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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. It is unclear if topical phellodendron is beneficial in patients with acne. Details: A small clinical study in patients with mild to moderate acne shows that applying a facial mask containing an unknown dose of phellodendron for 15-20 minutes daily for 3 days, then every other day for 8 weeks, reduces the number of acne lesions when compared to baseline. About 33% of patients showed a moderate improvement and 11% showed an excellent improvement in overall lesions at week 8. However, no significant difference in the total number of lesions was seen (97317).
• Benign prostatic hyperplasia (BPH). Oral phellodendron has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with BPH shows that taking five tablets of a specific traditional Chinese medicine product containing phellodendron bark, gardenia fruit, licorice root, safflower, Indian long pepper, and other ingredients three times daily with conventional therapy for 6 months improves storage-related lower urinary tract symptoms, such as urinary frequency, urinary urgency, and nocturia, when compared with placebo plus conventional therapy. However, this product did not appear to improve voiding-related symptoms (109450).
• Diabetes. Although there has been interest in using oral phellodendron for diabetes, there is insufficient reliable information about the clinical effects of phellodendron for this purpose.
• Diabetic foot ulcers. Topical phellodendron has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A large clinical study in adults with diabetic foot ulcers shows that applying gauze soaked in a Traditional Chinese Medicine (TCM) solution containing phellodendron, forsythia, honeysuckle, dandelion, and Scolopendra once daily for 4 weeks is associated with a higher rate of clinical efficacy and greater reduction in wound area when compared with applying gauze soaked with a Kangfuxin control solution (106438). Kangfuxin is an herbal TCM solution commonly used in the treatment of diabetic foot ulcers. The validity of these findings is limited by the unclear reporting of outcomes and discrepancies in the data. Additionally, it is unclear how these findings would compare with the use of standard care. A small clinical study in adults undergoing negative pressure wound aspiration therapy (NPWT) for diabetic foot ulcers shows that the addition of liquid compound phellodendron TCM irrigation to NPWT for 30 days improves wound symptom scores and wound healing and bacterial cultures compared with saline control (112389). A moderate size clinical study in adults undergoing ultrasonic debridement for diabetic foot ulcers shows that rinsing the wound with a liquid compound phellodendron TCM for 4 weeks reduces wound area and bacterial cultures and improves healing rate and efficacy compared with a Kangfuxin control solution (112390). The lack of blinding and randomization limits the validity of these findings. Additionally, in all three trials the phellodendron solution contained other TCM ingredients such as forsythia, honeysuckle, dandelion, golden cypress, and centipede (106438,112389,112390). Thus, it is unclear if the effects are due to phellodendron, other ingredients, or the combination.
• Obesity. Oral phellodendron has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study in overweight individuals shows that taking a specific blend of phellodendron and sweet orange extracts (Citrofen, Next Pharmaceuticals) 740 mg twice daily for 8 weeks reduces body weight by 3.7% when compared with placebo (94902,94903). This blend also seems to reduce levels of low-density lipoprotein (LDL) cholesterol by about 30% and triglycerides by about 14% when compared with placebo. It also appears to reduce systolic and diastolic blood pressure and fasting glucose (94902). Another specific combination product containing a combination of extracts of phellodendron plus magnolia (Relora, Next Pharmaceuticals) has been evaluated for weight loss in females who have a tendency to eat during stressful situations. One small clinical study in overweight, postmenopausal individuals shows that taking this product 250 mg three times daily for 6 weeks prevents weight gain when compared with placebo (14349). However, another small clinical study in overweight, postmenopausal individuals shows that taking this product at the same dose for 6 weeks does not decrease appetite, caloric intake, body weight, or waist or hip circumference when compared with placebo (94901).
• Osteoarthritis. Oral phellodendron has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with osteoarthritis of the knee shows that taking a specific blend of phellodendron and sweet orange extracts (Citrofen, Next Pharmaceuticals) 740 mg twice daily for 8 weeks improves functional measures of joint pain and movement by 16% to 41% when compared with placebo (94903).
• Peptic ulcers. Although there has been interest in using oral phellodendron for peptic ulcers, there is insufficient reliable information about the clinical effects of phellodendron for this purpose.
• Stress. Oral phellodendron has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with moderate stress shows that taking a specific product containing a combination of extracts of phellodendron plus magnolia (Relora, Next Pharmaceuticals) 250 mg twice daily for 4 weeks improves stress and mood by 11% when compared with placebo (94904).
• Tuberculosis. Although there has been interest in using oral phellodendron for tuberculosis, there is insufficient reliable information about the clinical effects of phellodendron for this purpose.
• Wound healing. Topical phellodendron has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate sized clinical trial in adults recovering from anal fistulotomy shows that using 200 mL of compound phellodendron decoction in 1.8 liters of warm water for fumigation and sitting (sitz) bath for 7 days reduces pain, wound edema and exudation, and total wound healing time compared with fumigation and sitz bath with warm water alone (112391). Four other herbs were in the decoction, so it is unclear if the effects are due to phellodendron, other ingredients, or the combination. More evidence is needed to rate phellodendron for these uses.

