Drug Interaction Report

GENERALLY AVOID: Coadministration with potent inducers of CYP450 2B6 may significantly decrease the plasma concentrations of bupropion. In vitro findings suggest that CYP450 2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, one of three active metabolites of bupropion. In 12 study patients with mood disorders, administration of a single 150 mg dose of bupropion during treatment with the potent CYP450 2B6 inducer carbamazepine (mean dose 942 mg/day for at least 3 weeks) decreased mean bupropion peak plasma concentration (Cmax) and systemic exposure (AUC) by 87% and 90%, respectively, compared to administration with placebo. Mean Cmax and AUC of two active metabolites were also significantly reduced (86% and 96%, respectively, for erythrohydrobupropion; 81% and 86%, respectively, for threohydrobupropion), while Cmax and AUC of hydroxybupropion increased by 71% and 50%, respectively. Although reduced therapeutic effects of bupropion may be anticipated from the interaction, the full clinical impact is uncertain, since metabolites are present in substantially higher plasma levels than the parent drug but have reduced potencies and possibly varied pharmacologic effects. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized in humans. In an antidepressant screening test performed on mice, hydroxybupropion was found to be one-half as potent as bupropion and both erythrohydrobupropion and threohydrobupropion were 5-fold less potent than bupropion.

MANAGEMENT: Concomitant use of bupropion with potent CYP450 2B6 inducers should be avoided when possible, particularly fixed-dose combination products such as bupropion-naltrexone and bupropion-dextromethorphan. For other bupropion products, increases in bupropion dosage should be guided by clinical response; however, the maximum recommended dosage should not be exceeded.

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MONITOR CLOSELY: The use of bupropion is associated with a dose-related risk of seizures. The risk may be further increased when coadministered with other agents that can reduce the seizure threshold, including antidepressants, CNS stimulants, acetylcholinesterase inhibitors, phenothiazines, and dopaminergic blocking agents such as neuroleptics and metoclopramide. These agents are often individually epileptogenic and may have additive effects when combined. The estimated incidence of seizures is approximately 0.4% for immediate-release bupropion hydrochloride at dosages between 300 to 450 mg/day (equivalent to 348 to 522 mg/day of bupropion hydrobromide), but increases almost tenfold between 450 mg and 600 mg/day (equivalent to 522 and 696 mg/day of bupropion hydrobromide). Data for sustained-release (SR) bupropion hydrochloride revealed a seizure incidence of approximately 0.1% at dosages up to 300 mg/day and 0.4% at 400 mg/day. Likewise, in clinical trials, an overall seizure incidence of approximately 0.1% has been reported with extended-release (XL) bupropion hydrochloride at dosages up to 450 mg/day and approximately 0.39% at 450 mg/day. The 0.4% seizure incidence may exceed that of other marketed antidepressants by as much as 4-fold.

ADJUST DOSE: Coadministration with bupropion may increase the plasma concentrations of drugs that are metabolized by CYP450 2D6, including many antidepressants, neuroleptics, CNS stimulants (e.g., amphetamines), metoclopramide, and some acetylcholinesterase inhibitors (e.g., donepezil, galantamine). The mechanism is decreased clearance due to inhibition of CYP450 2D6 activity by bupropion and its metabolite, hydroxybupropion. Approximately 93% of Caucasians and more than 98% of Asians and individuals of African descent are extensive metabolizers of CYP450 2D6 and may be affected by this interaction. In a study of 15 male volunteers who were extensive metabolizers of CYP450 2D6, administration of a single 50 mg dose of desipramine following treatment with bupropion 150 mg twice daily increased the desipramine peak plasma concentration (Cmax), systemic exposure (AUC) and half-life by an average of 2-, 5-, and 2-fold, respectively. The effect was present for at least 7 days after the last dose of bupropion. A case report describes a 4-fold increase in plasma levels of imipramine and its metabolite, desipramine, in a 64-year-old woman following the addition of bupropion 225 mg/day. Plasma levels of desipramine were increased twofold more than the imipramine levels, which is consistent with the fact that desipramine is primarily metabolized by CYP450 2D6 while imipramine is also metabolized by other CYP450 isoenzymes. In another report, an 83-year-old woman became unsteady, confused, and lethargic following the addition of bupropion SR 300 mg/day. Her nortriptyline level was found to have increased by 185%. A later rechallenge prompted recurrence of the interaction. Likewise, a 62-year-old woman with no history of seizures developed a generalized tonic-clonic seizure in association with toxic trimipramine plasma levels following the addition of bupropion 300 mg/day. No further seizures occurred following dosage reductions of both drugs.

