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Dosage adjustment for cytotoxics in renal impairment

Dosage Adjustment for Cytotoxics in Hepatic
Impairment
Dosage Adjustment for Cytotoxics in Hepatic Impairment
This table is a guide only. Pharmacokinetic, Summary of Product Characteristics (SPC), relevant pharmaceutical company data and various references have been reviewed for each drug. From this information, a recommendation has been suggested. Input of the full clinical picture of the patient should always be taken into account. If a patient is following a specific clinical trial or protocol, it is advisable to follow the associated dose modifications. The reference ranges for UCL Hospitals NHS Trust are as follows: Please note that reference ranges will vary from hospital to hospital and this should be taken into account when interpreting the data. Pharmacokinetics
Available Information
Recommendation
Alemtuzumab
SPC (Bayer 2008)– No studies have been conducted in patients with hepatic
Schering – No information, but the drug is cleared intracellularly and therefore
malignant lymphocytosis. Different unlikely to require reduction. pharmacokinetic properties may be BC Cancer Agency – No information found
related to different tumour burden and distribution. Alemtuzumab is primarily metabolised intracellularly. Amsacrine
SPC (Goldshield 2005) – for patients with impaired liver function, reduce dose
BC Cancer Agency – if bilirubin 26-51μmol/L, give 40% of usual dose. If
bilirubin> 51 μmol/L then reduce further or omit. AML 17 – if bilirubin >34μmol/L give 60% dose.
Arsenic Trioxide
SPC (Cephalon 2008) – the safety of the drug in patients with hepatic
Clinical decision – unlikely to require Johns et al1 – A phase I study was conducted in 23 subjects with unresectable,
carcinoma with varying degrees of hepatic dysfunction. Doses were escalated from 0.25mg/kg to 0.5mg/kg and then by increments of 0.5mg/kg. The authors found the drug was well tolerated in this group of subjects. UCLH - Dosage Adjustment for Cytotoxics in Hepatic Impairment (Version 3 - updated January 2009) Pharmacokinetics
Available Information
Recommendation
ATRA (tretinoin)
SPC (Roche 2008) – Due to limited information reduce dose to 25mg/m2 in
BC cancer agency – 25mg/m2 is recommended in patients with hepatic
impairment as no studies have been done. metabolites found in urine were formed by oxidation and glucuronidation. Azacitadine
Pharmion – In the 3 NCI studies involving azacitadine there was no significant
increase in adverse reactions in patients with hepatic impairment compared with starting dose of 75mg/m2. Clinical those with normal hepatic function. However the drug should be used with caution as it is metabolised by hepatic enzymes. In addition there is also some limited data suggesting that azacitadine may be hepatotoxic in patients with The starting dose for the drug is 75mg/m2 SC for 7 days this is regardless of hepatic function and no dose adjustments should be made. The dose is titrated up to 100mg/m2 if no toxicity occurs and benefit has not been seen with the starting dose. Bevacizumab
SPC (Roche 2008) – The safety and efficacy have not been studied in this
Roche – Decision on whether to use should be based on risk versus benefit.
ICON 7 – Current trial studying bevacizumab in ovarian cancer excludes
patients with bilirubin >1.5XULN and serum transaminases 2.5XULN. primarily on elimination through kidneys or liver. Bexarotene
SPC (Cephalon 2007) – Contraindicated in hepatic insufficiency.
Likely to require reduction – clinical Bleomycin
SPC (Kyowa Hakko 2006) – No information.
Kyowa Hakko – Patients with abnormal liver function tend to develop lung
BC Cancer Agency – No adjustment required.
Inactivation takes place primarily in the liver. ~ 2/3 of drug are excreted unchanged in the urine, probably by glomerular filtration. Bortezomib
SPC (Janssen Cilag 2008) – Not studied in hepatic impairment. Significant
impairment may have an impact on clearance. Patients with hepatic dysfunction hepatic impairment, likely to require should be treated with extreme caution and a dose reduction should be considered. Contraindicated in severe impairment.
Ortho Biotech – As SPC
BC cancer agency – Use with caution
UCLH - Dosage Adjustment for Cytotoxics in Hepatic Impairment (Version 3 - updated January 2009) Pharmacokinetics
Available Information
Recommendation
Busulfan
The mean elimination t½ is 2.57hrs. SPC (Pierre Fabre 2008) - The drug has not been studied in patients with
hepatic impairment therefore advises to use with caution in severe hepatic least 12 metabolites. After low and impairment. high doses, 1 & 2% respectively of GSK – no information.
BC cancer agency – no information
urine. The majority of an oral dose is excreted in the urine as methanesulfonic acid, an inactive metabolite. Capecitabine
SPC (Roche 2009) – insufficient safety and efficacy data are available in
patients with hepatic impairment to provide dose adjustment recommendation. No information is available on hepatic impairment due to cirrhosis or hepatitis. Twelves et al2 have evaluated the use of capecitabine in patients with mild to
moderate hepatic dysfunction caused by liver metastases. No significant differences in the pharmacokinetic parameters of the main metabolites were seen in this group compared with patients with normal function indicating there
is no need for prior adjustment of the dose in this patient population.
