chapter
Grapefruit juice
Pages 13

Attributed to ≠ elimination halflife of paracetamol caused by grapefruit juice

Be aware

GRAPEFRUIT JUICE DICLOFENAC Although low doses (1mg/kg) of grapefruit juice did not potentiate the effect of diclofenac, higher doses ≠ anti-inflammatory effect (as assessed by an effect on rat’s paw oedema)

Diclofenac undergoes phenyl hydroxylation catalysed by CYP2C9 and CYP3A4. High dose of grapefruit juice possibly ≠ effects by inhibiting CYP3A4

Be aware as all the effects of diclofenac, including toxic effects, may ≠

GRAPEFRUIT JUICE METHADONE ≠ plasma concentrations and ≠ risk of adverse effects. Interaction is considered to be of rapid onset but of minor clinical significance

Methadone is metabolized by intestinal CYP3A4, which is inhibited by grapefruit juice

Prudent to be aware and warn users and carers

GRAPEFRUIT JUICE MORPHINE Grapefruit juice ≠ morphine antinociception. Gradually ↓ CSF and blood concentrations following repeated treatment with morphine

Grapefruit juice is considered to ≠ intestinal absorption of morphine due to inhibition of P-gp, which also probably contributes to ↓ CSF concentrations

This interaction is unlikely to be of clinical significance, but be aware

GRAPEFRUIT JUICE ANTHELMINTICS

GRAPEFRUIT JUICE ALBENDAZOLE ≠ plasma levels of albendazole by nearly threefold. Risk of toxic effects of albendazole

Albendazole is metabolized by intestinal CYP3A4, which is inhibited by grapefruit juice

Monitor for toxic effects of albendazole

M ISC

ELLA N

EO U

S G

R A

PEFR U

ITJU IC

E721

MISCELLANEOUS GRAPEFRUIT JUICE

threefold). In human liver, maximum concentration ≠ 1.6-fold and AUC 1.9-fold

Possibly via a role of P-gp – inhibition of P-gp may ≠ plasma concentrations

Be aware and watch for toxic effects of praziquantel

GRAPEFRUIT JUICE ANTIARRHYTHMICS

GRAPEFRUIT JUICE AMIODARONE Markedly ≠ plasma concentrations of amiodarone (AUC 50%, maximum concentration 84%). Possibly ↓ effect of amiodarone (↓ in P-R and Q-Tc intervals). This could lead to ↓ therapeutic effect due to ↓ production of active metabolite

Due to inhibition of CYP3A4mediated metabolism of amiodarone by grapefruit juice, which results in near-complete inhibition of the production of N-DEA (desethylamiodarone, the active and major metabolite of amiodarone)

Warn patients to avoid grapefruit juice; if amiodarone becomes less effective, ask the patient about grapefruit juice ingestion

GRAPEFRUIT JUICE AMLODIPINE ≠ plasma amlodipine levels (AUC ≠ by 116%, maximum concentration ≠ by 115%) but no adverse haemodynamic (no changes in PR, heart rate) effects. Unlikely to be clinically significant

There is report of pharmacokinetic interaction between amlodipine and grapefruit in healthy volunteers (maximum concentration and AUC were significantly higher when amlodipine 5 mg was administered with grapefruit compared with water)

Considering the interindividual variation in the pharmacokinetics of amlodipine, the possible interaction between amlodipine and grapefruit juice cannot be negelcted in the clinical setting even though the interaction does not seem to be of great clinical significance in human volunteer studies

GRAPEFRUIT JUICE DISOPYRAMIDE Likely interaction with possibility of ≠ plasma concentrations and toxic effects of disopyramide. However, the clinical significance is not yet known as the interaction has not been scientifically tested

Unclear Monitor ECG and side-effects more closely

with ↓ CYP2D6 activity – poor metabolizers

Propafenone is primarily metabolized by CYP2D6, the secondary metabolic pathways being CYP1A2 and CYP3A4. Lower CYP2D6 levels cause a shift of propafenone metabolism to CYP3A4 isoenzymes, which are inhibited by grapefruit juice

Be aware that there are significant numbers of CYP2D6 poor metabolizers in some communities. Therefore, there is a need to monitor for toxic effects of propafenone at least twice weekly on initiating treatment

GRAPEFRUIT JUICE QUINIDINE Absorption of quinidine is delayed (e.g. from 1.6 to 3.3 hours) by grapefruit juice in a dosedependent manner

