The

Dispensing

Guide

2004

2

The Dispensing Guide 2004

6th

edition

REVIEW PANEL

Sharon Gardiner

Carl Kirkpatrick

Ellen McCrae

Earle Shaw

PUBLISHED BY

Pharmaceutical Society of New Zealand (Incorporated)

Pharmacy House

PO Box 11 640, 124 Dixon St

Wellington

NEW ZEALAND

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Copyright: 2004 (6th ed) 2001 (5th ed) 1997 (4th ed) 1995 (3rd ed) 1993 (2nd ed) 1992 (1st ed) ISBN: 0-476-00758-5 Apart from any fair dealing for the purposes of private study, research, criticism or review, as permitted under the Copyright Act, no part may be reproduced by any process without written permission of the Pharmaceutical Society of New Zealand (Incorporated).

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Contents

Preface 6

Introduction to The Dispensing Guide 2004 7

Review Topics

1. Important points on patient education 8

2. Basic pharmacokinetics 10

3. Clinically significant medicine interactions 12

4. Medicine interactions with food 14

5. Medicine interactions with cigarette smoking 16

6. Medicine interactions with caffeine 17

7. Medicine interactions with herbal remedies 19

8. Adverse medicine reactions 21

9. Medicines in pregnancy 22

10. Medicines in human milk 24

11. Medicines and the child 26

12. Medicines and the elderly 27

13. Medicine use in renal impairment 28

14. Medicine use in liver disease 30

Medicine information centres 32

Useful references 33

Cautionary and Advisory labelling 34

Purpose of each label and reference 35

The labels and references in the scheme 45

Appendices

Appendix 1 Medicines requiring labels and references 46

Appendix 2 Sugar free medicines 63

Appendix 3 Manufacturers whose preparations do not contain gluten 67

Appendix 4 Interactions for medicines requiring label 5a 69

Appendix 5 Interactions of over-the-counter and prescription medicines 71

Appendix 6 Products requiring refrigeration 74

Appendix 7 MAOI diet 77

Appendix 8 Safety of condoms and diaphragms with vaginal antifungals 78

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Appendix 9 Computer generated labels minimum requirements 79

Appendix 10 Label specifications 80

Review mechanism 81

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Preface The aim of The Dispensing Guide is to provide a pocket sized ready reference of useful information for the safe and effective dispensing of prescribed medicines. This current version is the first to be available in two formats a small book and a larger A4-sized document that can be downloaded from the Pharmaceutical Society of New Zealand (Inc) website: www.psnz.org.nz. The electronic document will allow more frequent updates and revisions of the guide, whereas the smaller book may be easier to use in daily practice but any amendments will need to be made by hand. In the future we will investigate options of improving the electronic document such as inclusion of mechanisms for searching to find topics more readily eg. a keyword search for grapefruit or sugar free. The overall philosophy and content of the guide remains unchanged. However, as with each new edition, the review panel has expanded on the previous editions and has incorporated new summaries on various pharmacological topics (see Introduction to The Dispensing Guide, page 7). The Dispensing Guide is not exhaustive in the range of data presented nor is it a definitive guide on the topics addressed. All information has been individually verified with appropriate specialist persons where applicable, however its use and interpretation should always be considered in conjunction with professional judgement. The shape, size, colour and wording of the Cautionary and Advisory (C & A) labels has been verified as suitable in terms of readability and content. To maintain The Dispensing Guide as an up-to-date reference reflecting current clinical practice, a review mechanism has been established whereby updates or reprints will become available as necessary. The review panel encourages readers to contribute material, suggestions, comments or advice where deemed appropriate (see Review Mechanism, page 81).

Sharon Gardiner

Carl Kirkpatrick

Ellen McCrae

Earle Shaw

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Introduction to The Dispensing Guide 2004 All sections of The Dispensing Guide have been reviewed and updated where necessary, and every effort has been made to ensure that it is accurate at the time of publication. Some of the review topics and information on Cautionary and Advisory (C & A) labelling have been changed to keep the guide relevant to current practice. In particular, the information pertaining to C & A label 11 (Grapefruit or grapefruit juice may interact with this medicine. Discuss with your pharmacist, page 41) has been revised and expanded to provide data on the change in medicine blood concentrations that occurs with grapefruit juice and recommendations for management of the interactions. In addition, there have been two new sections added to this edition that we believe will complement the other sections and enhance the usefulness of this guide:

Review Topic 6 Medicine Interactions with Caffeine: This section highlights the potential interactions between caffeine and medicines (see page 17).

Review Topic 7 Medicine Interactions with Herbal Remedies: This section provides an overview of some of the mechanisms involved in interactions between medicines and herbal remedies, with some specific examples (see page 19).

Appendix 1 has traditionally been a challenge to complete due to the constantly changing availability and subsidy of medicines. This year we have made the difficult decision to return to using generic names only ie. trade names are no longer used in the guide. Exceptions include Appendices 2, 3 and 6, which have been sorted by drug company and trade name. Products that are a combination of two or more medicines are referred to by the individual active ingredients.

We have also started using the International Nonproprietary Name (INN) which is a unique generic name that facilitates identification of pharmaceutical substances internationally. INNs are designed to be distinctive in sound and spelling, not liable to confusion with other names in use and able to be used in a number of languages. Some changes that are likely to affect New Zealand include: e is used instead of ae or oe (eg. estradiol instead of oestradiol) i is used instead of y (eg. ciclosporin instead of cyclosporin) f is used instead of ph (eg. sulfamethoxazole instead of sulphamethoxazole). Further information can be found on the World Health Organisation website: www.who.int/medicines/organization/qsm/activities/qualityassurance/inn/orginn.shtml. It is expected that New Zealand will adopt INN to some extent in the future (in line with other countries eg. Britain), and some hospital pharmacies in New Zealand have already adopted this nomenclature. However, as a formal decision has not yet been made about the policy we have elected to include both names in most sections of the guide as the conventional generic name with the INN name in brackets eg. frusemide (furosemide).

We have also included some recommendations regarding useful reference sources on the internet, many of which are available at no cost.

Finally, the review panel of the 6th edition of The Dispensing Guide would like to acknowledge the work of Dr Stephen Duffull on the first four editions of this book. His work has made picking up the pieces and moving forward with the latest editions relatively easy. We would also like to thank the following people for their assistance with the preparation and/or constructive criticism of parts of this document: Mr Euan Galloway, Ms Jan Clare, Prof Evan Begg, Mr Bob Buckham, and the pharmaceutical manufacturers.

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1. Important Points on Patient Education Pharmacists play an important role in the delivery of healthcare to the community and are often the last point of contact with patients. Therefore, they carry the responsibility of ensuring that the patient has an adequate understanding of their therapeutic regimens so that safe and effective use of medicines will occur. Patient compliance can be improved by:

Providing patients with knowledge about their medicines

Expressing a positive attitude to therapy where appropriate

Ensuring the patient has had all their questions answered

Offering continued interest in the outcome of the prescribed medicine

Providing clear instructions, especially when a number of medicines and/or a complicated dose regimen are involved

Our effectiveness as pharmacists in improving patient compliance depends both on the quality of the information given to the patient and on the quality of the communication with that patient. The information given to the patient should give a balanced view of the potential therapeutic benefits and risks. Ideally, the patient should have knowledge of the following:

1. Name and description of the medicine

2. Intended purpose and expected action

3. Route of administration, dosage, dosage form and administration schedule

4. Any special directions or precautions to be taken

5. Common side-effects that may be encountered, ways in which to minimise them and action required if they occur

6. Details of discontinued medicines and their relationship to new medicines

7. Appropriate storage requirements

8. Length of therapy and source of further supplies

9. Action to be taken in the event of a missed dose Communication is a sharing of facts, information, ideas, attitudes and feelings. It is an interactive process based on active listening ie. paying attention to the messages the patient is sending and pausing to allow those messages to be verbalised. To elicit information from the patient efficiently and accurately, the asking of questions is important. Remember:

Keep questions open-ended whenever possible

Ensure the patient understands the point of the question

Match the pace of your questions to the patients ability to respond easily

Do not ask leading questions

Avoid using a question when a statement is meant

Good questions are clear, understandable and unambiguous. On completion of the questioning it is helpful to summarise the information that has been provided to allow a review and an invitation to the patient to correct or add to the information gathered.

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When communicating further information to patients, be aware that:

Most patients are nave about medicines. Therefore, avoid jargon and technical terms and remember people often confuse the meanings of words

Many patients are anxious and do not concentrate on what they are being told. Low levels of anxiety are linked with poor recall as the patient is unlikely to pay attention while a high level of anxiety may cause the patient not to concentrate fully on the explanation

All people forget at least part of what they are told. Use shorter words and sentences and keep the number of key items to a minimum, remembering that those pieces of information that come near the beginning and near the end of a list are recalled best

People often misinterpret information especially if it does not agree with personally held beliefs. Make statements clear and precise

Information may be distorted by such things as difficulty in hearing, language barriers (including accents), noise etc

Finally, remember to ensure that the patient has understood the explanation (positive feedback). It is most important that the patient goes away satisfied with the attention and the explanation given, and ready to adhere to the treatment as intended.