BC Cancer Agency – no dose adjustment required in mild to moderate hepatic
impairment if due to liver metastases. Drug has not been studied in severe
hepatic impairment.
Carboplatin
SPC (Hospira 2006) – no information. Transient increases in liver enzymes
have been reported. ALP was increased in 30% patients, AST increased in 15% necessary. Mayne Pharma – no further information.
BC Cancer Agency – no adjustment required.
Carmustine
SPC (Bristol Myers Pharmaceuticals 2007) – when high doses have been
used, a reversible type of hepatic toxicity, manifested by increased transaminases, ALP and bilirubin levels, has been reported in a small activity may be due to metabolites. BMS – very little information.
~60-70% of the total dose is
BC Cancer Agency – No guidelines available. Dosage adjustment may be
UCLH - Dosage Adjustment for Cytotoxics in Hepatic Impairment (Version 3 - updated January 2009) Pharmacokinetics
Available Information
Recommendation
Cetuximab
SPC (Merck Sorono 2008) – Only patients with adequate hepatic impairment
have been studied to date i.e. those with serum transaminases <5 x ULN and bilirubin <1.5 x ULN. Pharmacokinetic data suggests that hepatic status does not affect the pharmacokinetic characteristics of cetuximab. Chlorambucil
SPC (GSK 2007) – Consider dose reduction in patients with gross hepatic
slowed and decreased by 10-20% if dysfunction. BC Cancer Agency – Dose adjustments should be considered but no
tolerance is established after the first GSK – – Experiments in mice have lead to the hypothesis that hepatic
cytochrome P-450 is involved in the metabolism. The drug has been administered to patients with hepatic impairment in the treatment of primary biliary cirrhosis. There are no absolute recommendations on the necessity of a dose reduction. Given the pharmacokinetics of the drug it is advised to reduce the dose in severe hepatic impairment then titrate upwards according to response. Chlormethine
SPC - no information available
(Mustine)
minutes. Less than 0.01% of the drug is excreted unchanged in the urine. 50% is excreted in the urine as metabolites after 24 hours. Cisplatin
SPC (Pharmacia 2008) – no information.
Mayne Pharma – no information
BC Cancer Agency – no adjustments required
kidneys, liver and intestine. Distributes into third spaces such as ascites and pleural fluid. The elimination of intact drug and metabolites is via the urine. In the first 24hrs 20-80% is excreted. Cladribine
Pro-drug - activated by intracellular SPC (Lipomed GmbH 2008) – There is inadequate data on dosing of patients
with hepatic insufficiency. Contraindicated in moderate or severe hepatic Janssen-Cilag – The role of the liver in cladribine clearance has not been
determined. In a pharmacokinetic study, it was found that the lowest cladribine clearance was in one patient with a bilirubin of 39μmol/L. UCLH - Dosage Adjustment for Cytotoxics in Hepatic Impairment (Version 3 - updated January 2009) Pharmacokinetics
Available Information
Recommendation
Clofarabine
SPC (Genzyme Therapeutics 2008) – No experience in patients with hepatic
renal and non-renal excretion. After impairment. Contraindicated in severe hepatic impairment and should be used with caution in mild to moderate impairment. Severe being defined as
Bioenvision – as above.
Crisantaspase
SPC (OPi 2005) - no information
Opi – As a general rule the product should not be used in severe hepatic
impairment. In cases of hepatic failure the company cannot recommend its use
unless the clinician deems it a risk versus benefit case.
UKALL2003 – no dose modifications recommended
Cyclophosphamide
SPC (Pharmacia 2007) - not recommended in patients with a bilirubin
>17μmol/L or serum transaminases or ALP more than 2-3 x upper limit of normal. In all such cases doses should be reduced. Asta Medical – In patients with severely impaired hepatic function, there is a
decrease in the peak plasma alkylating activity but the overall t½ is significantly not be necessary. increased and the total exposure to alkylating metabolites is the same as in patients with normal hepatic function. It has been reported that disorders of liver function without signs of jaundice may not be a contraindication and that dosage adjustment may not be necessary.
BC Cancer Agency – no adjustments required
Cytarabine
SPC (Pharmacia 2008) – the human liver apparently detoxifies a substantial
fraction of the administered dose. The drug should be used with caution and at a reduced dose when liver function is poor. Faulding – Limited guidance indicates that the drug should be started at 50% of
the regular dose in those patients with severe hepatic dysfunction (bilirubin >34umol/L). Subsequent doses can be escalated in the absence of toxicity. The hepatotoxic properties of the drug have not been proven. Pfizer – No further information.
BC Cancer agency – As above
Dacarbazine
SPC (Medac GmbH 2008) – If mild to moderate hepatic insufficiency alone
dose reductions are not required. In patients with combined renal and hepatic impairment, elimination of dacarbazine is prolonged. No validated recommendations on dose reductions can be given currently. Bayer – No further information.
BC Cancer Agency – Adjustment required, alternatively monitor for toxicity.