Possibly due to effects on intestinal CYP3A4

Be aware

GRAPEFRUIT JUICE TALINOLOL Significant risk of ↓ therapeutic effects

Talinolol is a substrate of P-gp, and less than 1% is metabolized in the liver. However, inhibition by grapefruit juice of an intestinal uptake process other than P-gp is considered likely

Do not co-administer

GRAPEFRUIT JUICE ANTIBIOTICS – CLARITHROMYCIN, ERYTHROMYCIN

Significant delay in onset of action of clarithromycin (≠ from 82 to 148 minutes). ≠ plasma concentrations of erythromycin (maximum concentration ≠, AUC ≠ 1.5-fold)

Due to inhibition of absorption attributed to effect on P-gp

The interaction is unlikely to cause clinically relevant ↓ antimicrobial activity of clarithromycin Telithromycin is unlikely to be affected by grapefruit juice. Be aware

GRAPEFRUIT JUICE ANTICANCER AND IMMUNOMODULATING DRUGS

GRAPEFRUIT JUICE BEXAROTENE Possibly ≠ efficacy and ≠ adverse effects

Possibly via inhibition of intestinal CYP3A4

Clinical significance unknown. Monitor more closely

M ISC

ELLA N

EO U

S G

R A

PEFR U

ITJU IC

E

Mechanism Precautions

M ISC

ELLA N

EO U

S G

R A

PEFR U

ITJU IC

E723

MISCELLANEOUS GRAPEFRUIT JUICE

Due to ↓ metabolism of doxorubicin by CYP3A4 isoenzymes due to inhibition of those enzymes

Monitor for ≠ myelosuppression, peripheral neuropathy, myalgias and fatigue

GRAPEFRUIT JUICE ERLOTINIB Markedly ≠ plasma concentrations of erlotinib (≠ AUC, ≠ maximum concentration). Likely to cause toxic effects of erlotinib

Due to inhibition of metabolism of erlotinib by grapefruit juice as CYP3A4 inhibition is known to result in a 2.1-fold ≠ in erlotinib exposure

Monitor for toxic effects of erlotinib

GRAPEFRUIT JUICE ETOPOSIDE ↓ in plasma concentrations of etoposide (AUC ↓ 1.32-fold). Clinical significance is uncertain. Possibly ↓ efficacy

↓ bioavailability. Unclear Interindividual variability is considerable. Be aware. Advise patients to ↓ intake of foods and beverages containing bioflavonoids. Monitor therapeutic effects closely

GRAPEFRUIT JUICE IFOSFAMIDE ↓ plasma concentrations of 4-hydroxyifosfamide, the active metabolite of ifosfamide, and risk of inadequate therapeutic response

Due to inhibition of the isoenzymatic conversion to active metabolites

Monitor clinically the efficacy of ifosfamide and ≠ dose accordingly

GRAPEFRUIT JUICE IMATINIB Likely interaction. ≠ imatinib levels with ≠ risk of toxicity (e.g. abdominal pain, constipation, dyspnoea) and of neurotoxicity (e.g. taste disturbances, dizziness, headache, paraesthesia, peripheral neuropathy)

Due to inhibition of CYP3A4mediated metabolism of imatinib. Clinical significance is not yet known as the interaction has not been scientifically tested

Monitor for clinical efficacy and for the signs of toxicity listed, along with convulsions, confusion and signs of oedema (including pulmonary oedema). Monitor electrolytes, liver function and for cardiotoxicity

GRAPEFRUIT JUICE IRINOTECAN ≠ plasma concentrations of SN-38 (active metabolite of irinotecan) and ≠ toxicity of irinotecan, e.g. diarrhoea, acute cholinergic syndrome, interstitial pulmonary disease

Due to inhibition of metabolism of irinotecan by CYP3A4 isoenzymes by grapefruit juice

Peripheral blood counts should be checked before each course of treatment. Monitor lung function. Recommendation is to ↓ dose of irinotecan by 25%

Due to effect of grapefruit juice as an inhibitor of CYP3A4

The dose of nilotinib should not exceed 400 mg once daily (a dose ↓ to half the usual daily dose)

GRAPEFRUIT JUICE TAMOXIFEN Likely interaction Due to inhibition of CYP3A4mediated metabolism of tamoxifen. Clinical significance is not yet known as the interaction has not been scientifically tested

Be aware. Advise patients to ↓ intake of foods and beverages containing bioflavonoids

GRAPEFRUIT JUICE VINBLASTINE, VINCRISTINE ≠ adverse effects of vinblastine and vincristine