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2. Basic Pharmacokinetics Pharmacokinetics is derived from the terms pharmaco meaning medicine and kinetics meaning movement. Simply, this deals with the movement of medicines within the body or what the body does to the medicine. A knowledge of pharmacokinetics is necessary for determining the most appropriate dose regimen of a medicine for an individual. Whether medicines are administered orally, intramuscularly or topically, a certain proportion of the dose will reach the systemic circulation. This fraction that gets on board is termed the availability, and is dependent on both the ability of the medicine to cross membranes and also any elimination that occurs during this process. Availability (oral) is often used interchangeably with bioavailability, but in the strict sense of the words this is not correct. The term bioavailability encompasses not only the extent of absorption but also the rate, whereas oral availability is only concerned with extent. In The Dispensing Guide we have only used the term availability to avoid confusion. Once on board medicines distribute into tissues, have actions at different sites, and are eliminated, usually via the kidneys or liver. Medicines given chronically are said to reach steady-state when the amount given equals the amount eliminated. The volume in which a medicine distributes into tissues is described by the volume of distribution. The rate at which the blood is cleared of medicine is termed clearance. These two parameters are the most important determinants of medicine dosing.

Volume of distribution (units = Litres)

The volume of distribution describes the volume into which a medicine would apparently distribute if it had a uniform concentration throughout the body. It describes the relationship between the amount in the body (in all tissues) and the amount in the blood (the measurable component). For example, if a medicine distributes extensively into lipophilic tissue (eg. fat or brain) and only a small amount remains in the blood then it would be said to have a large volume of distribution (eg. tricyclic antidepressants). Conversely if the medicine distributes largely within the blood with only minimal tissue distribution it would be said to have a small volume of distribution (eg. heparin). In many cases the volume of distribution may bear no relationship to body size eg. amitriptyline

has a volume of distribution of 4000 litres (clearly much bigger than an average person). The medicine in the tissues is at equilibrium with the medicine in the blood. The volume of distribution is used to determine loading doses ie. the amount that is required to fill up all the body tissues, where: loading dose = volume of distribution x desired blood concentration

Clearance (units = Litres/hour)

The body usually eliminates medicines in an exponential manner (termed first order). This means that the more medicine that is presented to the organ responsible for its elimination, the more medicine is eliminated. The body will normally eliminate a fraction of the medicine that is in the blood at any given time. Hence, although the total amount of medicine (eg. in milligrams) that is eliminated may vary, the fraction of medicine that is eliminated is always constant. Clearance is a constant that describes the relationship between the concentration of medicine presented in the blood to the organ of elimination and the rate that it is eliminated.

Using a bath tub analogy: The rate that water is eliminated from a bathtub is related to both the amount of water in the tub, and the size of the plug hole. The greater the amount (height) of water in the bathtub the more pressure at the plug hole, and hence the faster the rate of elimination. The constant that describes the relationship between the amount of water in the bathtub and the rate of

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elimination is the size of the plug hole (ie. clearance). In practice clearance describes the relationship between the concentration of medicine in the blood and the rate of elimination. If the body has a reduced ability to clear a medicine eg. a person with kidney or liver impairment, or if they are very old or young, the clearance will be reduced. At steady-state, where the amount given equals the amount eliminated, the following describes the relationship between dose and blood concentration:

dose rate (mg/hr) = elimination rate (mg/hr)

dose rate (mg/hr) = clearance (L/hr) x desired blood concentration (mg/L)

Half-life (units = hours)

This parameter comprises both the volume of distribution and clearance. It represents the length of time required for the medicine concentration in the blood to halve. In order for the concentration to halve the medicine must have time to both redistribute from the tissues back into the blood and also to be cleared. The half-life is useful to determine both how long a medicine will remain in the body, and how long it takes to achieve steady-state. For instance, if a mother is advised against breast feeding her child while taking a medicine, it may be necessary for her to wait until the medicine has been eliminated from her body. If the half-life of the medicine is 6 hours, then at 6 hours after the dose the amount in her body would have halved (ie. 50% would be left), at 12 hours after the dose the amount in her body would have halved again (ie. 25% would be left)... and so on. At four half-lives only 6.125% would be left which is negligible. Similarly, if a loading dose of a medicine has not been given then it will take four half-lives to achieve > 90% of the new steady-state concentration. After one half-life, 50% of the steady-state concentration will be attained, after two, 75%, after three, 87.5%, after four, 93.5%, and so on.

Further reading

Begg EJ. Instant Clinical Pharmacology. Blackwell Publishing, 2003.

Birkett DJ. Pharmacokinetics Made Easy. McGraw-Hill Book Co Australia Pty Ltd, 1999.

Thompson A. A series available online at www.pjonline.com: - Back to Basics: Pharmacokinetics. The Pharmaceutical Journal 2004; 272: 769-771. - Variability in drug dosage requirements. The Pharmaceutical Journal 2004; 272: 806-808.

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3. Clinically Significant Medicine Interactions Medicine interactions are widely reported in the literature, however in many cases the interaction is of little clinical significance. It is reported that on every prescription of four items at least one interaction would be expected. The number of interactions increases as the number of items on the prescription increases. Despite the large number of potential interactions that exist between

medicines it is probable that only 10% of these are serious in nature. In the majority of cases medicine interactions are predictable with a knowledge of the medicines pharmacokinetic and pharmacodynamic profiles. There are two major categories of medicine interactions:

1. PHARMACOKINETIC interactions (What the body does to medicines)

These interactions are more difficult to predict because of the many sites where an interaction might occur. They seldom require medicine withdrawal, but modification of dosages or their timing may be necessary. These reactions can be subdivided into two groups: a) Absorpt ion. The combination of two or more medicines may complex to form insoluble salts,

alter gastrointestinal motility, or alter gut flora (normal bacterial growth in the intestine) and therefore may reduce or enhance the oral availability of another medicine. For example, norfloxacin (a quinolone antibiotic) complexes with the metal ions present in antacids and becomes inactive. Another well known example is the interaction between antibiotics and the oral contraceptive where antibiotics, due to their actions, decrease bacterial gut flora and reduce the absorption of the oestrogen which may lead to contraceptive failure.

b) Clearance. One medicine may decrease or enhance the renal excretion or metabolism of

another. For example, phenytoin increases the metabolism of the oral contraceptive which may lead to contraceptive failure, fluoxetine inhibits the metabolism of tricyclic antidepressants thereby leading to toxicity, and diltiazem reduces the renal clearance of digoxin.

2. PHARMACODYNAMIC interactions (What medicines do to the body)

These can usually be anticipated based on the known action of the medicine, although the extent is often unpredictable. In some instances it may be necessary to withdraw one or other of the medicines. These reactions can be subdivided into two groups: a) Direct effects. Both medicines act at the same site of activity eg. Sinemet (levodopa and

carbidopa) stimulates dopamine receptors thereby improving symptoms of Parkinsons disease and haloperidol antagonises dopamine receptors thereby aggravating Parkinsons disease.

b) Indirect ef fects. Both medicines act at a different site and may either potentiate or

antagonise their pharmacological effects eg. CNS depression with tricyclic antidepressants may be potentiated by the addition of a benzodiazepine or alcohol.

Important contributing factors

In order to help determine which interactions will be significant clinically, the following points may be helpful. Factors that increase the risk associated with medicine interactions include: patient related factors, types of medicine and factors associated with underlying disease processes. Patient related factors : Very young patients have underdeveloped kidney and liver function Elderly patients have reduced kidney and liver function

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Medicine related factors : Medicines used in prevention (eg. anticonvulsants, antiarrhythmics) Medicines with a narrow therapeutic index (the difference between the plasma concentration

required for efficacy and that which causes toxicity is small) eg. anticonvulsants, anticoagulants, digoxin, theophylline, lithium

Medicines that may cause significant toxicity in rare circumstances eg. cisapride and ventricular arrhythmias

Disease related factors : Brittle conditions. Certain presentations of some diseases are more difficult to control eg.

some patients with diabetes Conditions of major clinical importance eg. recent myocardial infarction Disease of the organ of elimination eg. renal dysfunction In the majority of cases these factors are associated with a lack of reserve capacity. Any alteration in drug concentration or effect may be of greater clinical significance. Think of medicine interactions particularly with the following medicines/classes: amiodarone, antacids, anticoagulants, anticonvulsants, cimetidine, cyclosporin (ciclosporin), digoxin, macrolides, methotrexate, MAO inhibitors, oral contraceptives, quinolones, rifampicin, SSRIs and theophylline.