UCLH - Dosage Adjustment for Cytotoxics in Hepatic Impairment (Version 3 - updated January 2009) Pharmacokinetics
Available Information
Recommendation
Dactinomycin
SPC (MSD 2006) - No recommendations.
MSD – Some correspondence of children with Wilms tumour and
hepatotoxicity3. Because of the sensitivity to chemotherapy of Wilms’ tumour, lower doses may be appropriate (0.5 – 1mg/m2). Case reports of veno-occlusive disease have been reported when patients have administered the drug in a multidrug regimen. No information on dose reductions.
BC Cancer Agency – t½ is prolonged in patients with hepatic dysfunction,
adjustments required but no guidelines.
Dasatinib
SPC (BMS 2008) – No clinical trials were conducted in patients with decreased
liver function. Exposure to dasatinib is thought to increase with impaired liver function. The drug should be used with caution in moderate to severe excreted in the faeces and 4% in the BMS- as above plus data that was presented to the FDA demonstrates that
urine.
elevations in LFTs did occur when on treatment Daunorubicin
Daunorubicin is rapidly taken up by SPC (Winthrop pharmaceuticals 2008) – A dose reduction is recommended
Bilirubin
in patients with impaired hepatic function. See recommendations. Aventis – As SPC
UKALL 2003 – Check LFTs only if patient jaundiced. Do not alter dose for
BC Cancer Agency – as guidelines however recommends not to give if
daunorubicinol is also active. It is excreted slowly in the urine, mainly as metabolites with 25% excreted within 5 days. Biliary excretion accounts for 40% elimination. Docetaxel
SPC (Sanofi-Aventis 2008) – If ALT +/or AST > 1.5xULN and ALP
If Bilirubin >22μmol/L +/or ALT/AST >3.5ULN with ALP >6xULN, docetaxel should not be used unless strictly indicated. and faecal route respectively within 7 days. Terminal t½ = 2.5 hours. SPC (Pfizer 2006) – for bilirubin 20 - 51μmol/L, give 50% dose. For bilirubin
Bilirubin
Doxorubicin
Mainly metabolised in the liver by cytochrome P450. Rapidly cleared /μmol/L
from plasma and slowly excreted in Koren et al4, suggest the above and if bilirubin >85μmol/L, give 0% dose. If
UKALL 2003 – Check LF Ts only if patient jaundiced. Do not alter dose for
BC Cancer Agency- As recommendations.
If AST 2-3 x normal, give 75% dose. If AST >3x ULN, give 50% dose UCLH - Dosage Adjustment for Cytotoxics in Hepatic Impairment (Version 3 - updated January 2009) Pharmacokinetics
Available Information
Recommendation
Epirubicin
SPC (Hospira 2006) – for bilirubin 24 - 51μmol/L, give 50% dose, for bilirubin Bilirubin
/μmol/L
BC Cancer Agency: If AST 2-4 x ULN or bili 21-51μmol/L give 50% dose , if
AST >4 x ULN or bili >51 μmol/L then give 25% dose Estramustine
SPC (Pharmacia 2008) – Use with caution in hepatic impairment
BC Cancer Agency –Administer with caution but no recommendations.
Etoposide
Liver metabolised, yielding inactive SPC (BMS 2007) – Etoposide reaches high concentrations in the liver and
kidney. Etoposide use is contra-indicated in patients with severe hepatic administered dose is excreted in the dysfunction. BMS – Creatinine clearance is the strongest predictor of etoposide clearance.
There is conflicting information. Some studies indicate that toxicity, clearance Bilirubin >51 or AST >180 – clinical and t½ are not altered in impaired hepatic function. Koren et al4 suggest the following:
Bilirubin: 26-51μmol/L or AST: 60-180 units/L -50% dose
Bilirubin: >51μmol/L or AST: >180 units/L - omit dose
BC Cancer Agency – Bilirubin 25-50μmol/L: 50% dose, 50-85μmol/L: 25%
dose, >85 μmol/L – do not administer. Minor alterations in liver function e.g.
transaminase elevations do not require dose reduction if renal function is
normal.
Fludarabine
SPC (Bayer 2008) – No information in this group of patients therefore use with
Schering – Fludarabine is mainly eliminated by the renal route, therefore dose
reductions are not necessary. However, there have been reports of liver dysfunction (<1 in 1000) – mainly raised LFTs. Use with extreme caution. BC Cancer Agency- use with caution if benefit outweighs risk.
UCLH - Dosage Adjustment for Cytotoxics in Hepatic Impairment (Version 3 - updated January 2009) Pharmacokinetics
Available Information
Recommendation
SPC (medac GmbH 2007) – Dose reduction is advisable in impaired hepatic
Bilirubin
Fluorouracil
Fluorouracil is distributed through the body water. Activated in target /μmol/L
Faulding – Although ~50% of fluorouracil is metabolised by the hepatic route,
the clinical significance is unclear. Some studies of plasma and tissue concentration of the drug and derivatives in patients with hepatocellular carcinoma and liver cirrhosis or liver metastases detected no change in drug disposition relating to liver dysfunction, indicating no dose reduction is required. However, a dose reduction of the initial dose is advised of 1/3 to 1/2 Koren et al4 suggest a 50% dose reduction, then increase if no toxicity.
