Ultra MFP by Douglas Laboratories

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Diabetes. Preliminary clinical research in adults with type 2 diabetes shows that taking an Artemisia herba-alba water extract modestly reduces fasting and postprandial blood sugar when compared with baseline (15075,15077).
• Intestinal parasite infection. A report of 8 adults and 2 children with pinworm infections suggests that taking an Artemisia herba-alba water extract might reduce symptoms and increase the cure rate after 3 days of treatment (15076). The validity of these findings is limited by the lack of a comparator group. More evidence is needed to rate Artemisia herba-alba for these uses.

(Read more about ARTEMISIA HERBA-ALBA)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Although there is interest in using topical burdock for acne, there is insufficient reliable information about the clinical effects of burdock for this purpose.
• Aging skin. It is unclear if topical burdock is beneficial for reducing wrinkles. Details: A very small study in females aged 39-65 years shows that applying an emulsion containing burdock fruit extract 1.2% to the face twice daily for 4 weeks slightly reduces skin wrinkles around the eyes when compared with placebo (37420).
• Atopic dermatitis (eczema). Although there is interest in using topical burdock for eczema, there is insufficient reliable information about the clinical effects of burdock for this condition.
• Breast cancer. Oral burdock root has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Population research in breast cancer patients has found that using a specific product containing burdock root, sheep sorrel, slippery elm bark, and Indian rhubarb (Essiac, Resperin Canada Limited) is not associated with improved quality of life when compared with no intervention (37419).
• Common cold. Although there is interest in using oral burdock for symptoms of the common cold, there is insufficient reliable information about the clinical effects of burdock for this condition.
• Diabetes. Although there is interest in using oral burdock for diabetes, there is insufficient reliable information about the clinical effects of burdock for this condition.
• Diverticulitis. It is unclear if oral burdock is beneficial in patients with diverticulitis. Details: A small open-label clinical study in patients with colonic diverticulitis shows that taking burdock tea (Ajikan, Co., Ltd.) providing 1.5 grams three times daily for a median of 26 months is associated with an acute diverticulitis recurrence rate of 11%, compared with 32% of those not taking burdock tea. Furthermore, the recurrence-free duration was increased by about 14 months. However, taking burdock tea for a median of 16 months does not prevent colonic diverticular bleeding recurrence (102696).
• Dry skin. Although there is interest in using topical burdock for dry skin, there is insufficient reliable information about the clinical effects of burdock for this purpose.
• Gout. Although there is interest in using oral burdock for gout, there is insufficient reliable information about the clinical effects of burdock for this condition.
• Hepatitis. Although there is interest in using oral burdock for hepatitis, there is insufficient reliable information about the clinical effects of burdock for this condition.
• Metabolic syndrome. It is unclear if oral burdock is beneficial in patients with metabolic syndrome. Details: A very small clinical study in patients with metabolic syndrome shows that drinking burdock extract 100 mL three times daily after meals for 16 weeks does not reduce body weight, abdominal fat, blood pressure, lipid levels, or glucose when compared with baseline or control (105667).
• Obesity. Although there is interest in using oral burdock for obesity, there is insufficient reliable information about the clinical effects of burdock for this condition.
• Urinary tract infections (UTIs). Although there is interest in using oral burdock for UTI, there is insufficient reliable information about the clinical effects of burdock for this condition.
• Vaginitis. Topical burdock has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Observational research in adults and children with vaginitis has found that applying a specific solution containing burdock, chamomile, and aloe (Zelesse, ITF Research Pharma S.L.U., Alcobendas) to the vaginal area once or twice daily for 5-20 days is associated with moderate improvements in symptoms such as pruritus, erythema, and discharge when compared with baseline (102695,102697). The validity of this finding is limited by its observational nature and the lack of a control group. More evidence is needed to rate burdock for these uses.

(Read more about BURDOCK)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Although there has been interest in using topical grapefruit oil for acne, there is insufficient reliable information about the clinical effects of grapefruit for this purpose.
• Asthma. It is unclear if oral grapefruit is beneficial in patients with asthma. Details: There is some evidence that consumption of vitamin C-rich citrus fruits, including grapefruit and others, might improve lung function in people with asthma. Intake of citrus fruits 1-2 times weekly has produced this benefit in some studies (6049,6055,6056). However, other studies have shown no benefit (6057,6058).
• Atherosclerosis. Although there has been interest in using oral grapefruit to treat or prevent atherosclerosis, there is insufficient reliable information about the clinical effects of grapefruit for this purpose.
• Atopic dermatitis (eczema). It is unclear if oral grapefruit seed extract is beneficial in patients with atopic dermatitis. Details: One small, uncontrolled clinical study in patients with atopic dermatitis shows that taking a specific grapefruit seed extract product (ParaMicrocidin, Allergy Research Group) 150 mg three times daily for one month can decrease complaints of constipation, flatulence, and abdominal discomfort, possibly due to changes in intestinal microflora (5866). The validity of these findings is limited by a lack of control group.
• Depression. Although there has been interest in using inhaled grapefruit oil as aromatherapy for depression, there is insufficient reliable information about the clinical effects of grapefruit oil for this purpose.
• Gingivitis. Although there has been interest in using topical grapefruit oil as a rinse for gingivitis, there is insufficient reliable information about the clinical effects of grapefruit oil for this purpose.
• Headache. Although there has been interest in using inhaled grapefruit oil as aromatherapy for headache, there is insufficient reliable information about the clinical effects of grapefruit oil for this purpose.
• Hypercholesterolemia. It is unclear if oral grapefruit is beneficial in patients with hypercholesterolemia. Details: One small clinical study in patients with hypercholesterolemia shows that taking capsules containing grapefruit pectin 5 grams three times daily for 16 weeks decreases total cholesterol by 8% and the ratio of low-density lipoprotein (LDL) to high-density lipoprotein (HDL) cholesterol by 10% when compared to baseline (2216). The validity of these findings is limited by the lack of a comparator group.
• Hypertriglyceridemia. It is unclear if oral grapefruit is beneficial in patients with hypertriglyceridemia. Details: One small clinical study in patients with hypertriglyceridemia that is not well controlled on statin therapy shows that consuming one red or white grapefruit daily for 30 days reduces total cholesterol by 8% to 15.5% and low-density lipoprotein (LDL) cholesterol by 11% to 20% when compared with placebo. In addition, consuming one red, but not one white, grapefruit daily reduces triglyceride levels by 17% when compared with placebo in these patients (53352).
• Intestinal parasite infection. Although there has been interest in using oral grapefruit seed extract for intestinal parasite infections, there is insufficient reliable information about the clinical effects of grapefruit for this purpose.
• Lice. It is unclear if topical grapefruit extract is beneficial in children with head lice. Details: One small clinical study in children aged 2-9 years with head lice shows that applying 50 mL of a specific shampoo containing grapefruit extract (Licatack shampoo) to the hair for 10-20 minutes and then rinsing with water and combing can eliminate adult lice. Applying a second application after 10 days seems to help remove any remaining nits (91417). The validity of these findings is limited by a lack of control group.
• Obesity. While some small studies suggest that oral grapefruit extract, taken in combination with other citrus extracts, may modestly improve weight loss, the effect of oral grapefruit alone is unclear. Details: One small clinical study in obese adults shows that consuming one and a half fresh grapefruits daily for 12 weeks reduces body weight by 1.3 kg when compared with placebo. Also, although drinking 8 ounces of grapefruit juice or taking grapefruit capsules three times daily for 12 weeks did not improve body weight when compared with placebo in the overall study population, a sub-group analysis of obese adults with metabolic syndrome shows that taking grapefruit capsules or drinking grapefruit juice increases weight loss and improves insulin resistance when compared with placebo (53353). Grapefruit has also been evaluated in combination with other citrus ingredients. Two clinical studies shows that taking a specific combination product (Sinetrol, Fytexia) containing sweet orange, blood orange, and grapefruit extracts for 12 weeks can decrease body weight, body fat percentage, and body mass index (BMI) in otherwise healthy overweight adults (95517,95518). In one study, taking this supplement as 450 mg twice daily for 12 weeks reduced body weight by 1 kg and body fat percentage by 6.5% when compared with placebo. Hip circumference, waist circumference, and blood glucose were also reduced when compared with placebo (95518). In another study, taking this same supplement as 700 mg twice daily for 12 weeks reduced body weight by 5.6 kg, body fat percentage by 5%, and BMI by 2% when compared to baseline. Patients taking placebo experienced no significant improvements from baseline (95517). It is not clear if these effects are due to grapefruit extract, other ingredients, or the combination.
• Pharyngitis. Although there has been interest in using topical grapefruit oil as a gargle for pharyngitis, there is insufficient reliable information about the clinical effects of grapefruit oil for this purpose.
• Psoriasis. Although there has been interest in using oral grapefruit for psoriasis, there is insufficient reliable information about the clinical effects of grapefruit for this purpose.
• Stress. Although there has been interest in using inhaled grapefruit oil as aromatherapy for stress, there is insufficient reliable information about the clinical effects of grapefruit oil for this purpose.
• Upper respiratory tract infection (URTI). Although there has been interest in using grapefruit oil as aromatherapy for various upper respiratory tract infections, including influenza and the common cold, there is insufficient reliable information about the clinical effects of grapefruit oil for these conditions.
• Vaginal candidiasis. Although there has been interest in using oral and topical grapefruit seed extract for vaginal candidiasis, there is insufficient reliable information about the clinical effects of grapefruit seed extract for this purpose. More evidence is needed to rate grapefruit for these uses.

