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  • CLASSES

    Centrally-Acting Antiobesity Products

    DEA CLASS

    Rx, schedule IV

    DESCRIPTION

    Combination of an anorectic sympathomimetic amine and an antiepileptic drug.
    Used adjunctively for treatment of obesity if BMI >= 30 kg/m2 or if BMI >= 27 kg/m2 with at least one weight related comorbid condition.
    Available through Qsymia REMS program; additional information at www.QsymiaREMS.com or 1—888—998—4887.

    COMMON BRAND NAMES

    Qsymia

    HOW SUPPLIED

    Qsymia Oral Cap ER: 11.25-69mg, 15-92mg, 3.75-23mg, 7.5-46mg

    DOSAGE & INDICATIONS

    For the treatment of obesity as an adjunct to a reduced-calorie diet and increased physical activity.
    Oral dosage (phentermine and topiramate extended release capsules, e.g., Qsymia)
    Adults

    Initially, 3.75 mg/23 mg (phentermine/topiramate extended-release) PO once daily in the morning (avoid evening dosing) for 14 days. Increase to the recommended dose of 7.5 mg/46 mg PO once daily after 14 days. Evaluate weight loss at recommended dose after 12 weeks; if the patient has not lost at least 3% of baseline weight, discontinue therapy OR increase to 11.25 mg/69 mg PO once daily for 14 days, followed by a final increase to 15 mg/92 mg PO once daily. Evaluate weight loss at highest dose after an additional 12 weeks; if the patient has not lost at least 5% of baseline weight, discontinue as the patient is not likely to achieve and sustain meaningful weight loss with continued treatment. Discontinue the 15 mg/92 mg dose gradually by dosing every other day for at least 1 week prior to stopping treatment altogether, to avoid precipitating a seizure. The Qsymia 3.75 mg/23 mg and 11.25 mg/69 mg dosage strengths are for titration purposes only. Treatment is intended for those with an initial body mass index (BMI) of 30 kg/m2 or more, or those with a BMI of 27 kg/m2 or more in the presence of at least one weight-related comorbid condition (e.g., hypertension, dyslipidemia, type 2 diabetes). The BMI is calculated using the body weight in kilograms divided by height in meters squared. Safety and efficacy have not been established for coadministration with other products intended for weight loss, including prescription drugs, over-the-counter drugs, and dietary supplements/herbal preparations.

    MAXIMUM DOSAGE

    Adults

    15 mg phentermine/92 mg topiramate extended-release PO daily.

    Geriatric

    15 mg phentermine/92 mg topiramate extended-release PO daily.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Do not use.

    Neonates

    Do not use.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Mild hepatic impairment (Child Pugh Class A): No dose adjustment required.
    Moderate hepatic impairment (Child Pugh Class B): Do not exceed 7.5 mg/46 mg PO once daily.
    Severe hepatic impairment (Child Pugh Class C): Avoid use.

    Renal Impairment

    CrCl >= 50 ml/min: No dose adjustment required.
    CrCl 30 ml/min to less than 50 ml/min: Do not exceed 7.5 mg/46 mg PO once daily.
    CrCl < 30 ml/min: Do not exceed 7.5 mg/46 mg PO once daily. For patients with renal failure or end-stage renal disease (ESRD) on dialysis;, avoid use.
     
    Intermittent hemodialysis
    Avoid use in patients with end-stage renal disease on dialysis.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Consistent with good practices, do not open, crush, cut, or chew phentermine; topiramate extended release capsules or the capsule contents.
    Administer the capsules once daily in the morning with or without food.
    Avoid late evening administration because of the possibility of insomnia.

    STORAGE

    Qsymia:
    - Protect from moisture
    - Store between 59 to 77 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Phentermine; Topiramate is contraindicated in any person hypersensitive to the effects of the sympathomimetic amines.

    MAOI therapy

    Because of the risk of hypertensive crisis, phentermine is contraindicated during or within 14 days following the administration of monoamine oxidase inhibitors (MAOIs). Therefore, a proper wash-out period should elapse between MAOI therapy and the use of phentermine; topiramate.

    Cardiac arrhythmias, cardiac disease, heart failure, myocardial infarction, stroke

    Phentermine; topiramate can cause an increase in resting heart rate. In clinical evaluation, a greater number of patients receiving phentermine;topiramate experienced heart rate increases from baseline of more than 5, 10, 15, and 20 beats per minute compared to placebo. The clinical significance of a heart rate elevation with treatment is unclear, but may be of concern especially for those with cardiac disease and cerebrovascular disease (such as patients with a history of myocardial infarction or stroke in the previous 6 months, life-threatening cardiac arrhythmias, or congestive heart failure). Periodic measurement of resting heart rate is advised for all patients, especially those at high risk for a cardiovascular event; in addition, monitoring during dose initiation and escalation is recommended for all patients. Clinicians should instruct their patients to inform health care providers of palpitations or feelings of a racing heartbeat while at rest. For patients who experience a sustained increase in resting heart rate during therapy, dose reduction or discontinuation should be considered. Of note, the effect of phentermine; topiramate on cardiovascular morbidity and mortality has not been established.

    Hyperthyroidism, thyroid disease

    Because phentermine is a sympathomimetic agent, phentermine; topiramate is contraindicated in patients with hyperthyroidism. It should also be used with caution in patients with thyroid disease.

    Dialysis, renal failure, renal impairment

    Both phentermine and topiramate are cleared by renal excretion. Therefore, exposure to phentermine; topiramate extended-release is increased in patients with moderate (CrCl 30 ml/min to less than 50 ml/min) and severe (CrCl < 30 ml/min) renal impairment; doses require adjustment in these populations. The use of this product has not been studied in patients with renal failure or end-stage renal disease on dialysis; avoid use in this patient population.

    Glaucoma, increased intraocular pressure

    Phentermine; topiramate is contraindicated in patients with glaucoma. Topiramate has been associated with the onset of acute myopia associated with secondary angle closure glaucoma. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include myopia, anterior chamber shallowing, ocular hyperemia (redness), and increased intraocular pressure. Mydriasis may or may not be present. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Patients with preexisting ocular disease should initiate phentermine; topiramate treatment with extreme caution and monitor for symptoms of increased intraocular pressure. Symptoms typically occur within 1 month of initiating treatment with topiramate, but may occur at any time during therapy. The primary treatment to reverse symptoms is immediate discontinuation.

    Ambient temperature increase, anticholinergic medications

    Topiramate has been associated with oligohidrosis and hyperthermia, infrequently resulting in hospitalization. Decreased sweating and an elevation in body temperature above normal characterized these cases. Some of the cases have been reported with topiramate after exposure to elevated environmental temperatures. Therefore, patients taking phentermine; topiramate should be instructed to limit exposure to ambient temperature increase (i.e., elevated environmental temperature) or other temperature extremes that might aggravate temperature regulation. To help prevent oligohidrosis and hyperthermia, proper hydration is suggested before and during strenuous activity or exposure to warm temperatures. Use caution when prescribing with other drugs that predispose patients to heat-related disorders, such as anticholinergic medications and carbonic anhydrase inhibitors.

    Anxiety, depression, insomnia, suicidal ideation

    Treatment with phentermine; topiramate may cause mood disorders, including depression, anxiety, and insomnia. Patients and/or caregivers should be alert for unusual changes in mood or behaviors during treatment. If bothersome mood and sleep disorders persist with treatment, consider dose reduction or discontinuation; discontinuation is expected to resolve drug-related symptoms. Antiepileptic drugs (AEDs), including topiramate, increase the risk of suicidal thoughts or behavior. Avoid use in patients with a history of suicidal attempts or active suicidal ideation. Patients with a history of depression may be at increased risk of recurrent depression or other mood disorders during treatment. Discontinuation is warranted in individuals with suicidal ideation or behavior. During post-marketing experience with phentermine; topiramate therapy, suicidal ideation and behavior have been reported

    Driving or operating machinery, ethanol ingestion

    Phentermine; topiramate extended-release has the potential to cause somnolence, fatigue, dizziness and difficulty with concentration, particularly in the first month of therapy. Advise patients to use caution when driving or operating machinery, or performing other tasks that require mental alertness until they are aware of how therapy will affect their mental and/or motor performance. Rapid titration or high initial doses may be associated with higher rates of cognitive events such as attention, memory and language/word-finding difficulties. If cognitive impairment persists, consider dose reduction; consider a withdrawal of therapy for symptoms that are moderate to severe, bothersome, or those which fail to resolve with dose reduction. In general, ethanol ingestion may aggravate these effects. Advise patients to avoid alcohol while taking phentermine; topiramate.

    Nephrolithiasis

    Phentermine; Topiramate should be used with caution in patients with a history of kidney stones (nephrolithiasis). Topiramate is a carbonic anhydrase inhibitor and promotes kidney stone formation by reducing urinary citrate excretion and by increasing urinary pH. During clinical trials of topiramate for epilepsy, 1.3—1.5% of topiramate-treated patients developed kidney stones; this incidence is about 2—4 times that expected in a similar, untreated population and was higher in men. The concomitant use of topiramate with other carbonic anhydrase inhibitors or in patients on a ketogenic diet may create a physiological environment that increases the risk of kidney stone formation, and should therefore be avoided. Patients who are receiving phentermine; topiramate, especially those who have a history of kidney stones, should be instructed to maintain adequate fluid intake in order to reduce the formation of kidney stones.

    Chronic obstructive pulmonary disease (COPD), diarrhea, emphysema, hypokalemia, metabolic acidosis, status asthmaticus, status epilepticus, surgery

    Phentermine; topiramate has been associated with metabolic acidosis. Topiramate is a carbonic anhydrase inhibitor that can promote metabolic acidosis and also hypokalemia. Conditions that may predispose patients to acidosis [i.e., diarrhea, ketogenic diet, severe pulmonary disease (chronic obstructive pulmonary disease (COPD), emphysema, status asthmaticus), surgery, status epilepticus or administration with other bicarbonate-lowering drugs] may have an additive risk for this complication. Measurement of baseline and periodic serum bicarbonate, along with other serum chemistries, is recommended during therapy. In clinical trials, the peak reduction in serum bicarbonate occurred by week 4, and in most subjects there was a correction of bicarbonate by week 56, without any change to study drug. However, if persistent metabolic acidosis develops, reduce the dose or taper to discontinue the dose. Hypokalemia risk may be aggravated by the use of diuretic therapy.

    Hepatic disease

    Exposure to phentermine was higher in patients with mild or moderate (Child-Pugh Class A and B) hepatic impairment. A 7.5 mg/46 mg daily dose should not be exceed in patients with moderate hepatic improvement. Phentermine; topiramate has not been studied in patients with severe hepatic disease (Child-Pugh Class C); avoid use in this patient population.

    Diabetes mellitus

    In general, weight reduction may increase the risk of hypoglycemia in patients with type 2 diabetes mellitus treated with insulin and/or insulin secretagogues (e.g., sulfonylureas). Blood glucose monitoring is warranted in patients with type 2 diabetes prior to starting and during phentermine; topiramate treatment. Dosage adjustments of anti-diabetic medications should be considered. If a patient develops hypoglycemia during treatment, adjust anti-diabetic drug regimen accordingly. Of note, phentermine; topiramate has not been studied in combination with insulin.

    Hypotension

    In general, weight reduction may increase the risk of hypotension in patients being treated with antihypertensive medications. Baseline and periodic blood pressure monitoring is recommended in patients taking phentermine; topiramate who also take antihypertensive medications. If a patient develops symptoms associated with low blood pressure after starting phentermine; topiramate, appropriate changes should be made to the antihypertensive drug regimen.

    Geriatric

    Clinical studies of phentermine; topiramate did not include sufficient numbers of elderly subjects to determine whether they respond differently from younger subjects. In those studied, no age-related differences were observed. Nevertheless, use caution when selecting a dose for a geriatric patient, given their propensity to have concurrent disease states that may influence drug tolerability, usually starting at the low end of the dosing range.

    Anorexia nervosa, substance abuse

    Phentermine; topiramate extended-release for weight reduction is not recommend for use in those patients with a history of anorexia nervosa or other eating disorders. In general it is advisable to use phentermine-containing agents with se caution in patients with a known history of substance abuse. Phentermine is related chemically and pharmacologically to the amphetamines. The possibility of abuse of phentermine should be kept in mind when evaluating the desirability of including a drug as part of a weight reduction program. However, the abuse and dependence potential of phentermine; topiramate extended-release has not been systematically evaluated. As with most controlled substances, the least amount reasonable should be prescribed or dispensed at one time in order to limit the potential for overuse or drug diversion.

    Abrupt discontinuation

    Abrupt discontinuation of phentermine; topiramate, particularly at a dose of 15 mg/92 mg once daily, should be avoided since withdrawal of topiramate has been associated with seizures in individuals without a history of seizures or epilepsy. If immediate discontinuation is medically necessary, careful monitoring and symptom management is warranted. Patients discontinuing therapy due to lack of efficacy, should follow recommended tapering of higher dose (e.g., every other day dosing for 1 week) to avoid precipitating a seizure.

    Labor, obstetric delivery, pregnancy

    Phentermine; topiramate is contraindicated during pregnancy (FDA pregnancy risk category X), because weight loss offers no potential benefit to a pregnant woman and may result in fetal harm. Further, data from pregnancy registries and epidemiology studies indicate an increased risk in oral clefts (cleft lip with or without cleft palate) with first trimester exposure to topiramate. Females of reproductive potential should have a negative pregnancy test before starting therapy and monthly thereafter. Females of reproductive potential should use contraception during therapy. If phentermine; topiramate is inadvertently used during pregnancy, or if a patient becomes pregnant while on therapy, discontinue treatment immediately and inform patient of the potential hazard to the fetus. The Qsymia Pregnancy Surveillance Program is a maternal-fetal outcomes program which monitors pregnancies that occur during therapy; healthcare professional and patients are encouraged to report pregnancies to the program by calling 1—888—998—4887. The effect of phentermine; topiramate on labor and obstetric delivery in humans is unknown. Further, metabolic acidosis has been reported in patients treated with phentermine; topiramate. The development of induced metabolic acidosis in the mother and/or in the fetus might affect the fetus’s ability to tolerate labor.

    Breast-feeding

    According to the manufacturer, a decision should be made whether to discontinue nursing or to discontinue phentermine; topiramate, taking into account the importance of therapy to the mother. Both topiramate and amphetamines (phentermine has pharmacologic activity and a chemical structure similar to amphetamines) are excreted in human milk. During lactation, first line weight loss strategies include a healthy diet and exercise, if appropriate. Sufficient calories and nutrition are important for proper lactation. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Children, infants, neonates

    The safety and effectiveness of phentermine; topiramate in children below the age of 18 have not been established. Serious adverse reactions seen in pediatric patients using topiramate include acute angle glaucoma, oligohidrosis and hyperthermia, metabolic acidosis, cognitive and neuropsychiatric reactions, hyperammonemia and encephalopathy, and nephrolithiasis. Therefore, therapy is not recommended in children or adolescents. There is no known indication for the use of obesity drugs in infants or neonates.

    ADVERSE REACTIONS

    Severe

    suicidal ideation / Delayed / Incidence not known
    ocular hypertension / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    pemphigus / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known

    Moderate

    constipation / Delayed / 7.9-16.1
    impaired cognition / Early / 2.1-7.6
    blurred vision / Early / 4.0-6.3
    depression / Delayed / 2.8-4.3
    palpitations / Early / 0.8-2.4
    nephrolithiasis / Delayed / 0.2-1.2
    sinus tachycardia / Rapid / Incidence not known
    chest pain (unspecified) / Early / Incidence not known
    hypertension / Early / Incidence not known
    psychosis / Early / Incidence not known
    euphoria / Early / Incidence not known
    myopia / Delayed / Incidence not known
    bullous rash / Early / Incidence not known
    metabolic acidosis / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    memory impairment / Delayed / Incidence not known
    impotence (erectile dysfunction) / Delayed / Incidence not known
    hyperammonemia / Delayed / Incidence not known
    hypokalemia / Delayed / Incidence not known
    physiological dependence / Delayed / Incidence not known
    psychological dependence / Delayed / Incidence not known
    withdrawal / Early / Incidence not known