BC Cancer Agency – Bilirubin above 86 μmol/L – omit dose
initial dose by 1/2. Increase dose if no toxicity Gemcitabine
SPC (Lilly 2007) – use with caution in patients with hepatic insufficiency.
Lilly – Very limited information available. Egorin et al looked at 8 patients
blood and other tissues. The active with AST >2xULN and 19 patients with bilirubin (28 – 196μmol/L) No dose limiting toxicities were observed in patients with AST elevations. Half If bilirubin > 27 μmol/L, initiate of the patients in the raised bilirubin group developed dose limiting toxicities. BC Cancer Agency - Use a lower starting dose of 800 mg/m2 with total
Terminal t½ is ~1 hour – this increases if the drug is administered over a longer period. Gemtuzumab
Wyeth – Proposed major pathways involved in the elimination of gemtuzumab
ozogamicin are via internalization and intracellular breakdown after binding to the CD33 antigen and hepatic metabolism. Use with caution in patients with hepatic impairment as they are more likely to suffer from veno-occlusive disorder. The drug has not been studied in patients with a bilirubin >34 μmol/L.
the CD33 antigen, gemtuzumab ozogamicin is eliminated in the plasma by internalisation into the cells. Secondly, results from animal studies suggest that the hepatic excretory/metabolism route and gastrointestinal secretion is probably the major elimination pathway, however, renal elimination was seen to a smaller extent. At this time the exact elimination pathway in humans has yet to be described. UCLH - Dosage Adjustment for Cytotoxics in Hepatic Impairment (Version 3 - updated January 2009) Pharmacokinetics
Available Information
Recommendation
Hydroxycarbamide After oral administration,
SPC (medac GmbH 2006) – no information in this group of patients therefore
(Hydroxyurea)
BMS – no information.
BC Cancer Agency – monitor haematological parameters
concentrations are reached by 2hrs. 50% of dose recovered in urine within 12 hours, mainly as intact drug. The rest is excreted as carbon dioxide via the lungs or via the urine as urea. t½ = 2-4 hours. Idarubicin
Oral idarubicin has rapid but erratic SPC (Pharmacia 2008) – in a number of Phase III clinical trials, treatment was
Bilirubin
not given if bilirubin >34μmol/L. For other anthracyclines, 50% dose reduction /μmol/L
if bilirubin in range 21-34μmol/L. Contra-indicated in severe liver impairment. Pfizer – no further information
Cancer Chemotherapy Handbook - If bilirubin >85μmol/L, then the drug
Zanette et al – no changes in idarubicin pharmacokinetics were seen in patients
with abnormal LFT’s (Bilirubin 1.5-2x ULN and ALP 1- 4x ULN) but it ‘cannot be excluded that the clearance of the drug and its metabolite may be affected in 8% (oral) is recovered in the faeces patients with severe hepatic dysfunction7. BC Cancer Agency – if bilirubin 40-85 μmol/L, then give 50% dose reduction.
(oral) is recovered in the urine over If bilirubin >85μmol/L, then CI. Ifosfamide
SPC (Baxter 2007) – contra-indicated in patients with a bilirubin >17μmol/L or
serum transaminases or ALP more than 2.5 x upper normal limit. Asta Medical – Good liver function is important for both activation and
elimination of ifosfamide. Ifosfamide is itself not hepatotoxic, however, concomitant hepatotoxic drug administration should be avoided. Imatinib
SPC (Novartis 2008) –If bilirubin >3xULN or liver transaminases >5X ULN
withhold imatinib until bilirubin < 1.5 x ULN or liver transaminases < 2.5 x demethylated piperazine derivative. ULN. Treatment can be continued at a reduced dose – In adults- 400 mg od → 300 mg od; 600 mg od → 400 mg od, 800 mg od → 600 mg od. In children from 340 to 260mg/m2/day. Patients with mild/moderate/severe impairment should be given the minimum recommended dose of 400mg/day and this should excreted in faeces and 13% in urine be reduced if it is not tolerated. BC Cancer Agency – as SPC
UCLH - Dosage Adjustment for Cytotoxics in Hepatic Impairment (Version 3 - updated January 2009) Pharmacokinetics
Available Information
Recommendation
Irinotecan
SPC (Pfizer 2008) – In patients with a bilirubin <1.5xULN, give 350mg/m2.