Inhibition of CYP3A4-mediated metabolism. Also inhibition of intestinal P-gp efflux of vinblastine. Quercetin constituent of grapefruit juice enhances the phosphorylation of P-gp

Advice patients to ↓ intake foods and beverages containing bioflavonoids. Monitor FBC and watch for early features of toxicity (pain, numbness, tingling in the fingers and toes, jaw pain, abdominal pain, constipation, paralytic ileus). Consider selecting an alternative drug

GRAPEFRUIT JUICE TOREMIFENE ≠ plasma concentrations of toremifene

Due to inhibition of metabolism of toremifene by the CYP3A4 isoenzymes by grapefruit juice

Clinical relevance is uncertain. Necessary to monitor for clinical toxicities

GRAPEFRUIT JUICE CICLOSPORIN ≠ plasma concentrations of ciclosporin, with risk of nephrotoxicity, myelosuppression, neurotoxicity, excessive immunosuppression and post-transplant lymphoproliferative disease

Inhibition of CYP3A4-mediated metabolism of ciclosporin; these inhibitors vary in potency. Grapefruit juice is classified as a potent inhibitor

Avoid grapefruit juice while taking ciclosporin

M ISC

ELLA N

EO U

S G

R A

PEFR U

ITJU IC

E

Mechanism Precautions

M ISC

ELLA N

EO U

S G

R A

PEFR U

ITJU IC

E725

MISCELLANEOUS GRAPEFRUIT JUICE

quate response to stress scenarios (e.g. septic shock). However, studies have shown only moderate ≠ plasma concentrations of methylprednisolone and minimal or no changes with prednisolone

Due to inhibition of metabolism of corticosteroids

Monitor cortisol levels and warn patients to report symptoms such as fever and sore throat

GRAPEFRUIT JUICE SIROLIMUS, TACROLIMUS Possibly ≠ efficacy and ≠ adverse effects of sirolimus

Possibly ≠ bioavailability via inhibition of intestinal CYP3A4 and effects of P-gp

Avoid concomitant use

GRAPEFRUIT JUICE ANTICOAGULANTS – ORAL ≠ efficacy and ≠ adverse effects of warfarin, e.g. ≠ INR, haemorrhage

Unclear. Possibly via inhibition of intestinal CYP3A4

Monitor INR more closely. Avoid concomitant use if unstable INR

GRAPEFRUIT JUICE ANTIDEPRESSANTS

GRAPEFRUIT JUICE FLUVOXAMINE, SERTRALINE

Possibly ≠ efficacy and ≠ adverse effects due to ≠ plasma concentrations

Possibly ↓ metabolism Clinical significance unclear

GRAPEFRUIT JUICE CLOMIPRAMINE ≠ risk of clomipramine toxicity. Not known whether ≠ plasma concentration is sustained

Clomipramine metabolism involves several CYP isoenzymes (e.g. CYP1A2, CYP3A4, ↓ CYP2D6)

Be aware

GRAPEFRUIT JUICE ANTIDIABETIC DRUGS – REPAGLINIDE

Possibly ≠ repaglinide levels Due to inhibition of CYP3A4 isoenzymes, which metabolize repaglinide

Uncertain if clinically significant. May need to monitor blood glucose more closely

maximum concentration ≠), which is of clinical significance because of the narrow therapeutic index of carbamazepine; thus, toxic effects are likely. ≠ efficacy and ≠ adverse effects

Grapefruit juice irreversibly inhibits intestinal CYP3A4. Transport via P-gp and MRP-2 efflux pumps is also inhibited

Monitor for ≠ side-effects/toxicity and check carbamazepine levels weekly. If levels or control of fits are variable, remove grapefruit and grapefruit juice from the diet

GRAPEFRUIT JUICE ANTIFUNGALS

GRAPEFRUIT JUICE ITRACONAZOLE Co-administration of grapefruit juice ↓ AUC and maximum concentration of itraconazole by 47% and 35% respectively

↓ absorption, possibly by inhibition of intestinal CYP3A4, affecting P-gp or lowering duodenal pH. Effect appears to be greater in females

Clinical significance is unknown. The effect of the interaction may vary between capsules and oral liquid preparations

GRAPEFRUIT JUICE IVABRADINE ≠ levels with grapefruit juice Uncertain Avoid co-administration GRAPEFRUIT JUICE ANTIHISTAMINES/ANTI-ALLERGY DRUGS

GRAPEFRUIT JUICE ASTEMIZOLE Likely ≠ in cardiotoxicity. Likely ≠ in Q-Tc interval

