Aspirin + Bile-acid binding resins

Colestyramine and colestipol do not appear to have any clinically important effects on the
absorption of aspirin. Clinical evidence, mechanism, importance and management
(a) Colestipol
In 12 healthy subjects the extent of absorption of a single 650-mg dose of aspirin was
unaffected by colestipol 10 g. However, the rate of aspirin absorption was increased by
colestipol: at 60 minutes after the dose the plasma level was increased by about 40%. No
particular precautions seem to be necessary during concurrent use.
(b) Colestyramine
A study in 3 healthy subjects and 3 patients, and a later study in 7 healthy subjects, found that
colestyramine 4 gdelayed the absorption of a single 500-mg dose of aspirin (time to peak
levels extended from 30 to 60 minutes) but the total amount absorbed was only reduced by 5
to 6%. Some of the subjects had slightly higher serum aspirin levels while taking
colestyramine.Similar results were reported in another study (a 31% lower plasma aspirin
level at 60 minutes, but no difference in total absorption). There would seem to be little
reason for avoiding concurrent use unless rapid analgesia is needed.
Coumarins + Bile-acid binding resins
The anticoagulant effects of phenprocoumon and warfarin can be reduced by colestyramine,
especially if the coumarin is given at the same time. An isolated report describes unexpected
sensitivity to warfarin in a patient taking colestyramine, which was attributed to a possible
reduction in vitamin K absorption with colestyramine. Colestipol did not alter the absorption
or effect of phenprocoumon or warfarin and colesevelam did not alter the pharmacokinetics
of warfarin.
Clinical evidence
(a) Colesevelam
Colesevelam 4.5 g had no effect on the pharmacokinetics of warfarin 10 mg in a single-dose
study in 24 healthy subjects.
(b) Colestipol
In a placebo-controlled, single-dose study in 4 healthy subjects, phenprocoumonplasma levels
and the prothrombin response were unaffected by colestipol 8 g given at the same time as
phenprocoumon12 mg. Similarly, in an study quoted in a review, the concurrent use of
colestipol 10 g did not cause any changes in the absorption of a single 10-mg dose of
warfarinin healthy subjects.
(c) Colestyramine
1. Phenprocoumon. It was noted that establishing effective anticoagulation was difficult in
patients taking phenprocoumon with colestyramine, in spite of doubling the dose of
phenprocoumon. This prompted a study in healthy subjects in which it was found that
concurrent single doses of
phenprocoumon and colestyramine markedly reduced phenprocoumon

plasma levels and effect. In another study using intravenousphenprocoumon, colestyramine

reduced the effect of the anticoagulant by this route, presumably by reducing enterohepatic
recycling. This fact has been used clinically to enhance the elimination of phenprocoumon
after phenprocoumon overdose. In one case, the half-life of phenprocoumon was measured as
6.8 days without colestyramine, and 3.5 days with colestyramine 4 g three times daily.
A patient stabilised on phenprocoumon developed a fatal valve thrombosis after starting
colestyramine, despite separation of doses in accordance with the manufacturers instructions.
2. Warfarin. Ten subjects were treated for one-week periods with warfarin alone then warfarin
with colestyramine 8 g given three times daily, with the warfarin taken 30 minutes after
colestyramine for one week, then 6 hours after colestyramine for one week. When warfarin
was taken 30 minutes after colestyramine, peak warfarin levels were reduced by 52% and the
prolongation in prothrombin times was reduced by 27%, compared with warfarin alone.
However, when warfarin was taken 6 hours after colestyramine, peak warfarin levels were
reduced by only 16%, and the prolongation in prothrombin times was the same as with
warfarin alone.
Comparable results were found in another similar study; simultaneous administration of
warfarin and colestyramine reduced the prothrombin time response by 21%, and separation
by 3 hours still caused an 11% reduction in the prothrombin time response.
Another study using intravenouswarfarin has shown that colestyramine also reduces the effect
of warfarin by this route, presumably by reducing enterohepatic recycling.
Another report describes a patient taking colestyramine 4 g three times daily who was
successfully stabilised on warfarin with alternating doses of 5 mg and 7.5 mg daily. The
warfarin was given at 8 am, then the colestyramine at 12 noon with lunch, with dinner, and
with an evening snack.
In contrast, an isolated report describes a 77-year-old patient taking multiple medications
including colestyramine who was found to have a very high prothrombin time of 78.9
seconds and microscopic haematuria 6 weeks after starting warfarin 5 mg daily. Four days
after starting the warfarin her prothrombin time was 17.1 seconds, and it had not been
checked again. However, as it is not certain that this patient was properly stabilised on
warfarin this may simply have been an effect of the warfarin alone.
Mechanism
Colestyramine binds to coumarin anticoagulants in the gut, thereby preventing their
absorption. Data with intravenous warfarin and phenprocoumon show that they undergo
enterohepatic recycling, and that colestyramine can reduce this as well. Long-term use of
colestyramine also reduces the absorption of fat-soluble vitamins such as vitamin K so that it
can have some direct hypoprothrombinaemic effects of its own. This may to some extent
offset the full effects of its interaction with anticoagulants. Colestipol on the other hand
appears not to bind to any great extent at the pH values in the gut. The paradoxical increase in
the effects of warfarin in the isolated case cited above was attributed to the effect of
colestyramine on vitamin K.
Importance and management

