx

(incidence 1 5) m bone mairow Irnnsplant pis

Caspofunoin (Canodas)

70 mg IV on day 1 lolkiwed by 50 mg IV q24h

(reduce to 35 mg IV t|24h Willi moderate hepatic Insufllctencyl

70 mg $424 44. 50 mg $329 47 ot $8485 26 lor 21-day course

An echinocamjn wiiich inhibits synthesis ol B-( t ,31-D-gtucan Fungicidal again*! Candida (MIC <2 meg per mL) including those resistant to other antifungals & active against asperrpltus ¡MIC 0 4-2 7incgper mL) Interestingly hi some precuneal slwies very tugli drug concentrations lound lobo less elfecltve (AAC 48 3407. 2004). but Ihis has not been demonslraled clmrcyiy Approved indications lor caspo include empirical tx lor febrile, neutfoponic pis, ix ol candidemia Candida inlta-abdominal abscesses, penlonitis. & pleural space intectians esophageal candtiiasis. & invasive aspeigillosis in pis relracloty lo nt intoleiaril ol other therapies Serum levels on rec dosages peak 12, ttough I 3 (24 hts) meg per mL Toxicity remarkably non-toxic (Mycosis 48 227. 2005. Neph Dial Transplant, July 5, 2005) Only 2% ol 263 pis in double-blind llial dc drug duo lo drug-relaled adverse event (Trarispl Inl Dis I 25,20021 !4%had T liansaminases (similai lo tiiazotes) Most common adverse oflect pruutus at Inlusion site & headache, lever, chills, vomiting, & diattliea associated Willi inlusion T setum ctealinino in 8% on caspo vs 21% slum-course ampho B in 422 pts Willi candidemia (Ln. Oct. 12. 2005, online) Diuu metabolized in liver & dosage i lo 35 mg in moderate lo severe hepatic failure Class C lot pregnancy p in rats & rabbits) Son Tallies, page 146 lor drug-drug interactions. asp cyclosporin) (liepatictooaty) & tacrolimus Idiug ¡metmantle

(embtyotoxlc ii___________,__________-- ____________-

loctunmvtided) Reversible lliromliocvtopeiiia tepoited (Pliaimacotnet 24 ( 408. 2034)

lortng

Micafungln (Mycamine)

50 mg per day lor prophyiaxispost-bone mairow stem cefl tiansplanl $95 pet day ISOmgfVperdaylortx $280 50petday (50 mq vials I $5890 30 toi 150 mg IV ii24h for ¿1 days (Med Let147 52. 2005)_

Anidulafungin

200 mg IV on day I lollow«! tiy 100 mg pel day IV (FDA approval ponding). Ini escxihageaJ candidiasis 100 mg IV times 1 then 50 mg IV q24h (no cost data available)___

Tlio T eclnnocandm approved by the FDA (March 2005) loi rx of esophageal carxtKliasis & for prophylaxis against Candida infections in HSCT recipients Active against most strains ol carxida sp & aspetailus sp including liiose resistanl to fluconazole such as C qlabrala & C krusii No anlagomsm seen wtien combmod Willi other antifungal drugs & occ synergism with ampho B (AAC 49 2994, 2005) No dosage adjustment lor severe renalTailuro or moderate hepatic impairment Watch lor drug-drug interactions with siioltmus or nifedipine Micafungin is well tolerated & common adverse events includo nausea 7 8%. vomiting 2.4%. & headache 2 4% Transient t LFTs. BUN. creatinine repotted, two cases ol significant hepatitis & renal insuHiciency (pacKage insert lor micatunqin)

An ochinocandin with antilungal activity (cidall against Candida sp & uspotgillus sp including ampho B- & Inazole-iesislant strains Eltoclive in dimcal lilals ol esophageal candidiasis & in 1 Itial was suponor to fluconazole in rx ol invasivo candidiasis/candidomia in 245 pis (75 6% vs 602%) (ICAAC 2005/ Likeolher ecWnocandins, tematkably nixi-loxic. most common snie eilects nausea, vonnting, I Mg, I K & headachein 11-13%of pis Nodose adjustments lex tonal or hepatic insuHiciency Few drug-dhjg Interactions (see Table 22)

Fluconazole (Diflucan)

100 mg labs NB S9 öOj G $1 73 150 mg labs NB$16 G $7 200 mg tabs NB $16 G$t 400 mg IV NB $170. G SI 52 Oral suspension 50 mg pel 5 mL. $40/35 mL bottle— NB