Due to effects of grapefruit juice grapefruit juice on CYP isoenzymes and P-gp

Do not co-administer as there are suitable alternatives that are less harmful, e.g. loratidine, cetrizine, desloratidine

GRAPEFRUIT JUICE FEXOFENADINE ↓ plasma concentrations of fexofenadine (AUC 2.7-fold, maximum concentration 2.1-fold). Risk of lack of therapeutic effects. Possibly ↓ efficacy

↓ absorption, possibly by affecting P-gp and direct inhibition of uptake by intestinal OATP1A2

Clinical significance unclear. No clinically significant changes in ECG parameters were observed in the study. Suitable alternatives are available

GRAPEFRUIT JUICE RUPATADINE ≠ risk of cardiac toxicity due to threefold ≠ plasma concentrations of rupatadine

Due to effects of grapefruit juice on CYP isoenzymes and P-gp

Do not co-administer as there are suitable alternatives that are less harmful, e.g. loratidine, cetrizine, desloratidine

M ISC

ELLA N

EO U

S G

R A

PEFR U

ITJU IC

E

Mechanism Precautions

M ISC

ELLA N

EO U

S G

R A

PEFR U

ITJU IC

E727

MISCELLANEOUS GRAPEFRUIT JUICE

maximum concentration and T max. Two-fold ≠ half-life. Possibly ≠ efficacy and ≠ adverse effects, e.g. torsade de pointes

Altered metabolism so the parent drug accumulates. Due to effects of grapefruit juice on CYP isoenzymes and P-gp

Avoid concomitant intake. Suitable alternatives that are less harmful are available, e.g. loratidine (which is also metabolized by CYP2D6), cetrizine, desloratidine. This is despite a report that no significant cardiotoxicity is likely in normal subjects

GRAPEFRUIT JUICE ANTIMALARIALS

GRAPEFRUIT JUICE ARTEMETHER (WITH LUMEFANTRINE)

≠ plasma concentrations of artemether (AUC by 2.5-fold, maximum concentration twofold. There were no signs of bradycardia or evidence of Q-Tc prolongation

Very likely to be due to inhibition of intestinal CYP3A4 by grapefruit juice, which suggests a role for the presystemic metabolism of artemether

Monitor more closely. No ECG changes were seen in the study. Be aware

GRAPEFRUIT JUICE CHLOROQUINE ≠ plasma concentrations of chloroquine (AUC ≠ 1.3-fold, ≠ maximum concentration). The interaction has not been studied in patients with malaria

Due to inhibition of metabolism of chloroquine

Be aware

GRAPEFRUIT JUICE HALOFANTRINE Markedly ≠ plasma concentrations of halofantrine (AUC ≠ 2.8-fold, maximum concentration ≠ 3.2-fold). Maximum Q-Tc prolongation was ≠ from 17 msec to 31 msec, thus giving a risk of cardiotoxicity

Due to inhibition of metabolism of CYP3A4-mediated metabolism of halofantrine

Do not co-administer because of Q-Tc interval prolongation effects

GRAPEFRUIT JUICE QUININE Report of ↓ heart rate and PR that returned to normal 4-6 hours after intake of quinine. Not considered to be clinically significant

Due to inhibition of metabolism of CYP3A4-mediated metabolism. However, metabolism of quinine is predominantly hepatic and thus unaffected by grapefruit juice

Be aware

≠ heart rate

Unclear Monitor PR and BP

GRAPEFRUIT JUICE ANTIPSYCHOTICS – PIMOZIDE

Possibly ≠ efficacy and ≠ adverse effects. Interaction may occur rapidly, but clinical significance is uncertain

Not evaluated in clinical trials Avoid concomitant use. No interaction was observed with haloperidol

GRAPEFRUIT JUICE ANTIVIRALS

GRAPEFRUIT JUICE EFAVIRENZ Possibly ≠ efficacy and ≠ adverse effects

Unclear Monitor more closely

GRAPEFRUIT JUICE SAQUINAVIR (Invirase hard capsules)

Possibly ≠ efficacy with oral (and not when administered intravenous) preparations. The AUC of oral saquinavir ≠ by 50%, but maximum concentration, T max and terminal half-life were not significantly altered in one study

Possibly ≠ bioavailability; ↓ presystemic metabolism. Constituents of grapefruit juice and grapefruit irreversibly inhibit intestinal cytochrome CYP3A4. Transport via P-gp and MRP-2 efflux pumps is also inhibited

