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Virostatikum/Neuraminidasehemmer
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J06BB16
No recommendations provided.
Valaciclovir
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J05AB11
Cidofovir (parenteral)
J05AB12s According to
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Tipranavir (oral)
J05AE09
According to pharmacokinetic data and
product information, no dosage adjustment of the tipranavir-ritonavir
combination is necessary in patients with mild liver disease. Dose may be
adjusted by means of clinical effect and dose-dependent adverse
reactions. n Tipranavir is contraindicated in patients with moderate
hepatic insufficiency due to potential hepatotoxicity.l Tipranavir is
contraindicated in patients with severe hepatic insufficiency due to
potential hepatotoxicity.
Darunavir (oral)
J05AE10W gastrointestinal
disturbances (diarrhea, nausea, vomiting), headache, lipodystrophy
[1]
According to pharmacokinetic data and product information, no
dosage adjustment is necessary for the darunavir-ritonavir combination in
patients with mild liver disease. Adjust maintenance dose by means of
clinical effect and dose-dependent adverse effects.
According to
pharmacokinetic data and product information, no dosage adjustment is
necessary for the darunavir-ritonavir combination in patients with
moderate liver disease. Adjust maintenance dose by means of clinical
effect and dose-dependent adverse effects.
Virostatikum/HCV-ProteaseHemmer
Telaprevir (oral)
J05AE11g Avoid the telaprevir-peginterferon
alfa-ribavirin combination in patients with moderate liver disease.
e Avoid the telaprevir-peginterferon alfa-ribavirin combination in
patients with severe liver disease.
Boceprevir
(oral)
J05AEz Boceprevir in combination with peginterferon alfa and
ribavirin is contraindicated in patients with severe liver disease.
: Nucleoside and nucleotide reverse transcriptase
inhibitors
Antimycotics for systemic use
Antibiotics! Antimykotikum/Polyen-Antibiotikum& Amphotericin B (oral,
ORL, parenteral)
J02AA01, A01AB04, A07AA07
Stavudine
(oral)
J05AF04„ Intracellular activation to triphosphate. Hydrolysis
to thymine and sugar probable [1]. The pharmacokinetic data refer to
stavudine.
Lamivudine (oral)
J05AF05
Abacavir
(oral)
J05AF06
Tenofovir disoproxil (oral)
J05AF07) Filtration and
tubular secretion (hOAT1).
Adefovir dipivoxil
(oral)
J05AF08ª Aronson JK, editor. Meyler's Side Effects of Drugs:
The International Encyclopedia of Adverse Drug Reactions and
Interactions. 15th Edition, Onlinedition: Elsevier;
2006.m gastrointestinal disturbances (diarrhea, nausea, vomiting),
neurotoxicity (dizziness, headache, insomnia) [1]
Telbivudine
(oral)
J05AF11/ Non-nucleoside reverse transcriptase
inhibitors< Virostatikum/nichtnukleosidaler Reverse-TranskriptaseHemmer
Nevirapine (oral)
J05AG01f Nevirapine is contraindicated in
case of severe liver disease due to potential hepatotoxicity of
drug.
Efavirenz (oral)
J05AG03
Etravirine
(oral)
J05AG04Å According to pharmacokinetic data, start with normal
initial dose and reduce maintenance dose by up to 50%. Adjust maintenance
dose by means of clinical effect and dose-dependant adverse reactions.
Hydrazides
Tuberkulostatikum
Isoniazid (oral)
J04AC01> No
clinical studies available in patients with liver disease.
Oseltamivir
(oral)
J05AH02
Other
antivirals
Virostatikum/Fusionsinhibitor
Enfuvirtide
(parenteral)
J05AX07! Virostatikum/HIV-Integrase-Hemmer
Raltegravir
(oral)
J05AX08} gastrointestinal disturbances (abdominal pain,
diarrhea, nausea), headache, dizziness, peripheral neuropathy,
neutropenia [1]S No specific dosage recommendations can be made due to
lack of pharmacok<
inetic data.
Virostatikum/CCR5Antagonist
Maraviroc (oral)
J05AX09
Tubular
reabsorption.m hepatotoxicity, arthralgia, myalgia, hyperuricemia, gout,
gastrointestinal disturbances, CNS stimulation [1] ž According to
pharmacokinetic data, use normal initial dose and adjust maintenance dose
by means of clinical effect and dose-dependent adverse drug reactions.
Ethambutol (oral)
J04AK02
Antivirals for systemic use
Direct
acting antiviralsC Nucleosides and nucleotides, excl. reverse
transcriptase inhibitors Virostatikum/Nukleosid-Analogon
Aciclovir
(oral, parenteral)
J05AB01
Ribavirin (oral)
J05AB04
Ganciclovir
(parenteral)
J05AB06„ Minimal metabolism. Activation by
phosphorylation mostly in virus infected cells [1]. The pharmacokinetic
data refer to ganciclovir.
Famciclovir
(oral)
J05AB09! Clarithromycin (oral, parenteral)
J01FA09
14hydroxyclarithromycin
3' Non-linear, dose-dependent
elimination.
Brivudine (oral)
J05AB15æ gatrointestinal disturbances
(nausea, vomiting, abdominal pain, diarrhea, constipation), hematologic
disturbances (anemia, eosinophilia, granulocytopenia), elevation of liver
enzymes, insomnia, headache, dizziness, paresthesia [1]¯ According to
pharmacokinetic data and product information, short term (7 days as
recommended) therapy can be administered as usual in patients with mild
hepatic insufficiency.³ According to pharmacokinetic data and product
information, short term (7 days as recommended) therapy can be
administered as usual in patients with moderate hepatic
insufficiency.
Phosphonic acid derivatives" Virostatikum/PyrophosphatAnalogon
Foscarnet (parenteral)
J05AD01
Protease inhibitors
Virostatikum/HIV-Protease-Hemmer
Saquinavir (oral)
J05AE01
Hepatic metabolism by CYP P450 3A4 to mono- and di-hydroxylated
inactive compounds. Saquinavir is combined with ritonavir, a strong
inhibitor of CYP 3A4, to ensure efficient levels of saquinavir [1]. The
pharmacokinetic data refer to the combination with ritonavir.
Ð gastrointestinal disturbances (diarrhea, dyspepsia, nausea, emesis),
neurotoxicity (headache, confusion, ataxia), nephrolithiasis,
lipodystrophy, hepatotoxicity, orthostatic hypotension, hyponatremia [1,
178]
Indinavir (oral)
J05AE02b Arzneimittel-Kompendium der Schweiz
(online). Basel: Documed AG, 2009/2010/2011.
www.kompendium.ch¼ Physicians' Desk Reference (electronic version),
Thomson Reuters (Healthcare) Inc., Greenwood Village, Colorado, uSA.
Available at: http://www.thomsonhc.com (cited: 01/01/200912/31/2011).Æ Micromedex® 1.0 (Healthcare Series), (electronic version).
Thomson Reuters (Healthcare) Inc., Greenwood Village, Colorado, USA.
Available at: http://www.thomsonhc.com (cited: 01/01/200912/31/2011).[ Dollery C (editor). Therapeutic Drugs. 2nd edition,
Edinburgh: Churchill Livingstone, 1999.… Bircher J, Sommer W. Klinischpharmakologische Datensammlung. 2. Auflage. Wissenschaftliche
Verlagsgesellschaft mbH, Stuttgart, 1999.
Ritonavir
(oral)
J05AE03
IsopropylthiazoleÝ According to pharmacokinetic data,
start with normal initial dose and reduce maintenance dose by up to 50%.
Adjust maintenance dose according to clinical effect and dose-dependent
adverse effects. Monitor liver function. i Ritonavir is contraindicated
in patients with severe liver insufficiency due to potential
hepatotoxicity.
Nelfinavir (oral)
J05AE04
M8h Due to high
variability of pharmacokinetic parameters, no hepatic extraction category
could be defined. W Due to high variability of pharmacokinetic data, no
dose recommendations are possible.
Lopinavir / Ritonavir
(oral)
J05AE06
0.95 / 0.95
5 / 4
98.5 / 98.5
0.55 / 0.41
6 / 8.8
0.11 / 0.15
Fosamprenavir (oral)
J05AE07p gastrointestinal
disturbances (diarrhea, abdominal pain, nausea, vomiting), headache,
fatigue, lipodystrophy [1]‹ Dosage adjustment according to product
information. Adjust maintenance dose by means of clinical effect and
dose-dependent adverse effects.
Atazanavir
(oral)
J05AE08
2Þ According to pharmacokinetic data and clinical
studies, start with normal intial dose and reduce maintenance dose by up
to 50%. Adjust maintenance dose by means of clinical effect and dosedependent adverse drug reactions.
Ornidazole (oral,
parenteral)
J01XD03, P01AB03
Nitrofuran
derivatives
Antiinfektivum/Urologikum
Nitrofurantoin
(oral)
J01XE01k Filtration and tubular secretion. The urinary
excretion is pH-dependent and increases with alkaline urine. ¼ According
to pharmacokinetic data, use normal doses, provided that renal function
is normal. Adjust maintenance dose by means of clinical effect and dosedependent adverse drug reactions.
Fosfomycin
(oral)
J01XX01
Antibiotikum/Oxazolidinone
parenteral)
J01XX08
Linezolid (oral,
According to pharmacokinetic data and clinical study, start with normal
initial dose. In patients with severe liver insufficiency, maintenance
dose should be reduced by up to 50%. Adjust maintenance dose according to
clinical effect and dose-dependent adverse effects.
LipopeptidAntibiotikum
Daptomycin (parenteral)
J01XX09
0.1¬ According to
pharmacokinetic data and product information, use normal doses. Adjust
maintenance dose by means of clinical effect and dose-dependent adverse
drug reactions. Ö According to pharmacokinetic data and product
information, use normal initial dose and reduce maintenance dose by 50%.
Adjust maintenance dose by means of clinical effect and dose-dependent
adverse drug reactions. ' Beta-lactam antibacterials,
penicillins" Penicillins with extended
spectrum
Antibiotikum/Aminopenicillin- Amoxicillin (oral,
parenteral)
J01CA04
0.3
Tubular secretion.' Amphotericin B
(liposomal) (parenteral)
J02AA01- Antimykotikum/ImidazolDerivat
Ketoconazole (oral)
J02AB02
Non-linear pharmacokinetics.
… No specific dosage recommendations can be made due to lack of
pharmacokinetic data. Contraindicated according to product
information.
Triazole derivatives
Antimykotikum/TriazolDerivat- Fluconazole (oral, parenteral)
J02AC01 Itraconazole (oral,
parenteral)
J02AC02
Hydroxy-itraconazole
According to
pharmacokinetic data, start with dose in the lower range of normal
(normal if administered parenterally) and reduce maintenance dose by 50%.
Adjust maintenance dose according to clinical effect and dose-dependent
adverse effects or plasma levels. Voriconazole (oral,
parenteral)
J02AC03
Emtricitabine (oral)
J05AF09& F oral 93%
(capsule) or 75% (solution)Ú gastrointestinal disturbances (diarrhea,
nausea, abdominal pain), neurotoxicity (dizziness, headache, insomina),
elevated creatine kinase, hematologic disorders (neutropenia), elevated
triglycerides, hyperglycemia [1]
Entecavir (oral)
J05AF10
1 (oral);
0 (parenteral)
Cefamandole (parenteral)
J01DC03
0.24Ó According to
pharmacokinetic data and literature, administer normal initial dose and
reduce maintenance dose by 50%. Adjust maintenance dose by means of
clinical effect and dose-dependent adverse drug
reactions.Ñ A c c o r d i n g
t o
p h a r m a c o k i n e t i c
d a t a
a n d
l i t e r a t u r e ,
a d m i n i s t e r
n o r m a l
i n i t i a l
d o s e
a n d
r e d u c e
m a i n t e n a n c e
d o s e
e"5 0 % .
A d j u s t
m a i n t e n a n c e
d o s e
b y
m e a n s
o f
c l i n i c a l
e f f e c t
a n d
d o s e - d e p e n d e n t
a d v e r s e
d r u g
r e a c t i o n s .
Posaconazole
(oral)
J02AC04æ According to pharamcokinetic data and literature,
choose initial dose in the lower range of normal and reduce maintenance
dose by 50%. Adjust maintenance dose by means of clinical effect and
dose-dependent adverse drug reactions. # Other antimycotics for systemic
use
Antimykotikum
Flucytosine (parenteral)
J02AX01
5-Fluorouracil
Antimykotikum/Echinocandin
Caspofungin
(parenteral)
J02AX04ž fever, gastrointestinal disturbances, edemas,
possible histamine-mediated reactions (sensation of warmth, rash,
pruritus, swelling), hematological changes [1]Ó According to
pharmacokinetic data, use normal initial dose and reduce maintenance dose
(35mg instead of 50mg dai<
ly). Adjust maintenance dose by means of
clinical effect and dose-dependent adverse drug reactions.Ä According to
pharmacokinetic data, use normal initial dose and reduce maintenance dose
(<35mg daily). Adjust maintenance dose by means of clinical effect and
dose-dependent adverse drug reactions.
Anidulafungin
(parenteral)
J02AX06Ž According to pharmacokinetic data and primarily
extrahepatic metabolism, no dosage adjustment seems necessary in patients
with liver disease. L Caution in patients with cholestasis due to
significant biliary elimination.
Antimycobacterials# Drugs for
treatment of tuberculosis- Antibiotikum/Tuberkulostatikum
Rifampicin
(oral, parenteral)
J04AB02
25-O-desacetylrifampicin
Formylrifampicin½ gastrointestinal disturbances, central
and peripheral neurotoxicity (headache, drowsiness, dizziness, confusion,
visual disturbances, psychosis, paresthesias, seizures), hepatotoxicity
[1] l Isoniazid is contraindicated in patients with severe liver disease
due to potential hepatotoxicity of drug. ) Other drugs for treatment of
tuberculosis
Pyrazinamide (oral)
J04AK01
Pyrazinoic acid
PB range 5-50%
25-O-deatcetyl-rifabutin
30-hydroxy-rifabutin
31hydroxy-rifabutin
Ertapenem (parenteral)
J01DH03
0.12Ä According
to pharmacokinetic data, start with normal initial dose and reduce
maintenance dose by up to 50%. Adjust maintenance dose according to
clinical effect and dose-dependent adverse effects.
Doripenem
(parenteral)
J01DH04" Betalactam-Antibiotikum/Carbapenem
Imipenem/Cilastatin (parenteral)
J01DH51
1 (cilastatin)
N-Acetylcilastatin
0.3 / 0.3
1 / 0.9
20 / 15
11.8 / 12.4
0.07 / 0.07
Sulfonamides and trimethoprim@ Combinations of
sulfonamides and trimethoprim, incl.
Derivatives> Antiinfektivum/Sulfonamid / Antiinfektivum/FolsäureAntagonist2 Sulfamethoxazole / Trimethoprim (oral,
parenteral)
J01EE01
1 (Trimethoprim)
4-Hydroxytrimethoprim
3Hydroxytrimethoprim
alpha-Hydroxytrimethoprim
0.8 / 0.45
11 / 10
66 / 46
0.2 / 1.3
90 / 90
1.2 / 6
0.02 / 0.05
1 / 1+ Macrolides, lincosamides and streptogramins
Macrolides
Makrolid-Antibiotikum Erythromycin (oral,
parenteral)
J01FA01
1.1
Spiramycin (oral)
J01FA02
Cefaclor
(oral)
J01DC04
Cefprozil (oral)
J01DC10½ According to clinical
studies, normal initial dose can be used in patients with liver disease.
Adjust maintenance dose by means of clinical effect and dose-dependent
adverse drug reactions.
Azithromycine (oral)
J01FA10
Lincosamides
Lincosamid-Antibiotikum- Clindamycin (oral,
parenteral)
J01FF01
N-dimethyl clindamycin
Clindamycin
sulfoxid
Aminoglycoside antibacterials
Other
aminoglycosides
Aminoglykosid-Antibiotikum# Tobramycin (inahaltive,
parenteral)
J01GB01
Mainly glomerular filtration. Gentamicin
(parenteral, sponge)
J01GB03
No specification.
Amikacin
(parenteral)
J01GB06
No specification.
Quinolone
antibacterials
Fluoroquinolones$ Antibiotikum/Chinolon
(Gyrasehemmer)
Ofloxacin (oral, parenteral)
J01MA01} According to
pharmacokinetic data and clinical studies, no dose adjustment seems
necessary in patients with liver cirrhosis.
Ciprofloxacin (oral,
parenteral)
J01MA02
Sulfociprofloxacin
Oxociprofloxacin
Formylcip
rofloxacin
2.5! Tubular filtration and secretion.
Norfloxacin
(oral)
J01MA06
No information provided.
Levofloxacin (oral,
parenteral)
J01MA12
1.36 Moxifloxacin (oral,
parenteral)
J01MA14K According to pharmacokinetic data and clinical
studies, start with normal initial dose and reduce maintenance dose by up
to 50%. Adjust maintenance dose according to clinical effect and dosedependent adverse effects. According to product information, moxifloxacin
is contraindicated if ALT/AST are >5 ULN (upper limit of normal).
^ According to product information, moxifloxacin is contraindicated in
patients with severe liver disease. If treatment is considered, according
to pharmacokinetic data and clinical studies, start with normal initial
dose and reduce maintenance dose by up to 50%. Adjust maintenance dose
according to clinical effect and dose-dependent adverse effects.
Other
antibacterials
Glycopeptide antibacterials
GlycopeptidAntibiotikum
Vancomycin (oral, parenteral)
J01XA01,
A07AA09
0.6
Glomerular filtration.á According to pharmacokinetic
data, start with normal intial dose and reduce maintenance dose by up to
50%. Adjust dosage according to clinical effect and dose-dependent
adverse effects. Monitoring of liver function necessary.
Imidazole
derivatives2 Antibiotikum/Protozoenmittel/Nitroimidazol-Derivat
Metronidazole (oral, parenteral)
J01XD01, P01AB01
Hydroxy
metabolite
0.74 Third-generation cephalosporins
Ceftazidime
(parenteral)
J01DD02
0.23
Ceftriaxone
(parenteral)
J01DD04‘ According to pharmacokinetic data and clinical
studies, dosage adjustment is only needed in patients with concomitant
liver and renal impairment.’ According to pharmacokinetic data and
clinical studies, dosage adjustment is only needed in patients with
concomitant liver and renal impairment.
Cefixime
(oral)
J01DD08Ö According to pharmacokinetic data and clinical
studies, start with normal initial dose. Reduce maintenance dose by up to
50%. Adjust maintenance dose according to clinical effect and dosedependent adverse effects.
Cefpodoxime (oral)
J01DD13
Ceftibuten
(oral)
J01DD14
trans isomer
Fourth-generation cephalosporins
Cefepime
(parenteral)
J01DE01
0.26
Monobactams
Monobactam-Antibiotikum
Aztreonam
(parenteral)
J01DF01
0.18
Carbapenems" Betalaktam-Antibiotikum/Carbapenem
Meropenem
(parenteral)
J01DH02$ Beta-lactamase sensitive
penicillins
Penicillin-Antibiotikum
Benzylpenicillin
(parenteral)
J01CE01
0.4! Filtration and tubular secretion.
No
recommendation provided. - Phenoxymethylpenicillin
(oral)
J01CE02
0.5- Glomerular filtration and tubular secretion.
$ Beta-lactamase resistant penicillins! Flucloxacillin (oral,
parenteral)
J01CF05
5-Hydroxymethylflucloxacillinr gastrointestinal
disturbances, intestinal overgrowth by non-susceptible organisms,
neurotoxicity (convulsions) [1]< Combinations of penicillins, incl.
beta-lactamase inhibitors
Betalactamasehemmer. Amoxicillin/Clavulanic
acid (oral, parenteral)
J01CR02
0.15 / 0.55
1.5 / 1
18 / 25
0.3 / 0.23
89 / 70
15 / 13
0.04 / 0.13
0 / 0 Amoxicillin: Tubular secretion.+ PenicillinAntibiotikum/Betalactamasehemmer$ Piperacillin/Tazobactam
(parenteral)
J01CR05
0.3 / 0.2
1 / 0.7
19 / 23
0.2 / 0.2
10
/ 22
0.06 / 0.08
4 / 4\ According to pharmacokinetic data, monitor
creatinine clearance and adjust dose accordingly.