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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Asthma. It is unclear if dietary citrus fruits are beneficial in patients with asthma. Details: There is some evidence that consumption of vitamin C-rich citrus fruits, including sweet orange and others, might improve lung function in people with asthma. However, this is controversial. Some studies show that intake of citrus fruits 1-2 times per week produces significant benefit (6049,6055,6056), while other studies have not found this benefit (6057,6058).
• Common cold. It is unclear if drinking sweet orange juice prevents the common cold. Details: Preliminary clinical research in healthy individuals ages 17 to 25 years suggests that drinking sweet orange juice 180 mL daily for 72 days might decrease the risk of developing common cold-related symptoms (15328).
• Depression. It is unclear if drinking sweet orange juice or using sweet orange essential oil as aromatherapy is beneficial for depression. Details: Preliminary clinical research in adults with depression shows that drinking flavonoid-rich sweet orange juice 190 mL three times daily for 8 weeks modestly improves depression scores when compared to baseline, but not when compared with a low-flavonoid orange drink (110045). Sweet orange has also been studied as part of a combination aromatherapy. A very small clinical study in community-dwelling older adults shows that massage therapy to the upper body with sweet orange, lavender, and bergamot oils twice weekly for 8 weeks improves symptoms of depression in 65% of patients when compared with no intervention. Twice weekly inhalation of the same essential oils via nebulizer, without massage, also improves symptoms of depression in 55% of patients when compared with no intervention (98474).
• Hypercholesterolemia. It is unclear if drinking sweet orange juice improves blood lipid levels. Details: A very small clinical study in hypercholesterolemic patients shows that drinking large amounts of sweet orange juice (750 mL daily for four weeks) seems to increase high-density lipoprotein (HDL) cholesterol by 21% and reduce the ratio of low-density lipoprotein (LDL) to HDL cholesterol by 16% when compared to baseline. This effect was not seen with 250-500 mL of sweet orange juice. Because consumption of this large amount of juice daily provides approximately 20% of the daily energy requirement, this regimen may not be practical (3340).
• Insomnia. Sweet orange essential oil as aromatherapy has only been evaluated in combination with other essential oils; its effect when used alone is unclear. Details: Preliminary clinical research in adults undergoing hemodialysis shows that inhaling aromatherapy with sweet orange and lavender oil nightly before bed for one month improves overall sleep quality by 72% and fatigue by about 78% when compared with no treatment (98508).
• Kidney failure. It is unclear if sweet orange oil massage can improve fatigue or symptoms of restless leg syndrome (RLS) in adults receiving hemodialysis. Details: A small clinical study shows that receiving an 18-minute foot massage with sweet orange oil 1.5% for 3 weeks during hemodialysis sessions modestly improves sleep quality and symptoms of RLS when compared with routine care. However, it does not seem to be more effective than using lavender oil (109859).
• Kidney stones (nephrolithiasis). It is unclear if drinking sweet orange juice is beneficial for preventing kidney stones. Details: Consuming 400 mL of sweet orange juice three times a day, providing a total of 100 mEq of citrate daily, increases urinary pH and urinary citrate levels (15171). Theoretically, this might reduce kidney stone formation in patients with calcium nephrolithiasis. However, this outcome has not been evaluated in clinical research.