Bilirubin
Dose/mg/m2
Patients with a bilirubin 1.5–3xULN give 200mg/m2. Patients with a bilirubin /μmol/L
beyond 3xULN should not be treated with irinotecan. No data is available in patients with hepatic impairment that are treated with a irinotecan combination Aventis - treatment of patients with initial total bilirubin levels > 3xULN with a
starting dose of 100mg/m2 is currently under investigatiom. Pfizer- if using a weekly regimen maximum tolerated dose if bilirubin 1.5-
3xULN, ALT >5xULN is 60mg/m2, if bilirubin 3.1-5xULN, ALT <5xULN is 50mg/m2, if bilirubin <1.5 x ULN, ALT is 5-20 x ULN is 60mg/m2, if bilirubin 1.5-5 x ULN, ALT is 5-20 x ULN is 40mg/m2. BC Cancer Agency – If using a 3 or 4 weekly cycle then consider a dose
reduction if the bilirubin is between 17-35μmol/L and the patient has a
combined history of pelvic/abdominal radiation. If using a 6 weekly cycle then
consider starting the dose at 100mg/m2 if the bilirubin is between 17-35μmol/L
and the patient has a combined history of pelvic/abdominal radiation.
Lenalidomide
Celgene – No information regarding safety in this group of patients. Thus far
trials involving lenalidomide have excluded patients with hepatic impairment. SPC – no information.
Bilirubin
Liposomal
Gilead Sciences from American prescribing information – see
/μmol/L
Daunorubicin
a 200-400 fold reduction in volume Suggest extra caution and do not exceed 100mg/m2. Monitor toxicities in UCLH - Dosage Adjustment for Cytotoxics in Hepatic Impairment (Version 3 - updated January 2009) Pharmacokinetics
Available Information
Recommendation
Liposomal
SPC (Schering Plough 2008) – Liposomal doxorubicin pharmacokinetics
Bilirubin
Doxorubicin
determined in a small number of patients with elevated total bilirubin levels do /μmol/L
not differ from patients with normal total bilirubin levels. However dose reductions are recommended in this group of patients based on breast and ovarian clinical trials. Dose reductions are as recommendations. If the patient tolerates the first dose without an increase in bilirubin or liver enzymes then the next dose can be increased by 25% and the dose can be titrated to the full dose serves as a slow-release preparation on subsequent cycles. The drug can be administered to patients with for free doxorubicin. bilirubin/liver enzymes up to 4 times the ULN.
BC Cancer Agency – as recommendations, in addition patients with Kaposi
sarcoma; bilirubin 21-51μmol/L – reduce dose by 50%, >51μmol/L then reduce
dose by 75%. Do not escalate dose in this group of patients.


Lomustine
SPC (Medac GmbH 2007) – liver function should be assessed periodically.
BC Cancer Agency – Hold Lomustine if AST>5xULN and bilirubin is >25
μmol/L until liver function returns to normal. hepatic microsomal enzymes. Metabolites predominantly excreted by kidneys; 10% excreted as CO2 and <5% in faeces. Melphalan
SPC (GSK 2007) – no information.
absorption - 25-89% post oral dose; BC Cancer Agency – no adjustments required.
taken with food. Spontaneous degradation rather than enzymatic metabolism. Percentage of dose excreted in the urine as active or toxic moiety ranges from 11-93%. 20-50% excreted in the faeces within 6 days. t½ ~ 1.5-2hrs. UCLH - Dosage Adjustment for Cytotoxics in Hepatic Impairment (Version 3 - updated January 2009) Pharmacokinetics
Available Information
Recommendation
Mercaptopurine
SPC (GSK 2007) – Mercaptopurine is hepatotoxic and liver function tests
should be monitored weekly during treatment. More frequent monitoring may be advisable in those with pre-existing liver disease or receiving other potentially hepatotoxic therapy. Consider decreased dose in impaired hepatic UKALL 2003 guidelines – Check LFT’s only if patient jaundiced, if bilirubin
>50μmol/L omit mercaptopurine until it is less than 20μmol/L and then restart result in a 5-fold variation in AUC. at half of the previously attained dose. Escalate from 50% to 75% to 100% dose at 10-day intervals provided hyperbilirubinaemia does not recur. Do not modify BC Cancer Agency – dosage adjustment recommended but no details.
doses. t½ = 1-3 hrs (PO) and 0.3-1 hr (IV). SPC (Hospira 2009) – Contra-indicated in significantly impaired hepatic
Bilirubin
Methotrexate
The dose is well absorbed at doses < 30mg/m2 – bioavailability is /μmol/L
Mayne – see recommendations.
Koren et al4, Although eliminated mainly by the kidney, methotrexate should
be used with caution in patients with liver dysfunction because of its hepatotoxic potential, which may lead to fibrosis and cirrhosis. The clearance rate is not likely to alter in patients with liver dysfunction who have normal the kidneys (>90%), although small renal function. Conversely, liver disease often is associated with decreased protein-binding of drugs and, therefore may theoretically lead to increased higher in children than in adults. t½ toxicity of methotrexate. UKALL 2003 guidelines – Check LFT’s only if patient jaundiced, if bilirubin
>50μmol/L omit methotrexate until it is less than 20μmol/L and then restart at half of the previously attained dose. Escalate from 50% to 75% to 100% dose at occasionally hyperbilirubinemia. 10-day intervals provided hyperbilirubinaemia does not recur. Do not modify BC Cancer agency – as recommendations.
infusion and are not considered toxicity requiring discontinuation of repeated administration of methotrexate. Persistant hyperbilirubinemia and/or grade 3-4 hypertransaminasemia for longer than 3 weeks should result in discontinuation of the drug. Dose reduce, particularly in patients with concomitantly impaired renal function. Severe hepatic impairment – CI UCLH - Dosage Adjustment for Cytotoxics in Hepatic Impairment (Version 3 - updated January 2009) Pharmacokinetics
Available Information
Recommendation
Mitomycin C
SPC (Kyowa Hakko 2007) –.No information.
