17 Cautions and contraindications

Question 1

Define caution

Answer 1

A situation in which additional care in the use of a medicinal product is required because the risk: benefit balance is altered

Question 2

Define contra-indication

Answer 2

A situation in which a medicinal product should not be used because the risk outweighs potential benefits

Question 3

Erythropoietin

Answer 3

• Stimulates red blood cell production
• Used to treat anaemia in cancer patients receiving chemotherapy
• 27 Feb 2008 Meta-analysis – increased risk of death in cancer patients.
• 7 March 2008 Amgen adds caution - Aranesp can speed up tumour growth and increase risk of death
• 13 March 2008 FDA allow continued marketing of Aranesp and Procrit but restrict use to incurable cancer

Question 4

Contraindication occurs when..

Answer 4

expected ADR outweighs benefit
Situation or condition
• Increased expectation of ADR
• Decreased benefit of therapy

– If benefit outweighs risk but ADR is possible a caution may be appropriate instead

Question 5

Contra-indications occur because..

Answer 5

• Drug exacerbates disease (“drug-disease interaction”) – Condition being treated orAnother pre-existing condition
• Adverse events are more likely due to an existing condition or demographic factor
– Drug creates a safety issue because of the condition • Pregnancy, Lactation, Age
• Subgroups of patients have a predisposition to ADR
• Immunological factors (e.g. allergy, hypersensitivity)
• Metabolic factors
• Drug-drug interaction should also be considered

Question 6

Example of drug-disease interaction (1):

Sumatriptan and ischaemic heart disease

Answer 6

Sumatriptan contraindicated in patients with ischaemic

heart disease, previous MI, hypertension

Question 7

Example Drug-disease interaction (2): β antagonists and Asthma

Answer 7

• Remember: β2 agonists (eg salbutamol) are used to treat Asthma –bronchodilator
• β antagonists used for heart conditions (angina, MI, arrhytmias) and open-angle glaucoma
• Non-selective β antagonist contraindication with asthma but cautioned in COPD

Question 8

Example Drug-disease interaction (2): β antagonists and Asthma

Bronchiole..

Answer 8

Blocks bronchodilation, exacerbates asthma

Question 9

Example Drug-disease interaction (2): β antagonists and Asthma

β2 receptor
Agonist -
Antagonist -

Answer 9

Agonist - dilation

Antagonist - constriction

Question 10

Example Drug-disease interaction (2): β antagonists and Asthma

β Antagonist Levobunolol
Timolol

Answer 10

Eye - Reduced ocular pressure (glaucoma)

Question 11

Example Drug-disease interaction (2): β antagonists and Asthma

β Antagonist
Nadolol, Sotalol Propanolol,

Answer 11

Heart - Decrease rate & bp (hypertension, anxiety, tachycardia)

Question 12

Example drug-disease interaction (3):

amiodarone and thyroid dysfunction

Answer 12

Amiodarone
•Treat Arrhythmia ( 200 mg, 3 times daily; maintenance 200 mg daily)
•Inhibits K+ channels – prolong cardiac

• Interferes with thyroid hormone at several levels – can induce hypothyroidism
• Large iodine intake (exceeds r.d.a.)
• inhibition of thyroidal iodide uptake and thyroid hormone synthesis
• inhibition of fractional conversion of T4 to T3 intracellularly (inhibits 5’-deiodinase)
• inhibition of T4, T3 entry into cells
• T3 receptor antagonist

-Contraindicated in persons with thyroid dysfunction

Question 13

Contraindications based on Patient Condition(1): pregnancy

Answer 13

• 1st trimester –congenital malformations (teratogenesis)
• 2nd & 3rd –growth & development

Examples
• Thalidomide and pregnancy
• SSRI – avoid if possible, compare risk to benefit
• Often drugs contraindicated without human testing Slide

Question 14

Contraindication because of a condition (2): lactation

Answer 14

• Drugs in breast milk:
– Low amounts of drug may not be harmful or may cause hypersensitivity!
– Larger amounts may have a pharmacological effect

Examples:
• Hormone agonists and antagonists affecting the reproductive system may be contraindicated during lactation
– Fulvestrant
• estrogen receptor antagonist used in breast cancer
– Co-cyprindiol
• contains cyproterone-anti-androgen, used in severe acne
• Can cause feminization of male fetus