Further reading

Stockley IH (ed). Stockleys Drug Interactions, 6th edition. The Pharmaceutical Press, London, 2002.

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4. Medicine Interactions with Food There are many interactions between food and medicines, however few of these are clinically important. It is useful to consider that medicine interactions with food may occur at two levels. These are the effect of food on medicines and the effect of medicine on food.

Effects of food on medicines Food may alter the effectiveness of medicines in a variety of ways. These can be divided conveniently into two subcategories: pharmacokinetic and pharmacodynamic effects.

1. PHARMACOKINETIC interactions

Pharmacokinetics refers to the effects of food on the time course of the passage of medicines through the body. Food may affect medicines at a variety of levels including: absorption, metabolism and excretion. Of these, absorption interactions are generally more prevalent and of greater clinical significance.

a) Absorpt ion. Food affects the absorption behaviour of most medicines due to the

physiological effects of food on the gut. Some examples of these processes include:

Reduced rate of absorption. The rate of stomach emptying may be reduced significantly in the presence of food, especially large, hot and fatty meals. This may affect medicines by both delaying their absorption thereby delaying their actions and/or reducing the extent of action. For example, the maximum frusemide (furosemide) induced diuresis is attenuated due to slowed absorption in the presence of food, although the extent of absorption remains unchanged.

Reduced extent of absorption. The extent of absorption may be altered by the presence of food in the stomach. This may happen because more drug is degraded in the stomach (eg. erythromycin base, flucloxacillin), or drug is chelated into an insoluble and inactive complex (eg. tetracycline).

Increased extent of absorption. The extent of the absorption may be increased due to increased blood flow to the stomach and small intestine. This may increase the extent of absorption of drugs that have particularly high metabolic clearance eg. propranolol (see Medicine Use in Liver Disease, page 30).

b) Metabol ism. Some foods when ingested in large amounts may increase metabolic

clearance eg. barbecued foods, some vegetables (eg. broccoli, cabbage). These have been associated with increased metabolism of drugs such as warfarin. Other foods may decrease metabolism eg. grapefruit juice which has been shown to increase the effects of some calcium channel blockers, cyclosporin (ciclosporin) etc (see discussion regarding grapefruit juice interactions, page 41).

c) Excret ion. There are few clinically important examples of this type of interaction. Probably

the most notable example is the interaction between lithium and salt intake, where high salt intake increases lithium excretion.

2. PHARMACODYNAMIC interactions

These refer to the effects of food on the activity of a medicine at its site of action. The most important example of this type of interaction is probably the potentiation of the central nervous system effects of some medicines when combined with alcohol. These interactions are of considerable importance in clinical practice and are the reason for Cautionary and Advisory labels 1 and 2. There are few other interactions of note, with the possible exceptions of:

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The presence of vitamin K in some foods (eg. leafy green vegetables, beef liver) that when ingested in large quantities have been shown to antagonise the effects of warfarin

Excessive ingestion of liquorice may decrease the effectiveness of antihypertensives

Effects of medicines on food There are only few clinically significant examples of the effects of medicines on food. One particularly important example is the effect of monoamine oxidase inhibitors (MAOIs) on the metabolism of tyramine and dopa, although given the low use of MAOIs these interactions are now rare. Phenelzine and tranylcypromine are the two original irreversible non-selective MAOIs that are still used clinically. The mechanism of the interaction has been well established and is related to a potentiation of the pressor effects of tyramine and dopa due to an inhibition of their metabolism. These effects are dose-dependent (of the food item) and tranylcypromine is the more likely of the two original MAOIs to cause the reaction (See Appendix 7 MAOI Diet, page 77) Significant interactions are unlikely (although are theoretically possible) with the reversible selective inhibitor of MAO-A, moclobemide, the reversible non-selective inhibitor of MAO, linezolid, and the irreversible selective inhibitor of MAO-B, selegiline. A more common example is the effect of diuretics and laxatives on electrolytes and fluid balance. These agents increase, predictably, the loss of electrolytes and fluid which may require correction by supplementation. Other effects of medicines on food are limited to isolated cases. Two examples include:

a) Reduction in body stores of folate by sulphasalazine (sulfasalazine) and enzyme inducers (eg. carbamazepine)

b) Inhibition of the metabolism of alcohol by metronidazole and some cephalosporins potentially resulting in a disulfiram reaction

General recommendations

Food may affect medicines and medicines affect food. In general, these interactions are related to the size of the meal and simple methods may be used to combat them.

If a rapid effect is desired eg. pain relief, then it might be appropriate to take the first dose on an empty stomach eg. paracetamol, diclofenac dispersible

If the medicines actions are significantly impaired by food then advising the patient on appropriate times to take the medicine is important (eg. flucloxacillin)

If the medicines actions may be affected by food, but not to the extent as to negate the medicines actions, then the patient could be advised to take the medicine at the same time in relation to food eg. frusemide (furosemide), metoprolol

If the drug is required to be taken with food to reduce gastric side effects then the patient could be advised that the food does not necessarily have to constitute a full meal

There is no perceived difference between immediately before, during, immediately after or with food

Reassure the patient that a single dose taken at the wrong time will usually be of little significance

Remember that elderly patients and those patients taking medicines that have a small therapeutic range are most likely to be affected.

In all cases the medicine should be dosed to clinical response

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5. Medicine Interactions with Cigarette Smoking It has been estimated that up to 25% of the New Zealand population smoke tobacco products, and this is the cause of considerable morbidity and mortality. Nicotine can cause pharmacodynamic effects that may result in altered effect of medicines. In particular, nicotine increases heart rate and blood pressure, causes a decrease in peripheral blood flow (vasoconstriction), increases platelet adhesiveness, and causes CNS stimulation. Therefore, these actions can work against many drugs, particularly those reducing blood pressure, anxiety/insomnia, and blood coagulation. In addition to nicotine, tobacco products contain many hydrocarbons or tar-like products. These agents cause induction (up regulation) of several drug metabolising enzymes in the liver, particularly cytochrome P450 1A2 (CYP1A2). This can result in reduced concentrations of drugs that are metabolised by this pathway, and therefore reduced clinical effect. These are pharmacokinetic drug interactions.

Smoking cessation On stopping (or starting) smoking there is potential for pharmacokinetic and pharmacodynamic interactions to occur.

1. PHARMACOKINETIC interactions

When the hydrocarbons are no longer inhaled, the liver enzymes down regulate and return to normal over about a one month period. This means that the clearance of drugs metabolised via these enzymes will gradually decline causing increased concentrations and potentially toxicity (see list below). When stopping smoking, either an effect (eg. blood pressure, sedation) or concentration (eg. theophylline, blood glucose) should be monitored where possible. Dosage reduction may often be required.

Important drugs

caffeine

chlorpromazine

clozapine

flecainide

haloperidol

imipramine

insulin*

mexiletine

olanzapine

propranolol

theophylline

warfarin

*Not cytochrome P450 mediated. This interaction is due to enhanced peripheral blood flow, causing an increase in the subcutaneous absorption of insulin.

2. PHARMACODYNAMIC interactions

Particular note should be made when patients who are stopping smoking are taking cardiovascular and/or psychoactive medications. Take extra special care in those patients who have brittle conditions such as heart failure, diabetes, hypertension and mental illness.

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6. Medicine Interactions with Caffeine

Caffeine via tea, coffee or other beverages is probably the most widely consumed drug in the world. Caffeine is used everyday by a large proportion of the population therefore it is often considered relatively harmless and unlikely to cause any problems with medicines. Administration of caffeine to caffeine-nave patients causes an array of effects including central nervous system stimulation, alterations (increases and decreases) in cardiovascular effects (eg. blood pressure, heart rate), increased renal diuresis, and stimulatory effects on muscle work capacity. However, a single dose of caffeine is unlikely to result in a clinically significant pharmacokinetic or pharmacodynamic interaction with medicines. It is well recognised that caffeine could be considered a drug of abuse, as chronic users develop tolerance to many of its effects and physical dependence can occur which is clearly illustrated by withdrawal symptoms on abrupt cessation of intake eg. headache, irritability, fatigue. Most interactions between caffeine and prescribed medicines are pharmacokinetic in nature.

1. PHARMACOKINETIC interactions

Chronic caffeine ingestion causes alteration in several drug metabolising enzymes, particularly cytochrome P450 1A2 (CYP1A2) which is the key enzyme involved in its metabolism. Initially, caffeine induces its own metabolism reducing its half-life from approximately 8 hours to 4 hours with chronic ingestion. Despite the fact that caffeine appears to be an inducer of CYP1A2 (as its own clearance is increased), the majority of pharmacokinetic drug interactions with caffeine are due to competitive inhibition ie. caffeine and the interacting medicine compete with each other to be metabolised by the CYP1A2 enzyme. This is likely to result in increased concentrations of caffeine or the medicine due to decreased clearance of i) caffeine, ii) the competing medicine, or iii) both caffeine and the competing medicine. Examples of i) and ii) are well documented in the literature. However, the only conclusive example of iii) is the interaction with theophylline and caffeine.