(Read more about GRAPEFRUIT)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Diabetic nephropathy. Preliminary clinical research shows that taking a specific combination tablet containing lovage root, centaury herb, and rosemary leaf (Canephron N, Bionorica), as two tablets three times daily for 6 months in conjunction with antidiabetes medication and enalapril 20 mg daily, reduces microalbuminuria by 73% and the albumin to creatinine ratio by 46%, increases high-density lipoprotein (HDL) cholesterol by 25%, and lowers triglyceride levels by 43% when compared to baseline. These improvements are greater than those observed for patients treated with antidiabetes medications and enalapril alone (91726). More evidence is needed to rate lovage for this use.

(Read more about LOVAGE)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Dyspepsia. Oral olive leaf extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small study in healthy adults shows that taking a specific combination product containing olive leaf extract 24% and prickly pear cactus 33% (Mucosave, Bionap S.R.L.) 400 mg daily for 8 weeks seems to improve dyspepsia and other gastrointestinal symptoms when compared with placebo (105904). It is unclear if this benefit would occur in patients with clinically diagnosed dyspepsia.
• Exercise-induced respiratory infections. It is unclear if oral olive leaf extract is beneficial for reducing respiratory infections from exercise. Details: A small clinical study in high school athletes shows that taking one tablet of olive leaf extract providing eleuropein 100 mg daily for 2 months during training season does not reduce the incidence of the common cold when compared with placebo. While it may reduce the number of sick days by 28%, a sub-group analysis suggests that this reduction is only evident in female athletes (101860).
• Gastroesophageal reflux disease (GERD). Although there is interest in using oral olive leaf for GERD, there is insufficient reliable information about the clinical effects of olive for this condition.
• Herpes zoster (shingles). Although there is interest in using oral olive leaf for shingles, there is insufficient reliable information about the clinical effects of olive for this condition.
• Influenza. Although there is interest in using oral olive leaf for influenza, there is insufficient reliable information about the clinical effects of olive for this condition.
• Metabolic syndrome. It is unclear if oral olive leaf extract is beneficial for improving body composition and cardiovascular risk factors in patients with metabolic syndrome. Details: A small clinical trial in overweight, middle-aged males at risk for metabolic syndrome shows that taking four capsules of olive leaf extract providing oleuropein 51.1 mg and hydroxytyrosol 9.7 mg daily for 12 weeks improves insulin sensitivity by 15% when compared with placebo. However, body composition, blood pressure, cholesterol levels, and other cardiovascular risk factors were not improved (92245).
• Osteoarthritis. It is unclear if oral olive fruit or leaf extract is beneficial for improving osteoarthritis. Details: Preliminary clinical research shows that taking a freeze-dried aqueous extract of olive fruit 400 mg daily for 8 weeks decreases pain and increases mobility in people with osteoarthritis (14844). Other preliminary clinical research in adults with knee osteoarthritis shows that taking olive leaf extract 50.1 mg daily for 4 weeks improves overall pain measurements by 14%, compared to only 4% in the placebo group. However, many individual measurements of pain are not improved (92252).
• Osteoporosis. It is unclear if oral olive leaf extract is beneficial for osteoporosis. Details: Clinical research shows that taking olive leaf extract (Bonolive, BioActor BV) 250 mg daily for 12 months, along with elemental calcium 400 mg daily, increases osteocalcin levels by about 32% when compared to baseline; this increase was significant when compared to those taking calcium 400 mg plus placebo, who showed a 6% decrease in osteocalcin levels. However, taking olive leaf extract does not significantly increase bone mineral density of the lumbar spine or femur neck when compared with placebo (92247).
• Rheumatoid arthritis (RA). It is unclear if oral olive fruit extract is beneficial for improving RA symptoms. Details: Preliminary clinical research in adults with RA shows that taking an aqueous freeze-dried extract of olive fruit 400 mg daily for 8 weeks does not improve symptoms when compared with control (14844). More evidence is needed to rate the effectiveness of olive for these uses.

(Read more about OLIVE)

There is insufficient reliable information available about the safety of Artemisia herba-alba.

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.