Question 15

Contraindication because of a condition (3): Age

Answer 15

Examples
• Aspirin & Reyes Syndrome
– Reye’s syndrome, a rare but severe illness characterized by acute encephalopathy and fatty liver
– 1981 -1997, 1207 cases in children reported to the U.S. Centers for Disease Control and Prevention.
– >80% associated with aspirin treatment – mechanism unknown but mitochondrial toxicity

– Contraindication - Children who are under 16 years of age should not take aspirin, unless for Kawasaki syndrome and prevention of thrombus formation after cardiac surgery

Question 16

Cautions/Contraindications because of changes in ADME

Answer 16

• Liver Disease
– Reduced elimination
– Reduced production of serum binding proteins
– BNF
• Increased Sensitivity to CNS drugs often seen
• Coagulation impaired–increased sensitivity to anti-coagulants
– Avoid drug or dose reduction

• Renal disease
– Reduced excretion
– BNF
• Avoid drug or dose reduction according to renal function (glomerular filtration rate)

• BUT – drugs also may be contraindicated in liver/renal disease because they can potentially worsen the disease eg ACE inhibitors and impaired renal perfusion

Question 17

ACE inhibitors and renal disease

Answer 17

• ACE inhibitors used in treatment of hypertension
• Prevent AngII →vasoconstriction & aldosterone release
• Contraindicated in patients with significantly reduced renal perfusion
-
Slide 29
• Vasodilation further reduces renal pressure driving glomerular filtration

Question 18

How do ACE inhibitors work?

Answer 18

ACE inhibitors work preferentially on efferent rather than afferent arteriole. Hence lowers glomerular pressure and filtration rate

Question 19

Types of Cautionary label

Answer 19

• How to take/use the medicine
– Eg dissolve in water, dissolve under tongue, suck, chew, swallowed whole, spread thinly
• When to take/use the medicine
– Eg regular intervals, Before or after food, Not to stop taking medicine, completing
course of treatment, maximum amount in a period
• Potential adverse events & effects on driving or work – Eg drowsiness, avoid driving & machinery, blurred vision, coloured urine
• Food, medicine to be avoided
– Eg indigestion remedies, Fe, Zn, milk; avoid alcohol, sunlight; avoid aspirin,
paracetamol
• Storage
– Flammable, fridge

Question 20

Example drug-drug interaction (PD): antagonistic effects (2)

Answer 20

• Histamine H1 antagonists
– Eg used to treat hay fever, rash
• Histamine H1 agonists – Betahistine
– Used to treat vertigo because it has an effect on the blood supply to the ear
– Vasodilation of arteries supplying inner ear.

Question 21

Example drug-drug interaction (PD): additive effects

Answer 21

• Amiodarone and sotalol
• Both prolong cardiac action potential – risk of additive QT prolongation •Found in 2/1135 patients. Drug Safety 2005 28 67

•Triptans and Ergot alkaloids cause vasoconstriction and hypertension if taken together

Triptans

• 5HT agonists
• Sumatriptan
• Rizatriptan
• Zolmitriptan

Ergot Alkaloids

• 5 HT, & DA, NA
• Ergotamine (Migraine)
• Bromocriptine (Parkinsons)

Question 22

Example: drug-drug interaction (PK)

Answer 22

Azole Antifungals (eg Ketoconazole Fluconazole Itraconazole) inhibit cytochrome P450 3A4

• Cyp 3A4 most abundant in liver and metabolizes largest number of drugs •Azole antifungals can inhibit metabolism of some benzodiazepines •Increased benzodiazepine in plasma
• Increased sedation – may lead to contraindication.

Question 23

Balancing risks & benefits of

off-label use

Answer 23

• Risk for adverse effects
– Unknown adverse effects
– Use of (older) drugs with data available,
but more adverse effects
• Risk for suboptimal efficacy
– Use of (older) drugs with data available,
but lesser effect
– Underdosing, if data for correct dosing not
available

Question 24

Example drug-drug interaction (PD):
antagonistic effects (1)

Answer 24

dopamine
agonist
Eg bromocriptine - Parkinson’s disease

dopamine
antagonist
Eg
chlorpromazine
Schizophrenia

Question 25

Some examples of why cautionary labels

are required

Answer 25

6 Do not take indigestion remedies or medicines containing iron or zinc 2 hours before or after you take this
medicine - Ofloxacin
M2+ (Quinolone – metal complexes have altered PK & PD properties)

21 Take with or just after food - Sporanox capsules

30 Contains Paracetamol. Do not take anything else containing paracetamol while taking this medicine - Co-dydramol.