Medicines that alter caffeine metabolism Medicines that increase caffeine concentrations by > 20% or decrease the clearance of caffeine by > 20% are listed below.

5-methoxypsoralen

cimetidine

ciprofloxacin

diltiazem

fluconazole

fluvoxamine*

methoxsalen

mexiletine

norfloxacin

olanzapine

terbinafine

theophylline (190%)

verapamil

*Not readily available in New Zealand

Patients starting these medicines should be aware that they may experience side effects related to excessive caffeine concentrations eg. jitteriness or shakes, tachycardia etc. To prevent these effects the patient should minimise or reduce their caffeine intake. Note: The proton pump inhibitors, lansoprazole and omeprazole, appear to induce the metabolism of caffeine ie. they increase its clearance. However, only omeprazole does this to a clinically significant extent with an increase in clearance of approximately 40%.

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Pharmacokinetic interactions caused by caffeine Medicines that have their concentrations increased by >20% or have their clearance reduced by > 20% are listed below.

Drug Effect Clinical significance

clozapine concentration (50%) toxicity

theophylline concentration (33%), clearance (~25%) toxicity

lithium concentration (25%) therapeutic failure*

For chronic caffeine users who start therapy with these drugs, the dose of the medicine will be titrated to clinical effect and/or a target concentration therefore the final dose will take into account this interaction. However, problems may arise if the patient decides to stop or reduce their caffeine use once stabilised. This will result in lowering of their steady-state concentration and possible therapeutic failure.

*The lithium interaction is not mediated via cytochrome P450 enzymes. Caffeine increases the renal clearance of lithium, resulting in lower lithium concentrations. For chronic caffeine users who start lithium therapy the dose will be titrated to a target concentration which will account for this interaction. Again, problems may arise if the patient stops or reduces their caffeine intake while on lithium therapy.

2. PHARMACODYNAMIC interactions

Caffeine can interact with medicines that have similar pharmacodynamic effects. For example, caffeine may potentiate the diuretic effects of medicines such as frusemide (furosemide); co-administration of excessive amounts of caffeine with methylphenidate or amphetamines (amfetamines) may increase central nervous system stimulation.

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7. Medicine Interactions with Herbal Remedies Herbal and other alternative or complementary remedies are increasingly used. A herbal remedy may be considered to be any plant, plant product or mixture of plant products in any form. Herbal medicines are often considered to be distinct from conventional medicines, yet many of the latter were originally plant derived eg. atropine, cocaine, codeine, colchicine, digoxin, ephedrine, quinine, senna and vincristine.

Herbal medicines are often erroneously perceived as being harmless because they are natural. However, they frequently have several or many active constituents and have the ability to cause adverse or toxic reactions and interactions with conventional medicines in addition to potentially having beneficial effects. Unfortunately, information on the pharmacology, toxicity and tolerability of herbal remedies is often limited because they have been studied less intensively than conventional medicines. Interactions between herbal remedies and conventional medicines may be either pharmacokinetic or pharmacodynamic. In many cases, these are theoretical interactions and have not been well studied.

1. PHARMACOKINETIC interactions

Pharmacokinetic interactions between herbal and conventional medicines are most likely to be through effects on absorption or metabolism. For example, tannin-containing herbs such as feverfew, saw palmetto and chamomile may inhibit the absorption of iron. Perhaps the most well known herb for pharmacokinetic interactions with conventional medicines is St Johns wort (Hypericum perforatum). This herb induces the drug metabolising enzyme cytochrome P450 3A4 (CYP3A4) which is involved in the metabolism of up to 50% of all medicines. Therefore, St Johns wort may lower serum concentrations of many medicines (see Appendix 5,page 71). In particular, it must not be used with carbamazepine, ciclosporin, oral contraceptives and protease inhibitors (eg. ritonavir).

2. PHARMACODYNAMIC interactions

There are many potential pharmacodynamic interactions between herbal and conventional medicines, some of which are outlined below. Among the more serious and well-documented interactions are those herbal remedies that potentiate bleeding, or those with cardiovascular, central nervous system or endocrine effects.

Bleeding. Herbs such as feverfew, garlic, ginger, ginkgo and ginseng may increase the risk of bleeding via different mechanisms eg. ginkgo antagonises platelet aggregation. Increased risk of bleeding will occur with aspirin, warfarin or heparin. These herbs should be stopped prior to surgery to reduce the risk of excessive bleeding peri-operatively.

Cardiovascular ef fects . Siberian ginseng can have cardiovascular stimulatory effects causing altered heart rhythm and increased blood pressure (high doses). Liquorice has aldosterone-like effects and may antagonise the effects of spironolactone and other antihypertensives.

Serotonin toxic ity. St Johns wort has complex neuropharmacology and may inhibit the reuptake of serotonin. It is best avoided with medicines that increase serotonin concentrations such as SSRIs, MAOIs, tricyclic antidepressants (especially tertiary amines eg. amitriptyline which are more serotonergic than secondary amines eg. nortriptyline), nefopam, pethidine, tramadol and dextropropoxyphene.

Central nervous system effects . Siberian ginseng has central nervous system (CNS) stimulant properties (which is often what it is used for) and should be used with caution in individuals who have anxiety, manic or schizophrenic psychiatric disorders. Sedative herbs such as kava and valerian may potentiate the effects of other CNS depressants such as tricyclic antidepressants, sedating antihistamines and anaesthetics.

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Other effects. Many other problems may result from co-administration of conventional and herbal medicines. For example, echinacea has immunostimulating effects and may antagonise the effects of immunosuppressants such as cyclosporin (ciclosporin). Gingko can lower the seizure threshold and is best avoided in patients with epilepsy and in patients on other drugs known to lower the seizure threshold eg. antipsychotics. Horseradish and kelp have a high iodine content and may affect thyroid function complicating treatment with thyroxine.

Further reading

Myers SP. Interactions between complementary medicines and warfarin. Australian Prescriber 2003; 25(3): 54-56 (www.australianprescriber.com).

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8. Adverse Medicine Reactions Adverse medicine reactions (AMRs) have been cited as the cause of approximately 2 4% of all hospital admissions. However, some reports indicate that AMRs may be a significant contributing factor in up to 17% of admissions. In most cases further analysis found that AMRs directly resulting in hospitalisation were highest amongst the elderly. Despite the high prevalence of AMRs it is estimated that only 5 10% of all AMRs are reported. In many cases this is the only way that a particular event will reach the literature. It is often useful to classify AMRs in order to determine both the likely causative agent and plan future therapy. AMRs are normally classified as either type A or type B.

Type A Type A (A = Augmented) adverse reactions represent either a quantitatively abnormal response, eg. daytime sedation due to hypnotics, or a response caused by a medicines diverse pharmacodynamic activity eg. anticholinergic effects due to tricyclic antidepressants. In almost all cases type A responses are predictable, dose-dependent and based on the pharmacological actions of the medicine. These reactions comprise approximately 90% of AMRs and are predictably more common in the elderly and those patients with concurrent diseases, especially renal and hepatic disorders, due to a reduced ability to clear the drug.

Type B Type B (B = Bizarre) reactions are characterised by a bizarre abnormal response to a medicine. This type of reaction is generally unpredictable and not dose-dependent eg. a rash due to penicillins. There are however some factors that may increase the probability that such a reaction will occur:

Patients with a history of allergic conditions eg. asthma or eczema often have a higher incidence or have more severe allergic reactions to medicines.

The chemical structure of the medicine may increase the probability of an AMR eg. medicines containing arylamine groups (eg. phenytoin), or sulphydryl (eg. captopril) or sulphonamide/sulphonamide-like groups (eg. cotrimoxazole), have been reported to have a higher incidence of hypersensitivity reactions.

Other important considerations pertaining to type B reactions that complicates prediction of AMRs include:

The reaction could be due to the pharmaceutical excipients rather than the active ingredient, eg. hydroxybenzoates.

Topical skin testing may not be diagnostically conclusive as often it is the metabolite or the process of biotransformation that initiates the hypersensitivity response. In some other instances the medicine may be directly irritating when applied topically eg. chlorbutol (chlorobutanol) but may not elicit such a reaction when given systemically.

Clearly there are examples of AMRs that do not sit comfortably in either category, but management of AMRs is often easier if considered in the light of this classification.

General guidelines

Type A reactions can often be overcome by reducing the dose or changing to another similar therapeutic agent that has a slightly different pharmacological profile.

Type B reactions usually require discontinuation of the medicine. If the reaction was moderate or severe, the medicine and structurally similar agents should be avoided in future.