MANAGEMENT: Extreme caution is advised if bupropion is administered with any substance that can reduce the seizure threshold, particularly in the elderly and in patients with a history of seizures or other risk factors for seizures (e.g., head trauma; brain tumor; severe hepatic cirrhosis; metabolic disorders; CNS infections; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; diabetes treated with oral hypoglycemic agents or insulin). Bupropion as well as concomitant medications should be initiated at the lower end of the dosage range and titrated gradually as needed and as tolerated. The maximum recommended dosage for the specific bupropion formulation should not be exceeded. Clinical and laboratory monitoring may be appropriate for concomitant medications that are substrates of CYP450 2D6 whenever bupropion is added to or withdrawn from therapy. Bupropion should be discontinued and not restarted in patients who experience a seizure during treatment.

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GENERALLY AVOID: Coadministration with fluoxetine may significantly increase the plasma concentrations of some tricyclic antidepressants (TCAs). The proposed mechanism is fluoxetine inhibition of CYP450 2D6, the isoenzyme responsible for the metabolic clearance of many antidepressant and psychotropic drugs. Seizures and delirium have been reported, as well as a fatality attributed to fluoxetine-induced chronic amitriptyline toxicity. Pharmacodynamically, the combination of fluoxetine (or any other selective serotonin reuptake inhibitor) and a TCA may potentiate the risk of serotonin syndrome, which is a rare but serious and potentially fatal condition thought to result from hyperstimulation of brainstem 5HT1A receptors.

MANAGEMENT: In general, the use of fluoxetine (or other SSRIs) with TCAs should be avoided if possible, or otherwise approached with caution if potential benefit is deemed to outweigh the risk. Pharmacologic response and plasma TCA levels should be monitored more closely whenever fluoxetine is added to or withdrawn from therapy in patients stabilized on their existing antidepressant regimen, and the TCA dosage adjusted as necessary. Patients should be monitored closely for signs and symptoms of TCA toxicity (e.g., sedation, dry mouth, blurred vision, constipation, urinary retention) and/or excessive serotonergic activity (e.g., CNS irritability, altered consciousness, confusion, myoclonus, ataxia, abdominal cramping, hyperpyrexia, shivering, pupillary dilation, diaphoresis, hypertension, and tachycardia). Due to the long half-life of fluoxetine and its active metabolite, norfluoxetine, the risk of interaction may persist for several weeks after discontinuation of fluoxetine. For this reason, some authorities recommend a washout period of two to five weeks before and after treatment with fluoxetine.

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MONITOR CLOSELY: The use of bupropion is associated with a dose-related risk of seizures. The risk may be further increased when coadministered with other agents that can reduce the seizure threshold, including antidepressants, CNS stimulants, acetylcholinesterase inhibitors, phenothiazines, and dopaminergic blocking agents such as neuroleptics and metoclopramide. These agents are often individually epileptogenic and may have additive effects when combined. The estimated incidence of seizures is approximately 0.4% for immediate-release bupropion hydrochloride at dosages between 300 to 450 mg/day (equivalent to 348 to 522 mg/day of bupropion hydrobromide), but increases almost tenfold between 450 mg and 600 mg/day (equivalent to 522 and 696 mg/day of bupropion hydrobromide). Data for sustained-release (SR) bupropion hydrochloride revealed a seizure incidence of approximately 0.1% at dosages up to 300 mg/day and 0.4% at 400 mg/day. Likewise, in clinical trials, an overall seizure incidence of approximately 0.1% has been reported with extended-release (XL) bupropion hydrochloride at dosages up to 450 mg/day and approximately 0.39% at 450 mg/day. The 0.4% seizure incidence may exceed that of other marketed antidepressants by as much as 4-fold.