Other beta-lactam
antibacterials First-generation cephalosporins
CephalosporinAntibiotikum
Cefazolin (parenteral)
J01DB04
0.13
Secondgeneration cephalosporins
Cefuroxime (oral,
parenteral)
J01DC02- Teicoplanin (oral, parenteral)
J01XA02
Polymyxins
Polypeptid-Antibiotikum
Colistin
(inhalative)
J01XB01
No recommendations provided.
Steroid
antibacterials
Antibiotikum
Fusidic acid (oral)
and usual dosage
Pharmacokinetics
nur falls vorhanden
J01XC01( Route of administration
Kidney
Liver& Zusatzinformation,
Beschreibung
Drug
ATC-code
inhal
oral
ORL
Andere
parenteral
rektal
Prodrug (1=ja, 0=nein)
MetabolismS Active Metabolite (1=es gibt aktive Metabolite;
2=möglicherweise aktive Metabolite)
Metabolite 1
Metabolite 2
Q0
Metabolite 3
Q05 Additional information about elimination pathway /
Q0 met1
Q0 met2
Q0 met3
T1/2 term. [h]
T1/2 met1 [h]
T1/2 met2 [h]
T1/2 met3 [h]
Vss [L/kg]
F oral [%]
PB [%]
CL sys [L/h]
hepatic extraction rate E? Additional information to
the single pharmacokinetic parametersE B i l i a r y
e l i m i n a t i o n
( 0 = m i n o r
( 0 - 4 9 % ) ,
1 = y e s
( e"5 0 % ) ,
2 = a m o u n t
u n k n o w n )
Renal
elimination¯ Hepatic extraction category (1=high hepatic extraction,
2=intermediate hepatic extraction, 3=low hepatic extraction, 4=mainly
renal elimination, 5=unknown elimination pathway)<
Hepatic adverse
reactionsQ Potentially dose-dependent and serious adverse reactions
(list is not exhaustive)] Personal dose recommendations for patients
with moderate hepatic insufficiency (Child Pugh B)[ Personal dose
recommendations for patients with severe hepatic insufficiency (Child
Pugh C)8 Personal dose recommendations for patients with ascites
< Personal dose recommendations for patients with cholestasis
G Personal dose recommendations for patients with hepatic encephalopathy
? Personal dose recommendations for patients with hypoalbuminemia
References Antiinfectives for systemic use Antibacterials for
systemic use
Tetracyclines
Tetracyclin-Antibiotikum- Doxycycline (oral,
parenteral)
J01AA02= No clinical studies available in patients with
liver disease.µ According to pharmacokinetic data, start with normal
initial doses. Reduce maintenance dose by up to 50%. Adjust maintenance
dose according to clinical effect and adverse reactions.¶ According to
pharmacokinetic data, start with normal initial doses. Reduce maintenance
dose by up to 50%. Adjust maintenance dose according to clinical effect
and adverse reactions.
Lymecycline (oral)
J01AA04
1.5N Caution in
patients with cholestasis due to significant biliary elimination.
Minocycline (oral)
J01AA08ú According to pharmacokinetic data,
start with normal initial dose and reduce maintenance dose by up to 50%.
Adjust maintenance dose according to clinical effect and dose-dependent
adverse effects. Monitor liver function for adverse hepatic
reactions.[ According to product information, minocycline is
contraindicated in patients wtih severe liver disease. If treatment is
considered, start with normal initial dose and reduce maintenance dose by
up to 50%. Adjust maintenance dose according to clinical effect and dosedependent adverse effects. Monitor liver function for adverse hepatic
reactions.% Tetracyclin-Antibiotikum/Glycylcyclin
Tigecycline
(parenteral)
J01AA12c Caution in patients with cholestasis due to
significant biliary elimination. Best avoid rifampicin.
Rifabutin
(oral)
J04AB04
F after inhalation 12%. Ú gastrointestinal
disturbances, pancreatitis, neurotoxicity (asthenia, malaise, dizziness,
headache, peripheral sensory neuropathy), myalgia, lipodystrophy, lactic
acidosis, hematologic disorders (macrocytosis) [1, 178]F Use with
caution in patients with hypoalbuminemia due to decreased
PB.l Pharmacokinetics in patients with HBV-infection similar to those of
healthy or HIV-infected individuals [1].\ Caution in patients with
hepatic encephalopathy due to possible drug-induced
hyperammonemia.ª Cheema U, Ahmed M, Vogler C, Cumpa E, Ali A.
Ceftriaxone induced acute autoimmune hepatitis and fulminant hepatic
failure. Am J Gastroenterol. 2011; 106 Suppl. 2): S291. u Due to lack of
pharmacokinetic data of the saquinavir-ritonavir combination, no dosage
recommendations are possible. T No specific dosage recommendations can
be made due to lack of pharmacokinetic data. ª Johnson HJ, Han K,
Capitano B, Blisard D, Husain S, et al. Voriconazole pharmacokinetics in
liver transplant recipients. Antimicrob Agents Chemother. 2010; 54(2):
852-9. ª Lipp HP. Clinical pharmacodynamics and pharmacokinetics of the
antifungal extended-spectrum triazole posaconazole: an overview. Br J
Clin Pharmacol. 2010; 70(4): 471-80.
4 / 3m According to product
information, use approximately 50% lower doses than normal (150mg or
200mg twice daily).
According to product information, abacavir is contraindicated in
patients with moderate liver insufficiency. If treatment is considered,
use approximately 50% lower doses than normal. Adjust dosage by means of
clinical effect and dose-dependent adverse drug reactions.
According to product information, abacavir is contraindicated in
patients with severe liver insufficiency. If treatment is considered, use
approximately 50% lower doses than normal. Adjust dosage by means of
clinical effect and dose-dependent adverse drug reactions., Cholestasis
may be an adverse drug reaction.4 In spite of pharmacokinetic data
showing high hepatic extraction, boceprevir can be used as recommended in
patients with mild liver disease. Evidence for marked pharmacokinetic
alterations in liver disease is lacking in clinical studies. Refer also
to the recommendations of peginterferon alfa and ribavirin.4 According
to pharmacokinetic data, choose initial dose in the lower range of normal
and reduce maintenance dose by 50%. Adjust maintenance dose by means of
virological and clinical effect and dose-dependent adverse events (mainly
peripheral neuropathy and pancreatitis). Consider therapeutic drug
monitoring.
According to pharmacokinetic data, use normal initial dose
and reduce maintenance dose by up to 50%. Adjust maintenance dose by
means of virological and clinical effect and dose-dependent adverse drug
reactions (mainly peripheral neuropathy and pancreatitis).
According to
pharmacokinetic data, use normal initial dose and reduce maintenance dose
by up to 50%. Adjust maintenance dose by means of virological and
clinical effect and dose-dependent adverse drug reactions (mainly
peripheral neuropathy and pancreatitis). ã
According to pharmacokinetic
data and product information, use normal initial doses in patients with
mild liver disease. Adjust maintenance dose by means of virological and
clinical effect and dose-dependent adverse reactions.Ï
According to
pharmacokinetic data, use normal initial dose and reduce maintenance dose
by up to 50%. Adjust maintenance dose by means of virological and
clinical effect and dose-dependent adverse reactions.æ According to
pharmacokinetic data and product information, use normal initial dose and
reduce maintenance dose by up to 50%. Adjust maintenance dose by means of
virological and clinical effect and dose-dependent adverse
reactions.P According to product information, efavirenz is
contraindicated in patients with severe liver disease. If treamtent is
considered, according to pharmacokinetic data, use normal initial dose
and reduce maintenance dose by up to 50%. Adjust maintenance dose by
means of virological and clinical effect and dose-dependent adverse
reactions.Š According to pharmacokinetic data, dose adjustment is not
necessary, since inhaled zanamivir has low F and the therapeutic range is
broad.Ñ A c c o r d i n g
t o
p r o d u c t
i n f o r m a t i o n ,
s t a r t
w i t h
n o r m a l
i n i t i a l
d o s e
i n
p a t i e n t s
w i t h
C h i l d
P u g h
A
c i r r h o s i s
( d e s p i t e
h i g h
h e p a t i c
e x t r a c t i o n )
a n d
r e d u c e
m a i n t e n a n c e
d o s e
e"5 0 % .
M o n i t o r
p a t i e n t s
f o r
h e p a t o t o x i c i t y . Ñ A c c o r d i n g
t o
p r o d u c t
i n f o r m a t i o n ,
s t a r t
w i t h
n o r m a l
i n i t i a l
d o s e
i n
p a t i e n t s
w i t h
C h i l d
P u g h
B
c i r r h o s i s
( d e s p i t e
h i g h
h e p a t i c
e x t r a c t i o n )
a n d
r e d u c e
m a i n t e n a n c e
d o s e
e"5 0 % .
M o n i t o r
p a t i e n t s
f o r
h e p a t o t o x i c i t y . ¤ C o n s i d e r
r e d u c t i o n
o f
i n i t i a l
d o s e
i n
p a t i e n t s
w i t h
C h i l d
P u g h
C
l i v e r
c i r r h o s i s
b y
u p
t o
5 0 %
a n d
r e d u c e
m a i n t e n a n c e
d o s e
e"5 0 % .
M o n i t o r
p a t i e n t s
f o r
h e p a t o t o x i c i t y . ý
According to literature, start with
50% of normal dose (normal if administered parenterally) and adjust
maintenance dose by means of plasma drug levels, virological and clinical
effect, and/or dose-dependent adverse reactions (mainly
myelosuppression).• According to pharmacokinetic data and literature,
choose normal initial dose and adjust maintenance dose or dosage interval
by means of creatinine clearance.q According to pharmacokinetic data,
choose normal initial dose and adjust dose according to creatinine
clearance. } According to pharmacokinetic data, choose normal initial
dose and adjust maintenance dose according to creatinine clearance. <
Ä According to pharmacokinetic data, choose normal initial dose and
adjust maintenance dose or dosage interval by means of creatinine
clearance. Consider stopping therapy if liver function worsens.
Ž According to pharmacokinetic data, choose normal initial dose and
adjust maintenance dose or dosage interval by means of creatinine
clearance.ΠAccording to pharmacokinetic data, use normal initial dose
and adjust maintenance dose or dosage interval by means of creatinine
clearance. { According to pharmacokinetic data, choose normal initial
dose and adjust maintenance dose by means of creatinine
clearance.’ According to pharmacokinetic data, choose normal initial
dose and adjust maintenance dose and/or dosage interval by means of
creatinine clearance.§ According to pharmacokinetic data and clinical
studies, choose normal initial dose and adjust maintenance dose and/or
dosage interval by means of creatinine clearance.À According to
pharmacokinetic data, choose normal initial dose and adjust maintenance
dose and/or dosage interval by means of creatinine clearance. Monitoring
of liver function is recommended.
According to pharmacokinetic data,
no dose adjustment seems necessary in patients with liver disease.Choose
normal initial dose and adjust maintenance dose by means of creatinine
clearance. Due to the risk for hepatic adverse effects, better
alternatives may be chosen. > Mainly hepatic oxidation by CYP P450 3A4.
N-dealkylation, glucuronidation, hydrolysis. 79% (21% unchanged) of a
dose eliminated in feces, 13% (7% unchanged) recovered in urine.
Atazanavir is combined with ritonavir, a strong inhibitor of CYP 3A4 [1].
The pharmacokinetic data refer to the combination with ritonavir. u Due
to lack of pharmacokinetic data of the atazanavir-ritonavir combination,
no dosage recommendations are possible. ¦ Due to lack of pharmacokinetic
data of the atazanavir-ritonavir combination, no dosage recommendations
are possible. Contraindicated according to product information.z E from
[1]. Since hepatic metabolism is small and CL disproportionately higher,
extrahepatic metabolism is postulated [1].• According to product
information, rifampicin is contraindicated in patients with acute liver
disease. If treatment is considered in patients with mild liver disease,
according to pharmacokinetic data and literature, start with normal
initial dose and reduce maintenance dose by up to 50%. Adjust maintenance
dose by means of clinical effect and dose-dependent adverse effects.
Monitor liver enzymes. ” According to product information, rifampicin is
contraindicated in patients with acute liver disease. If treatment is
considered in patients with moderate liver disease, according to
pharmacokinetic data and literature, start with normal initial dose and
reduce maintenance dose by up to 50%. Adjust maintenance dose by means of
clinical effect and dose-dependent adverse effects. Monitor liver
enzymes. ’ According to product information, rifampicin is
contraindicated in patients with acute liver disease. If treatment is
considered in patients with severe liver disease, according to
pharmacokinetic data and literature, start with normal initial dose and
reduce maintenance dose by up to 50%. Adjust maintenance dose by means of
clinical effect and dose-dependent adverse effects. Monitor liver
enzymes. / If treatment is considered in patients with mild liver
disease, according to pharmacokinetic data and literature, initial dose
in the lower range of normal can be used. Reduce maintenance dose by 50%
and adjust it by means of clinical effect and dose-dependent adverse
reactions. Monitor liver enzymes. 3 If treatment is considered in
patients with moderate liver disease, according to pharmacokinetic data
and literature, initial dose in the lower range of normal can be used.
Reduce maintenance dose by 50% and adjust it by means of clinical effect
and dose-dependent adverse reactions. Monitor liver enzymes. g Adjust
initial dose according to body weight and choose maintenance dose in the
lower range of normal.
Pyrazinamide is contraindicated in patients
with liver insufficiency. Pyrazinamide can be considered for certain
patients when there are no better alternatives.‘ According to
pharmacokinetic data, no dose adaptation is necessary in patients with
liver disease. Adjust dose according to creatinine clearance.ó According
to pharmacokinetic data and literature, start with a dose in the lower
range of normal and reduce maintenance dose by 50%. Adjust dose according
to clinical effect and dose-dependent adverse effects (mainly hemolysis)
or drug levels.R According to product information, ribavirin is
contraindicated in patients with severe liver disease. If treatment is
considered, start with a dose in the lower range of normal and reduce
maintenance dose by 50%. Adjust maintenance dose according to clinical
effect and dose-dependent adverse reactions (mainly hemolysis) or drug
levels. ~ According to product information, ribavirin is contraindicated
in patients with decompensated liver cirrhosis. If treatment is
considered, according to pharmacokinetic data and literature, start with
a dose in the lower range of normal and reduce maintenance dose by 50%.
Adjust dose according to clinical effect and dose-dependent adverse
effects (mainly hemolysis) or drug levels.u According to pharmacokinetic
data, adjust maintenance dose and/or dosage interval according to
creatinine clearance. Q According to pharmacokinetic data, adjust dose
according to creatinine clearance.„ Adjust initial dose according to
body weight and choose maintenance dose in the lower range of normal.
Monitor serum concentrations.
According to pharmacokinetic data and
product information, reduce dosage to 600mg every 8 hours in patients
with mild liver cirrhosis. Adjust maintenance dose by means of clinical
effect and dose-dependent adverse drug reactions or indinavir serum
concentration.
According to pharmacokinetic data and product information, reduce
dosage to 600mg every 8 hours in patients with moderate liver cirrhosis.
Adjust maintenance dose by means of clinical effect and dose-dependent
adverse drug reactions or indinavir serum concentration. ð No data
available in patients with severe liver disease. Reduce initial dose to
at least 600mg every 8 hours. Adjust maintenance dose by means of
clinical effect and dose-dependent adverse drug reactions or by indinavir
serum concentration.È gastrointestinal disturbances (mainly diarrhea),
neurotoxicity (headache, insomnia, asthenia, paresthesia), lipodystrophy,
hyperglycemia, QTc prolongation, torsades de pointes, hepatotoxicity [1,
178]‘
The syrup is contraindicated in patients with impaired hepatic
function (propylene glycol). For tablets, according to pharmacokinetic
data, start with normal initial dose of the lopinavir-ritonavir
combination and reduce maintenance dose by up to 50%. Adjust maintenance
dose by means of lopinavir plasma concentration or clinical effect and
dose-dependent adverse reactions. Monitor liver function. ‘
The syrup
is contraindicated in patients with impaired hepatic function (propylene
gylcol). For tablets, according to pharmacokinetic data, start with
normal initial dose of the lopinavir-ritonavir combination and reduce
maintenance dose by up to 50%. Adjust maintenance dose by means of
lopinavir plasma concentration or clinical effect and dose-dependent
adverse reactions. Monitor liver function.
3 / 3e Adjust initial dose
according to body weight and maintenance dose according to creatinine
clearance. @ According to pharmacokinetic data and clinical studies, no
dose adjustment seems necessary in patients with liver cirrhosis.
According to product information, sulfamethoxazole/trimethoprim is
contraindicated in patients with marked parenchymal liver injury. Caution
is warranted in patients with impaired liver function.
3 /
4‰ According to product information, reduce maximal daily dose to 1g and
adjust maintenance dose according to clinical and adverse effects.
ò According to product information, erythromycin is contraindicated in
patients with severe liver insufficiency. If treatment is considered,
reduce maximal<
daily dose to 1g and adjust maintenance dose
according to clinical and adverse effects. Ó
According to
pharmacokinetic data and literature, initial dose should be chosen in the
lower range of normal and maintenance dose adjusted according to clinical
effect and dose-dependent adverse drug reactions.* Choose doses in the
lower range of normal.Ø According to pharmacokinetic data, start with
normal initial dose and reduce maintenance dose by up to 50%. Adjust
maintenance dose according to clinical and adverse effects. Monitoring of
liver function recommended.× Aminoglycosides are considered
contraindicated in liver cirrhosis. If no other possibilities exist, use
weight-adapted initial dose and adjust maintenance dose by therapeutic
drug monitoring. Monitor renal function.v Adjust initial dose according
to body weight and choose maintenance dose according to plasma
concentration monitoring.¹ Based on pharmacokinetic data, use normal
initial dose and adjust maintenance dose and/or dosage interval according
to creatinine clearance. Maximum dose of 400 mg daily is recommended.‘
According to pharmacokinetic data, use normal initial dose and adjust
maintenance dose and/or dosage interval according to creatinine
clearance.´ Based on pharmacokinetic data, use normal initial dose and
adjust maintenance dose and/or dosage interval according to creatinine
clearance. Monitoring of serum levels recommended.¯ According to
pharmacokinetic data and clinical studies, use normal initial dose and
adjust maintenance dose according to creatinine clearance. Clinical
monitoring recommended.• According to pharmacokinetic data, start with
normal dose and adjust maintenance dose and/or dosage interval according
to creatinine clearance.í
If use is considered in patients with severe
liver insufficiency (Child Pugh C), use normal initial dose and reduce
maintenance dose by up to 50%. Adjust maintenance dose by means of
clinical effect and dose-dependent adverse
reactions.u Lopinavir/ritonavir is contraindicated in patients with
severe hepatic insufficiency due to potential
hepatotoxicity.ë Metabolized by CYP3A4. In presence of ritonavir,
metabolism is minimal. 82.3% (79.9% unchanged) of a dose eliminated in
feces, 4.4% (0.5% unchanged) recovered in urine [1]. Pharmacokinetic data
refer to the combination with ritonavir. k According to product
information, darunavir is contraindicated in patients wtih severe liver
insufficiency.} According to product information, no dosage adjustment
of telaprevir is necessary in patients with mild liver insufficiency.
’ According to pharmacokinetic data, no dosage adjustment seems
necessary in patients with liver disease. Adjust maintenance dose to
renal function.ó According to pharmacokinetic and clinical data, start
with normal initial dose and reduce dosage interval as recommended in the
product information. Adjust maintenance dose by means of clinical effect
and dose-dependent adverse drug reactions.® According to pharmacokinetic
and clinical data, start with normal initial dose. Adjust maintenance
dose by means of clinical effect and dose-dependent adverse drug
reactions.¨ Based on the pharmacokinetic data, no dosage adjustment
seems necessary in patients with liver insufficiency. Adjust maintenance
dose according to creatinine clearance.¢ According to pharmacokinetic
data and clinical study, start with normal initial dose. Adjust
maintenance dose according to dose-dependent adverse drug reactions. µ
According to pharmacokinetic data, administer normal initial dose. Adjust
maintenance dose by means of clinical effect and dose-dependent adverse
reactions (mainly nephrotoxicity).; According to product information,
amphotericin B is contraindicated in patients wtih severe liver disease.