(Read more about ARTEMISIA HERBA-ALBA)

LIKELY SAFE ...when used in amounts commonly found in foods (12659,12660). Burdock root is commonly eaten as a vegetable (37422,92153,92154)

POSSIBLY SAFE ...when used topically, short-term. An emulsion containing burdock fruit extract 1.2% has been safely applied to the face twice daily for 4 weeks (37420). There is insufficient reliable information available about the safety of burdock when used orally in supplemental doses.

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.

(Read more about BURDOCK)

LIKELY SAFE ...when used orally in amounts commonly found in foods. Grapefruit has Generally Recognized as Safe status (GRAS) in the US (4912).

POSSIBLY SAFE ...when used orally and appropriately for medicinal purposes. A grapefruit seed extract has been safely used in clinical research (5866). In addition, capsules containing grapefruit pectin 15 grams daily have been used in clinical research for up to 16 weeks (2216).

POSSIBLY UNSAFE ...when used orally in excessive amounts. Preliminary population research shows that consuming a quarter or more of a whole grapefruit daily is associated with a 25% to 30% increased risk of postmenopausal breast cancer (14858). Grapefruit juice is thought to reduce estrogen metabolism resulting in increased endogenous estrogen levels. More evidence is needed to validate this finding.

PREGNANCY AND LACTATION:
There is insufficient reliable information available about the safety of using medicinal amounts of grapefruit during pregnancy and lactation; avoid using.

(Read more about GRAPEFRUIT)

LIKELY SAFE ...when used orally in amounts commonly found in foods. Lovage has Generally Recognized As Safe status (GRAS) for use in foods in the US (4912).

POSSIBLY SAFE ...when used orally and appropriately, short-term (12). Lovage root 36 mg daily, in combination with centaury and rosemary (Canephron N, Bionorica), has been used with apparent safety for 6 months (91726).

PREGNANCY: LIKELY UNSAFE
when used orally; lovage is reported to have uterine and menstrual stimulant effects (12).

LACTATION:
Insufficient reliable information available; avoid using.

(Read more about LOVAGE)

LIKELY SAFE ...when olive fruit is used orally and appropriately in amounts commonly found in foods.

POSSIBLY SAFE ...when olive leaf extract is used orally and appropriately. Olive leaf extract providing 51-100 mg oleuropein daily has been used with apparent safety for 6-8 weeks (92245,92247,101860). There is insufficient reliable information available about the safety of olive fruit extract when used in amounts greater than those found in foods.

PREGNANCY AND LACTATION:
Insufficient reliable information available; stick with amounts commonly found in foods.

(Read more about OLIVE)

(Read more about ARTEMISIA HERBA-ALBA)

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking burdock with anticoagulant or antiplatelet drugs might increase the risk of bleeding.  Details In vitro research shows that lignans from burdock reduce rabbit platelet aggregation by inhibiting platelet activating factor (12619). This interaction has not been reported in humans.

(Read more about BURDOCK)

ACEBUTOLOL (Sectral) Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Possible •  Level of Evidence = B Grapefruit juice can decrease blood levels of acebutolol, potentially decreasing the clinical effects of acebutolol.  Details Clinical research shows that grapefruit juice can modestly decrease acebutolol levels by 7% and reduce peak plasma concentration by 19% by inhibiting organic anion transporting polypeptide (OATP) (17603,18101). The acebutolol half-life is also extended by 1.1 hours when grapefruit juice is consumed concomitantly (18101). Grapefruit juice is thought to affect OATP for only a short time. Therefore, separating drug administration and consumption of grapefruit by at least 4 hours is likely to prevent this interaction (17603,17604).

ALISKIREN (Tekturna, Rasilez) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Grapefruit juice can decrease blood levels of aliskiren, potentially decreasing the clinical effects of aliskiren.  Details Clinical research shows that grapefruit juice can decrease aliskiren levels by approximately 60% by inhibiting organic anion transporting polypeptide (OATP) (91428). Grapefruit juice is thought to affect OATP for only a short time. Therefore, separating drug administration and consumption of grapefruit by at least 4 hours is likely to prevent this interaction (17603,17604).

AMIODARONE (Cordarone) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of amiodarone, potentially increasing the effects and adverse effects of amiodarone.  Details Clinical research shows that grapefruit juice inhibits metabolism and increases absorption of amiodarone. Grapefruit juice increases amiodarone plasma levels by 50% and peak concentration by 84% (17601,17672,22120).

AMPRENAVIR (Agenerase) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Grapefruit juice might decrease blood levels of amprenavir, although this is not likely to be clinically significant.  Details Some clinical research shows that grapefruit juice can slightly decrease amprenavir levels (17673); however, this is probably not clinically significant.

ARTEMETHER (Artenam, Paluther) Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B Grapefruit juice can increase blood levels of oral artemether, potentially increasing the effects and adverse effects of artemether.  Details Clinical research shows that grapefruit juice increases the levels of oral artemether by 90% to 250% in healthy males (5065,5066).

BENZODIAZEPINES Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = B Grapefruit juice might increase blood levels of some oral benzodiazepines, potentially increasing the effects and adverse effects of these drugs.  Details Clinical research shows that grapefruit juice can increase plasma triazolam concentrations. Repeated consumption of grapefruit juice greatly increases triazolam concentrations and prolongs the half-life, probably due to inhibition of cytochrome P450 3A4 (CYP3A4) (7776,22118,22131,22133). Some studies show that grapefruit juice, particularly when taken in large quantities, reduces the clearance and increases the maximum blood levels, area under the plasma concentration curve (AUC), and duration of effect of midazolam. However, there is no effect on intravenous midazolam (4300,10159,11275,17601,22117,22119,16711,91427,95978). Grapefruit juice has also been shown to increase the maximum blood levels and duration of effect of diazepam, but the clinical significance of this is not known (3228). This interaction does not appear to occur with alprazolam (17674).

BLONANSERIN (Lonasen) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of blonanserin, potentially increasing the effects and adverse effects of blonanserin.  Details Blonanserin is metabolized primarily by cytochrome P450 3A4 (CYP3A4). A small clinical study shows that taking grapefruit juice along with oral blonanserin increases exposure to blonanserin almost 6-fold due to inhibition of intestinal CYP3A4 by grapefruit juice and prolongs the elimination half-life of blonanserin by 2.2-fold due to inhibition of hepatic CYP3A4 by grapefruit juice (96943).

BUDESONIDE (Entocort, UCERIS) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of budesonide, potentially increasing the effects and adverse effects of budesonide.  Details Budesonide is metabolized by cytochrome P450 3A4 (CYP3A4). A small clinical study shows that taking grapefruit juice along with oral budesonide increases the plasma concentration of budesonide. This effect is attributed to grapefruit-induced inhibition of CYP3A4 in both the colon and small intestine (91425).

BUSPIRONE (BuSpar) Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B Grapefruit juice can increase blood levels of buspirone, potentially increasing the effects and adverse effects of buspirone.  Details Clinical research shows that grapefruit juice increases absorption and plasma concentrations of buspirone (3771).

