Drug Interactions with Anticonvulsant Medications in Veterinary Patients: Phenobarbital, Potassium Bromide, and Levetiracetam

By Dr. Zubair Khalid, DVM, MS, PhD · 2026-08-11

Key Takeaways

• Phenobarbital is a potent hepatic enzyme inducer, accelerating the metabolism of co-administered drugs by upregulating CYP450 enzymes and glucuronosyltransferases, necessitating dose adjustments of concurrent medications and potentially phenobarbital itself (autoinduction).
• Potassium bromide's renal excretion is directly influenced by serum chloride levels; high chloride intake (e.g., high-salt diet, IV saline) increases bromide clearance, while chloride depletion (e.g., furosemide, low-salt diet) elevates serum bromide and toxicity risk.
• Levetiracetam is primarily renally excreted and does not significantly induce or inhibit hepatic enzymes, resulting in a narrower interaction profile, though drugs affecting renal blood flow or tubular secretion could theoretically alter its clearance.
• Enzyme induction by phenobarbital can decrease the efficacy of cardiovascular drugs like calcium channel blockers (e.g., felodipine) and antiarrhythmics (e.g., ivabradine), requiring dose escalation of these agents and careful monitoring for breakthrough events.
• Protein binding displacement has limited clinical relevance for phenobarbital and levetiracetam due to their low protein binding percentages; the primary concern with phenobarbital is its enzyme-inducing effect, not displacement of other drugs.
• Monitoring serum concentrations of phenobarbital and potassium bromide is crucial, with rechecks recommended 2-4 weeks after adding or removing enzyme-modifying drugs for phenobarbital, and after changes in salt intake or renal function for potassium bromide.

This article reviews clinically significant drug interactions involving the three most commonly prescribed anticonvulsants in canine and feline patients: phenobarbital, potassium bromide, and levetiracetam. It is written for practicing veterinarians who need to anticipate, identify, and manage interactions when epileptic patients receive concurrent medications for comorbid conditions. The focus is on pharmacokinetic interactions that alter anticonvulsant drug concentrations, pharmacodynamic interactions that affect seizure threshold or adverse effect profiles, and practical monitoring strategies.

The clinical questions addressed include: which concurrent drugs will lower or raise serum anticonvulsant concentrations, when should therapeutic drug monitoring be repeated after adding or removing a medication, and how do enzyme induction and protein binding displacement differ among these three agents. Species differences between dogs and cats are highlighted where they affect interaction risk or clinical decision-making.

At a Glance

Pharmacokinetic Foundations of Anticonvulsant Interactions

The three anticonvulsants differ fundamentally in their pharmacokinetic profiles, and these differences determine their interaction potential. Phenobarbital is a potent hepatic enzyme inducer that upregulates cytochrome P450 enzymes and glucuronosyltransferases, accelerating the metabolism of many co-administered drugs. This induction develops over one to several weeks and persists for weeks after phenobarbital withdrawal. The clinical consequence is that drugs metabolized by these pathways may require dose escalation when phenobarbital is added, and dose reduction when phenobarbital is discontinued.

Potassium bromide is eliminated almost entirely by renal excretion, with minimal hepatic metabolism. Its renal handling is linked to chloride reabsorption in the proximal tubule. High chloride intake, such as from a high-salt diet or intravenous saline, increases bromide clearance and lowers serum bromide concentrations. Conversely, chloride depletion, as occurs with furosemide therapy or low-salt diets, increases bromide reabsorption and can raise serum bromide to toxic levels. Bromide also competes with chloride for gastrointestinal absorption, so concurrent oral chloride supplementation can reduce bromide bioavailability.

Levetiracetam undergoes minimal hepatic metabolism in dogs and cats, with the majority of the dose excreted unchanged in urine. It does not induce or inhibit cytochrome P450 enzymes and does not displace other drugs from protein binding sites. Its interaction profile is therefore substantially narrower than that of phenobarbital. However, because renal excretion is the dominant elimination pathway, drugs that alter renal blood flow or compete for tubular secretion may theoretically affect levetiracetam clearance, although clinically significant interactions are uncommon.