The interaction of colestyramine with phenprocoumon and warfarin is established, and can be
clinically important. If concurrent use is thought necessary, prothrombin times should be
monitored and the dosage of the anticoagulant increased appropriately. Giving the
colestyramine 4 to 6 hours after the anticoagulant has been shown to minimise the effects of
this interaction, and it is a standard recommendation that other drugs should be given 1 hour
before or 4 to 6 hours after colestyramine. However, despite adequate separation of doses,
one patient taking phenprocoumon developed fatal valve thrombosis when given
colestyramine, leading the authors to suggest that colestyramine should not be used in
patients taking oral anticoagulants. Information about other anticoagulants is lacking but as
colestyramine interacts with dicoumarol and ethyl biscoumacetate in animals it would be
prudent to expect all coumarins to interact similarly. Bear in mind that long-term
colestyramine can reducevitamin K absorption and can cause hypoprothrombinaemia. This
might result in an increased effect of warfarin, as has been suggested in one unconfirmed case
report but there seems to be no other evidence to suggest that this is clinically relevant.
No special precautions appear necessary if warfarin or phenprocoumon and colestipol or
colesevelam are given concurrently.

Antidiabetics + Bile-acid binding resins

A report suggests that the hypocholesterolaemic effect of colestipol is unaffected in insulintreated diabetics but it may be ineffective in those taking phenformin and sulphonylureas.
Diabetic control was not affected. Colestyramine may enhance the effect of acarbose, and
insulin levels may rebound if both drugs are stopped at the same time. There isevidence that
the absorption of glipizide may be reduced by about 30% if it is taken at the same time as
colestyramine, but tolbutamide does not appear to be affected.
Clinical evidence
(a) Colestipol
The concurrent use of phenforminand a sulphonylurea (chlorpropamide, tolbutamideor
tolazamide) inhibited the normal hypocholesterolaemic effects of the colestipol in 12
diabetics with elevated serum cholesterol levels. No such antagonismwas seen in two patients
with type 2 diabetes receiving insulin. The control of diabetes was not affected by the
colestipol.
(b) Colestyramine
1. Acarbose. Colestyramine 12 g daily for 6 days, given to 8 healthy subjects taking acarbose
100 mg three times daily, improved the reduction in postprandial insulin levels. The mean
serum insulin levels fell by 23% while taking both drugs, but showed a rebound 31%
increase above baseline when both were stopped.
2. Glipizide. Colestyramine 8 g in 150 mL of water reduced the absorption of a single 5-mg
dose of glipizide in 6 healthy subjects by a mean of 29%. One subject had a 41% reduction in
glipizide levels. Peak serum levels were reduced by 33%. The AUC0-10 was used to measure
absorption.

3. Tolbutamide. A single-dose study indicated that colestyramine 8 g, given 2 minutes before,

and 6 and 12 hours after a 500-mg dose of tolbutamide, did not reduce the amount of
tolbutamide absorbed, although the rate of absorption may have changed.
Mechanism
Colestyramine is an anion-exchange resin, intended to bind to bile acids within the gut, but it
can also bind with some acidic drugs thereby reducing the amount available for absorption.
Importance and management
Information about glipizide is limited to a single-dose study so that the clinical importance of
the reduction in glipizide levels with colestyramine is unknown, but it would seem prudent to
monitor the effects of concurrent use in patients. It has been suggested that the glipizide
should be taken 1 to 2 hours before the colestyramine to minimise admixture in the gut, but
this may only be partially effective because it is believed that glipizide undergoes some
entero-hepatic circulation (i.e. after absorption it is excreted in the bile and reabsorbed). The
effect of colestyramine on other sulphonylureas is uncertain, with the exception of
tolbutamide, which is reported not to interact. The clinical importance of the effects of
colestyramine on acarbose in diabetics is uncertain, although the manufacturers note that
some enhancement of the effects of acarbose may occur, and they suggest care if both drugs
are stopped at the same time because of the possible rebound phenomenon with respect to
insulin levels.
The study with colestipol suggests that it may not be suitable for lowering the blood
cholesterol levels of diabetics taking chlorpropamide, tolbutamide, or tolazamide or
phenformin, but more study is needed to confirm these findings. Phenformin has been
withdrawn from many countries because of severe, often fatal, lactic acidosis.