On re-exposure to the agent type A reactions normally present similarly, but type B reactions often present more quickly and severely.

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9. Medicines in Pregnancy Up to 95% of women take four or more medicines at some stage during pregnancy (excluding vitamin supplements). There are two major considerations when using medicines during pregnancy:

1. The effect of medicines on pregnancy

All medicines will diffuse across the placenta to some extent and therefore some foetal exposure will occur. Drugs may be associated with pharmacological (largely predictable) and dysmorphogenic (largely unpredictable) effects: Pharmacological r isks. These are predictable based on the pharmacological activity of the medicine eg. NSAIDs may cause premature closure of the ductus arteriosus in the latter stages of pregnancy, which may result in foetal pulmonary hypertension. The patency of the ductus is maintained by prostaglandins. Other examples include the potential for vasoconstricting agents to reduce placental blood flow causing foetal hypoxia, and neonatal withdrawal syndrome after maternal use of opiates. Teratogenicity. This is largely an unpredictable effect. Approximately 2 4% of all live births are associated with a foetal abnormality and in most cases the cause is not known. Drugs cause 1 5% of all malformations ie. they affect less than 0.25% of all pregnancies. However, medicine-associated malformations remain an important consideration as they are largely preventable. Malformations are most likely to occur with exposure during the first trimester, particularly during the first eight weeks post-conception, and all medicines should be avoided during this period where possible. It is important to make careful medicine choices for women of reproductive age since approximately 50% of all pregnancies are unplanned and much of the critical time for malformations will occur before the woman knows that she is pregnant. Therefore, it is best to avoid known teratogens and new medicines with little data of teratogenicity potential in premenopausal women where possible. Some drugs that are classified as teratogenic include antineoplastics (some), carbamazepine, carbimazole, ethanol, lithium, misoprostil, penicillamine, phenytoin, tetracyclines, valproate, vitamin A derivatives (eg. isotretinoin) and warfarin. In most cases, use of these medicines during pregnancy will not result in a malformed foetus (notable exceptions are thalidomide and vitamin A derivatives which are highly teratogenic). Much of the available information on the teratogenic effect of medicines is obtained through retrospective studies, spontaneous reporting data and/or animal data. This sort of information is often flawed. For example, a medicine that is used in a pregnancy associated with a malformed baby is more likely to be reported as an adverse event than medicine use during a pregnancy with a successful outcome. Therefore, it is difficult to define a clear relationship between medicines and malformations except where the effect is gross (eg. thalidomide, vitamin A derivatives). The FDA have comprised a categorisation system (A, B, C, D, X) for the use of medicines in pregnancy whereby medicines of no demonstrable risk are assigned category A (eg. replacement doses of thyroid hormones) and those that are contraindicated are assigned an X (eg. thalidomide). An Australian system also exists. In general, these systems should not be used as the sole reference source for assessing medicine use during pregnancy as they are often oversimplified and difficult to interpret.

The risk:benefit ratio must be considered when medicines are used during pregnancy,

especially during the first-trimester

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2. The effects of pregnancy on medicines

Pharmacokinetic parameters are altered during pregnancy:

Clearance is increased due to an increase in cardiac output resulting in an increase in renal and liver blood flow. Therefore those medicines that display flow-dependent kinetics (eg. propranolol, tricyclic antidepressants) or are extensively cleared by the kidneys (eg. digoxin) may require an increase in maintenance dosage. Volume of distr ibut ion is increased by approximately 10 20% for both lipid and water soluble medicines. Therefore a corresponding increase in loading dose may be needed.

General recommendations

Stop all drugs prior to conception if possible

Avoid all medicines during pregnancy if possible, especially in the first-trimester

Many conditions are self-limiting and can be managed with lifestyle (non-pharmacological) treatments eg. relaxation techniques for tension headaches

If drug treatment is required during pregnancy, select the medicine with the best safety record

Use the lowest effective dose. Note: uncontrolled maternal disease (eg. epilepsy, inflammatory bowel disease) may also carry significant risk to the foetus or to the maintenance of the pregnancy

Remember that mothers may have unrealistic fears about the risks of drug exposure on their baby and this may affect compliance with drug therapy, or may result in unnecessary terminations of pregnancy

Have a low threshold for consultation with specialists in the area (see Medicine Information Centres, page 32)

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10. Medicines in Human Milk Breast milk, like other body fluids, is an aqueous environment into which all medicines will transfer to some extent. Milk contains more fat and less protein than blood and therefore medicine concentrations in the milk may differ from those of blood in accordance with their physicochemical properties.

All medicines diffuse into human milk to some extent it is the amount and potential toxicity of this amount that is important

The risk of medicine ingestion by the infant via breast milk may be considered from two views:

a) The amount of medicine ( dose) ingested by the infant . This is usually expressed in terms of the percentage of the maternal dose (on a weight adjusted basis ie. mg/kg/day of likely infant dose compared with mg/kg/day of the maternal dose). Remember that infants < 6 months of age will have reduced renal and metabolic clearance compared with an adult.

b) The potential toxic ity of the medicine . If the medicine is highly toxic even minimal exposure might be considered undesirable eg. cytotoxics.

Based on these considerations a list of medicines considered to be safe for breast feeding mothers if the infants are healthy and full-term includes normal doses of antipsychotics,

benzodiazepines, -lactam antibiotics, NSAIDs (except piroxicam), oral contraceptives and tricyclic

antidepressants. Other specific safe medicines include*:

acyclovir (aciclovir) fexofenadine paracetamol

captopril heparin paroxetine

carbamazepine labetalol phenytoin

citalopram loratadine prednisone**

clarithromycin magnesium sulphate propranolol

codeine mebendazole quinapril

cotrimoxazole methyldopa sumatriptan

digoxin metoprolol trimethoprim

diltiazem moclobemide triprolidine

domperidone morphine (low dose) valproate

enalapril nefopam verapamil

erythromycin nifedipine warfarin

famotidine nitrofurantoin

* Safe is defined as infant doses of < 10% of the maternal dose (on a dose/kg basis) and a low likelihood of infant toxicity (considering that the infant does not require the medicine)

**less than 20 mg/day This list of medicines is to be used as a guide only. Consultation with specialists in the area is advised in the case of premature infants, glucose-6-phosphate dehydrogenase deficiency, unusually high doses or overdose, or use of social or illicit drugs.

General recommendations

Infant exposure is generally low for most medicines, but the risk:benefit ratio should be considered in each case

Medicines that are very toxic (eg. cytotoxics) should usually be avoided even if exposure is low

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Infants, especially if premature, will have reduced medicine clearance compared with adults (corrected for weight), and will attain higher medicine blood concentrations for a given dose

Some medicines have the potential to increase (eg. phenothiazines, domperidone) or decrease (eg. oestrogens, cabergoline) milk production

If the decision is made to breastfeed during maternal drug therapy, the infant should be monitored for adverse effects eg. poor suckling, failure to thrive, altered bowel habit

Infant exposure can often be reduced if the dose is taken just after breasfeeding. Occasionally, it may be appropriate to reduce infant exposure by alternating breast and bottle feeding

It should be remembered that when a mother takes a medicine throughout pregnancy and then initiates breast feeding, that in virtually all circumstances the in utero foetal exposure will be considerably greater than any likely infant exposure via the milk

Contact the Christchurch Drug Information Service (contact details are on page 32) regarding medicines that are not on the list.

The risk:benefit ratio must be considered when medicines are used during breast feeding

Further reading Gardiner SJ, Begg EJ. Drug safety in lactation. Prescriber update. May 2001

(www.medsafe.govt.nz/Profs/PUarticles/lactation.htm).

Ilett KF, Kristensen JH, Begg EJ. Drug distribution in human milk. Australian Prescriber 1997; 20: 35-40 (www.australianprescriber.com).

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11. Medicines and the Child

Infants and children do not always represent small adults and therefore scaling down doses of medicines may not always be appropriate. There are two major considerations when dosing medicines in paediatric patients. For the terms of these guidelines, paediatrics will include ages 1 month to 12 years:

1. The PHARMACOKINETIC response

A number of physiological processes are either different or underdeveloped in paediatric patients, especially those less than 6 months of age. Body composit ion. The water/fat composition of the paediatric patient varies markedly with time and infants less than 6 months have a higher content of water compared to adults. However, this balances out at about 1 year of age. Clearance. Both renal and hepatic routes are underdeveloped in infants less than 6 months of age. At one month an infant has approximately 30% to 60% of the renal and hepatic clearance, and by 6 9 months approximately 100% of the clearance of an adult (on a surface area adjusted basis). This continues to increase until about 2 5 years of age. Medicines with a narrow therapeutic index should be monitored more frequently eg. aminoglycosides, anticoagulants, anticonvulsants, cyclosporin (ciclosporin), digoxin, theophylline, vancomycin.