Enzyme Induction and Its Clinical Consequences

Phenobarbital's enzyme-inducing effect is the most consequential interaction mechanism in veterinary anticonvulsant therapy. The induction affects also drugs metabolized by the liver but also endogenous compounds such as thyroid hormones, bilirubin, and vitamin D metabolites. When phenobarbital is added to a regimen, the metabolism of co-administered drugs such as corticosteroids, theophylline, cyclosporine, and certain antimicrobials can increase by 30% to 50%, often requiring empiric dose adjustments and therapeutic drug monitoring where available.

The onset and offset of enzyme induction follow a predictable time course. Induction begins within days of initiating phenobarbital and reaches steady state after approximately two to three weeks. When phenobarbital is withdrawn, enzyme activity declines gradually over two to four weeks. During this transition period, serum concentrations of co-administered drugs may rise, and dose reductions may be necessary to avoid toxicity. The same principle applies when phenobarbital is added to an existing regimen: serum concentrations of the existing drug will fall, and the clinician should anticipate the need for dose increases based on clinical response and, where available, serum drug monitoring.

Enzyme induction also affects phenobarbital itself, a phenomenon known as autoinduction. Phenobarbital accelerates its own metabolism, which explains why serum concentrations may decline during the first weeks of therapy and why dose adjustments are often needed before steady state is achieved. This autoinduction is more pronounced in dogs than in cats, and it complicates the interpretation of early serum drug concentrations.

Protein Binding Displacement

Protein binding displacement is a mechanism that receives considerable attention in human pharmacology but has limited clinical relevance for the anticonvulsants discussed here. Phenobarbital is only approximately 45% protein bound in dogs, and levetiracetam is less than 10% bound. Potassium bromide is not protein bound to any meaningful degree. For a displacement interaction to be clinically significant, the drug must be highly protein bound, have a narrow therapeutic index, and the displaced fraction must be large enough to alter pharmacodynamics.

In veterinary patients, the more relevant concern is the opposite direction: phenobarbital, as an enzyme inducer, can increase the production of drug-binding proteins such as albumin, which may transiently lower free drug concentrations of highly bound co-administered drugs. This effect is usually clinically insignificant because free drug concentration returns to baseline as total concentration adjusts. The practical guidance is to interpret serum drug concentrations in the context of clinical response instead of to make dose adjustments based solely on calculated free fractions.

Cardiovascular Drug Interactions

Patients with epilepsy frequently develop cardiac disease, and the interaction between anticonvulsants and cardiovascular medications is a common clinical scenario. Enzyme-inducing anticonvulsants such as phenobarbital accelerate the metabolism of several cardiovascular agents, including calcium channel blockers such as felodipine and verapamil, and the antiarrhythmic agents ivabradine and ranolazine. The clinical consequence is reduced efficacy of the cardiovascular drug, which may manifest as inadequate blood pressure control or breakthrough arrhythmias. Conversely, some cardiovascular drugs have proconvulsant or anticonvulsant properties that may alter seizure control independent of pharmacokinetic interactions, as reviewed in the literature on drug treatments in patients with cardiac diseases and epilepsy drug treatments in patients with cardiac diseases and epilepsy.

When adding a cardiovascular drug to an epileptic patient already receiving phenobarbital, the veterinarian should anticipate reduced cardiovascular drug exposure and plan for dose titration based on clinical endpoints such as blood pressure, heart rate, or rhythm control. When phenobarbital is discontinued in a patient stabilized on a cardiovascular drug, the cardiovascular drug concentration may rise, and toxicity may emerge. This scenario requires proactive communication with the owner and, where feasible, monitoring of the cardiovascular drug effect.

Interactions Affecting Seizure Threshold

Beyond pharmacokinetic interactions, some concurrent medications can lower the seizure threshold and reduce the efficacy of anticonvulsant therapy. Psychostimulants, certain antidepressants, and some antimicrobials have been associated with proconvulsant effects. The decision to use a potentially proconvulsant drug in a patient with epilepsy requires a risk-benefit assessment that considers the severity of the seizure disorder, the availability of alternative therapies, and the potential for dose-dependent effects. A structured approach to evaluating the safety of such drugs, including review of prescribing information and consultation with the manufacturer, has been described for modafinil and armodafinil in human patients with seizure disorders a method for deciding about the possible safety of modafinil and armodafinil in patients with seizure disorder. The same logic applies in veterinary medicine: the clinician should seek evidence on seizure risk, consider the dose-response relationship, and monitor the patient closely after initiation.