If treatment is considered, according to pharmacokinetic data, administer
normal initial dose. Adjust maintenance dose by means of clinical effect
and dose-dependent adverse reactions (mainly nephrotoxicity).Ÿ According
to pharmacokinetic data, use normal initial dose and adjust maintenance
dose according to creatinine clearance. Monitor patients for
hepatotoxicity. $ Pharmacokinetics dose-dependent [1].´ According to
pharmacokinetic data and the case described, no dosage adjustment is
necessary in patients with hepatic insufficiency. Adjust dosage according
to creatinine clearance.à According to pharmacokinetic data, use normal
initial dose and reduce maintenance dose by up to 50% (35mg instead of
50mg daily). Adjust maintenance dose by means of clinical effect and
dose-dependent adverse drug reactions.{ According to pharmacokinetic
data, start with normal first dose and adjust further doses according to
creatinine clearance.f Adjust initial dose according to body weight and
adjust maintenance dose according to renal function. 8 In spite of
pharmacokinetic data showing high hepatic extraction, boceprevir can be
used as recommended in patients with moderate liver disease. Evidence for
marked pharmacokinetic alterations in liver disease is lacking in
clinical studies. Refer also to the recommendations of peginterferon alfa
and ribavirin.k Adjust initial dose according to body weight and adjust
maintenance dose according to creatinine clearance.0 Studies performed
in patients with liver disease5 Product information (regarding hepatic
insufficiency)
1, 2, 3, 4, 5, 6, 7, 8ß gastrointestinal disturbances,
esophageal ulcerations, intestinal overgrowth by non-susceptible
organisms, discolouration of teeth, decreased plasma prothrombin
activity, benign intracranial hypertension, rise in BUN [1, 2]~
No
significant metabolism. Enterohepatic cycling. A part is inactivated by
chelation (Ca2+, Mg2+) in the intestine [1, 2, 3].
X
Z
^
`
\
Rare: hepatitis, cholestatic liver injury [1, 4].
Case report: microvesicular steatosis [5].
2
>
Ÿ Prodrug of
tetracycline. The data reported refer to tetracycline. About 5% of
tetracycline is metabolized by C-4 epimerization [2]. Enterohepatic
circulation.
gastrointestinal disturbances, esophageal ulcerations,
discolouration of teeth, intestinal overgrowth by non-susceptible
organisms, decreased plasma prothrombin activity, neuromuscular blockade,
increase in BUN, benign intracranial hypertension, dizziness, convulsions
[1, 2, 9]
1, 2, 9K
Rare: liver function disturbances, jaundice,
steatosis of the liver [1, 9].
“ 20% excreted unchanged by the feces.
Metabolism to a significant degree to 9-hydroxyminocycline and
demethylated derivatives (all inactive) [1, 3].$ 1, 2, 3, 4, 6, 7, 10,
11, 12, 13, 14«
Rare: liver enzyme elevation, hepatic failure,
autoimmune hepatitis, hypersensitivity reaction (with hepatitis),
hyperbilirubinemia, macrovesicular steatosis [4, 10, 11].
gastrointestinal disturbances, esophageal ulcerations, vestibular
disorders (dizziness, vertigo, ataxia, tinnitus), intestinal overgrowth
by non-susceptible organisms, decreased plasma prothrombin activity,
benign intracranial hypertension, discolouration of teeth, rise in BUN
[1, 2, 12]
: Minor metabolism by glucuronidation, N-acetylation
[1, 9].® In patients with liver cirrhosis Child Pugh A, B, and C
compared to healthy subjects (CL = 29.8L/h), mean tigecycline CL was
31.2L/h, 22.1L/h, and 13.5L/h, respectively [16].
1, 2, 9, 12, 15, 16,
17, 18Ÿ
Frequent: elevated AST, ALT, AP, elevated bilirubin.
Occasionally: liver injury (mainly cholestatic), jaundice. Postmarketing: liver insufficiency [1, 9, 15].
4
C
p
~
Þ
gastrointestinal disturbances, iintestinal
overgrowth by non-susceptible organisms, decreased plasma prothrombin
activity, pseudotumor cerebri, discolouration of teeth, rise in BUN, QT
prolongation, pancreatitis [1, 2, 12]Ó
Ô
£ 1 0 - 2 5 %
i s
m e t a b o l i z e d
i n
t h e
l i v e r
b y
h y d r o l y s i s
o f
t h e
² - l a c t a m
r i n g
t o
p e n i c i l l o i c
a c i d ,
w h i c h
i s
e x c r e t e d
i n
t h e
u r i n e .
E n t e r o h e p a t i c
c i r c u l a t i o n
o c c u r s
[ 1 ,
2 ] . £ gastrointestinal
disturbances, intestinal overgrowth by non-susceptible organisms,
crystalluria, neurotoxicity (agitatio<
n, anxiety, confusion,
convulsions) [1, 12]
1, 2, 4, 6, 7, 8, 12, 19‡
Rare: transient
elevations of liver enzymes, hyperbilirubinemia, cholestatic liver
injury, acute hepatic dysfunction, hepatitis [1, 4].
ƒ Mainly renal
elimination, but also partially metabolized to inactive benzylpenicilloic
acid by hydrolysis of the lactam ring [2].
1, 2, 6, 8, 9, 20,
21o
Rare: cholestasis and/or hepatitis, elevated AST, often in
combination with idiosyncratic reactions [1, 9,
20].
Ü
gastrointestinal disturbances, intestinal overgrowth by nonsusceptible organisms, neurotoxicity (agitation, anxiety, confusion,
visual disturbances, convulsions), hematological disturbances (e.g.
neutropenia) [1, 2, 21]Ñ
Ò
y Metabolism to phenoxymethylpenicilloic
acid and small amounts of 6-amino penicilloic acid; enterohepatic cycling
[1, 2].
1, 2, 6, 9, 14, 22F
Rare: transient increase of liver
enzymes, hepatotoxic reactions [1].
¹
gastrointestinal
disturbances, intestinal overgrowth by non-susceptible organisms,
neurotoxicity (agitation, anxiety, confusion, visual disturbances,
convulsions), encephalopathy [1, 2]²
³
3
Serum t1/2 independent of
hepatic dysfunction [13].
Q
A single dose study of combined amoxicillin/clavulanic acid
(1000/200mg) in cirrhotic patients showed an increased t1/2 of
amoxicillin (274 min in ascitic vs. 53 min in non-ascitic subjects)
probably due to increased Vd in patients with ascites. However, no dose
recommendations were made. Monitoring of patients might be advisable
[19].t
w
m Mainly renal elimination. Metabolism to active 5hydroxymethylfloxacillin and inactive penicilloic acid [1]. l Adjust
initial dose according to body weight and adjust maintenance dose
according to creatinine clearance. ” According to pharmacokinetic data,
choose normal initial dose and adjust maintenance dose and/or dosage
interval according to creatinine clearance. ú According to
pharmacokinetic data and product information, no dose modification seems
necessary in patients with liver disease if renal function is normal.
Adjust maintenance dose by means of clinical effect and dose-dependent
adverse drug reactions.
1, 2, 8, 9½
Rare: transient increase in liver enzymes, hepatitis,
cholestatic liver injury (onset may be delayed, protracted liver
dysfunction has been observed following withdrawal of therapy) [1,
9].
ñ A m o x i c i l l i n :
1 0 - 2 5 %
i s
m e t a b o l i z e d
i n
t h e
l i v e r
b y
h y d r o l y s i s
o f
t h e
² - l a c t a m
r i n g
t o
p e n i c i l l o i c
a c i d ,
w h i c h
i s
e x c r e t e d
i n
t h e
u r i n e .
E n t e r o h e p a t i c
c i r c u l a t i o n
o c c u r s
[ 1 ,
2 ] .
C l a v u l a n i c
a c i d :
3 5 - 6 0 %
m e t a b o l i z e d
t o
i n a c t i v e
m e t a b o l i t e s
[ 1 ] . ! 1, 2, 4, 6,
7, 12, 14, 19, 23, 24Æ
Rare: transient elevations of liver enzymes,
hyperbilirubinemia, cholestatic liver injury (believed to be principally
related to clavulanic acid moiety), acute hepatic dysfunction, hepatitis
[1, 4].
Y
A single dose study of combined amoxicillin/clavulanic
acid (1000/200mg) in cirrhotic patients showed an increased t1/2 of
amoxicillin (274 min in ascitic vs. 53 min in non-ascitic subjects) and
clavulanic acid (200 min in ascitic vs. 54 min in non-ascitic subjects)
probably due to increased Vd in patients with ascites. However, no dose
recommendations were made [19]. Monitoring of patients might be
advisable. Treatment of bacterial infections including spontaneous
bacterial peritonitis with 1000/200mg amoxicillin/clavulanic acid 3-4
times daily in cirrhotic patients has been reported [23, 24].t
w
&
'
ç gastrointestinal disturbances, intestinal overgrowth by nonsusceptible organisms, neurotoxicity (agitation, headache, hallucination,
confusion, convulsion), hematological disturbances (e.g. leukopenia,
thrombocytopenia) [1, 2, 12]! 1, 2, 6, 7, 9, 12, 14, 25, 26,
27è
Piperacillin: Mainly renal elimination. 10-20% are excreted
unchanged into the bile. Some metabolism to desethylpiperacillin
(inactive) [1, 9]. Tazobactam: Mainly renal elimination. Some metabolism
to an inactive metabolite [1, 9].
•
œ
p
Occasionally: elevated AST, ALT. Rare: elevated
bilirubin, GGT, AP, hepatitis, cholestatic liver disease [1, 9].
!
'
‰
Piperacillin: Plasma t1/2 of piperacillin was prolonged
in cirrhotic patients compared to controls and even longer in those with
ascites (1.95h vs 0.91h; p<0.01) [25]. All patients had normal creatinine
values. Total body CL was reduced in cirrhotics (not statistically
significant). Mean Vd was similar in both groups. Tazobactam: No clinical
studies available in patients with liver disease.
"
#
@
K
/ 80-100% is excreted unchanged in the urine
[1].š gastrointestinal disturbances, intestinal overgrowth by nonsusceptible organisms, neurotoxicity (agitation, confusion, seizures),
encephalopathy [2, 21].
1, 2, 6, 7, 8, 9, 21
1, 2, 6, 7, 8, 9, 21,
28e
Occasionally: elevation of liver enzymes and bilirubin. Rare:
hepatitis, cholestatic jaundice [1, 9].
=
z
E l i m i n a t i o n
t 1 / 2
o f
f a z o l i n
w a s
s i g n i f i c a n t l y
s h o r t e r
. 8 2 h
v s
2 . 5 7 h )
a n d
p l a s m a
P B
o f
f a z o l i n
w a s
s i g n i f i c a n t l y
r e d u c e d
1 8 . 4 %
i n
c i r r h o s i s
c o m p a r e d
t o
a l t h y
v o l u n t e e r s
[ 2 8 ] .
I n
p a t i e n t s
t h
o b s t r u c t i v e
b i l i a r y
d i s e a s e ,
f a z o l i n e
b i l e
l e v e l s
a r e
n s i d e r a b l y
l o w e r
t h a n
s e r u m
l e v e l s
1 . 0
¼ g / m L )
[ 9 ] .
N o
d o s e
r e d u c t i o n
n e c e s s a r y
i n
s e v e r e
h e p a t i c
p a i r m e n t
[ 2 8 ] .
 After p.o. application, cefuroxime axetil (prodrug) is
hydrolyzed in the intestine to cefuroxime. Cefuroxime is mainly renally
eliminated [1, 2, 9]. The pharmacokinetic data refer to
cefuroxime.• gastrointestinal disturbances, intestinal overgrowth by
non-susceptible organisms, neurotoxicity (headache, dizziness, seizures)
[1, 2, 12, 21]
1, 2, 6, 7, 9, 12, 21, 29, 30y
Frequent: increase in
ALT, AST. Occasionally: increase in AP and bilirubin. Rare: hepatitis,
cholestatic jaundice [1, 9].
L
Q
n
Pharmacokinetics
were not affected in cirrhotic patients without ascites compared to
healthy volunteers [29]. m
7 No metabolism occurs. Mainly renal
elimination [1, 2]. œ gastrointestinal disturbances, intestinal
overgrowth by non-susceptible organisms, neurotoxicity (agitation,
confusion, seizures), encephalopathy [1, 2, 21]y
Unknown frequency:
liver enzyme elevations (ALT, AST, AP), increase in bilirubin, hepatitis,
cholestatic jaundice [1, 9].
Q Mainly renal elimination. Up to 15%
are metabolized or otherwise degraded [1, 2].Πgastrointestinal
disturbances, intestinal overgrowth by non-susceptible organisms,
neurotoxicity (agitation, confusion, seizures) [1, 2, 21]
1, 2, 6, 7,
9, 21u
Occasionally: liver enzyme elevations (AST, ALT, AP). Rare:
hepatitis, cholestatic liver injury with jaundice [1, 9].
c
(
c
b
h
w
c
c
(
i
i
8
e
1
e
y
e
i
e
o
<
s
m
6
;
# Mainly renal elimination [1, 2, 9].
1, 2, 6, 9, 31,
32’
Frequent: increased ALT, AST. Occasionally: increase of AP. Rare:
increase of bilirubin, cholestatic jaundice [1, 9]. Case report:
hepatitis [31].
+
<
A
v
‚
ˆ
gastrointestinal
disturbances, intestinal overgrowth by non-susceptible organisms,
neurotoxicity (headache, dizziness, confusion) [1, 2]•
‚
Å
Beside
a moderate prolongation of elimination t1/2 of cefprozil (27-37%), no
statistically significant difference was observed between subjects with
hepatic impairment and healthy volunteers [32]. /
2
Mainly renal
elimination [1, 2].t Dose adjustment is not necessary in patients with
hepatic dysfunction, provided renal function is not impaired [18].
1,
2, 6, 7, 8, 9, 18, 33h
Frequent: liver enzyme elevations (ALT, AST,
GGT, AP). Rare: increase of bilirubin, jaundice [1, 9, 12].<
7
<
³
gastrointestinal disturbances, intestinal overgrowth by
non-susceptible organisms, neurotoxicity (headache, dizziness,
paresthesia, seizures, myoclonia), encephalopathy [1, 2,
12]¨
©
r
In a single dose study of 1g i.v. in patients with
cirrhosis and ascites, t1/2 was significantly prolonged probably due to
slow return from the ascetic compartment. Nevertheless, the overall CL
did not differ significantly [33]. Hepatic dysfunction had no effect on
the pharmacokinetics of ceftazidime in individuals administered 2 g i.v.
every 8 hours for 5 days [18]. K
N
| 40-50% are excreted unchanged
in the bile, where it is metabolized by the intestinal flora into
inactive metabolites [1, 2].
Non-linear pharmacokinetics
[1].µ gastrointestinal disturbances, intestinal overgrowth by nonsusceptible organisms, neurotoxicity (headache, dizziness, seizures),
biliary pseudolithiasis, nephrolithiasis [1, 2, 12]1 1, 2, 6, 7, 8, 12,
34, 35, 36, 37, 38, 39, 40, 41G
Frequent: liver enzyme elevations
(AST, ALT, AP), precipitation of calcium salts in the gallbladder
(children), reversible cholelithiasis (children), increased bilirubin.
Rare: jaundice, reversible biliary pseudolithiasis, gallbladder sludge
[1, 2, 12, 34]. Case report: autoimmune hepatitis and fulminant hepatic
failure [35].
«
¯
•
In patients with chronic liver
damage (alcoholic fatty liver, cirrhosis with and without ascites),
pharmacokinetics were similar to healthy subjects after 1g ceftriaxone
(single dose). Vd was significantly increased in cirrhotics with ascites,
but t1/2 was not different, probably because of lower PB [36-39]. Similar
results were seen in another study [40]. One study showed increase in fu
up to 320% in patients with cirrhosis and ascites compared to healthy
controls [37]. Due to the wide therapeutic range, no dose adjustment is
necessary in chronic liver disease [37], but indicated in patients with
concomitant renal and hepatic impairment [38, 41].º
»
ù
ü
…
†
6 No metabolic pathways have yet been identified [1, 2].
1, 2, 4,
6, 7, 8, 21, 42, 43]
Rare: mild and transient elevations in liver
enzymes, hepatitis, cholestatic jaundice [1, 4].
Œ
gastrointestinal
disturbances, intestinal overgrowth by non-susceptible organisms,
neurotoxicity (headache, dizziness, agitation) [1, 2, 21]•
‚
Ñ
In
a single dose study with 200mg in patients with moderate to
seve
!
.
@
R
"
/
A
T
g
$
1
C
%
2
D
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re cirrhosis, t1/2 was
significantly increased (6.4h) due to an increased Vd. Renal CL (+43%)
was also increased significantly (possibly because of reduced extra-renal
CL), AUC and Cmax remained unchanged. Despite a twofold increase in t1/2,
modification of kinetics were judged as modest [42, 43]. No dose
adjustment was considered necessary in patients with moderate to severe
cirrhosis [42, 43].R
U
Ž
•
ù
ü
0
3
Í Cefpodoxime
proxetil is a prodrug and hydrolyzed presystemically in the small
intestine to the active cefpodoxime. Cefpodoxime is mainly renally
eliminated [1, 2, 9]. The kinetic data refer to
cefpodoxime.¢ gastrointestinal disturbances, intestinal overgrowth by
non-susceptible organisms, neurotoxicity (headache, dizziness, tinnitus,
paresthesia), asthenia [1, 2, 21]„ Pharmacokinetics in cirrhotic
patients are only minimally altered [1]. No effect of ascites on the
pharmacokinetics of the drug [2].\
Occasionally: moderate and
transient increase in AST, ALT, AP. Rare: elevated bilirubin. [1]
?
E
$ Mainly renal elimination [1, 9, 44].Š gastrointestinal
disturbances, intestinal overgrowth by non-susceptible organisms,
neurotoxicity (dizziness, paresthesia, seizure) [1, 21]© The
pharmacokinetics do not change significantly in patients with chronic
active hepatitis, liver cirrhosis, alcoholic hepatopathy, or other
necrotic liver diseases [1].
1, 6, 9, 14, 21, 44R
Occasionally:
elevated liver enzymes and bilirubin. Case reports: jaundice [1, 9].
4
A
` Mainly renal elimination. 7% is metabolized to
methylpyrrolidine oxide (tertiary amine) [1, 9]. • Pharmacokinetics of
cefepime were unaltered in patients with impaired hepatic function who
received a single 1 g dose (n=11) [1].
1, 6, 8, 9, 14, 18A
Frequent
(1-2%): increases in liver enzymes and bilirubin [1,
9].
ª
gastrointestinal disturbances, intestinal overgrowth by nonsusceptible organisms, neurotoxicity (blurred vision, tinnitus,
paresthesia, seizures), encephalopathy [1, 18]¢
£
] A b o u t
2 0 %
a r e
m e t a b o l i z e d
i n
t h e
l i v e r
b y
h y d r o l y t i c
o p e n i n g
o f
t h e
² - l a c t a m
r i n g
[ 1 ,
2 ,
4 5 ] . X Dose reduction of 20-25% recommended
during long-term therapy in patients with alcoholic cirrhosis. For
patients with stable gallbladder cirrhosis or other chronic liver disease
dose adjustment is not necessary, provided that renal function is normal
[1]. In patients with hepatic impairment monitoring of liver function is
recommended [1, 2]. Ñ
According to pharmacokinetic data and clinical
studies, choose normal initial dose and adjust maintenance dose by means
of creatinine clearance. For patients with alcoholic cirrhosis, see
product information. ¼
1, 2, 6, 7, 9, 21, 45, 46, 47V
Frequent:
elevations of liver enzymes and bilirubin. Rare: hepatitis, jaundice [1,
9].
5
:
—
gastrointestinal disturbances, intestinal overgrowth
by non-susceptible organisms, neurotoxicity (headache, dizzines,
paresthesia, seizures) [1, 2, 21]Œ
•
ƒ
After 1g aztreonam i.v.