    Mild

    paresthesias / Delayed / 4.2-19.9
    xerostomia / Early / 6.7-19.1
    infection / Delayed / 12.2-15.8
    pharyngitis / Delayed / 9.4-12.5
    headache / Early / 7.0-10.6
    insomnia / Early / 5.0-9.4
    dysgeusia / Early / 1.3-9.4
    metallic taste / Early / 1.3-9.4
    dizziness / Early / 2.9-8.6
    sinusitis / Delayed / 6.8-7.8
    influenza / Delayed / 4.4-7.5
    nausea / Early / 3.6-7.2
    back pain / Delayed / 5.4-6.6
    diarrhea / Early / 5.0-6.4
    fatigue / Early / 4.4-5.9
    cough / Delayed / 3.3-4.8
    anxiety / Delayed / 1.8-4.1
    irritability / Delayed / 1.7-3.7
    alopecia / Delayed / 2.1-3.7
    hypoesthesia / Delayed / 0.8-3.7
    gastroesophageal reflux / Delayed / 0.8-3.2
    musculoskeletal pain / Early / 0.8-3.0
    muscle cramps / Delayed / 2.8-2.9
    dyspepsia / Early / 2.1-2.8
    rash (unspecified) / Early / 1.7-2.6
    xerophthalmia / Early / 0.8-2.5
    ocular pain / Early / 2.1-2.2
    dysmenorrhea / Delayed / 0.4-2.1
    nasal congestion / Early / 1.2-2.0
    restlessness / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    tremor / Early / Incidence not known
    libido decrease / Delayed / Incidence not known
    libido increase / Delayed / Incidence not known
    hypothermia / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Dolutegravir; Lamivudine: (Moderate) Caution is warranted when dolutegravir is administered with topiramate as there is a potential for decreased dolutegravir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Dolutegravir is partially metabolized by this isoenzyme.
    Abciximab: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates or platelet inhibitors may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Acarbose: (Moderate) Sympathomimetics may increase blood glucose concentrations. Monitor for loss of diabetic control when therapy with sympathomimetic agents is instituted. Also, adrenergic medications may increase glucose uptake by muscle cells and may potentiate the actions of some antidiabetic agents. Monitor blood glucose to avoid hypoglycemia or hyperglycemia.
    Acebutolol: (Major) Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Acetaminophen; Butalbital; Caffeine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Because phentermine is a sympathomimetic and anorexic agent (i.e., psychostimulant) it should not be used in combination with other sympathomimetics. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmias.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Major) Because phentermine is a sympathomimetic and anorexic agent (i.e., psychostimulant) it should not be used in combination with other sympathomimetics. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmias.
    Acetaminophen; Dextromethorphan; Doxylamine: (Major) Although not specifically studied, coadministration of CNS depressant drugs with topiramate may potentiate CNS depression such as dizziness or cognitive adverse reactions, or other centrally mediated effects of these agents. Monitor for increased CNS effects if coadministering.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Major) Because phentermine is a sympathomimetic and anorexic agent (i.e., psychostimulant) it should not be used in combination with other sympathomimetics. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmias.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Major) Because phentermine is a sympathomimetic and anorexic agent (i.e., psychostimulant) it should not be used in combination with other sympathomimetics. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmias.
    Acetaminophen; Diphenhydramine: (Major) Although not specifically studied, coadministration of CNS depressant drugs with topiramate may potentiate CNS depression such as dizziness or cognitive adverse reactions, or other centrally mediated effects of these agents. Monitor for increased CNS effects if coadministering.
    Acetaminophen; Guaifenesin; Phenylephrine: (Major) Because phentermine is a sympathomimetic and anorexic agent (i.e., psychostimulant) it should not be used in combination with other sympathomimetics. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmias.
    Acetaminophen; Tramadol: (Moderate) Topiramate may contribute to the CNS depression seen with tramadol; tramadol may also decrease the seizure threshold in some patients and thus, potentially, interfere with the ability of anticonvulsants to control seizures.
    Albiglutide: (Moderate) Sympathomimetics may increase blood glucose concentrations. Monitor for loss of diabetic control when therapy with sympathomimetic agents is instituted. Also, adrenergic medications may increase glucose uptake by muscle cells and may potentiate the actions of some antidiabetic agents. Monitor blood glucose to avoid hypoglycemia or hyperglycemia.
    Albuterol: (Major) Caution and close observation should be used when albuterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Albuterol; Ipratropium: (Major) Caution and close observation should be used when albuterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Aliskiren; Amlodipine: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as topiramate, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly. (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as topiramate, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Alogliptin: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving alogliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Alogliptin; Metformin: (Major) Concurrent use of topiramate and metformin is contraindicated in patients with metabolic acidosis. Topiramate frequently causes metabolic acidosis, a condition for which the use of metformin is contraindicated. During a drug interaction study evaluating concurrent use of topiramate and metformin in healthy volunteers, the following changes in metformin pharmacokinetics were observed: the mean Cmax was increased by 17%, the mean AUC was increased by 25%, and the oral plasma clearance was decreased by 20%. The oral plasma clearance of topiramate was reduced, but the extent of the change is unknown. (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving alogliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Phentermine may increase blood sugar via stimulation of beta2-receptors which leads to increased glycogenolysis. Diabetic patients may have decreased requirements of antidiabetic agents in association with the use of phentermine.
    Alogliptin; Pioglitazone: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving alogliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Reductions in AUC and Cmax have been noted in pioglitazone and the active metabolites when coadministered with topiramate. The clinician may suggest that the patient more frequently monitor blood glucose when these drugs are added or deleted from therapy.
    Alpha-blockers: (Major) Sympathomimetics can antagonize the effects of antihypertensives such as alpha-blockers when administered concomitantly.
    Alpha-glucosidase Inhibitors: (Moderate) Sympathomimetics may increase blood glucose concentrations. Monitor for loss of diabetic control when therapy with sympathomimetic agents is instituted. Also, adrenergic medications may increase glucose uptake by muscle cells and may potentiate the actions of some antidiabetic agents. Monitor blood glucose to avoid hypoglycemia or hyperglycemia.
    Alprazolam: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines. Concurrent use of topiramate and benzodiazepines associated with thrombocytopenia (e.g., clonazepam, lorazepam, and clobazam), may also increase the risk of bleeding; monitor patients appropriately during benzodiazepine therapy.
    Ambrisentan: (Major) Sympathomimetics, such as phentermine, can antagonize the effects of vasodilators such as ambrisentan when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
    Amiloride; Hydrochlorothiazide, HCTZ: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Aminosalicylate sodium, Aminosalicylic acid: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Amitriptyline: (Major) Avoid use of tricyclic antidepressants with phentermine whenever possible. Tricyclic antidepressants (TCAs) may potentiate the pressor response to sympathomimetic agents, such as phentermine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience side effects like hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. Patients should be closely monitored if use together is unavoidable. (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold. In addition, during concurrent use of topiramate and amitriptyline the Cmax and AUC of amitriptyline were increased by 12%. Dosage adjustments of amitriptyline may be needed based upon tolerability to the regimen during combined use of amitriptyline and topiramate.
    Amitriptyline; Chlordiazepoxide: (Major) Avoid use of tricyclic antidepressants with phentermine whenever possible. Tricyclic antidepressants (TCAs) may potentiate the pressor response to sympathomimetic agents, such as phentermine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience side effects like hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. Patients should be closely monitored if use together is unavoidable. (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines. Concurrent use of topiramate and benzodiazepines associated with thrombocytopenia (e.g., clonazepam, lorazepam, and clobazam), may also increase the risk of bleeding; monitor patients appropriately during benzodiazepine therapy. (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold. In addition, during concurrent use of topiramate and amitriptyline the Cmax and AUC of amitriptyline were increased by 12%. Dosage adjustments of amitriptyline may be needed based upon tolerability to the regimen during combined use of amitriptyline and topiramate.
    Amlodipine: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as topiramate, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Atorvastatin: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as topiramate, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Benazepril: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as topiramate, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly. (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as topiramate, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly. (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as topiramate, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Olmesartan: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as topiramate, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Telmisartan: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as topiramate, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Valsartan: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as topiramate, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amoxapine: (Major) Concomitant use of amoxapine with sympathomimetics should be avoided whenever possible; use with caution when concurrent use cannot be avoided. One drug information reference suggests that cyclic antidepressants potentiate the pharmacologic effects of direct-acting sympathomimetics, but decrease the pressor response to indirect-acting sympathomimetics, however, the data are not consistent. (Moderate) Amoxapine, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Some anticonvulsants, such as phenobarbital or carbamazepine, may potentially induce the metabolism of amoxapine as well. Monitor patients for side effects or altered responses to drug therapy.
    Amphetamines: (Severe) Because phentermine is a sympathomimetic and anorexic agent (i.e., psychostimulant) it should generally not be used in combination with other sympathomimetics or psychostimulants. Cardiovascular or CNS side effects may increase, and some may be serious. The safety and efficacy of coadministration of phentermine with other products intended for weight loss or ADHD including prescription drugs (e.g., amphetamines) have not been established. (Major) Concurrent use of amphetamines and urinary alkalinizers, such as topiramate, should be avoided. Urinary alkalinizers diminish the urinary excretion of amphetamines by increasing the proportion of non-ionized amphetamines, resulting in increased renal tubular reabsorption of these compounds. The half-life and therapeutic actions of amphetamines will be prolonged in the presence of these drugs. In addition, patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary.
    Anagrelide: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates or platelet inhibitors may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Anticholinergics: (Moderate) Use caution if carbonic anhydrase inhibitors are administered with anticholinergics and monitor for excessive anticholinergic adverse effects. The use of topiramate with agents that may increase the risk for heat-related disorders, such as anticholinergics, may lead to oligohidrosis, hyperthermia and/or heat stroke.
    Antithrombin III: (Moderate) Concurrent use of topiramate and anticoagulants (e.g., warfarin, enoxaparin, dabigatran) may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Anxiolytics; Sedatives; and Hypnotics: (Major) Although not specifically studied, coadministration of CNS depressant drugs (e.g., anxiolytics, sedatives, and hypnotics) with topiramate may potentiate CNS depression such as dizziness or cognitive adverse reactions, or other centrally mediated effects of these agents. Monitor for increased CNS effects if coadministering.
    Apixaban: (Moderate) Concurrent use of topiramate and anticoagulants (e.g., warfarin, enoxaparin, dabigatran) may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if topiramate and aprepitant, fosaprepitant are used concurrently and monitor for a possible decrease in the efficacy of aprepitant for several days after administration of a multi-day aprepitant regimen. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer; aprepitant is a CYP3A4 substrate. When a single dose of aprepitant (375 mg, or 3 times the maximum recommended dose) was administered on day 9 of a 14-day rifampin regimen (a strong CYP3A4 inducer), the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased by 3-fold. The manufacturer of aprepitant recommends avoidance of administration with strong CYP3A4 inducers, but does not provide guidance for weak-to-moderate inducers. After administration, fosaprepitant is rapidly converted to aprepitant and shares the same drug interactions.
    Arformoterol: (Moderate) Caution and close observation should be used when arformoterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Argatroban: (Moderate) Concurrent use of topiramate and anticoagulants (e.g., warfarin, enoxaparin, dabigatran) may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Aripiprazole: (Moderate) Because aripiprazole is partially metabolized by CYP3A4, concurrent use of CYP3A4 inducers such as topiramate may result in decreased plasma concentrations of aripiprazole. If these agents are used in combination, the patient should be carefully monitored for a decrease in aripiprazole efficacy. An increase in aripiprazole dosage may be clinically warranted in some patients. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. There are no dosing recommendations for Aristada during use of a mild to moderate CYP3A4 inducer.
    Aspirin, ASA: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Aspirin, ASA; Carisoprodol: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Aspirin, ASA; Dipyridamole: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation. (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates or platelet inhibitors may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Aspirin, ASA; Omeprazole: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Aspirin, ASA; Oxycodone: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Aspirin, ASA; Pravastatin: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Atazanavir: (Moderate) Caution is warranted when atazanavir is administered with topiramate as there is a potential for decreased concentrations of atazanavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Atazanavir is a substrate of CYP3A4.
    Atazanavir; Cobicistat: (Moderate) Caution is warranted when atazanavir is administered with topiramate as there is a potential for decreased concentrations of atazanavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Atazanavir is a substrate of CYP3A4. (Moderate) Caution is warranted when cobicistat is administered with topiramate as there is a potential for decreased concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Cobicistat is a substrate of CYP3A4.
    Atenolol: (Major) Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Atenolol; Chlorthalidone: (Major) Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Atomoxetine: (Major) Due to the potential for increases in blood pressure and heart rate, atomoxetine should be used cautiously with drugs with sympathomimetic activity such as phentermine. Consider monitoring the patient's blood pressure and heart rate at baseline and regularly if sympathomimetics are coadministered with atomoxetine.
    Atovaquone; Proguanil: (Minor) Proguanil is metabolized to cycloguanil by CYP2C19. Potential interactions between proguanil or cycloguanil and other drugs that are CYP2C19 inhibitors are unknown. Use caution when combining atovaquone; proguanil with CYP2C19 inhibitors, such as topiramate.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Carbonic anhydrase inhibiting drugs, such as topiramate (a weak carbonic anhydrase inhibitor) can alkalinize the urine, thereby decreasing the effectiveness of methenamine by inhibiting the conversion of methenamine to formaldehyde. (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Axitinib: (Moderate) Use caution if coadministration of axitinib with topiramate is necessary, due to the risk of decreased efficacy of axitinib. Axitinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2, CYP2C19, and UGT1A1. Topiramate is a weak CYP3A4 inducer. Coadministration with a strong CYP3A4/5 inducer, rifampin, significantly decreased the plasma exposure of axitinib in healthy volunteers. Topiramate is also a weak CYP2C19 inhibitor, which theoretically could increase exposure to axitinib; however, the effects of topiramate on CYP2C19 are not expected to overcome its effects on CYP3A4, as CYP3A4 is the major route of metabolism for axitinib.
    Azilsartan; Chlorthalidone: (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Barbiturates: (Moderate) Although topiramate is not extensively metabolized (70% renally eliminated), an interaction with barbiturates via hepatic isoenzyme activity is possible. In patients receiving either phenobarbital or primidone in combination with topiramate, there was a < 10% change in phenobarbital or primidone plasma concentrations; the effects on topiramate plasma concentrations were not evaluated. Barbiturates may cause additive sedation or other CNS depressive effects when used concurrently with topiramate. When topiramate is combined with phentermine for the treatment of obesity, a greater risk of CNS depression exists. Concurrent use of topiramate and drugs that cause thrombocytopenia, such as the barbiturates, may also increase the risk of bleeding; monitor patients appropriately.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Phentermine, which increases catecholamine release, can increase blood pressure; this effect may be additive with the prolonged vasoconstriction caused by ergot alkaloids. Monitoring for cardiac effects during concurrent use of ergot alkaloids with phentermine may be advisable.
    Benazepril; Hydrochlorothiazide, HCTZ: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Bendroflumethiazide; Nadolol: (Major) Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Benzodiazepines: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines. Concurrent use of topiramate and benzodiazepines associated with thrombocytopenia (e.g., clonazepam, lorazepam, and clobazam), may also increase the risk of bleeding; monitor patients appropriately during benzodiazepine therapy.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Carbonic anhydrase inhibiting drugs, such as topiramate (a weak carbonic anhydrase inhibitor) can alkalinize the urine, thereby decreasing the effectiveness of methenamine by inhibiting the conversion of methenamine to formaldehyde. (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Beta-blockers: (Major) Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Betaxolol: (Major) Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Bethanechol: (Moderate) Bethanechol offsets the effects of sympathomimetics at sites where sympathomimetic and cholinergic receptors have opposite effects.
    Bismuth Subsalicylate: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Bisoprolol: (Major) Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree. (Major) Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Bivalirudin: (Moderate) Concurrent use of topiramate and anticoagulants (e.g., warfarin, enoxaparin, dabigatran) may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering topiramate with boceprevir due to the potential for boceprevir treatment failure. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of topiramate and boceprevir. Topiramate is a weak inducer of the hepatic isoenzyme CYP3A4; boceprevir is a substrate of this isoenzyme. When used in combination, the plasma concentrations of boceprevir may decrease.
    Bosentan: (Moderate) Bosentan is a significant inducer of CYP2C9 hepatic isoenzymes.Theoretically, bosentan can increase the hepatic clearance of topiramate, a potential CYP2C9 substrate.
    Bretylium: (Major) The action of sympathomimetics may be enhanced in patients receiving bretylium. Increased sensitivity to sympathomimetics should be expected in patients receiving bretylium.
    Brexpiprazole: (Moderate) Because brexpiprazole is partially metabolized by CYP3A4, concurrent use of CYP3A4 inducers such as topiramate may result in decreased plasma concentrations of brexpiprazole. If these agents are used in combination, the patient should be carefully monitored for a decrease in brexpiprazole efficacy. An increase in brexpiprazole dosage may be clinically warranted in some patients. Similar precautions apply to combination products containing topiramate such as phentermine; topiramate.
    Brimonidine; Timolol: (Major) Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Bromocriptine: (Moderate) The combination of bromocriptine with phentermine may cause headache, tachycardia, other cardiovascular abnormalities, seizures, and other serious effects. Concurrent use of bromocriptine and phentermine should be approached with caution.
    Brompheniramine; Carbetapentane; Phenylephrine: (Major) Because phentermine is a sympathomimetic and anorexic agent (i.e., psychostimulant) it should not be used in combination with other sympathomimetics. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmias.
    Budesonide; Formoterol: (Moderate) Caution and close observation should be used when formoterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Bumetanide: (Moderate) Topiramate is a carbonic anhydrase inhibitor. Concurrent use of topiramate with non-potassium sparing diuretics (e.g., loop diuretics) may potentiate the potassium-wasting action of these diuretics. Monitor baseline and periodic potassium concentrations during coadministration.
    Bupivacaine; Lidocaine: (Moderate) Concomitant use of systemic lidocaine and topiramate may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; topiramate induces CYP3A4.
    Bupropion: (Major) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, such as phentermine, may be associated with an increased seizure risk; therefore, seizures may be more likely to occur in patients receiving this weight loss aide with bupropion. Patients should be closely monitored if this combination is necessary. Do not combine therapy with phentermine or phentermine-combinations and bupropion; naltrexone due to this risk and the duplication of therapy for weight loss. (Moderate) Bupropion should not be used by patients with a preexisting seizure disorder because it may lower the seizure threshold. Bupropion may also interact pharmacokinetically with anticonvulsant drugs that induce hepatic microsomal isoenzyme function such as carbamazepine, barbiturates, or phenytoin, as well as fosphenytoin and ethotoin.
    Bupropion; Naltrexone: (Major) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, such as phentermine, may be associated with an increased seizure risk; therefore, seizures may be more likely to occur in patients receiving this weight loss aide with bupropion. Patients should be closely monitored if this combination is necessary. Do not combine therapy with phentermine or phentermine-combinations and bupropion; naltrexone due to this risk and the duplication of therapy for weight loss. (Moderate) Bupropion should not be used by patients with a preexisting seizure disorder because it may lower the seizure threshold. Bupropion may also interact pharmacokinetically with anticonvulsant drugs that induce hepatic microsomal isoenzyme function such as carbamazepine, barbiturates, or phenytoin, as well as fosphenytoin and ethotoin.
    Buspirone: (Major) Although not specifically studied, coadministration of CNS depressant drugs with topiramate may potentiate CNS depression such as dizziness or cognitive adverse reactions, or other centrally mediated effects of these agents. Monitor for increased CNS effects if coadministering.
    Cabazitaxel: (Moderate) Cabazitaxel is a CYP3A4 substrate and concomitant use with CYP3A4 inducers such as topiramate may lead to reduced concentrations of cabazitaxel. Caution should be utilized when CYP3A4 inducers are coadministered with cabazitaxel, and alternative therapies with low enzyme induction potential should be considered.
    Cabergoline: (Minor) In theory, an interaction is possible between cabergoline, an ergot derivative, and some sympathomimetic agents such as vasopressors (e.g., norepinephrine, dopamine), cocaine, epinephrine, phenylpropanolamine, ephedra, ma huang, pseudoephedrine, amphetamines, and phentermine. Use of the ergot derivative bromocriptine for lactation suppression in conjunction with a sympathomimetic (i.e., isometheptene or phenylpropanolamine) for other therapeutic uses has resulted in adverse effects such as worsening headache, hypertension, ventricular tachycardia, seizures, sudden loss of vision, and cerebral vasospasm.