Valproate + Bile-acid binding resins

Colestyramine causes a very small reduction in the absorption of valproate. No interaction
occurs if administration of the drugs is separated by 3 hours. Colesevelam does not interact.
Clinical evidence
(a) Colesevelam
Colesevelam 4.5 g had no effect on the pharmacokinetics of valproic acid 250 mg in a singledose study in 26 healthy subjects.
(b) Colestyramine
A single 250-mg dose of valproic acid was given to 6 healthy subjects either alone, at the
same time as colestyramine 4 g twice daily, or with the colestyramine taken 3 hours after the
valproic acid. The bioavailability of valproate taken alone and when separated from the
colestyramine by 3 hours remained the same. When the valproate was taken at the same time
as the colestyramine the valproate AUC fell by 15% and the maximum serum levels fell by
21%.

Mechanism
Colestyramine is an ion-exchange resin intended to bind with bile acids in the gut, but it can
also bind with drugsas well, leading to a reduction in their absorption. This apparently occurs
to a limited extent with valproate.
Importance and management
Direct information about colestyramine and valproate appears to be limited to this single
study, but what happened is consistent with the way colestyramine interacts with a number of
other drugs. The fall in the bioavailability is small and probably of very limited clinical
importance, but the interaction can be totally avoided by separating the dosages by 3 hours so
that admixture in the gut is minimised. Colesevelam does not interact.

Beta blockers + Bile-acid binding resins

Although both colestyramine and colestipol can moderately reduce the absorption of
propranolol, this doesnot seem to reduce its effects. Colesevelam does not appear to affect
the absorption of metoprolol.
Clinical evidence
(a) Colesevelam
A single-dose study in 33 healthy subjects found that colesevelam 4.5 g did not cause a
clinically relevant alteration in the plasma levels of sustained-release metoprolol100 mg.
(b) Colestipol
When 6 healthy subjects took a single 120-mg dose of propranololwith a 10-g dose of
colestipol the peak plasma propranolollevels were raised by 30%. However, if an additional
10 g dose of colestipol was taken 12 hours before the propranololthe peak plasma levels were
decreased by 36% and the AUC was reduced by about 30%. No changes in blood pressure or
pulse rates were seen.
(c) Colestyramine
When 6 healthy subjects took a single 120-mg dose of propranolol with an 8-g dose of
colestyramine the peak propranololplasma levels were reduced by almost 25% and the AUC
was reduced by 13%. An additional dose of colestyramine 12 hours before the
propranololreduced the AUC by 43%. However, no changes in blood pressure or pulse rate
were seen. Preliminary results of another study found that colestyramine (single unstated
dose) caused no significant changes in the blood levels of propranololin 5 patients with type
II hyperlipidaemia taking propranolol 40 mg four times daily.
Mechanism
Uncertain. It seems probable that both colestyramine and colestipol can bind to propranolol in
the gut, thereby reducing its absorption.

Importance and management

Information is limited. Even though both colestyramine and colestipol can apparently reduce
the absorption of a single dose of propranolol, no changes in its effects were reported,
suggesting that the interaction is of minimal clinical importance. There is therefore no
obvious reason for avoiding concurrent use. However, note that it is usually recommended
that other drugs are given 1 hour before or 4 to 6 hours after colestyramine, and 1 hour before
or 4 hours after colestipol.

Calcium-channel blockers+ Bile-acid binding resins

Colesevelam slightly reduces the bioavailability of verapamil and colestipol slightly reduces
the bioavailability of diltiazem. These interactions are unlikely to be clinically important.
Clinical evidence, mechanism,importance and management
(a) Colesevelam
A study in 31 healthy subjects found that a single 4.5-g dose of colesevelam reduced the peak
plasma levels and AUC of a single 240-mg dose of verapamil by about 33% and about 15%,
respectively. These changes were not considered to be clinically significant.1
(b) Colestipol
A study in 12 healthy subjects found that colestipol reduced the AUC and peak plasma levels
of a single 120-mg dose of sustained-releasediltiazem by 22% and 36%, respectively, and
those of a single 120-mg dose of immediate-releasediltiazemby 27% and 33%, respectively.
In a further study sustained-releasediltiazem120 mg was given alone, or 1 hour before or 4
hours after multiple doses of colestipol. The AUC of diltiazem was decreased by 17% when it
was taken 1 hour before colestipol and by 22% when taken 4 hours after colestipol. This
suggests that the effects of colestipol on diltiazembioavailability are not reduced by
separating their administration. However, these small reductions in levels are unlikely to
result in reduced diltiazemefficacy, but the authors advise caution if these drugs are used
concurrently.