(single dose), t1/2 was 1.82 h in healthy volunteers, 6.6 h in cirrhotic
patients with ascites, and 8.87 h in patients with cirrhosis, ascites and
d
S
e
#
0
B
renal failure [46]. T1/2 was significantly longer (+68%) and serum CL
decreased (-27%) in alcoholic cirrhotics compared to normal subjects
[47]. Patients with primary biliary cirrhosis had only a longer t1/2
(+16%). (
+
À
Ã
w
z
P 25% are metabolized by
dihydropeptidase-I to an inactive derivative [1, 9, 48].
• gastrointestinal disturbances, intestinal overgrowth by nonsusceptible organisms, neurotoxicity (headache, paresthesia, seizures)
[1, 2, 18]™ No difference in pharmacokinetics were found between
subjects with stable alcoholic cirrhosis and eight matched controls with
normal liver function [49].
1, 2, 7, 9, 18, 48, 49|
Frequent: liver
enzyme elevations (ALT, AST, AP, GGT). Occasionally: increased bilirubin.
Rare: cholestatic jaundice [1, 9].
7
D
Z
`
e Hydrolysis by the
renal dehydropeptidase enzyme [1, 9]. About 10% of a dose excreted into
the faeces.# PB is dose-dependnet (85-95%) [1]. • gastrointestinal
disturbances, intestinal overgrowth by non-susceptible organisms,
confusion, hallucination, dizziness, tremor, seizure [1, 9]
1, 9, 12, 50•
Frequent: elevated ALT, AST, AP. Occasionally:
elevated bilirubin. Rare: cholecystitis, jaundice, elevated urobilinogen
[1, 9].
!
.
C
H
Dehydropeptidase I [1, 9].7 Glomerular
filtration, active tubular secretion [1, 9].‚ gastrointestinal
disturbances, intestinal overgrowth by non-susceptible organisms,
neurotoxicity (headache seizures), rash [1, 51]
1, 9, 51(
Frequent:
elevated liver enzymes [1, 9].
¸ gastrointestinal disturbances, intestinal overgrowth by nonsusceptible organisms, neurotoxicity (dizzines, paresthesia,
hallucinations, confusion, seizures), encephalopathy [1, 2, 12]
1, 2,
6, 7, 12, 14
Imipenem: Imipenem would be extensively metabolized in
the kidney by the dehydropeptidase-1 if administered without cilastatin,
a dehydropeptidase-1-inhibitor [1, 9]. Cilastatin: 10% metabolized to Nacetyl metabolite with similar hydropeptidase-1 inhibitory activity [1,
9].
§
²
7
Imipenem: Glomerular filtration and tubular
secretion.
s
Frequent: elevated ALT, AST, AP. Occasionally:
elevated bilirubin. Rare: jaundice, hepatitis, liver failure [1, 9].
.
C
I
@ gastrointestinal disturbances, intestinal overgrowth by
non-susceptible organisms, neurotoxicity (headache, dizziness, ataxia,
convulsions, vertigo, tinnitus, hallucinations), crystalluria,
hypoglycemia, hypokalemia, folate deficiency, hematolgical disturbances
(leukopenia, agranulocytosis,<
thrombocytopenia) [1, 2, 18]
1, 2,
7, 14, 18, 52, 53, 54«
S u l f a m e t h o x a z o l e :
N a c e t y l a t i o n
( N a c e t y l s u l f a m e t h o x a z o l e )
a n d
g l u c u r o n i d a t i o n
[ 1 ,
2 ] .
T r i m e t h o p r i m :
M e t a b o l i s m
t o
1 a n d
3 o x i d e s ,
3
a n d
4
h y d r o x y d e r i v a t i v e s
[ 1 ,
2 ] .
‰
Rare:
liver necrosis, elevated liver enzymes, hepatitis, hyperbilirubinemia,
cholestasis, jaundice, vanishing bile duct syndrome [1, 52].
L
In
patients with alcoholic liver cirrhosis (incl. Child C) no significant
difference in pharmacokinetics was observed after a single dose of 800mg
sulfamethoxazole (SMX)/160mg trimethoprim (TMP) compared to healthy
subjects [53]. Sporadic increases of t1/2 of TMP up to 2-fold have been
observed in cirrhotics, but also in healthy subjects. No dose adjustment
was considered necessary [53]. After multiple doses (800mg SMX/160mg TMP
every 12 hours for 7 days) differences in kinetics disappeared after the
third day of administration, suggesting that no dose adjustment is
required [54]. ý
h Inactivation by N-demethylation by CYP 3A to
des-N-methylerythromycin. Enterohepatic cycling [1, 2, 4]. " PB is dosedependnet (46-74%) [1].% 1, 2, 4, 6, 7, 12, 14, 21, 27, 55, 56•
Rare:
cholestatic hepatitis, jaundice (10-14 days after the start of
treatment), associated with raised AST/ALT levels and eosinophilia [1,
2].
gastrointestinal disturbances, increased gut motility,
intestinal overgrowth by non-susceptible organisms, ototoxicity,
convulsions, paraesthesia, ataxia, psychosis, cholestatic jaundice,
arrhythmia (QT-prolongation, torsades de pointes), aggravation of
myasthenia gravis [1, 2, 12, 21]
%
AUC and Cmax were higher (no
significance) and t1/2 significantly longer (3.2h vs 2h) in patients with
alcoholic liver disease compared to normal subjects [27, 55]. Clinical
significance unknown. In patients with alcoholic cirrhosis (Child B and
C), fu (58.3% vs 30.5%; due to decreased levels of alpha1-acid
glycoprotein) and Vd (86L vs 58L) were significantly increased, CL of
unbound erythromycin was significantly reduced (42.2L/h vs 113.2L/h)
[56]. Because of a large therapeutic index of erythromycin, dosage
adjustment probably not necessary.
0
3
û
ü
H
I
[ The exact metabolic pathway is unknown.
Enterohepatic circulation may occur [1, 2, 57, 58].| gastrointestinal
disturbances, intestinal overgrowth by non-susceptible organisms,
paresthesia, cholestatic hepatitis [1, 2]Ê Hepatic dysfunction appears
not to markedly affect the kinetics of spiramycin [2]. It is accepted
that no dose reduction is necessary, but patients with liver cirrhosis
should be monitored [59, 60, 61].
1, 2, 9, 57, 58, 59, 60, 61M
Rare:
elevated liver enzymes, hepatitis with and without cholestasis [1,
10].
^ N-demethylation, hydroxylation to 14-hydroxyclarithromycin.
Substrate of CYP P450 3A4 [1, 2]. - gastrointestinal disturbances, taste
perversion, intestinal overgrowth by non-susceptible organisms,
ototoxicity, neurotoxicity (headache, dizziness, convulsions,
hallucinations, paraesthesia, ataxia), arrhythmias (QT-prolongation,
torsades de pointes), cholestatic hepatitis [1, 2, 12]u No differences
in pharmacokinetics of clarithromycin observed in cirrhotic patients
(Child A, B and C) compared to healthy controls [62, 63, 64], but AUC of
14-(R)-hydroxyclarithromycin was significantly lower in patients with
severe liver cirrhosis [62, 63]. Caution if the hydroxy-metabolite is
necessary for antimicrobial activity (e.g. haemophilus influenzae) [63,
65].l No changes in kinetics observed in patients with mild liver
disease. Concentration of the active metabolite was generally lower in
these patients. Because of its high hepatic metabolism, monitoring of
patients with severe liver disease is recommended [1]. No dosage
adjustment necessary in the presence of hepatic impairment in case of
normal renal function [12]. ( 1, 2, 4, 6, 8, 9, 12, 21, 62, 63, 64,
65‚
Frequent: elevated AST, ALT. Rare: hepatocellular and/or
cholestatic hepatitis, with or without jaundice, liver failure [1, 2, 4].
!
p Metabolism mainly by N-demethylation, but also Odemethylation and hydroxylation (metabolites inactive) [1, 2].
gastrointestinal disturbances, intestinal overgrowth by nonsusceptible organisms, ototoxicity, neurotoxicity (headache, dizziness,
convulsions, asthenia, paresthesia), palpitations, arrhythmias (QTprolongation, torsades de pointes), cholestatic hepatitis, neutropenia
[1, 2, 12]§ Despite its hepatic metabolism, no dose modification seems
necessary according to the results from a single dose study with 500mg
azithromycin in 16 cirrhotic patients with mild or moderate hepatic
impairment (Child-Pugh Class A and B) [66]. No clinical data are
available for patients with severe hepatic impairment (Child-Pugh Class
C) or in patients with cholestasis. Azithromycin is not recommended in
these cases [67].
1, 2, 6, 7, 12, 14, 66, 67š
Occasionally:
reversible asymptomatic elevations of liver enzymes (> 3x ULN). Rare:
hepatitis, cholestatic jaundice, liver necrosis, liver failure [1, 2].
N
S
^ N-demethylation, sulfoxidation (by CYP 3A4), hydrolysis to
some active metabolites [1, 2, 68]." PB is dose-dependent (40-90%)
[1].´ gastrointestinal disturbances, intestinal overgrowth by nonsusceptible organisms, hypotension, cardiac arrest (after too rapid
injection), liver enzyme elevations, jaundice [1, 2]8 1, 2, 4, 6, 7, 8,
10, 68, 69, 70, 71, 72, 73, 74, 75, 76î
Frequent: 40-50% of patients
develop elevated liver enzymes which may return to normal despite
continuation of the treatment. Occasionally: jaundice. Rare:
hepatocellular toxicity, exacerbation of preexisting liver disease [1, 4,
10, 69].
~
‹
–
›
)
Studies revealed 1.2-5 fold increase
in t1/2 in patients with severe liver disease (hepatitis, cirrhosis,
obstructive jaundice) [70, 71], one study only in cirrhotics but not in
those with hepatitis [72]. Concentration after 5h was 3 times higher in
patients with moderate to severe hepatic dysfunction compared to normal
controls [73]. Positive correlation between t1/2, serum concentration and
AST [70, 71, 73] or indirect bilirubin [74] found in some reports, but
not in others [72, 74]. Monitoring of drug level and liver function
recommended [72]. )
,
o
r
Mainly renal elimination
[1].Ù ototoxicity, vestibular toxicity, neurotoxicity (paresthesia,
convulsions), lethargy, confusion, neuromuscular blockade (aggravation of
myasthenia gravis, postoperative respiratory distress), nephrotoxicity
[1, 2, 21]
1, 2, 6, 7, 9, 14, 21, 77J
Occasionally: increased liver
enzymes (ALT, AST, AP) and bilirubin [1, 9].
—
While no significant effect was observed for CL and t1/2 in
cirrhotics, Vd was significantly larger when ascites was present (0.32 vs
0.26 L/kg) [77]. 5
8
I
J
! Mainly renal elimination [1, 9].
ototoxicity, vestibular toxicity, neurotoxicity (hallucinations,
encephalopathy, convulsions), pseudotumor cerebri, visual disturbances,
neuromuscular blockade (aggravation of myasthenia gravis, postoperative
respiratory distress), nephrotoxicity [1, 2, 21]
1, 2, 6, 7, 8, 9, 21,
78, 79T
Occasionally: elevations of liver enzymes and bilirubin,
transient hepatomegaly [1].
£
The t1/2 and effect of jaundice on excretion was evaluated in
neonates. The presence of icterus or hyperbilirubinemia did not delay
excretion in any patient [78].
A No metabolism. 90-98% is
excreted unchanged in the urine [1, 9]. ø ototoxicity, vestibular
toxicity, neurotoxicity (convulsions, hallucination, encephalopathy),
visual disturbances, neuromuscular blockade (aggravation of myasthenia
gravis, postoperative respiratory distress), nephrotoxicity,
hypomagnesemia [1, 21]h
Rare: liver enzyme elevations (ALT, AST, AP),
elevated bilirubin, hepatomegaly, hepatic necrosis [1, 9].
m Less
than 10% are metabolized by glucuronidation, demethylation and Noxidation to inactive metabolites [2].
gastrointestinal disturbances,
intestinal overgrowth by non-susceptib<
le organisms, neurotoxicity
(dizziness, confusion, insomnia, seizures, hearing disturbances, visual
disturbances, paresthesias), depression, psychotic reaction,
hallucination, tremor, tendinitis [1, 2, 21]% 1, 2, 6, 7, 9, 14, 21, 80,
81, 82, 83
Vss and CLsys according to [80].
m
Rare: elevations of liver enzymes and bilirubin, cholestatic
jaundice, hepatitis, severe liver injury [1, 9].
©
T1/2 and Vd were
significantly increased by 55% and 33%, respectively, in cirrhotic
patients (Child A) compared to controls [81]. A reduction in renal CL was
observed (32%; not significant), although renal function was apparently
normal. T1/2 was also increased by 66% in another study, probably related
to impairment of tubular secretion [82]. No dose adjustment seems
necessary in patients with cirrhosis and ascites [83].
ï
ò
› About 16% are eliminated unchanged by the feces,
enterohepatic recirculation has been suggested. Metabolism to active and
inactive metabolites [1, 2, 12]. å gastrointestinal disturbances,
intestinal overgrowth by non-susceptible organisms, neurotoxicity
(dizziness, tremor, confusion, hallucinations, seizures), depression,
psychotic reaction, vision and hearing disturbances [1, 2, 12]- 1, 2, 4,
9, 12, 84, 85, 86, 87y
Occasionally: elevated liver enzymes and
bilirubin. Rare: hepatic necrosis, hepatitis, cholestatic jaundice [1, 2,
4, 9].
4
8
Various studies showed no difference in pharmacokinetics
between patients with liver cirrhosis (Child A, B and C) and healthy
controls [84, 85], except one study [86]. Patients with Child C had
higher Cmax, t1/2 and AUC. In one study, significant smaller quantities
of oxociprofloxacin were found, probably due to decreased hepatic
metabolism [87]. Pharmacokinetics were impaired in cirrhotics with
moderate renal insufficiency [85]. Administration at usual doses in
cirrhotics with normal renal function seems safe [84, 85, 87]. Ê
Í
Ð
Ó
Metabolites derived from chemical substitutions on the piperazine
ring and glucuronidation. Main metabolite oxo-piperazine. Active
metabolites with less antimicrobial potency than norfloxacin. A possible
first pass effect and enteric recirculation is discussed [1, 2, 9, 88].
gastrointestinal disturbances, intestinal overgrowth by nonsusceptible organisms, neurotoxicity (dizziness, confusion, insomnia,
seizures, hearing disturbances, visual disturbances, paresthesias),
depression, hallucination, psychotic reactions, crystalluria, tendinitis
[1, 2, 12]Í No specific dosage recommendations can be made due to lack
of pharmacokinetic data. However, dose of 400mg up to twice daily is used
for prophylaxis of spontaneous bacterial peritonitis in cirrhotics
[91].& 1, 2, 4, 9, 12, 14, 21, 88, 89, 90, 91”
Frequent: elevated
liver enzymes. Rare: hepatocellular injury, cholestatic jaundice,
hepatitis, hepatic failure (including fatalities) [1, 2, 4, 9].
"
&
X
A single dose study (400mg) has reported that serum
t1/2 and AUC were only slightly and not significantly altered in patients
with moderate hepatic dysfunction (patients recovering from acute HBV
infection) [89]. It is uncertain whether or not the liver is a major site
of excretion of norfloxacin [88, 90]. No dose adjustment is probably
necessary for patients with mild to moderate hepatic insufficiency. In
cirrhotics, norfloxacin may be indicated as prophylaxis of spontaneous
bacterial peritonitis at a dose of 400mg once or twice daily in cirrhotic
patients with gastrointestinal bleeding [91].5
8
z Only minor
metabolism to desmethyl-levofloxacin and levofloxacin N-oxide. Less than
4% is excreted into the faeces [1, 9].
1, 6, 9, 12–
Frequent: elevations of liver enzymes. Occasionally:
elevations of serum bilirubin. Rare: hepatitis, liver failure, hepatic
necrosis, jaundice [1, 9].
'
5
T
Y
gastrointestinal disturbances, intestinal
overgrowth by non-susceptible organisms, neurotoxicity (dizziness,
hearing disturbances, tremors, confusion, seizures, asthenia, visual
disturbances), hallucination, depression, torsade de pointes,
hypoglycemia, tendinitis [1, 12]
• Liver metabolism does not
involve CYP P450 system but phase II metabolism (sulfation,
glucuronidation) generating inactive metabolites [1,
92].! gastrointestinal disturbances, intestinal overgrowth by nonsusceptible organisms, neurotoxicity (dizziness, asthenia, somnolence,
confusion, insomnia, seizures, paresthesias, tremors), hallucination,
depression, psychotic reaction, tendinitis, torsade de pointes, QTcprolongation [1, 12]
Pharmacokinetics were similar in cirrhotics and
healthy subjects [95, 96, 97]. AUC of moxifloxacin was 23% lower in
cirrhotics (Child A and B), AUC of the sulfo-metabolite was 4 times
higher compared to healthy controls [95, 96]. No dose adjustment
necessary [95, 96, 97].
1, 9, 12, 92, 93, 94, 95, 96, 97²
F r e q u e n t :
e l e v a t e d
A L T ,
A S T .
O c c a s i o n a l l y :
i n c r e a s e
i n
o t h e r
l i v e r
e n z y m e s
( d" 3
U L N ) .
R a r e :
a c u t e
l i v e r
f a i l u r e ,
c h o l e s t a t i c
h e p a t i t i s ,
j a u n d i c e ,
h e p a t i c
n e c r o s i s
[ 1 ,
9 ,
9 3 ,
9 4 ] .
)
V
[
Metabolism negligible [1, 2].
1, 2, 6, 7,
14, 21, 98, 99
Foral negligible.
—
ototoxicity,
nephrotoxicity, gastrointestinal disturbances, intestinal overgrowth by
non-susceptible organisms, neutropenia, agranulocytosis [1, 2,
21]Œ
•
ð
Mean t1/2 in patients with different liver diseases and
normal renal function was 7.8h (no controls) [98]. Renal CL was enhanced
due to a reduction in PB and nonrenal CL was reduced, resulting in liver
disease having no effect on total CL.
|
Parenteral
administration: Based on pharmacokinetic data, adjust maintenance dose
according to creatinine clearance. Monitoring of plasma concentration
recommended (reference values: Cmin 5-10 mg/l, Cmax <40 mg/l [99]). Oral
administration: Use normal dose since oral absorption is low. Monitor
dose-dependent toxicity. Determine serum concentration in case of
possible toxicity. ¸
»
È
Ë
§ No absorption takes place if given
orally and thus serves as local therapy in the intestine. There is no
evidence for extensive hepatic metabolism of the drug [1, 9].
Ä ototoxicity, nephrotoxiciy, gastrointestinal disturbances, intestinal
overgrowth by non-susceptible organisms, neurotoxicity (headache,
drowsiness, seizures, rigor), fever, thrombocytopenia [1, 2]
1, 2, 6, 9, 14C
T1/2 ranges from 70h to 150h due to biphasic
pharmacokinetics [1].
F
Occasionally: elevated liver enzymes.
Rare: cholestatic hepatitis [1].
&
+
… Colistimethate sodium is a prodrug and hydrolyzed to the
active principle, colistin [9]. The pharmacockinetic data refer to
colistin.# PB and oral absorption are low [2].- Can exacerbate
porphyrias [1].c nephrotoxicity, neurotoxicity (paresthesia, muscle
weakness), oral candidiasis, bronchospasm [1, 2]
1, 2, 9, 100˜ Metabolism in the liver to glucuronic acid conjugates,
dicarboxylic acid metabolite, hydroxy metabolite [1, 2]. Metabolites have
weak or no bioactivity.Ä gastrointestinal disturbances,
hyperbilirubinemia, jaundice, liver enzyme elevations, hematological
reactions (neutropenia, granulocytopenia, agranulocytosis), lethargy,
drowsiness, fatigue [1, 2]( In patients with hypoalbuminemia with no
cholestasis, cholestasis or hyperbilirubinemia, CL was higher compared to
values in normal subjects because of increased free fraction [104]. In
patients with bilirubinemia, this effect was offset by competition for
the glucuronidation step by bilirubin. S No data in patints with liver
disease. Caution in patients with liver disease and/or impaired bilirubin
transport or metabolism [1]. Caution in patients with mild and moderate
liver disease and bile duct obstruction. Fusidic acid should not be used
in patients with severe hepatic failure [2]. Monitoring of liver function
recommended [2].- 1, 2, 4, 9, 101, 102, 103, 104
CLsys according to
[101].