Metabolism is predominantly in the Faulding – Following metabolism at numerous sites, mitomycin is excreted in
the urine and bile. Although sources have suggested that elevated AST levels may produce a prolonged plasma t½, dosage adjustment may not be necessary. BC Cancer Agency: No information found.
to saturation of the degradative pathways. ~10% is excreted unchanged in the urine. Since metabolic pathways are saturated at low doses, the % dose excreted in the urine increases with increasing dose. Mitotane
SPC (HRA pharma 2008) – Since mitotane is metabolised through the liver,
plasma levels of the drug are thought to increase if the liver function is impaired. There is no experience in using the drug in patients with liver as metabolites. 10-25% excreted in impairment and therefore data is insufficient to give dose recommendations in the urine as metabolites. this group. The drug is not recommended to be used in severe hepatic
impairment and it should be used with caution in those that have mild to
moderate impairment.
BC cancer agency – adjustments required but no details found.

Mitoxantrone
SPC (Wyeth 2008) - Careful supervision is recommended when treating
patients with severe hepatic insufficiency. Wyeth – t½ is significantly longer in patients with abnormal LFT’s (increased
from 38 to 70hrs). A dose of 12mg/m2 in hepatocellular carcinoma has a manageable toxicity. In some breast cancer trials, if bilirubin >50μmol/L, then give 50% dose. Chlebowski8 used a dose of 14mg/m2 in breast cancer patients with hepatic dysfunction, but haematological toxicity was more severe. Patients Bilirubin <59μmol/L & good PS – with bilirubin 22-59μmol/L tolerate full dose, especially if they have good performance status (PS). Patients with bilirubin >60μmol/L and good PS tolerate 8mg/m2. Bilirubin >60μmol/L and poor PS, not advised. Bilirubin >60μmol/L & good PS – max 8mg/m2 (i.e. 40% dose reduction) Bilirubin >60μmol/L & poor PS – not recommended. UCLH - Dosage Adjustment for Cytotoxics in Hepatic Impairment (Version 3 - updated January 2009) Pharmacokinetics
Available Information
Recommendation
Oxaliplatin
SPC (Sanofi-aventis 2007)– In a phase I study including patients with several
levels of hepatic impairment, frequency and severity of hepato-biliary disorders appeared to be related to progressive disease and impaired liver function tests at Clinical decision baseline. No specific dose adjustment for patients with abnormal LFTs was BC Cancer Agency – No dose adjustments required for mild to moderate
impairment. No information found on severe. mainly by renal excretion. By day 5, ~54% of the total dose was recovered in the urine and <3% in the faeces. SPC (medac GmbH 2008) – Patients with hepatic impairment may be at
Bilirubin
Paclitaxel
Hepatic metabolism and biliary clearance is the principal increased risk of toxicity, particularly grade III-IV myelosuppression. No /μmol/L
evidence that toxicity increased when given as a 3-hour infusion to patients with mildly abnormal liver function. No data available in severe baseline cholestasis. < 26 When paclitaxel is given as a longer infusion, increased myelosuppression may be seen in patients with moderate to severe hepatic impairment. Paclitaxel is not >51 recommended in patients with severely impaired hepatic function. SPC (Abraxis 2009) - Patients with severe hepatic impairment (bilirubin > 5 x
ULN or AST/ALT > 10 x ULN) should not be treated with Paclitaxel.
BMS – clearance, in particular, metabolite clearance, was reduced in patients
with impaired liver function. This effect was positively correlated with
bilirubin, transaminase and ALP levels. When liver function improves during treatment, paclitaxel and metabolite levels normalise. If bilirubin <1.25 normal value and transaminase levels < 10x normal value, a dose of 175mg/m2 seems
safe, although more haematological toxicity is seen.
Venook et al9 - See recommendations. Ambiguous information, if bilirubin <
26 μmol/L assume that up to 17μmol/L is normal and dose as normal.
BC Cancer Agency- If bilirubin 1.26-2xULN give 135mg/m2, if 2-5xULN
90mg/m2 and if >5xULN not recommended.
Pentostatin
SPC (Hospira 2009) – Because of limited experience treating patients with
metabolised. It is primarily excreted abnormal liver function, treat with caution. 90% excreted by kidneys within 24 hours. Pemetrexed
SPC (lilly 2009) - No relationships between AST, ALT ,or total bilirubin and
pemetrexed pharmacokinetics were identified. However patients with hepatic impairment such as bilirubin >1.5 x ULN and/or transaminase > 3.0 x ULN (hepatic metastases absent) or > 5.0 x ULN (hepatic metastases present) have not been specifically studied. UCLH - Dosage Adjustment for Cytotoxics in Hepatic Impairment (Version 3 - updated January 2009) Pharmacokinetics
Available Information
Recommendation
Procarbazine
SPC (Cambridge Labs 2006) – Caution advisable in patients with hepatic
completely absorbed. Procarbazine BC Cancer Agency – if bilirubin is > 50 μmol/L, dose reduce.