No dose adjustment is advised. Oral bioavailability is very low and is enhanced beneficially with grapefruit juice or grapefruit. Soft gel capsules have greater bioavailability so may interact to a lesser degree. No dose adjustments are recommended by manufacturers for indinavir

GRAPEFRUIT JUICE ANXIOLYTICS AND HYPNOTICS

GRAPEFRUIT JUICE BUSPIRONE-ORAL Significant ≠ pharmacodynamic effects. AUC ≠ 9.2-fold and maximum concentration 4.3-fold, with ≠ in T max. Possibly ≠ efficacy and ≠ adverse effects, e.g. sedation, CNS depression

Possibly ≠ bioavailability; ↓ presystemic metabolism. Constituents of grapefruit juice irreversibly inhibit intestinal cytochrome CYP3A4. Transport via P-gp and MRP-2 efflux pumps is also inhibited

Avoid concomitant use. Be particularly vigilant in elderly patients or those with impaired liver function. Consider an alternative, e.g. temazepam

M ISC

ELLA N

EO U

S G

R A

PEFR U

ITJU IC

E

Mechanism Precautions

M ISC

ELLA N

EO U

S G

R A

PEFR U

ITJU IC

E729

MISCELLANEOUS GRAPEFRUIT JUICE

DIAZEPAM ALPRAZOLAM

maximum concentration with triazolam that was accompanied by a ≠ in reaching peak effects (from 1.6 to 2.5 hours). There is ≠ AUC, maximum concentration and T max of quazepam and its active metabolite 2-oxoquazepam. No change is seen in psychomotor function with alprazolam, while with diazepam there was ≠ maximum concentration. With midazolam, there was minor ≠ reaction time (and minor ≠ digital symbol substitution test results)

With alprazolam, due to its inherent high bioavailability, grapefruit juice is unlikely to produce a significant change, in contrast to midazolam and triazolam. There is less contribution to presystemic metabolism by intestinal CYP3A4 for alprazolam. Grapefruit juice caused ↓ CYP3A12 activity in the liver and ≠ CYP3A12 activity in the intestine when tested with diazepam. This was attributed to the bergamotton constituent of grapefruit juice

Alprazolam is probably the BZD least affected by grapefruit juice, although many consider that the effect of grapefruit juice on midazolam is unlikely to be clinically important with 300 mL of juice. ≠ plasma concentrations of diazepam are considered to be clinically insignificant – be aware of impaired cognition

GRAPEFRUIT JUICE BETA-BLOCKERS – CELIPROLOL (not available in USA)

Very likely to be ineffective therapeutically due to a great ↓ plasma concentrations (AUC ↓ by 85% and maximum concentration by 95%)

Attributed mainly to marked ↓ absorption. This may be due to physicochemical factors or due to an inhibition of drug uptake transporters

Do not co-administer

GRAPEFRUIT JUICE BRONCHODILATORS – THEOPHYLLINES

Possibly ↓ efficacy Unclear. ↓ bio-availability (significant from 1 to 4 hours)

Avoid concomitant intake if slowrelease theophylline preparations are used. Monitor levels and clinical state weekly if intake of grapefruit is altered

BLOCKERS

≠ bioavailability of felodipine and nisoldipine (with reports of adverse effects), and ≠ bioavailability of isradipine, lacidipine, lercanidipine, nicardipine, nifedipine, nimodipine (threefold ≠ bioavailability) and verapamil (without reported adverse clinical effects)

Postulated that flavonoids in grapefruit juice (and possibly Seville oranges and limes), inhibit intestinal (but not hepatic) CYP3A4. Further grapefruit juice limits apical to basal transport by P-gp and MRP-2, which limits drug excretion of and ≠ bioavailability of drugs, e.g. verapamil, nimodipine

Be aware. Avoid concurrent use of felodipine, nimodipine or nisoldipine and grapefruit juice. However, there is considerable interindividual variation, and if concomitant use is necessary, be aware of interaction, the severity of which may vary between drugs

GRAPEFRUIT JUICE AZELNIDIPINE ≠ in plasma concentrations of azelnidipine 2.5-fold, and ≠ AUC 3.3-fold. Risk of azelnidipine toxicity

Azelnidipine is metabolized by CYP3A4 isoenzymes in the intestinal wall, and this metabolism is inhibited by grapefruit juice

GRAPEFRUIT JUICE CANDESARTAN, EPROSARTAN, TELMISARTAN, VALSARTAN

Likely interaction. Clinical significance is uncertain and not confirmed by scientific testing