/
Rare: liver enzyme elevations, hyperbilirubinemia,
reversible ch<
olestatic jaundice, hepatorenal syndrome [1, 2, 4, 102,
103]. Jaundice may be due to intrahepatic cholestasis because of
competition with the excretory pathways of hepatic bile acids related to
the steroid-like structure of the drug [104].
¤ 30-60% metabolized in
the liver by side-chain-oxidation (hydroxy metabolite, acetic acid
metabolite), glucuronide conjugation. Enterohepatic circulation [1, 2,
21].Ô Dosage reduction and monitoring of drug levels recommended in
patients with severe liver disease. Caution in patients with hepatic
encephalopathy [1]. 50% dose reduction in patients with liver
insufficiency [2]. > 1, 2, 4, 6, 7, 8, 9, 14, 21, 105, 106, 107, 108,
109, 110, 111Z
Rare: abnormal liver function tests, hepatocellular and
cholestatic hepatic injury [1, 4].
gastrointestinal disturbances,
metallic taste, intestinal overgrowth by non-susceptible organisms,
peripheral neuropathy, confusion, hallucination, seizures,
encephalopathy, paresthesia, ataxia, visual disturbances, discolocration
of urine, hematological reactions [1, 2]
¡
No significant alterations of kinetics in patients with decompensated
liver cirrhosis or schistosomiasis in one study [105]. Decompensated
liver disease: t1/2 152% higher, Vd and CL 21% and 66% lower compared to
healthy controls [106]; significant reduction in Cmax and AUC of hydroxy
metabolite [107]. T1/2 prolonged 2-fold in patients with hepatic and
partly renal insufficiency compared to controls [108]. Alcoholic liver
disease: t1/2 18.3h, Vd 0.77L/kg, and systemic CL 0.51mL/min per kg
(equivalent to 2.1L/h) [109].Elimination more affected in patients with
obstructive liver disease than in patients with hepatocellular liver
injury [110]. T1/2 increased with severity of liver disease [111].
Decompensated liver disease: recommended to administer 0.5g i.v. 2x
instead of 3x a day; oral dose 200mg 4x a day [107]. Alcoholic liver
disease: recommended to reduce intravenous dosage from 500mg every 6h to
every 12h [109]. ›
ž
®
0
3
³
¶
¿
À
‰
Œ
¥ Over 90% are metabolized in the liver by odixative pathway and
hydrolysis [1, 112]. The two major metabolites have almost the same
activity as the parent compound.
gastrointestinal disturbances,
metallic taste, intestinal overgrowth by non-susceptible organisms,
central and peripheral neuropathy (confusion, dizziness, drowsiness,
seizures, paraesthesia, ataxia, tremor, rigidity), discolocration of
urine, hematological reactions [1, 9]0 1, 9, 14, 112, 113, 114, 115,
116, 117, 118, 119^
Case reports: hepatitis, autoimmune hepatitis,
cholestatic jaundice [113, 114, 115, 116, 117].
K
Single 500mg i.v. dose in patients with alcoholic liver
cirrhosis: significant increase of t1/2 (22 vs 14 h) and decrease of
plasma CL (35 vs 51 mL/min) [118]. The interval between repeated doses
could be doubled. Patients with hepatitis, noncholestatic cirrhosis and
extrahepatic cirrhosis: CL decreased by 26-48% and t1/2 increased by 1938% compared to healthy volunteers. No clear difference could be
established between the different patient groups. Plasma concentration of
active metabolites increased as a result of reduced elimination including
decreased biliary excretion [119].\
_
@
C
G Glucuronidation, Nacetylation, not exclusively in the liver [1, 2, 9].ó gastrointestinal
disturbances (nausea, emesis, loss of appetite, diarrhea), headache,
dizziness, nystagmus, increased intracranial pressure , psychosis,
peripheral polyneuropathy (paresthesia, burning feet syndrome, muscle
weakness) [1, 2, 21]
1, 2, 6, 9, 14, 21, 120œ
Rare: hepatic
reactions from acute forms such as hepatitis or cholestasis to chronic
forms such as chronic active hepatitis or severe liver necrosis [1,
9].
< No metabolism. Enterohepatic recirculation observed [1, 2].
B gastrointestinal disturbances, dizziness, vertigo, asthenia [1,
2]¦ No specification in the Swiss product information. Fosfomycin is not
metabolized and dosing adjustments are not required in patients with
hepatic insufficiency [9].
1, 2, 9, 1211
Case report: acute fatty liver (steatosis) [121].
Ø Metabolism to inactive ring-open metabolites probably by slow
nonenzymatic morpholine-ring oxidation mediated by reactive oxygen
species [1, 122]. About 9% of the dose are excreted as metabolites into
the faeces [1].ç gastrointestinal disturbances, metallic taste,
intestinal overgrowth by non-susceptible organisms, neurotoxicity
(dizziness, insomnia, vertigo, paresthesia, seizure, peripheral and optic
neuropathy), haematological reactions [1, 9]! 1, 9, 12, 122, 123, 124,
125, 126•
Frequent: abnormal liver function tests [1]. Case report:
elevated bilirubin [123], severe cholestatic liver injury (with
concomitant lactic acidosis) [124].
8
[
In patients with
mild to moderate liver disease by Child-Pugh scores, AUC and t1/2 both
increased about 1.3-fold, while renal CL decreased by a factor of 1.3
compared to healthy volunteers. Urinary excretion of the two major
metabolites was decreased [125]. Therapeutic drug monitoring is
recommended for patients with severe liver disease [126]. O
R
L In
vitro studies showed no metabolism of daptomycin by CYP P450 enzymes
[1].
gastrointestinal disturbances, intestinal overgrowth by nonsusceptible organisms, peripheral neuropathy, paraesthesia, dizziness,
insomnia, anxiety, elevations of creatine phosphokinase incl. Myositis,
muscle pain, muscle weakness and rhabdomyolysis, nephrotoxicity [1,
9]Ý Pharmacokinetics of daptomycin (single i.v. dose 6mg/kg total body
weight) in subjects with moderate hepatic liver disease (Child-Pugh B)
were similar compared to healthy volunteers matched by weight, age, and
sex [127]. ® According to pharmacokinetic data, start with normal intial
dose. Adjust maintenance dose according to clinical effect, dosedependent adverse effects, and/or plasma levels.
1, 7, 9, 127B
Frequent: elevations of liver enzymes. Occasionally:
jaundice [1].
'
4
s Metabolism unknown. 40% of a dose (i.v.)
excreted renally after 7 days. Biliary excretion may be of importance
[1].ë nephrotoxicity, gastrointestinal disturbances, hematological
disturbances, thrombophlebitis, neuropathy (dizziness, convulsions,
visual disturbances), arrhythmia, infusion related reactions (chills,
fever, nausea, vomiting) [1, 12, 21]B Serum levels not altered in
patients with liver insufficiency [1].- 1, 2, 4, 6, 7, 8, 12, 21, 128
C
Rare: elevated liver enzymes, jaundice, acute liver failure [1,
4].
- Metabolism unknown [1, 9, 12].@ nephrotoxicity (less than with
the sodium desoxycholate [4]), gastrointestinal disturbances,
hematological disturbances, thrombophlebitis, central and peripheral
neuropathy (dizziness, convulsions, visual disturbances), arrhythmia,
hepatotoxicity, infusion related reactions (chills, fever, nausea,
vomiting) [1, 12, 21]Î Monitor renal function, liver function,
electrolyte (potassium and magnesium) levels and blood picture and reduce
dosage accordingly [1]. No pharmacokinetic data in patients with hepatic
insufficiency [12].
1, 2, 6, 7, 8, 9, 12, 21W
Non-linear
pharmacokinetics due to saturable CL [1]. T1/2 after single dose 7-10h
[9].7
:
”
Frequent: hyperbilirubinemia, elevated AP, elevated
liver enzymes [1]. Rare: hepatomegaly, veno-occlusive liver disease,
hepatocellular damage [12].
G
L
² Oxidation and degradation as
well as oxidative O-dealkylation and aromatic hydroxylation. First-pass
elimination may be saturable. Enterohepatic circulation possible [1, 2,
129].• gastrointestinal disturbances, neurotoxicity (headache,
dizziness, photophobia, paresthesia), adrenal insufficiency, gynecomastia
[1, 2, 21] 1 Single doses in hepatic insufficiency (case-control): After
200mg AUC increased almost three-fold, after 400mg no increase seen.
Plateau of concentrations after both doses. During 8h of sampling, no
elimination phase detected. But no evidence for accumulation [129].
Hepatic cirrhosis: Significantly decreased albumin concentration (36.2g/L
vs. 46.5g/L) resulting in a significantly increased free fraction of
ketoconazole (6% vs. 3%) [130]. Histoplasma-affected patient w<
ith
severe liver impairment: no drug accumulation after 400mg/d for 12 months
[131, 132]., 1, 2, 4, 6, 7, 8, 12, 21, 129, 130, 131,
132˜
Occasionally: elevated liver enzymes. Rare: hepatitis,
hepatocellular and mixed jaundice, hepatic necrosis, liver failure,
including fatalities [1, 4].
&
*
l Minimal metabolism to 1,2,3-triazole and N-dealkylated
products. Glucuronidation and N-oxidation [1, 2, 9]. g gastrointestinal
disturbances, neurotoxicity (headache, dizziness, seizures),
hepatotoxicity [1, 9, 21]
1, 2, 6, 7, 8, 9, 21, 133È
Frequent:
elevated ALT, AST and AP. Occasionally: hyperbilirubinemia, jaundice,
cholestasis, hepatocellular injury. Rare: hepatitis, hepatocellular
necrosis, hepatic failure, including fatalities [1].
$
2
t
y
•
Child Pugh B and C (case-control): T1/2 and AUC
significantly increased (89.5h vs. 32.7h and 200hmg/L vs. 69.4hmg/L,
respectively), probably due to diuretic-induced reductions in GFR and
further interactions with concomitant medication [133]. In patients with
Child Pugh B and C liver cirrhosis, the drug should be used with caution,
but no general dose reduction is justified [133].$
'
• Extensive
saturable metabolism by CYP P450 3A4 with hydroxy-itraconazole as major
metabolite. Enterohepatic circulation [1, 9].• hepatotoxicity,
gastrointestinal disturbances, photophobia, headache, dizziness, heart
failure, hypokalemia, adrenal insufficiency [1, 2, 21]ö Generally,
itraconazole exposure after oral administratioin was similar between
patients with liver cirrhosis and healthy subjects. Limited data in
patients wtih liver disease, use with caution. In patients with elevated
liver enzymes or active liver disease, start or continue treatment only
if benefit outweighs the risk of hepatic injury. Careful monitoring is
recommended [1]. Oral F may be decreased in patients with liver
cirrhosis. In cirrhotics, it is advisable to monitor plasma levels [2].
! 1, 2, 4, 6, 7, 8, 9, 21, 134, 135‚
Rare: elevated liver enzymes,
hepatotcellular and cholestatic injury, hepatitis, acute liver failure,
including fatalities [1, 4].
Cirrhosis: Cmax, AUC and elimination
t1/2 of oral itraconazole similar to the values in healthy volunteers
[134]. Oral 100mg single dose in cirrhotics: AUC was unchanged, Cmax
decreased significantly by 47% and elimination t1/2 increased (37 vs.
21h) [135].
&
)
¬
¯
à
ã
W Extensive metabolism by CYP P450 2C19
(polymorphic), 2C9 (polymorphic), and 3A4 [1, 9].
1, 9, 12, 136, 137,
138, 139æ
Frequent: elevated liver enzymes (AST, ALT, AP, GGT) and
bilirubin, (cholestatic) jaundice. Occasionally: cholecystitis,
gallstones, hepatomegaly, hepatitis, liver failure, including fatalities.
Post-marketing: liver necrosis [1].
\
h
Ã
Ò
1
gastrointestinal disturbances, fever,
neurotoxicity (visual disturbances, headache, hallucinations), edemas,
renal failure, arrhythmias (QTc prolongation, torsade de pointes),
respiratory disorders, hypoglycemia, adrenal cortex insufficiency,
hematological changes, hepatotoxicity, skin reactions [1, 136]
M
Case report: After multiple administration of 2mg/kg p.o. twice daily
(normal maintenance dose) to a patient with Child Pugh C liver cirrhosis,
t1/2 was prolonged (53.1h vs. 6h), Vd was reduced (0.13L/kg vs. 3.3L/kg),
and CL rate was decreased (0.1L/h vs. 7.4L/h) [137]. Oral CL was
decreased by ~50% in patients with moderate liver disease compared to
those without hepatic impairment, Cmax was decreased by ~20%, AUC was
similar [138]. In patients after liver transplantation, the following
mean values for CL, Vss, and t1/2 were reported: 5.8L/h, 1.4L/kg, and
15.5h, respectively [139].
‘
”
´
µ
„
‡
¨ Less than 30% of posaconyzole is metabolized mainly by
glucuronidation [1, 140]. 77% (66% unchanged) eliminated in the feces and
14% (<0.2% unchanged) in the urine [1].$ Pharmacokinetics dose-dependent
[9].… In a single and mutliple-dose study with different dosages (range
of 50 to 1200mg), the adverse events were not dose-dependent [141].
1,
9, 12, 140, 141, 142
Frequent: elevated liver values (AST, ALT, AP,
GGT, bilirubin). Occasionally: liver cell injury, hepatitis, jaundice,
hepatomegaly. Rare: liver insufficiency, cholestatic hepatitis,
cholestasis, enlarged liver and spleen, liver tenderness, fatal
hepatotoxicity [1].
@
M
„
Š
<
Limited data (study with 12 patients with liver
disease): t1/2 increased in patients with mild (26.6h), moderate (35.3h),
and severe (46.1h) hepatic insufficiency compared to individuals with
normal hepatic function (22.1h). Exposure is expected to increase twofold
in patients with severe hepatic insufficiency [1].;
>
[ Less than 1%
metabolized through deamination to 5-fluorouracil or dihydrofluorouracil
[2]. þ hematological disturbances (myelosuppression), gastrointestinal
disturbances, neurotoxicity (headache, dizziness, drowsiness,
paresthesias, mental disorders), hepatotoxicity, nephrotoxicity (rise in
creatinine and BUN, cristalluria, azotaemia) [1, 2, 21]n In patients
with mild to moderate cirrhosis (case reports): serum drug levels not
significantly altered [143].
1, 2, 6, 7, 8, 9, 14, 21, 143€
Rare:
elevated liver enzymes, hyperbilirubinemia, jaundice, hepatic necrosis,
acute hepatic injury, including fatalities [1, 9].
” Plasma and
liver: Slow metabolism through N-acetylation*, hydrolysis and spontanoues
ring opening [1, 9]. *poor metabolizers: Europe 50%, Asia 10%.
# Pharmacokinetics polyphasic [1, 9].¿ Child Pugh A: After a single
70mg dose, AUC increased by 55%. After multiple dosing (14 days), AUC
increased 19-25%. Child Pugh B: After a single 70mg dose, AUC increased
by 76% [1, 12, 144].
1, 7, 9, 12, 144, 145¶
Frequent: elevated ALT,
AST, AP, and bilirubin. Occasionally: cholestasis, hepatomegaly,
jaundice, hepatic dysfunction. Unknown frequency: hepatic failure,
hepatic necrosis [1, 12].
0
=
w
Š
< Slow non-enzymatic metabolism to an inactive
peptide [1, 9].¸ gastrointestinal disturbances, elevated liver enzymes,
nephrotoxicity (elevated creatinine, BUN), hematological changes,
coagulopathy, flushing, rash, pruritus, convulsions [1, 9,
146]æ Anidulafungin concentrations were not different in patients with
liver disease Child Pugh A, B, or C. In patients with Child Pugh C, a
minimal decrease of AUC and Cmax was observed, but not considered
clinically relevant [1, 147].
1, 9, 146, 147°
Frequent: elevated ALT, AST, AP, GGT, bilirubin.
Occasionally: cholestasis. Rare: impaired liver function, hepatitis,
worsening of liver insufficiency, hepatic necrosis [1, 9].
1
>
L
Q
„
Desacetylation to mainly 25-O-desacetyl-rifampicin
and formylrifampicin. Enterohepatic circulation. Induces its own
metabolism [1].Ù gastrointestinal disturbances, neurotoxicity
(drowsiness, headache, confusion, ataxia), hepatotoxicity,
nephrotoxicity, brownish-red or orange discoloration of the skin, urine,
sweat, saliva, tears, and feces [1, 148]› Contraindicated in case of
acute liver disease or history of drug-induced hepatitis. Liver disease
and other hepatotoxic drugs are risk factors for hepatotoxicity. Monitor
liver function (especially AST and ALT). Consider dose adaptation in
cases of severe liver disease. Stop rifampicin if symptoms of liver
injury develop [1]. Severe liver disease and jaundice: Contraindication
due to biliary excretion [2]. M 1, 2, 4, 6, 7, 14, 148, 149, 150, 151,
152, 153, 154, 155, 156, 157, 158, 159i
Frequent: liver enzyme
elevations. Rare: hepatitis, jaundice, liver failure, including
fatalities [1, 4].
#
(
B
V i r a l
h e p a t i t i s
i s
a
r i s k
f a c t o r
f o r
h e p a t o t o x i c i t y
a n d
i n
s u c h
p a t i e n t s ,
s e r u m
l e v e l s
o f
r i f a m p i c i n
w e r e
h i g h e r
[ 1 4 9 ,
1 5 0 ,
1 5 1 ,
1 5 2 ] .
I n
p a t i e n t s
w i t h
l i v e r
c i r r h o s i s
[ 1 5 3 ,
1 5 4 ]
o r
o t h e r
l i v e r
d i s e a s e
[ 1 5 5 ] ,
s e r u m
l e v e l s
( 8 . 5
v s .
6 . 5 ¼ g / m l
[ 1 5 4 ] )
a n d
t 1 / 2
( 5 . 4 2
v s .
2 . 8 h
[ 1 5 4 ] <
)
w e r e
i n c r e a s e d .
I n
p a t i e n t s
w i t h
s e v e r e
c h r o n i c
l i v e r
i m p a i r m e n t
( c i r r h o s i s
/
o t h e r ) ,
r i f a m p i c i n
6 - 8
m g / k g
b i w e e k l y
l e d
t o
b l o o d
l e v e l s
c o m p a r a b l e
t o
t h o s e
a f t e r
1 2 m g / k g
b i w e e k l y
i n
h e a l t h y
p a t i e n t s
a n d
s h o u l d
n o t
b e
e x c e e d e d
[ 1 5 6 ] .
S e r u m
b i l i r u b i n
> 5 0
¼ m o l e / L :
D o s a g e
r e d u c t i o n
s u g g e s t e d
[ 1 5 7 ,
1 5 8 ] . ü
ÿ
— Extensive presystemic metabolism, possibly in the
gut, by deacetylation and hydroxylation to active metabolites. Induces
its own metabolism [1, 2, 9]. ‰ gastrointestinal disturbances,
neurotoxicity (drowsiness, headache, asthenia, ataxia), uveitis,
arthralgia/arthritis syndrome [1, 2, 160]' No dose adjustment in
patients with mild liver disease. Caution in patients with severe liver
disease. Monitor hepatic enzymes in all patients [1]. No dose adjustment
in patients with mild liver disease. Caution in patients with severe
liver disease. Monitor hepatic enzymes in all patients [2].! 1, 2, 6, 7,
9, 160, 161, 162, 163=
Frequent: elevated liver enzymes. Ocassionally:
jaundice [1].
"
/
m
I n
p a t i e n t s
w i t h
v a r y i n g
d e g r e e s
o f
l i v e r
i n s u f f i c i e n c y ,
A U C
a n d
t 1 / 2
a f t e r
a
s i n g l e
3 0 0 m g
o r a l
d o s e
s i g n i f i c a n t l y
i n c r e a s e d
o n l y
i n
p a t i e n t s
w i t h
s e v e r e
h e p a t i c
i m p a i r m e n t
( C h i l d
P u g h
e" 1 0 )
[ 1 6 1 ,
1 6 2 ,
1 6 3 ] .