The interaction between anticonvulsants and drugs acting at the GABA receptor complex deserves specific mention. Benzodiazepines and neuroactive steroids potentiate GABAergic inhibition, and their combination with phenobarbital can produce additive sedation and ataxia. Experimental work in mice has shown that neuroactive steroids can potentiate the antiseizure efficacy of benzodiazepines, but also that the combination produces motor incoordination at doses that are individually benign evaluation of in vivo interactions in mice between flurazepam and two neuroactive steroids. This illustrates the general principle that pharmacodynamic synergy at the GABA receptor can be therapeutically useful but carries a narrow margin between benefit and adverse effects.

Clinical Assessment Sequence for Suspected Interactions

When an adverse interaction is suspected, the evaluation should proceed in a defined order. First, confirm the timing relationship between drug administration and the observed clinical change. Second, verify that the patient is receiving the intended dose of each medication, because owner administration errors and pharmacy dispensing errors produce clinical pictures identical to pharmacokinetic interactions. Third, review the complete medication list, including topical products, ophthalmic preparations, nutritional supplements, and any compounded formulations, since these are frequently omitted from the history.

The next step is to determine whether the change reflects altered drug exposure or altered drug effect. Serum drug concentration measurement is the decisive test for phenobarbital and potassium bromide. Levetiracetam concentration monitoring is less routinely available and less clearly correlated with clinical response, so the assessment relies more heavily on clinical observation and exclusion of other causes. If concentrations are within the therapeutic range but toxicity is present, consider protein binding displacement or pharmacodynamic interactions. If concentrations are subtherapeutic, suspect enzyme induction or reduced absorption.

Document the baseline seizure frequency, the nature of the adverse effect, and the temporal relationship to the added medication. This record becomes the reference point for judging whether an interaction is clinically significant after intervention. Recheck serum concentrations at the expected time to steady state after any change in the interacting drug, which for phenobarbital is approximately two weeks and for potassium bromide is two to three months.

Monitoring Parameters and Their Interpretation

The table below summarizes the monitoring approach for each anticonvulsant and the interactions most likely to require adjustment.

For phenobarbital, the free fraction increases in hypoalbuminaemic patients, so a total concentration in the upper therapeutic range may correspond to a toxic free concentration. This situation arises in patients with hepatic disease, protein-losing enteropathy, or malnutrition. Measure albumin when interpreting phenobarbital concentrations in these populations. The MSD Veterinary Manual professional edition provides species-specific reference ranges and interpretive guidance for anticonvulsant therapeutic drug monitoring.

Interaction Management Strategies

When an interaction is identified, the first decision is whether to continue the interacting drug. If the interacting medication is essential and no alternative exists, adjust the anticonvulsant dose and monitor. If the interacting drug can be replaced with one that does not affect the anticonvulsant, substitution is often the simpler path.

For enzyme induction, the induced state develops over one to three weeks. Recheck phenobarbital concentration two weeks after starting or stopping the inducer. Dose adjustments should be made in increments of 10 to 20 percent, with repeat concentration measurement after each change. When the inducer is discontinued, phenobarbital concentrations rise over the same time course, and the dose must be reduced pre-emptively to avoid toxicity. This is a common failure mode when a patient finishes a course of an inducing drug and the anticonvulsant dose is not reduced.

For protein binding displacement, the acute rise in free drug concentration may produce transient sedation or ataxia. The total concentration falls as the free fraction is cleared, and a new steady state is reached within one to two weeks. The clinical rule is to treat the patient, not the number, and to avoid dose increases based on a low total concentration during the adaptation period.

For potassium bromide, interactions that alter renal chloride handling have the largest effect. High chloride intake from a change in diet or from intravenous saline increases bromide clearance and lowers serum bromide concentration. Chloride depletion from vomiting, diuretic use, or a low-chloride diet increases bromide reabsorption and raises the risk of bromide toxicity. Monitor serum chloride alongside bromide, and correct chloride derangements before adjusting the bromide dose.

Species-Specific Considerations

Cats differ from dogs in several relevant ways. Feline hepatic glucuronidation capacity is limited, which affects the metabolism of some concurrent drugs but has less direct impact on phenobarbital, which is metabolised by cytochrome P450 enzymes. Cats are more sensitive to the sedative effects of phenobarbital and potassium bromide, so adverse effect scoring must account for species-specific normal behavior. Levetiracetam is used more frequently in cats because of its favourable tolerability profile, and dose adjustments for renal insufficiency are particularly relevant in older cats with chronic kidney disease.