Furosemide + Bile-acid binding resins

Colestyramine and colestipol markedly reduce the absorption and diuretic effects of
furosemide.
Clinical evidence
In 6 healthy subjects colestyramine8 g reduced the absorption of a single 40-mg dose of
furosemide by 95%. The 4-hour diuretic response was reduced by 77% (urinary output
reduced from 1510 to 350 mL). Colestipol 10 g reduced the furosemide absorption by 80%
and the 4-hour diuretic response by 58% (urinary output reduced from 1510 to 630 mL).

Mechanism
Both colestyramine and colestipol are anionic exchange resins, which can bind with
furosemide within the gut, thereby reducing its absorption and its effects.
Importance and management
An established interaction, although direct evidence seems to be limited to this study. The
absorption of furosemide is relatively rapid so that giving it 2 to 3 hours before either the
colestyramine or colestipol should be an effective way of overcoming this interaction. This
needs confirmation. Note that it is normally recommended that other drugs are given 1 hour
before or 4 to 6 hours after colestyramine and 1 hour before or 4 hours after colestipol.

Corticosteroids + Bile-acid binding resins

Colestyramine and possibly colestipol reduce the absorption of oral hydrocortisone.
Colestyramine does not appear to affect prednisolone absorption.
Clinical evidence
(a) Colestyramine
In 10 healthy subjects, colestyramine 4 g reduced the AUC of a 50-mg oral dose of
hydrocortisoneby 43%. Peak levels were reduced and delayed (by about 50 minutes). Two of
the subjects were given both 4 g and 8 g of colestyramine, and their AUCs were reduced by
47% and 59% by the 4-g dose and by 97% and 86% by the 8-g dose.
In contrast, an 8-g dose of colestyramine did not affect the bioavailability of prednisolonein 2
patients receiving long-term prednisolone.
(b) Colestipol
A man with hypopituitarism taking hydrocortisone20 mg each morning and 10 mg each
evening became lethargic, ataxic, and developed headaches (all signs of
hydrocortisoneinsufficiency) within 4 days of starting to take colestipol 15 g three times daily
for hypercholesterolaemia. He re sponded rapidly when given intravenous hydrocortisone100
mg, and was discharged with the colestipol replaced by a statin.
Mechanism
It seems that hydrocortisone can become bound to colestyramine or colestipol in the gut,
thereby reducing its absorption.
Importance and management
Information is limited, but these interactions with hydrocortisone appear to be established
(they are consistent with the interactions of both of these bile-acid resins with other drugs).
Separate the administration of the drugs as much as possible to minimise admixture in the
gut, although the authors of one report warn that this may not necessarily avoid this
interaction because their data show that the colestyramine may remain in the gut for a
considerable time. The usual recommendation is to give other drugs one hour before or 4 to 6

hours after taking colestyramine, and one hour before or 4 hours after taking colestipol.
Monitor the effects and increase the hydrocortisone dosage, or use an alternative to
colestyramine, if necessary. Prednisolone may be a non-interacting alternative, but the
evidence for this is extremely limited.

Ursodeoxycholic acid (Ursodiol) + Bile-acid binding resins

The absorption of ursodeoxycholicacid can be more than halved by colestilan or
colestyramine given simultaneously, and efficacy might be reduced.
Clinical evidence
(a) Colestilan
Following a test meal with an overnight fast, 5 healthy subjects were given 200 mg of
ursodeoxycholic acid alone or with 1.5 g of colestilan granules. It was found that the
ursodeoxycholic acid serum levels at 30 minutes were reduced by the colestilan by more than
50% in 4 out of the 5 subjects, and the mean level was decreased from 9.2 to 3.4 micromol/L.
(b) Colestyramine
Simultaneous administration of colestyramine 4 g daily with ursodeoxycholic acid reduced
the fasting serum levels of ursodeoxycholic acid by about 60% in a study in 5 healthy
subjects. Separation of administration by 5 hours tended to diminish the reduction (serum
levels reduced by less than 40%).
Mechanism
The mechanism of this interaction would appear to be that the bile-acid binding resins bind
with ursodeoxycholic acid (a bile acid) in the intestine and thereby reduce its absorption.
Importance and management
These interactions would appear to be established, and are probably clinically important. One
UK manufacturer actually advises that colestipoland colestyramine should be avoided when
ursodeoxycholic acid is given, as they may limit the effectiveness of therapy. The authors of
the reports recommend that in order to reduce the effects of this interaction, these two drugs
should be separated, by at least 2 hours.