N o
d o s e
a d j u s t m e n t
i n
p a t i e n t s
w i t h
m i l d
t o
m o d e r a t e
l i v e r
d y s f u n c t i o n .
I n
s e v e r e
h e p a t i c
i n s u f f i c i e n c y ,
d o s e
r e d u c t i o n
m i g h t
b e
a d v i s a b l e
[ 1 6 1 ,
1 6 2 ,
1 6 3 ] .
B
E
¾
¿
ª Acetylation* and hydrolysis to
acetyl-isoniazid, isonicotinic acid and acetylhydrazine. Partly
hepatotoxic metabolites [1, 150]. *poor metabolizers: Europe 50%, Asia
10% ) 1, 2, 4, 6, 7, 9, 150, 154, 159, 164, 165•
Pharmacokinetic data
reported for extensive acetylators. Slow acetylators: Q0 0.7, t1/2 term
3h, CLsys 15.5L/h, hepatic extraction rate E 0.20.L
M
T
W
X
\
c
f
¤
Frequent: elevated liver enzymes. Occasionally:
jaundice, hepatitis. Rare: hepatocellular injury, hepatic necrosis,
hepatic failure, including fatalities [1, 4, 9].
"
0
E
I
Ú
In patients with liver disease (acute or
chronic viral hepatitis, alcoholism) or liver cirrhosis, t1/2 increased
by 28% correlating with elevation of serum bilirubin [164, 165] or to 6.7
(vs. 3.2h) [154], respectively.c
f
p Hepatic hydrolysis to
pyrazinoic acid, hydroxylation by xanthine oxidase to an inactive
metabolite [1, 2, 166]. # 1, 2, 4, 6, 7, 9, 14, 159, 166, 167–
Frequent: elevated liver enzymes. Ocassionally: liver sensitivity.
Rare: jaundice, acute liver necrosis, hepatic failure, including
fatalities [1, 4].
"
/
C
G
Å
T1/2 increased to 15h in
patients with liver cirrhosis [9]. To reduce risk of hepatotoxicity, best
avoid pyrazinamide in patients with liver cirrhosis and other preexisting liver disease [2, 167].
- Minimal hepatic oxidation
[1].‘ retrobulbar neuritis, gastrointestinal disturbances, central
(headache, dizziness, confusion) and peripheral neuropathy, hyperuricemia
[1, 2, 21]
1, 2, 4, 6, 7, 8, 9, 21z
Unknown frequency: elevated
liver enzymes, cholestatic jaundice, hepatitis, liver failure, including
fatalities [1, 4, 9].
³ Minimal liver metabolism to 9carboxymethoxymethylguanine (inactive). Intracellular activation to the
triphosphate derivative [1, 2]. The pharmacokinetic data refer to
aciclovir. ß gastrointestinal disturbances, neurologic disturbances
(headache, dizziness, confusion, hallucinations, psychosis, seizures),
elevated serum creatinine and BUN, cristaluria, renal failure,
hematological reactions [1, 2, 12]q No recommendations provided by the
Swiss product information. Caution in patients with hepatic abnormalities
[2].
1, 2, 4, 6, 7, 9, 12, 14, 168V
Frequent: elevated liver
enzymes. Rare: elevated bilirubin, hepatits, jaundice [1, 4].
"
'
Phosphorylation to the active triphosphate.
Degradation by deribosylation and amide hydrolysis to triazole
carboxamide and tricarboxylic acid [12]. Gastrointestinal metabolism
seems to be more important than hepatic metabolism [169]. The
pharmacokinetic data refer to ribavirin.• hemolytic anemia, pulmonary
symptoms (e.g. dyspnea), metallic taste, increased thirst,
gastrointestinal disturbances [1, 2, 12]- 1, 2, 4, 6, 7, 9, 12, 169,
170Î
Frequent: hyperbilirubinemia, hepatomegaly [1, 12]. Occasionally
to rare: elevated liver enzymes, jaundice, hyperammonemia, fatty liver
disease, cholangitis, hepatic malignancy, liver failure [1, 4, 9, 12].
4
I
8
C h i l d
P u g h
A / B / C
a f t e r
6 0 0 m g
s i n g l e
d o s e :
A U C
n o t
s i g n i f i c a n t l y
c h a n g e d .
C m a x
i n c r e a s e d
( m a x i m a l l y
2 - f o l d )
w i t h
s e v e r i t y
o f
h e p a t i c
d i s e a s e .
I n i t i a l
d o s e
a d j u s t m e n t
u n n e c e s s a r y
[ 9 ,
1 2 ,
1 6 9 ] .
I f
p l a s m a
c o n c e n t r a t i o n
a t
w e e k
1
o f
t h e r a p y
> 1 . 5 ¼ g / m L ,
d o s a g e
a d j u s t m e n t
r e c o m m e n d e d
t o
a v o i d
s e v e r e
s i d e
e f f e c t s
[ 1 7 0 ] . J
M
· myelosuppression (neutropenia, thrombopenia), infertility, renal
insufficiency, gastrointestinal disturbances, confusion, paresthesias,
hallucinations, seizures, hepatotoxicity [1, 2]
1, 2, 6, 7, 8y
Occasionally: elevated AST and bilirubin. Rare:
elevated ALT, jaundice, hepatitis [1]. Post-marketing: liver failure [9].
*
/
W
f
ÿ Famciclovir is a prodrug. Hepatic
deacetylation to 6-deoxy-penciclovir (inactive), oxidation by aldehyde
oxidase to penciclovir (active form). Little or no famciclovir is
detected in plasma or urine [1, 9] . The pharmacokinetic data refer to
penciclovir.S gastrointestinal disturbances, headache, fatigue,
confusion, nephrotoxicity [1, 2]
1, 2, 6, 7, 9, 171, 172D
Postmarketing: elevated liver enzymes, cholestatic jaundice [1, 9].
Ë
T w o
s t u d i e s
w i t h
a d m i n i s t r a t i o n
o f
a
s i n g l e
d o s e
o f
5 0 0 m g
f a m c i c l o v i r
i n
p a t i e n t s
w i t h
c o m p e n s a t e d
c h r o n i c
l i v e r
d i s e a s e
( c h r o n i c
h e p a t i t i s ,
c h r o n i c
e t h a n o l
a b u s e ,
p r i m a r y
b i l i a r y
c i r r h o s i s ) :
n o
e f f e c t
o n
a v a i l a b i l i t y
o f
p e n c i c l o v i r
[ 1 7 1 ] .
C m a x
d e c r e a s e d
( 4 4 %
[ 1 7 2 ] ;
2 . 0 4
v s .
3 . 5 3 ¼ g / m L
[ 1 7 1 ] ) ,
t m a x
i n c r e a s e d
( b y
0 . 7 5 h
[ 1 7 2 ] ;
2 . 5 9
v s
0 . 8 h
[ 1 7 1 ] )
c o m p a r e d
t o
h e a l t h y
s u b j e c t s .
N o
s t u d i e s
i n
p a t i e n t s
w i t h
s e v e r e
u n c o m p e n s a t e d
h e p a t i c
i m p a i r m e n t
[ 9 ,
1 7 1 ,
1 7 2 ] .
ñ
ô
'
*
+ Valaciclovir is a prodrug; following oral administration,
it is bioactivated to aciclovir. No metabolism by CYP P450 enzymes. No
valaciclovir detectable in plasma. But high plasma aciclovir levels (3-5x
higher than after oral aciclovir) [173, 174, 175]. The pharmacokinetic
data refer to aciclovir. þ gastrointestinal disturbances, neurologic
disturbances (headache, dizziness, confusion, hallucinations, psychosis,
seizures), elevated serum creatinine and BUN, renal failure,
hematological reactions, elevated liver enzymes, hepatotoxicity [1, 2,
12, 21]& 1, 2, 6, 9, 12, 21, 173, 174, 175, 1760
Rare: elevated liver
enzymes, hepatitis [1, 12].
L
Liver insufficiency: Cmax and AUC are
increased, excretion is unchanged [1].
<
=
Caution if high
doses (8g/d) are administered. Mild or moderate liver cirrhosis with
intact synthesis function: After a single dose of 1g no dose reduction
was necessary. Severe cirrhosis (reduced synthesis function and signs of
portosystemic shunting): According to pharmacokinetic data, no dose
adjustment is necessary, but clinical experience is limited [1]. Moderate
or severe liver disease: the rate of conversion of valacyclovir to
acyclovir reduced, but not the extent. Acyclovir t1/2 not affected.
Dosage reduction not recommended for patients with cirrhosis [12]. è
ë
› gastrointestinal disturbances, neutropenia, nephrotoxicity
(proteinuria, elevation of creatinine, hypouricemia), fever, asthenia,
metabolic acidosis [1, 9]
1, 6, 7, 9ô
Intracellular phosphorylation, both in virus-infected
and non-infected cells, to its monophosphate (inactive) and diphosphate
forms (active, t1/2 17-65h) and a cidofovir-phosphate-cholin adduct [1].
The pharmacokinetic data refer to cidofovir. Ž
‘
ì Valganciclovir is
a prodrug; following oral administration it is hydrolysed by esterases to
ganciclovir. Ganciclovir is activated by phosporylation mainly in virus
infected cells [1, 12]. The pharmacokinetic data refer to ganciclovir.
1, 2, 9, 12d
Unknown frequency: abnormal hepatic function, elevated
liver enzymes, jaundice, hepatitis [1, 12].
.
t Metabolism by
pyrimidine phosphorylase to bromovinyluracil (inactive). Further
metabolism to uracil acetic acid [1].
1, 9, 177‹
Occasionally:
fatty liver, elevation of ALT, AST, AP, GGT. Rare: elevated bilirubin,
hepatitis. Unknown frequency: acute liver failure [1].
;
@
`
s
Z
Child Pugh A and B: AUC, Cmax and terminal t1/2
similar to values in healthy subjects [1].
,
/
No
metabolism [1]. > myelosuppression, nephrotoxicity, electrolyte
disturbances (e.g. hypocalcemia leading to tetania, cardiac disturbances
and hyperphosphatemia; hypomagnesemia, hypokalemia), gastrointestinal
disturbances, neurotoxicity (headache, paresthesia, edema, seizures,
dizziness, hallucinations, ataxia), genital ulcer [1, 2, 21]
1, 2, 6, 7, 21>
Frequent: elevated AST, ALT, GGT, abnormal liver
function [1].
1, 2, 6, 9, 178, 179, 180ò
Frequent: elevations
of AST, ALT, GGT and bilirubin. Rare: exacerbation of liver disease,
portal hypertension, hepatitis, cholelithiasis, cholangitis,
hepatomegaly, liver damage, jaundice, ascites, liver failure (including
fatalities) [1, 9].
5
;
¹
Hemophiliac, advanced HIV-infected
patients with HCV co-infection and liver cirrhosis: Cmin 182-555ng/mL
(vs. 46ng/mL if liver function normal) [179]. Mild to moderate liver
impairment: No initial dosage adjustment required. Severe liver
impairment: Caution [180]. In patients with moderate liver disease,
pharmacokinetic data indicated a reduced saquinavir exposure by
approximately 30% compared to patients with normal liver function [1]. X
[
v Hepatic metabolism by oxidation (CYP P450 3A4) and
glucuronidation. Minor antiviral activity of metabolites [1,
12].
gastrointestinal disturbances, crystalluria,
nephrolithiasis/urolithiasis, renal insufficiency, lipodystophy,
neurototxicity (fatigue, dizziness, asthenia, oral paresthesias),
hyperbilirubineamia, hepatotoxicity, skin reactions (rash, pruritus,
dermatitis) [1, 12, 178] ñ HBV or HCV infection: increased risk for
nephrolithiasis, possibly due to decreased hepatic metabolism of
indinavir and increased renal excretion. Plasma concentration increased,
200mg b.i.d. (boosted with ritonavir) was possible [181, 182].
1, 2, 4,
6, 9, 12, 178, 181, 182¹
Frequent: hyperbilirubinemia, liver enzyme
elevations. Rare: hepatocellular injury, hepatitis, cholecystitis,
cholestasis, jaundice, hepatic failure including fatalities [1, 4, 9,
12].
7
<
Mild and moderate liver cirrhosis: Reduce dosage to 600 mg every 8
hours. After single 400mg dose in patients with mild and moderate liver
cirrhosis: mean AUC increased by 60%, t1/2 increased to 2.8h (vs. 1.8h)
[1]. Severe hepatic insufficiency: No data available [12]. ²
µ
Ž Heaptic oxidation by CYP 3A4 and 2D6 (polymorphic) to five
metabolites. Major metabolite active. Induction of own metabolism
possible [1, 12].Õ gastrointestinal disturbances, taste perversions,
neurotoxicity (headache, insomnia, asthenia, perioral and peripheral
paresthesias, visual and hearing disturbances), hyperglycemia, myalgia,
hepatotoxicity [1, 12]ô Contraindicated in patients with severe liver
disease. No dosage adjustment is necessary in patients with mild or
moderate liver disase. HBV or HCV co-infection: increased risk for severe
hepatic adverse effects. Monitoring recommended [1, 12].
1, 6, 9, 12,
183•
Frequent: elevated ALT, AST, GGT, AP, bilirubin. Rare:
cholangitis, hepatitis, cholestatic jaundice, hepatomegaly, liver injury
including fatalities [1, 12].
1
5
;
After low-dose
ritonavir in patients with mild and moderate liver disease, AUC12 / Cmax
increased by 39% / 61% and 181% / 221%, respectively [183]. In mild and
moderate hepatic impairment, steady-state concentration was similar to
controls and decreased by 40%, respectively. PB was not significantly
altered [12]. N
P
T
W
j Oxidation by CYP3A, 2C19 (polymorphic),
2C9 (polymorphic), 2D6 (polymorphic). One major metabolite M8 [1]., 1,
9, 120, 178, 181, 184, 185, 186, 187, 188f
Occasionally: elevated ALT,
AST. Rare: hepatitis, cholestatic disease, jaundice, liver failure [1,
9].
!
&
°
C h i l d
P u g h
A
a n d
B :
C L
d e c r e a s e d
( < 3 0 L / h ) ,
t 1 / 2
i n c r e a s e d
( > 5 h ) .
F o r m a t i o n
o f
m a j o r
m e t a b o l i t e
( C Y P
2 C 1 9 )
d e c r e a s e d ,
e v e n
i n
r a p i d
m e t a b o l i z e r s
[ 1 8 4 ] .
T h e
p h a r m a c o k i n e t i c s
o f
n e l f i n a v i r
a n d
i t s
a c t i v e
m e t a b o l i t e
M 8
w a s
n o t
s i g n i f i c a n t l y
a l t e r e d
i n
m i l d
l i v e r
d i s e a s e .
I n
m o d e r a t e
l i v e r
d i s e a s e ,
A U C s s
/
C m a x
i n c r e a s e d
b y
6 2 %
/
2 2 %
a n d
4 6 %
/
3 5 %
f o r
n e l f i n a v i r
a n d
M 8 ,
r e s p e c t i v e l y .
U n b o u n d
M 8
i n c r e a s e d
[ 1 8 5 ] .
P a t i e n t s
w i t h
H C V
i n f e c t i o n
w i t h
/
w i t h o u t
c i r r h o s i s ,
h a d
l o w e r
n e l f i n a v i r
C L
( b y
2 8 %
/
5 8 % )
a n d
i n c r e a s e d
A U C .
T h e
p a t i e n t s
w i t h
c i r r h o s i s
h a d
a
l o w e r
a b s o r p t i o n
r a t e ,
a n
i n c r e a s e d
t m a x
a n d
l o w e r
M 8
/
n e l f i n a v i r
r a t i o
[ 1 8 6 ] .
I n
H C V / H I V
c o - i n f e c t e d
p a t i e n t s ,
a
t r e n d
t o w a r d s
h i g h e r
n e l f i n a v i r
p l a s m a
l e v e l s
w a s
o b s e r v e d
i n
p a t i e n t s
w i t h
c i r r h o s i s
c o m p a r e d
t o
t h o s e
w i t h o u t
c i r r h o s i s
( 6 . 6
v s .
5 . 8
¼ g / m l ,
p
0 . 1 2 )
[ 1 8 7 ] .
N e l f i n a v i r ,
e f a v i r e n z
a n d
s t a v u d i n e
u s e d
i n
h e p a t i c
d i s e a s e :
A U C
/
C s s
o f
n e l f i n a v i r
i n c r e a s e d
b y
1 6 8 %
/
1 5 4 %
[ 1 8 8 ] . ,
/
*
,
0
3
Q
T
€
‚
†
HBV or HCV co-infection: increased risk
for severe hepatic adverse effects. Single dose in patients with
different degrees of hepatic insufficiency: AUC of nelfinavir and its
major active metabolite increased by 29-50%, t1/2 increased. In another
study including patients with mild and moderate liver disease, AUC/Cmax
were similar and increased by 62%/22%, respectively. In general: safety
and efficacy not tested. No dosage recommendations given. High
interindividual variability. Therapeutic drug monitoring recommended [1].
Moderate and severe liver insufficiency: Avoid nelfinavir. Mild liver
insufficiency: No dose adjustment necessary [9].Ý
à
;
>
/ Metabolism by CYP P450 3A4 to active 4-oxo-lopinavir and 4hydroxy-lopinavir and other i<
nactive metabolites. Lopinavir is
combined with low-dose ritonavir, a strong inhibitor of CYP 3A4, to
ensure high plasma levels of lopinavir [1, 12]. The pharmacokinetic data
refer to the combination with ritonavir.! 1, 9, 12, 183, 187, 189, 190,
191Í
Frequent: elevated GGT, ALT, AST. Occasionally: elevated
bilirubin, hepatitis, hepatomegaly, liver tenderness, liver fatty
deposit. Rare: cholangitis, cholecystitis, jaundice, fatal hepatotoxicity
[1, 12].
"
0
„
Š
º
gastrointestinal disturbances
(diarrhea), neurotoxicity (headache, insomnia, asthenia, paresthesia,
visual and hearing disturbances), lipodystrophy, hyperglycemia,
hepatotoxicity [1, 12]”
•
•
H I V - 1
a n d
H C V
c o i n f e c t e d
p a t i e n t s
w i t h
o r
w i t h o u t
l i v e r
c i r r h o s i s
( m i l d
o r
m o d e r a t e ) :
N o
s t a t i s t i c a l l y
s i g n i f i c a n t
c h a n g e
i
d
A
(
a
m
A
P
f
n
o
c
2
n
i
U
B
p h a r m a c o k i n e t i c s ,
d o s e
a d j u s t m e n t
s
n o t
s e e m
n e c e s s a r y
[ 9 ,
1 8 7 ] .
i v e
H C V :
L o p i n a v i r
C m i n
l o w e r
2 5
v s .
5 . 9 3 ¼ g / m L )
[ 1 8 9 ] .
H I V - 1
H C V
c o - i n f e c t e d
p a t i e n t s
w i t h
d
t o
m o d e r a t e
h e p a t i c
i m p a i r m e n t :
i n c r e a s e d
b y
3 0 % ,
C m a x
b y
2 0 % ,
l o w e r
( 9 9 . 0 9
v s .
9 9 . 3 1 % )
[ 1 2 ] . c
1, 9, 12, 192, 193, 194
CLsys according to [192].
Frequent: elevated ALT, AST [1].
AUC, Cmax and steady-state concentration increased by 50-60% and
by ~20% in patients with liver cirrhosis and chronic hepatitis,
respectively [192]. After fosamprenavir without RTV in patients with
liver cirrhosis (compared to the combination with RTV in non-cirrhotic
patients) Cmin, AUC(0-12), and t1/2 decreased by ~85%, 60%, and 58%,
respectively. CL increased by ~150% [193]. After amprenavir: AUC
increased 2.5- and 4.5-fold, CL was decreased by ~50% and ~75% in
patients with moderate and severe liver cirrhosis, respectively [12,
194].
&
0
À
e
t
.
d
l
C
Child Pugh A: Reduce dosasge of ritonavir to 100mg once daily. Child
Pugh B: Reduce dosage of ritonavir to 100mg once daily and of
fosamprenavir to 450mg twice daily. Child Pugh C: reduce dosage of
ritonavir to 100mg once daily and of fosamprenavir to 300mg twice daily.
