Major interaction on record — check this product against your medications before combining. Based on 4 of 8 ingredients. Check your meds →
Dietary supplement

Tone & Define Pink Lemonade Ingredients & Drug Interactions

by GNC Total Lean Advanced

Tone & Define Pink Lemonade label
See full label image
Powder Category: Other Combinations
Most serious interaction: Major
Clinical methodology reviewed by · Updated Sep 16, 2026 · Label data from the NIH DSLD
What is this page for?

First and foremost: checking Tone & Define Pink Lemonade against your medications. The heart of this page is the interaction checker and the full interaction report — how this product’s ingredients may interact with prescription and over-the-counter medicines you may be taking.

Around that, we add a pharmacist’s high-level view of the product as a whole — what’s inside, the evidence for its stated use, how transparent the label is, and what safety data exists — so you can see the full picture in one place. It’s educational information from our licensed clinical databases and the clinical staff at HelloPharmacist — not medical advice — and we don’t sell or endorse products. Our editorial policy

The interaction bottom line Most serious interaction: Major

Tone & Define Pink Lemonade is a dietary supplement by GNC Total Lean Advanced with 8 active ingredients. Its ingredients are commonly taken for replacing fluids and electrolytes, preventing dehydration during exercise or illness, treating low blood sodium (under medical care).Based on those ingredients, 1,376 medications have a known interaction with it, the most serious rated major. The ingredients most likely to interact are Grapefruit extract, Guarana extract, Sweet Orange extract. Use the checker below to test your specific medication, or read the full HelloPharmacist Interaction Report.

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Check Your Meds Against Tone & Define Pink Lemonade by GNC Total Lean Advanced

Ask about any prescription or over-the-counter medication and we check it for interactions with Tone & Define Pink Lemonade by GNC Total Lean Advanced — and tell you which ingredient is responsible.

Pharmacist-reviewed data Checks every ingredient Answer in seconds
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HelloPharmacist Scorecard of Tone & Define Pink Lemonade by GNC Total Lean Advanced

Our pharmacy team’s full take, with four database checks built into the cards below — a summary of what is known, not a grade of the product itself.

From our pharmacy team — supplement deep dive

Generated from HelloPharmacist’s pharmacist-curated databases and editorial rules · Last generated Jul 11, 2026

What’s inside

Low disclosure
Ingredient Transparency · database check
Low

Most active ingredients don't disclose an individual amount — you can't tell how much of each you're getting.

Why this rating?
  • The label discloses an exact amount for 3 of its 7 active ingredients.
  • “Citri-Sculpt(TM) Blend” is a proprietary blend — the label gives one combined amount (450 mg) without saying how much of each component you get.

Tone & Define Pink Lemonade contains seven active ingredients. Sodium is a mineral that helps regulate fluid balance and nerve function, though the product delivers it as a supplement rather than relying on dietary sources alone.

EGCG (a plant compound from green tea), Clarinol CLA (a form of conjugated linoleic acid), Sweet Orange and Blood Orange extracts, Grapefruit extract, and Guarana extract (which is high in caffeine) round out the blend. There are also inactive ingredients — citric acid, natural flavors, sucralose, silica, acesulfame potassium, beet, and grape — that serve as sweeteners, thickeners, and flavor boosters.

Does it work?

Not established
Evidence for Intended Use · database check
By FDA rules, dietary supplements can’t claim to treat, cure, or prevent disease — so labels speak in careful marketing language. We discern each product’s intended use from its name, label claims, and label statements, then grade the clinical evidence for that use. How these ratings are computed
Not established

The graded evidence we hold for these ingredients covers different conditions than the ones this product is marketed for, so there's no established rating for its stated use.

Why this rating?
  • The label markets this product for: Low-stimulant body sculpting.
  • We looked for evidence on: Athletic performance, Obesity, Body composition, Muscle tone, Weight management.
  • The closest evidence on file: Sweet Orange is rated "Insufficient Reliable Evidence To Rate" for Obesity (Natural Medicines).
  • Also on file: Guarana is rated "Insufficient Reliable Evidence To Rate" for Athletic performance, Obesity.
  • Also on file: Grapefruit is rated "Insufficient Reliable Evidence To Rate" for Obesity.

The evidence for this product's active ingredients is limited. Sodium is likely effective for cystic fibrosis and possibly effective for preventing kidney damage from the antibiotic amphotericin B, but data on its use in congestive heart failure and bipolar disorder is insufficient to rate.

Sweet Orange extract, Blood Orange extract, Grapefruit extract, and Guarana extract all lack reliable evidence for the conditions their makers typically promote them for — anxiety, asthma, athletic performance, fatigue, depression, and upper respiratory infection all show insufficient evidence to rate. We hold no effectiveness data for EGCG and Clarinol CLA in our records.

The evidence, ingredient by ingredient Sodium Sweet Orange Grapefruit Guarana

How safe is it?

Well-documented data
Safety Information · database check
Well characterized

Adverse-effect, pregnancy, and general safety data are on file for most of these ingredients.

Why this rating?
  • We hold adverse-effect (side-effect) data for 4 of the 4 matched ingredients.
  • Pregnancy & breastfeeding safety ratings cover 4 of 4.
  • General safety write-ups exist for 4 of 4.
  • Remember: this measures how much safety information exists. Thin data is not the same as being safe.

Sodium is well tolerated in normal dietary amounts up to the recommended level of 2.3 grams daily, but excess intake is linked to high blood pressure, heart strain, and kidney disease. Sweet Orange and Blood Orange extracts are generally safe as whole fruits in normal food amounts, though concentrated supplements lack thorough safety testing — intestinal cramping has been reported in children who ate large amounts of orange peel.

Grapefruit is safe to eat as food for most people, but concentrated extracts are not well studied; rare serious side effects from large quantities include heart rhythm problems and an increased breast cancer risk in postmenopausal women who consume a quarter or more of a whole grapefruit daily. Guarana is high in caffeine and generally well tolerated in small amounts but can cause stomach burning, nausea, dizziness, insomnia, nervousness, tremors, and anxiety with overuse.

Pregnancy and lactation data shows sodium is likely safe during pregnancy but possibly unsafe during lactation, Sweet Orange and Blood Orange are likely safe in both, and Guarana's safety data is not on file — talk with your doctor or pharmacist before using during pregnancy or while breastfeeding. We hold no pregnancy/lactation data for EGCG and Clarinol CLA.

Side effects, ingredient by ingredient Sodium Sweet Orange Grapefruit Guarana

Meds to double-check

Major interaction found
Known Interaction Concern · database check
Major identified

At least one ingredient has a documented Major-severity interaction. Check your medications for a personalized result.

Why this rating?
  • 4 of the 4 matched ingredients can interact with medications — Sweet Orange, Guarana, Grapefruit, Sodium.
  • The most serious interaction on file is rated Major.
  • Some involve high-stakes drug classes: anticoagulant / antiplatelet drugs; immunosuppressants / transplant drugs; diabetes medications; heart-rhythm medications; lithium.
  • For scale: 1,377 individual medications appear in the full list. A big number alone doesn't make a product dangerous — what matters is whether YOUR medication is on it, so run yours through the interaction checker on this page.

