Herb-Drug Interactions: Cranberry

Vaccinium macrocarpon Aiton (Ericaceae)

Synonym(s) and related species

Large cranberry (Vaccinium macrocarpon) is the cultivated species.

European cranberry or Mossberry (Vaccinium oxycoccus) has also been used.

Pharmacopoeias

Cranberry Liquid Preparation (The United States Ph 32).

Constituents

The berries contain anthocyanins and proanthocyanidins (mainly oligomers of epicatechin), and organic acids including malic, citric, quinic and benzoic acids.

Note that, although salicylic acid does not appear as a constituent of the juice in many cranberry monographs, some studies have shown low levels of salicylates in commercial cranberry juice (e.g. 7mg/L), which resulted in detectable plasma and urine levels of salicylic acid in women who drank 250 mL of cranberry juice three times daily.

Use and indications

The main use of cranberries and cranberry juice is for the prevention and treatment of urinary tract infections, although they have also been used for blood and digestive disorders. Cranberries are commonly used in food and beverages.

Pharmacokinetics

There is high absorption and excretion of cranberry anthocyanins in human urine, as shown by a study where 11 healthy subjects drank 200 mL of cranberry juice containing 651 micrograms of total anthocyanins. The urinary levels of anthocyanins reached a maximum between 3 and 6 hours, and the recovery of total anthocyanins in the urine over 24 hours was estimated to be 5% of the amount consumed.

Some in vitro and animal studies have suggested that cranberry may affect the cytochrome P450 isoenzymes CYP2C9 (see flurbiprofen,) and CYP3A4 (see nifedipine). However, clinical studies with tizanidine (a substrate of CYP1A2), flurbiprofen (a substrate of CYP2C9), and midazolam (a substrate of CYP3A4) have found no evidence of a significant interaction in humans.

Interactions overview

Clinical studies suggest that cranberry juice and/or extracts do not affect the pharmacokinetics of ciclosporin, flurbiprofen, midazolam, tizanidine and warfarin. Despite this, there have been some case reports of raised INRs and significant bleeding with cranberry and warfarin. Cranberry juice is unlikely to affect the pharmacokinetics of nifedipine to a clinically relevant extent.

Cranberry + Ciclosporin

Occasional consumption of cranberry juice does not appear to affect the bioavailibility of ciclosporin. Regular daily consumption has not been studied.

Evidence, mechanism, importance and management

In a well-controlled, single-dose study, 12 healthy fasted subjects were given a 200-mg dose of oral ciclosporin simultaneously with 240 mL of cranberry juice or water. Cranberry juice was found to have no clinically significant effect on the pharmacokinetics of ciclosporin. In this study, the cranberry juice used was reconstituted from frozen concentrate (Ocean Spray).

This study suggests that cranberry juice does not affect the absorption of ciclosporin, and that drinking the occasional glass of cranberry juice with ciclosporin should not affect ciclosporin levels. However, note that a study of regular daily cranberry juice consumption is required to also rule out an interaction affecting ciclosporin elimination, which may have a bearing on the safety of regular (e.g. daily) intake of cranberry juice with ciclosporin.

Cranberry + Flurbiprofen

Limited evidence suggests that cranberry juice does not appear to affect the pharmacokinetics of flurbiprofen.

Clinical evidence

In a study in 14 healthy subjects, 230mLof cranberry juice taken the night before, and 30 minutes before a single 100-mg dose of flurbiprofen, had no significant effect on the pharmacokinetics of flurbiprofen. Fluconazole, used as a positive control, increased the flurbiprofen AUC by about 80%.’ In this study, the cranberry juice used was Ocean Spray cranberry juice cocktail from concentrate containing 27% cranberry juice.

Experimental evidence

In an in vitro study, cranberry juice inhibited flurbiprofen hydroxylation by about 44%, which was less than that of the positive control sulfaphenazole (79%).

Mechanism

Flurbiprofen is metabolised by the cytochrome P450 isoenzyme CYP2C9, and the clinical study appears to suggest that cranberry has no clinically relevant effect on this particular isoenzyme, despite the fact that it had some weak inhibitory effects in vitro.

Importance and management

Both the study in humans and the supporting experimental metabolic data suggest that no pharmacokinetic interaction occurs between flurbiprofen and cranberry juice. Therefore no dosage adjustment appears to be necessary if patients taking flurbiprofen wish to drink cranberry juice.

Flurbiprofen is used as a probe drug for CYP2C9 activity, and therefore these results also suggest that a pharmacokinetic interaction as a result of this mechanism between cranberry juice and other CYP2C9 substrates is unlikely.