CAFFEINE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Grapefruit juice can decrease the clearance of caffeine, potentially increasing the effects and adverse effects of caffeine.  Details Clinical research shows that grapefruit juice decreases caffeine clearance (4300).

CALCIUM CHANNEL BLOCKERS Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B Grapefruit juice can increase blood levels of oral calcium channel blockers, potentially increasing the effects and adverse effects of these drugs.  Details Clinical research shows that grapefruit juice increases absorption and plasma concentrations of amlodipine (523), nifedipine (528,22114), nisoldipine (529), verapamil (7779,8285), felodipine, nimodipine, nicardipine, diltiazem, pranidipine, nitrendipine, and manidipine (524,528,1388,4300,7780,11276,22136,53338,22138,22139) (22140,22141,22142,22143,22147,22148,22149,53367,22158), This interaction is likely the result of the inhibition of intestinal metabolism of these drugs by CYP3A4 (7779,7780), although some research suggests grapefruit may alter plasma drug levels by reducing the rate of gastric emptying (22167). Consuming grapefruit juice 1 liter daily increases steady state concentrations of verapamil by as much as 50% (8285). However, some references dispute the clinical relevance of the interactions with amlodipine, diltiazem, and verapamil (3230,4300,22159). Other research in healthy individuals suggests plasma levels of felodipine and nifedipine are not affected when given intravenously (22144,22146). There is considerable interindividual variability in the effect of grapefruit juice on drug metabolism, which might account for inconsistent study results (7777,7779,8285). In healthy older adults, the hemodynamic response to felodipine plus grapefruit juice might be influenced by altered autonomic regulation. In older healthy adults, a single dose of grapefruit juice and felodipine enhanced the blood pressure-lowering effects of felodipine. However, after a week of grapefruit juice and felodipine (steady state), the hypotensive activity was reduced, possibly due to compensatory tachycardia (1392). Research indicates it is necessary to withhold grapefruit juice for as long as 3 days to avoid interactions with felodipine and nisoldipine (5068,5069,6453,22145).

CARBAMAZEPINE (Tegretol) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = B Grapefruit juice can increase blood levels of carbamazepine, potentially increasing the effects and adverse effects of carbamazepine.  Details Clinical research shows that grapefruit juice increases absorption and plasma concentrations of carbamazepine (524).

CARVEDILOL (Coreg) Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B Grapefruit juice can increase blood levels of carvedilol, potentially increasing the effects and adverse effects of carvedilol.  Details Clinical research shows that grapefruit juice increases the bioavailability of a single dose of carvedilol by 16% (5071).

CELIPROLOL (Celicard) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can decrease blood levels of celiprolol, potentially decreasing the clinical effects of celiprolol.  Details In human research, taking grapefruit juice within two hours of celiprolol appears to decrease absorption and blood levels of celiprolol by approximately 85% (91421). This interaction is due to grapefruit-induced inhibition of organic anion transporting polypeptide (OATP) (17603,17604,22161). Grapefruit juice is thought to affect OATP for only a short time. Therefore, separating drug administration and consumption of grapefruit by at least 4 hours is likely to prevent this interaction (17603,17604).

CISAPRIDE (Propulsid) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = B Grapefruit juice can increase blood levels of cisapride, potentially increasing the effects and adverse effects of cisapride.  Details Clinical research shows that grapefruit juice increases the absorption and plasma concentrations of cisapride. According to the cisapride prescribing information, grapefruit juice is contraindicated in patients taking cisapride (1383,3226,17601,22164,22165).

CLOMIPRAMINE (Anafranil) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Theoretically, grapefruit juice might increase blood levels of clomipramine, potentially increasing the effects and adverse effects of clomipramine.  Details Case reports have shown that clomipramine trough levels increase significantly after the addition of grapefruit juice to the therapeutic regimen (5064).

CLOPIDOGREL (Plavix) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can decrease blood levels of the active metabolite of clopidogrel, thereby decreasing the antiplatelet effect of clopidogrel.  Details Clopidogrel is an antiplatelet prodrug that is metabolized primarily by cytochrome P450 2C19 (CYP2C19) to form the active metabolite. A small clinical study shows that taking grapefruit juice with clopidogrel decreases plasma levels of the active metabolite by more than 80% and impairs the antiplatelet effect of clopidogrel. This effect is possibly due to grapefruit-induced inhibition of CYP2C19 (91419).

COLCHICINE Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, grapefruit juice might increase blood levels of colchicine, potentially increasing the effects and adverse effects of colchicine.  Details Colchicine is an alkaloid that undergoes P-glycoprotein (P-gp) mediated drug efflux in the intestines, followed by metabolism by cytochrome P450 3A4 (CYP3A4). There is concern that grapefruit juice will increase the effects and adverse effects of colchicine due to grapefruit-induced inhibition of P-gp and/or CYP3A4. In vitro evidence shows that grapefruit juice increases absorption of colchicine by inhibiting P-gp (94158). A case of acute colchicine toxicity has been reported for an 8-year-old female who drank grapefruit juice while taking high-dose colchicine, long-term (94157). However, one small clinical study in healthy adults shows that drinking grapefruit juice 240 mL twice daily for 4 days does not affect the bioavailability or adverse effects of a single dose of colchicine 0.6 mg taken on the fourth day (35762).

CYCLOSPORINE (Neoral, Sandimmune) Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B Grapefruit juice can increase blood levels of oral cyclosporine, potentially increasing the effects and adverse effects of cyclosporine.  Details Clinical research shows that grapefruit juice increases the absorption and plasma concentrations of cyclosporine (522,11270,22113,22150,22152,22153,22154,22155). The mechanism of action is unclear. However, there is no effect on intravenous cyclosporine (22151).

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, grapefruit juice might increase levels of drugs metabolized by CYP1A2.  Details In vitro research suggests that grapefruit juice might inhibit CYP1A2 enzymes (12479). So far, this interaction has not been reported in humans.

CYTOCHROME P450 2C19 (CYP2C19) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, grapefruit juice might increase levels of drugs metabolized by CYP2C19.  Details In vitro research suggests that grapefruit juice might inhibit CYP2C19 enzymes (12479). Also, a small clinical study shows that taking grapefruit juice with clopidogrel, an antiplatelet prodrug that is metabolized primarily by CYP2C19, decreases plasma levels of the active metabolite and impairs the antiplatelet effect of clopidogrel. This effect is likely due to grapefruit-induced inhibition of CYP2C19 (91419).