ADJUST DOSE: Coadministration with bupropion may increase the plasma concentrations of drugs that are metabolized by CYP450 2D6, including many antidepressants, neuroleptics, CNS stimulants (e.g., amphetamines), metoclopramide, and some acetylcholinesterase inhibitors (e.g., donepezil, galantamine). The mechanism is decreased clearance due to inhibition of CYP450 2D6 activity by bupropion and its metabolite, hydroxybupropion. Approximately 93% of Caucasians and more than 98% of Asians and individuals of African descent are extensive metabolizers of CYP450 2D6 and may be affected by this interaction. In a study of 15 male volunteers who were extensive metabolizers of CYP450 2D6, administration of a single 50 mg dose of desipramine following treatment with bupropion 150 mg twice daily increased the desipramine peak plasma concentration (Cmax), systemic exposure (AUC) and half-life by an average of 2-, 5-, and 2-fold, respectively. The effect was present for at least 7 days after the last dose of bupropion. A case report describes a 4-fold increase in plasma levels of imipramine and its metabolite, desipramine, in a 64-year-old woman following the addition of bupropion 225 mg/day. Plasma levels of desipramine were increased twofold more than the imipramine levels, which is consistent with the fact that desipramine is primarily metabolized by CYP450 2D6 while imipramine is also metabolized by other CYP450 isoenzymes. In another report, an 83-year-old woman became unsteady, confused, and lethargic following the addition of bupropion SR 300 mg/day. Her nortriptyline level was found to have increased by 185%. A later rechallenge prompted recurrence of the interaction. Likewise, a 62-year-old woman with no history of seizures developed a generalized tonic-clonic seizure in association with toxic trimipramine plasma levels following the addition of bupropion 300 mg/day. No further seizures occurred following dosage reductions of both drugs.

MANAGEMENT: Extreme caution is advised if bupropion is administered with any substance that can reduce the seizure threshold, particularly in the elderly and in patients with a history of seizures or other risk factors for seizures (e.g., head trauma; brain tumor; severe hepatic cirrhosis; metabolic disorders; CNS infections; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; diabetes treated with oral hypoglycemic agents or insulin). Bupropion as well as concomitant medications should be initiated at the lower end of the dosage range and titrated gradually as needed and as tolerated. The maximum recommended dosage for the specific bupropion formulation should not be exceeded. Clinical and laboratory monitoring may be appropriate for concomitant medications that are substrates of CYP450 2D6 whenever bupropion is added to or withdrawn from therapy. Bupropion should be discontinued and not restarted in patients who experience a seizure during treatment.

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MONITOR CLOSELY: Concomitant use of agents with serotonergic activity such as serotonin reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, 5-HT1 receptor agonists, ergot alkaloids, cyclobenzaprine, lithium, St. John's wort, phenylpiperidine opioids, dextromethorphan, and tryptophan may potentiate the risk of serotonin syndrome, which is a rare but serious and potentially fatal condition thought to result from hyperstimulation of brainstem 5-HT1A and 2A receptors. Symptoms of the serotonin syndrome may include mental status changes such as irritability, altered consciousness, confusion, hallucination, and coma; autonomic dysfunction such as tachycardia, hyperthermia, diaphoresis, shivering, blood pressure lability, and mydriasis; neuromuscular abnormalities such as hyperreflexia, myoclonus, tremor, rigidity, and ataxia; and gastrointestinal symptoms such as abdominal cramping, nausea, vomiting, and diarrhea.