Cranberry + Food

No interactions found. Note that cranberry juice is widely used in food and beverages.

Cranberry + Herbal medicines

No interactions found.

Cranberry + Midazolam

Limited evidence suggests that cranberry juice does not appear to affect the pharmacokinetics of midazolam.

Clinical evidence

In a randomised, crossover study in 10 healthy subjects, 200 mL of cranberry juice three times daily for 10 days had no significant effect on the pharmacokinetics of a single 500-microgram oral dose of midazolam taken on day 5. In this study, the cranberry juice used was a concentrate (Kontiomehu sokeroitu karpalomehu) diluted 1 to 4 with tap water before use.

Experimental evidence

No relevant data found.

Mechanism

This study suggests that cranberry juice has no clinically relevant effect on CYP3A4 activity.

Importance and management

Although the evidence is limited to this particular study, there appears to be no need for special precautions when taking cranberry juice with midazolam.

Midazolam is used as a probe drug for CYP3A4 activity, and therefore these results also suggest that a pharmacokinetic interaction between cranberry juice and other CYP3A4 substrates is unlikely.

Cranberry + Nifedipine

The interaction between cranberry juice and nifedipine is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

In a study in human liver microsomes and rat intestinal microsomes, cranberry juice slightly decreased the cytochrome P450 isoenzyme CYP3A4-mediated metabolism of nifedipine by around 12% to 18%. Similarly, intraduodenal administration of cranberry juice to rats appeared to reduce the apparent clearance and increase the AUC of nifedipine 30mg/kg by 44% and 60%, respectively, when compared with a control group. However, other pharmacokinetic parameters such as the mean residence time, volume of distribution, and elimination rate constant were not significantly affected.

Mechanism

The experimental evidence suggests that cranberry juice may slightly inhibit the cytochrome P450 isoenzyme CYP3A4 in vitro and in rats. However, note that in a clinical study, cranberry had no effect on a single dose of midazolam, a well-established probe CYP3A4 substrate.

Importance and management

Evidence appears to be limited to two experimental studies. Taken on its own, this evidence suggests the possibility of a modest interaction, and therefore some caution might be warranted in patients taking nifedipine who drink cranberry juice. However, a clinical study with midazolam, a sensitive, specific substrate for CYP3A4, found no evidence of an interaction, and this suggests that cranberry juice would be unlikely to affect the pharmacokmetics of nifedipine to a clinically relevant extent.

Cranberry + Tizanidine

Limited evidence suggests that cranberry juice does not appear to affect the pharmacokmetics of tizanidine.

Clinical evidence

In a randomised, crossover study in 10 healthy subjects 200 mL of cranberry juice three times daily for 10 days had no significant effect on the pharmacokmetics of a single 1-mg oral dose of tizanidine taken on day 5. In this study, the cranberry juice used was a concentrate (Kontiomehu sokeroitu karpalomehu) diluted 1 to 4 with tap water before use.

Experimental evidence

No relevant data found.

Mechanism

This study suggests that cranberry juice has no clinically relevant effect on CYP1A2 activity.

Importance and management

Although the evidence is limited to this particular study, there appears to be no need for any special precautions when taking cranberry juice with tizanidine.

Tizanidine is used as a probe drug for CYP1A2 activity, and therefore these results also suggest that a pharmacokinetic interaction between cranberry juice and other CYP1A2 substrates is unlikely.

Cranberry + Warfarin and related drugs

A number of case reports suggest that cranberry juice can increase the INR of patients taking warfarin, and one patient has died as a result of this interaction. Other patients have developed unstable INRs or, in one isolated case, a reduced INR. However, in four controlled studies, cranberry juice did not alter the anticoagulant effect of warfarin, or had only very minor effects on the INR. Neither cranberry juice nor the extract altered warfarin pharmacokinetics.

Clinical evidence

(a) Case reports

In September 2003, the MHRA/CSM in the UK noted that they had received 5 reports suggesting an interaction between warfarin and cranberry juice since 1999 (3 cases of INR increases, one case of unstable INR and one case of a decrease in INR). By October 2004, the MHRA/CSM reported that they had now received 12 reports of a suspected interaction, including 5 additional cases of bleeding episodes and two additional cases of unstable INRs in patients drinking cranberry juice while taking warfarin. The most serious case involved a man taking warfarin whose INR markedly increased (INR greater than 50) 6 weeks after starting to drink cranberry juice. He died from gastrointestinal and pericardial haemorrhages. Further details of this case included that he had recently been treated with cefalexin (not known to interact) for a chest infection, and had been eating virtually nothing for at least 2 weeks, a fact that would have contributed to the increase in anticoagulation.