2. The PHARMACODYNAMIC response

Due to the immaturity of many body systems and other idiosyncratic factors, paediatric patients may be more sensitive to some effects of some medicines. For example:

Type A react ions. Medicines with sedative properties will cause more notable sedation on a scaled down dose than in an adult.

Type B react ions . For example, Reyes syndrome is almost entirely a paediatric condition and is thought to be related to the use of aspirin especially after a viral infection.

General recommendations

If the infant is less than 1 month (a neonate) refer to a prescriber or someone with specialised knowledge in this area.

The dose the infant receives should be scaled down from an adult dose by using surface area available from nomograms. Surface area may be approximated by (weight)0.70. The fraction of the adult dose may therefore be calculated:

child dose = adult dose x Take into account reduced elimination capacity if infant is less than 9 months.

The choice of medicine should be considered in terms of the likely effect and side effect profile in the paediatric patient.

Where possible, avoid medicines known to depress growth eg. corticosteroids, or medicines that may alter development eg. ciprofloxacin.

weight of child

70kg

0.70

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12. Medicines and the Elderly Elderly patients are not representative of the general population both in their response to medicines and in their handling of medicines. More than 90% of the elderly population (>65 years) receive prescription medicines and it is estimated that approximately 30% of these patients suffer from adverse medicine reactions (only 10% of patients aged 20 30 are estimated to experience adverse medicine reactions). Two major factors are altered in the elderly patient:

1. The PHARMACOKINETIC response

A number of physiological changes take place with aging. However, there is no ideal guide to assess the degree to which these alter the way the body handles medicines. Important changes that occur include:

Bioavai labi l i ty. High clearance medicines (eg. some -blockers, calcium channel blockers, antidepressants, antipsychotics) often have increased bioavailability leading to possible toxicity. Clearance. Both renal and hepatic function is reduced. For example, it is estimated that renal clearance reduces by approximately 1% per year from age 20 to 80 years. A reduction in elimination is often greater for high clearance medicines (see Review Topics 13 and 14 on pages 28 and 30, respectively). Medicines with a narrow therapeutic index should be monitored more frequently eg. aminoglycosides, anticoagulants, anticonvulsants, cyclosporin (ciclosporin), digoxin, lithium, theophylline, vancomycin.

2. The PHARMACODYNAMIC response

Changes in the pharmacodynamic response are less well defined. Homeostatic adaptation is less efficient and target organ sensitivity may be altered. Homeostat ic response. This is the ability of the body to cope with changes and maintain normal function. For example, orthostatic hypotension associated with risperidone tends to be more pronounced in elderly patients due to a reduced ability of the baroreceptors to compensate for changes in blood pressure. Target organ sensit ivity . It has been suggested that alterations in receptor function occur with age eg. impairment of cholinergic function associated with confusion which is exacerbated by anticholinergics. A decreased responsiveness of adrenergic receptors may also occur.

General recommendations

A reduction in dose should be considered for patients over 55 years old. It should be noted, however, that chronological age is not always a good measure of biological age (which represents the patients functional ability)

Medicines known to cause alterations in the bodys normal homeostatic functions should be

dosed low initially and doses gradually increased to avoid precipitating adverse reactions

Start low - go slow

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13. Medicine Use in Renal Impairment Medicines that may require dosage adjustments are those that are extensively renally cleared unchanged. Dose adjustments should be relative to the degree of renal impairment. The degree of renal impairment is predictable based on the patients serum creatinine, age, weight and gender.

Assessment of renal impairment

A reduction in renal function is usually accompanied by an elevation in serum creatinine and an increase in serum urea concentration. These are only indirect measures and are inversely related to renal function. It is usual to estimate renal function from a calculation of the creatinine clearance using a formula such as the Cockroft and Gault equation. The serum creatinine may be within the normal range, while creatinine clearance (CrCl) is reduced since CrCl is also dependent on the patients age, gender and muscle mass. Therefore, the creatinine clearance should be calculated for all patients over the age of 55 yrs. (Normal CrCl is > 1.5 mL/s).

(mmol/L)creatinineserum50,000

(kg)LBWage)(140(mL/s)CrCl

a) The calculated value for CrCl is multiplied by a factor of 0.85 for females.

b) The factor of 50,000 may be changed to yield the calculated creatinine clearance in different units ie. 815 will give mL/min.

c) This equation cannot be used for children < 18 yrs of age.

d) LBW = lean body weight.

LBW (kg) males: 50 kg + 0.9 kg for every cm over 150 cm height

LBW (kg) females: 45 kg + 0.9 kg for every cm over 150 cm height

Example: A 60 yr old female, weighing 60 kg (LBW) with a serum creatinine of 0.10 mmol/L (within the normal range) will have a CrCl of 0.8 mL/s (~50% of normal). A 50% dosage reduction of a medicine that is highly renally cleared will therefore reduce possible toxicity, save costs and may increase compliance (especially if the medicine is usually dosed multiple times per day). This dosage reduction can be made by either halving the dose received or doubling the interval between doses. Even without a knowledge of the patients serum creatinine the following guidelines can be applied. These guidelines assume the serum creatinine is normal (0.08 mmol/L), and the lean body weight is 60 kg.

Age (yr) Maximum renal function

Females Males

50 75% 90% 60 66% 75% 70 60% 70% 80 50% 60%

90 40% 48%

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If a decreasing lean body mass is also taken into account their maximum renal function (assuming a normal serum creatinine) will be even lower.

In all cases the dose of the medicine should be based on a defined clinical outcome

A list of medicines (or their active metabolites) that are extensively cleared by the kidneys (>60%) is provided below.

ACE inhibitors fluconazole

acetazolamide frusemide (furosemide)

acyclovir (aciclovir) H2-antagonists

allopurinol (active metabolite, oxypurinol) hydrochlorothiazide

amantadine lithium

amiloride metformin

Aminoglycosides methyldopa

atenolol morphine (active metabolite, morphine-6-glucuronide)

chloroquine penicillins

ciprofloxacin sotalol

clonidine tetracyclines

digoxin vancomycin

Fibrates

General recommendations

Dosage adjustments for medicines that are extensively renally cleared (see list above) should be made in direct proportion to renal function

ie. dose/dayemaintenancnormalmL/s 1.5

CrCL Observed

It is particularly important to consider dosage adjustments for medicines that have a small therapeutic index eg. digoxin, lithium, aminoglycosides.

Dosage adjustments may be made by either reducing the dose or increasing the interval so that the dose received per day will be reduced appropriately ie. for a medicine dosed multiple times per day (eg. captopril, methyldopa, lithium) it would be reasonable to increase the interval whereas for medicines that are dosed only once per day (eg. digoxin, allopurinol) it would be more appropriate to reduce the dose.

It should be noted that some drugs that are cleared renally eg. trimethoprim and frusemide (furosemide) may need to be continued at the same dose in patients with renal impairment, as those without renal impairment, or their dose may need to be increased to maintain their effectiveness

All dosage adjustments should be considered in the light of the patients current clinical status

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14. Medicine Use in Liver Disease Unlike renal impairment there is no reliable measure of the degree of hepatic impairment and therefore dosing is empirical. A reduction in medicine metabolism in the liver may occur for two reasons: a) decreased enzyme metabolising capacity b) decreased liver blood flow and/or intra/extra hepatic shunting

In the elderly patient often both liver blood flow and the enzyme metabolising capacity may be reduced. Dosage adjustment may therefore be necessary for extensively metabolised medicines, especially those with high clearance (see below).

Medicines that have particularly high metabolic clearance are more susceptible to alterations in liver function as a result of decreased blood flow and decreased enzyme capacity. In contrast, medicines that have low clearance will only be affected by decreased enzyme capacity. Some examples of high and low clearance drugs are provided below.

High clearance Low clearance

Antidepressants Anticonvulsants

Antipsychotics Benzodiazepines (most)

-blockers NSAIDs

Calcium channel blockers warfarin

Nitrates

Opioids

Assessment of liver impairment Albumin concentrations, prothrombin measurements and cholesterol concentrations reflect the ability of the liver to synthesise compounds (eg. proteins) and therefore are indicative of the livers ability to metabolise medicines. These measures are insensitive to rapid changes in liver function and only depict severe, chronic dysfunction. (Chronic liver disease is more predictably associated with impaired metabolism than acute liver disease.)

Marker Normal range Liver dysfunction

Albumin 36 55 g/L < 30 g/L

INR 0.8 1.2 > 1.2

Diseases of the liver that decrease medicine metabolism include: cirrhosis, alcoholic liver disease, viral hepatitis (may increase or decrease metabolism), porphyria and hepatoma. Note: Cirrhosis, porphyria and hepatoma do not seem to alter glucuronidation reactions and therefore medicines solely undergoing glucuronidation are likely to be affected less eg. morphine, temazepam.