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, grapefruit juice might increase levels of drugs metabolized by CYP2C9.  Details In vitro research suggests that grapefruit juice might inhibit CYP2C9 enzymes (12479). So far, this interaction has not been reported in humans.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B Grapefruit juice can increase levels of drugs metabolized by CYP3A4.  Details Clinical research shows that grapefruit juice can inhibit CYP3A4 metabolism of drugs, causing increased drug levels and potentially increasing the risk of adverse effects (3227,3774,8283,8285,8286,22129,91427,104190). When taken orally, effects of grapefruit juice on CYP3A4 levels appear to last at least 48 hours (91427). Grapefruit's ability to inhibit CYP3A4 has even been harnessed to intentionally increase levels of venetoclax, which is metabolized by CYP3A4, in an elderly patient with acute myeloid leukemia who could not afford full dose venetoclax. The lower dose of venetoclax in combination with grapefruit juice resulted in serum levels of venetoclax in the therapeutic reference range of full dose venetoclax and positive treatment outcomes for the patient (112287). Professional consensus recommends the consideration of patient age, existing medical conditions, additional medications, and the potential for additive adverse effects when evaluating the risks of concomitant use of grapefruit juice with any medication metabolized by CYP3A4. While all patients are at risk for interactions with grapefruit juice consumption, patients older than 70 years of age and those taking multiple medications are at the greatest risk for a serious or fatal interaction with grapefruit juice (95970,95972).

DAPOXETINE (Priligy) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of dapoxetine, potentially increasing the effects and adverse effects of dapoxetine.  Details Pharmacokinetic research shows that drinking grapefruit juice 250 mL prior to taking dapoxetine 60 mg can increase the maximum plasma concentration of dapoxetine by 80% and prolong the elimination half-life by 43%. This effect is attributed to the inhibition of both intestinal and hepatic cytochrome P450 3A4 (CYP3A4) by grapefruit (95975).

DEXTROMETHORPHAN (Robitussin DM, others) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of dextromethorphan, potentially increasing the effects and adverse effects of dextromethorphan.  Details Clinical research shows that grapefruit juice can inhibit cytochrome P450 3A4 (CYP3A4) metabolism, causing increased dextromethorphan levels (11362).

ERYTHROMYCIN Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of erythromycin, potentially increasing the effects and adverse effects of erythromycin.  Details Clinical research shows that concomitant use of erythromycin with grapefruit can inhibit cytochrome P450 3A4 (CYP3A4) metabolism of erythromycin, increasing plasma concentrations of erythromycin by 35% (8286).

ESTROGENS Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of estrogens, potentially increasing the effects and adverse effects of estrogens.  Details Clinical research shows that grapefruit increases the levels of endogenous and exogenous estrogens by inhibiting cytochrome P450 3A4 (CYP3A4) enzymes (525,526,14858). Grapefruit juice increases exogenously administered 17-beta-estradiol by about 20% in females without ovaries and ethinyl-estradiol in healthy females (525,526,22160).

ETOPOSIDE (VePesid) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can decrease blood levels of etoposide, potentially decreasing the clinical effects of etoposide.  Details Clinical research shows that grapefruit juice decreases the absorption and plasma concentrations of etoposide. There is some evidence that grapefruit juice co-administered with oral etoposide can reduce levels of etoposide by about 26% (8744). Grapefruit juice seems to inhibit organic anion transporting polypeptide (OATP), which is a drug transporter in the gut, liver, and kidney (7046,17603,17604). Grapefruit juice is thought to affect OATP for only a short time. Therefore, separating drug administration and consumption of grapefruit by at least 4 hours is likely to prevent this interaction (17603,17604).

FEXOFENADINE (Allegra) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Likely •  Level of Evidence = B Grapefruit juice can decrease blood levels of fexofenadine, thereby decreasing the clinical effects of fexofenadine.  Details Clinical research shows that grapefruit juice can significantly decrease oral absorption and blood levels of fexofenadine. In one study, consuming a drink containing grapefruit juice 25% decreased bioavailability of fexofenadine by about 24%. Consuming a full-strength grapefruit juice drink reduced bioavailability by 67% (7046). In another study, consuming grapefruit juice 300 mL decreased fexofenadine levels by 42%. Consuming 1200 mL of grapefruit juice reduced levels by 64% (17602). Similarly, drinking grapefruit juice 240 mL decreased the oral bioavailability of fexofenadine by 25% in another pharmacokinetic study (112288). Fexofenadine manufacturer data indicates that concomitant administration of grapefruit juice and fexofenadine results in larger wheal and flare sizes in research models. This suggests that grapefruit also reduces the clinical response to fexofenadine (17603). Grapefruit juice seems to inhibit organic anion transporting polypeptide (OATP), which is a drug transporter in the gut, liver, and kidney (7046,17603,17604,22161). Grapefruit juice is thought to affect OATP for only a short time. Therefore, separating drug administration and consumption of grapefruit by at least 4 hours is likely to prevent this interaction (17603,17604).

FLUVOXAMINE (Luvox) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Grapefruit juice can increase blood levels of fluvoxamine, potentially increasing the effects and adverse effects of fluvoxamine.  Details Clinical research shows that grapefruit juice inhibits metabolism and increases fluvoxamine levels and peak concentration (17675).

HALOFANTRINE Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of halofantrine, potentially increasing the effects and adverse effects of halofantrine.  Details Clinical research shows that grapefruit juice inhibits cytochrome P450 3A4 (CYP3A4) metabolism, which increases halofantrine levels and peak concentration, as well as a marker of ventricular tachyarrhythmia potential (22129).

HMG-CoA REDUCTASE INHIBITORS ("Statins") Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B Grapefruit juice can increase blood levels of statins that are metabolized by cytochrome P450 3A4 (CYP3A4), potentially increasing the effects and adverse effects of these statins. Additionally, grapefruit juice might interfere with the bioavailability of statins that are substrates of organic anion transporting polypeptides (OATP).  Details Clinical research shows that grapefruit juice inhibits metabolism and increases absorption and plasma concentrations of statins that are metabolized by CYP3A4. These include lovastatin (527,11274), simvastatin (3774,7782,22127), and atorvastatin (3227,12179,22126). Keep in mind that there is considerable variability in the effect of grapefruit juice on drug metabolism, so individual patient response is difficult to predict (7777,7781). Some statins, including pravastatin, fluvastatin, pitavastatin, and rosuvastatin, are not metabolized by CYP3A4. However, grapefruit juice might still affect the bioavailability of these statins. These statins are substrates of OATP. Grapefruit juice can inhibit OATP. Therefore, grapefruit juice may reduce the bioavailability or increase drug levels of these statins depending on the type of OATP. However, grapefruit juice affects OATP for only a short time. Therefore, separating drug administration by at least 4 hours is likely to avoid this interaction (3227,12179,17601,22126,91420).

ITRACONAZOLE (Sporanox) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Grapefruit juice can interfere with itraconazole absorption, although the clinical significance of this interaction is unclear.  Details Clinical research shows that grapefruit juice can affect itraconazole absorption and might increase or decrease itraconazole levels (310,17601,22123).

LEVOTHYROXINE (Synthroid, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Grapefruit juice can decrease blood levels of levothyroxine, potentially decreasing the effectiveness of levothyroxine.  Details Clinical research shows that grapefruit juice modestly decreases levothyroxine levels by 11% by inhibiting organic anion transporting polypeptide (OATP) (17604,22163). Grapefruit juice is thought to affect OATP for only a short time. Therefore, separating drug administration and consumption of grapefruit by at least 4 hours is likely to prevent this interaction (17603,17604).