Dogs show greater variability in phenobarbital metabolism, and breed differences in cytochrome P450 activity have been described, although the clinical significance is not always predictable. The FDA Center for Veterinary Medicine maintains approved labeling information that includes species-specific warnings and adverse event reporting pathways for anticonvulsant products.

In patients with cardiac disease, the interaction between anticonvulsants and cardiovascular drugs requires particular attention. Enzyme-inducing anticonvulsants reduce the concentrations of several calcium channel blockers and other cardiovascular agents, which may lead to loss of blood pressure control or arrhythmia management. Conversely, some cardiovascular drugs have proconvulsant properties at high doses, and the combination with anticonvulsants requires careful titration. A review of drug treatments in patients with cardiac disease and epilepsy identifies the most important interactions as occurring between enzyme-inducing antiseizure medications and ivabradine, ranolazine, and the calcium channel blocker felodipine, among others drug treatments in patients with cardiac diseases and epilepsy.

Documentation and Communication

The medical record should include the indication for each anticonvulsant, the target serum concentration range, the baseline seizure frequency, and the adverse effect baseline. When an interaction is suspected, record the suspected mechanism, the evidence supporting it, and the planned monitoring interval. Include a clear statement of what change would trigger a dose adjustment and what change would trigger discontinuation of the interacting drug.

Owner communication should cover the expected time course of the interaction, the signs of anticonvulsant toxicity to watch for, and the importance of not discontinuing anticonvulsants abruptly. Abrupt withdrawal of phenobarbital or potassium bromide can precipitate withdrawal seizures, and this risk must be weighed against the interaction being managed. The AVMA practice resources provide guidance on client communication and medical record standards that apply to chronic medication management.

When the interacting drug is an antimicrobial, the principles of antimicrobial stewardship apply. The choice of antimicrobial should consider also spectrum and resistance patterns but also the potential for enzyme induction or inhibition that affects anticonvulsant concentrations. The AVMA antimicrobial use and stewardship guidance supports a framework in which the antimicrobial is selected based on culture and susceptibility results, and the anticonvulsant dose is adjusted proactively when an interaction is anticipated.

Recognized Complications and Early Detection

The most consequential failure mode in anticonvulsant polypharmacy is silent loss of seizure control. Owners may attribute breakthrough seizures to disease progression when a newly added drug has lowered the anticonvulsant concentration. Early detection depends on timed serum concentration measurement, not on clinical impression. For phenobarbital, a trough sample drawn 2 weeks after any drug addition or removal identifies induction or inhibition before the owner observes a pattern of increasing seizure frequency. For potassium bromide, the long half-life means steady state is not reached for months, so early changes in serum bromide concentration are small and easily misinterpreted as laboratory noise. A rising bromide concentration with unchanged dosing should prompt a review of concurrent drugs that compete for renal chloride reabsorption, particularly loop diuretics or corticosteroids.

Hepatotoxicity from enzyme-inducing anticonvulsants is a second recognized complication. Phenobarbital raises serum alkaline phosphatase through hepatic enzyme induction alone, which does not indicate injury. Discriminating induction from true hepatotoxicity requires paired measurement of alanine aminotransferase, bile acids, and albumin. A rising ALT with falling albumin or abnormal bile acids supports injury, whereas isolated ALP elevation with normal bile acids is expected induction. Serial trends matter more than single values.

Pancreatitis has been associated with potassium bromide in dogs, although the causal link remains debated. Vomiting, anorexia, and cranial abdominal pain in a dog receiving bromide should trigger lipase measurement and abdominal ultrasound, not automatic dose reduction. The bromide dose should be held only if pancreatitis is confirmed, because abrupt withdrawal can precipitate status epilepticus.

Common Errors and Corrective Action

Less experienced clinicians frequently misinterpret a subtherapeutic phenobarbital concentration as proof of noncompliance. The more common explanation is enzyme induction by a concurrently administered drug, particularly another CYP inducer. The corrective action is to review the complete medication list, including topical products, before increasing the phenobarbital dose.