Before taking this product, double-check these medication types with your pharmacist: drugs that use the OATP transport system in your gut (Major), pravastatin and other cholesterol drugs (Major), ivermectin and antiparasitic medications (Major), celiprolol and beta-blockers that work similarly (Major), cyclosporine and other immune-suppressing drugs (Major), amiodarone and other heart rhythm medications (Major), dextromethorphan and cough suppressants (Major), buspirone and anti-anxiety medications (Major), blood pressure medications and antihypertensives (Moderate), seizure preventers like valproate and carbamazepine (Moderate), lithium and mood stabilizers (Moderate), and disulfiram or antabuse (Moderate).

Check your own medication Run your meds through the checker above

The bottom line

Scorecard at a glanceFormula with limited ingredient disclosure with no established evidence rating for its marketed use. Major medication interactions have been identified, and safety information is well characterized.

If you take any blood pressure medications, heart drugs, seizure preventers, cancer medications, immune-suppressing drugs, or cough suppressants, run your exact medications through the checker on this page before adding this product. The sodium and caffeine content means it's not ideal if you have high blood pressure or heart rhythm problems.

Talk with your pharmacist about whether it fits your personal health picture.

Educational only — not medical advice; always confirm with your pharmacist. Our editorial policy · How we use AI

Assessment coverage: 5 of 7 active ingredients matched to our full ingredient reviews (monographs). Based on the product label dated Jul 24, 2015.

This Scorecard evaluates available label information, ingredient evidence, and known medication-safety considerations. It does not independently verify product identity, purity, potency, contamination, or manufacturing quality. How these ratings are computed

At a glance

General information

Key facts about Tone & Define Pink Lemonade, straight from the product label.

Brand GNC Total Lean Advanced
Barcode (UPC) 048107155575
Net contents 5.8 Oz(s); 165.6 Gram(s)
Market status On market
Date entered into DSLD Jul 24, 2015
DSLD ID 47950
Product type Other Combinations
Supplement form Powder
Dietary claims / uses All Other, Structure/Function
Intended target group(s) Adult (18 - 50 Years)
From the label
Everything in this section is reproduced from the manufacturer’s own product label — it’s the label speaking, not HelloPharmacist. We show it so you can see exactly what the maker states; we don’t verify or endorse those statements.

Supplement Facts

The label details for Tone & Define Pink Lemonade by GNC Total Lean Advanced, sourced from the NIH Dietary Supplement Label Database.

Supplement Facts

Daily Value (DV) Target Group(s):
Adults and children 4 or more years of age
Minimum serving Sizes:
6.9 Gram(s)
Maximum serving Sizes:
6.9 Gram(s)
Servings per container
24
UPC/BARCODE
048107155575
IngredientAmount% DV
Calories35 {Calories}--
Total Carbohydrates3 Gram(s)1%
Sugar0 Gram(s)--
Calories from Fat25 {Calories}--
Sodium10 mg1%
Total Fat2.5 Gram(s)4%
EGCG25 mg--
Clarinol CLA1.7 Gram(s)--
Sweet Orange extract0 NP--
Blood Orange extract0 NP--
Grapefruit extract0 NP--
Guarana extract0 NP--
Citri-Sculpt(TM) Blend450 mg--

Other ingredients: Citric Acid, Natural Flavors, Sucralose, Silica, Acesulfame Potassium, Beet, Grape

Tap any ingredient to jump to its full detail below.

Label statements
These statements are the manufacturer’s wording, reproduced from the product label — the label is saying it, not HelloPharmacist. We don’t verify or endorse them.
General Statements

Low-stimulant body sculpting

G5711601

NEW

Tone & Define

Body Toning Breakthrough Low stim diet support Enhances fitness & definition Improves body shape Fuels fat metabolism

Natural flavors

Clinically studied

Total Lean(TM) Advanced Body Toning System Start a new phase in your weight management journey with this next-level, weight-loss innovation designed specifically for those who strive for body tone and definition. With fat metabolism and body sculpting at the core, this comprehensive approach includes targeted solutions to help you transform common weight loss challenges into results that you can see and feel. Theses research-based solutions are designed by our weight management experts to provide you with personalized supplement and meal plans, plus body-defining exercise regimens. Get started now witht he enclosed overview and visit GNC.com/TotalLeanAdvanced today!

Notice: Significant product settling can occur.

Precautions

Keep out of reach of children.

Contains: Milk and Soybeans.

Contains 19 mg of caffeine.

Storage

Store in a cool, dry place.

FDA Disclaimer Statement

These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.

Brand IP Statement(s)

GNC Total Lean(TM) Advanced

When used in conjunctions with the Total Lean(TM) Advanced Body Toning System.

Calrinol(R) CLA is a trademark of Stepan Lipid Nutrition. (U.S. Patents: 6,271,4041, 6,160,140, 5,581,663, and 5,760,082.

FDA Statement of Identity

Dietary Supplement

Formulation

Sugar Free

Formula

With Grapefruit and Citrus extracts

Contains: Milk and Soybeans.

Contains 19 mg of caffeine.

General

CODE 732234 IPG

Suggested/Recommended/Usage/Directions

Directions: As a dietary supplement, mix one scoop (6.9 g) into 10-12 fl. oz. of cold water and enjoy daily. For maximum results, use two servings per day. Use in conjunction with Total Lean(TM) Advanced Lean Shake(TM) Burn for additional energizing and calorie burning support. For personalized stacking suggestions and to learn more, visit www.GNC.com/TotalLeanAdvanced.

Shake your container prior to every use.

Seals/Symbols

Clarinol(R)

Is this label outdated? Report a formula or label change and our pharmacy team will review it.

See for yourself

Tone & Define Pink Lemonade by GNC Total Lean Advanced label

The label scan from the NIH Dietary Supplement Label Database. Tap to enlarge.

Tone & Define Pink Lemonade label

Label images are published by the NIH Dietary Supplement Label Database for the version of this product on file. Always read your actual product label.

View the full label (PDF)
What’s inside

The Ingredients in Tone & Define Pink Lemonade by GNC Total Lean Advanced

These are the 8 active ingredients this product is made of. Select any to open its full monograph.

Serving size6.9 Gram(s) Dosage formPowder Servings per container24 Amounts shown are per serving.

Most supplement products combine several ingredients, and a medication can interact with the product through any one of them. Each ingredient below shows whether it has known drug interactions.

Sugar

0 Gram(s) per serving

Sodium

Interacts with
205 drugs
10 mg per serving

Sodium is an essential mineral and electrolyte your body needs to balance fluids, support nerves, and help muscles work. Most people in modern diets g...

Sodium monograph & interactions

EGCG

25 mg per serving Form: decaffeinated Green Tea extract

Clarinol CLA

1.7 Gram(s) per serving Form: Safflower Oil

Citri-Sculpt(TM) Blend

450 mg per serving

Other (inactive) ingredients: Citric Acid, Natural Flavors, Sucralose, Silica, Acesulfame Potassium, Beet, Grape. These complete the product’s ingredient list but are not active constituents.