MANAGEMENT: In general, the concomitant use of multiple serotonergic agents should be avoided if possible, or otherwise approached with caution if potential benefit is deemed to outweigh the risk. Patients should be closely monitored for symptoms of the serotonin syndrome during treatment. Particular caution is advised when increasing the dosages of these agents. The potential risk for serotonin syndrome should be considered even when administering serotonergic agents sequentially, as some agents may demonstrate a prolonged elimination half-life. For example, some experts suggest a 5-week washout period following use of fluoxetine and 3 weeks following the use of vortioxetine before administering another serotonergic agent. Individual product labeling for washout periods should be consulted for current recommendations. If serotonin syndrome develops or is suspected during the course of therapy, all serotonergic agents should be discontinued immediately and supportive care rendered as necessary. Moderately ill patients may also benefit from the administration of a serotonin antagonist (e.g., cyproheptadine, chlorpromazine). Severe cases should be managed under consultation with a toxicologist and may require sedation, neuromuscular paralysis, intubation, and mechanical ventilation in addition to the other measures.

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MONITOR CLOSELY: The use of bupropion is associated with a dose-related risk of seizures. The risk may be further increased when coadministered with selective serotonin reuptake inhibitors (SSRI antidepressants or anorectics), monoamine oxidase inhibitors, neuroleptic agents, central nervous system stimulants, opioids, tricyclic antidepressants, other tricyclic compounds (e.g., cyclobenzaprine, phenothiazines), systemic steroids, or any substance that can reduce the seizure threshold (e.g., carbapenems, cholinergic agents, fluoroquinolones, interferons, chloroquine, mefloquine, lindane, theophylline). These agents are often individually epileptogenic and may have additive effects when combined. The estimated incidence of seizures is approximately 0.4% for immediate-release bupropion hydrochloride at dosages between 300 to 450 mg/day (equivalent to 348 to 522 mg/day of bupropion hydrobromide), but increases almost tenfold between 450 mg and 600 mg/day (equivalent to 522 and 696 mg/day of bupropion hydrobromide). Data for sustained-release (SR) bupropion hydrochloride revealed a seizure incidence of approximately 0.1% at dosages up to 300 mg/day and 0.4% at 400 mg/day. Likewise, in clinical trials, an overall seizure incidence of approximately 0.1% has been reported with extended-release (XL) bupropion hydrochloride at dosages up to 450 mg/day and approximately 0.39% at 450 mg/day. The 0.4% seizure incidence may exceed that of other marketed antidepressants by as much as 4-fold.

MANAGEMENT: Extreme caution is advised if bupropion is administered with any substance that can reduce the seizure threshold, particularly in the elderly and in patients with a history of seizures or other risk factors for seizures (e.g., head trauma; brain tumor; severe hepatic cirrhosis; metabolic disorders; CNS infections; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; diabetes treated with oral hypoglycemic agents or insulin). Bupropion as well as concomitant medications should be initiated at the lower end of the dosage range and titrated gradually as needed and as tolerated. The maximum recommended dosage for the specific bupropion formulation should not be exceeded. Bupropion should be discontinued and not restarted in patients who experience a seizure during treatment.

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MONITOR CLOSELY: Concomitant use of agents with serotonergic activity such as serotonin reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, 5-HT1 receptor agonists, ergot alkaloids, cyclobenzaprine, lithium, St. John's wort, phenylpiperidine opioids, dextromethorphan, and tryptophan may potentiate the risk of serotonin syndrome, which is a rare but serious and potentially fatal condition thought to result from hyperstimulation of brainstem 5-HT1A and 2A receptors. Symptoms of the serotonin syndrome may include mental status changes such as irritability, altered consciousness, confusion, hallucination, and coma; autonomic dysfunction such as tachycardia, hyperthermia, diaphoresis, shivering, blood pressure lability, and mydriasis; neuromuscular abnormalities such as hyperreflexia, myoclonus, tremor, rigidity, and ataxia; and gastrointestinal symptoms such as abdominal cramping, nausea, vomiting, and diarrhea.