    Caffeine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Caffeine; Ergotamine: (Major) Phentermine, which increases catecholamine release, can increase blood pressure; this effect may be additive with the prolonged vasoconstriction caused by ergot alkaloids. Monitoring for cardiac effects during concurrent use of ergot alkaloids with phentermine may be advisable. (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Canagliflozin: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving canagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Canagliflozin; Metformin: (Major) Concurrent use of topiramate and metformin is contraindicated in patients with metabolic acidosis. Topiramate frequently causes metabolic acidosis, a condition for which the use of metformin is contraindicated. During a drug interaction study evaluating concurrent use of topiramate and metformin in healthy volunteers, the following changes in metformin pharmacokinetics were observed: the mean Cmax was increased by 17%, the mean AUC was increased by 25%, and the oral plasma clearance was decreased by 20%. The oral plasma clearance of topiramate was reduced, but the extent of the change is unknown. (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving canagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Phentermine may increase blood sugar via stimulation of beta2-receptors which leads to increased glycogenolysis. Diabetic patients may have decreased requirements of antidiabetic agents in association with the use of phentermine.
    Candesartan; Hydrochlorothiazide, HCTZ: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Captopril; Hydrochlorothiazide, HCTZ: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Carbamazepine: (Moderate) Although topiramate is not extensively metabolized (70% renally eliminated), hepatic enzyme inducers. such as carbamazepine, have been shown to reduce topiramate serum concentrations. In patients receiving carbamazepine with topiramate, plasma concentrations of topiramate were decreased by 40% with < 10% change in carbamazepine plasma concentrations. Concurrent use of topiramate and drugs that cause thrombocytopenia, such as carbamazepine and oxcarbazepine, may also increase the risk of bleeding; monitor patients appropriately.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Major) Because phentermine is a sympathomimetic and anorexic agent (i.e., psychostimulant) it should not be used in combination with other sympathomimetics. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmias.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Major) Although not specifically studied, coadministration of CNS depressant drugs with topiramate may potentiate CNS depression such as dizziness or cognitive adverse reactions, or other centrally mediated effects of these agents. Monitor for increased CNS effects if coadministering. (Major) Because phentermine is a sympathomimetic and anorexic agent (i.e., psychostimulant) it should not be used in combination with other sympathomimetics. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmias.
    Carbetapentane; Guaifenesin; Phenylephrine: (Major) Because phentermine is a sympathomimetic and anorexic agent (i.e., psychostimulant) it should not be used in combination with other sympathomimetics. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmias.
    Carbetapentane; Phenylephrine: (Major) Because phentermine is a sympathomimetic and anorexic agent (i.e., psychostimulant) it should not be used in combination with other sympathomimetics. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmias.
    Carbetapentane; Phenylephrine; Pyrilamine: (Major) Because phentermine is a sympathomimetic and anorexic agent (i.e., psychostimulant) it should not be used in combination with other sympathomimetics. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmias.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Major) Because phentermine is a sympathomimetic and anorexic agent (i.e., psychostimulant) it should not be used in combination with other sympathomimetics. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmias.
    Carbinoxamine; Phenylephrine: (Major) Because phentermine is a sympathomimetic and anorexic agent (i.e., psychostimulant) it should not be used in combination with other sympathomimetics. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmias.
    Carbonic anhydrase inhibitors: (Major) Avoid concurrent use of acetazolamide or methazolamide with topiramate. Topiramate is a weak carbonic anhydrase inhibitor. Concomitant use of topiramate with acetazolamide or methazolamide may create a physiological environment that increases the risk of renal stone formation associated with topiramate use. Additionally, through an additive effect, the use of topiramate with agents that may increase the risk for heat-related disorders (acetazolamide and methazolamide), may lead to oligohidrosis, hyperthermia and heat stroke.
    Cardiac glycosides: (Major) Concomitant use of cardiac glycosides with sympathomimetics can cause arrhythmias because sympathomimetics enhance ectopic pacemaker activity. Caution is warranted during co-administration of digoxin and sympathomimetics.
    Cariprazine: (Major) Cariprazine and its active metabolites are extensively metabolized by CYP3A4. Concurrent use of cariprazine with CYP3A4 inducers, such as topiramate, has not been evaluated and is not recommended because the net effect on active drug and metabolites is unclear.
    Carteolol: (Major) Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Carvedilol: (Major) Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Celecoxib: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Chlophedianol; Guaifenesin; Phenylephrine: (Major) Because phentermine is a sympathomimetic and anorexic agent (i.e., psychostimulant) it should not be used in combination with other sympathomimetics. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmias.
    Chlordiazepoxide: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines. Concurrent use of topiramate and benzodiazepines associated with thrombocytopenia (e.g., clonazepam, lorazepam, and clobazam), may also increase the risk of bleeding; monitor patients appropriately during benzodiazepine therapy.
    Chlordiazepoxide; Clidinium: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines. Concurrent use of topiramate and benzodiazepines associated with thrombocytopenia (e.g., clonazepam, lorazepam, and clobazam), may also increase the risk of bleeding; monitor patients appropriately during benzodiazepine therapy.
    Chlorothiazide: (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly. (Moderate) Topiramate is a carbonic anhydrase inhibitor. Concurrent use of topiramate with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Monitor baseline and periodic potassium concentrations during coadministration.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Because phentermine is a sympathomimetic and anorexic agent (i.e., psychostimulant) it should not be used in combination with other sympathomimetics. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmias.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Because phentermine is a sympathomimetic and anorexic agent (i.e., psychostimulant) it should not be used in combination with other sympathomimetics. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmias.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Major) Because phentermine is a sympathomimetic and anorexic agent (i.e., psychostimulant) it should not be used in combination with other sympathomimetics. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmias.
    Chlorpheniramine; Phenylephrine: (Major) Because phentermine is a sympathomimetic and anorexic agent (i.e., psychostimulant) it should not be used in combination with other sympathomimetics. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmias.
    Chlorpromazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Chlorthalidone: (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Chlorthalidone; Clonidine: (Major) Sympathomimetics can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Choline Salicylate; Magnesium Salicylate: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Cilostazol: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as cilostazol may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation. In addition, cilostazol is metabolized by the cytochrome P450 CYP2C19 hepatic isoenzyme and may interact with medications that are inhibitors of CYP2C19, including topiramate.
    Citalopram: (Moderate) The plasma concentration of citalopram, a CYP2C19 substrate, may be increased when administered concurrently with topiramate, a CYP2C19 inhibitor. Because citalopram causes dose-dependent QT prolongation, the maximum daily dose should not exceed 20 mg per day in patients receiving CYP2C19 inhibitors. In addition, concurrent use of topiramate and drugs that affect platelet function such as selective serotonin reuptake inhibitors (SSRIs) may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Clomipramine: (Major) Avoid use of tricyclic antidepressants with phentermine whenever possible. Tricyclic antidepressants (TCAs) may potentiate the pressor response to sympathomimetic agents, such as phentermine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience side effects like hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. Patients should be closely monitored if use together is unavoidable. (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold. In addition, during concurrent use of topiramate and amitriptyline the Cmax and AUC of amitriptyline were increased by 12%. Dosage adjustments of amitriptyline may be needed based upon tolerability to the regimen during combined use of amitriptyline and topiramate.
    Clonazepam: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines. Concurrent use of topiramate and benzodiazepines associated with thrombocytopenia (e.g., clonazepam, lorazepam, and clobazam), may also increase the risk of bleeding; monitor patients appropriately during benzodiazepine therapy.
    Clonidine: (Major) Sympathomimetics can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Clopidogrel: (Major) Topiramate may reduce the antiplatelet activity of clopidogrel by inhibiting clopidogrel's metabolism to its active metabolite. Use clopidogrel and topiramate together with caution and monitor for reduced efficacy of clopidogrel. Clopidogrel requires hepatic biotransformation via 2 cytochrome dependent oxidative steps; the CYP2C19 isoenzyme is involved in both steps. Topiramate is an inhibitor of CYP2C19.
    Clorazepate: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines. Concurrent use of topiramate and benzodiazepines associated with thrombocytopenia (e.g., clonazepam, lorazepam, and clobazam), may also increase the risk of bleeding; monitor patients appropriately during benzodiazepine therapy.
    Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with topiramate as there is a potential for decreased concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Cobicistat is a substrate of CYP3A4.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Caution is warranted when cobicistat is administered with topiramate as there is a potential for decreased concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Cobicistat is a substrate of CYP3A4. (Moderate) Caution is warranted when elvitegravir is administered with topiramate as there is a potential for decreased elvitegravir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Elvitegravir is a CYP3A4 substrate.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is warranted when cobicistat is administered with topiramate as there is a potential for decreased concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Cobicistat is a substrate of CYP3A4. (Moderate) Caution is warranted when elvitegravir is administered with topiramate as there is a potential for decreased elvitegravir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Elvitegravir is a CYP3A4 substrate.
    Cobimetinib: (Moderate) If concurrent use of cobimetinib and topiramate is necessary, use caution and monitor for decreased efficacy of cobimetinib. Cobimetinib is a CYP3A substrate in vitro, and topiramate is a weak inducer of CYP3A. The manufacturer of cobimetinib recommends avoiding coadministration of cobimetinib with moderate or strong CYP3A inducers based on simulations demonstrating that cobimetinib exposure would decrease by 73% or 83% when coadministered with a moderate or strong CYP3A inducer, respectively. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inducers.
    Codeine; Phenylephrine; Promethazine: (Major) Because phentermine is a sympathomimetic and anorexic agent (i.e., psychostimulant) it should not be used in combination with other sympathomimetics. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmias.
    Colchicine: (Minor) The response to sympathomimetics may be enhanced by colchicine.
    Conjugated Estrogens; Medroxyprogesterone: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception may also be needed.
    Dabigatran: (Moderate) Concurrent use of topiramate and anticoagulants (e.g., warfarin, enoxaparin, dabigatran) may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Dapagliflozin: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Dapagliflozin; Metformin: (Major) Concurrent use of topiramate and metformin is contraindicated in patients with metabolic acidosis. Topiramate frequently causes metabolic acidosis, a condition for which the use of metformin is contraindicated. During a drug interaction study evaluating concurrent use of topiramate and metformin in healthy volunteers, the following changes in metformin pharmacokinetics were observed: the mean Cmax was increased by 17%, the mean AUC was increased by 25%, and the oral plasma clearance was decreased by 20%. The oral plasma clearance of topiramate was reduced, but the extent of the change is unknown. (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Phentermine may increase blood sugar via stimulation of beta2-receptors which leads to increased glycogenolysis. Diabetic patients may have decreased requirements of antidiabetic agents in association with the use of phentermine.
    Dapagliflozin; Saxagliptin: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Sympathomimetics may increase blood glucose concentrations. Monitor for loss of diabetic control when therapy with sympathomimetic agents is instituted. Also, adrenergic medications may increase glucose uptake by muscle cells and may potentiate the actions of some antidiabetic agents. Monitor blood glucose to avoid hypoglycemia or hyperglycemia.
    Dapsone: (Minor) The metabolism of dapsone may be accelerated when administered concurrently with topiramate, a known inducer of CYP3A4. Coadministration is expected to decrease the plasma concentration of dapsone and increase the formation of dapsone hydroxylamine (a metabolite associated with hemolysis). If these drugs must be administered together, closely monitor for a reduction in dapsone efficacy and signs of hemolytic anemia.
    Darunavir: (Moderate) Caution is warranted when darunavir is administered with topiramate as there is a potential for decreased concentrations of darunavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Darunavir is a substrate of CYP3A4.
    Darunavir; Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with topiramate as there is a potential for decreased concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Cobicistat is a substrate of CYP3A4. (Moderate) Caution is warranted when darunavir is administered with topiramate as there is a potential for decreased concentrations of darunavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Darunavir is a substrate of CYP3A4.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of topiramate with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in decreased concentrations of dasabuvir, paritaprevir, and ritonavir. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Ritonavir, paritaprevir, and dasabuvir (minor) are all metabolized by this enzyme. Caution and close monitoring are advised if these drugs are administered together. (Moderate) Concurrent administration of topiramate with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in decreased concentrations of dasabuvir, paritaprevir, and ritonavir. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Ritonavir, paritaprevir, and dasabuvir (minor) are all metabolized by this enzyme. Caution and close monitoring are advised if these drugs are administered together. (Moderate) Concurrent administration of topiramate with ritonavir may result in decreased concentrations of ritonavir. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Ritonavir is metabolized by this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Delavirdine: (Moderate) Delavirdine is a potent inhibitor of cytochrome P450 2C9 and might decrease topiramate metabolism leading to increased topiramate serum concentrations and a risk of adverse reactions.
    Desflurane: (Major) Halogenated anesthetics may sensitize the myocardium to the effects of the sympathomimetics. Because of this, and its effects on blood pressure, phentermine should be discontinued several days prior to surgery.
    Desiccated Thyroid: (Moderate) Sympathomimetic amines should be used with caution in patients with thyrotoxicosis since these patients are unusually responsive to sympathomimetic amines. Based on the cardiovascular stimulatory effects of sympathomimetic drugs, the concomitant use of sympathomimetics and thyroid hormones can enhance the effects on the cardiovascular system. Patients with coronary artery disease have an increased risk of coronary insufficiency from either agent. Concomitant use of these agents may increase this risk further. In addition, dopamine at a dose of >= 1 mcg/kg/min and dopamine agonists (e.g., apomorphine, bromocriptine, levodopa, pergolide, pramipexole, ropinirole, rotigotine) may result in a transient reduction in TSH secretion. The reduction in TSH secretion is not sustained; hypothyroidism does not occur.
    Desipramine: (Major) Avoid use of tricyclic antidepressants with phentermine whenever possible. Tricyclic antidepressants (TCAs) may potentiate the pressor response to sympathomimetic agents, such as phentermine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience side effects like hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. Patients should be closely monitored if use together is unavoidable. (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold. In addition, during concurrent use of topiramate and amitriptyline the Cmax and AUC of amitriptyline were increased by 12%. Dosage adjustments of amitriptyline may be needed based upon tolerability to the regimen during combined use of amitriptyline and topiramate.
    Desirudin: (Moderate) Concurrent use of topiramate and anticoagulants (e.g., warfarin, enoxaparin, dabigatran) may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Desvenlafaxine: (Moderate) Use phentermine and selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) together with caution; use together may be safe and efficacious for some patients based on available data, provided the patient is on a stable antidepressant regimen and receives close clinical monitoring. Regular appointments to assess the efficacy of the weight loss treatment, the emergence of adverse events, and blood pressure monitoring are recommended. Watch for excessive serotonergic effects. Phentermine is related to the amphetamines, and there has been historical concern that phentermine might exhibit potential to cause serotonin syndrome or cardiovascular or pulmonary effects when combined with serotonergic agents. One case report describes adverse reactions with phentermine and fluoxetine. However, recent data suggest that phentermine's effect on MAO inhibition and serotonin augmentation is minimal at therapeutic doses, and that phentermine does not additionally increase plasma serotonin levels when combined with other serotonergic agents. In large controlled clinical studies, patients were allowed to start therapy with phentermine or phentermine; topiramate extended-release for obesity along with their antidepressants (e.g., SSRIs or SNRIs, but not MAOIs or TCAs) as long as the antidepressant dose had been stable for at least 3 months prior to the initiation of phentermine, and the patient did not have suicidal ideation or more than 1 episode of major depression documented. In analyses of the results, therapy was generally well tolerated, especially at lower phentermine doses, based on discontinuation rates and reported adverse events. Because depression and obesity often coexist, the study data may be important to providing optimal therapies.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Major) Although not specifically studied, coadministration of CNS depressant drugs with topiramate may potentiate CNS depression such as dizziness or cognitive adverse reactions, or other centrally mediated effects of these agents. Monitor for increased CNS effects if coadministering. (Major) Because phentermine is a sympathomimetic and anorexic agent (i.e., psychostimulant) it should not be used in combination with other sympathomimetics. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmias.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Major) Because phentermine is a sympathomimetic and anorexic agent (i.e., psychostimulant) it should not be used in combination with other sympathomimetics. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmias.
    Diazepam: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines. Concurrent use of topiramate and benzodiazepines associated with thrombocytopenia (e.g., clonazepam, lorazepam, and clobazam), may also increase the risk of bleeding; monitor patients appropriately during benzodiazepine therapy.
    Dichlorphenamide: (Moderate) Use dichlorphenamide and topiramate, another carbonic anhydrase inhibitor, together with caution as both drugs can cause metabolic acidosis. Concurrent use may increase the severity of metabolic acidosis. Measure sodium bicarbonate concentrations at baseline and periodically during dichlorphenamide treatment. If metabolic acidosis occurs or persists, consider reducing the dose or discontinuing dichlorphenamide therapy.
    Diclofenac: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Diclofenac; Misoprostol: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Dienogest; Estradiol valerate: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception may also be needed.
    Diflunisal: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Digitoxin: (Major) Concomitant use of cardiac glycosides with sympathomimetics can cause arrhythmias because sympathomimetics enhance ectopic pacemaker activity. Caution is warranted during co-administration of digoxin and sympathomimetics.
    Digoxin: (Major) Concomitant use of cardiac glycosides with sympathomimetics can cause arrhythmias because sympathomimetics enhance ectopic pacemaker activity. Caution is warranted during co-administration of digoxin and sympathomimetics. (Moderate) Serum digoxin AUC was decreased by 12% when coadministered with topiramate. Although the clinical relevance has not been determined, the clinician should be aware that serum digoxin concentrations may be affected when digoxin and topiramate are used concomitantly.
    Dihydroergotamine: (Major) Phentermine, which increases catecholamine release, can increase blood pressure; this effect may be additive with the prolonged vasoconstriction caused by ergot alkaloids. Monitoring for cardiac effects during concurrent use of ergot alkaloids with phentermine may be advisable.
    Diltiazem: (Moderate) Coadministrator topiramate with diltiazem with caution. Concomitant administration of diltiazem (240 mg) with topiramate (150 mg/day) resulted in a 10% decrease in Cmax and a 25% decrease in diltiazem AUC, a 27% decrease in Cmax and an 18% decrease in desacetyl diltiazem AUC, and no effect on N-desmethyl diltiazem. Co-administration of topiramate with diltiazem resulted in a 16% increase in Cmax and a 19% increase in AUC of topiramate. Monitor for loss of diltiazem efficacy and or increased adverse events coming from the topiramate component of phentermine;topiramate.
    Diphenhydramine: (Major) Although not specifically studied, coadministration of CNS depressant drugs with topiramate may potentiate CNS depression such as dizziness or cognitive adverse reactions, or other centrally mediated effects of these agents. Monitor for increased CNS effects if coadministering.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Major) Although not specifically studied, coadministration of CNS depressant drugs with topiramate may potentiate CNS depression such as dizziness or cognitive adverse reactions, or other centrally mediated effects of these agents. Monitor for increased CNS effects if coadministering. (Major) Because phentermine is a sympathomimetic and anorexic agent (i.e., psychostimulant) it should not be used in combination with other sympathomimetics. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmias.
    Diphenhydramine; Ibuprofen: (Major) Although not specifically studied, coadministration of CNS depressant drugs with topiramate may potentiate CNS depression such as dizziness or cognitive adverse reactions, or other centrally mediated effects of these agents. Monitor for increased CNS effects if coadministering. (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Diphenhydramine; Naproxen: (Major) Although not specifically studied, coadministration of CNS depressant drugs with topiramate may potentiate CNS depression such as dizziness or cognitive adverse reactions, or other centrally mediated effects of these agents. Monitor for increased CNS effects if coadministering. (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Diphenhydramine; Phenylephrine: (Major) Although not specifically studied, coadministration of CNS depressant drugs with topiramate may potentiate CNS depression such as dizziness or cognitive adverse reactions, or other centrally mediated effects of these agents. Monitor for increased CNS effects if coadministering. (Major) Because phentermine is a sympathomimetic and anorexic agent (i.e., psychostimulant) it should not be used in combination with other sympathomimetics. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmias.
    Dipyridamole: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates or platelet inhibitors may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Dolutegravir: (Moderate) Caution is warranted when dolutegravir is administered with topiramate as there is a potential for decreased dolutegravir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Dolutegravir is partially metabolized by this isoenzyme.
    Dopamine: (Major) Because phentermine is a sympathomimetic and anorexic agent (i.e., psychostimulant) it should not be used in combination with other sympathomimetics. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmias.
    Dorzolamide; Timolol: (Major) Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Doxazosin: (Major) Sympathomimetics can antagonize the effects of antihypertensives such as alpha-blockers when administered concomitantly.
    Doxepin: (Major) Avoid use of tricyclic antidepressants with phentermine whenever possible. Tricyclic antidepressants (TCAs) may potentiate the pressor response to sympathomimetic agents, such as phentermine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience side effects like hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. Patients should be closely monitored if use together is unavoidable. (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold. In addition, during concurrent use of topiramate and amitriptyline the Cmax and AUC of amitriptyline were increased by 12%. Dosage adjustments of amitriptyline may be needed based upon tolerability to the regimen during combined use of amitriptyline and topiramate.