Interaction report

Tone & Define Pink Lemonade by GNC Total Lean Advanced Drug Interactions

Want to check YOUR meds against Tone & Define Pink Lemonade?

Ask about interactions with your drugs in plain English — “Can I take it with lisinopril?” — and we find you the answer in seconds, ingredient by ingredient.

 Go to the checker
1,376Drugs
784 Major 499 Moderate 93 Minor

Ingredients driving the most interactions

Grapefruit extract 990
Guarana extract 655
Sweet Orange extract 246
Sodium 205

Individual Drug Interactions

The ingredients in Tone & Define Pink Lemonade interact with 1,376 drugs. Click any drug to see the details.

4 of the 8 ingredients in Tone & Define Pink Lemonade interact with drugs. Each result below shows which ingredient is responsible. Grapefruit extract Guarana extract Sweet Orange extract Sodium

Each ingredient & the kinds of drugs it affects

For each ingredient in Tone & Define Pink Lemonade with known interactions, here are the types of medications they can affect. Open any type for the detail — or search your exact drug in the checker above.

Grapefruit extract62 drug types · 990 drugs

Amiodarone (Cordarone)

Grapefruit juice can increase blood levels of amiodarone, potentially increasing the effects and adverse effects of amiodarone.
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%.

Likelihood Probable Evidence B
Artemether (Artenam, Paluther)

Grapefruit juice can increase blood levels of oral artemether, potentially increasing the effects and adverse effects of artemether.
Clinical research shows that grapefruit juice increases the levels of oral artemether by 90% to 250% in healthy males.

Likelihood Likely Evidence B
Benzodiazepines

Grapefruit juice might increase blood levels of some oral benzodiazepines, potentially increasing the effects and adverse effects of these drugs.
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). 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. 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. This interaction does not appear to occur with alprazolam.

Likelihood Likely Evidence B
Buspirone (Buspar)

Grapefruit juice can increase blood levels of buspirone, potentially increasing the effects and adverse effects of buspirone.
Clinical research shows that grapefruit juice increases absorption and plasma concentrations of buspirone.

Likelihood Likely Evidence B
Calcium Channel Blockers

Grapefruit juice can increase blood levels of oral calcium channel blockers, potentially increasing the effects and adverse effects of these drugs.
Clinical research shows that grapefruit juice increases absorption and plasma concentrations of amlodipine, nifedipine, nisoldipine, verapamil, felodipine, nimodipine, nicardipine, diltiazem, pranidipine, nitrendipine, and manidipine, This interaction is likely the result of the inhibition of intestinal metabolism of these drugs by CYP3A4, although some research suggests grapefruit may alter plasma drug levels by reducing the rate of gastric emptying. Consuming grapefruit juice 1 liter daily increases steady state concentrations of verapamil by as much as 50%. However, some references dispute the clinical relevance of the interactions with amlodipine, diltiazem, and verapamil. Other research in healthy individuals suggests plasma levels of felodipine and nifedipine are not affected when given intravenously. There is considerable interindividual variability in the effect of grapefruit juice on drug metabolism, which might account for inconsistent study results. 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. Research indicates it is necessary to withhold grapefruit juice for as long as 3 days to avoid interactions with felodipine and nisoldipine.

Likelihood Likely Evidence B
Carbamazepine (Tegretol)

Grapefruit juice can increase blood levels of carbamazepine, potentially increasing the effects and adverse effects of carbamazepine.
Clinical research shows that grapefruit juice increases absorption and plasma concentrations of carbamazepine.

Likelihood Likely Evidence B
Carvedilol (Coreg)

Grapefruit juice can increase blood levels of carvedilol, potentially increasing the effects and adverse effects of carvedilol.
Clinical research shows that grapefruit juice increases the bioavailability of a single dose of carvedilol by 16%.

Likelihood Likely Evidence B
Celiprolol (Celicard)

Grapefruit juice can decrease blood levels of celiprolol, potentially decreasing the clinical effects of celiprolol.
In human research, taking grapefruit juice within two hours of celiprolol appears to decrease absorption and blood levels of celiprolol by approximately 85%. This interaction is due to grapefruit-induced inhibition of organic anion transporting polypeptide (OATP). 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.

Likelihood Probable Evidence B
Cisapride (Propulsid)

Grapefruit juice can increase blood levels of cisapride, potentially increasing the effects and adverse effects of cisapride.
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.

Likelihood Likely Evidence B
Clomipramine (Anafranil)

Theoretically, grapefruit juice might increase blood levels of clomipramine, potentially increasing the effects and adverse effects of clomipramine.
Case reports have shown that clomipramine trough levels increase significantly after the addition of grapefruit juice to the therapeutic regimen.

Likelihood Probable Evidence D
Clopidogrel (Plavix)

Grapefruit juice can decrease blood levels of the active metabolite of clopidogrel, thereby decreasing the antiplatelet effect of clopidogrel.
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.

Likelihood Probable Evidence B
Cyclosporine (Neoral, Sandimmune)

Grapefruit juice can increase blood levels of oral cyclosporine, potentially increasing the effects and adverse effects of cyclosporine.
Clinical research shows that grapefruit juice increases the absorption and plasma concentrations of cyclosporine. The mechanism of action is unclear. However, there is no effect on intravenous cyclosporine.

Likelihood Likely Evidence B
Cytochrome P450 3A4 (Cyp3A4) Substrates

Grapefruit juice can increase levels of drugs metabolized by CYP3A4.
Clinical research shows that grapefruit juice can inhibit CYP3A4 metabolism of drugs, causing increased drug levels and potentially increasing the risk of adverse effects. When taken orally, effects of grapefruit juice on CYP3A4 levels appear to last at least 48 hours. 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.
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.

Likelihood Likely Evidence B
Dextromethorphan (Robitussin Dm, Others)

Grapefruit juice can increase blood levels of dextromethorphan, potentially increasing the effects and adverse effects of dextromethorphan.
Clinical research shows that grapefruit juice can inhibit cytochrome P450 3A4 (CYP3A4) metabolism, causing increased dextromethorphan levels.

Likelihood Probable Evidence B
Estrogens

Grapefruit juice can increase blood levels of estrogens, potentially increasing the effects and adverse effects of estrogens.
Clinical research shows that grapefruit increases the levels of endogenous and exogenous estrogens by inhibiting cytochrome P450 3A4 (CYP3A4) enzymes. Grapefruit juice increases exogenously administered 17-beta-estradiol by about 20% in females without ovaries and ethinyl-estradiol in healthy females.

Likelihood Probable Evidence B
Etoposide (Vepesid)

Grapefruit juice can decrease blood levels of etoposide, potentially decreasing the clinical effects of etoposide.
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%. Grapefruit juice seems to inhibit organic anion transporting polypeptide (OATP), which is a drug transporter in the gut, liver, and kidney. 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.

Likelihood Probable Evidence B
Halofantrine

Grapefruit juice can increase blood levels of halofantrine, potentially increasing the effects and adverse effects of halofantrine.
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.