IV-ixal dose because ol excellent bioavailability Pharmacology absorbed po. water solubility enables IV Peak setum levels (see Table 9 rwge 62) T -. 30 ms (range 20-50 hrs) 12% protein bound CSF levels 50-90% of serum In normals : m menincplis No eft"<:l on mammalian steroid meltitxilisri Drug-drug Interactions common, see Table 22 Side etfocls overall 16% [more common in HIV - pts |21%)l Nausea 3 7%. headache I 9%. skin tash 1.8%, abdominal pain I 7%, vomiting 1 7%. cfarihea 1 5%. t SGOT 20% Alopecia (scalp, puac cresl) in 12-20% pis on ¿400 mqpoq24h alter median ol 3 months (reversible in approx 6mos.| (AnIM 123 354. 11395) Rare severe liepatotoxlcity ICID 41 301. 2005), oxloliative dermatitis Anaphylaxis (BMJ 302 1341. 1991) fell NEJM330.263. 1994_

Flucytosine (Ancobnn) 5(X)mgcap$9

AEs Overall 30% Gl 6% (dlaiitieo, anorexia, mL (osp. In azotemic pts)|. hopatoloxidl creatinine un EKTACHEM analyzer (JAC26

dlairhea, anorexia, nausea, vomiting), hemaloiogic 22% [leukopenia. Ihioml: . hopntoloxidty (asymptomallc t SGOT. iiivarsiblet skin rasti 7%. aplastic £ analyzer (JAC26:171 2000)_

Griseofulvln (Fulvicin. Giiliitvin Gnsuctiri) Photosensitivity, uitlcana, Gl upset, fatigue, leukopenia (tare) irilorlntes witti warfarin drugs increases blood and uunn pnt|>hyrins should not be used

500 mq G $3 45. susp 125 mg per mL 120 mL $52 lin pationls wilh porphyria Minnt disull'iatn-iike leadions Exacerbation ol systemic lupus erythematosus

Imidazoles topical

For vaginal arxVor skm use

INol tecommended in Isilnmester ol pregnancy. Local reactions 0 5-15% dyspaieurua. mid vagmal or vulvar erythema, burning, pninlus. urticaria, rash Rarely similai symptoms in sexual pailner

DHUC MAHE^GENEHICjTOADE)/ USUAL | ADVERSE EFFECTS-COMMENTS

DHUC MAHE^GENEHICjTOADE)/ USUAL | ADVERSE EFFECTS-COMMENTS

Itraconazole {Sixxanox) 100 mg cap $10

10 ma pet rnL oral solution (lasting state)

IV usual dose 200 mg bid times 4 doses (ollowtid by 200 mg q24h lor a maximum ot 14 days (S213/250 mg)

Itraconazole tablet and solution forms are not Interchangeable, solution preferred. Many authorities tecommond measuring drug serum concentraluxi alter 2 wfcs lo ensure satisfactory absorption To obtain the highest plasma concentration, trie tablet is gnren with food and acidic cbriks (e g . cola) while the solution is taken m tho lasled stale, undet these conditiotis. Hie peak com: ol the capsule is approx 3 meg pet mL and of the solution 5 4 meg pel mL Peak levols aro readied taster (2 2 vs 5 his) with IIhi solution Peak plaama concentrations after IV Injection (200 mg) compared to oral capsule (200 mg): 2.8 meg per mL (on day

7 of rx) vs 2 meg per mL (on day 36 of rx). Protein-boding tor both pieparatians is civet 99% which explains the viilual atisence ol penetration into the CSF (do not use to treat meningitis) Most common adverse ellocts are dose-ieiated nausea 10%. diaithea 8%. vomiting 6%, arid abdominal drscomtod 5 7% Allergic rash

8 6%. T bilirubin 6%. edema 3.5%, and hepatitis 2 7% reported T doses may produce hypokalemia 8% and T blood pressure 3 2% Delirium 4 ponplieial neuropathy reported /Psychosomatic^. 44 260. 2003. Dmtiotns Care 28 225. 2005) Reported to produce Impairment In cardiac function isee lootnore 2 page B0) Seven-liver lailure requiring transplant in pts receiving pulse rx lot onychomycosis FDA reports 24 cases with 11 deaths out o( 50 million people who received the drug ptior to 2001 (Eur Acad Deim & Vonoreol (9.205. 2005)

Other concern, as with tluconazoli' and kelocotwoli' i. drug-drug interactions: see Table 22 Some interactions can be htc-throalemng

Ketoconazole iNizoiall 200 mg tab $2 25

Gastric acid reqiired lot absorption—omelKleie. omeprazole antacids block absorption In acNotliydna. dissolve tabid in 4 mL 0 2N HO dnnk with a straw Coca Cola T absorption by 65% (AAC 39 (671. 1995) CSF levels 'none Drug-drug interactions important, see Table 22 Some Interactions can be IHe-threstening. Dose- dependent nausea and vomiting.