MANAGEMENT: In general, the concomitant use of multiple serotonergic agents should be avoided if possible, or otherwise approached with caution if potential benefit is deemed to outweigh the risk. Patients should be closely monitored for symptoms of the serotonin syndrome during treatment. Particular caution is advised when increasing the dosages of these agents. The potential risk for serotonin syndrome should be considered even when administering serotonergic agents sequentially, as some agents may demonstrate a prolonged elimination half-life. For example, some experts suggest a 5-week washout period following use of fluoxetine and 3 weeks following the use of vortioxetine before administering another serotonergic agent. Individual product labeling for washout periods should be consulted for current recommendations. If serotonin syndrome develops or is suspected during the course of therapy, all serotonergic agents should be discontinued immediately and supportive care rendered as necessary. Moderately ill patients may also benefit from the administration of a serotonin antagonist (e.g., cyproheptadine, chlorpromazine). Severe cases should be managed under consultation with a toxicologist and may require sedation, neuromuscular paralysis, intubation, and mechanical ventilation in addition to the other measures.

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MONITOR: Carbamazepine may decrease serum concentrations of tricyclic antidepressants. The mechanism may be related to carbamazepine induction of CYP450 enzymes responsible for tricyclic antidepressant metabolism. Serum concentrations of carbamazepine may be increased by an unknown mechanism. Carbamazepine toxicity has been reported with desipramine. Additionally, tricyclic antidepressants may counteract the anticonvulsant effects of carbamazepine by lowering the seizure threshold.

MANAGEMENT: Clinical monitoring of serum concentrations, patient response, seizure control, and tolerance is recommended whenever either agent is added to or discontinued from an existing regimen, or when the dosage is changed.

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MONITOR: Fluoxetine may inhibit the hepatic metabolism of carbamazepine. Carbamazepine toxicity is possible. Data have been conflicting and one study has reported no significant pharmacokinetic interaction. A case of toxic serotonin syndrome has occurred in one patient who was taking both carbamazepine and fluoxetine.

MANAGEMENT: Until more information is available, close observation for clinical and laboratory evidence of carbamazepine toxicity is recommended. Dose adjustments may be required. Patients should be advised to report possible symptoms of carbamazepine toxicity (nausea, visual disturbances, dizziness, or ataxia) or serotonin syndrome (uncontrollable shivering, agitation, incoordination, restlessness, involuntary movements, hyperreflexia, and hyperarousal).

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MONITOR: Central nervous system- and/or respiratory-depressant effects may be additively or synergistically increased in patients taking multiple drugs that cause these effects, especially in elderly or debilitated patients. Sedation and impairment of attention, judgment, thinking, and psychomotor skills may increase.

MANAGEMENT: During concomitant use of these drugs, patients should be monitored for potentially excessive or prolonged CNS and respiratory depression. Cautious dosage titration may be required, particularly at treatment initiation. Ambulatory patients should be counseled to avoid hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

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GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of carbamazepine. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

In a small, randomized, crossover study, the administration of carbamazepine with grapefruit juice (compared to water) increased plasma drug concentrations by approximately 40%. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

MANAGEMENT: Patients receiving carbamazepine should be advised to avoid or limit consumption of alcohol. Given the drug's narrow therapeutic index, patients receiving carbamazepine therapy should preferably avoid the regular consumption of grapefruits and grapefruit juice to prevent any undue fluctuations in plasma drug levels. Patients should be advised to report signs of carbamazepine toxicity (nausea, visual disturbances, dizziness, or ataxia) to their physicians.