Likelihood Probable Evidence B
Hmg-Coa Reductase Inhibitors ("Statins")

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).
Clinical research shows that grapefruit juice inhibits metabolism and increases absorption and plasma concentrations of statins that are metabolized by CYP3A4. These include lovastatin, simvastatin, and atorvastatin. 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.
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.

Likelihood Likely Evidence B
Methadone (Dolophine)

Grapefruit juice can increase blood levels of methadone, potentially increasing the effects and adverse effects of methadone.
Clinical research shows that grapefruit juice inhibits the metabolism of methadone, increasing methadone levels and peak concentrations. 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.

Likelihood Probable Evidence B
Methylprednisolone

Grapefruit juice can increase blood levels of methylprednisolone, potentially increasing the effects and adverse effects of methylprednisolone.
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%.

Likelihood Likely Evidence B
Organic Anion-Transporting Polypeptide Substrates (Oatp)

Grapefruit juice can decrease levels of drugs that are substrates of OATP.
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. 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.

Likelihood Likely Evidence B
Praziquantel (Biltricide)

Grapefruit juice can increase blood levels of praziquantel, potentially increasing the effects and adverse effects of praziquantel.
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.

Likelihood Probable Evidence B
Qt Interval-Prolonging Drugs

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.
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. The effect of smaller quantities of grapefruit juice on the QT interval is unclear.

Likelihood Probable Evidence B
Quetiapine (Seroquel)

Grapefruit juice may increase blood levels of quetiapine, increasing the effects and adverse effects of quetiapine.
Quetiapine is metabolized by cytochrome P450 3A4 (CYP3A4). Grapefruit can inhibit CYP3A4. 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.

Likelihood Probable Evidence B
Quinidine

Grapefruit juice can alter blood levels of quinidine, potentially increasing or decreasing the clinical effects of quinidine.
Clinical research shows that grapefruit juice decreases quinidine absorption, clearance, and metabolism, and prolongs the half-life by about 20%.

Likelihood Probable Evidence B
Grapefruit extract full monograph & all 62 interactions

Guarana extract41 drug types · 655 drugs

Ephedrine

Theoretically, concomitant use might increase the risk for stimulant adverse effects.
Guarana contains caffeine. Use of ephedrine with caffeine can increase the risk of stimulatory adverse effects. There is evidence that using ephedrine with caffeine might increase the risk of serious life-threatening or debilitating adverse effects such as hypertension, myocardial infarction, stroke, seizures, and death.

Likelihood Probable Evidence D
Adenosine (Adenocard)

Theoretically, guarana might decrease the vasodilatory effects of adenosine and interfere with its use prior to stress testing.
Guarana contains caffeine. Caffeine is a competitive inhibitor of adenosine at the cellular level. However, caffeine does not seem to affect supplemental adenosine because high interstitial levels of adenosine overcome the antagonistic effects of caffeine. It is recommended that methylxanthines and methylxanthine-containing products be stopped 24 hours prior to pharmacological stress tests. However, methylxanthines appear more likely to interfere with dipyridamole (Persantine) than adenosine-induced stress testing.

Likelihood Possible Evidence B
Anticoagulant/Antiplatelet Drugs

Theoretically, guarana may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.
In vitro and animal research suggests that guarana extract can inhibit platelet aggregation. This effect may be due to the caffeine in guarana, which is also reported to have antiplatelet activity. This interaction has not been reported in humans.

Likelihood Possible Evidence D
Beta-Adrenergic Agonists

Theoretically, concomitant use might increase the clinical effects of beta-adrenergic agonists.
Guarana contains caffeine. Theoretically, concomitant use of large amounts of caffeine might increase cardiac inotropic effects of beta-agonists.

Likelihood Probable Evidence D
Carbamazepine (Tegretol)

Theoretically, guarana might reduce the effects of carbamazepine and increase the risk for convulsions.
Animal research suggests that taking caffeine can lower the anticonvulsant effects of carbamazepine and can induce seizures when given to animals in doses above 400 mg/kg. Human research has shown that taking caffeine 300 mg in three divided doses along with carbamazepine 200 mg reduces the bioavailability of carbamazepine by 32% and prolongs the plasma half-life of carbamazepine two-fold in healthy individuals.

Likelihood Possible Evidence D
Cimetidine (Tagamet)

Theoretically, concomitant use might increase the effects and adverse effects of caffeine in guarana.
Guarana contains caffeine. Cimetidine decreases the rate of caffeine clearance by 31% to 42%.

Likelihood Likely Evidence B
Clozapine (Clozaril)

Theoretically, guarana might increase the levels and adverse effects of clozapine and acutely exacerbate psychotic symptoms.
Guarana contains caffeine. Caffeine can increase the effects and toxicity of clozapine. Caffeine doses of 400-1000 mg per day inhibit clozapine metabolism. Clozapine is metabolized by cytochrome P450 1A2 (CYP1A2). Researchers speculate that caffeine might inhibit CYP1A2. However, there is no reliable evidence that caffeine affects CYP1A2. There is also speculation that genetic factors might make some patients more sensitive to the interaction between clozapine and caffeine.

Likelihood Possible Evidence B
Dipyridamole (Persantine)

Theoretically, guarana might decrease the vasodilatory effects of dipyridamole and interfere with its use prior to stress testing.
Guarana contains caffeine. Caffeine might inhibit dipyridamole-induced vasodilation. It is recommended that methylxanthines and methylxanthine-containing products be stopped 24 hours prior to pharmacological stress tests. Methylxanthines appear more likely to interfere with dipyridamole than adenosine-induced stress testing.

Likelihood Probable Evidence B
Disulfiram (Antabuse)

Theoretically, disulfiram might increase the risk of adverse effects from caffeine.
In human research, disulfiram decreases the clearance and increases the half-life of caffeine.

Likelihood Probable Evidence D
Diuretic Drugs

Theoretically, using guarana with diuretic drugs might increase the risk of hypokalemia.
Guarana contains caffeine. Caffeine, especially in excessive amounts, can reduce potassium levels due to stimulation of the sodium-potassium pump. Diuretics can also lower potassium levels.

Likelihood Possible Evidence D
Estrogens

Theoretically, estrogens might increase the levels and adverse effects of caffeine.
Guarana contains caffeine. Estrogen inhibits caffeine metabolism.

Likelihood Probable Evidence B
Ethosuximide (Zarontin)

Theoretically, guarana might reduce the effects of ethosuximide and increase the risk for convulsions.
Guarana contains caffeine. Animal research shows that caffeine 92.4 mg/kg can decrease the anticonvulsant activity of ethosuximide. This effect has not been observed in humans.

Likelihood Possible Evidence D
Felbamate (Felbatol)

Theoretically, guarana might reduce the effects of felbamate and increase the risk for convulsions.
Guarana contains caffeine. Animal research shows that a high dose of caffeine 161.7 mg/kg can decreases the anticonvulsant activity of felbamate. This effect has not been observed in humans.