• Obesity. It is unclear if drinking sweet orange juice or taking oral sweet orange extract improves weight loss or other metabolic parameters in adults with overweight or obesity. Most studies suggest that any effects are unlikely to be considered clinically relevant. Details: Some preliminary clinical research in adults with overweight or obesity shows that taking a specific sweet orange extract (Morosil, Bionap S.R.L.) 400 mg orally once daily for six months reduces waist circumference, body weight, fat mass, and body mass index (BMI) by 2% to 5% when compared with placebo (110046). However, other preliminary clinical research in this population shows that drinking red sweet orange juice 750 mL daily for 8 weeks does not reduce body weight or BMI when compared with baseline (92309). A meta-analysis of clinical research in adults, most of whom were overweight or obese at baseline, shows that drinking 250-750 mL of various types of sweet orange juice daily for 2-12 weeks does not reduce body weight, BMI, waist circumference, or body fat percentage (BFP) when compared with control groups, which included either no supplementation, pomegranate juice, or exercise (107853). The validity of this meta-analysis is limited due to the population heterogeneity and variety of orange juice formulations and controls utilized. Some clinical studies have also evaluated sweet orange juice for improving cardiovascular risk factors in overweight and obese adults. Although some research has shown benefit, not all research agrees (110046,110047). A meta-analysis of randomized clinical trials in adults with overweight or obesity shows that drinking sweet orange juice 250-600 mL daily for 2-13 weeks modestly increases high-density lipoprotein cholesterol levels and decrease average systolic blood pressure by 1 mmHg when compared with control. However, drinking sweet orange juice does not affect other blood lipid levels, blood glucose levels, or markers of insulin resistance (110048). The validity of this study is limited by high heterogeneity and a small sample size. In addition, these improvements are unlikely to be considered clinically relevant. Sweet orange extract has also been studied in combination with other ingredients. Some clinical research in overweight adults shows that taking a specific combination product (Sinetrol, Fytexia) 450-700 mg twice daily containing sweet orange, blood orange, and grapefruit extracts for 12 weeks reduces body weight, BFP, and BMI when compared with placebo or baseline (95517,95518). It is unclear if these effects are due to sweet orange, other ingredients, or the combination.
• Pre-procedural anxiety. It is unclear if inhaling sweet orange essential oil as aromatherapy reduces anxiety before surgeries or invasive procedures. Details: A small, low-quality study suggests that inhaling the scent from 3 drops of sweet orange essential oil applied to a cotton ball for 5 minutes modesty reduces anxiety and pain scores in patients undergoing needle insertion for hemodialysis when compared with performing a breathing exercise for 3 minutes (105455).
• Prostate cancer. It is unclear if drinking sweet orange juice reduces prostate cancer risk. Details: Observational research has found that increasing dietary intake of sweet orange or sweet orange juice is not associated with a reduced risk of developing prostate cancer (15172).
• Stress. It is unclear if inhaling sweet orange essential oil as aromatherapy is beneficial for stress. Details: Preliminary clinical research shows that using up to 10 drops of sweet orange essential oil as aromatherapy helps prevent some anxiety and tension associated with stressful tasks when compared with control (90505). More evidence is needed to rate sweet orange for these uses.