These angiotensin II receptor blockers have low bioavailability, attributed to P-gp, which is inhibited by grapefruit juice. Thus ≠ bioavailability is likely

Be aware

GRAPEFRUIT JUICE CARDIAC GLYCOSIDES – DIGOXIN

Possible ≠ efficacy and ≠ adverse effects

Possibly via altered absorption Most patients were unaffected. Consider if unexpected bradycardia or heart block with digoxin. Rationale is based on the theoretical concept that digoxin is a substrate of P-gp

GRAPEFRUIT JUICE CISAPRIDE ≠ plasma concentrations and likely ≠ risk of adverse effects ( e.g. cardiotoxicity, Q-T prolongation, torsade de pointes)

≠ oral bioavailability and slight but significant ≠ elimination half-life

Although a study in volunteers did not show any changes in heart rate, PR or Q-T prolongation, avoid concurrent use

M ISC

ELLA N

EO U

S G

R A

PEFR U

ITJU IC

E

Mechanism Precautions

M ISC

ELLA N

EO U

S G

R A

PEFR U

ITJU IC

E731

MISCELLANEOUS GRAPEFRUIT JUICE

≠ gangrene

Oral administration only. ≠ bioavailability; ↓ presystemic metabolism. Constituents of grapefruit juice and grapefruit irreversibly inhibit intestinal cytochrome CYP3A4. Transport via P-gp and MRP-2 efflux pumps is also inhibited

Monitor for ≠ side-effects; stop intake of grapefruit preparations if side-effects occur

GRAPEFRUIT JUICE 5-HT1 AGONISTS – ALMOTRIPTAN, ELETRIPTAN

≠ plasma concentrations of almotriptan and eletriptan, with risk of toxic effects, e.g. flushing, sensations of tingling, heat, heaviness, pressure or tightness of any part of body including the throat and chest, dizziness

Almotriptan and eletriptan are metabolized mainly by CYP3A4 isoenzymes. Most CYP isoenzymes are inhibited by grapefruit juice to varying degrees, and since there is an alternative pathway of metabolism by MAOA, toxicity responses vary between individuals

The CSM has advised that if chest tightness or pressure is intense, the triptan should be discontinued immediately and the patient investigated for ischaemic heart disease by measuring cardiac enzymes and doing an ECG. Avoid concomitant use in patients with coronary artery disease and in those with severe or uncontrolled hypertension

GRAPEFRUIT JUICE LIPID-LOWERING DRUGS – ATORVASTATIN, SIMVASTATIN

Grapefruit juice ≠ plasma levels of simvastatin 16-fold, and the 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibition was also ≠. ≠ levels with simvastatin, and a slight rise with atorvastatin. ≠ risk of adverse effects such as myopathy. Threefold ≠ AUC for atorvastatin and atorvastatin lactone

Constituent of grapefruit juice inhibits CYP3A4-mediated metabolism of simvastatin and atorvastatin. CYP3A4 plays only a minor role in the metabolism of fluvastatin

Patients taking simvastatin and atorvastatin should avoid grapefruit juice. Use an alternative statin not influenced by CYP3A4 activity, e.g. rosuvastatin

Grapefruit juice inhibits the formation of cotinine from nicotine, ≠ renal clearance of cotinine and ↓ plasma concentrations of cotinine by 15%

Be aware in patients using varying forms of nicotine replacement therapy for stopping smoking

GRAPEFRUIT JUICE OESTROGENS – ESTRADIOL, POSSIBLY ETHINYLESTRADIOL

≠ efficacy and ≠ adverse effects Oral administration only. ≠ bioavailability; ↓ presystemic metabolism. Constituents of grapefruit juice and grapefruit irreversibly inhibit intestinal cytochrome CYP3A4. Transport via P-gp and MRP-2 efflux pumps is also inhibited

Monitor for ≠ side-effects

GRAPEFRUIT JUICE PHOSPHODIESTERASE TYPE 5 INHIBITORS (e.g. sidenafil, tadalafil, vardenafil)

Possibly ≠ efficacy and ≠ adverse effects, e.g. hypotension

Small ≠ bioavailability. ≠ variability in pharmacokinetics, i.e. interindividual variations in metabolism

Safest to advise against intake of grapefruit juice for at least 48 hours prior to intending to take any of these preparations. When necessary, the starting dose of sildenafil should not exceed 25-50 mg and that of tadalafil 10 mg. Avoid co-administration with vardenafil

M ISC

ELLA N

EO U

S G

R A

PEFR U

ITJU IC

E

Mechanism Precautions