Likelihood Possible Evidence D
Flutamide (Eulexin)

Theoretically, guarana might increase the levels and adverse effects of flutamide.
Guarana contains caffeine. In vitro evidence shows that caffeine can inhibit the metabolism of flutamide. However, this effect has not been reported in humans.

Likelihood Probable Evidence D
Fluvoxamine (Luvox)

Theoretically, fluvoxamine might increase the levels and adverse effects of caffeine.
Guarana contains caffeine. Fluvoxamine reduces caffeine metabolism.

Likelihood Probable Evidence D
Lithium

Theoretically, abrupt guarana withdrawal might increase the levels and adverse effects of lithium.
Guarana contains caffeine. Theoretically, abrupt caffeine withdrawal might increase serum lithium levels. There are two case reports of lithium tremor that worsened upon abrupt coffee withdrawal.

Likelihood Probable Evidence D
Monoamine Oxidase Inhibitors (Maois)

Theoretically, concomitant use might increase the risk of a hypertensive crisis.
Guarana contains caffeine. Caffeine has been shown to inhibit MAO-A and -B in laboratory studies. Concomitant intake of large amounts of caffeine with MAOIs might precipitate a hypertensive crisis. In a case report, a patient that consumed 10-12 cups of caffeinated coffee and took the MAOI tranylcypromine presented with severe hypertension. Hypertension was resolved after the patient switched to drinking decaffeinated coffee.

Likelihood Possible Evidence D
Nicotine

Theoretically, concomitant use might increase the risk of hypertension.
Guarana contains caffeine. Concomitant use of caffeine and nicotine has been shown to have additive cardiovascular effects, including increased heart rate and blood pressure. Blood pressure was increased by 10.8/12.4 mmHg when the agents were used concomitantly.

Likelihood Probable Evidence D
Pentobarbital (Nembutal)

Theoretically, guarana might decrease the effects of pentobarbital.
Guarana contains caffeine. In vivo evidence suggests that caffeine can negate the hypnotic effects of pentobarbital in humans. However, animal research suggests that guarana does not alter the hypnotic effect of pentobarbital.

Likelihood Possible Evidence B
Phenobarbital (Luminal)

Theoretically, guarana might reduce the effects of phenobarbital and increase the risk for convulsions.
Guarana contains caffeine. Animal research shows that caffeine can decrease the anticonvulsant activity of phenobarbital. The exact mechanism of this interaction is unclear.

Likelihood Possible Evidence D
Phenylpropanolamine

Theoretically, phenylpropanolamine might increase the risk of hypertension, as well as the levels and adverse effects of caffeine.
Guarana contains caffeine. Concomitant use of phenylpropanolamine and caffeine might cause an additive increase in blood pressure. Phenylpropanolamine also seems to increase caffeine serum levels.

Likelihood Probable Evidence B
Phenytoin (Dilantin)

Theoretically, guarana might reduce the effects of phenytoin and increase the risk for convulsions.
Guarana contains caffeine. Animal research shows that caffeine can decrease the anticonvulsant activity of phenytoin. The effect does not seem to be related to the seizure threshold-lowering effects of caffeine. However, the exact mechanism of this interaction is unclear.

Likelihood Possible Evidence D
Pioglitazone (Actos)

Theoretically, guarana might increase the levels and clinical effects of pioglitazone.
Guarana contains caffeine. Animal research suggests that caffeine can modestly increase the maximum concentration, area under the curve, and half-life of pioglitazone, and also reduce its clearance. This increased the antidiabetic effects of pioglitazone. However, the exact mechanism of this interaction is unclear.

Likelihood Possible Evidence D
Riluzole (Rilutek)

Theoretically, concomitant use might increase the levels and adverse effects of both caffeine and riluzole.
Guarana contains caffeine. Caffeine and riluzole are both metabolized by cytochrome P450 1A2 (CYP1A2), and concomitant use might reduce the metabolism of one or both agents.

Likelihood Possible Evidence D
Stimulant Drugs

Theoretically, concomitant use might increase stimulant adverse effects.
Guarana contains caffeine. Due to the central nervous system (CNS) stimulant effects of caffeine, concomitant use with stimulant drugs can increase the risk of adverse effects.

Likelihood Possible Evidence D
Guarana extract full monograph & all 41 interactions

Sweet Orange extract7 drug types · 246 drugs

Celiprolol (Celicard)

Consuming sweet orange with celiprolol can decrease oral absorption of celiprolol.
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). Recommend separating drug administration and consumption of sweet orange by at least 4 hours.

Likelihood Likely Evidence B
Ivermectin (Stromectol, Others)

Consuming sweet orange juice with ivermectin can decrease the oral absorption of ivermectin.
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.

Likelihood Likely Evidence B
Organic Anion-Transporting Polypeptide Substrates (Oatp)

Consuming sweet orange juice can decrease oral absorption of OATP substrates. Separate administration by at least 4 hours.
Clinical research shows that consuming sweet orange juice inhibits OATP, which reduces bioavailability of oral drugs that are substrates of OATP. 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%. 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.

Likelihood Likely Evidence B
Pravastatin (Pravachol)

Consuming sweet orange juice with pravastatin can increase the absorption of pravastatin.
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. Sweet orange juice does not seem to affect simvastatin levels, but it is not known if sweet orange affects any of the other statins.

Likelihood Likely Evidence B
Fexofenadine (Allegra)

Consuming sweet orange juice with fexofenadine can decrease oral absorption of fexofenadine.
Clinical research shows that coadministration of sweet orange juice 1200 mL decreases bioavailability of fexofenadine by about 72%. In an animal model, sweet orange juice decreased bioavailability of fexofenadine by 31%. 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. Theoretically, this occurs due to short-term inhibition of organic anion transporting polypeptide (OATP). Recommend separating drug administration and consumption of sweet orange by at least 4 hours.

Likelihood Likely Evidence B
P-Glycoprotein Substrates

Sweet orange juice seems to modulate P-glycoprotein (P-gp), which might affect the blood levels of P-gp substrates.
Animal and in vitro research suggest that orange juice extract inhibits drug efflux by P-gp, increasing absorption and levels of P-gp substrates. 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). Until more is known, sweet orange juice should be used cautiously in people taking P-gp substrates.

Likelihood Possible Evidence B
Quinolone Antibiotics

Calcium-fortified sweet orange juice might reduce quinolone absorption.
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.

Likelihood Possible Evidence D
Sweet Orange extract full monograph & interactions

Sodium7 drug types · 205 drugs

Antihypertensive Drugs

Theoretically, a high intake of dietary sodium might reduce the effectiveness of antihypertensive drugs.
High intake of dietary sodium can increase systolic and diastolic blood pressure. Also, high intake of sodium may necessitate increased use of antihypertensive medications to achieve blood pressure control in some patients, such as those with chronic kidney disease.

Likelihood Probable Evidence A
Corticosteroids

Concomitant use of mineralocorticoids and some glucocorticoids with sodium supplements might increase the risk of hypernatremia.
Mineralocorticoids and some glucocorticoids (corticosteroids) cause sodium retention. This effect is dose-related and depends on mineralocorticoid potency. It is most common with hydrocortisone, cortisone, and fludrocortisone, followed by prednisone and prednisolone.