LOSARTAN (Cozaar) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can decrease blood levels of the active metabolite of losartan, potentially decreasing the clinical effects of losartan.  Details Losartan is an inactive prodrug which must be metabolized to its active form, E-3174, to be effective. In one human study, grapefruit juice reduced losartan metabolism, increased losartan AUC, and reduced the AUC of the major active losartan metabolite, E-3174 (1391).

METHADONE (Dolophine) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of methadone, potentially increasing the effects and adverse effects of methadone.  Details Clinical research shows that grapefruit juice inhibits the metabolism of methadone, increasing methadone levels and peak concentrations (17676). In one case, a 51-year-old male taking methadone 90 mg daily and no other medications was found unresponsive. The patient reported drinking grapefruit juice 500 mL daily for 3 days prior to the event. Methadone is a substrate of cytochrome P450 3A4 (CYP3A4), and grapefruit juice-induced inhibition of CYP3A4 is the likely cause of this interaction (102056).

METHYLPREDNISOLONE Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B Grapefruit juice can increase blood levels of methylprednisolone, potentially increasing the effects and adverse effects of methylprednisolone.  Details Clinical research shows that grapefruit juice can increase the plasma concentration of orally administered methylprednisolone. Grapefruit juice 200 mL three times daily given with methylprednisolone 16 mg increased methylprednisolone half-life by 35%, peak plasma concentration by 27%, and total area under the curve by 75% (3123).

NADOLOL (Corgard) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Grapefruit juice might decrease blood levels of nadolol, potentially decreasing the clinical effects of nadolol.  Details Nadolol is a substrate of organic anion transporting polypeptide 1A2 (OATP1A2) (17603,17604,22161). Some research shows that grapefruit juice and its constituent naringin can inhibit organic anion transporting polypeptides (OATP), which can reduce the bioavailability of OATP substrates (17603,17604,22161,91427). However, preliminary clinical research shows that grapefruit juice containing a low amount of naringin does not significantly affect levels of nadolol (91422). It is not known if grapefruit juice containing higher amounts of naringin reduces the bioavailability of nadolol.

NILOTINIB (Tasigna) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of nilotinib, potentially increasing the effects and adverse effects of nilotinib.  Details Clinical research shows that grapefruit juice inhibits metabolism and increases absorption of nilotinib. Grapefruit juice increases nilotinib levels by 29% and peak concentration by 60% (17677).

ORGANIC ANION-TRANSPORTING POLYPEPTIDE SUBSTRATES (OATP) Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B Grapefruit juice can decrease levels of drugs that are substrates of OATP.  Details In vitro and clinical research show that consuming grapefruit juice inhibits OATP, which reduces the bioavailability of oral drugs that are substrates of OATP. Various clinical studies have shown reduced absorption of OATP substrates when taken with grapefruit, including fexofenadine, acebutolol, aliskiren, celiprolol, levothyroxine, nadolol, and pitavastatin (17603,17604,18101,22126,22134,22161,22163,91420,91427,91428,112288). Grapefruit juice is thought to affect OATP for only a short time. Therefore, separating drug administration and consumption of grapefruit by at least 4 hours is likely to prevent this interaction (17603,17604).

OXYCODONE (Oxycontin) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of oxycodone, potentially increasing the effects and adverse effects of oxycodone.  Details Oxycodone is metabolized by both cytochrome P450 3A4 (CYP3A4) and cytochrome P450 2D6 (CYP2D6). A small clinical study shows that grapefruit juice can increase plasma levels of oral oxycodone about 1.7-fold by inhibiting CYP3A4. While the analgesic effects of oxycodone do not seem to be affected, taking grapefruit juice along with oxycodone may theoretically increase the adverse effects of oxycodone (91423).

P-GLYCOPROTEIN SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Grapefruit juice does not seem to affect renal P-glycoprotein (P-gp). Theoretically, it might inhibit intestinal P-gp, but evidence is conflicting.  Details While most in vitro research shows that grapefruit products inhibit P-gp, (1390,11270,11278,11362,95976), research in humans is less clear. Two small clinical studies in healthy adults using digoxin as a probe substrate show that grapefruit juice does not inhibit P-gp in the kidneys (11277,11282). It is unclear whether this applies to intestinal P-gp, for which digoxin is not considered to be a sensitive probe (105568). Grapefruit juice has been shown to reduce levels of fexofenadine (7046,17602,112288), and increase levels of quinidine (5067,22121). However, as both of these drugs are also substrates of other enzymes and transporters, it is unclear what role, if any, intestinal P-gp has in these findings.

PITAVASTATIN (Livalo) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Likely •  Level of Evidence = B Grapefruit juice can increase blood levels of pitavastatin, potentially increasing the effects and adverse effects of pitavastatin.  Details Pharmacokinetic research shows that taking grapefruit juice with pitavastatin 2-4 mg can increase blood levels of pitavastatin by 13% to 14%. Unlike simvastatin and atorvastatin, pitavastatin is not significantly metabolized by cytochrome P450 3A4 (CYP3A4) enzymes. Grapefruit juice appears to increase levels of pitavastatin by inhibiting its uptake by organic anion transporting polypeptide 1B1 (OATP1B1) into hepatocytes for metabolism and clearance from the body (22126,91420). Grapefruit juice seems to increase levels of pitavastatin to a greater degree in patients homozygous for a specific polymorphism (388A>G) in the OATP1B1 gene compared to those heterozygous for this polymorphism (91420).

PRASUGREL (Effient) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can decrease blood levels of the active metabolite of prasugrel, thereby decreasing the antiplatelet effect of prasugrel.  Details Prasugrel is a prodrug that is metabolized by cytochrome P450 3A4 (CYP3A4) into its active metabolite. A small pharmacokinetic study in healthy volunteers shows that drinking grapefruit juice 200 mL three times daily for 4 days and taking a single dose of prasugrel 10 mg with an additional 200 mL of grapefruit juice on day 3, results in a 49% lower peak plasma level and a 26% lower overall plasma exposure to the active metabolite when compared with drinking water. However, despite the reduced exposure, platelet aggregation seems to be reduced by an average of only 5% (105567). The clinical significance of this interaction is unclear.

PRAZIQUANTEL (Biltricide) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of praziquantel, potentially increasing the effects and adverse effects of praziquantel.  Details Clinical research shows that grapefruit juice can inhibit cytochrome P450 3A4 (CYP3A4) metabolism of praziquantel. Plasma concentrations of praziquantel can increase by as much as 160% when administered with 250 mL of commercially available grapefruit juice (8282).

PRIMAQUINE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Grapefruit juice may increase blood levels of primaquine, potentially increasing the effects and adverse effects of primaquine.  Details Clinical research shows that grapefruit juice increases the bioavailability of primaquine by approximately 20% (22130). The clinical significance of this interaction is not clear.