Hepatitis B or C co-infection: increased risk for severe hepatic adverse
effects. Monitor liver values. After fosamprenavir with ritonavir (RTV,
100mg/d) in patients with liver cirrhosis, amprenavir Cmax / AUC
increased (Child Pugh A by 17% / 22%, Child Pugh B unknown / by 70%).
Cmin comparable to controls. Patients with Child Pugh C (fosamprenavir
300mg/12h, RTV 100mg/24h) compared to controls (normal dosage, without
liver disease) had 19%, 23%, and 38% lower amprenavir Cmax, AUC, and
Cmin, respectively. Unbound Cmin similar. In spite of RTV dose interval
prolongation, Cmax, Caverage, and Cmin increased by 64%, 40%, and 38% in
patients with severe liver disease, respectively [1].ì
ï
û
þ
Q
T
W
^
e
h
© gastrointestinal disturbances (diarrhea,
abdominal pain, nausea, vomiting), headache, jaundice, arrhythmias (QTc
prolonged, RP interval prolonged), lipodystrophy [1, 12]
1, 6, 8, 9,
12, 120, 195, 196¤
Frequent: jaundice, elevated ALT, AST, unconjugated
bilirubin. Occasionally: hepatitis. Rare: hepatospelnomegaly,
cholecystitis, cholelithiasis, cholestasis [1, 9].
?
M
X
^
X
After boosted or unboosted atazanavir, no
pharmacokinetic alterations observed in cirrhotic HCV/HIV co-infected
patients compared to patients without cirrhosis [187]. Liver disease:
elevated atazanavir plasma concentration observed after unboosted
atazanavir. Child Pugh A: no data, caution, but normal dose can be used,
monitor liver enzymes. Child Pugh B and C: AUC increased by 42%, t1/2 by
6h [9]. After unboosted atazanavir 400mg/d in patients with end-stage
liver disease for 24 weeks, AUC, Cmin, and Cmax were similar to or below
the values reported in the Swiss product information for unboosted
300mg/d atazanavir. Efficacious drug levels were achieved in most
patients. Atazanavir being an inhibitor of UGT1A1, unconjugated bilirubin
increased, indirectly suggesting no influence of liver disease on the
glucuronidation of atazanavir [195, 196]. ƒ
†
ò
õ
ü
ÿ
˜ Fosamprenavir is a phosphate ester prodrug of amprenavir and is
rapidly converted enzymatically in the intestinal epithelium and serum.
Amprenavir: Oxidation by CYP P450 3A4, glucuronidation. Fosamprenavir is
combined with low-dose ritonavir (RTV), a strong inhibitor of CYP3A4 [1].
The pharmacokinetic data refer to the active form (amprenavir) after
administration of fosamprenavir combined with
ritonavir.• gastrointestinal disturbances (diarrhea, nausea, vomiting),
insomnia, nervousness, headache, hepatotoxicity, triglyceride elevations
[1, 197]
1, 9, 12, 197/ Single- and multiple-dose study (tipranavir-ritonavir
combination) in patients with mild (N=9) and moderate (N=3) hepatic
impairment compared to controls: Mild hepatic impairment: similar
pharmacokinetic data. Moderate hepatic impariement: AUC increased by 35%,
but without statistic significance [197].¦ Child Pugh A: administration
possible if no alternatives available. No dosage adjustment necessary,
caution and frequent monitoring for hepatotoxicity. Contraindicated in
patients with Child Pugh B/C or ALT/AST > 5ULN. Hepatitis B or C coinfection: increased risk for severe hepatic adverse effects. Stop
therapy definitely if ALT, AST >10ULN [1]. Stop therapy if ALT/AST
between 5-10ULN with total bilirubin >2.5ULN [9].½
Frequent: elevated
ALT, AST, GGT. Occasionally: hepatitis, cytolytic hepatitis, toxic
hepatitis, hepatic steatosis. Rare: hepatic failure (including
fatalities), hyperbilirubinemia [1, 12].
"
/
t
x
Ù Metabolized by CYP P450 3A4 to oxidative
metabolites. 79.5% (41.2% unchanged) of a dose eliminated in feces, 13.9%
(7.7% unchanged) recovered in urine [1]. Pharmacokinetic data refer to
the combination with ritonavir.6 Plasma concentration of total darunavir
(combined with ritonavir) unaltered in patients with mild and moderate
(Child Pugh A and B) liver disease. However, darunavir free plasma
concentration increased by 55% and 100% in mild and moderate liver
cirrhotics, respectively. No data in Child Pugh C patients [198].
1, 9, 198, 199r
Frequent: elevated ALT, AST, AP, GGT, bilirubin.
Rare: acute hepatitis, liver injury, including fatalities [1, 9].
1
6
x Metabolism by hydrolysis, oxidation and reduction.
CYP3A4 is the major CYP enzyme invovled in the metabolism [1, 9,
12].¦ rash, pruritus, myelosuppression (anemia, thrombocytopenia,
leucopenia), gastrointestinal disturbances (nausea, emesis, diarrhea,
loss of appetite, dysgeusia) [1, 12]r
In patients with mild and
moderate liver disease, telaprevir exposure decreased by 15% and 46%,
respectively [1].
1, 9, 12$
Frequent: hyperbilirubinemia [1, 9].
S Main metabolism by aldo-keto reductase, minor metabolism by
CYP3A4/3A5 [1, 9, 12]. F myelosuppression (anemia, neutropenia,
thrombocytopenia, leucopenia), chills, asthenia, decreased appetite,
gastrointestinal disturbances, arthralgia, myalgia, neurotoxicity
(insomnia, irritability, visual and hearing disturbances, depression,
paresthesia), triglyceride elevations, palpitations, chest pain,
exanthema [1, 12]¹ Contraindicated in autoimmune hepatitis. No dosage
adjustment necessary in patients with mild, moderate, or severe liver
disease. No clinically significant pharmacokinetic alterations observed.
The combination with peginterferon and ribavirin is contraindicated in
patients with severe liver disease or decompensated liver cirrhosis [1].
No data on safety and efficacy in patients with decompensated liver
cirrhosis or HBV co-infection [12].:
Occasionally: elevated bilirubin.
Rare: cholecystitis [1].
"
'
V
In patients with moderate and severe liver disease
compared to patients with normal liver function, the mean AUC of the
active diastereomer of boceprevi<
r was 32% and 45% higher,
respectively. Mean Cmax was 28% and 62% higher, respectively. Patients
with mild liver disease had unaltered exposure to the active diastereomer
of boceprevir [12].Æ
É
¨ Glucuronidation and reductive
biotransformation by CYP P450. Intracellular phosphorylation to active
triphosphate [1, 12]. The pharmacokinetic data refer to zidovudine.
myelosuppression (anemia, neutropenia, leucopenia), gastrointestinal
disturbances, taste disturbance, pancreatitis, neurotoxicity (headache,
asthenia, mailaise, paresthesias, peripheral neuropathy, depression),
myalgia, lipodystrophy, lactic acidosis [1, 12, 21, 178]9 1, 2, 4, 9,
12, 14, 21, 120, 178, 200, 201, 202, 203, 204¦
Frequent: elevated
liver enzymes and bilirubin. Rare: hepatitis, hepatomegaly with
macrovesicular steatosis (due to lactic acidosis), cholestatic jaundice
[1, 3, 12].
0
5
ª
After 200mg / 250mg single doses or 100mg /
6h orally in patients with liver disease of variable severity, CL
decreased (by 70% [200], up to 8-fold [201]), AUC increased (up to 8-fold
[201]), Cmax and t1/2 increased (2- to 3-fold) [200, 201, 202, 203]. In
hemophilic patients with HIV/HCV co-infection without cirrhosis,
pharmacokinetics were not significantly altered. T1/2 of metabolites was
prolonged [204]. Dosage reduction of 50%, doubling of dosage interval
[200], or therapeutic drug monitoring [201] were proposed for patients
with variable severity of liver disease. No dosage reduction is necessary
in hemophilic patients with HIV/HCV co-infection without cirrhosis
[204].Á
Ä
Ê
Í
s
v
9 gastrointestinal disturbances (diarrhea,
nausea, emesis), pancreatitis (elevation of serum amylase), neurotoxicity
(peripheral neuropathy, headache, asthenia), liver dysfunction,
hematologic disorders, myalgia, lipodystrophy, lactic acidosis,
hyperglycemia, hyperuricemia, retinal changes, optic neuritis [1,
205]
1, 2, 6, 7, 9, 205ý
Intracellular activation to
dideoxyadenosine (t1/2 12h), whereof the triphosphate is the active
principle. Supposed metabolism via the same pathways responsible for
elimination of endogenous purines [1, 9]. The
pharmacokine•
‚
ƒ
„
…
†
‡
ˆ
‰
Š
‹
Œ
•
Ž
•
•
‘
’
“
”
•
–
—
˜
™
š
›
œ
•
ž
Ÿ
¡
¢
£
¤
¥
¦
§
¨
©
ª
«
¬
®
¯
°
±
²
³
´
µ
¶
·
¸
¹
º
»
¼
½
¾
¿
À
Á
Â
Ã
Ä
Å
Æ
Ç
È
É
Ê
Ë
Ì
Í
Î
Ï
Ð
Ñ
Ò
Ó
Ô
Õ
Ö
×
Ø
Ù
Ú
Û
Ü
Ý
Þ
ß
à
á
â
ã
ä
å
æ
è
ýÿÿÿé
ê
ë
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ð
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ò
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ÿ
tic data refer
to didanosine. /
2
Õ
Frequent: elevated ALT, AST, AP.
Occasionally: elevated bilirubin. Rare: hepatitis, liver failure,
hepatomegaly with steatosis (due to lactic acidosis), liver necrosis,
(non-cirrhotic) portal hypertension [1, 9].
/
B
H
0
Single dose in hemophiliac patients with
chronically elevated liver enzymes: no significant pharmacokinetic
alterations. In patients with moderate or severe liver disease, AUC and
Cmax after a single dose increased by 13% and 19%, the values were within
the pharmacokinetic variability of didanosine [1].µ
¸
© No dosage
adjustment necessary in patients with impaired hepatic function. Efficacy
and safety not tested in patients with significant liver disease. Monitor
patients and consider to stop therapy, if hepatic function worsens.
Hepatitis B or C co-infection: increased risk for severe hepatic adverse
effects. Caution in patients with hepatomegaly, hepatitis, or other risk
factors for hepatic diseases or hepatosteatosis [1]. n
Glucuronidation
may be imipaired. Insufficient data to recommend a specific dose. Dose
should be reduced or dosage interval prolonged by means of plasma drug
levels or dose-dependent advese reactions. Caution in patients with
hepatomegaly, hepatitis, or other risk factors for hepatic diseases or
hepatosteatosis. Monitor patients for hepatic adverse reactions
[1].
Not recommended in patients with moderate or severe (Child Pugh B
or C) or decompensated liver disease. In patients with mild liver disease
(Child Pugh A), no dosage adjustment is necessary. Not recommended in
patients with concomitant HBV/HCV infection due to lack of data
[1].Ð Mild and moderate hepatic impairment: Multiple-dose study (600mg
darunavir, 100mg ritonavir) b.i.d.: pharmacokinetics similar to those in
healthy subjects, thus no dosage adjustment is necessary. Monitor
patients for hepatotoxicity. Consider to stop therapy in case of
worsening hepatic function. Severe hepatic impairment: No data.
Contraindicated. Hepatitis B or C co-infection or other liver dysfunction
are risk factors for severe hepatic adverse effects [1]. N Child Pugh B
and C: Contraindication. Child Pugh A: limited data, but normal dose of
the atazanavir-ritonavir combination can be used under monitoring of
liver values (transaminases, bilirubin). Hepatitis B or C co-infection:
increased risk for severe hepatic adverse effects. Consider to stop
therapy, if liver function worsens [1]. È No dosage recommendations
provided. The syrup is contraindicated in patients with hepatic
insufficiency due to possible cumulation of propylene glycol. Mild to
moderate hepatic impairment: Caution, no data available, therapeutic drug
monitoring recommended. Severe hepatic insufficiency: Contraindication.
Hepatitis B, C or pronounced elevation of transaminases: increased risk
for severe hepatic adverse effects. Liver function monitoring recommended
[1].ª The combination with ritonavir is contraindicated in patients with
severe or decompensated liver disease. Mild liver impairment: no dosage
adjustment necessary. Moderate liver disease: no dosage adjustment seems
necessary, but data are limited. Caution. Monitoring of efficacy and
safety recommended. Hepatitis B or C co-infection, cirrhosis, chronic
alcoholism or other liver disease: worsening of liver disease reported
[1].Æ
No dosage adjustment necessary. Avoid brivudine in patients with
proliferative liver disease (e.g. hepatitis). Risk for hepatitis is
increased during longer than recommended (7 days) treatment [1].ø
No
recommendations provided. After liver transplantation: an oral dose of
900mg resulted in an unchanged absolute Foral. The achieved AUC was
comparable to the one after i.v. dosing of 5mg/kg ganciclovir to
patients with liver transplantation [1].s
w
^ No studies on safety
and efficacy in patients with liver insufficiency, use with caution [1].
• No dose adjustment necessary in patients with compensated liver
insufficiency. No data for patients with decompensated liver
insufficiency [1].
No recommendations provided. After liver
transplantation: an oral dose of 900mg valganciclovir resulted in an
unchanged absolute F. The achieved AUC was comparable to the one after
i.v. dosing of 5mg/kg ganciclovir to patients with liver transplantation
[1].z Ribavirin is contraindicated in decompensated or severe liver
disease or in patients with anamnestic autoimmune hepatitis. Otherwise,
no dose adaptation is necessary. Monitor patients and stop therapy, if
coagulopathy develops. The initiaion of the combination therapy with
peginterferon-alfa 2a is contraindicated in HIV/HCV co-infected patients
with a Child Pugh score >5 [1].- Monitor liver parameters in all
patients [1].Z
Contraindicated in patients with porphyria, history of
isoniazid-induced hepatitis, acute hepatitis or during 6 months after
recovery. T1/2 increased in patients with liver insufficiency. Monitor
liver parameters. If signs of hepatic injury develop, stop therapy. Liver
disease and other hepatotoxic drugs are risk factors for hepatotoxicity
[1].ˆ
‹
³
Dosage should be reduced to prevent adverse effects.
T1/2 increased to 5-7h. Monitor liver enzymes. Contraindicated in
patients with severe liver disease and acute hepatitis [1]. 6
9
] No
dosage adjustment necessary in patients with mild, moderate, or severe
liver disease [1]. … No dose reduction for patients with mild liver
disease. For patients with moderate liver disease, use normal (treatment
of invasive candidiasis, invasive aspergillosis or febrile neutropenia)
or reduced (treatment of esophageal or oropharyngeal candidiasis) initial
dose and reduce maintenance dose in all patients (35mg instead of
50mg/day). No data for liver cirrhosis Child Pugh C [1]. * Monitor liver
function during therapy [1].d No recommendations for dosage adjustment
possible. Exercise caution and monitor liver function [1]. y
In acute
liver disease (increased ALT, AST up to 5x ULN), no dose adaptation is
necessary. After 200mg oral dose in<
Child Pugh A and B: AUC
increased (233%). PB unchanged. Maintenance dose should be halved. Child
Pugh C: No data available. Start treatment only if benefit outweighs the
risk of hepatic injury. Close monitoring of patients with liver disease
recommended [1]. œ Potential hepatotoxicity. Monitor liver function
regularly. Stop fluconazole if symptoms of liver disease or elevations in
liver function tests develop [1].J Pharmacokinetics were not
significantly altered in patients with liver disease compared to healthy
subjects. Ketoconazole is potentially hepatotoxic and thus
contraindicated in patients with acute or chronic liver disease. If liver
function is impaired, dose reduction is indicated and the patient should
be monitored closely [1].
Parenteral administration is contraindicated
in severe hepatic insufficiency. Liver disease has no effect on
amphotericin serum levels. Monitor renal function, liver function,
electrolyte (potassium and magnesium) levels and blood picture and reduce
dosage accordingly [1]. 8 No difference in pharmacokinetics in patients
with liver insufficiency (Child B) compared to matched normal controls.
No dose adjustment indicated in patients with moderate liver impairment.
Caution in patients with liver cirrhosis Child C, because the safety has
not been studied in this group of patients [1]. 0 No dosage adjustment
is necessary in patients with cirrhosis Child-Pugh A and B. Linezolid
pharmacokinetics in patients with severe hepatic failure have not been
evaluated. Due to limited data available, linezolid should only be given
to patients with liver disease if the benefit outweighs the risk
[1].V No recommendation provided. Monitoring of liver function during
long-term therapy [1].×
Compared to healthy subjects t1/2 is prolonged
and CL decreased. Dosage interval should be doubled in patients with
severe liver impairment. The ampullas contain alcohol, caution in
patients with liver disease [1]. !
»
No information provided.
Periodic hematological studies, renal, liver and auditory function tests
are advised during prolonged treatment. Monitoring Cmin (reference value:
5-15mg/L) [1]. –
™
¤ No significant difference of pharmacokinetics
of moxifloxacin in cirrhotics compared to healthy controls. AUC of the
sulfo-metabolite was up to 6-fold higher, AUC of the glucuronide
metabolite was 1.5-fold higher in cirrhotics Child B compared to healthy
subjects. No dose adjustment necessary in patients with mild liver
disease. Contraindicated in patients with cirrhosis Child C or
transaminase elevations >5ULN [1]. † Due to the limited extent of
levofloxacin metabolism, no dosage adjustment is necessary in patients
with impaired liver function [1]. ÿ In patients with liver disease,
elimination of ciprofloxacin is only minimally altered. According to its
metabolism, accumulation in patients with liver disease seems unlikely.
Dose adjustment is not necessary, provided that renal function is normal
[1]. Á A dose of 400 mg per day should not be exceeded in patients with
severe liver function disorders such as cirrhosis with ascites. The
excretion of ofloxacin in these patients may be reduced [1].£ No studies
in patients with liver disease. Since minor metabolism of tobramycin
occurs, liver disease is not expected to have an impact on tobramycin
exposure [1].ã
T1/2 is increased in patients with severe liver
dysfunction, but dose adjustment not necessary in patients with mild and
moderate liver disease. Use with caution and monitor clindamycin levels
in case of high dose regimen [1].
Ÿ
In cirrhotic patients with
Child Pugh A and B no significant differences in pharmacokinetics were
observed after a single dose compared to healthy subjects. Renal CL seems
to be increased instead. No data is available for multiple dosing.
Caution in patients with liver insufficiency, due to its high hepatic
elimination. No dose adjustment seems necessary in patients with mild and
moderate liver dysfunction [1].Z Caution in patients with liver
insufficiency due to the risk of cholestatic jaundice [1].
î Contraindicated in patients with severe liver insufficiency. Use with
caution in patients with impaired hepatic function. Maximal daily dose 1g
in patients with liver insufficiency. Monitoring for oto- and hepatotoxic
adverse effects [1].
Contraindicated in patients with marked
parenchymal liver injury. Risk for severe adverse effects may be
increased in patients with liver disease. Caution with high doses in
patients with severe hepatic insufficiency, even though kinetics are not
considerably altered [1].„ Monitoring of hematopoetic, renal and hepatic
function recommended during long-term treatment. No dose recommendations
provided [1].Ê No studies available. Since there is no evidence for
hepatic metabolism of doripenem, liver insufficiency is not expected to
influence the drugs pharmacokinetics. No dosage adjustment is necessary
[1]. ê No studies available. However, because metabolism in the liver
seems negligible, no major change in pharmacokinetics is expected in
patients with liver disease. No dose adjustment required in patients with
impaired liver function [1].
A pharmacokinetic study in patients with hepatic impairment has shown
no effects of liver disease on the pharmacokinetics of meropenem. No
dosage adjustment is needed in patients with liver impairment. Monitor
liver function regularly in patients with liver disease [1].o No dosage
adjustments are necessary for patients with hepatic dysfunction in case
of normal renal function [1].
No recommendation provided.: Dosage
adjustment is not necessary in these patients [1]. B Citation of the
same results as reported in clinical studies [1]. Þ In patients with
impaired hepatic function, pharmacokinetics of ceftriaxone are minimally
altered. Renal route of elimination may increase. Thus, no dose
adjustment is necessary provided that renal function is normal [1].