A second recurring error is adding levetiracetam without adjusting the phenobarbital dose when phenobarbital concentrations are already at the upper reference range. Levetiracetam does not induce phenobarbital metabolism, so the combination may push the patient into sedation without added efficacy. The corrective action is to measure both drugs after steady state and to reduce phenobarbital if sedation is disproportionate.

Students often assume that protein binding displacement is clinically important for phenobarbital because it is highly protein bound. This is incorrect. Phenobarbital has a low extraction ratio and a large volume of distribution, so displacement transiently raises free fraction but total concentration falls and free concentration returns to baseline. The clinically relevant displacement interactions occur with drugs that are both highly bound and narrow therapeutic index, which is not the case for the three anticonvulsants covered here.

Limitations of the Evidence and Divergent Expert Opinion

The veterinary evidence base for anticonvulsant interactions is largely extrapolated from human medicine and from experimental animal models. Direct comparative studies in dogs and cats are scarce, and most dosing recommendations derive from clinical experience instead of controlled trials. The interaction between phenobarbital and cardiovascular drugs such as calcium channel blockers is well documented in humans, but the magnitude of the effect in dogs is inferred, not measured. Clinicians should therefore expect individual variation and verify with serum concentrations instead of assume a predictable percentage change.

Expert opinion diverges on the value of routine therapeutic drug monitoring for levetiracetam. Some neurologists argue that the wide therapeutic index makes monitoring unnecessary, while others recommend trough measurement in refractory cases to document exposure. Both positions are defensible, and the decision should rest on whether the result will change management. A similar divergence exists on the use of potassium bromide as a first-line agent versus a rescue drug, which affects how aggressively interactions are investigated before the drug is chosen.

Referral, Specialist Consultation, and Regulatory Reporting

Referral to a veterinary neurologist is warranted when seizures remain uncontrolled despite documented therapeutic concentrations of two anticonvulsants, when status epilepticus recurs, or when a suspected interaction cannot be resolved by dose adjustment. Specialist consultation is also appropriate before adding a third anticonvulsant, because the evidence for specific combinations is limited and the risk of cumulative sedation rises.

Laboratory involvement is indicated when hepatotoxicity is suspected, when serum concentrations are discordant with clinical response, or when a patient requires monitoring of both renal function and bromide concentration. Reference laboratories can provide interpretive comments that flag potential interactions.

Regulatory reporting applies when an adverse drug event occurs in a patient receiving an approved animal drug. The FDA Center for Veterinary Medicine maintains an adverse event reporting system for animal drugs, and veterinarians in the United States should report suspected adverse reactions, including suspected interactions, through that channel. The FDA Center for Veterinary Medicine animal drug information provides the reporting pathway. Professional guidance on responsible medication use and stewardship is available through the AVMA antimicrobial use and stewardship resources, which, while focused on antimicrobials, outlines the same principles of judicious prescribing that apply to chronic anticonvulsant therapy.

Frequently Asked Questions

How should I adjust anticonvulsant monitoring when a client cannot afford repeated serum drug concentration measurements?

When therapeutic drug monitoring is cost-prohibited, shift the emphasis to structured clinical observation. Ask the owner to maintain a seizure calendar recording date, time, duration, and character of each event, plus any observed sedation, ataxia, or polyphagia. Use the lowest effective dose and titrate slowly, allowing two to three weeks for steady state after each change. If an interacting drug is added, schedule a recheck examination at the expected time of peak interaction, usually two to four weeks later. Clinical signs of neurotoxicity or breakthrough seizures should prompt dose adjustment even without serum levels. Document the financial constraint and the monitoring plan in the medical record so subsequent clinicians understand the basis for therapeutic decisions.

What practical steps reduce interaction risk when therapeutic drug monitoring is unavailable in an emergency setting?

In an emergency hospital without same-day drug concentration assays, obtain a thorough medication history including over-the-counter and compounded products. Identify all enzyme-inducing or enzyme-inhibiting drugs before prescribing new anticonvulsant therapy. Choose agents with fewer protein binding and hepatic metabolism interactions when possible, such as levetiracetam, which has minimal hepatic metabolism. If an interacting drug must be used, start at the lower end of the labelled dose range and extend the dosing interval if sedation develops. Contact a veterinary clinical pharmacologist or a reference laboratory offering next-day assays for guidance. The FDA Center for Veterinary Medicine maintains approved product information that can clarify metabolic pathways and labelled interaction warnings.