    Doxorubicin: (Major) Topiramate is a mild CYP3A4 inducer; doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of topiramate and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
    Doxylamine: (Major) Although not specifically studied, coadministration of CNS depressant drugs with topiramate may potentiate CNS depression such as dizziness or cognitive adverse reactions, or other centrally mediated effects of these agents. Monitor for increased CNS effects if coadministering.
    Doxylamine; Pyridoxine: (Major) Although not specifically studied, coadministration of CNS depressant drugs with topiramate may potentiate CNS depression such as dizziness or cognitive adverse reactions, or other centrally mediated effects of these agents. Monitor for increased CNS effects if coadministering.
    Dronabinol, THC: (Moderate) Concurrent use of dronabinol, THC with sympathomimetics may result in additive hypertension, tachycardia, and possibly cardiotoxicity. Dronabinol, THC has been associated with occasional hypotension, hypertension, syncope, and tachycardia. In a study of 7 adult males, combinations of IV cocaine and smoked marijuana, 1 g marijuana cigarette, 0 to 2.7% delta-9-THC, increased the heart rate above levels seen with either agent alone, with increases plateauing at 50 bpm. (Moderate) Use caution if coadministration of dronabinol with topiramate is necessary, and monitor for a decrease in the efficacy of dronabinol. Dronabinol is a CYP2C9 and 3A4 substrate; topiramate is a weak inducer of CYP3A4. Concomitant use may result in decreased plasma concentrations of dronabinol.
    Dronedarone: (Major) The concomitant use of dronedarone and CYP3A4 inducers should be avoided. Dronedarone is metabolized by CYP3A. Topiramate induces CYP3A4. Coadministration of CYP3A4 inducers, such as topiramate, with dronedarone may result in reduced plasma concentration and subsequent reduced effectiveness of dronedarone therapy.
    Droperidol: (Major) Although not specifically studied, coadministration of CNS depressant drugs with topiramate may potentiate CNS depression such as dizziness or cognitive adverse reactions, or other centrally mediated effects of these agents. Monitor for increased CNS effects if coadministering.
    Drospirenone; Estradiol: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception may also be needed.
    Drospirenone; Ethinyl Estradiol: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception may also be needed.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception may also be needed.
    Droxidopa: (Major) Because phentermine is a sympathomimetic and anorexic agent (i.e., psychostimulant) it should not be used in combination with other sympathomimetics. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmias.
    Dulaglutide: (Moderate) Sympathomimetics may increase blood glucose concentrations. Monitor for loss of diabetic control when therapy with sympathomimetic agents is instituted. Also, adrenergic medications may increase glucose uptake by muscle cells and may potentiate the actions of some antidiabetic agents. Monitor blood glucose to avoid hypoglycemia or hyperglycemia.
    Duloxetine: (Moderate) Use phentermine and selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) together with caution; use together may be safe and efficacious for some patients based on available data, provided the patient is on a stable antidepressant regimen and receives close clinical monitoring. Regular appointments to assess the efficacy of the weight loss treatment, the emergence of adverse events, and blood pressure monitoring are recommended. Watch for excessive serotonergic effects. Phentermine is related to the amphetamines, and there has been historical concern that phentermine might exhibit potential to cause serotonin syndrome or cardiovascular or pulmonary effects when combined with serotonergic agents. One case report describes adverse reactions with phentermine and fluoxetine. However, recent data suggest that phentermine's effect on MAO inhibition and serotonin augmentation is minimal at therapeutic doses, and that phentermine does not additionally increase plasma serotonin levels when combined with other serotonergic agents. In large controlled clinical studies, patients were allowed to start therapy with phentermine or phentermine; topiramate extended-release for obesity along with their antidepressants (e.g., SSRIs or SNRIs, but not MAOIs or TCAs) as long as the antidepressant dose had been stable for at least 3 months prior to the initiation of phentermine, and the patient did not have suicidal ideation or more than 1 episode of major depression documented. In analyses of the results, therapy was generally well tolerated, especially at lower phentermine doses, based on discontinuation rates and reported adverse events. Because depression and obesity often coexist, the study data may be important to providing optimal therapies.
    Dyphylline: (Major) Coadministration of dyphylline with sympathomimetics should be approached with caution. Coadministration may lead to adverse effects, such as tremors, insomnia, seizures, or cardiac arrhythmias, and should be avoided if possible.
    Dyphylline; Guaifenesin: (Major) Coadministration of dyphylline with sympathomimetics should be approached with caution. Coadministration may lead to adverse effects, such as tremors, insomnia, seizures, or cardiac arrhythmias, and should be avoided if possible.
    Edoxaban: (Moderate) Concurrent use of topiramate and anticoagulants (e.g., warfarin, enoxaparin, dabigatran) may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Elbasvir; Grazoprevir: (Moderate) Caution is advised when administering elbasvir with topiramate. Topiramate is a mild CYP3A inducer, while elbasvir is a substrate of CYP3A. Use of these drugs together may decrease the plasma concentrations of elbasvir and could result in decreased virologic response. (Moderate) Caution is advised when administering elbasvir; grazoprevir with topiramate. Topiramate is a mild CYP3A inducer, while grazoprevir is a substrate of CYP3A. Use of these drugs together may decrease the plasma concentrations of grazoprevir and could result in decreased virologic response.
    Elvitegravir: (Moderate) Caution is warranted when elvitegravir is administered with topiramate as there is a potential for decreased elvitegravir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Elvitegravir is a CYP3A4 substrate.
    Empagliflozin: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Empagliflozin; Linagliptin: (Major) Inducers of CYP3A4 (e.g., topiramate) can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such drugs, an alternative to linagliptin is strongly recommended. (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Empagliflozin; Metformin: (Major) Concurrent use of topiramate and metformin is contraindicated in patients with metabolic acidosis. Topiramate frequently causes metabolic acidosis, a condition for which the use of metformin is contraindicated. During a drug interaction study evaluating concurrent use of topiramate and metformin in healthy volunteers, the following changes in metformin pharmacokinetics were observed: the mean Cmax was increased by 17%, the mean AUC was increased by 25%, and the oral plasma clearance was decreased by 20%. The oral plasma clearance of topiramate was reduced, but the extent of the change is unknown. (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Phentermine may increase blood sugar via stimulation of beta2-receptors which leads to increased glycogenolysis. Diabetic patients may have decreased requirements of antidiabetic agents in association with the use of phentermine.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Close clinical monitoring is advised when administering topiramate with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Topiramate is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Close clinical monitoring is advised when administering topiramate with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Topiramate is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Enalapril; Hydrochlorothiazide, HCTZ: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Enflurane: (Major) Halogenated anesthetics may sensitize the myocardium to the effects of the sympathomimetics. Because of this, and its effects on blood pressure, phentermine should be discontinued several days prior to surgery.
    Ephedrine: (Major) Because phentermine is a sympathomimetic and anorexic agent (i.e., psychostimulant) it should not be used in combination with other sympathomimetics. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmias.
    Epoprostenol: (Major) Sympathomimetics can antagonize the antihypertensive effects of adrenergic agonists when administered concomitantly. Close monitoring of blood pressure or the selection of alternative therapeutic agents may be needed.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Eptifibatide: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates or platelet inhibitors may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Ergoloid Mesylates: (Major) Phentermine, which increases catecholamine release, can increase blood pressure; this effect may be additive with the prolonged vasoconstriction caused by ergot alkaloids. Monitoring for cardiac effects during concurrent use of ergot alkaloids with phentermine may be advisable.
    Ergonovine: (Major) Phentermine, which increases catecholamine release, can increase blood pressure; this effect may be additive with the prolonged vasoconstriction caused by ergot alkaloids. Monitoring for cardiac effects during concurrent use of ergot alkaloids with phentermine may be advisable.
    Ergot alkaloids: (Major) Phentermine, which increases catecholamine release, can increase blood pressure; this effect may be additive with the prolonged vasoconstriction caused by ergot alkaloids. Monitoring for cardiac effects during concurrent use of ergot alkaloids with phentermine may be advisable.
    Ergotamine: (Major) Phentermine, which increases catecholamine release, can increase blood pressure; this effect may be additive with the prolonged vasoconstriction caused by ergot alkaloids. Monitoring for cardiac effects during concurrent use of ergot alkaloids with phentermine may be advisable.
    Erlotinib: (Major) Avoid the coadministration of erlotinib with topiramate if possible due to the risk of decreased erlotinib efficacy; if concomitant use is unavoidable, the manufacturer recommends increasing the dose of erlotinib by 50 mg increments at 2-week intervals, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Topiramate is a weak CYP3A4 inducer. Coadministration with topiramate decreased the AUC and Cmax of another CYP3A4 substrate, diltiazem, by 25% and 10%, respectively. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days; coadministration with topiramate may also decrease erlotinib exposure.
    Esmolol: (Major) Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Esomeprazole; Naproxen: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Estazolam: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines. Concurrent use of topiramate and benzodiazepines associated with thrombocytopenia (e.g., clonazepam, lorazepam, and clobazam), may also increase the risk of bleeding; monitor patients appropriately during benzodiazepine therapy.
    Estradiol Cypionate; Medroxyprogesterone: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception may also be needed.
    Estradiol; Levonorgestrel: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception may also be needed.
    Estradiol; Norethindrone: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception may also be needed.
    Estradiol; Norgestimate: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception may also be needed.
    Estrogens: (Major) Topiramate can increase the clearance of estrogens and compromise the efficacy of estrogens used as hormone replacement therapies or contraceptives. Patients taking oral contraceptives, non-oral combination contraceptives, or progestions for contraception or patients taking estrogens or progestins for hormone replacement therapy should report changes in their bleeding patterns to their prescribers. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of the products may need adjustment; the manufacturer of topiramate recommends that an oral contraceptive containing 50 mcg of ethinyl estradiol be used. Different or additional forms of contraception may also be needed.
    Ethacrynic Acid: (Moderate) Topiramate is a carbonic anhydrase inhibitor. Concurrent use of topiramate with non-potassium sparing diuretics (e.g., loop diuretics) may potentiate the potassium-wasting action of these diuretics. Monitor baseline and periodic potassium concentrations during coadministration.
    Ethanol: (Major) Ethanol consumption is contraindicated within 6 hours prior to and 6 hours after administration of topiramate extended-release capsules. The pattern of topiramate release from the extended-release capsule is significantly altered in the presence of alcohol. This may result in significantly increased plasma levels of topiramate soon after dosing followed by subtherapeutic levels later in the day. Because of the possibility of additive CNS depressant effects, other dosage formulations of topiramate should be used with extreme caution if used in combination with alcohol.
    Ethinyl Estradiol; Desogestrel: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception may also be needed.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception may also be needed.
    Ethinyl Estradiol; Etonogestrel: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception may also be needed.
    Ethinyl Estradiol; Levonorgestrel: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception may also be needed.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception may also be needed.
    Ethinyl Estradiol; Norelgestromin: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception may also be needed.
    Ethinyl Estradiol; Norethindrone Acetate: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception may also be needed.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception may also be needed.
    Ethinyl Estradiol; Norethindrone: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception may also be needed.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception may also be needed.
    Ethinyl Estradiol; Norgestimate: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception may also be needed.
    Ethinyl Estradiol; Norgestrel: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception may also be needed.
    Etodolac: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Etonogestrel: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception may also be needed.
    Etoposide, VP-16: (Moderate) Monitor for clinical efficacy of etoposide if used concomitantly with topiramate. Topiramate is a weak inducer of CYP3A4; etoposide, VP-16 is a CYP3A4 substrate. Coadministration of etoposide with a strong CYP3A4 inducer (phenytoin) resulted in increased etoposide clearance and reduced efficacy, as did coadministration with a weak inducer of CYP3A4 and P-glycoprotein (P-gp) (valproic acid).
    Exenatide: (Moderate) Sympathomimetics may increase blood glucose concentrations. Monitor for loss of diabetic control when therapy with sympathomimetic agents is instituted. Also, adrenergic medications may increase glucose uptake by muscle cells and may potentiate the actions of some antidiabetic agents. Monitor blood glucose to avoid hypoglycemia or hyperglycemia.
    Ezogabine: (Moderate) Concurrent use of topiramate and drugs that cause thrombocytopenia such as the anticonvulsant ezogabine, may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (23%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Famotidine; Ibuprofen: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Felbamate: (Moderate) Concurrent use of topiramate and drugs that cause thrombocytopenia such as the anticonvulsant felbamate may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Fenoprofen: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Flibanserin: (Major) The concomitant use of flibanserin with CYP3A4 inducers significantly decreases flibanserin exposure compared to the use of flibanserin alone. Therefore, concurrent use of flibanserin and CYP3A4 inducers, such as topiramate is not recommended.
    Fluoxetine: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as selective serotonin reuptake inhibitors (SSRIs) like fluoxetine may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Fluoxetine; Olanzapine: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as selective serotonin reuptake inhibitors (SSRIs) like fluoxetine may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Fluphenazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Flurazepam: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines. Concurrent use of topiramate and benzodiazepines associated with thrombocytopenia (e.g., clonazepam, lorazepam, and clobazam), may also increase the risk of bleeding; monitor patients appropriately during benzodiazepine therapy.
    Flurbiprofen: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Fluticasone; Salmeterol: (Moderate) Caution and close observation should also be used when salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Administer sympathomimetics with caution with beta-agonists such as vilanterol. The cardiovascular effects of beta-2 agonists may be potentiated by concomitant use. Monitor the patient for tremors, nervousness, increased heart rate, or other additive side effects.
    Fluticasone; Vilanterol: (Moderate) Administer sympathomimetics with caution with beta-agonists such as vilanterol. The cardiovascular effects of beta-2 agonists may be potentiated by concomitant use. Monitor the patient for tremors, nervousness, increased heart rate, or other additive side effects.
    Fluvoxamine: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as selective serotonin reuptake inhibitors (SSRIs) like fluvoxamine may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Fondaparinux: (Moderate) Concurrent use of topiramate and anticoagulants (e.g., warfarin, enoxaparin, dabigatran) may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Food: (Moderate) Topiramate may influence the pharmacokinetic profile of cannabinoids in Marijuana and may also influence the pharmacodynamic profile. This may result in an altered adverse event profile of one or both drugs. Topiramate is an inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of marijuana's most psychoactive compound, delta-9-tetrahydrocannabinol (THC). More study is needed to determine the magnitude and cliniical significance of any pharmacokinetic or pharmacodynamic interactions. Additive drowsiness and CNS depression is possible. Monitor for changes in moods or behaviors, or for other CNS effects.
    Formoterol: (Moderate) Caution and close observation should be used when formoterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Formoterol; Mometasone: (Moderate) Caution and close observation should be used when formoterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Furosemide: (Moderate) Topiramate is a carbonic anhydrase inhibitor. Concurrent use of topiramate with non-potassium sparing diuretics (e.g., loop diuretics) may potentiate the potassium-wasting action of these diuretics. Monitor baseline and periodic potassium concentrations during coadministration.
    Gefitinib: (Moderate) Monitor for clinical response of gefitinib if used concomitantly with topiramate. Gefitinib is metabolized significantly by CYP3A4 and topiramate is a weak CYP3A4 inducer; coadministration may increase gefitinib metabolism and decrease gefitinib concentrations. This also applies to combination products containing topiramate, such as phentermine; topiramate. While the manufacturer has provided no guidance regarding the use of gefitinib with mild or moderate CYP3A4 inducers, administration of a single 500 mg gefitinib dose with a concurrent strong CYP3A4 inducer (rifampin) resulted in reduced mean AUC of gefitinib by 83%.
    Glimepiride; Pioglitazone: (Moderate) Reductions in AUC and Cmax have been noted in pioglitazone and the active metabolites when coadministered with topiramate. The clinician may suggest that the patient more frequently monitor blood glucose when these drugs are added or deleted from therapy.
    Glipizide; Metformin: (Major) Concurrent use of topiramate and metformin is contraindicated in patients with metabolic acidosis. Topiramate frequently causes metabolic acidosis, a condition for which the use of metformin is contraindicated. During a drug interaction study evaluating concurrent use of topiramate and metformin in healthy volunteers, the following changes in metformin pharmacokinetics were observed: the mean Cmax was increased by 17%, the mean AUC was increased by 25%, and the oral plasma clearance was decreased by 20%. The oral plasma clearance of topiramate was reduced, but the extent of the change is unknown. (Moderate) Phentermine may increase blood sugar via stimulation of beta2-receptors which leads to increased glycogenolysis. Diabetic patients may have decreased requirements of antidiabetic agents in association with the use of phentermine.
    Glyburide: (Minor) Coadministration of glyburide with topiramate may decrease systemic exposure to glyburide. A pharmacokinetic drug interaction study evaluated the combination of topiramate and glyburide. Reductions in AUC and Cmax were noted for glyburide and the active metabolites.
    Glyburide; Metformin: (Major) Concurrent use of topiramate and metformin is contraindicated in patients with metabolic acidosis. Topiramate frequently causes metabolic acidosis, a condition for which the use of metformin is contraindicated. During a drug interaction study evaluating concurrent use of topiramate and metformin in healthy volunteers, the following changes in metformin pharmacokinetics were observed: the mean Cmax was increased by 17%, the mean AUC was increased by 25%, and the oral plasma clearance was decreased by 20%. The oral plasma clearance of topiramate was reduced, but the extent of the change is unknown. (Moderate) Phentermine may increase blood sugar via stimulation of beta2-receptors which leads to increased glycogenolysis. Diabetic patients may have decreased requirements of antidiabetic agents in association with the use of phentermine. (Minor) Coadministration of glyburide with topiramate may decrease systemic exposure to glyburide. A pharmacokinetic drug interaction study evaluated the combination of topiramate and glyburide. Reductions in AUC and Cmax were noted for glyburide and the active metabolites.
    Glycopyrrolate; Formoterol: (Moderate) Caution and close observation should be used when formoterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Green Tea: (Major) Some, but not all, green tea products contain caffeine. Additive CNS stimulant effects are likely to occur when caffeine is coadministered with other CNS stimulants or psychostimulants. Caffeine should be avoided or used cautiously with phentermine.
    Guaifenesin; Phenylephrine: (Major) Because phentermine is a sympathomimetic and anorexic agent (i.e., psychostimulant) it should not be used in combination with other sympathomimetics. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmias.
    Guanabenz: (Major) Sympathomimetics can antagonize the antihypertensive effects of adrenergic agonists when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Guarana: (Major) Caffeine, an active constituent of guarana, is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Use of guarana should be avoided with amphetamine, dextroamphetamine, methylphenidate, modafinil, pemoline, pseudoephedrine, beta-agonists or other sympathomimetics. When combined with any of these medications, nervousness, irritability, insomnia, and/or cardiac arrhythmias may result.
    Halogenated Anesthetics: (Major) Halogenated anesthetics may sensitize the myocardium to the effects of the sympathomimetics. Because of this, and its effects on blood pressure, phentermine should be discontinued several days prior to surgery.
    Halothane: (Major) Halogenated anesthetics may sensitize the myocardium to the effects of the sympathomimetics. Because of this, and its effects on blood pressure, phentermine should be discontinued several days prior to surgery.
    Heparin: (Moderate) Concurrent use of topiramate and anticoagulants (e.g., warfarin, enoxaparin, dabigatran) may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Hydantoins: (Moderate) Although topiramate is not extensively metabolized (70% renally eliminated), hepatic enzyme inducers, such as hydantoins, have been shown to reduce topiramate serum concentrations.Topiramate may increase phenytoin concentrations through its inhibitory effects on CYP2C19. In some patients receiving phenytoin concurrently with topiramate, plasma concentrations of phenytoin were increased by 25% and topiramate plasma concentrations were decreased by 48%. These patients were generally receiving dosage regimens of phenytoin twice-daily. Other patients experienced a change of < 10% in phenytoin plasma concentrations. A similar reaction would be expected with fosphenytoin or ethotoin. Concurrent use of topiramate and drugs that cause thrombocytopenia, such as the hydantoins, may also increase the risk of bleeding; monitor patients appropriately.
    Hydralazine; Hydrochlorothiazide, HCTZ: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Hydrochlorothiazide, HCTZ: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Hydrochlorothiazide, HCTZ; Irbesartan: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Hydrochlorothiazide, HCTZ; Lisinopril: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Hydrochlorothiazide, HCTZ; Losartan: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree. (Major) Phentermine has vasopressor effects and may limit the benefit of antihypertensive agents particularly sympatholytic agents such as methyldopa. Concomitant use of phentermine with methyldopa may antagonize the antihypertensive effects of these agents. Although leading drug interaction texts differ in the potential for an interaction between phentermine and this group of antihypertensive agents, these effects are likely to be clinically significant and have been described in hypertensive patients on these medications. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree. (Major) Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Hydrochlorothiazide, HCTZ; Moexipril: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Hydrochlorothiazide, HCTZ; Olmesartan: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Hydrochlorothiazide, HCTZ; Propranolol: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree. (Major) Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Hydrochlorothiazide, HCTZ; Quinapril: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Hydrochlorothiazide, HCTZ; Spironolactone: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Hydrochlorothiazide, HCTZ; Telmisartan: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Hydrochlorothiazide, HCTZ; Triamterene: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Hydrochlorothiazide, HCTZ; Valsartan: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Hydrocodone; Ibuprofen: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Hydrocodone; Phenylephrine: (Major) Because phentermine is a sympathomimetic and anorexic agent (i.e., psychostimulant) it should not be used in combination with other sympathomimetics. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmias.