¦ The pharmacokinetics are not significantly affected in the presence of
hepatic impairment. No dosage adjustment is required in patients with
hepatic dysfunction [1]. J Monitor hemogram, liver and renal function
during long-term treatment [1].… In case of treatment with cefamandole
50mg/kg over a few days, liver and renal function should be monitored, as
well as hemogram [1].¬ No dose recommendations provided. Cefazoline can
cause coagulation disorders, monitor quick values in patients with an
elevated risk for bleedings (e.g. liver disease) [1].‚ The excretion of
piperacillin/tazobactam is decreased in patients with liver dysfunction,
but no dose reduction is necessary [1]. é Contraindicated in patients
with anamnestic jaundice or liver dysfunction associated with the
combination of amoxicillin/clavulanic acid. Caution in patients with
liver disease. Monitor liver function during long-term treatment [1].
' Contraindicated in patients with anamnestic jaundice or liver
dysfunction associated with flucloxacillin. The active metabolite
contributes up to 10% to the total activity. Due to its possible
hepatotoxicity, flucloxacillin should be used with caution in patients
with hepatic insufficiency [1].
Generally no dose reduction is necessary in patients with mild to
moderate liver insufficiency because of its low toxicity. Caution in
patients with severe liver disease. T1/2 may be prolonged in patients
with severe liver disease and cocomitant renal impairment [1].¬
¯
7 Monitor liver function during long-term treatment [1]. • No
pharmacokinetic alterations in patients with mild liver insufficiency. In
patients with moderate or severe liver insufficiency, systemic CL
prolonged by 25% and 55% and half-life by 23% and 43%, respectively. No
dosage adjustment necessary in patients with Child Pugh A and B liver
disease. Reduction of maintenance dose to 25mg/12h recommended in
patients with Child Pugh C liver disease [1].
Contraindicated in patients with severe liver disease. Minocycline is
excreted significantly by biliary tract. In the case of cholestatic liver
disease, accumulation may occur. Caution in patients with liver
dysfunction or if combined with other hepatotoxic drugs [1]. - Caution
in patients <
with liver diseases [1]. n Caution in patients with
severe liver dysfunction. No pharmacokinetic data in patients with liver
disease [1].G Child-Pugh B or C 40mg single dose: pharmacokinetics not
altered [206].ù No dosage adjustment necessary in patients with liver
insufficiency. Pharmacokinetics similar in patients with and without
hepatic impairment. Efficacy and safety not tested in patients with
significant liver disease. Monitor patients and consider to stop therapy,
if hepatic function worsens. Patients with underlying hepatitis B or C:
increased risk for severe hepatic adverse effects. Caution in patients
with hepatomegaly, hepatitis, or other risk factors for hepatic diseases
or hepatosteatosis [1].
1, 2, 6, 9, 178, 206›
Frequent: elevations
of ALT, AST, GGT. Occasionally: hepatitis, jaundice. Rare: liver failure,
hepatomegaly with steatosis (due to lactic acidosis) [1,
9].
'
5
J
O
ž Intracellular activation to triphosphate. 5-10%
is metabolized (only known metabolite: trans-sulfoxide) [1, 12]. The
pharmacokinetic data refer to lamivudine.È gastrointestinal
disturbances, neurotoxicity (headache, dizziness, paresthesias, malaise,
asthenia), lipodystrophy, lactic acidosis, alopecia, pancreatitis,
myalgia, hematologic disorders [1, 12, 178]” One study showed that no
dose adjustment is necessary in patients with liver insufficiency [181],
which is in line with the pharmacokinetic profile.u Moderate/severe
hepatic insufficiency: Pharmacokinetics not significantly altered. No
dosage adjustment necessary in patients with moderate or severe liver
disease, unless concomitant renal impairment is present. Caution in
patients with hepatomegaly, hepatitis, or other risk factors for hepatic
diseases or hepatosteatosis [1]. Decompensated liver disease: No data
[12].
1, 6, 9, 12, 178, 181„
Occasionally: elevation of ALT, AST,
hepatomegaly, hepatosteatosis (due to lactic acidosis). Rare: hepatitis,
liver failure [1, 12].
]
a
S
According to pharmacokinetic data, adjust dose according
to creatinine clearance. Ç Alcohol dehydrogenase and glucuronyl
transferase metabolism to inactive metabolites. Intracellular formation
of the active carbovir-5'-triphophate [1, 12]. The pharmacokinetic data
refer to abacavir.¾ gastrointestinal disturbances, pancreatitis,
neurotoxicity (headache, fatigue, asthenia, paresthesia, anxiety,
lethargy), myalgia, lipodystrophy, hyperglycemia, lactic acidosis [1,
12, 178]¸ Mild hepatic insufficiency: Dose reduction to 150mg twice
daily (oral solution for appropriate dosing). Moderate and severe hepatic
insufficiency: No data, contraindicated. Caution in patients with
hepatomegaly, hepatitis, or other risk factors for hepatic diseases or
hepatosteatosis [1]. Mild hepatic insufficiency: Dose reduction to 200mg
twice daily recommended. Moderate and severe hepatic insufficiency: No
data, contraindicated [12].
1, 9, 12, 178s
Frequent: elevation of ALT, AST. Rare: liver failure,
hepatomegaly with steatosis (due to lactic acidosis) [1, 12].
!
&
600mg single dose in patients with Child Pugh A: AUC
increased by 89%, t1/2 by 58%. AUC of metabolites not altered, but rates
of formation and elimination decreased [1, 12].H
K
Ô Tenofovir
disoproxil is a diester-prodrug and is rapidly hydrolysed by plasma
esterases to tenofovir. Intracellular phosphorylation to the active
diphosphate [1, 12]. The pharmacokinetic data refer to tenofovir.
ù gastrointestinal disturbances, hypophosphatemia, neurotoxicity
(headache, asthenia, dizziness, peripheral neuropathy), myalgia,
pancreatitis, nephrotoxicity, lipodystrophy, elevated liver enzymes,
lactic acidosis, hematologic disorders [1, 12, 178]_ Single 300mg dose
in Child Pugh B and C: No significant pharmacokinetic alterations [12,
207]. £ No dosage adjustment necessary. Single 245mg dose in patients
with moderate and severe hepatic impairment: AUC increased by 13% and
34%, respectively. Limited safety and efficacy data in patients with
decompensated liver disease. Caution in patients with hepatomegaly,
hepatitis, or other risk factors for hepatic diseases or hepatosteatosis
[1]. No dosage adjustment necessary in patients with hepatic impairment
[12].
1, 9, 12, 178, 207•
Unknown frequency: elevations of ALT, AST,
GGT. Rare: hepatitis, liver failure, hepatomegaly with steatosis (due to
lactic acidosis) [1, 12].
0
5
Adefovir dipivoxil is a
dipivaloyloxymethylester-prodrug of adefovir and is rapidly converted
enzymatically in the GIT and possibly in the liver. Intracellular
phosphorylation to the active diphosphate [1, 9, 12]. The pharmacokinetic
data refer to adefovir. ‹ gastrointestinal disturbances, neurotoxicity
(headache, asthenia), nephrotoxicity (elevated serum creatinine), lactic
acidosis [1, 12, 178]Â 10 mg single dose in patients with non-chronic
HBV infection with hepatic impairment (moderate and severe): No
significant pharmacokinetic alterations observed compared to healthy
patients [12].» No dosage adjustment necessary in patients with hepatic
insufficiency. Caution in patients with hepatomegaly, hepatitis, or other
risk factors for hepatic diseases or hepatosteatosis [1].{ According to
pharmacokinetic data, choose normal initial dose and adjust dosage
interval according to creatinine clearance.
1, 9, 12, 208¶
Frequent (after discontinuation of therapy): liver
enzyme elevations, exacerbation of hepatitis. Rare: liver failure,
hepatomegaly with steatosis (due to lactic acidosis) [1, 9, 12].`
g
` Oxidation of thiol to the 3'-sulfoxid-diastereomer,
glucuronidation to the 2'-O-glucuronide [1].® Not enough data to make
dose recommendations in patients with liver disease. Since only a small
fraction (13%) of emtricitabine is metabolized and it is primarily
renally eliminated, necessity for dosage adjustment seems unlikely. Due
to severe hepatic adverse effects (hepatomegaly, steatosis), caution is
advised in patients with liver disease or risk factors therefore.
Consider to stop therapy, if liver function worsens [1]. n
Frequent:
elevated AST, ALT, bilirubin. Rare: hepatomegaly with steatosis (due to
lactic acidosis) [1, 9, 12].
(
j Hepatic imapirment (Child Pugh
B or C) has no relevant effects on the pharmacokinetics of entecavir
[209]./ Pharmacokinetics in patients with liver insufficiency similar to
the pharmacokinetics in healthy subjects. No dosage adjustment necessary.
Monitor patients. Liver cirrhosis may be a risk factor for severe hepatic
adverse effects. Patients after liver transplantation: Efficacy and
safety not tested [1].
1, 9, 12, 209, 210, 211Ð
Minimal metabolism
to glucuronide and sulfate conjugates. Intracellular phosphorylation to
the active triphosphate derivative (intracellular t1/2 of 15 hours) [1].
The pharmacokinetic data refer to entecavir.Ž
‘
Vss 63-110L/kg
”
Frequent: elevated AST, ALT, bilirubin.
Occasionally: hepatitis exacerbation. Rare: hepatomegaly with steatosis
(due to lactic acidosis) [1, 9, 12].
'
6
L
T
ë Telbivudine is intracellularly activated to the
triphosphate derivative. No other metabolites could be detected [1, 9].
Telbivudine is mainly renally eliminated as unchanged drug [1, 212]. The
pharmacokinetic data refer to telbivudine.< No dose-dependent adverse
reactions could be detected. [213]{ Pharmacokinetics in patients with
hepatic insufficiency comparable to those in patients with normal hepatic
function [214].‡ No dose adaptation necessary in patients with liver
insufficiency. Pharmacokinetics not altered after single doses in
patients with different stages of liver disease. Decompensated liver
cirrhosis / liver transplantation: Safety and efficacy not tested.
Patients with decompensated liver cirrhosis had more severe hepatic
adverse reactions than patients with compensated liver function [1].
1,
9, 12, 212, 213, 214
Q0 not known.
·
Frequent: elevated ALT. Occasionally:
elevated AST. Rare: elevated bilirubin, hepatomegaly with steatosis (due
to lactic acidosis). Unknown frequency: hepatitis exacerbation [1, 12].
&
3
:
„
–
V Oxidation by CYP P450 3A and 2B6,
glucuronidation. Induces its own m<
etabolism [1, 12].º elevated
ALT/AST, gastrointestinal disturbances (nausea, emesis), neurotoxicity
(headache, drowsiness, paresthesia, insomnia), fever, erythema nodosum,
edema, loss of body weight [1, 12]¤ Risk for drug accumulation in
patients wtih impaired hepatic funciton. Caution in patients with
moderate liver disease. Contraindicated in patients with severe liver
disease or AST/ALT >5ULN. Risk factors for hepatic adverse effects:
females, CD4 cells >250/mm3 (females) or >400/mm3 (males), underlying
hepatitis B or C, elevated liver enzymes (ALT/AST). Monitor patients
closely, especially in the first 18 weeks of treatment. Treatment should
be stopped if liver enzyme levels increase >5 ULN or in case of other
symptoms consistent with liver dysfunction [1]. It is unknown if dosage
adjustment is necessary in patients with mild or moderate liver disease.
Caution [12].
1, 6, 9, 12, 215Æ
Frequent: elevated ALT, AST, AP,
GGT, bilirubin, hepatits. Rare: cholestatic hepatitis and jaundice, liver
necrosis, hepatomegaly, fulminant hepatitis, hepatic failure, including
fatalities [1, 12].
;
@
¬
200mg single dose, Child Pugh A or
B: no significant pharmacokinetic changes. In one patient (Child Pugh B,
ascites), AUC increased significantly. Steady state study, mild,
moderate, or severe fibrosis (Child Pugh A): pharmacokinetic disposition
not altered. In ~15%, Cmin increased two-fold. Careful monitoring for
drug-induced toxicity [1, 12]. HCV co-infection (hepatic function
unimpaired): Pharmacokinetics unaltered [215].
ƒ Oxidation by CYP P450 3A4 and 2B6 (polymorphic),
glucuronidation. Enterohepatic recirculation. Induces its own metabolism
[1, 12]. ð neurotoxicity (dizziness, insomnia, impaired concentration,
somnolence, abnormal dreaming, euphoria, confusion, agitation, amnesia,
hallucinations, stupor, severe mental disorders), gastrointestinal
symptoms, liver enzyme elevations [1, 12]ÿ I n
H C V / H I V
c o i n f e c t e d
p a t i e n t s ,
e f a v i r e n z
p l a s m a
c o n c e n t r a t i o n
w a s
s i g n i f i c a n t l y
i n c r e a s e d
i n
p a t i e n t s
w i t h
c i r r h o s i s
c o m p a r e d
t o
t h o s e
w i t h o u t
c i r r h o s i s
( 3 . 4
v s .
1 . 9
¼ g / m L )
[ 1 8 7 ] .
T w o
c a s e s
o f
h e p a t i c
d i s e a s e
( e l e v a t e d
l i v e r
e n z y m e s
3 - 4 x
U L N ,
H C V - i n d u c e d
l i v e r
c i r r h o s i s )
d u r i n g
t r e a t m e n t
w i t h
n e l f i n a v i r ,
e f a v i r e n z
a n d
s t a v u d i n e :
A U C
a n d
s t e a d y - s t a t e
c o n c e n t r a t i o n s
o f
e f a v i r e n z
i n c r e a s e d
b y
2 8 8 %
a n d
3 6 3 % ,
r e s p e c t i v e l y
[ 2 1 6 ] .
I n
a
p a t i e n t
w i t h
l i v e r
c i r r h o s i s ,
e f a v i r e n z
p l a s m a
c o n c e n t r a t i o n
i n c r e a s e d
u p
t o
5 1 . 8 7 ¼ g / m L
a f t e r
a
t h e r a p y
o f
4
w e e k s ,
l e a d i n g
t o
a g g r e s s i v e
m o o d
c h a n g e s ;
9
w e e k s
a f t e r
s t o p p i n g
e f a v i r e n z ,
p l a s m a
c o n c e n t r a t i o n s
w e r e
i n
t h e
t h e r a p e u t i c
r a n g e
o f
1 - 4 ¼ g / m L
w i t h
1 . 5 8 ¼ g / m L
[ 2 1 7 ] .
I n
p a t i e n t s
w i t h
l i v e r
d i s e a s e
( H C V
o r
H B V
i n f e c t i o n ,
a l c o h o l i c
l i v e r
d i s e a s e ) ,
p l a s m a
c o n c e n t r a t i o n s
w e r e
n o t
s i g n i f i c a n t l y
d i f f e r e n t
c o m p a r e d
t o
H I V - i n f e c t e d
p a t i e n t s
w i t h o u t
l i v e r
d i s e a s e
[ 2 1 8 ] .
P l a s m a
c o n c e n t r a t i o n
n o t
s i g n i f i c a n t l y
a l t e r e d
i n
p a t i e n t s
w i t h
H C V / H B V
c o - i n f e c t i o n
w i t h o u t
l i v e r
f a i l u r e
[ 2 1 9 ,
2 2 0 ] . n Mild or moderate hepatic insufficiency: Normal dose should
be administered. Careful monitoring for dose-dependent adverse drug
reactions and especially for CNS-symptoms and worsening of liver disease.
Child Pugh C: t1/2 doubled, accumulation tendency. Contraindicated.
Patients with underlying hepatitis B or C: increased risk for severe
hepatic adverse effects [1].& 1, 9, 12, 187, 216, 217, 218, 219,
220]
Frequent: elevated ALT, AST, GGT. Occasionally: acute hepatitis.
Rare: liver failure [1, 12].
"
/
A
G
˜ Hepatic oxidation by
CYP P450 3A4, 2C9 (polymorphic), and 2C19 (polymorphic); glucuronidation.
81.2-86.4% of a dose excreted unchanged in feces [1,
12].• gastrointestinal disturbances (diarrhea, nausea), elevated
triglycerides, peripheral neuropathy, headache, hypertension [1,
12]¦ Child Pugh A and B: In a multiple dose study, pharmacokinetics were
similar compared to healthy subjects. Patients with hepatitis B or C coinfection: CL reduced [1].Ð No dose adjustment necessary in patients
with liver cirrhosis Child Pugh A, B or hepatitis B/C co-infection. Child
Pugh C: no data, usage not recommended. Caution in patients with HBV or
HCV co-infection [1].}
Frequent: elevated AST, ALT, bilirubin.
Occasionally: cytolytic hepatitis, steatosis hepatis, hepatitis,
hepatomegaly [1, 9].
(
6
No metabolism [1, 12]. "
No dose
adaptation necessary [1].Æ Oseltamivir phosphate is a prodrug and is
rapidly hydrolysed to oseltamivir carboxylate by gastrointestinal and
hepatic esterases [1, 12]. The pharmacokinetic data refer to oseltamivir
carboxylate. ! nausea, vomiting, vertigo [1, 12]ä According to in vitro
and animal studies no significant increase of systemically disposable
oseltamivir or active metabolite is expected. Clinical studies confirmed
this in patients with mild and moderate hepatic impairment [1].t No dose
adjustment required in patients with mild and moderate liver disease. No
data for severe liver disease [1].
1, 9, 12, 221:
12].
Post-marketing: elevated liver enzymes, hepatitis [1,
m
Enfuvirtide is a peptide. Assumed catabolism to its amino acids.
Hydrolysis to deamidate metabolite [1, 9]. ‡ Pharmacokinetic studies of
enfuvirtide have not been conducted in patients with hepatic impairment.
No recommendation is available [1].
1, 9, 12, 222P
Frequent: elevation of ALT, AST, GGT. Unknown
frequency: toxic hepatitis [1, 9].
&
9
c
gastrointestinal
disturbances (nausea, diarrhea, vomiting), fatigue, peripheral neuropathy
[1, 222]
o Glucuronidation mainly by UGT1A1. 51% of a dose
eliminated in feces, 32% (9% unchanged) recovered in urine [1].t Child
Pugh B: No significant pharmacokinetic changes observed in patients with
moderate hepatic impairment [1, 223].Á No dosage adjustment necessary in
patients with mild and moderate liver disease. Child Pugh C: no data
available. HBV and HCV co-infection: increased risk for severe hepatic
adverse events [1].
1, 9, 12, 223, 224c
Occasionally: elevated AST,
ALT, bilirubin, hepatitis, hepatomegaly [1]. Rare: liver carcinoma [9].
H
O
^ Oxidation, N-dealkylation by CYP P450 3A4. Major inactive
metabolite is a secondary amine [1].L dizziness, postural hypotension,
increased pulse rate, asthenia [1, 12, 225]Ù
Caution in patients with
liver disease or hepatitis B or C co-infection, risk for hepatotoxicity
may be increased. Monitor patients closely [1]. In Child Pugh A and B
generally no dose adjustments are necessary [9].
1, 9, 12, 225,
226K
T1/2 after i.v. application: 13.2h. After oral application: 1418h [1, 12].
Ž
Frequent: elevation of ALT, AST, bilirubin.
Occasionally: cholestatic jaundice, liver cirrhosis, liver failure,
portal vein thrombosis [1, 9].
,
:
Child Pugh A: Cmax and
AUC increased by 11% and 25%, respectively. Child Pugh B: Cmax and AUC
increased by 32% and 46%, respectively. Child Pugh C: No data [1].R
U
‹ upper respiratory tract infections, otitis media, rhinitis,
cough, fever, rash, gastrointestinal disturbances (nausea, vomiting) [1,
9, 12]6
Occasionally: elevated liver enzymes (ALT, AST) [1, 9]
Y Personal dose recommendations for patients with mild hepatic
insufficiency (Child < i Pugh A)»
Malavaud B, Dinh B, Bonnet E,
Izopet J, Payen JL, et al. Increased incidence of indinavir
nephrolithiasis in patients with hepatitis B or C virus infection.
Antivir Ther. 2000; 5(1): 3-5.
!
Œ
Jamjian MC, McNicholl IR. Enfuvirtide: first fusion inhibitor for
treatment of HIV infection. Am J Health Syst Pharm. 2004; 61(12): 12427.
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