1.

Cefaclor halam 367

1. Cefaclor. Over the period 1979 to 1997, there had been 3 cases of raised INRs with or
without clinical bleeding in patients taking acenocoumarol, warfarin or an unknown
anticoagulant and cefaclor reported to the CSM in the UK.7 No cases seem to have been
published.
Mekanisme
Cephalosporins with an N-methylthiotetrazole side-chain can, like the oral anticoagulants, act
as vitamin K antagonists to reduce the production of some blood clotting factors. They can
therefore cause bleeding on their own. For example, serious bleeding following the use of
cefamandole (in the absence of an anticoagulant) has been described in 3 out of 37 patients
in one report,10 and a further report highlights a further 16 cases.11 Other similar
cephalosporins and related beta lactams that have been reported to cause
hypoprothrombinaemia when used alone include cefoperazone,12-16 cefotetan,17
ceftriaxone,18 cefalotin,19 cefazolin,20-22 and latamoxef.23,24 The incidence is very
variable: in some instances only isolated cases have been reported whereas a 15% bleeding
rate was found in one study24 wit latamoxef alone, 22% in another23, but only 8% with
cefoxitin alone.23 These cephalosporins might therefore worsen the risk of bleeding by
simple addition if given with coumarin or indanedione anticoagulants. In addition, some of
them may also inhibit platelet function.25 Ceftriaxone seems to act similarly although it has
an N-methylthiotriazine ring instead, as does cefazolin, which has an Nmethylthiadiazolethiol side-chain. Aztreonam can also increase the prothrombin time.26-29
See also antibacterials, (p.365).
Importance and management
Most cephalosporins and related beta lactams do not normally cause bleeding so would not be
expected to have an additive interaction with the oral anticoagulants. In contrast,
cephalosporins with the N-methylthiotetrazole side-chain appear to increase the risk of
bleeding, and might therefore interact. Both cefamandole and to a lesser extent cefazolin
have been shown to increase the response to warfarin, and cases of over-anticoagulation have
been reported for cefonicid and cefotiam. All other cephalosporins and related beta-lactams
with the N-methylthiotetrazole or similar side-chain might be expected to behave similarly,
but have not so far been reported to do so. These include cefalotin, cefmenoxime,
cefmetazole, cefminox, cefoperazone, ceforanide, cefotetan, cefpiramide, ceftriaxone,
and latamoxef. Aztreonam has also been predicted to interact similarly, although, again
there are no reports. Although not having an N-methylthiotetrazole side-chain, the
manufacturers of cefixime and cefaclor have on record a few cases of over-anticoagulation.
Patients most at risk seem to be those whose intake of vitamin K is restricted (poor diet,
malabsorption syndromes, etc.) and those with renal failure. The use of an anticoagulant
represents just another factor that may precipitate bleeding. A possible solution to the
problem is to use a non-interacting cephalosporin. Alternatively you should monitor the
outcome closely, particularly in the early stages of treatment, adjusting the anticoagulant
dosage if necessary. Excessive hypoprothrombinaemia can be controlled with vitamin K.
2. Cyclophospamid ( halaman 382 )
(c) Cyclophosphamide
A woman taking warfarin had a marked rise in her prothrombin time when her treatment
with cyclophosphamide was withdrawn.9

Mechanism
Not well understood. Mercaptopurine possibly increases the synthesis or activation of
prothrombin.22 Azathioprine is metabolised to mercaptopurine,and would therefore be
expected to interact similarly.
Importance and management
The absence of problems in early small studies using warfarin as an adjunct to
chemotherapy,23,24 and the small number of reports describing difficulties, suggest that
many of these interactions may be uncommon events. The concurrent use of these drugs need
not be avoided but there is clearly a need to be aware that any antineoplastic regimen might
increase the response to anticoagulants. It would also be prudent to note that mercaptopurine
and azathioprine may decrease the anticoagulant response. The anticoagulant dosages may
need adjustment. Note that, from a disease perspective, when treating venous
thromboembolic disease in patients with cancer, warfarin is generally inferior (higher risk of
major bleeds and recurrent thrombosis) to low-molecular-weight heparins.25
3. Chlormethine (h) Mercaptopurine
A man well stabilised on warfarin had a marked reduction in his anticoagulant response on
two occasions while taking mercaptopurine, but no changes occurred when he took busulfan,
cyclophosphamide, cytarabine, hydroxycarbamide, mitobronitol, demecolcine or
melphalan.15 A woman needed a marked increase in her dosage of acenocoumarol, from 21
to 70 mg weekly, when she was given mercaptopurine 100 mg daily.16 Another patient
required about a 25% increase in warfarin dose while taking mercaptopurine 100 mg daily
Mechanism
Not well understood. Mercaptopurine possibly increases the synthesis or activation of
prothrombin.22 Azathioprine is metabolised to mercaptopurine, and would therefore be
expected to interact similarly.
Importance and management
The absence of problems in early small studies using warfarin as an adjunct to
chemotherapy,23,24 and the small number of reports describing difficulties, suggest that
many of these interactions may be uncommon events. The concurrent use of these drugs need
not be avoided but there is clearly a need to be aware that any antineoplastic regimen might
increase
the response to anticoagulants. It would also be prudent to note that mercaptopurine and
azathioprine may decrease the anticoagulant response. The anticoagulant dosages may need
adjustment. Note that, from a disease
perspective, when treating venous thromboembolic disease in patients with cancer, warfarin
is generally inferior (higher risk of major bleeds and recurrent thrombosis) to low-molecularweight heparins.25
4. Cisapride
Ketoconazole, erythromycin, and clarithromycin can cause a marked rise in serum
cisapride levels, increasing the risk of serious and life-threatening ventricular
arrhythmias including torsadede pointes. Nefazodone and protease inhibitors are also
predicted to have this effect. Although there do not appear to be any specific reports,
cisapride should not be used with other drugs that prolong the QT interval (see also
Drugs that prolong the QT interval + Other drugs that prolong the QT interval,

p.257). No clinically relevant interactions with cisapride are apparent when it is given
with antacids, cimetidine, esomeprazole, fluoxetine or pantoprazole, but two isolated
reports attribute cardiotoxicity to the concurrent use of cisapride and ranitidine or
diltiazem. Cisapride increases the rate of absorption of bromperidol, ciclosporin,
diazepam, disopyramide, and nifedipine, but appears to have no important effect on
digoxin, morphine, paracetamol (acetaminophen) or propranolol. The effects of
anticoagulants may be altered by cisapride.
Clinical evidence, mechanism, importance and management
In many countries cisapride has been withdrawn from the market, or is only available for
restricted use because of its potential to cause torsade depointes arrhythmias, especially when
cisapride serum levels are elevated.1 This can lead to cardiac arrest and sudden death. The
interactions of cisapride and their importance and management are summarised in Table
27.2, (p.964).