l MEDICINAL FORMS There can be variation in the licensing of
different medicines containing the same drug.
▶ Viper venom antiserum, European (equine) (Imported (Croatia))
European viper snake venom antiserum 100 mg per 1 ml Viper
venom antiserum, European (equine) 1g/10ml solution for injection
Emergency treatment of poisoning
Changes have been made to the interactions content in BNF
publications. For more information, see www.bnf.org/new-bnfinteractions/.
Two or more drugs given at the same time can exert their
effects independently or they can interact. Interactions may
be beneficial and exploited therapeutically; this type of
interaction is not within the scope of this appendix. Many
interactions are harmless, and even those that are
potentially harmful can often be managed, allowing the
drugs to be used safely together. Nevertheless, adverse drug
interactions should be reported to the Medicines and
Healthcare products Regulatory Agency (MHRA), through
the Yellow Card Scheme (see Adverse reactions to drugs
p. 12), as for other adverse drug reactions.
Potentially harmful drug interactions may occur in only a
small number of patients, but the true incidence is often
hard to establish. Furthermore the severity of a harmful
interaction is likely to vary from one patient to another.
Patients at increased risk from drug interactions include the
elderly and those with impaired renal or hepatic function.
Interactions can result in the potentiation or antagonism
of one drug by another, or result in another effect, such as
renal impairment. Drug interactions may develop either
through pharmacokinetic or pharmacodynamic mechanisms.
These are interactions between drugs which have similar or
antagonistic pharmacological effects or side-effects. They
might be due to competition at receptor sites, or occur
between drugs acting on the same physiological system.
They are usually predictable from a knowledge of the
pharmacology of the interacting drugs; in general, those
demonstrated with one drug are likely to occur with related
These occur when one drug alters the absorption,
distribution, metabolism, or excretion of another, thus
increasing or decreasing the amount of drug available to
produce its pharmacological effects. Pharmacokinetic
interactions occurring with one drug do not necessarily
occur uniformly across a group of related drugs.
Affecting absorption The rate of absorption and the total
amount absorbed can both be altered by drug interactions.
Delayed absorption is rarely of clinical importance unless a
rapid effect is required (e.g. when giving an analgesic).
Reduction in the total amount absorbed, however, can result
Affecting distribution Due to changes in protein binding: To a
variable extent most drugs are loosely bound to plasma
proteins. Protein-binding sites are non-specific and one drug
can displace another thereby increasing the proportion free
to diffuse from plasma to its site of action. This only
produces a detectable increase in effect if it is an extensively
bound drug (more than 90%) that is not widely distributed
throughout the body. Even so displacement rarely produces
more than transient potentiation because this increased
concentration of free drug will usually be eliminated.
Displacement from protein binding plays a part in the
potentiation of warfarin by sulfonamides but these
interactions become clinically relevant mainly because
warfarin metabolism is also inhibited.
Induction or inhibition of drug transporter proteins: Drug
transporter proteins, such as P-glycoprotein, actively
transport drugs across biological membranes. Transporters
can be induced or inhibited, resulting in changes in the
concentrations of drugs that are substrates for the
transporter. For example, rifampicin induces P-glycoprotein,
particularly in the gut wall, resulting in decreased plasma
concentrations of digoxin, a P-glycoprotein substrate.
Affecting metabolism Many drugs are metabolised in the
liver. Drugs are either metabolised by phase I reactions
(oxidation, reduction, or hydrolysis) or by phase II reactions
Phase I reactions are mainly carried out by the cytochrome
P450 family of isoenzymes, of which CYP3A4 is the most
important isoenzyme involved in the metabolism of drugs.
Induction of cytochrome P450 isoenzymes by one drug can
increase the rate of metabolism of another, resulting in
lower plasma concentrations and a reduced effect. On
withdrawal of the inducing drug, plasma concentrations
increase and toxicity can occur.
Conversely when one drug inhibits cytochrome P450
isoenzymes, it can decrease the metabolism of another,
leading to higher plasma concentrations, resulting in an
increased effect with a risk of toxicity.
Isoenzymes of the hepatic cytochrome P450 system
interact with a wide range of drugs. With knowledge of which
isoenzymes are involved in a drug’s metabolism, it is
possible to predict whether certain pharmacokinetic
interactions will occur. For example, carbamazepine is a
potent inducer of CYP3A4, ketoconazole is potent inhibitor
of CYP3A4, and midazolam is a substrate of CYP3A4.
Carbamazepine reduces midazolam concentrations, and it is
therefore likely that other drugs that are potent inducers of
CYP3A4 will interact similarly with midazolam.
Ketoconazole, however, increases midazolam
concentrations, and it can be predicted that other drugs that
are potent inhibitors of CYP3A4 will interact similarly.
Less is known about the enzymes involved in phase II
reactions. These include UDP-glucuronyltransferases which,
for example, might be induced by rifampicin, resulting in
decreased metabolism of mycophenolate (a substrate for this
enzyme) to its active form, mycophenolic acid.