    Hydroxychloroquine: (Moderate) Caution is warranted with the coadministration of hydroxychloroquine and antiepileptic drugs, such as topiramate. Hydroxychloroquine can lower the seizure threshold; therefore, the activity of antiepileptic drugs may be impaired with concomitant use.
    Hydroxyprogesterone: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception may also be needed.
    Hydroxyzine: (Major) Although not specifically studied, coadministration of CNS depressant drugs with topiramate may potentiate CNS depression such as dizziness or cognitive adverse reactions, or other centrally mediated effects of these agents. Monitor for increased CNS effects if coadministering.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) Carbonic anhydrase inhibiting drugs, such as topiramate (a weak carbonic anhydrase inhibitor) can alkalinize the urine, thereby decreasing the effectiveness of methenamine by inhibiting the conversion of methenamine to formaldehyde. (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Ibuprofen: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Ibuprofen; Oxycodone: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Ibuprofen; Pseudoephedrine: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Iloprost: (Major) Sympathomimetics can antagonize the antihypertensive effects of adrenergic agonists when administered concomitantly. Close monitoring of blood pressure or the selection of alternative therapeutic agents may be needed.
    Imatinib: (Moderate) Imatinib is a potent inhibitors of cytochrome P450 2C9 and might decrease topiramate metabolism leading to increased topiramate serum concentrations and a risk of adverse reactions.
    Imipramine: (Major) Avoid use of tricyclic antidepressants with phentermine whenever possible. Tricyclic antidepressants (TCAs) may potentiate the pressor response to sympathomimetic agents, such as phentermine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience side effects like hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. Patients should be closely monitored if use together is unavoidable. (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold. In addition, during concurrent use of topiramate and amitriptyline the Cmax and AUC of amitriptyline were increased by 12%. Dosage adjustments of amitriptyline may be needed based upon tolerability to the regimen during combined use of amitriptyline and topiramate.
    Incretin Mimetics: (Moderate) Sympathomimetics may increase blood glucose concentrations. Monitor for loss of diabetic control when therapy with sympathomimetic agents is instituted. Also, adrenergic medications may increase glucose uptake by muscle cells and may potentiate the actions of some antidiabetic agents. Monitor blood glucose to avoid hypoglycemia or hyperglycemia.
    Indacaterol: (Moderate) Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Caution and close observation is needed if indacaterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Indacaterol; Glycopyrrolate: (Moderate) Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Caution and close observation is needed if indacaterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Indapamide: (Moderate) Sympathomimetics can antagonize the antihypertensive effects of vasodilators when administered concomitantly. Patients should be monitored to confirm that the desired antihypertensive effect is achieved.
    Indomethacin: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Insulin Degludec; Liraglutide: (Moderate) Sympathomimetics may increase blood glucose concentrations. Monitor for loss of diabetic control when therapy with sympathomimetic agents is instituted. Also, adrenergic medications may increase glucose uptake by muscle cells and may potentiate the actions of some antidiabetic agents. Monitor blood glucose to avoid hypoglycemia or hyperglycemia.
    Insulin Glargine; Lixisenatide: (Moderate) Sympathomimetics may increase blood glucose concentrations. Monitor for loss of diabetic control when therapy with sympathomimetic agents is instituted. Also, adrenergic medications may increase glucose uptake by muscle cells and may potentiate the actions of some antidiabetic agents. Monitor blood glucose to avoid hypoglycemia or hyperglycemia.
    Insulins: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Iohexol: (Major) Phentermine lowers the seizure threshold and should be discontinued at least 48 hours before and for at least 24 hours after intrathecal use of contrast media.
    Iopamidol: (Major) Phentermine lowers the seizure threshold and should be discontinued at least 48 hours before and for at least 24 hours after intrathecal use of contrast media.
    Iopromide: (Major) Phentermine lowers the seizure threshold and should be discontinued at least 48 hours before and for at least 24 hours after intrathecal use of contrast media.
    Ioversol: (Major) Phentermine lowers the seizure threshold and should be discontinued at least 48 hours before and for at least 24 hours after intrathecal use of contrast media.
    Isavuconazonium: (Moderate) Caution and close monitoring are warranted when isavuconazonium is administered with topiramate as there is a potential for decreased concentrations of isavuconazonium. Decreased isavuconazonium concentrations may lead to a reduction of antifungal efficacy and the potential for treatment failure. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate of this enzyme.
    Isocarboxazid: (Severe) In general, all types of sympathomimetics and psychostimulants should be avoided in patients receiving MAOIs due to an increased risk of hypertensive crisis. This applies to sympathomimetics including stimulants for ADHD, narcolepsy or weight loss, nasal, oral, and ophthalmic decongestants and cold products, and even respiratory sympathomimetics (e.g., beta agonist drugs). Some local anesthetics also contain a sympathomimetic (e.g., epinephrine). In general, medicines containing sympathomimetic agents should not be used concurrently with MAOIs or within 14 days before or after their use.
    Isoflurane: (Major) Halogenated anesthetics may sensitize the myocardium to the effects of the sympathomimetics. Because of this, and its effects on blood pressure, phentermine should be discontinued several days prior to surgery.
    Isosulfan Blue: (Major) Phentermine lowers the seizure threshold and should be discontinued at least 48 hours before and for at least 24 hours after intrathecal use of contrast media.
    Ivabradine: (Major) Avoid coadministration of ivabradine and topiramate. Ivabradine is primarily metabolized by CYP3A4; topiramte is a weak inducer of CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Ivacaftor: (Moderate) Use caution when administering ivacaftor and topiramate concurrently; the clinical impact of this interaction has not yet been determined. Ivacaftor is a CYP3A substrate and topiramate is a weak CYP3A inducer. Administration of ivacaftor with strong CYP3A inducers is not recommended because sub-therapeutic ivacaftor exposure could result; the impact of mild inducers is not known.
    Kava Kava, Piper methysticum: (Major) The German Commission E warns that any substances that act on the CNS, including anticonvulsants, may interact with kava kava. While the interactions can be pharmacodynamic in nature, kava kava has been reported to inhibit many CYP isozymes (i.e., CYP1A2, 2C9, 2C19, 2D6, 3A4, and 4A9/11) and important pharmacokinetic interactions with CNS-active agents that undergo oxidative metabolism via these CYP isozymes are also possible. Persons taking an anticonvulsant should discuss the use of herbal supplements with their health care professional prior to consuming them.
    Ketoprofen: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Ketorolac: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Labetalol: (Major) Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Lamotrigine: (Moderate) Use caution when coadministering lamotrigine and topiramate. Concurrent use of topiramate and drugs that cause thrombocytopenia, such as lamotrigine, may increase the risk of bleeding. In pediatric patients who underwent craniotomy for epilepsy surgery (n = 84), treatment for confirmed or suspected coagulopathy was required in 5 of 7 patients taking a regimen of topiramate and lamotrigine, approximately one-third of the overall study population requiring blood products. Concurrent use may also result in significant CNS depression. Further, co-administration of topiramate and lamotrigine resulted in a 13% decrease in topiramate concentration; however, the clinical significance of this finding is unknown. Plasma concentrations of lamotrigine do not appear to be affected by the combined use of the drugs.
    Lansoprazole; Naproxen: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Lepirudin: (Moderate) Concurrent use of topiramate and anticoagulants (e.g., warfarin, enoxaparin, dabigatran) may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Leuprolide; Norethindrone: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception may also be needed.
    Levalbuterol: (Major) Caution and close observation should be used when albuterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Levetiracetam: (Moderate) Concurrent use of topiramate and drugs that cause thrombocytopenia such as the anticonvulsant levetiracetam, may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Levobetaxolol: (Major) Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Levobunolol: (Major) Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Levomilnacipran: (Moderate) Use phentermine and selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) together with caution; use together may be safe and efficacious for some patients based on available data, provided the patient is on a stable antidepressant regimen and receives close clinical monitoring. Regular appointments to assess the efficacy of the weight loss treatment, the emergence of adverse events, and blood pressure monitoring are recommended. Watch for excessive serotonergic effects. Phentermine is related to the amphetamines, and there has been historical concern that phentermine might exhibit potential to cause serotonin syndrome or cardiovascular or pulmonary effects when combined with serotonergic agents. One case report describes adverse reactions with phentermine and fluoxetine. However, recent data suggest that phentermine's effect on MAO inhibition and serotonin augmentation is minimal at therapeutic doses, and that phentermine does not additionally increase plasma serotonin levels when combined with other serotonergic agents. In large controlled clinical studies, patients were allowed to start therapy with phentermine or phentermine; topiramate extended-release for obesity along with their antidepressants (e.g., SSRIs or SNRIs, but not MAOIs or TCAs) as long as the antidepressant dose had been stable for at least 3 months prior to the initiation of phentermine, and the patient did not have suicidal ideation or more than 1 episode of major depression documented. In analyses of the results, therapy was generally well tolerated, especially at lower phentermine doses, based on discontinuation rates and reported adverse events. Because depression and obesity often coexist, the study data may be important to providing optimal therapies.
    Levonorgestrel: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception may also be needed.
    Levothyroxine: (Moderate) Sympathomimetic amines should be used with caution in patients with thyrotoxicosis since these patients are unusually responsive to sympathomimetic amines. Based on the cardiovascular stimulatory effects of sympathomimetic drugs, the concomitant use of sympathomimetics and thyroid hormones can enhance the effects on the cardiovascular system. Patients with coronary artery disease have an increased risk of coronary insufficiency from either agent. Concomitant use of these agents may increase this risk further. In addition, dopamine at a dose of >= 1 mcg/kg/min and dopamine agonists (e.g., apomorphine, bromocriptine, levodopa, pergolide, pramipexole, ropinirole, rotigotine) may result in a transient reduction in TSH secretion. The reduction in TSH secretion is not sustained; hypothyroidism does not occur.
    Lidocaine: (Moderate) Concomitant use of systemic lidocaine and topiramate may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; topiramate induces CYP3A4.
    Linagliptin: (Major) Inducers of CYP3A4 (e.g., topiramate) can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such drugs, an alternative to linagliptin is strongly recommended. (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Linagliptin; Metformin: (Major) Concurrent use of topiramate and metformin is contraindicated in patients with metabolic acidosis. Topiramate frequently causes metabolic acidosis, a condition for which the use of metformin is contraindicated. During a drug interaction study evaluating concurrent use of topiramate and metformin in healthy volunteers, the following changes in metformin pharmacokinetics were observed: the mean Cmax was increased by 17%, the mean AUC was increased by 25%, and the oral plasma clearance was decreased by 20%. The oral plasma clearance of topiramate was reduced, but the extent of the change is unknown. (Major) Inducers of CYP3A4 (e.g., topiramate) can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such drugs, an alternative to linagliptin is strongly recommended. (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Phentermine may increase blood sugar via stimulation of beta2-receptors which leads to increased glycogenolysis. Diabetic patients may have decreased requirements of antidiabetic agents in association with the use of phentermine.
    Linezolid: (Major) Phentermine should not be administered during or within 14 days following the use of linezolid. Linezolid is an antibiotic that is also a weak, reversible nonselective inhibitor of monoamine oxidase (MAO). Drugs that possess MAO-inhibiting activity, such as linezolid, can prolong and intensify the cardiac stimulation and vasopressor effects of phentermine which may invoke a hypertensive reaction. Additonally, phentermine has a weak ability to dose-dependently raise serotonin levels. Linezolid has the potential for interaction with serotonergic agents, which may increase the risk for serotonin syndrome. If coadministration is necessary, closely monitor for increased blood pressure and signs of serotonin syndrome.
    Liothyronine: (Moderate) Sympathomimetic amines should be used with caution in patients with thyrotoxicosis since these patients are unusually responsive to sympathomimetic amines. Based on the cardiovascular stimulatory effects of sympathomimetic drugs, the concomitant use of sympathomimetics and thyroid hormones can enhance the effects on the cardiovascular system. Patients with coronary artery disease have an increased risk of coronary insufficiency from either agent. Concomitant use of these agents may increase this risk further. In addition, dopamine at a dose of >= 1 mcg/kg/min and dopamine agonists (e.g., apomorphine, bromocriptine, levodopa, pergolide, pramipexole, ropinirole, rotigotine) may result in a transient reduction in TSH secretion. The reduction in TSH secretion is not sustained; hypothyroidism does not occur.
    Liotrix: (Moderate) Sympathomimetic amines should be used with caution in patients with thyrotoxicosis since these patients are unusually responsive to sympathomimetic amines. Based on the cardiovascular stimulatory effects of sympathomimetic drugs, the concomitant use of sympathomimetics and thyroid hormones can enhance the effects on the cardiovascular system. Patients with coronary artery disease have an increased risk of coronary insufficiency from either agent. Concomitant use of these agents may increase this risk further. In addition, dopamine at a dose of >= 1 mcg/kg/min and dopamine agonists (e.g., apomorphine, bromocriptine, levodopa, pergolide, pramipexole, ropinirole, rotigotine) may result in a transient reduction in TSH secretion. The reduction in TSH secretion is not sustained; hypothyroidism does not occur.
    Liraglutide: (Moderate) Sympathomimetics may increase blood glucose concentrations. Monitor for loss of diabetic control when therapy with sympathomimetic agents is instituted. Also, adrenergic medications may increase glucose uptake by muscle cells and may potentiate the actions of some antidiabetic agents. Monitor blood glucose to avoid hypoglycemia or hyperglycemia.
    Lithium: (Moderate) In patients, the pharmacokinetics of lithium were unaffected during treatment with topiramate at doses of 200 mg/day; however, there was an observed increase in systemic exposure of lithium (27% for Cmax and 26% for AUC) following topiramate doses up to 600 mg/day. Lithium levels should be monitored; monitor patients for adequate control of symptoms when phentermine; topiramate is added to lithium therapy.
    Lixisenatide: (Moderate) Sympathomimetics may increase blood glucose concentrations. Monitor for loss of diabetic control when therapy with sympathomimetic agents is instituted. Also, adrenergic medications may increase glucose uptake by muscle cells and may potentiate the actions of some antidiabetic agents. Monitor blood glucose to avoid hypoglycemia or hyperglycemia.
    Loop diuretics: (Moderate) Topiramate is a carbonic anhydrase inhibitor. Concurrent use of topiramate with non-potassium sparing diuretics (e.g., loop diuretics) may potentiate the potassium-wasting action of these diuretics. Monitor baseline and periodic potassium concentrations during coadministration.
    Loperamide: (Moderate) The plasma concentration and efficacy of loperamide may be reduced when administered concurrently with topiramate. Loperamide is metabolized by the hepatic enzyme CYP3A4; topiramate is a mild inducer of this enzyme.
    Loperamide; Simethicone: (Moderate) The plasma concentration and efficacy of loperamide may be reduced when administered concurrently with topiramate. Loperamide is metabolized by the hepatic enzyme CYP3A4; topiramate is a mild inducer of this enzyme.
    Lopinavir; Ritonavir: (Moderate) Concurrent administration of topiramate with ritonavir may result in decreased concentrations of ritonavir. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Ritonavir is metabolized by this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Lorazepam: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines. Concurrent use of topiramate and benzodiazepines associated with thrombocytopenia (e.g., clonazepam, lorazepam, and clobazam), may also increase the risk of bleeding; monitor patients appropriately during benzodiazepine therapy.
    Lorcaserin: (Major) The safety and efficacy of coadministration of lorcaserin with other products intended for weight loss including prescription drugs (e.g., phentermine, fenfluramine, dexfenfluramine, orlistat, phendimetrazine, amphetamines), over-the-counter drugs (e.g., orlistat, phenylpropanolamine, ephedrine), and herbal preparations (ephedra, Ma huang) have not been established. Some of these agents (fenfluramine, dexfenfluramine) are known to increase the risk for cardiac valvulopathy and pulmonary hypertension. Coadministration of sibutramine with other serotonergic medications is contraindicated due to the risk for serotonin-related adverse effects, such as serotonin syndrome.
    Low Molecular Weight Heparins: (Moderate) Concurrent use of topiramate and anticoagulants (e.g., warfarin, enoxaparin, dabigatran) may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Lumacaftor; Ivacaftor: (Moderate) Use caution when administering ivacaftor and topiramate concurrently; the clinical impact of this interaction has not yet been determined. Ivacaftor is a CYP3A substrate and topiramate is a weak CYP3A inducer. Administration of ivacaftor with strong CYP3A inducers is not recommended because sub-therapeutic ivacaftor exposure could result; the impact of mild inducers is not known.
    Lurasidone: (Moderate) Because lurasidone is primarily metabolized by CYP3A4, decreased plasma concentrations of lurasidone may theoretically occur when the drug is co-administered with inducers of CYP3A4 such as topiramate.
    Macitentan: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking macitentan with a sympathomimetic.
    Magnesium Salicylate: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Maprotiline: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches. (Moderate) Maprotiline, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when maprotiline is used concurrently. Because of the lowering of seizure threshold, an alternative antidepressant may be a more optimal choice for patients taking drugs for epilepsy.
    Maraviroc: (Minor) Use caution if coadministration of maraviroc with topiramate is necessary, due to a possible decrease in maraviroc exposure. Maraviroc is a CYP3A substrate and topiramate is a CYP3A4 inducer. Monitor for a decrease in maraviroc efficacy with concomitant use.
    Meclofenamate Sodium: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Medroxyprogesterone: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception may also be needed.
    Mefenamic Acid: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Mefloquine: (Moderate) Coadministration of mefloquine and anticonvulsants may result in lower than expected anticonvulsant concentrations and loss of seizure control. Monitoring of the anticonvulsant serum concentration is recommended. Dosage adjustments may be required during and after therapy with mefloquine.
    Megestrol: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception may also be needed.
    Meglitinides: (Moderate) Sympathomimetics may increase blood glucose concentrations. Monitor for loss of diabetic control when therapy with sympathomimetic agents is instituted. Also, adrenergic medications may increase glucose uptake by muscle cells and may potentiate the actions of some antidiabetic agents. Monitor blood glucose to avoid hypoglycemia or hyperglycemia.
    Meloxicam: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Mesoridazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Mestranol; Norethindrone: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception may also be needed.
    Metaproterenol: (Major) Caution and close observation should also be used when metaproterenol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Metformin: (Major) Concurrent use of topiramate and metformin is contraindicated in patients with metabolic acidosis. Topiramate frequently causes metabolic acidosis, a condition for which the use of metformin is contraindicated. During a drug interaction study evaluating concurrent use of topiramate and metformin in healthy volunteers, the following changes in metformin pharmacokinetics were observed: the mean Cmax was increased by 17%, the mean AUC was increased by 25%, and the oral plasma clearance was decreased by 20%. The oral plasma clearance of topiramate was reduced, but the extent of the change is unknown. (Moderate) Phentermine may increase blood sugar via stimulation of beta2-receptors which leads to increased glycogenolysis. Diabetic patients may have decreased requirements of antidiabetic agents in association with the use of phentermine.
    Metformin; Pioglitazone: (Major) Concurrent use of topiramate and metformin is contraindicated in patients with metabolic acidosis. Topiramate frequently causes metabolic acidosis, a condition for which the use of metformin is contraindicated. During a drug interaction study evaluating concurrent use of topiramate and metformin in healthy volunteers, the following changes in metformin pharmacokinetics were observed: the mean Cmax was increased by 17%, the mean AUC was increased by 25%, and the oral plasma clearance was decreased by 20%. The oral plasma clearance of topiramate was reduced, but the extent of the change is unknown. (Moderate) Phentermine may increase blood sugar via stimulation of beta2-receptors which leads to increased glycogenolysis. Diabetic patients may have decreased requirements of antidiabetic agents in association with the use of phentermine. (Moderate) Reductions in AUC and Cmax have been noted in pioglitazone and the active metabolites when coadministered with topiramate. The clinician may suggest that the patient more frequently monitor blood glucose when these drugs are added or deleted from therapy.
    Metformin; Repaglinide: (Major) Concurrent use of topiramate and metformin is contraindicated in patients with metabolic acidosis. Topiramate frequently causes metabolic acidosis, a condition for which the use of metformin is contraindicated. During a drug interaction study evaluating concurrent use of topiramate and metformin in healthy volunteers, the following changes in metformin pharmacokinetics were observed: the mean Cmax was increased by 17%, the mean AUC was increased by 25%, and the oral plasma clearance was decreased by 20%. The oral plasma clearance of topiramate was reduced, but the extent of the change is unknown. (Moderate) Phentermine may increase blood sugar via stimulation of beta2-receptors which leads to increased glycogenolysis. Diabetic patients may have decreased requirements of antidiabetic agents in association with the use of phentermine.
    Metformin; Rosiglitazone: (Major) Concurrent use of topiramate and metformin is contraindicated in patients with metabolic acidosis. Topiramate frequently causes metabolic acidosis, a condition for which the use of metformin is contraindicated. During a drug interaction study evaluating concurrent use of topiramate and metformin in healthy volunteers, the following changes in metformin pharmacokinetics were observed: the mean Cmax was increased by 17%, the mean AUC was increased by 25%, and the oral plasma clearance was decreased by 20%. The oral plasma clearance of topiramate was reduced, but the extent of the change is unknown. (Moderate) Phentermine may increase blood sugar via stimulation of beta2-receptors which leads to increased glycogenolysis. Diabetic patients may have decreased requirements of antidiabetic agents in association with the use of phentermine.
    Metformin; Saxagliptin: (Major) Concurrent use of topiramate and metformin is contraindicated in patients with metabolic acidosis. Topiramate frequently causes metabolic acidosis, a condition for which the use of metformin is contraindicated. During a drug interaction study evaluating concurrent use of topiramate and metformin in healthy volunteers, the following changes in metformin pharmacokinetics were observed: the mean Cmax was increased by 17%, the mean AUC was increased by 25%, and the oral plasma clearance was decreased by 20%. The oral plasma clearance of topiramate was reduced, but the extent of the change is unknown. (Moderate) Phentermine may increase blood sugar via stimulation of beta2-receptors which leads to increased glycogenolysis. Diabetic patients may have decreased requirements of antidiabetic agents in association with the use of phentermine. (Moderate) Sympathomimetics may increase blood glucose concentrations. Monitor for loss of diabetic control when therapy with sympathomimetic agents is instituted. Also, adrenergic medications may increase glucose uptake by muscle cells and may potentiate the actions of some antidiabetic agents. Monitor blood glucose to avoid hypoglycemia or hyperglycemia.