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POSSIBLY SAFE ...when used orally and appropriately in combination with other ingredients, short-term. A specific product containing a combination of extracts of phellodendron plus magnolia (Relora, Next Pharmaceuticals) 250 mg 2-3 times daily has been used with apparent safety in clinical trials lasting up to 6 weeks (14349,94901,94904). Also, a specific product containing a combination of extracts of phellodendron plus sweet orange (Citrofen, Next Pharmaceuticals) 740 mg twice daily has been used with apparent safety for up to 8 weeks (94903). ...when used topically (97317). There is insufficient reliable information available about the safety of phellodendron when used orally as a single ingredient.

CHILDREN: LIKELY UNSAFE
when used orally in newborns. The berberine constituent of phellodendron can cause kernicterus in newborns, particularly preterm neonates with hyperbilirubinemia (2589).

PREGNANCY: LIKELY UNSAFE
when used orally. The berberine constituent of phellodendron is thought to cross the placenta and may cause harm to the fetus. Kernicterus has developed in newborn infants exposed to berberine (2589).

LACTATION: LIKELY UNSAFE
when used orally. The berberine constituent of phellodendron and other harmful constituents can be transferred to the infant through breast milk (2589).

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LIKELY SAFE ...when sweet orange juice or fruit is used orally in amounts commonly found in foods (1310,3340,15171,92309).

POSSIBLY SAFE ...when the essential oil of sweet orange is inhaled as aromatherapy, short-term (35735,58060,90505,105455). There is insufficient reliable information available about the safety of sweet orange peel when used orally.

CHILDREN: LIKELY SAFE
when sweet orange juice or fruit is used orally in amounts commonly found in foods.

CHILDREN: POSSIBLY UNSAFE
when the sweet orange peel is used orally in excessive amounts. There have been reports of intestinal colic, convulsions, and death in children given large amounts of sweet orange peel (11).

PREGNANCY AND LACTATION: LIKELY SAFE
when sweet orange juice or fruit is used orally in amounts commonly found in foods (1310,3340).

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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, phellodendron might increase the risk of bleeding when used with anticoagulant or antiplatelet drugs.  Details Phellodendron contains berberine. In vitro and in vivo research suggest that berberine can inhibit platelet aggregation (33660,33694). Theoretically, phellodendron might also inhibit platelet aggregation.

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, phellodendron may increase the risk of hypoglycemia when taken with antidiabetes drugs.  Details Phellodendron contains berberine. Clinical research shows that berberine may lower blood glucose levels (20579,34247,34265,34282). Theoretically, phellodendron might also lower blood glucose levels.

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, phellodendron might have additive effects with antihypertensive drugs.  Details Phellodendron contains berberine. Animal research suggests that berberine can have hypotensive effects (33692,34308). Also, a clinical study suggests that taking berberine in combination with amlodipine can lower systolic and diastolic blood pressure when compared with amlodipine alone (91956). Theoretically, phellodendron might also reduce blood pressure.

CNS DEPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, phellodendron might increase the sedative effects of CNS depressants.  Details Phellodendron contains berberine. Animal research suggests that berberine may have sedative effects (13519,33650,33664,33692). Theoretically, phellodendron might also have CNS depressants effects.

CYCLOSPORINE (Neoral, Sandimmune) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, phellodendron might increase blood levels of cyclosporine.  Details Phellodendron contains berberine. Preliminary clinical research shows that berberine can reduce metabolism of cyclosporine and increase serum levels, likely through inhibition of cytochrome P450 3A4 (CYP3A4), which metabolizes cyclosporine (13524). Theoretically, phellodendron might also reduce the metabolism of cyclosporine.

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, phellodendron might increase serum levels of drugs metabolized by CYP2C9.  Details Phellodendron contains berberine. Preliminary clinical research shows that berberine can inhibit CYP2C9 (34279). Theoretically, phellodendron might also inhibit CYP2C9.

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, phellodendron might increase serum levels of drugs metabolized by CYP2D6.  Details Phellodendron contains berberine. In vitro research and preliminary clinical evidence show that berberine can inhibit CYP2D6 (21117,34279,34297). Theoretically, phellodendron might also inhibit CYP2D6.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, phellodendron might increase serum levels of drugs metabolized by CYP3A4.  Details Phellodendron contains berberine. In vitro research and preliminary clinical research show that berberine moderately inhibits CYP3A4 (13524,21114,34279,34297). Theoretically, phellodendron might also inhibit CYP3A4.