Likelihood Possible Evidence D
Didanosine (Videx)

Concomitant use of didanosine with additional sodium from dietary or supplemental sources may increase the risk of hypernatremia.
Didanosine formulations contain a significant amount of sodium.

Likelihood Probable Evidence C
Lithium

Altering dietary intake of sodium might alter the levels and clinical effects of lithium.
High sodium intake can reduce plasma concentrations of lithium by increasing lithium excretion. Reducing sodium intake can significantly increase plasma concentrations of lithium and cause lithium toxicity in patients being treated with lithium carbonate. Stabilizing sodium intake is shown to reduce the percentage of patients with lithium level fluctuations above 0.8 mEq/L. Patients taking lithium should avoid significant alterations in their dietary intake of sodium.

Likelihood Probable Evidence B
Sodium Phosphates

Theoretically, concomitant use of sodium phosphate with sodium supplements might increase the risk of hypernatremia.
Use of high doses (> 45 mL in 24 hours) of sodium phosphate, such as those used for bowel cleansing before surgery, can lead to serious electrolyte disturbances, including hypernatremia. The risk of hypernatremia is highest in the elderly and people with other risk factors for electrolyte disturbances.

Likelihood Possible Evidence D
Sodium-Containing Drugs

Concomitant use of sodium-containing drugs with additional sodium from dietary or supplemental sources may increase the risk of hypernatremia and long-term sodium-related complications.
The Chronic Disease Risk Reduction (CDRR) intake level of 2.3 grams of sodium daily indicates the intake at which it is believed that chronic disease risk increases for the apparently healthy population. Some medications contain high quantities of sodium. When used in conjunction with sodium supplements or high-sodium diets, the CDRR may be exceeded. Additionally, concomitant use may increase the risk for hypernatremia; this risk is highest in the elderly and people with other risk factors for electrolyte disturbances.

Likelihood Possible Evidence D
Tolvaptan (Samsca)

Theoretically, concomitant use of tolvaptan with sodium might increase the risk of hypernatremia.
Tolvaptan is a vasopressin receptor 2 antagonist that is used to increase sodium levels in patients with hyponatremia. Patients taking tolvaptan should use caution with the use of sodium salts such as sodium chloride.

Likelihood Probable Evidence C
Sodium full monograph & interactions
The maker

Brand information

Manufacturer and brand details for Tone & Define Pink Lemonade, from the product label.

GNC Total Lean Advanced

See all GNC Total Lean Advanced products
Name
General Nutrition Corporation
City
Pittsburgh
State
PA
ZipCode
15222
Pharmacist Counseling Corner

Tone & Define Pink Lemonade by GNC Total Lean Advanced: Common Questions

Does Tone & Define Pink Lemonade by GNC Total Lean Advanced interact with any medications?
Yes. Based on its ingredients, Tone & Define Pink Lemonade has a known interaction with 1,376 medications, including 784 rated major. Use the checker to see how it interacts with a specific drug.
How can one product interact with so many drugs?
Tone & Define Pink Lemonade contains 8 active ingredients, and an interaction can come from any of them. We check every ingredient, combine the results into one list per medication, and show which ingredient and mechanism is responsible.
Where does this information come from?
The product label data comes from the NIH Dietary Supplement Label Database (DSLD); the interaction data is built on the Natural Medicines database and reviewed by HelloPharmacist pharmacists.
Is there caffeine in this product?
Yes — Guarana extract is a key ingredient, and guarana is high in caffeine. This can cause jitteriness, insomnia, nervousness, dizziness, and tremors if you're sensitive or take too much. If you're sensitive to caffeine or have a heart rhythm problem, check with your pharmacist first.
Is this safe to take if I'm pregnant or breastfeeding?
The data isn't clear enough for a straight answer. Sodium is likely safe in pregnancy but possibly unsafe while breastfeeding; Sweet Orange and Blood Orange are likely safe in both. Guarana's safety during pregnancy and lactation is not on file. Talk with your doctor or pharmacist for personalized advice based on your specific situation.
What does the sodium in this do?
Sodium is a mineral that helps your body regulate fluids and nerve function. It's essential in small amounts, but too much is linked to high blood pressure and heart strain. If you already get plenty of sodium from food, adding a supplement may not be necessary — ask your pharmacist.
Will this help me lose weight or build muscle?
The data we have doesn't establish that these ingredients work for weight loss or muscle building. Sweet Orange, Blood Orange, Grapefruit, and Guarana all lack sufficient evidence to rate for the conditions they're commonly promoted for.
Are there any side effects from the orange extracts?
Orange extracts are generally well tolerated as food, but in concentrated supplement form they haven't been thoroughly studied. Large amounts of orange peel have caused intestinal cramping in children. Stick to the dose on the label.
What about the grapefruit in this — does it interact with my medications?
Yes, grapefruit extract can interact significantly with many drugs including cyclosporine, amiodarone, buspirone, and others. Use the checker on this page to search your medications against grapefruit's known interactions.

Written and reviewed by the HelloPharmacist editorial staff. Our editorial policy

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Label information is sourced from the NIH Dietary Supplement Label Database and reflects the product version on file; always read your actual product label. This page is for education only and is not a substitute for professional medical advice. Confirm with your pharmacist or doctor before combining supplements and medications.

Tone & Define Pink Lemonade label
Go deeper

The Full Monographs Behind Tone & Define Pink Lemonade’s Ingredients

Every ingredient we hold a full HelloPharmacist monograph for — uses, evidence, safety, and the complete interaction list.

Herb & supplement monograph

Sodium

Interacts with 205 drugs

Sodium is an essential mineral and electrolyte your body needs to balance fluids, support nerves, and help muscles work. Most people in modern diets get more than enough—often too much—from...

Read the full Sodium monograph → Herb & supplement monograph

Sweet Orange

Interacts with 246 drugs

Sweet orange is a common citrus fruit that is a good source of vitamin C, fiber, and antioxidants, and is enjoyed as a food worldwide. Its peel and essential oil are used in aromatherapy and...

Read the full Sweet Orange monograph → Herb & supplement monograph

Grapefruit

Interacts with 990 drugs

Grapefruit is a nutritious citrus fruit rich in vitamin C and other nutrients, and it is generally safe to eat. However, grapefruit is famous for serious interactions with many prescription...

Read the full Grapefruit monograph → Herb & supplement monograph

Guarana

Interacts with 655 drugs

Guarana is an Amazonian seed that is naturally high in caffeine, which explains most of its stimulant and energy effects. While it may give a short-term boost in alertness and reduce fatigue...

Read the full Guarana monograph →
Sources

Sources & How We Checked

Tone & Define Pink Lemonade's label data comes from the NIH Dietary Supplement Label Database; the ingredient interaction data is from the Natural Medicines database, reviewed by our pharmacists.

Content is written and reviewed by licensed HelloPharmacist pharmacists. See our data sources and editorial standards for how this information is built and checked.