Cholestatic jaundice Theoretically, medicines or their active metabolites that are extensively cleared unchanged via the bile will have impaired elimination in cholestatic jaundice. However, there are only a few medicines used in general practice for which this is important eg. amoxycillin (amoxicillin), ceftriaxone, doxorubicin, erythromycin, tetracycline.

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General recommendations A significant reduction in medicine metabolism is not usually seen except in severe liver impairment. In cases where the markers, albumin or prothrombin times (INR), are significantly altered, then dosage reductions are necessary, especially for medicines affected by both decreased metabolism and altered liver blood flow (see above). A useful rule is a 50% reduction in dose for medicines affected by hepatic blood flow as well as enzyme capacity (so called high clearance drugs), and a 25% reduction for medicines only affected by enzyme metabolising capacity (low clearance drugs).

All dosage adjustments should be considered in the light of the patients current clinical status

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Medicine Information Centres Most hospitals in New Zealand offer some degree of specialised medicine information service, with larger services attached to the main regional hospitals. It is generally recommended to contact the hospital in your area first.

Major Medicine Information Centres

Medicines Information Department Pharmacy Department Auckland Hospital Park Road, Private Bag 92 024 AUCKLAND Tel: (09) 307 4949 ext. 7388 Fax: (09) 375 4316 E-mail: akpharmdi@adhb.govt.nz

Medicine Information Service Middlemore Hospital Private Bag 93 311 Otahuhu AUCKLAND Tel: (09) 276 0257 Fax: (09) 276 0057 E-mail: MedInfoService@middlemore.co.nz

Medicines Information Centre Wellington Hospital Private Bag 7902 WELLINGTON Tel: (04) 385 5853 Fax: (04) 385 5966 E-mail: druginfo.centre@ccdhb.org.nz

Drug Information Service Christchurch Hospital PO Box 4710 CHRISTCHURCH Tel: (03) 364 0900 or 0800 DRUG INFO (0800 378 446) Fax: (03) 364 0902 E-mail: druginfo@cdhb.govt.nz Website: www.druginformation.co.nz

Medicines Information Service Dunedin Hospital 201 Great King St DUNEDIN Tel: (03) 474 7658 Fax: (03) 474 7638

Poisons Information Centre

National Poisons Centre Department of Preventative and Social Medicine University of Otago PO Box 913 DUNEDIN Tel: 0800 POISON (0800 764 766) Fax: (03) 477 0509 E-mail: poisons@otago.ac.nz Website: www.toxinz.com

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Useful References

General references

British National Formulary (BNF) 47. British Medical Association and the Royal Pharmaceutical Society of Great Britain, London, 2004*

Lacy CF et al., (ed). Drug Information Handbook, 12th edition. Lexi-comp, Hudson, 2004*

McEvoy GK et al., (ed). AHFS Drug Information 2004. American Society of Health-System Pharmacists, Bethesda, 2004

Medicines in pregnancy and breastfeeding

Bennett PN (ed), Drugs and Human Lactation, 2nd edition, Elsevier, Amsterdam, 1996

Briggs GG et al (ed). Drugs in Pregnancy and Lactation, 6th edition, Lippincott, Williams & Wilkins, Philadelphia, 1998

Gardiner SJ, Begg EJ. Drug Safety in Lactation. Prescriber Update: May 2001 (www.medsafe.govt.nz)*

Hale TW. Medication and Mothers Milk, 11th edition. Pharmasoft Publishing, Amarillo, 2004* Therapeutic Goods Administration. Prescribing Medicines in Pregnancy, 4th edition, 1999 (http://www.tga.gov.au/docs/html/medpreg.htm)*

Medicine interactions

Bachmann KA et al (ed). Drug Interactions Handbook. Lexi-Comp, Hudson, 2003*

Stockley IH (ed). Stockleys Drug Interactions, 6th edition. The Pharmaceutical Press, London, 2002

Pharmacology (including pharmacokinetics, effects of age, disease etc)

Begg EJ. Instant Clinical Pharmacology. Blackwell Publishing, Cornwall, 2003*

Holford NHG. Clinical Pharmacokinetics. Drug Data Handbook. Adis Press, Auckland, 1998* Walker R, Edwards C. Clinical Pharmacy and Therapeutics, 3rd edition. Churchill Livingstone, 2002*

Alternative remedies Jellin JM (ed). Natural Medicines Database. www.naturalmedicines.com*

Websites (only free sites that are referred to in the guide are included) Christchurch Drug Information Service. www.druginformation.co.nz*

National Poisons Centre. www.toxinz.com* *indicates references that cost less than or close to $150

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Cautionary and Advisory labelling Newer dosage forms aim to reduce side effects and improve effectiveness and compliance. It is important the patient understands how and when to use these formulations correctly. The problems of poor compliance and adverse effects from medicines can be minimised when the pharmacist takes the time to ensure the patient understands the dosage instructions. This patient education should be supported by clear written directions.

The reasons for using a Cautionary and Advisory label are: 1) to prevent or reduce adverse reactions from medicines and to warn of important side effects

2) to ensure that the medicine is taken in the most effective manner Warnings of possible side effects, information on underlying disease conditions and normal dosages should accompany dispensed medicines where the benefit to the patient is clear. An example of a situation that warrants advice on the normal dose is the case of analgesics where two tablets when required for pain has been prescribed. Advice on the usual recommended maximum frequency of administration (eg. up to every four hours) and/or the total daily dose (eg. up to 8 tablets per day) should be given to minimise the chance of overdose. It is also useful to supply the patient with an information leaflet about their medicine in addition to both the Cautionary and Advisory labelling and patient education. The information leaflet should be one that is specifically designed to meet the needs of patients eg. it avoids using unnecessary medical jargon. The label should not replace verbal advice. It is of major importance that the patient is educated as to the meaning of the label and how it affects them personally. Instructions to the patient must be concise and easily understood. No patient should leave the pharmacy with a medicine without a clear understanding of how to use it correctly, how much to use, when to use it, and how often to use it.

The Cautionary and Advisory labels should be attached to the medicine container without obscuring the main label directions. They should be used regardless of whether an abbreviated version of the label is included on the main label. The Cautionary and Advisory labels have been designed to provide a specific instruction to aid patients in the effective use of their medicines. A Cautionary and Advisory label that is attached to the container of a medicine is likely to be seen on each occasion it is used.

If the person collecting the medicines is not the patient, it is important that they are also given any necessary additional advice. In preparing this document every effort has been made to ensure that the information is correct. Where any discrepancy occurs between the recommendations in the guide and other references, pharmacists are expected to use their professional judgement. The list is not exhaustive. In order to comply with obligations contained in the Code of Ethics, pharmacists are strongly recommended to use the Cautionary and Advisory labels on dispensed medicines.

Opting out procedure

A prescriber who for any reason does not wish a Cautionary and Advisory label to be used in a

particular case should endorse the prescription - N.C.L. (No Cautionary Label).

35

The purpose of each label and reference In all cases these labels must be used in conjunction with patient education and with a knowledge of the patients current clinical status.

Label 1

This medicine may make you sleepy and make it dangerous to drive or operate machinery. Limit alcohol intake.

The message of this label is NOT that the patient should stop taking the medicine if they intend to drive or operate machinery, but that they should determine whether or not drowsiness is a problem. For example, in the case of carbamazepine it is important to advise patients that they should always take the medication in order to continue being able to drive, but that they should be aware of the possibility of drowsiness.

This label applies to all medicines with effects that include sedation, and to all combination products that contain an ingredient having sedative properties. A label of this nature is already required by law in the sale of most antihistamines over the counter, and there can be no justification for omitting such a label when similar medicines are dispensed.

The term limit is included on the label to indicate that alcohol consumption is not prohibited, but should be moderated. This is to reduce the probability of patients stopping their medicines so as not to interact with their alcohol intake, while reinforcing that excess alcohol is not recommended. The reference to alcohol is added since ethanol is a central nervous system (CNS) depressant, and the concurrent administration may cause additive sedation. This interaction has been well documented in the literature, but the problem is frequently overlooked in practice. It is recognised that many road accidents are the result of the combination of excess alcohol and psychotropic/hypnotic medicines.

It is important to educate patients about the meaning of limit alcohol intake

Label 2

Do not drink alcohol while being treated with this medicine.

This label applies to those medicines where alcohol is not recommended. Alcohol may interact with medicines by two major mechanisms:

a) Additive effects of the medicine. The most common example of this reaction is additive central nervous system (CNS) depression with other CNS depressants (see also Label 1).

b) Alteration in the metabolism of alcohol. The most common is the disulfiram or disulfiram-like reaction caused by some antibiotics.

Alcohol may also alter the metabolism of some medicines. Acute high doses of alcohol may decrease metabolism whereas chronic exposure can increase metabolism. These effects are complex and generalisations are difficult to make.

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Label 3

Take each dose on an empty stomach - one hour before OR two hours after food.