In a further published case report, a patient stabilised on warfarin was found to have INRs of 10 to 12 in the surgical procedure, although he had no previous record of an INR greater than 4. Vitamin K was given, and heparin was substituted for warfarin. When warfarin was restarted postoperatively, the INR quickly rose to 8 and then to 11 with haematuria, and postoperative bleeding. The patient was drinking almost 2 litres of cranberry juice daily, because of recurrent urinary tract infections, and was advised to stop drinking this. Three days later the INR had stabilised at 3 with no further intervention. Another case of fluctuating INR (between 1 and 10) in a patient taking warfarin has been attributed to cranberry juice.

In the US, a case of major bleeding and a high INR has been reported in a man taking warfarin, which occurred shortly after cranberry juice 710mL daily was started. Another case describes an increase in the INR of a patient receiving warfarin, from below 3 to 6.45, without bleeding, after the patient drank about 2 litres of cranberry/apple juice over the last week. Of note, the patient was subsequently re-stabilised on a lower dose of warfarin and may have taken an extra dose of warfarin in the week before the raised INR was measured.

(b) Controlled studies

In one controlled crossover study, 7 male patients with atrial fibrillation who were taking stable doses of warfarin drank 250 mL of cranberry juice or placebo (daily) for a week without any significant change in their INR from baseline values. The same finding was reported in another very similar study in patients taking warfarin.’ However, note that the daily volume of cranberry juice in these studies was lower than the daily volume in the couple of case reports where cranberry juice intake is known. Nevertheless, in another controlled study in 10 healthy subjects, a higher volume of cranberry juice (200 mL three times daily) for 10 days did not alter the effect of a single 10-mg dose of warfarin (given on day 5) on the maximum thromboplastin time or AUC of the thromboplastin time.In addition, cranberry juice had no effect on warfarin pharmacokinetics, except that there was a slight non-significant 7% decrease in the AUC of S-warfarin.

In yet another study in 12 healthy subjects, cranberry juice concentrate 2 capsules three times daily for 21 days (equivalent to 57 g of fruit daily) had no effect on the maximum INR after a single 25-mg dose of warfarin given on day 15 (2.8 versus 2.6). However, the AUC of the INR was slightly increased by 28%, which was statistically significant, but the clinical relevance of this measure is uncertain. The cranberry concentrate had no effect on platelet aggregation, and had no effect on the pharmacokinetics of either R- or S-warfarin.

Experimental evidence

Because of the quality of the clinical evidence (controlled pharmacokinetic studies), experimental data have not been sought.

Mechanism

Not known. It was originally suggested that one or more of the constituents of cranberry juice might inhibit the metabolism of warfarin by the cytochrome P450 isoenzyme CYP2C9, thereby reducing its clearance from the body and increasing its effects. However, four studies have shown that cranberry juice or cranberry extracts do not alter the pharmacokmetics of warfarin, and cranberry juice had no effect on flurbiprofen pharmacokmetics, a drug used as a surrogate index of CYP2C9 activity. See also flurbiprofen. An interaction might therefore be via a pharmacodynamic mechanism. For example, the salicylate constituent of commercial cranberry juice might cause hypoprothrombinaemia.

Importance and management

An interaction is not established. Controlled studies have not found a pharmacokmetic interaction, and only one of four studies found any evidence for an increase in warfarin effect. Moreover, the clinical relevance of the finding of this study of a 0.2 increase in INR and 28% increase in AUC of the INR is likely to be slight at most, and does not fit with the sometimes marked increase in INR seen in some case reports. This might be explained if the interaction is dose dependent (in one of the cases where cranberry intake was mentioned a quantity of 2 litres daily was being consumed), or if it is product dependent (i.e. due to a constituent present in the cranberry juice that is not standardised for and varies widely). However, it could also be that there is no specific interaction, and that the case reports just represent idiosyncratic reactions in which other unknown factors (e.g. altered diet) were more important.

In 2004, on the basis of the then available case reports and lack of controlled studies, the CSM/MHRA in the UK advised that patients taking warfarin should avoid drinking cranberry juice unless the health benefits are considered to outweigh any risks. They recommended increased INR monitoring for any patient taking warfarin and who has a regular intake of cranberry juice. They also advised similar precautions with other cranberry products (such as capsules or concentrates). These might still be prudent precautions, although the controlled studies now available do provide some reassurance that, in otherwise healthy individuals, moderate doses of cranberry juice are unlikely to have an important impact on anticoagulation control.