DEXTROMETHORPHAN (Robitussin DM, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, phellodendron may increase serum levels of dextromethorphan.  Details Phellodendron contains berberine. Preliminary clinical research shows that berberine can inhibit cytochrome P450 2D6 (CYP2D6) activity and reduce the metabolism of dextromethorphan (34279). Theoretically, phellodendron may also inhibit the metabolism of dextromethorphan.

LOSARTAN (Cozaar) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, phellodendron might reduce the therapeutic effects of losartan by decreasing its conversion to its active form.  Details Phellodendron contains berberine. Preliminary clinical research suggests that berberine can inhibit cytochrome P450 2C9 (CYP2C9) activity and reduce metabolism of losartan (34279). Theoretically, phellodendron might also inhibit the metabolism of losartan.

METFORMIN (Glucophage) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, phellodendron might increase the therapeutic and adverse effects of metformin.  Details Phellodendron contains berberine. In vitro and animal studies show that berberine can increase the systemic exposure and half-life of metformin, potentially increasing metformin's effects and side effects. This interaction seems to be most apparent when berberine is administered 2 hours prior to metformin. Taking berberine and metformin at the same time does not appear to increase systemic exposure to metformin (103195). It is unclear if phellodendron might have this same effect.

MIDAZOLAM (Versed) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, phellodendron might reduce metabolism of midazolam, which might increase the risk of severe adverse effects.  Details Phellodendron contains berberine. Preliminary clinical research shows that berberine can inhibit cytochrome P450 3A4 (CYP3A4) activity and reduce metabolism of midazolam (34279). Theoretically, phellodendron might also inhibit the metabolism of midazolam.

PENTOBARBITAL (Nembutal) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, phellodendron might increase the sedative effect of pentobarbital.  Details Phellodendron contains berberine. Animal research shows that berberine can prolong pentobarbital-induced sleeping time (13519). Theoretically, phellodendron might increase the sedative effects of pentobarbital.

TACROLIMUS (Prograf) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, phellodendron might increase blood levels of tacrolimus.  Details Phellodendron contains berberine. In a 16-year-old patient with idiopathic nephrotic syndrome who was being treated with tacrolimus 6.5 mg twice daily, intake of berberine 200 mg three times daily increased the blood concentration of tacrolimus from 8 to 22 ng/mL. Following a reduction of the tacrolimus dose to 3 mg daily, blood levels of tacrolimus decreased to 12 ng/mL (91954). It is unclear if phellodendron might have this same effect.

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CELIPROLOL (Celicard) Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B Consuming sweet orange with celiprolol can decrease oral absorption of celiprolol.  Details A pharmacokinetic study in healthy volunteers shows that celiprolol levels, after a single dose of 100 mg, are decreased by up to 90% in people who drink sweet orange juice 200 mL three times daily. It's not known if lower consumption of sweet orange juice will have the same effect. Theoretically, this occurs due to short-term inhibition of organic anion transporting polypeptide (OATP) (12115,17603,17604). Recommend separating drug administration and consumption of sweet orange by at least 4 hours (17603,17604).

FEXOFENADINE (Allegra) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Likely •  Level of Evidence = B Consuming sweet orange juice with fexofenadine can decrease oral absorption of fexofenadine.  Details Clinical research shows that coadministration of sweet orange juice 1200 mL decreases bioavailability of fexofenadine by about 72% (7046,17604). In an animal model, sweet orange juice decreased bioavailability of fexofenadine by 31% (17605). Fexofenadine manufacturer data indicates that concomitant administration of sweet orange juice and fexofenadine results in larger wheal and flare sizes in research models. This suggests that sweet orange reduces the clinical response to fexofenadine (17603). Theoretically, this occurs due to short-term inhibition of organic anion transporting polypeptide (OATP) (7046). Recommend separating drug administration and consumption of sweet orange by at least 4 hours (17603,17604).