If bilirubin >85μmol/L or AST >180 Koren et al4 suggest if bilirubin >85μmol/L or AST >180 units, then omit dose.
alkylating agent. After 24hrs up to 70% of a dose is recovered in the urine. Raltitrexed
SPC (Astra Zeneca 2002) – No dose adjustment with mild to moderate
impairment. Due to some excretion via the faecal route, treatment is not recommended in patients with severe hepatic impairment. AstraZeneca – Studies included patients with mild to moderate impairment.
Patients with severe impairment were excluded and therefore no information. Liver metastases do not necessarily indicate impairment as 80% of all trial patients had liver metastases and responded well to treatment. No need to dose
reduce in this group of patients unless AST/ALT >5xULN. In patients without
liver metastases, treat if bilirubin <1.5xULN or AST/ALT <2.5xULN. (Patients
were ineligible for trials outside of these ranges).
BC Cancer Agency – if pre-existing bilirubin is < 10 x ULN, give 100% dose.
If drug induced then delay dose. Use not recommended if bilirubin>10XUNL.
Rituximab
Mean serum t1/2 increases with dose SPC (Roche 2008) – No dose reductions are recommended when given in
combination with CHOP or CVP chemotherapy, standard dose reductions for 1st infusion and 205.8 hours after 4th chemotherapeutic medicinal products should be applied. infusion. BC Cancer Agency – no dose adjustment required.
Temozolomide
SPC (Schering Plough 2009) – the pharmacokinetics of temozolomide were
comparable in patients with normal hepatic function and in those with mild or moderate hepatic function. No data is available for severe hepatic impairment. Based on pharmacokinetic properties of temozolamide, it is unlikely that dose reductions are required in patients with severe hepatic dysfunction. Schering-Plough – 38% of patients in clinical trials had grade I-IV raised
LFTs, in particular ALP. A reduction in dose or discontinuation of drug allowed LFTs to return to normal.
BC Cancer Agency – No adjustment required
Thalidomide
Pharmion – Doses in patients with hepatic impairment should be titrated with
observed tolerance and toxicity and the highest tolerated dose should be BC cancer agency – No adjustment required.
minimal hepatic metabolism and urinary excretion of thalidomide. UCLH - Dosage Adjustment for Cytotoxics in Hepatic Impairment (Version 3 - updated January 2009) Pharmacokinetics
Available Information
Recommendation
Thioguanine
SPC (GSK 2008) – Consideration should be given to reducing the dosage in
patients with impaired hepatic function. BC Cancer Agency – Dose reduction required but no information.
metabolism in the liver and other tissues to several active and inactive metabolites. 24-46% of the dose is excreted in the urine within 24 hours. Thiotepa
SPC (Cyanamid 2004) – Use lowest possible dose when there is existing
hepatic damage and only use if benefit outweighs risk. Goldshield – Use with extreme caution in hepatic failure and only in cases
where benefit outweighs risk. Start at lowest possible effective dose and use metabolites. (60% within 72 hours). BC Cancer Agency- Dose reduction required but no information.
Tipifarnib
Ortho Biotech – No clinical studies have been conducted in subjects with
hepatic impairment. Population pharmacokinetic studies show no relationship between the oral clearance and liver enzyme elevation. Total bilirubin concentrations exhibit a weak but statistically significant relationship with tipifarnib clearance. Topotecan
SPC (GSK 2009) – There is no experience of topotecan in patients with
severely impaired hepatic function (bilirubin >170μmol/L). Plasma clearance in patients with bilirubin 34-170μmol/L decreased by ~10%. t½ was increased hydroxyacid (carboxylate) form. A by ~30%. O’Reilly et al10 - 21 patients with hepatic dysfunction were studied. Toxicity
topotecan is metabolised by hepatic and pharmacokinetic profiles were similar to those seen in patients without impairment. The clearance was also unaffected. BC Cancer Agency- No adjustments required if bilirubin <170 μmol/L, above
Trastuzumab
SPC (Roche 2008) – Dedicated studies in patients with renal or hepatic
impairment have not been carried out. However, in a population pharmacokinetic analysis, renal impairment was not shown to affect BC Cancer Agency – No dose reduction required.
