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Smoking and warfarin

Last reviewed dd mmm yyyy. Last edited dd mmm yyyy

There are multiple constituents to tobacco smoke that may have the potential to induce hepatic cytochrome P450 (CYP) isoenzymes and other metabolic processes

polycyclic aromatic hydrocarbons (PAHs) are a product of incomplete tobacco combustion and an inducer of hepatic enzymes as well being one of the major lung carcinogens found in tobacco smoke
other compounds such as acetone, pyridine, heavy metals, benzene and carbon monoxide may also interact with hepatic enzymes, but their effects appear to be less significant
there are data that suggest PAHs induce CYP1A1, 1A2, 1B1, 2B6 and 2E1 as well as uridine diphosphate (UGT) - related metabolism
tobacco smoke also appears to inhibit CYP2A6 (2). Of the tobacco-induced isoenzymes, CYP1A2 is the most clinically significant as many drugs are substrates for CYP1A2

This table has been summarised based on a review of this topic (1) - if the affected drug is prescribed under the supervision of a specialist, their input should be sought if the patient changes their smoking status.:

Drug name	Nature of interaction	Clinical relevance	Action
Aminophylline Theophylline	Theophylline and aminophylline are metabolised in the liver by CYP1A2, 2E1 and 3A3 smoking can increase clearance of theophylline and aminophylline heavy smokers (20-40 cigarettes per day) may need much higher doses of than non-smokers full normalisation of hepatic function appears to take many months or even years after stopping aminophylline or theophylline	High (narrow therapeutic index drug)	When stopping smoking: a reduction in theophylline dose of up to 25-33% might be needed after one week If a patient starts to smoke: his/her dose may need to be increased as smokers often need higher maintenance doses Further advice with respect to theophylline (2): consider dose adjustment changes in smoking status have a clinically important effect individuals stopping or reducing cigarette smoking are at risk of toxicity or loss of clinical effect. Those starting or resuming smoking may require dose titration. Individuals must tell their specialist if they plan to stop or start smoking dose adjustment consider a gradual dose reduction of 25-33% over one week on stopping smoking on starting (or restarting) smoking, the dose will need to be increased monitoring theophylline plasma level should be monitored to inform further dose adjustments hospital admissions be aware that individuals admitted to hospital, and unable to smoke, are at risk of theophylline toxicity. Further dose adjustment and monitoring will be required on discharge if the individual restarts smoking
Clozapine	Clozapine is almost completely metabolised before excretion by CYP1A2 and 3A4, and to some extent by 2C19 and 2D6 smokers may need higher doses due to increased clearance of clozapine have been case reports of adverse effects in patients who abruptly stopped smoking	High	Take clozapine plasma level before stopping smoking. On stopping, reduce dose gradually (over 1 week) until around 75% of original dose reached (i.e. reduce by 25%) repeat plasma level 1 week after stopping anticipate further dose reductions. If a patient has stopped smoking and intends to re-start: take their clozapine plasma level before they do so increase dose to previous smoking dose over 1 week repeat plasma level If a patient starts smoking: has been suggested a 50% increase in clozapine dose should be anticipated Further advice (2) seek urgent specialist advice smoking status changes have a clinically important effect. Individuals stopping or reducing cigarette smoking are at risk of severe toxicity. Those starting or resuming smoking may require dose titration. Individuals must tell their specialist if they plan to stop or start smoking monitoring and dose adjustment dosage adjustment under specialist supervision will be needed if stopping smoking, take blood levels (in addition to any usual tests), and reduce dose as needed. Repeat blood levels after one week if starting (or restarting) smoking, take blood levels and titrate dose to maintain therapeutic effect. Repeat blood levels as needed hospital admissions review smoking status on and during admission; arrange blood levels and dose reduction if smoking is significantly reduced or stopped review changes if smoking is resumed.
Erlotinib	Erlotinib is metabolised primarily by CYP3A4 and to a lesser extent by 1A2 cigarette smoking has been shown to reduce erlotinib exposure by 50-60% smokers gain less benefit than non-smokers from erlotinib in clinical studies	High	Current smokers should be advised: to stop smoking as early as possible before initiation of treatment If the patient stops smoking the erlotinib dose should be immediately reduced to the indicated starting dose When given to patients who smoke, increase the daily dose of erlotinib in 50mg increments at 2-week intervals, up to a maximum daily dose of 300mg, the licensed maximum dose in smokers. Further advice (2) seek specialist advice changes in smoking status have a clinically important effect. Individuals are strongly advised to stop smoking before initiation and tell their specialist if their smoking status changes dose adjustments dosage adjustment will be needed; seek specialist advice and supervision. Plasma levels are reduced in smokers versus non-smokers rapid dose reduction is required on stopping smoking, to the usual dose for non-smokers. On starting (or restarting) smoking, the dose will need to be increased