Livei toxicity of hepatocellular type reported in about f 10.000 exposed pts—usually attet seveial days to weeks ot exposuie At doses ol ;>800 rnq per day setum leslostetono and plasma Cortisol levels tall Willi hiqh doses adtenal (Addisonian) crisis reported

Miconazole Monisl.it IV) 200 mq—noiavailable in US

IV miconazole inciicatod in pallenl critically ill with Scedosponum (Pseudalleschetia boydiil inlection Vnry toxic due to vehide needed to get drug into solution

Nystatin (Mycostatm)

30 gm cream NB $28. G $2 30 500.000 units oral tab $0 70

Topical virtually no advoiso ellocts Lass olleclive than imidazoles and Inazoles. PO large doses givo occasional Gl distress and dialihea

Posaconazole iFDA approval pending) 200 mg po q6h ot 400 mg po bid with lood No cos! dala available (See Drugs 65 1552. 2005)

An oral Iriazoio with activity against a wide range ot tungi refractory to nlher antifungal ix including aspotgllosis. zygomycosis. tusanosis. Scedosponum (Pseudalloscherial. phaedtyphomycosis. tuslofilasmosis. refractory candidiasis refractory cocdaradomycos'S reftaclory cryptococcosis 4 relractory dnomobiastomycosis Cliracal response in 75% ol 176 AIDS pis with azole-iefraclere oral/esophagoal candidiasis Posaconazole lias similar toxicities as olhet Inazoles nausea 9% vomiting 6% abd pam 5% headache 5%. darthea T ALT. AST 4 rash (3% each) In pts re lor >6 mos , serious sido-etlects repotted in 12/112 pis induded adtenal insuttiooncy. nephtoloxicity 4 OTc inlenraf ptolongatkm Siqiiilicarit drua-diuq intetadions, inhibits CYP3A4 (see Table 22)

Terbinatine ilamisil) 250 mg tab $10 50

In pts receiving lotbmatine lot onychomycosis, rare cases (8) ol idiosyncratic 4 symptomatic hepalic injury and moto raroty liver lailute loading lo death or liver Itansplanlalion The drug is not recommended (ot pts will chronic or active liver dlaease: hepatotoxicity may occut in pts with nt without pre-existing disease Pmlieatmen! serum transaminases (ALT & AST) advised & alternate rx used lor those with abnormal levels Pts stalled oil leitnnalme should be warned about symptoms suggesting livi* dyslunclion (persistent nausea anorexia, tatigue, vomiting. RUQ pairi. |aundice, daik urino ot pale stools) II symptoms develop, drug should bo discontinued & liver function immediately evaluated In controlled trials, changes in ocular lens and letina tepotlod—clinical signiticance unknown Ma|or drug-drug interaction is 100% T in rate ol clearance by rifampin AEs usually mild, transient and rarely caused discontinuation of rx % with At, tuibinaline vs placebo nauseo/diantiea 2 6-5 6 vs 2 9. rash 5 6 vs 2 2 lasle abnormality 2 8 vs 0 7 Inhibits CYP2D6 enzymes (see Table 221 An acute genotali/od exanlhematous pustulosis lias been reported in 13 cases IBin J Derm 152 780 2005) 4 5 cases ol sulwcule cutaneous lupus etylliemalosus (Aces Derm Venerol 84 472. 2004)

Voriconazole iVIend)

IV: Loading dose 6 mg per kg q12h times 1 day, then

4 mg per kg q12hlV lot invasive aspergillus S serious mold inteclions 3 mg per kg IV q12h tor serious Candida Intectkxis Oral: >40 kg body weight: 4:io mg po q12h times 1 day Ition 200 mg po q12h

<40 kg body weight: 200 mg po q12h times 1 day then 100mgpoq12h Take oral dose 1 hour before or 1 hour alter eating.