Affecting renal excretion Drugs are eliminated through the
kidney both by glomerular filtration and by active tubular
secretion. Competition occurs between those which share
active transport mechanisms in the proximal tubule. For
example, salicylates and some other NSAIDs delay the
excretion of methotrexate; serious methotrexate toxicity is
possible. Changes in urinary pH can also affect the
reabsorption of a small number of drugs, including
BNF 78 Appendix 1 Interactions 1373
Relative importance of interactions
Levels of severity: Most interactions have been assigned a
severity; this describes the likely effect of an unmanaged
Severe—the result may be a life-threatening event or have
a permanent detrimental effect.
Moderate—the result could cause considerable distress or
Mild—the result is unlikely to cause concern or
incapacitate the majority of patients.
Unknown—used for those interactions that are predicted,
but there is insufficient evidence to hazard a guess at the
Levels of evidence: Most interactions have been assigned
a rating to indicate the weight of evidence behind the
Study—for interactions where the information is based on
formal study including those for other drugs with same
mechanism (e.g. known inducers, inhibitors, or substrates of
cytochrome P450 isoenzymes or P-glycoprotein).
Anecdotal—interactions based on either a single case
report or a limited number of case reports.
Theoretical—interactions that are predicted based on
sound theoretical considerations. The information may have
been derived from in vitro studies or based on the way other
members in the same class act.
Action messages: Each interaction describes the effect
that occurs, and the action to be taken, either based on
manufacturer’s advice from the relevant Summary of
Product Characteristics or advice from a relevant authority
(e.g. MHRA). An action message is only included where the
combination is to be avoided, where a dose adjustment is
required, or where specific administration requirements (e.g
timing of doses) are recommended. Pharmacodynamic
interactions, with the exception of interactions with drugs
that may prolong the QT interval, do not have an action
message included as these will depend on individual patient
Drugs are listed alphabetically. If a drug is a member of a
drug class, all interactions for that drug will be listed
under the drug class entry; in this case the drug entry
provides direction to the relevant drug class where its
Within a drug or drug class entry, interactions are listed
alphabetically by the interacting drug or drug class. The
interactions describe the effect that occurs, and the action
to be taken, either based on manufacturer’s advice from
the relevant Summary of Product Characteristics or advice
from a relevant authority (e.g. MHRA). An action message
is only included where the combination is to be avoided,
where a dose adjustment is required, or where specific
administration requirements (e.g. timing of doses) are
recommended. If two drugs have a pharmacodynamic
is included at the end of the pharmacokinetic message.
The drugs that are members of a drug class are listed
underneath the drug class entry in a blue box. Interactions
for the class are then listed alphabetically by the
interacting drug or drug class. If the interaction only
applies to certain drugs in the class, these drugs will be
shown in brackets after the drug class name.
If a drug has additional important information to be
considered, this is shown in a blue box underneath the
drug or drug class entry. This information might be food
and lifestyle advice (including smoking and alcohol
consumption), relate to the pharmacology of the drug or
applicability of interactions to certain routes of
administration, or it might be advice about separating
Tables at the beginning of Appendix 1 cover
pharmacodynamic effects. If a drug is included in one or
more of these tables, this will be indicated at the top of the
list of interactions for the drug or drug class. In addition to
the list of interactions for a drug or drug class, these
tables should always be consulted.
Each table describes the relevant pharmacodynamic
effect and lists those drugs that are commonly associated
with the effect. Concurrent use of two or more drugs from
the same table is expected to increase the risk of the
pharmacodynamic effect occurring. Please note these
▶ Details of interaction between drug entry and another drug
or drug class. Action statement.ZEvidence
▶ Details of interaction between drug entry and another drug
or drug class. Action statement.ZEvidence
Drug entry → see Drug class entry
Drug A . Drug B . Drug C . Drug D. ▶ Details of interaction between drug class entry and another
drug or drug class. Action statement.ZEvidence
.3 Drug entry or Drug class entry
.4 Drug entry or Drug class entry → see TABLE 1
Name of pharmacodynamic effect
1374 Appendix 1 Interactions BNF 78
Drugs that cause hepatotoxicity
from the list might increase this risk.
Drugs that cause nephrotoxicity
from the list might increase this risk.
Drugs with anticoagulant effects
Drugs with antiplatelet effects
effects) might also increase this risk.
Drugs that cause thromboembolism
drugs from the list might increase this risk.
BNF 78 Appendix 1 Interactions 1375
list might increase this risk.
Drugs that cause first dose hypotension
more drugs from the list might increase this risk.
from the list might increase this risk.
1376 Appendix 1 Interactions BNF 78
Drugs that prolong the QT interval
potassium might further increase this risk (see table of drugs that reduce serum potassium).
manufacturers advise avoiding concurrent use with drugs that prolong the QT interval.
Drugs with antimuscarinic effects
Drugs with CNS depressant effects
tasks (see ’Drugs and Driving’ in Guidance on Prescribing p. 1).
BNF 78 Appendix 1 Interactions 1377
Drugs that cause peripheral neuropathy
drugs from the list might increase this risk.
Drugs that cause serotonin syndrome
increase the risk of hypoglycaemia.
Drugs that cause myelosuppression
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