QT INTERVAL-PROLONGING DRUGS Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit or grapefruit juice, especially if consumed in large amounts, can cause additive QT interval prolongation when taken with QT interval-prolonging drugs, potentially increasing the risk of ventricular arrhythmias.  Details Clinical research in healthy volunteers shows that drinking 6 liters of grapefruit juice over 6 hours prolonged the QTc by a peak amount of 14 milliseconds (ms). This prolongation was similar to the QT prolongation caused by the drug moxifloxacin. In individuals with long QT syndrome, a smaller dose of grapefruit juice, 1.5 liters, resulted in a greater peak QTc prolongation of about 30 ms (100249). The effect of smaller quantities of grapefruit juice on the QT interval is unclear.

QUETIAPINE (Seroquel) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice may increase blood levels of quetiapine, increasing the effects and adverse effects of quetiapine.  Details Quetiapine is metabolized by cytochrome P450 3A4 (CYP3A4). Grapefruit can inhibit CYP3A4 (3227,3774,8283,8285,8286,22129,91427,104190). In one case report, a healthy 28-year-old female with bipolar disorder stabilized on quetiapine 800 mg daily presented with quetiapine toxicity considered to be related to consuming a gallon of grapefruit juice over the past 24 hours (108848).

QUINIDINE Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can alter blood levels of quinidine, potentially increasing or decreasing the clinical effects of quinidine.  Details Clinical research shows that grapefruit juice decreases quinidine absorption, clearance, and metabolism, and prolongs the half-life by about 20% (5067,22121).

SAQUINAVIR (Fortovase, Invirase) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of saquinavir, potentially increasing the effects and adverse effects of saquinavir.  Details Clinical research shows that grapefruit juice increases the absorption and plasma concentrations of saquinavir (3773,22132).

SCOPOLAMINE (Transderm Scop) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of scopolamine, potentially increasing the effects and adverse effects of scopolamine.  Details Clinical research shows that grapefruit juice can inhibit cytochrome P450 3A4 (CYP3A4) metabolism of scopolamine, increasing its absorption and plasma concentrations. Oral bioavailability of scopolamine can increase by 30% when administered with 150 mL of grapefruit juice (8284).

SERTRALINE (Zoloft) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Grapefruit juice can increase blood levels of sertraline, potentially increasing the effects and adverse effects of sertraline.  Details Clinical research shows that grapefruit juice inhibits the cytochrome P450 3A4 (CYP3A4) metabolism of sertraline, increasing blood levels of sertraline (22122).

SILDENAFIL (Viagra) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of sildenafil, potentially increasing the effects and adverse effects of sildenafil.  Details Clinical research shows that grapefruit juice inhibits cytochrome P450 3A4 (CYP3A4) metabolism of sildenafil, increasing its absorption and plasma concentrations. Oral bioavailability of sildenafil can increase by 23% when administered with 500 mL of commercially available grapefruit juice (8283).

SUNITINIB (Sutent) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Unlikely •  Level of Evidence = B Grapefruit juice may slightly increase blood levels of sunitinib, potentially increasing the effects and adverse effects of sunitinib.  Details Sunitinib is metabolized by cytochrome P450 3A4 (CYP3A4). Grapefruit and grapefruit juice can inhibit CYP3A4 and increase levels of some drugs metabolized by this enzyme. One small clinical study shows that drinking 200 mL of grapefruit juice three times daily can increase the bioavailability of sunitinib by 11% (91429). While this effect is unlikely to be clinically significant, patients should use caution when using grapefruit along with sunitinib. Dose adjustments may be necessary.

TACROLIMUS (Prograf) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = B Grapefruit juice can increase blood levels of tacrolimus, potentially increasing the effects and adverse effects of tacrolimus.  Details Clinical research shows that drinking grapefruit juice 200 mL daily while taking tacrolimus 3 mg daily increases the trough blood concentration of tacrolimus by approximately 3-fold in patients with connective tissue diseases (95974). A single case has also reported a 10-fold increase in tacrolimus trough levels after the ingestion of grapefruit juice over 3 days (22122). This effect is attributed to the inhibition of cytochrome P450 3A4 (CYP3A4) by grapefruit (95974).

TADALAFIL (Cialis) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, grapefruit juice might increase blood levels of tadalafil, potentially increasing the effects and adverse effects of tadalafil.  Details Animal research shows that grapefruit juice increases tadalafil serum concentrations and overall exposure, likely through inhibition of cytochrome P450 3A4 enzymes (104189).

TALINOLOL Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Grapefruit juice might decrease blood levels of talinolol, potentially decreasing the clinical effects of talinolol.  Details Clinical research suggests that grapefruit juice reduces talinolol bioavailability, likely by inhibiting intestinal uptake (22135). The clinical significance of this effect is unclear.

TERFENADINE (Seldane) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of terfenadine, potentially increasing the effects and adverse effects of terfenadine.  Details Clinical research shows that grapefruit juice increases the absorption and plasma concentrations of terfenadine (530,22124,22125). The mechanism of action is unclear.

THEOPHYLLINE Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can decrease blood levels of theophylline, potentially decreasing the effectiveness of theophylline.  Details Clinical research shows that grapefruit juice seems to modestly decrease theophylline levels when given concurrently with sustained-release theophylline (11013). The mechanism of this interaction is unknown.

TICAGRELOR (Brilinta) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of ticagrelor, thereby increasing the effects and adverse effects of ticagrelor.  Details Ticagrelor is metabolized by cytochrome P450 3A4 (CYP3A4). Grapefruit can inhibit CYP3A4. A small clinical study shows that taking grapefruit juice with ticagrelor increases blood levels of ticagrelor more than two-fold and increases the antiplatelet activity of ticagrelor (91418).

TOLVAPTAN (Samsca) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of tolvaptan, potentially increasing the effects and adverse effects of tolvaptan.  Details Tolvaptan is metabolized by cytochrome P450 3A4 (CYP3A4). Grapefruit can inhibit CYP3A4. A small clinical study shows that grapefruit juice can increase the bioavailability and blood levels of tolvaptan by approximately 1.6-fold for up to 16 hours (91426).

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, drinking large amounts of grapefruit juice might increase the effects and adverse effects of warfarin.  Details In one case report, a patient experienced significantly increased international normalized ratio (INR) associated with consumption of 50 ounces of grapefruit juice daily (12061). However, smaller amounts of grapefruit juice might not be a problem. In a small clinical trial, consumption of 24 ounces of grapefruit juice daily for one week had no effect on INR in males treated with warfarin (12063).

(Read more about GRAPEFRUIT)

DIURETIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, lovage root might interfere with diuretic therapy due to its aquaretic effects (512).  Details Some diuretics include chlorothiazide (Diuril), chlorthalidone (Thalitone), furosemide (Lasix), hydrochlorothiazide (HCTZ, Hydrodiuril, Microzide), and others.