    Metformin; Sitagliptin: (Major) Concurrent use of topiramate and metformin is contraindicated in patients with metabolic acidosis. Topiramate frequently causes metabolic acidosis, a condition for which the use of metformin is contraindicated. During a drug interaction study evaluating concurrent use of topiramate and metformin in healthy volunteers, the following changes in metformin pharmacokinetics were observed: the mean Cmax was increased by 17%, the mean AUC was increased by 25%, and the oral plasma clearance was decreased by 20%. The oral plasma clearance of topiramate was reduced, but the extent of the change is unknown. (Moderate) Phentermine may increase blood sugar via stimulation of beta2-receptors which leads to increased glycogenolysis. Diabetic patients may have decreased requirements of antidiabetic agents in association with the use of phentermine. (Moderate) Sympathomimetics may increase blood glucose concentrations. Monitor for loss of diabetic control when therapy with sympathomimetic agents is instituted. Also, adrenergic medications may increase glucose uptake by muscle cells and may potentiate the actions of some antidiabetic agents. Monitor blood glucose to avoid hypoglycemia or hyperglycemia.
    Methenamine: (Moderate) Carbonic anhydrase inhibiting drugs, such as topiramate (a weak carbonic anhydrase inhibitor) can alkalinize the urine, thereby decreasing the effectiveness of methenamine by inhibiting the conversion of methenamine to formaldehyde.
    Methenamine; Sodium Acid Phosphate: (Moderate) Carbonic anhydrase inhibiting drugs, such as topiramate (a weak carbonic anhydrase inhibitor) can alkalinize the urine, thereby decreasing the effectiveness of methenamine by inhibiting the conversion of methenamine to formaldehyde.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Moderate) Carbonic anhydrase inhibiting drugs, such as topiramate (a weak carbonic anhydrase inhibitor) can alkalinize the urine, thereby decreasing the effectiveness of methenamine by inhibiting the conversion of methenamine to formaldehyde.
    Methyclothiazide: (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Methyldopa: (Major) Phentermine has vasopressor effects and may limit the benefit of antihypertensive agents particularly sympatholytic agents such as methyldopa. Concomitant use of phentermine with methyldopa may antagonize the antihypertensive effects of these agents. Although leading drug interaction texts differ in the potential for an interaction between phentermine and this group of antihypertensive agents, these effects are likely to be clinically significant and have been described in hypertensive patients on these medications.
    Methylergonovine: (Major) Phentermine, which increases catecholamine release, can increase blood pressure; this effect may be additive with the prolonged vasoconstriction caused by ergot alkaloids. Monitoring for cardiac effects during concurrent use of ergot alkaloids with phentermine may be advisable.
    Methysergide: (Major) Phentermine, which increases catecholamine release, can increase blood pressure; this effect may be additive with the prolonged vasoconstriction caused by ergot alkaloids. Monitoring for cardiac effects during concurrent use of ergot alkaloids with phentermine may be advisable.
    Metolazone: (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Metoprolol: (Major) Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Midazolam: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines. Concurrent use of topiramate and benzodiazepines associated with thrombocytopenia (e.g., clonazepam, lorazepam, and clobazam), may also increase the risk of bleeding; monitor patients appropriately during benzodiazepine therapy.
    Midodrine: (Major) Because phentermine is a sympathomimetic and anorexic agent (i.e., psychostimulant) it should not be used in combination with other sympathomimetics. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmias.
    Miglitol: (Moderate) Sympathomimetics may increase blood glucose concentrations. Monitor for loss of diabetic control when therapy with sympathomimetic agents is instituted. Also, adrenergic medications may increase glucose uptake by muscle cells and may potentiate the actions of some antidiabetic agents. Monitor blood glucose to avoid hypoglycemia or hyperglycemia.
    Milnacipran: (Moderate) Use phentermine and selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) together with caution; use together may be safe and efficacious for some patients based on available data, provided the patient is on a stable antidepressant regimen and receives close clinical monitoring. Regular appointments to assess the efficacy of the weight loss treatment, the emergence of adverse events, and blood pressure monitoring are recommended. Watch for excessive serotonergic effects. Phentermine is related to the amphetamines, and there has been historical concern that phentermine might exhibit potential to cause serotonin syndrome or cardiovascular or pulmonary effects when combined with serotonergic agents. One case report describes adverse reactions with phentermine and fluoxetine. However, recent data suggest that phentermine's effect on MAO inhibition and serotonin augmentation is minimal at therapeutic doses, and that phentermine does not additionally increase plasma serotonin levels when combined with other serotonergic agents. In large controlled clinical studies, patients were allowed to start therapy with phentermine or phentermine; topiramate extended-release for obesity along with their antidepressants (e.g., SSRIs or SNRIs, but not MAOIs or TCAs) as long as the antidepressant dose had been stable for at least 3 months prior to the initiation of phentermine, and the patient did not have suicidal ideation or more than 1 episode of major depression documented. In analyses of the results, therapy was generally well tolerated, especially at lower phentermine doses, based on discontinuation rates and reported adverse events. Because depression and obesity often coexist, the study data may be important to providing optimal therapies.
    Mirtazapine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed during co-administration of mirtazapine with other drugs that have serotonergic properties. As a drug related to the amphetamines, phentermine has the potential to cause serotonin syndrome when combined with serotonergic agents. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. Mirtazapine should be discontinued if a patient develops a combination of symptoms suggestive of serotonin syndrome.
    Molindone: (Moderate) Consistent with the pharmacology of molindone, additive effects may occur with other CNS active drugs such as anticonvulsants. In addition, seizures have been reported during the use of molindone, which is of particular significance in patients with a seizure disorder receiving anticonvulsants. Adequate dosages of anticonvulsants should be continued when molindone is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either molindone or the anticonvulsant.
    Monoamine oxidase inhibitors: (Severe) In general, all types of sympathomimetics and psychostimulants should be avoided in patients receiving MAOIs due to an increased risk of hypertensive crisis. This applies to sympathomimetics including stimulants for ADHD, narcolepsy or weight loss, nasal, oral, and ophthalmic decongestants and cold products, and even respiratory sympathomimetics (e.g., beta agonist drugs). Some local anesthetics also contain a sympathomimetic (e.g., epinephrine). In general, medicines containing sympathomimetic agents should not be used concurrently with MAOIs or within 14 days before or after their use.
    Nabilone: (Moderate) Concurrent use of nabilone with sympathomimetics (e.g., amphetamine or cocaine) may result in additive hypertension, tachycardia, and possibly cardiotoxicity. In a study of 7 adult males, combinations of cocaine (IV) and smoked marijuana (1 g marijuana cigarette, 0 to 2.7% delta-9-THC) increased the heart rate above levels seen with either agent alone, with increases reaching a plateau at 50 bpm.
    Nabumetone: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Nadolol: (Major) Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Naproxen: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Naproxen; Pseudoephedrine: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Naproxen; Sumatriptan: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Nebivolol: (Major) Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Nebivolol; Valsartan: (Major) Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Nintedanib: (Major) Coadministration of nintedanib with CYP3A4 inducers such as topiramate should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy. Topiramate is a mild CYP3A4 inducer and nintedanib is a minor substrate of CYP3A4.
    Nitrates: (Major) Concomitant use of nitrates with sympathomimetics can result in antagonism of the antianginal effects of nitrates. In addition, amyl nitrite can block the alpha-adrenergic effects of epinephrine, possibly precipitating tachycardia and severe hypotension.
    Non-Ionic Contrast Media: (Major) Phentermine lowers the seizure threshold and should be discontinued at least 48 hours before and for at least 24 hours after intrathecal use of contrast media.
    Nonsteroidal antiinflammatory drugs: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Norepinephrine: (Major) Because phentermine is a sympathomimetic and anorexic agent (i.e., psychostimulant) it should not be used in combination with other sympathomimetics. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmias.
    Norethindrone: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception may also be needed.
    Norgestrel: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception may also be needed.
    Nortriptyline: (Major) Avoid use of tricyclic antidepressants with phentermine whenever possible. Tricyclic antidepressants (TCAs) may potentiate the pressor response to sympathomimetic agents, such as phentermine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience side effects like hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. Patients should be closely monitored if use together is unavoidable. (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold. In addition, during concurrent use of topiramate and amitriptyline the Cmax and AUC of amitriptyline were increased by 12%. Dosage adjustments of amitriptyline may be needed based upon tolerability to the regimen during combined use of amitriptyline and topiramate.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of topiramate with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in decreased concentrations of dasabuvir, paritaprevir, and ritonavir. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Ritonavir, paritaprevir, and dasabuvir (minor) are all metabolized by this enzyme. Caution and close monitoring are advised if these drugs are administered together. (Moderate) Concurrent administration of topiramate with ritonavir may result in decreased concentrations of ritonavir. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Ritonavir is metabolized by this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Orlistat: (Moderate) Seizures have been reported in patients treated concomitantly with orlistat and anticonvulsants. Patients should be monitored for possible changes in the frequency and/or severity of convulsions. A mechanism for the potential interaction has not been stated. (Moderate) The safety and efficacy of coadministration of phentermine with other products intended for weight loss has not been established.
    Oxaprozin: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Oxazepam: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines. Concurrent use of topiramate and benzodiazepines associated with thrombocytopenia (e.g., clonazepam, lorazepam, and clobazam), may also increase the risk of bleeding; monitor patients appropriately during benzodiazepine therapy.
    Oxcarbazepine: (Moderate) Coadministration of carbamazepine has resulted in a clinically significant decrease in topiramate exposure; a topiramate dosage increase may be necessary. Additionally, concurrent use of topiramate and drugs that cause thrombocytopenia, such as carbamazepine, may also increase the risk of bleeding; monitor patients appropriately.
    Paroxetine: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as selective serotonin reuptake inhibitors (SSRIs) like paroxetine may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Pazopanib: (Moderate) Coadministration of pazopanib and topiramate may cause a decrease in systemic concentrations of pazopanib. Use caution when administering these drugs concomitantly. Pazopanib is a substrate for CYP3A4. Topiramate in a weak CYP3A4 inducer.
    Pemoline: (Major) A reduction in seizure threshold has been reported following concomitant administration of pemoline with anticonvulsant agents. Dosage adjustments of anticonvulsants may be necessary during simultaneous use of these drugs.
    Penbutolol: (Major) Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Pentosan: (Moderate) Concurrent use of topiramate and anticoagulants (e.g., warfarin, enoxaparin, dabigatran) may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Perampanel: (Moderate) During clinical trials, co-administration of topiramate and perampanel to patients led to a 20% decrease in the AUC of perampanel compared to patients not taking enzyme-inducing antiepileptic drugs. Topiramate is an inducer of CYP3A4, while perampanel is a substrate of this enzyme. Patients taking topiramate who begin treatment with perampanel should be closely monitored for adverse effects and receive a higher initial dose of perampanel. Addition or withdrawal of enzyme-inducing antiepileptic drugs may require a perampanel dose adjustment.
    Pergolide: (Major) Phentermine, which increases catecholamine release, can increase blood pressure; this effect may be additive with the prolonged vasoconstriction caused by ergot alkaloids. Monitoring for cardiac effects during concurrent use of ergot alkaloids with phentermine may be advisable.
    Perindopril; Amlodipine: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as topiramate, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Perphenazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Perphenazine; Amitriptyline: (Major) Avoid use of tricyclic antidepressants with phentermine whenever possible. Tricyclic antidepressants (TCAs) may potentiate the pressor response to sympathomimetic agents, such as phentermine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience side effects like hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. Patients should be closely monitored if use together is unavoidable. (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added. (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold. In addition, during concurrent use of topiramate and amitriptyline the Cmax and AUC of amitriptyline were increased by 12%. Dosage adjustments of amitriptyline may be needed based upon tolerability to the regimen during combined use of amitriptyline and topiramate.
    Phendimetrazine: (Severe) Phendimetrazine is a phenylalkaline sympathomimetic agent. All sympathomimetics and psychostimulants, including other anorexiants, should be used cautiously or avoided in patients receiving phendimetrazine. The safety of phendimetrazine when used with other anorexiants such as phentermine is controversial and concurrent use should be avoided. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmia. Similarly, phendimetrazine should not be used in combination with OTC preparations and herbal products that may contain ephedra alkaloids or Ma huang.
    Phenelzine: (Severe) In general, all types of sympathomimetics and psychostimulants should be avoided in patients receiving MAOIs due to an increased risk of hypertensive crisis. This applies to sympathomimetics including stimulants for ADHD, narcolepsy or weight loss, nasal, oral, and ophthalmic decongestants and cold products, and even respiratory sympathomimetics (e.g., beta agonist drugs). Some local anesthetics also contain a sympathomimetic (e.g., epinephrine). In general, medicines containing sympathomimetic agents should not be used concurrently with MAOIs or within 14 days before or after their use.
    Phenothiazines: (Major) Concurrent use of phentermine and phenothiazines may antagonize the anorectic effects of phentermine. In addition, psychostimulants can aggravate psychotic states. (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Phenoxybenzamine: (Major) Sympathomimetics can antagonize the effects of antihypertensives such as alpha-blockers when administered concomitantly.
    Phentolamine: (Major) Sympathomimetics can antagonize the effects of antihypertensives such as alpha-blockers when administered concomitantly.
    Phenylephrine: (Major) Because phentermine is a sympathomimetic and anorexic agent (i.e., psychostimulant) it should not be used in combination with other sympathomimetics. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmias.
    Phenylephrine; Promethazine: (Major) Because phentermine is a sympathomimetic and anorexic agent (i.e., psychostimulant) it should not be used in combination with other sympathomimetics. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmias.
    Pindolol: (Major) Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Pioglitazone: (Moderate) Reductions in AUC and Cmax have been noted in pioglitazone and the active metabolites when coadministered with topiramate. The clinician may suggest that the patient more frequently monitor blood glucose when these drugs are added or deleted from therapy.
    Pirbuterol: (Moderate) Caution and close observation should also be used when pirbuterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Piroxicam: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Pramlintide: (Moderate) Sympathomimetics may increase blood glucose concentrations. Monitor for loss of diabetic control when therapy with sympathomimetic agents is instituted. Also, adrenergic medications may increase glucose uptake by muscle cells and may potentiate the actions of some antidiabetic agents. Monitor blood glucose to avoid hypoglycemia or hyperglycemia.
    Prasugrel: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates or platelet inhibitors may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Prazosin: (Major) Sympathomimetics can antagonize the effects of antihypertensives such as alpha-blockers when administered concomitantly.
    Pregabalin: (Moderate) Concurrent use of topiramate and drugs that cause thrombocytopenia such as the anticonvulsant pregabalin, may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Probenecid: (Minor) Probenecid may increase the renal clearance of topiramate resulting in lower topiramate concentrations. Although not evaluated in humans, animal studies using probenecid along with topiramate showed a significant increase in renal clearance of topiramate. This suggests that topiramate may undergo renal tubular reabsorption. Probenecid may block renal tubular reabsorption of topiramate, thus increasing the renal clearance of the drug.
    Procarbazine: (Major) Because procarbazine exhibits some monoamine oxidase inhibitory (MAOI) activity, sympathomimetic drugs should be avoided. As with MAOIs, the use of a sympathomimetic drug with procarbazine may precipitate hypertensive crisis or other serious side effects. In the presence of MAOIs, drugs that cause release of norepinephrine induce severe cardiovascular and cerebrovascular responses. In general, do not use a sympathomimetic drug unless clinically necessary (e.g., medical emergencies, agents like dopamine) within the 14 days prior, during or 14 days after procarbazine therapy. If use is necessary within 2 weeks of the MAOI drug, in general the initial dose of the sympathomimetic agent must be greatly reduced. Patients should be counseled to avoid non-prescription (OTC) decongestants and other drug products, weight loss products, and energy supplements that contain sympathomimetic agents.
    Prochlorperazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Progesterone: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception may also be needed.
    Progestins: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception may also be needed.
    Propranolol: (Major) Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Protriptyline: (Major) Avoid use of tricyclic antidepressants with phentermine whenever possible. Tricyclic antidepressants (TCAs) may potentiate the pressor response to sympathomimetic agents, such as phentermine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience side effects like hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. Patients should be closely monitored if use together is unavoidable. (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold. In addition, during concurrent use of topiramate and amitriptyline the Cmax and AUC of amitriptyline were increased by 12%. Dosage adjustments of amitriptyline may be needed based upon tolerability to the regimen during combined use of amitriptyline and topiramate.
    Quazepam: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines. Concurrent use of topiramate and benzodiazepines associated with thrombocytopenia (e.g., clonazepam, lorazepam, and clobazam), may also increase the risk of bleeding; monitor patients appropriately during benzodiazepine therapy.
    Ramelteon: (Major) Although not specifically studied, coadministration of CNS depressant drugs with topiramate may potentiate CNS depression such as dizziness or cognitive adverse reactions, or other centrally mediated effects of these agents. Monitor for increased CNS effects if coadministering.
    Rasagiline: (Moderate) The concomitant use of rasagiline and sympathomimetics was not allowed in clinical studies; therefore, caution is advised during concurrent use of rasagiline and sympathomimetics including stimulants for ADHD and weight loss, non-prescription nasal, oral, and ophthalmic decongestants, and weight loss dietary supplements containing Ephedra. Although sympathomimetics are contraindicated for use with other non-selective monoamine oxidase inhibitors (MAOIs), hypertensive reactions generally are not expected to occur during concurrent use with rasagiline because of the selective monoamine oxidase-B (MAO-B) inhibition of rasagiline at manufacturer recommended doses. One case of elevated blood pressure has been reported in a patient during concurrent use of the recommended dose of rasagiline and ophthalmic tetrahydrozoline. One case of hypertensive crisis has been reported in a patient taking the recommended dose of another MAO-B inhibitor, selegiline, in combination with ephedrine. It should be noted that the MAO-B selectivity of rasagiline decreases in a dose-related manner as increases are made above the recommended daily dose and interactions with sympathomimetics may be more likely to occur at these higher doses.
    Reserpine: (Major) Phentermine has vasopressor effects and may limit the benefit of antihypertensive agents particularly sympatholytic agents such as reserpine. Concomitant use of phentermine with reserpine may antagonize the antihypertensive effects of these agents. Although leading drug interaction texts differ in the potential for an interaction between phentermine and this group of antihypertensive agents, these effects are likely to be clinically significant and have been described in hypertensive patients on these medications.
    Ribociclib: (Moderate) Use caution if coadministration of ribociclib with topiramate is necessary, as the systemic exposure of ribociclib may decrease resulting in decreased efficacy. Ribociclib is extensively metabolized by CYP3A4 and topiramate is a weak CYP3A4 inducer.
    Ribociclib; Letrozole: (Moderate) Use caution if coadministration of ribociclib with topiramate is necessary, as the systemic exposure of ribociclib may decrease resulting in decreased efficacy. Ribociclib is extensively metabolized by CYP3A4 and topiramate is a weak CYP3A4 inducer.
    Rilpivirine: (Moderate) Close clinical monitoring is advised when administering topiramate with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Topiramate is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Riociguat: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking riociguat with a sympathomimetic.
    Ritonavir: (Moderate) Concurrent administration of topiramate with ritonavir may result in decreased concentrations of ritonavir. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Ritonavir is metabolized by this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Rivaroxaban: (Moderate) Concurrent use of topiramate and anticoagulants may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation. However, coadministration of rivaroxaban and topiramate may result in decreased rivaroxaban exposure and may decrease the efficacy of rivaroxaban. Topiramate is a mild inducer of CYP3A4, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs of bleeding or lack of efficacy of rivaroxaban.
    Rofecoxib: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Romidepsin: (Moderate) Romidepsin is a substrate for CYP3A4. Coadministration of a CYP3A4 inducer, like topiramate, may decrease systemic concentrations of romidepsin. Use caution when concomitant administration of these agents is necessary.
    Rufinamide: (Moderate) Concurrent use of topiramate and drugs that cause thrombocytopenia such as the anticonvulsant rufinamide, may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Safinamide: (Moderate) Severe hypertensive reactions, including hypertensive crisis, have been reported in patients taking monoamine oxidase inhibitors (MAOIs), such as safinamide, and sympathomimetic medications, such as phentermine. If concomitant use of safinamide and phentermine is necessary, monitor for hypertension and hypertensive crisis.
    Salicylates: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Salmeterol: (Moderate) Caution and close observation should also be used when salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Salsalate: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Saxagliptin: (Moderate) Sympathomimetics may increase blood glucose concentrations. Monitor for loss of diabetic control when therapy with sympathomimetic agents is instituted. Also, adrenergic medications may increase glucose uptake by muscle cells and may potentiate the actions of some antidiabetic agents. Monitor blood glucose to avoid hypoglycemia or hyperglycemia.