This label applies to medicines with actions that are decreased in the presence of food (see Review Topic 4, page 14). The major mechanisms include:

a) Where the oral availability is reduced by >20% ie. an interaction that affects extent not rate of absorption eg. flucloxacillin.

b) Where the presence of food decreases the effectiveness of the medicine but this is unrelated to its absorption eg. bismuth subcitrate.

It is considered that the recommended label is more flexible for the patient than one which states specific dosage times. The pharmacist should support this label with verbal advice as to an appropriate dosage schedule that will ensure the medication is taken at evenly spaced intervals to gain maximum therapeutic effect. The essential element of this label is the empty stomach, and the patient should be reassured that they do not have to eat in order to comply with these recommendations.

The label should be used in conjunction with patient education and a knowledge of the patients medical history. It is not reasonable to recommend a patient changes to take a medicine on an empty stomach if they have always taken it otherwise. It must be remembered that oral availability is relative and almost all medicines are dosed to a particular clinical response. Similarly, to improve compliance or reduce side effects some medicines may be dosed in a manner that accounts for a reduced availability when taken with food.

Note: Some medicine effects are dependent on the peak concentrations in the plasma (therefore the rate of absorption) and the rate is reduced in the presence of food ie. an interaction that affects the rate with or without affecting the extent eg. frusemide (furosemide), paracetamol.

Label 4

Do not take indigestion remedies, iron or calcium preparations within 2 hours of taking this medicine.

This label applies to those medicines with actions that are significantly altered by antacids, iron or calcium. The major mechanisms include:

a) Where the actions of the medicine are reduced. In the majority of cases these medicines are

usually effective chelating agents of the di and tri valent cations Ca2+, Fe2+, Al3+, Mg2+. The resultant complexes are poorly absorbed from the gastrointestinal tract, or are inactivated. By avoiding administration of certain dietary supplements (eg. calcium or iron) and antacids within 2 hours (either before or after) of taking the medicine an adequate clinical response can be achieved. Although the administration of preparations containing calcium does not significantly influence the absorption of some medicines (eg. doxycycline), it should be noted that reduced absorption of these medicines can occur in the presence of high dose calcium (eg. 1 gram), and iron salts.

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b) Where the actions of the medicine are increased. In less common circumstances the oral availability of the medicine may be enhanced, often due to better absorption from a more alkaline environment. Given the intermittent nature of the use of most antacids, sudden increases in absorption may lead to toxicity.

Label 5

Avoid certain foods and alcoholic drinks. (See separate card).

This label applies to irreversible non-selective monoamine oxidase inhibitors (MAOIs) (see Appendix 7, page 77). Although the usage of this class of medicine is low, the seriousness of possible interactions warrants the special provision of an additional label. The pressor amine tyramine, present in many foods, is normally metabolised in the gut by the monoamine oxidase enzymes. With MAOI therapy this enzyme system is inhibited and a serious hypertensive reaction can result. Similar effects can be seen with the administration of ephedrine, pseudoephedrine and phenylephrine with MAOIs. Each patient must be given a card listing the foods that should either be avoided or taken in moderation during therapy, and a general warning about the concurrent administration of other medicines, except under medical direction. These cards may be purchased from the Pharmaceutical Society of New Zealand (Inc).

Label 5a

This medicine may not work as intended if taken with some other medicines. Ask your pharmacist.

This label is included on those medicines with pharmacokinetics or actions that are commonly altered by the concurrent use of other medicines eg. warfarin, cyclosporin (ciclosporin), oral contraceptives etc. It is intended for use on medicines that are affected by a large number of other medicines and where an interaction may result in adverse sequelae (see Appendix 4, page 69).

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Label 6 KEEP IN FRIDGE DO NOT FREEZE.

The storage conditions for many medicines are critical. This label will apply to those preparations where storage at temperatures between 2 and 8C is necessary. Products should not be frozen since this may result in crystal formation with a loss of activity and/or destruction of certain release characteristics, for example insulin formulations (see Appendix 6, page 74).

Always observe the manufacturers instructions

Label 7 or 7a

Do not use After //

Do not use. days after opening. (date opened: ../../..)

Certain products have a short shelf-life due to chemical instability or to the possibility of bacterial contamination.

Dilution or admixing of medicines affects strengths of preservatives, stabilising agents, suspending agents etc. and the stability of the preparation cannot be guaranteed.

Ophthalmic preparations carry the risk of contamination once the container is opened. Breakdown or loss of the preservative can occur, and coupled with the risk of bacterial contamination, the use of these products may be harmful. Some types of preparations which should receive expiry dating include: Diluted or admixed internal or external medicines Eye/Ear/Nose drops, sprays, ointments Reconstituted antibiotic mixtures Urine and blood testing reagents/strips

Label 7a is recommended to be used for preparations such as eye drops where the discard date should be related to the date on which the sealed container was opened by the patient. A space for that date is provided and patients should be advised to fill in the date when the bottle is opened.

Always observe the manufacturers instructions

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Label 8

Protect yourself from too much natural or artificial sunlight while being treated

with this medicine.

Some medicines cause serious photosensitivity reactions when patients taking them are exposed to sunlight. It is generally considered that there are two mechanisms for this reaction. 1. Phototoxic. This results from the binding of the chemical substance or its metabolite(s) to

cell components. Exposure to light causes activation of the chemical complex and subsequent tissue damage. This reaction is considered dose-dependent in terms of both medicine and sunlight exposure and may occur rapidly. The use of sunscreens may be beneficial if sunlight cannot be avoided.

2. Photoallergic. This reaction resembles the response to an allergen in a sensitised person.

The reaction usually occurs after a latent period of approximately one week, however on rechallenge it may be immediate and is generally dose-independent. Sunscreens are of limited value.

In some instances it is not possible to differentiate between photoallergic and phototoxic reactions and some medicines may possess both properties. In contrast, the mechanism for methotrexate induced photosensitivity appears to involve an alternative mechanism possibly associated with altered cell turnover. The photosensitivity reaction with methotrexate generally results in flare up of previous sunburn reactions. This may happen some days following resolution of the erythema. Since it is not possible to predict an individuals response to a photosensitising medicine, it is considered desirable for a warning label to be attached to medicines which have been shown to cause photosensitising reactions. The popularity of sun beds has introduced a new consideration. Reactions have been reported by patients on long-term tetracycline therapy for acne, attending such clinics. For patients in this category known to be attending or considering attending these clinics, Label 8 is appropriate. It is important to advise patients that the label does not apply to controlled exposure to artificial light on the advice of a doctor eg. as part of PUVA treatment.

It is important to educate patients about the meaning of too much

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Label 9

Do not stop taking this medicine without consulting your doctor.

This label is specifically applied to medicines that cause a reaction upon abrupt withdrawal which is greater, or different, from that which would be expected to occur if the condition had been left untreated. The types of reactions are characterised by: 1. Rebound effect. Where the abrupt withdrawal of an agent results in the condition becoming

worse than would have been expected if left untreated. Medicines commonly associated: anticonvulsants (rebound seizures), corticosteroids and some antihypertensives.

2. Adverse effects. Where the abrupt withdrawal of an agent gives rise to symptoms unrelated to the condition that have not been experienced previously by the patient. Medicines commonly associated: antidepressants, anticonvulsants (eg. carbamazepine used to treat neuralgia may precipitate seizures in non-epileptic patients upon abrupt withdrawal), corticosteroids.

This label is also recommended for medicines used in the treatment of tuberculosis and HIV since a break in therapy can result in emergence of resistant strains.

Label 10

Take each dose with a large glass of water.

This label applies to medicines that have been implicated as a cause of oesophagitis or oesophageal ulceration. Studies have demonstrated that tablets and capsules may be retained in the oesophagus for considerable periods of time. Damage occurs when an irritant medicine is retained in the oesophagus. The incidence can be reduced if patients are advised to take the medicine with water.

All solid dose forms of medicines should be taken with water while the patient is standing or sitting upright

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Label 11

Grapefruit or grapefuit juice may interact with this medicine. Discuss with your pharmacist.

This label applies to those medicines with an oral availability that is significantly altered (usually enhanced) by grapefruit or grapefruit juice (GFJ), and where there is potential for important clinical effects associated with the interaction. GFJ may increase the blood concentrations of some drugs by up to 38-fold* making GFJ interactions among the most significant interactions to date.

The medicines that are most affected by GFJ are those with a low oral availability due to metabolism by cytochrome P450 3A4 (CYP3A4) in the gut wall. The active constituents in GFJ (eg. 6,7-dihydroxybergamottin) inhibit this enzyme allowing more medicine to reach the systemic circulation. The inhibitory effect of GFJ on intestinal CYP3A4 appears to be maximal after the first glass. However, with higher consumption (eg. 6 glasses per day) hepatic CYP3A4 may also be affected. The magnitude of the interaction is gr