(Read more about LOVAGE)

(Read more about OLIVE)

General ...There is currently a limited amount of information on the adverse effects of Artemisia herba-alba. Orally, Artemisia herba-alba has been reported to cause decreased blood pressure and pulse rate in one small clinical trial (15075,15077). A single case of renal failure has been reported (96567).

Cardiovascular ...Orally, Artemisia herba-alba has been reported to cause a reduction in blood pressure and pulse rate in one small clinical trial (15075,15077).

Renal ...In one case report, a 59-year-old male with a history of diabetes mellitus developed acute renal failure with proteinuria and hyperkalemia after drinking a tea containing aqueous Artemisia herba-alba extract, 2 cups daily for 2 days. Recovery occurred after several sessions of dialysis (96567).

(Read more about ARTEMISIA HERBA-ALBA)

General ...Orally, burdock is well tolerated when consumed as a food. Although a thorough evaluation of safety outcomes is lacking, there has been long-standing historical use of burdock with few noted adverse effects.
Serious Adverse Effects (Rare):
All ROAs: Allergic reactions, including contact dermatitis and anaphylaxis.

Dermatologic ...Contact dermatitis has been reported secondary to burdock, especially after prolonged use of the root oil (37422). There are cases of allergic dermatitis secondary to using burdock plasters. Two males and a 14 year-old female developed erythematous and vesicular, pruritic, and exudative reactions in areas corresponding to the application of burdock root plasters (12667). Reactions occurred up to 7 days after initial use. Patch testing was positive for burdock sensitivity in all three patients and was nonreactive in matched controls.

Hematologic ...In one case report, a 38-year-old female developed immune-mediated thrombocytopenia after consuming a "cleansing" tea containing unknown amounts of burdock and yellow dock. The patient presented with bruising, mild weakness, and fatigue, which started 2-3 days after consuming the tea, and was found to have a platelet count of 5,000 per mcL. Symptoms resolved after platelet transfusion and treatment with oral dexamethasone (108971). It is unclear if these effects were caused by burdock, yellow dock, the combination, or other contributing factors.

Hepatic ...A case of idiosyncratic drug-induced liver disease (DILI) is reported in a 36-year-old female who presented with abdominal pain after 1 month of taking an herbal liver detox tea containing burdock and other ingredients. Remarkable laboratory values included elevated liver enzymes, alkaline phosphatase, and total bilirubin. The patient received a loading dose of N-acetylcysteine and was hospitalized for 12 days (112178). However, it is unclear if the adverse effect was due to burdock, other ingredients, or the combination.

Immunologic ...There is one case of anaphylactic shock secondary to eating boiled burdock. One hour after eating boiled burdock the patient presented with redness over the entire body and dyspnea. He was found to have low blood pressure and was treated with subcutaneous epinephrine 1 mg and intravenous lactated ringer's solution containing hydrocortisone 100 mg and dexamethasone 8 mg. The cause of anaphylactic shock was attributed to allergenicity to burdock based on positive skin prick test results. Previously, the patient had experienced urticaria after eating boiled burdock (12660).

Neurologic/CNS ...Anticholinergic reactions including dry mouth, dizziness, blurred vision, weakness, dilated pupils, inability to urinate, and bradycardia have been reported following the consumption of burdock products (12662,37421,37431,37434,37435). However, these anticholinergic reactions are believed result from contamination of burdock with belladonna alkaloids. Burdock itself does not contain atropine or other constituents that would be responsible for these reactions.

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General ...Orally, grapefruit and grapefruit juice are generally well tolerated.
Serious Adverse Effects (Rare):
Orally: Allergic reactions in sensitive individuals have been reported. When large quantities are consumed, arrhythmias, mineralocorticoid excess, QT prolongation, and pseudohyperaldosteronism have been reported. There is also some concern for increased breast cancer risk with grapefruit consumption.

Cardiovascular ...Orally, consumption of pink grapefruit juice 1000 mL can cause QT prolongation and cause arrhythmias in healthy patients and worsen arrhythmias in cardiomyopathy patients (13031,91424).

Endocrine ...Orally, high doses of grapefruit juice have been observed to cause pseudohyperaldosteronism and mineralocorticoid excess (53340,53346).

Gastrointestinal ...In a case report, grapefruit juice held against the teeth resulted in enamel and tooth surface loss (53368).

Immunologic ...Orally, grapefruit can cause allergic sensitization characterized by eosinophilic gastroenteritis, urticaria, and generalized pruritus (53351,53360).

Oncologic ...Preliminary population research shows that postmenopausal adults who consume a quarter or more of a whole grapefruit daily have a 25% to 30% increased risk of developing breast cancer (14858). Grapefruit is a potent inhibitor of cytochrome P450 3A4, which metabolizes estrogen. Consuming large amounts of grapefruit might significantly increase endogenous estrogen levels and therefore increase the risk of breast cancer. More evidence is needed to validate these findings. Until more is known, advise patients to consume grapefruit in moderation.

Renal ...In population research, consumption of 240 mL/day of grapefruit juice is associated with an increased risk of kidney stones (4216,53372).

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General ...A high-quality assessment of the adverse effects of lovage has not been conducted. However, long-term oral use of lovage may result in an increased risk of phototoxic reactions, including photosensitivity (2,5,6,8,11,12). Topical exposure may also result in photosensitivity or contact dermatitis (60058,94098).

Dermatologic ...Orally, long-term use of lovage may result in an increased risk of phototoxic reactions, including photosensitivity (2,5,6,8,11,12). Avoid excessive exposure to the sun or UV light if using lovage (2,12). A case of contact dermatitis has been reported in a 31-year-old female who applied undiluted lovage essential oil to the skin for 2 weeks. The skin healed after receiving topical and systemic steroids (94098). A case of photosensitivity has also been reported secondary to harvesting lovage (60058).

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General ...Orally, olive fruit is well tolerated when used in typical food amounts. Olive leaf extract seems to be well tolerated.
Most Common Adverse Effects:
Orally: Headache and stomach discomfort.

Dermatologic ...Orally, one patient in one clinical trial reported bad skin and acne after using olive leaf extract (101860).

Gastrointestinal ...Orally, three patients in one clinical trial reported stomach ache after using olive leaf extract (101860).

Neurologic/CNS ...Orally, three patients in one clinical trial reported headache after using olive leaf extract (101860).

Psychiatric ...In one case report, a 67-year-old female experienced irritability, anger, a lack of control, and feelings of sadness and negativity after consuming a multi-ingredient product containing olive leaf extract 5 grams, horseradish root, and eyebright daily for 38 days. All psychiatric symptoms disappeared within days of stopping the combined product. It is hypothesized that the hydroxytyrosol component of olive leaf extract contributed to these symptoms due to its chemical similarity to dopamine; however, it is not clear if these symptoms were due to the olive leaf extract or to the other ingredients (96245).

Pulmonary/Respiratory ...Olive tree pollen can cause seasonal respiratory allergy (1543).

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