IVERMECTIN (Stromectol, others) Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B Consuming sweet orange juice with ivermectin can decrease the oral absorption of ivermectin.  Details A pharmacokinetic study in healthy volunteers shows that taking ivermectin orally with sweet orange juice 750 mL over 4 hours reduces the bioavailability of ivermectin. This effect does not seem to be related to effects on P-glycoprotein. The effect on ivermectin is more pronounced in males compared to females (12154).

ORGANIC ANION-TRANSPORTING POLYPEPTIDE SUBSTRATES (OATP) Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B Consuming sweet orange juice can decrease oral absorption of OATP substrates. Separate administration by at least 4 hours.  Details Clinical research shows that consuming sweet orange juice inhibits OATP, which reduces bioavailability of oral drugs that are substrates of OATP (17603,17604). For example, sweet orange juice decreases bioavailability of fexofenadine, a substrate of OATP, by about 72% and of celiprolol, another OATP substrate, by up to 90% (7046,12115). Since sweet orange juice seems to affect OATP for a short time, recommend separating drug administration and consumption of sweet orange juice by at least 4 hours (17603,17604).

P-GLYCOPROTEIN SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Sweet orange juice seems to modulate P-glycoprotein (P-gp), which might affect the blood levels of P-gp substrates.  Details Animal and in vitro research suggest that orange juice extract inhibits drug efflux by P-gp, increasing absorption and levels of P-gp substrates (12116,15327). In contrast, pharmacokinetic research in humans shows that drinking large amounts of sweet orange juice decreases absorption and levels of the P-gp substrate celiprolol. This suggests that orange juice actually induces drug efflux by P-gp or affects drug levels by another mechanism such as inhibiting the gut drug transporter called organic anion transporting polypeptide (OATP) (7046,12115). Until more is known, sweet orange juice should be used cautiously in people taking P-gp substrates.

PRAVASTATIN (Pravachol) Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B Consuming sweet orange juice with pravastatin can increase the absorption of pravastatin.  Details A small pharmacokinetic study in healthy volunteers shows that consuming sweet orange juice 800 mL over 3 hours, including before, during, and after taking pravastatin 10 mg, increases pravastatin levels by about 149%, without affecting pravastatin elimination. Theoretically this effect might be due to modulation of organic anion transporting polypeptides (OATPs) by sweet orange juice (14348). Sweet orange juice does not seem to affect simvastatin levels, but it is not known if sweet orange affects any of the other statins.

QUINOLONE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Calcium-fortified sweet orange juice might reduce quinolone absorption.  Details Calcium binds to quinolones in the gut. Theoretically, the calcium in certain fortified orange juices can also bind to quinolone antibiotics and reduce their absorption and levels (4412,10339,13714,21638,38570).

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General ...Orally, phellodendron seems to be well tolerated.

Endocrine ...Orally, a combination product containing extracts of phellodendron plus magnolia has been associated with one report of thyroid dysfunction in one clinical trial (14349,94901). However, it is unknown if this is related to phellodendron or some other factor.

Gastrointestinal ...Orally, a combination product containing extracts of phellodendron plus magnolia has been associated with one report of heartburn in one clinical trial (14349,94901). However, it is unknown if this is related to phellodendron or some other factor.

Genitourinary ...Orally, a combination product containing extracts of phellodendron plus magnolia has been associated with one report of sexual dysfunction in one clinical trial (14349,94901). However, it is unknown if this is related to phellodendron or some other factor.

Neurologic/CNS ...Orally, a combination product containing extracts of phellodendron plus magnolia has been associated with single reports of shaking hands, perilabial numbness, fatigue, and headache in clinical research (14349,94901). However, it is unknown if this is related to phellodendron or some other factor.

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General ...Orally, sweet orange juice or fruit seem to be well tolerated. Large amounts of sweet orange peel may be unsafe, especially for children. When inhaled, sweet orange essential oil seems to be generally well tolerated.

Gastrointestinal ...There have been reports of intestinal colic in children following ingestion of large amounts of sweet orange peel (11).

Neurologic/CNS ...There have been reports of convulsions in children following ingestion of large amounts of sweet orange peel (11).

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