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GENERALLY AVOID: Excessive use or abrupt discontinuation of alcohol after chronic ingestion may precipitate seizures in patients receiving bupropion. Additionally, there have been rare postmarketing reports of adverse neuropsychiatric events or reduced alcohol tolerance in patients who drank alcohol during treatment with bupropion. According to one forensic report, a patient died after taking large doses of both bupropion and alcohol. It is uncertain whether a drug interaction was involved. Single-dose studies in healthy volunteers given bupropion and alcohol failed to demonstrate either a significant pharmacokinetic or pharmacodynamic interaction.

MANAGEMENT: The manufacturer recommends that alcohol consumption be minimized or avoided during bupropion treatment. The use of bupropion is contraindicated in patients undergoing abrupt discontinuation of alcohol.

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GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

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GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

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GENERALLY AVOID: Concomitant use of ethanol and a tricyclic antidepressant (TCA) may result altered TCA plasma levels and efficacy, and additive impairment of motor skills, especially driving skills. Acute ethanol ingestion may inhibit TCA metabolism, while chronic ingestion of large amounts of ethanol may induce hepatic TCA metabolism.

MANAGEMENT: Patients should be advised to avoid alcohol during TCA therapy. Alcoholics who have undergone detoxification should be monitored for decreased TCA efficacy. Dosage adjustments may be required.

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MONITOR: Additive or synergistic effects on blood pressure may occur when bupropion is combined with sympathomimetic agents such as nasal decongestants, adrenergic bronchodilators, ophthalmic vasoconstrictors, and systemic vasopressors. Treatment with bupropion can result in elevated blood pressure and hypertension. In clinical practice, hypertension, in some cases severe and requiring acute treatment, has been observed in patients receiving bupropion alone and in combination with nicotine replacement therapy. These events have occurred in both patients with and without evidence of preexisting hypertension. Furthermore, postmarketing cases of hypertensive crisis have been reported during the initial titration phase with bupropion-naltrexone treatment.

MANAGEMENT: Caution is advised when bupropion is used with other drugs that increase dopaminergic or noradrenergic activity due to an increased risk of hypertension. Blood pressure and heart rate should be measured prior to initiating bupropion therapy and monitored at regular intervals consistent with usual clinical practice, particularly in patients with preexisting hypertension. Dose reduction or discontinuation of bupropion should be considered in patients who experience clinically significant and sustained increases in blood pressure or heart rate.

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MONITOR: The concomitant use of bupropion and nicotine replacement for smoking cessation may increase the risk of hypertension. In a clinical study (n=250), 6.1% of patients who used sustained-release bupropion with nicotine transdermal system developed treatment-emergent hypertension, compared to 2.5% of patients treated with bupropion alone, 1.6% treated with nicotine alone, and 3.1% treated with placebo. Three patients in the bupropion plus nicotine group and one patient in the nicotine-only group discontinued treatment due to hypertension. The majority had evidence of preexisting hypertension.

MANAGEMENT: Blood pressure monitoring is recommended for patients concomitantly using bupropion and nicotine replacement for smoking cessation.

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The recommended maximum number of medicines in the 'Central Nervous System (CNS) Drugs' category to be taken concurrently is usually three. Your list includes five medicines belonging to the 'Central Nervous System (CNS) Drugs' category:

• amitriptyline
• fluoxetine
• Effexor (venlafaxine)
• Tegretol XR (carbamazepine)
• Wellbutrin (bupropion)

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.

The recommended maximum number of medicines in the 'psychotropic agents' category to be taken concurrently is usually three. Your list includes four medicines belonging to the 'psychotropic agents' category:

• amitriptyline
• fluoxetine
• Effexor (venlafaxine)
• Wellbutrin (bupropion)

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.

The recommended maximum number of medicines in the 'antidepressants' category to be taken concurrently is usually one. Your list includes four medicines belonging to the 'antidepressants' category:

• amitriptyline
• fluoxetine
• Effexor (venlafaxine)
• Wellbutrin (bupropion)

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.