The 326 references behind this product’s interaction data

Every citation that drives the interaction findings for this product’s ingredients, from the evidence-graded Natural Medicines (TRC Healthcare) database. Open an ingredient to browse its citations — links open the study on PubMed or the publisher’s site.

Sodium 38 references
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  2. Food and Drug Administration Science Background: Safety of Sodium Phosphates Oral Solution. September 17, 2001. Available at: http://www.fda.gov/cder/drug/safety/sodiumphospate.htm
  3. Coton T, Mallaret C, Coilliot C, Carre D, Guisset M. Severe acute ulcerated gastritis induced by salt. Presse Med 2009;38(3):499-500. PubMed
  4. Frings-Meuthen P, Buehlmeier J, Baecker N, et al. High sodium chloride intake exacerbates immobilization-induced bone resorption and protein losses. J Appl Physiol 2011;111(2):537-542. PubMed
  5. Frings-Meuthen P, Baecker N, Heer M. Low-grade metabolic acidosis may be the cause of sodium chloride-induced exaggerated bone resorption. J Bone Miner Res 2008;23(4):517-524. PubMed
  6. Alam S, Johnson AG. A meta-analysis of randomised controlled trials (RCT) among healthy normotensive and essential hypertensive elderly patients to determine the effect of high salt (NaCl) diet of blood pressure. J Hum Hypertens 1999;13(6):367-74.
  7. Boudville N, Ward S, Benaroia M, House AA. Increased sodium intake correlates with greater use of antihypertensive agents by subjects with chronic kidney disease. Am J Hypertens 2005;18(10):1300-5. PubMed
  8. Bennett WM. Drug interactions and consequences of sodium restriction. Am J Clin Nutr 1997;65(2 Suppl):678S-681S. PubMed
  9. Okusa MD, Crystal LJ. Clinical manifestations and management of acute lithium intoxication. Am J Med 1994;97(4):383-9. PubMed
  10. Food and Nutrition Board, Institute of Medicine. Dietary reference intakes for water, potassium, sodium, chloride, and sulfate. Washington, DC: National Academy Press, 2005. Available at: http://www.nap.edu/openbook.php?record_id=10925. DOI
  11. D'Elia L, Rossi G, Ippolito R, Cappuccio FP, Strazzullo P. Habitual salt intake and risk of gastric cancer: a meta-analysis of prospective studies. Clin Nutr 2012;31(4):489-98. PubMed
  12. Goldsmith SR. Hyponatremia in heart failure: time for a trial. J Card Fail 2013;19(6):398-400. PubMed
  13. Willocks L, Brettle R, Keen J, Valentine C, Pinching AJ. Formulations of didanosine (ddI) and salt overload. Lancet 1992;339(8786):190.
  14. Chen L, Zhang Z, Chen W, Whelton PK, Appel LJ. Lower Sodium Intake and Risk of Headaches: Results From the Trial of Nonpharmacologic Interventions in the Elderly. Am J Public Health. 2016;106(7):1270-5. PubMed
  15. Cook NR, Appel LJ, Whelton PK. Lower levels of sodium intake and reduced cardiovascular risk. Circulation. 2014;129(9):981-9. PubMed
  16. Cook NR, Appel LJ, Whelton PK. Sodium Intake and All-Cause Mortality Over 20 Years in the Trials of Hypertension Prevention. J Am Coll Cardiol. 2016;68(15):1609-1617. PubMed
  17. Mente A, O'Donnell M, Rangarajan S, et al. Associations of urinary sodium excretion with cardiovascular events in individuals with and without hypertension: a pooled analysis of data from four studies. Lancet. 2016;388(10043):465-75. PubMed
  18. Moosavian SP, Haghighatdoost F, Surkan PJ, Azadbakht L. Salt and obesity: a systematic review and meta-analysis of observational studies. Int J Food Sci Nutr. 2017;68(3):265-277. PubMed
  19. O'Donnell M, Mente A, Rangarajan S, et al. Urinary sodium and potassium excretion, mortality, and cardiovascular events. N Engl J Med. 2014;371(7):612-23. DOI
  20. Poggio R, Gutierrez L, Matta MG, Elorriaga N, Irazola V, Rubinstein A. Daily sodium consumption and CVD mortality in the general population: systematic review and meta-analysis of prospective studies. Public Health Nutr. 2015;18(4):695-704. PubMed
  21. Stallings VA, Harrison M, Oria M; Committee to Review the Dietary Reference Intakes for Sodium and Potassium, Food and Nutrition Board, Health and Medicine Division, National Academies of Sciences, Engineering, and Medicine. Washington (DC): National Acad
  22. Mahtani KR, Heneghan C, Onakpoya I, et al. Reduced Salt Intake for Heart Failure: A Systematic Review. JAMA Intern Med. 2018 Dec 1;178(12):1693-1700. PubMed
  23. Yancy CW. Sodium Restriction in Heart Failure: Too Much Uncertainty-Do the Trials. JAMA Intern Med. 2018 Dec 1;178(12):1700-1701. PubMed
  24. He FJ, Campbell NRC, Ma Y, MacGregor GA, Cogswell ME, Cook NR. Errors in estimating usual sodium intake by the Kawasaki formula alter its relationship with mortality: implications for public health. Int J Epidemiol. 2018;47(6):1784-1795. PubMed
  25. Murthy K, Ondrey GJ, Malkani N, et al. THE EFFECTS OF HYPONATREMIA ON BONE DENSITY AND FRACTURES: A SYSTEMATIC REVIEW AND META-ANALYSIS. Endocr Pract. 2019;25(4):366-378. PubMed
  26. Messerli FH, Hofstetter L, Syrogiannouli L, et al. Sodium intake, life expectancy, and all-cause mortality. Eur Heart J 2021;42(21):2103-2112. PubMed
  27. Graudal NA, Hubeck-Graudal T, Jurgens G. Effects of low sodium diet versus high sodium diet on blood pressure, renin, aldosterone, catecholamines, cholesterol, and triglyceride. Cochrane Database Syst Rev 2020;12(12):CD004022. PubMed
  28. Giatti S, Santos RB, Aielo AN, et al. Association of sodium with obstructive sleep apnea. The ELSA-Brasil study. Ann Am Thorac Soc 2021;18(3):502-510. PubMed
  29. Nan X, Lu H, Wu J, et al. The interactive association between sodium intake, alcohol consumption and hypertension among elderly in northern China: a cross-sectional study. BMC Geriatr 2021;21(1):135. PubMed
  30. Kyozuka H, Fukusda T, Murata T, et al. Impact of preconception sodium intake on hypertensive disorders of pregnancy: The Japan Environment and Children's study. Pregnancy Hypertens 2021;23:66-72. PubMed
  31. Zhao L, Ogden CL, Yang Q, et al. Association of usual sodium intake with obesity among US children and adolescents, NHANES 2009-2016. Obesity (Silver Spring) 2021;29(3):587-594. PubMed
  32. Ma Y, He FJ, Sun Q, et al. 24-Hour urinary sodium and potassium excretion and cardiovascular risk. N Engl J Med 2022;386(3):252-263. PubMed
  33. Liu J, Yang X, Zhang P, et al. Association of urinary sodium excretion and left ventricular hypertrophy in people with type 2 diabetes mellitus: A cross-sectional study. Front Endocrinol (Lausanne) 2021;12:728493. PubMed
  34. Filippini T, Malavolti M, Whelton PK, Vinceti M. Sodium intake and risk of hypertension: A systematic review and dose-response meta-analysis of observational cohort studies. Curr Hypertens Rep 2022;24(5):133-144. PubMed
  35. Wang DD, Li Y, Nguyen XT, et al. Dietary sodium and potassium intake and risk of non-fatal cardiovascular diseases: The million veteran program. Nutrients 2022;14(5):1121. PubMed
  36. Kwak JH, Park CH, Eun CS, et al. The associations of dietary intake of high sodium and low zinc with gastric cancer mortality: A prospective cohort study in Korea. Nutr Cancer 2022;74(10):3501-3508. PubMed
  37. George S, Maiti R, Mishra BR, Jena M, Mohapatra D. Effect of regulated add-on sodium chloride intake on stabilization of serum lithium concentration in bipolar disorder: A randomized controlled trial. Bipolar Disord 2023;25(1):66-75. PubMed
  38. Zhou TL, Schütten MTJ, Kroon AA, et al. Urinary Sodium Excretion and Salt Intake Are Not Associated With Blood Pressure Variability in a White General Population. J Am Heart Assoc 2023;12(1):e026578. PubMed