Olanzapine	Olanzapine is metabolised by glucuronidation and CYP1A2, both of which are induced by smoking, leading to increased clearance of olanzapine to a lesser extent olanzapine is also metabolised by CYP2D6 smokers have lower olanzapine serum levels and require higher daily doses compared to non-smokers there are case reports of extrapyramidal symptoms developing when a patient stops smoking	High	On stopping smoking reduce dose by 25%. Closely monitor patient and consider further dose reductions if necessary, according to patient response. If restarting smoking, increase dose to previous smoking dose over 1 week. Monitor the patient closely making further dose adjustments as needed, dependent upon patient response. If a patient starts smoking monitor them closely and increase dose if required, adjusted to patient response. If olanzapine plasma level monitoring is available, it may help to take levels before stopping/starting smoking and repeat them one week after the dose change. Further advice (2) consider dose adjustment be alert for increased adverse effects (such as dizziness, sedation, hypotension) on stopping smoking and reduced efficacy on starting smoking if adverse effects occur, reduce dose by 25%. If smoking is restarted, titrate towards dosage taken while previously smoking monitoring if possible, take plasma levels before changing smoking status, and repeat one week later
Riociguat	Riociguat is mainly metabolised by CYP1A1, 2C8, 2J2, 3A4 and 3A5 plasma concentrations of riociguat are reduced by 50-60% in smokers compared to non-smokers	High	Current smokers should be advised to stop smoking. A dose decrease may be required in patients who stop smoking. A dose increase to the maximum daily dose of 2.5mg three times daily may be required in patients who are smoking or start smoking during treatment. Further advice (2) Consider dose adjustment be alert for increased adverse effects (such as dizziness, headache, nausea, diarrhoea) on stopping, and reduced efficacy on starting smoking if adverse effects occur, reduce the dose the manufacturer notes smokers may need a dose increase to the licensed maximum of 2.5mg three times daily
Chlorpromazine	Chlorpromazine is extensively metabolised in the liver studies indicate clearance of chlorpromazine may be increased in patients who smoke a comparative study found smokers experienced a lower frequency of drowsiness than non-smokers a case report describes a patient experiencing increased sedation and dizziness when they gave up smoking	Moderate	When stopping smoking, monitor patient closely and consider dose reduction. If re-starting smoking, monitor patient closely and consider re-starting previous smoking dose Further advice (2) Consider dose adjustment be alert for increased adverse effects (such as dizziness, sedation, extra-pyramidal symptoms) on stopping smoking and reduced efficacy on starting smoking if adverse effects occur, consider dose reduction. If smoking is restarted, titrate towards dosage taken while previously smoking
Flecainide	In vitro studies have shown CYP1A2 to be involved in the metabolism of flecainide CYP2D6 also appears to be involved. The clearance of flecainide was found to be 50% higher in smokers than in non-smokers. Smokers are likely to require larger doses of flecainide than non-smokers to achieve the same therapeutic effects.	Moderate	If a patient abruptly stops smoking be alert for flecainide adverse effects and be aware that it is likely that the dose of flecainide will need to be reduced. Further advice (2) Consider dose adjustment be alert for dose-related adverse effects (such as dizziness, visual disturbances) on stopping smoking. If adverse effects occur, reduce the dose as necessary
Methadone	Methadone is metabolised in the liver by numerous enzymes including CYP1A2, 2B6 and 3A4 one case report of respiratory insufficiency and altered mental status was reported in a patient taking methadone as an analgesic who stopped smoking	Moderate	If a patient, who takes methadone, stops smoking they should be monitored for signs of methadone toxicity. The dose of methadone should be adjusted accordingly. Further advice (2) Consider dose adjustment be alert for signs of opioid toxicity on stopping smoking, and reduced efficacy on starting smoking if adverse effects occur, reduce the dose as necessary
Warfarin	Warfarin is partly metabolised by CYP1A2 and 2C9 smoking can increase warfarin clearance, leading to reduced warfarin effects and smokers requiring slightly higher doses	Moderate (narrow therapeutic index drug)	Monitoring of smoking status during warfarin therapy is advised. Routine INR monitoring should detect any need for dose adjustments. Be alert for the need to alter warfarin doses in patients who have changed their smoking status. Further advice (2) consider dose adjustment be alert for increased bleeding on stopping smoking, and reduced INR on starting smoking. Individuals should tell their clinicians if they plan to stop or start smoking monitoring routine INR monitoring should detect any need for dose adjustments. Additional INR monitoring would not usually be needed unless appointments are infrequent