Doesn’t require hepatic or renal metabolism for elimination. UCLH - Dosage Adjustment for Cytotoxics in Hepatic Impairment (Version 3 - updated January 2009) Pharmacokinetics
Available Information
Recommendation
Treosulphan
SPC (medac GmbH 2008) – No information.
bifunctional alkylating agent. High Medac – No information.
and relatively constant bioavailability. The mean urinary excretion of the parent compound is ~15% over 24hrs. SPC (Merck sorono 2008) – Use with caution in patients with renal or hepatic
(Tegafur-uracil)
impairment. Since hepatic disorders have been reported, liver function should be monitored during treatment in patients with mild to moderate hepatic dysfunction. Contraindicated in patients that have a known deficiency of hepatic BMS – UFT is contra-indicated in patients who have severe hepatic
impairment. Since hepatic disorders, including fulminant hepatitis, have been reported in patients receiving single agent UFT, appropriate testing should be performed on any patient receiving the UFT / folinate combination who hydroxy-metabolites are excreted in presents signs and symptoms of hepatic impairment. the urine. Vinblastine
SPC (Hospira 2004) - Liver disease may alter the elimination of vinblastine in
Bilirubin
the bile, markedly increasing toxicity to peripheral nerves and necessitating a /μmol/L
dosage modification in affected patients. SPC (Lilly) – As vinblastine is excreted principally by the liver, it may be
necessary to reduce initial doses in the presence of significantly impaired hepatic or biliary function. If bilirubin >51μmol/L, 50% dose is recommended. ● It has been suggested that if bilirubin 26-51μmol/L or AST / ALT 60-180 units give 50% dose. If the bilirubin >51μmol/L or AST /ALT >180 units, the
drug is not given11.
BC Cancer Agency: Bilirubin 25-50 μmol/L – give 50% of dose, grater than 50
Vincristine
SPC (Hospira 2004) – Patients with liver disease sufficient to decrease biliary
Bilirubin
excretion may experience an increase in the severity of side-effects. A 50% /μmol/L
reduction is recommended for patients with a bilirubin >51μmol/L. Lilly – as SPC
● It has been suggested that if bilirubin 26-51μmol/L or AST / ALT 60-180 metabolites). 10% excreted in urine units, give 50% dose. If the bilirubin >51μmol/L or AST /ALT >180 units, the drug is not given11.
UKALL 2003 guidelines state that LFTs should only be checked if the patient
is jaundiced. Withhold if total bilirubin >50μmol/L. Administer 50% of dose if
total bilirubin is 25-50 μmol/L. Do not alter dose for abnormal transaminases.
BC Cancer Agency – Bilirubin 26-50μmol/L-50% of dose, >50μmol/L then
25% of dose.
UCLH - Dosage Adjustment for Cytotoxics in Hepatic Impairment (Version 3 - updated January 2009) Pharmacokinetics
Available Information
Recommendation
Vindesine
SPC (Genus 2004) – Excreted principally by the liver, therefore may be
necessary to reduce initial doses in the presence of significantly impaired SPC (Medac GmbH 2007) – Vinorelbine metabolism and clearance are mostly
AST/ALT Bili
Vinorelbine
Metabolism appears to be hepatic. t½ is greater than 40hrs. Excretion hepatic. In breast cancer patients, clearance is not altered in presence of moderate liver metastases (i.e. <75% of liver volume replaced by the tumour). In these patients there is no pharmacokinetic rationale for reducing doses. In patients with massive liver metastases (i.e. >75% of liver volume replaced by the tumour), it is suggested that the dose is reduced by 1/3 and the
haematological toxicity closely followed.
Pierre Fabre – For patients presenting with severe liver impairment (bilirubin>
2xUNL and/or transaminases > 5xUNL), it is suggested that the dose be
reduced by 33% and the haematological parameters be closely monitored since
the maximum dose which was evaluated in this subset of patients was 20mg/m2.
BC Cancer Agency – Bilirubin 36-50 μmol/L – 50% of dose, >50μmol/L then
25% of dose.
Johns M, Chodkiewicz C, Dinwoodlie WR et al. European Journal of Cancer Supplements. 2006;4(12):96. Twelves C et al. Clin Cancer Res 1999; 5: 1696-1702 Lancet 1(8630): 168, Jan 21, 1989 (in letters to editor) Koren G, Beatty K, Seto A et al. Annals of pharmacotherapy 1992;26(3):363-371 Venook AP, Egorin MJ, Rosner GL, et al. J Clin Oncol 2000;18(14):2780-7 Cancer Chemotherapy Handbook, Dorr R, Von Hoff D. 2nd Ed (Appleton & Lange) ALL97/01(revised: November 1999, October 2001)Zanette L, Zucchetti, M et al Cancer Chemother Pharmacol (1990) 25:445-448 Chlebowski RT, Breast Cancer Research and Treat, 1989;14,267-274 Venook AP,et al ASCO proceedings 1994:13:Abstract 35011 Medical Research Council Working Party on Leukaemia in Children UK National Lymphoblastic Leukaemia (ALL) Trial O’Reilly S et al. J Natl Cancer Inst 1996; 88;817-824 The Chemotherapy Source Book. Ed. M Perry. (Williams & Wilkins) p644 UCLH - Dosage Adjustment for Cytotoxics in Hepatic Impairment (Version 3 - updated January 2009)

Source: http://www.eastmidlandscancernetwork.nhs.uk/Library/HepaticDosageAdjustment.pdf

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