See these in context on the Sodium monograph →

Sweet Orange 17 references
  1. Leung AY, Foster S. Encyclopedia of Common Natural Ingredients Used in Food, Drugs and Cosmetics. 2nd ed. New York, NY: John Wiley & Sons, 1996.
  2. FDA, CFSAN. FDA-approved potassium health claim notification for potassium containing foods. 2000. Available at: www.cfsan.fda.gov/~dms/hclm-k.html.
  3. Kurowska EM, Spence JD, Jordan J, et al. HDL-cholesterol-raising effect of orange juice in subjects with hypercholesterolemia. Am J Clin Nutr 2000;72:1095-100. PubMed
  4. Murry JJ, Healy MD. Drug-mineral interactions: a new responsibility for the hospital dietician. J Am Diet Assoc 1991;91:66-73.
  5. Bailey DG, Dresser GK, Munoz C, et al. Reduction of fexofenadine bioavailability by fruit juices. Clin Pharmacol Ther 2001;69:P21.
  6. Pletz MW, Petzold P, Allen A, et al. Effect of calcium carbonate on bioavailability of orally administered gemifloxacin. Antimicrob Agents Chemother 2003;47:2158-60.. PubMed
  7. Lilja JJ, Juntti-Patinen L, Neuvonen PJ. Orange juice substantially reduces the bioavailability of the beta-adrenergic-blocking agent celiprolol. Clin Pharmacol Ther 2004;75:184-90.
  8. Tian R, Koyabu N, Takanaga H, et al. Effects of grapefruit juice and orange juice on the intestinal efflux of P-glycoprotein substrates. Pharm Res 2002;19:802-9. PubMed
  9. Vanapalli SR, Chen Y, Ellingrod VL, et al. Orange juice decreases the oral bioavailability of ivermectin in health volunteers. Clin Pharmacol Ther 2003;73 (Abstract PDII-A-10):P94.
  10. Huang SM, Lesko LJ. Drug-drug, drug-dietary supplement, and drug-citrus fruit and other food interactions: what have we learned? J Clin Pharmacol 2004;44:559-69. PubMed
  11. Koitabashi Y, Kumai T, Matsumoto N, et al. Orange juice increased the bioavailability of pravastatin, 3-hydroxy-3-methylglutaryl CoA reductase inhibitor, in rats and healthy human subjects. Life Sci 2006;78:2852-9. PubMed
  12. Takanaga H, Ohnishi A, Yamada S, et al. Polymethoxylated flavones in orange juice are inhibitors of P-glycoprotein but not cytochrome P450 3A4. J Pharmacol Exp Ther 2000;293:230-6. DOI
  13. Greenblatt DJ. Analysis of drug interactions involving fruit beverages and organic anion-transporting polypeptides. J Clin Pharmacol 2009;49:1403-7. PubMed
  14. Bailey DG. Fruit juice inhibition of uptake transport: a new type of food-drug interaction. Br J Clin Pharmacol 2010;70:645-55. PubMed
  15. Kamath AV, Yao M, Zhang Y, Chong S. Effect of fruit juices on the oral bioavailability of fexofenadine in rats. J Pharm Sci 2005;94:233-9. PubMed
  16. Kays MB, Overholser BR, Mueller BA, et al. Effects of sevelamer hydrochloride and calcium acetate on the oral bioavailability of ciprofloxacin. Am J Kidney Dis. 2003;42(6):1253-9. PubMed
  17. Neuhofel, A. L., Wilton, J. H., Victory, J. M., Hejmanowsk, L. G., and Amsden, G. W. Lack of bioequivalence of ciprofloxacin when administered with calcium-fortified orange juice: a new twist on an old interaction. J Clin Pharmacol. 2002;42(4):461-466. DOI

See these in context on the Sweet Orange monograph →

Grapefruit 157 references
  1. Penzak SR, Gubbins PO, Gurley BJ, et al. Grapefruit juice decreases the systemic availability of itraconazole capsules in healthy volunteers. Ther Drug Monit 1999;21:304-9. PubMed
  2. Ioannides-Demos LL, Christophidis N, et al. Dosing implications of a clinical interaction between grapefruit juice and cyclosporine and metabolite concentrations in patients with autoimmune diseases. J Rheumatol 1997;24:49-54.
  3. Josefsson M, Zackrisson AL, Ahlner J. Effect of grapefruit juice on the pharmacokinetics of amlodipine in healthy volunteers. Eur J Clin Pharmacol 1996;51:189-93. PubMed
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  155. Piscitelli J, Nikanjam M, Capparelli EV, et al. Fexofenadine Plasma Concentrations to Estimate Systemic Exposure in Healthy Adults Using a Limited Sampling Strategy with a Population Pharmacokinetic Approach. Ther Drug Monit 2023;45(4):539-545. PubMed
  156. Abu Dayyih W, Zakaraya Z, Hailat M, et al. The Validation and Determination of Empagliflozin Concentration in the Presence of Grapefruit Juice Using HPLC for Pharmacokinetic Applications. Molecules 2024;29(6):1236. PubMed
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See these in context on the Grapefruit monograph →

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See these in context on the Guarana monograph →

Parts of this content are provided by the Therapeutic Research Center, LLC.

DISCLAIMER: Currently this does not check for drug-drug interactions. This is not an all-inclusive comprehensive list of potential interactions and is for informational purposes only. Not all interactions are known or well-reported in the scientific literature, and new interactions are continually being reported. Input is needed from a qualified healthcare provider including a pharmacist before starting any therapy. Application of clinical judgment is necessary.

© 2021 Therapeutic Research Center, LLC

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