when giving smoking cessation advice, be aware of a small number of drugs, in particular aminophylline, theophylline, clozapine, erlotinib, olanzapine and riociguat, which may require dose adjustment or increased monitoring when smoking status is altered
close monitoring of plasma levels (where useful), clinical progress and adverse effect occurrence and severity is essential when patients change their smoking status
patients taking narrow-therapeutic-index drugs should be monitored closely when any lifestyle modification is made
if the affected drug is prescribed under the supervision of a specialist, their input should be sought if the patient changes their smoking status.

Specific interactions with smoking

Further advice with respect to (2):

agomelatine
- consider dose adjustment
  - be alert for increased adverse effects (such as dizziness, sedation, nausea) on stopping smoking and reduced efficacy on starting smoking
  - if adverse effects occur, consider dose reduction
cinacalet
- seek specialist advice
  - smoking status changes are not expected to be clinically significant. However, individuals should inform their specialist if they start or stop smoking
- monitoring and dose adjustment
  - monitor parathyroid hormone levels; adjust dose if needed
clopidogrel
- no routine action
- smoking status changes are not expected to be clinically relevant in most individuals
- some studies suggest an increased antiplatelet effect in smokers, but a clinically significant interaction is not established
fluvoxamine
- consider dose adjustment
  - be alert for dose-related adverse effects (such as nausea, tremor, nystagmus) on stopping smoking, and reduced efficacy on starting smoking
haloperidol
- consider dose adjustment
  - be alert for increased adverse effects (such as drowsiness, extra-pyramidal effects) on stopping smoking, and reduced efficacy on starting smoking
  - if adverse effects occur, reduce dose by 25%. If smoking is restarted, titrate towards dosage taken while previously smoking
melatonin
- consider dose adjustment
  - be alert for dose-related adverse effects (such as drowsiness, headache, dizziness) on stopping smoking, and reduced efficacy on starting smoking
  - adjust dose if necessary
mexiletine
- consider dose adjustment
  - be alert for signs of adverse effects (nausea, tremor, hypertension) on stopping smoking, and reduced efficacy on starting smoking
  - adjust the dose if necessary
pirfenidone
- seek specialist advice
  - plasma levels of pirfenidone are expected to be lower in smokers compared with non-smokers. Individuals are strongly advised to stop smoking before starting treatment
riluzole
- consider dose adjustment
  - be alert for dose-related adverse effects (such as drowsiness, headache, dizziness) on stopping smoking, and reduced efficacy on starting smoking.
  - adjust dose if necessary
ropinirole
- consider dose adjustment
  - be alert for signs of adverse effects (such as nausea, dizziness) on stopping smoking, and reduced efficacy on starting smoking
  - adjust dose if necessary

For full details and guidance regarding these and other medications then see Managing specific interactions with smoking

Reference:

NHS Specialist Pharmacy Service (July 2020). What are the clinically significant drug interactions with tobacco smoking?
NHS Specialist Pharmacy Service (October 2023). Managing specific interactions with smoking

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