    Selective serotonin reuptake inhibitors: (Moderate) Use phentermine and selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) together with caution; use together may be safe and efficacious for some patients based on available data, provided the patient is on a stable antidepressant regimen and receives close clinical monitoring. Regular appointments to assess the efficacy of the weight loss treatment, the emergence of adverse events, and blood pressure monitoring are recommended. Watch for excessive serotonergic effects. Phentermine is related to the amphetamines, and there has been historical concern that phentermine might exhibit potential to cause serotonin syndrome or cardiovascular or pulmonary effects when combined with serotonergic agents. One case report has been received of adverse reactions with phentermine and fluoxetine. However, recent data suggest that phentermine's effect on MAO inhibition and serotonin augmentation is minimal at therapeutic doses, and that phentermine does not additionally increase plasma serotonin levels when combined with other serotonergic agents. In large controlled clinical studies, patients were allowed to start therapy with phentermine or phentermine; topiramate extended-release for obesity along with their antidepressants (e.g., SSRIs or SNRIs, but not MAOIs or TCAs) as long as the antidepressant dose had been stable for at least 3 months prior to the initiation of phentermine, and the patient did not have suicidal ideation or more than 1 episode of major depression documented. In analyses of the results, therapy was generally well tolerated, especially at lower phentermine doses, based on discontinuation rates and reported adverse events. Because depression and obesity often coexist, the study data may be important to providing optimal co-therapies.
    Selegiline: (Severe) In general, all types of sympathomimetics and psychostimulants should be avoided in patients receiving MAOIs due to an increased risk of hypertensive crisis. This applies to sympathomimetics including stimulants for ADHD, narcolepsy or weight loss, nasal, oral, and ophthalmic decongestants and cold products, and even respiratory sympathomimetics (e.g., beta agonist drugs). Some local anesthetics also contain a sympathomimetic (e.g., epinephrine). In general, medicines containing sympathomimetic agents should not be used concurrently with MAOIs or within 14 days before or after their use.
    Selexipag: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Serotonin norepinephrine reuptake inhibitors: (Moderate) Use phentermine and selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) together with caution; use together may be safe and efficacious for some patients based on available data, provided the patient is on a stable antidepressant regimen and receives close clinical monitoring. Regular appointments to assess the efficacy of the weight loss treatment, the emergence of adverse events, and blood pressure monitoring are recommended. Watch for excessive serotonergic effects. Phentermine is related to the amphetamines, and there has been historical concern that phentermine might exhibit potential to cause serotonin syndrome or cardiovascular or pulmonary effects when combined with serotonergic agents. One case report describes adverse reactions with phentermine and fluoxetine. However, recent data suggest that phentermine's effect on MAO inhibition and serotonin augmentation is minimal at therapeutic doses, and that phentermine does not additionally increase plasma serotonin levels when combined with other serotonergic agents. In large controlled clinical studies, patients were allowed to start therapy with phentermine or phentermine; topiramate extended-release for obesity along with their antidepressants (e.g., SSRIs or SNRIs, but not MAOIs or TCAs) as long as the antidepressant dose had been stable for at least 3 months prior to the initiation of phentermine, and the patient did not have suicidal ideation or more than 1 episode of major depression documented. In analyses of the results, therapy was generally well tolerated, especially at lower phentermine doses, based on discontinuation rates and reported adverse events. Because depression and obesity often coexist, the study data may be important to providing optimal therapies.
    Sertraline: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as selective serotonin reuptake inhibitors (SSRIs) like topiramate may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Sevoflurane: (Major) Halogenated anesthetics may sensitize the myocardium to the effects of the sympathomimetics. Because of this, and its effects on blood pressure, phentermine should be discontinued several days prior to surgery.
    Sibutramine: (Severe) Sibutramine is contraindicated in patients taking other centrally-acting appetite suppressant drugs, such as phentermine. In addition, many of these agents enhance central serotonergic activity by various mechanisms. Concurrent use of sibutramine with other serotonergic agents may increase the potential for serotonin syndrome or neuroleptic malignant syndrome-like reactions. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Simeprevir: (Major) Avoid concurrent use of simeprevir and topiramate. Induction of CYP3A4 by topiramate may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
    Simvastatin; Sitagliptin: (Moderate) Sympathomimetics may increase blood glucose concentrations. Monitor for loss of diabetic control when therapy with sympathomimetic agents is instituted. Also, adrenergic medications may increase glucose uptake by muscle cells and may potentiate the actions of some antidiabetic agents. Monitor blood glucose to avoid hypoglycemia or hyperglycemia.
    Sitagliptin: (Moderate) Sympathomimetics may increase blood glucose concentrations. Monitor for loss of diabetic control when therapy with sympathomimetic agents is instituted. Also, adrenergic medications may increase glucose uptake by muscle cells and may potentiate the actions of some antidiabetic agents. Monitor blood glucose to avoid hypoglycemia or hyperglycemia.
    Sodium Oxybate: (Severe) Because phentermine is a sympathomimetic and anorexic agent, it should not be used in combination with other psychostimulants.
    Sofosbuvir; Velpatasvir: (Major) Use caution when administering velpatasvir with topiramate. Taking these drugs together may decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Velpatasvir is a CYP3A4 substrate; topiramate is a weak inducer of CYP3A4.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Use caution when administering velpatasvir with topiramate. Taking these drugs together may decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Velpatasvir is a CYP3A4 substrate; topiramate is a weak inducer of CYP3A4.
    Solifenacin: (Moderate) Through an additive effect, the use of topiramate with agents that may increase the risk for heat related disorders, such as solifenacin, may lead to oligohidrosis, hyperthermia, and/or heat stroke.
    Sotalol: (Major) Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    St. John's Wort, Hypericum perforatum: (Major) St. John's wort (Hypericum perforatum) may reduce the neuronal uptake of monoamines and should be used cautiously with sympathomimetics.
    Sulfonylureas: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving sulfonylureas should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. Fenfluramine and dexfenfluramine may potentiate the actions of some antidiabetic agents via increasing glucose uptake by muscle cells. Monitor patients taking either of these drugs in combination with glyburide for hypoglycemia.
    Sulindac: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Tamoxifen: (Major) Topiramate is a CYP3A4 inducer and a weak CYP2C19 inhibitor. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Topiramate may affect the metabolism of tamoxifen to these metabolites; plasma concentrations of tamoxifen its active metabolites have been reduced when coadministered other CYP3A4 inducers. The clinical significance of this interaction is not known. If coadministration is necessary, monitor for tamoxifen efficacy.
    Tedizolid: (Moderate) Caution is warranted with the concurrent use of tedizolid and phentermine. Tedizolid is an antibiotic that is also a weak reversible, non-selective inhibitor of MAO which could potentially prolong and intensify the cardiac stimulation and vasopressor effects of phentermine. Phentermine should not be administered during or within 14 days following the use of drugs with MAO-inhibiting activity.
    Telithromycin: (Moderate) Caution is warranted when topiramate is administered with telithromycin as there is a potential for decreased telithromycin concentrations and loss of efficacy. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Telithromycin is a substrate of CYP3A4.
    Temazepam: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines. Concurrent use of topiramate and benzodiazepines associated with thrombocytopenia (e.g., clonazepam, lorazepam, and clobazam), may also increase the risk of bleeding; monitor patients appropriately during benzodiazepine therapy.
    Terazosin: (Major) Sympathomimetics can antagonize the effects of antihypertensives such as alpha-blockers when administered concomitantly.
    Terbinafine: (Moderate) Caution is advised when administering terbinafine with topiramate. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may alter the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP2C19 and CYP3A4; topiramate is an inducer of CYP3A4 and an inhibitor of CYP2C19. Monitor patients for adverse reactions and breakthrough fungal infections if these drugs are coadministered.
    Terbutaline: (Moderate) Concomitant use of sympathomimetics with beta-agonists might result in additive cardiovascular effects such as increased blood pressure and heart rate.
    Theophylline, Aminophylline: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible.
    Thiazide diuretics: (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Thiazolidinediones: (Moderate) Use caution in combining with phentermine with antidiabetic agents, as requirements for antidiabetic agents may be altered. Phentermine exhibits sympathomimetic activity. Sympathomimetics may increase blood sugar via stimulation of beta2-receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Additionally, diabetic patients may have decreased requirements of insulins, sulfonylureas, or other antidiabetic agents in association with the use of phentermine and the concomitant dietary regimen and weight loss. As long as blood glucose is carefully monitored to avoid hypoglycemia or hyperglycemia, it appears that phentermine can be used concurrently.
    Thiethylperazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Thioridazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Thrombin Inhibitors: (Moderate) Concurrent use of topiramate and anticoagulants (e.g., warfarin, enoxaparin, dabigatran) may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Thyroid hormones: (Moderate) Sympathomimetic amines should be used with caution in patients with thyrotoxicosis since these patients are unusually responsive to sympathomimetic amines. Based on the cardiovascular stimulatory effects of sympathomimetic drugs, the concomitant use of sympathomimetics and thyroid hormones can enhance the effects on the cardiovascular system. Patients with coronary artery disease have an increased risk of coronary insufficiency from either agent. Concomitant use of these agents may increase this risk further. In addition, dopamine at a dose of >= 1 mcg/kg/min and dopamine agonists (e.g., apomorphine, bromocriptine, levodopa, pergolide, pramipexole, ropinirole, rotigotine) may result in a transient reduction in TSH secretion. The reduction in TSH secretion is not sustained; hypothyroidism does not occur.
    Tiagabine: (Moderate) Concurrent use of topiramate and drugs that cause thrombocytopenia such as the anticonvulsant tiagabine, may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Ticagrelor: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates or platelet inhibitors may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Ticlopidine: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates or platelet inhibitors may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Timolol: (Major) Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Tirofiban: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates or platelet inhibitors may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Tolmetin: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Tolterodine: (Moderate) Through an additive effect, the use of topiramate (a weak carbonic anhydrase inhibitor) with agents that may increase the risk for heat-related disorders, such as antimuscarinics, may lead to oligohidrosis, hyperthermia and/or heat stroke.
    Tolvaptan: (Major) Tolvaptan is metabolized by CYP3A4. Topiramate is an inducer of CYP3A4. Coadministration may result in reduced plasma concentration and subsequent reduced effectiveness of tolvaptan therapy and should be avoided. If coadministration is unavoidable, an increase in the tolvaptan dose may be necessary and patients should be monitored for decreased effectiveness of tolvaptan.
    Torsemide: (Moderate) Topiramate is a carbonic anhydrase inhibitor. Concurrent use of topiramate with non-potassium sparing diuretics (e.g., loop diuretics) may potentiate the potassium-wasting action of these diuretics. Monitor baseline and periodic potassium concentrations during coadministration.
    Tramadol: (Moderate) Topiramate may contribute to the CNS depression seen with tramadol; tramadol may also decrease the seizure threshold in some patients and thus, potentially, interfere with the ability of anticonvulsants to control seizures.
    Tranylcypromine: (Severe) In general, all types of sympathomimetics and psychostimulants should be avoided in patients receiving MAOIs due to an increased risk of hypertensive crisis. This applies to sympathomimetics including stimulants for ADHD, narcolepsy or weight loss, nasal, oral, and ophthalmic decongestants and cold products, and even respiratory sympathomimetics (e.g., beta agonist drugs). Some local anesthetics also contain a sympathomimetic (e.g., epinephrine). In general, medicines containing sympathomimetic agents should not be used concurrently with MAOIs or within 14 days before or after their use.
    Trazodone: (Moderate) Trazodone can lower the seizure threshold of anticonvulsants, although the overall risk is low at therapeutic doses. Patients may require increased concentrations of anticonvulsants to achieve equivalent effects if trazodone is added.
    Treprostinil: (Major) Sympathomimetics can antagonize the vasodilatory effects of antihypertensive agents when administered concomitantly.
    Tretinoin, ATRA: (Moderate) Topiramate may increase the CYP450 metabolism of tretinoin, ATRA, potentially resulting in decreased plasma concentrations of tretinoin, ATRA. Monitor for decreased clinical effects of tretinoin, ATRA while receiving concomitant therapy.
    Triazolam: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines. Concurrent use of topiramate and benzodiazepines associated with thrombocytopenia (e.g., clonazepam, lorazepam, and clobazam), may also increase the risk of bleeding; monitor patients appropriately during benzodiazepine therapy.
    Tricyclic antidepressants: (Major) Avoid use of tricyclic antidepressants with phentermine whenever possible. Tricyclic antidepressants (TCAs) may potentiate the pressor response to sympathomimetic agents, such as phentermine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience side effects like hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. Patients should be closely monitored if use together is unavoidable. (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold. In addition, during concurrent use of topiramate and amitriptyline the Cmax and AUC of amitriptyline were increased by 12%. Dosage adjustments of amitriptyline may be needed based upon tolerability to the regimen during combined use of amitriptyline and topiramate.
    Trifluoperazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Trimipramine: (Major) Avoid use of tricyclic antidepressants with phentermine whenever possible. Tricyclic antidepressants (TCAs) may potentiate the pressor response to sympathomimetic agents, such as phentermine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience side effects like hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. Patients should be closely monitored if use together is unavoidable. (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold. In addition, during concurrent use of topiramate and amitriptyline the Cmax and AUC of amitriptyline were increased by 12%. Dosage adjustments of amitriptyline may be needed based upon tolerability to the regimen during combined use of amitriptyline and topiramate.
    Trospium: (Moderate) Oligohidrosis and hyperthermia have been reported in post-marketing experience with topiramate. Use caution when topiramate is prescribed with agents known to predispose patients to similar heat-related disorders such as trospium.
    Ulipristal: (Moderate) Ulipristal is a substrate of CYP3A4 and topiramate is a CYP3A4 inducer. Concomitant use may decrease the plasma concentration and effectiveness of ulipristal.
    Umeclidinium; Vilanterol: (Moderate) Administer sympathomimetics with caution with beta-agonists such as vilanterol. The cardiovascular effects of beta-2 agonists may be potentiated by concomitant use. Monitor the patient for tremors, nervousness, increased heart rate, or other additive side effects.
    Valdecoxib: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Valproic Acid, Divalproex Sodium: (Major) Concomitant administration of topiramate and valproic acid has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. In addition, concomitant administration of topiramate and valproic acid has been associated with hypothermia with or without hyperammonemia in patients who have tolerated either drug alone. Assessment of blood ammonia levels may be advisable in patients presenting with symptoms of hypothermia. Concurrent use of topiramate and drugs that cause thrombocytopenia, such as valproic acid, may also increase the risk of bleeding; monitor patients appropriately. In several case reports, children with localized epilepsy have presented with somnolence, seizure exacerbation, behavioral alteration, decline in speech and cognitive abilities, and ataxia while being treated with a combination of valproate and topiramate. Previously, the children tolerated valproic acid with other antiepileptic drugs. Children presented with elevated serum ammonia, normal or elevated LFTs, and generalized slowing of EEG background activity during encephalopathy, which promptly reverted to normal along with clinical improvement following withdrawal of valproate. The possible mechanism is topiramate-induced aggravation of all the known complications of valproic acid monotherapy; it is not due to a pharmacokinetic interaction. This condition is reversible with cessation of either valproic acid or topiramate.
    Vandetanib: (Moderate) Use caution if coadministration of vandetanib with topiramate is necessary. Topiramate is a weak inducer of CYP3A4 in vitro. In a crossover study (n = 12), coadministration of vandetanib with a strong CYP3A4 inducer, rifampicin, decreased the mean AUC of vandetanib by 40% (90% CI, 56% to 63%); a clinically meaningful change in the mean vandetanib Cmax was not observed. However, the AUC and Cmax of the active metabolite, N-desmethyl-vandetanib, increased by 266% and 414%, respectively. It is not clear if topiramate would reduce vandetanib exposure or increase metabolite exposure to a clinically relevant degree.
    Vasodilators: (Major) Sympathomimetics can antagonize the antihypertensive effects of vasodilators when administered concomitantly. Also, vasodilators can antagonize pressor responses to epinephrine. Patients should be monitored to confirm that the desired antihypertensive effect is achieved.
    Vasopressors: (Major) Because phentermine is a sympathomimetic and anorexic agent (i.e., psychostimulant) it should not be used in combination with other sympathomimetics. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmias.
    Vemurafenib: (Major) Concomitant use of vemurafenib and topiramate may result in decreased concentrations of vemurafenib. Vemurafenib is a CYP3A4 substrate and topiramate is a weak CYP3A4 inducer. Use caution and monitor patients for therapeutic effects.
    Venlafaxine: (Moderate) Use phentermine and selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) together with caution; use together may be safe and efficacious for some patients based on available data, provided the patient is on a stable antidepressant regimen and receives close clinical monitoring. Regular appointments to assess the efficacy of the weight loss treatment, the emergence of adverse events, and blood pressure monitoring are recommended. Watch for excessive serotonergic effects. Phentermine is related to the amphetamines, and there has been historical concern that phentermine might exhibit potential to cause serotonin syndrome or cardiovascular or pulmonary effects when combined with serotonergic agents. One case report describes adverse reactions with phentermine and fluoxetine. However, recent data suggest that phentermine's effect on MAO inhibition and serotonin augmentation is minimal at therapeutic doses, and that phentermine does not additionally increase plasma serotonin levels when combined with other serotonergic agents. In large controlled clinical studies, patients were allowed to start therapy with phentermine or phentermine; topiramate extended-release for obesity along with their antidepressants (e.g., SSRIs or SNRIs, but not MAOIs or TCAs) as long as the antidepressant dose had been stable for at least 3 months prior to the initiation of phentermine, and the patient did not have suicidal ideation or more than 1 episode of major depression documented. In analyses of the results, therapy was generally well tolerated, especially at lower phentermine doses, based on discontinuation rates and reported adverse events. Because depression and obesity often coexist, the study data may be important to providing optimal therapies.
    Vilazodone: (Moderate) Use phentermine and vilazodone together with caution; use together might be efficacious for some patients based on available data, provided the patient is on a stable antidepressant regimen and receives close clinical monitoring. Regular appointments to assess the efficacy of the weight loss treatment, the emergence of adverse events, and blood pressure monitoring are recommended. Watch for excessive serotonergic effects. Phentermine is related to the amphetamines, and there has been historical concern that phentermine might exhibit potential to cause serotonin syndrome or cardiovascular or pulmonary effects when combined with serotonergic agents. One case report describes adverse reactions with phentermine and the antidepressant fluoxetine. However, recent data suggest that phentermine's effect on MAO inhibition and serotonin augmentation is minimal at therapeutic doses, and that phentermine does not additionally increase plasma serotonin levels when combined with other serotonergic agents. In large controlled clinical studies, patients were allowed to start therapy with extended-release phentermine or extended-release phentermine combinations for obesity along with their antidepressants (e.g., SSRIs or SNRIs, but not MAOIs or TCAs) as long as the antidepressant dose had been stable for at least 3 months prior to the initiation of phentermine, and the patient did not have suicidal ideation or more than 1 episode of major depression documented. In analyses of the results, therapy was generally well tolerated, especially at lower phentermine doses, based on discontinuation rates and reported adverse events. Because depression and obesity often coexist, the study data may be important to providing optimal therapies.
    Vorapaxar: (Moderate) Use caution during concurrent use of vorapaxar and topiramate. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible when vorapaxar, a CYP3A4 substrate, is coadministered with topiramate, a mild inducer of CYP3A4 in vitro. In addition, concurrent use of topiramate and drugs that affect platelet function such as platelet inhibitors may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (23%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Vortioxetine: (Moderate) Use phentermine and vortioxetine together with caution; use together may be safe and efficacious for some patients based on available data, provided the patient is on a stable antidepressant regimen and receives close clinical monitoring. Regular appointments to assess the efficacy of the weight loss treatment, the emergence of adverse events, and blood pressure monitoring are recommended. Watch for excessive serotonergic effects. Phentermine is related to the amphetamines, and there has been historical concern that phentermine might exhibit potential to cause serotonin syndrome or cardiovascular or pulmonary effects when combined with serotonergic agents. One case report has been received of adverse reactions with phentermine and the antidepressant fluoxetine. However, recent data suggest that phentermine's effect on MAO inhibition and serotonin augmentation is minimal at therapeutic doses, and that phentermine does not additionally increase plasma serotonin levels when combined with other serotonergic agents. In large controlled clinical studies, patients were allowed to start therapy with phentermine or phentermine; topiramate extended-release for obesity along with their antidepressants (e.g., SSRIs or SNRIs, but not MAOIs or TCAs) as long as the antidepressant dose had been stable for at least 3 months prior to the initiation of phentermine, and the patient did not have suicidal ideation or more than 1 episode of major depression documented. In analyses of the results, therapy was generally well tolerated, especially at lower phentermine doses, based on discontinuation rates and reported adverse events. Because depression and obesity often coexist, the study data may be important to providing optimal co-therapies.
    Warfarin: (Moderate) Concurrent use of topiramate and anticoagulants (e.g., warfarin, enoxaparin, dabigatran) may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Yohimbine: (Major) At high doses, yohimbine may nonselectively inhibit MAO and also, at normal doses, activates the sympathetic nervous system. Traditional MAOIs can cause serious adverse effects when taken concomitantly with sympathomimetics.
    Zonisamide: (Moderate) Monitor for evidence of metabolic acidosis, kidney stones, heat intolerance, decreased sweating or increased body temperature and bleeding if coadministration of topiramate and zonisamide is necessary. Because both topiramate and zonisamide are carbonic anhydrase inhibitors, concurrent use may increase the severity of metabolic acidosis and increase the risk of kidney stone formation. In addition, zonisamide may cause decreased sweating, elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as topiramate. Zonisamide has also been associated with thrombocytopenia; concurrent use with topiramate may increase the risk of bleeding.