Oral suspension (40 mg pet mL) $36 49/200 mg dose Oral suspension dosing Same as lor oral lal>s Reduce lo V, maintenance dose lot moderato hepatic insuttiooncy

A tnazde Willi adrvity against Aspergillus sp Including Ampho resistant strains of A. lerreus i J Clin Micro 372343. 1999) Active vs Candida sp (inducing kiusei). Fusantau sp . 4 various molds Steady stale solum levels teach 2 5 4 meg per mL Toxicity similai lo other azoiesAnazoios induding uncommon serious hepalic toxicity (hepalilis. dioioslasis 4 lulminant hopatic lailure Uva function tests should be motmoted during rx 4 dtug de'd il abnormalities develop Rash reported in up lo 20%. occ |iliotosensitivity 4 i aie Slovens-Johnson. Iiallucinations [including musical hallucinations (Inteciion 32293. 2004)| 4 anapliylactoid intusion teactions with (ever and hypertension (Clin Exp Dermatol 26 648. 2001) 1 case ol OT ptoiongation with ventricular tachycardia in a 15 y/o pt with ALL reported (ClD 39 884. 2004) Approx. 21% experience a transient visual disturbance lollowiriij IV ot po Calteiwl/ennanced visual perception-, blurred ot colored visual change ot photophobia) within 30 60 minutes Visual etiangos resolve within 30 60 min atlw administration 4 are attenuated with repeat«! doses (do not drtvo at night for outpatient rx) No persistence of ettect teportwl Cause unknown In palients with ClCr <50 mL pot min . the drug should bo grvon orally, no! IV. since llie intravenous vehicle (S8ECD sullcibutylothet.B cydodoxltm) may accumulalo HalkKmations. hypoglycemia electrolyte disturbance 4 pneumonitis altnbutedto T diuq concentrations (ClD 39 1241. 2004) Potential lor drug-drug mletaclions high-see Table 22 (ClD 36 630. 1087. 1122. 2003) NOTE: Nol in urine in active torm Cost: 50 mq lab S9. 200 mq lab $36 200 mg IV SIM

• From 2005 Drug Topics Ret) Book. Modical Economics Data and Hospital Formulary Pricing Quid« Price is average wholesale price (AWP). See page 2 tor abbreviations Alt dosage recommendations ate tor adults (unless otherwise indicated) and assume normal renal function

• From 2005 Drug Topics Ret) Book. Modical Economics Data and Hospital Formulary Pricing Quid« Price is average wholesale price (AWP). See page 2 tor abbreviations Alt dosage recommendations ate tor adults (unless otherwise indicated) and assume normal renal function

_TABLE 12A: TREATMENT OF MYCOBACTERIAL INFECTIONS'_

Tuberculin skin lest (TST). Same as PPD WlW 52(RR-2) 15. 2003/

Cntetta lor positivo TST after 5 tubcrcukn units (intermediate PPO) read at 48-72 bouts mm inr Juration * HtV. immunosupptessed > 15 mg prednisone por day tieakxt TBc on chest x-tay. roconl dose contact ilOmmindutation loreign-born countries with high prevalence IVDUsers. low income NH residents, chronic illness silicosis 215 mm induration otherwise lie.ilthy

Two-stage In detect sluggish posttMty I11" PPO pos but < 10 mm. iriprial inlermedlate PPO in t week Response to T" PPD can also happen it pt leceived BCG in childhood

BCG vaccine i. child it >10 mm nxiuiation & iiom country witli TBc. should be attributed to M tuberculosis In areas ot low TB prevalence, TSTtooctionsol 518 mm more likely Itom BCG than TB

ICID 40 211 2005) Pnor BCG may lesull in boosler otlocl in 2-stage TST (MM 161 1760, 2001 Chn Micro let 10900. 2005)

Routine anergy tosling no longer recommended in HIV + or HIV negative patients (JAMA 283 2003, 2000)

Whole blood Interleroivgamma release assay |OuantiFERON-TB (0FT)| approved by U S FDA as diagnostic test lot TB UAMA 286 1740. 2001. CO 34 1449 4 1457. 2002) CDC tecommnnds TST lor TB suspects & pis at T nsk lor progression to aclive TB & suggesls eiiliei TST ot OFT lor individuals at T risk lot lalenl TB (LTBI) & tor persons who wan ant testing txil ni" drwned al krw ilsk toi LTBt ¡MMWR VIRR-2) IS. 2003] A more sensitive assay based on Mlbc-specilic antigens (QuantiFERON-TBGOLD) and an on/yrne-'inked immunospol method (EUSpotl using antigens specific lor MTB • - -------'----------------------ar— —------------------------^---z— JAMA■•■•.! .'■■'■'■

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