Does the interaction profile of phenobarbital differ between dogs and cats in ways that change clinical decisions?

Yes. Cats have a reduced capacity for hepatic glucuronidation compared with dogs, which alters the metabolism of several concurrently administered drugs. Phenobarbital induces hepatic enzymes in both species, but the clinical consequences of induction can differ because of species-specific metabolic pathways. Cats also show a higher incidence of adverse effects such as facial pruritus and exfoliative dermatitis with phenobarbital, so the risk-benefit calculation for adding an interacting drug shifts. Potassium bromide requires longer loading periods in cats because of its slower elimination half-life. The MSD Veterinary Manual provides species-specific pharmacological guidance that should be consulted before adjusting therapy in feline patients.

What records should I keep when managing a patient on anticonvulsants that are receiving additional interacting medications?

Maintain a current medication list in the medical record that includes dose, route, frequency, start date, and prescriber for every drug, including compounded and nutraceutical products. Record the indication for each drug and note any known interaction potential at the time of prescribing. When an interacting drug is added or withdrawn, document the anticipated direction of the effect, the monitoring plan, and the date for reassessment. Include a note describing the client conversation, particularly if the owner declined recommended monitoring. The AVMA practice resources offer guidance on medical record standards that support continuity of care and defensible clinical decisions.

How do I explain a drug interaction to an owner who is reluctant to add a second medication?

Use concrete language that connects the interaction to observable outcomes. Explain that one drug can change how the body processes another, making the seizure medication either less effective or more likely to cause side effects. Give the owner a specific sign to watch for, such as increased sedation, wobbliness, or a change in seizure frequency. State clearly what you will do if that sign appears, such as adjusting the dose or measuring the blood level. Provide written instructions and a follow-up appointment date. Acknowledge the owner's concern and ask what specific worry is driving the reluctance, then address that concern directly. Document the discussion and the owner's decision in the record.

When should I suspect an interaction instead of progression of the underlying epilepsy?

Suspect an interaction when a change in seizure control or adverse effects follows a recent addition, withdrawal, or dose change of any concurrent medication within a plausible time frame, usually one to four weeks. Worsening seizures without a change in anticonvulsant dose, accompanied by new sedation or ataxia, suggests increased drug exposure from enzyme inhibition. Breakthrough seizures with reduced sedation suggest enzyme induction lowering anticonvulsant concentrations. If the patient was previously stable for months, progression of epilepsy is less likely than an interaction. Review the complete medication list, including topical products and supplements. The interaction between antiseizure medications and cardiovascular drugs is well documented in the human literature and should prompt similar scrutiny in veterinary patients, as described in drug treatments in patients with cardiac diseases and epilepsy.

Related Clinical & Scientific Guides

• Veterinary Formulary Essentials: Navigating Drug References
• Drug Interactions with Antiepileptic Drugs in Veterinary Patients: Managing Polypharmacy
• Drug Interactions with Corticosteroids in Veterinary Patients: A Comprehensive Review

References and Further Reading

• Clinical, genetic and environmental factors associated with congenital vertebral malformations.. 2013.
• A method for deciding about the possible safety of modafinil and armodafinil in patients with seizure disorder.. 2016.
• Drug treatments in patients with cardiac diseases and epilepsy.. 2020.
• Evaluation of in vivo interactions in mice between flurazepam and two neuroactive steroids.. 1996.
• FDA Center for Veterinary Medicine: Animal Drug Information. FDA CVM.
• AVMA Antimicrobial Use and Stewardship. American Veterinary Medical Association.
• MSD Veterinary Manual, Professional Edition. MSD Veterinary Manual.
• American Veterinary Medical Association Practice Resources. American Veterinary Medical Association.
• WOAH Terrestrial Animal Health Code. WOAH.

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• Drug Interactions with Antacids and Gastroprotectants in Veterinary Patients
• Drug Interactions with Antidiabetic Medications in Dogs and Cats
• Drug Interactions with Antiemetics in Veterinary Patients: Clinical Considerations

This article is educational professional reference material for veterinary audiences. It is not a substitute for veterinary diagnosis, individual clinical judgment, current product labeling, or applicable regulatory requirements.