    PREGNANCY AND LACTATION

    Pregnancy

    According to the manufacturer, a decision should be made whether to discontinue nursing or to discontinue phentermine; topiramate, taking into account the importance of therapy to the mother. Both topiramate and amphetamines (phentermine has pharmacologic activity and a chemical structure similar to amphetamines) are excreted in human milk. During lactation, first line weight loss strategies include a healthy diet and exercise, if appropriate. Sufficient calories and nutrition are important for proper lactation. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Phentermine; topiramate are two medications, that when combined, are used for chronic weight management. The exact mechanism of action responsible for weight reduction with this combination is not known.
     
    Phentermine: Phentermine is an analog of methamphetamine. Similar to the amphetamines, phentermine increases the release of norepinephrine and dopamine from nerve terminals and inhibits their reuptake. Thus, phentermine is classified as an indirect sympathomimetic. Other effects include a weak ability to dose-dependently raise serotonin levels, although the effect on serotonin occurs is less potent than that of methamphetamine itself. The effect of phentermine on chronic weight management is likely mediated by release of catecholamines in the hypothalamus and limbic region, resulting in reduced appetite and decreased food consumption, but other metabolic effects may also be involved. The exact mechanism of action is not known. Phentermine is an analog of methamphetamine. Similar to the amphetamines, phentermine increases the release of norepinephrine and dopamine from nerve terminals and inhibits their reuptake. Other clinical effects include CNS stimulation and potential elevation of blood pressure. Tolerance to the anorexiant effects of phentermine usually develops within a few weeks of starting therapy. When tolerance develops to the anorexiant effects, it is generally recommended that phentermine be discontinued rather than the dose increased.
    Topiramate: The mechanism of action of topiramate on chronic weight management is not known. Its effect on obesity may be due to its effects on both appetite suppression and satiety enhancement, induced by a combination of pharmacologic effects including augmenting the activity of the neurotransmitter gamma-aminobutyrate, modulation of voltage-gated ion channels, inhibition of AMPA/kainite excitatory glutamate receptors, or inhibition of carbonic anhydrase.

    PHARMACOKINETICS

    Phentermine; topiramate extended-release is administered orally.
     
    Phentermine: Phentermine is 17.5% plasma protein bound. Phentermine has two metabolic pathways, p-hydroxylation on the aromatic ring and N-oxidation on the alipthatic side chain. Although not extensively metabolized, CYP3A4 accounts for the primary mode of metabolism. Approximately 70—80% of the parent drug remains unchanged in the urine. Population pharmacokinetic analysis estimates oral clearance (CL/F) at 8.79 L/h. The mean phentermine terminal half-life is about 20 hours.
    Topiramate: Topiramate is 15—41% plasma protein bound over the blood concentration range of 0.5 to 250 mcg/ml; as blood concentration increases, the bound fraction of topiramate decreases. Topiramate is not metabolized to a great extent. Six metabolites have been identified and are formed via hydroxylation, hydrolysis, and glucuronidation. None of these metabolites constitutes more than 5% of an administered dose. About 70% of an administered dose is eliminated as unchanged drug in the urine. Population pharmacokinetic analysis estimates oral clearance CL/F is 1.17 L/h. The mean topiramate terminal half-life is approximately 65 hours.

    Oral Route

    Phentermine: Following oral administration of a single phentermine; topiramate extended-release (15 mg/92 mg) dose, the Cmax, Tmax, and AUC for phentermine are 49.1 ng/ml, 6 hr, and 1990—2000 ng•h/ml, respectively. A high fat meal does not affect exposure. Phentermine exhibits approximately dose-proportional pharmacokinetics throughout the recommended dosing range. Upon dosing phentermine;topiramate to steady state, the mean phentermine accumulation ratios for AUC and Cmax are both approximately 2.5.
    Topiramate: Following oral administration of a single phentermine; topiramate extended-release (15 mg/92 mg) dose, the Cmax, Tmax, and AUC for topiramate are 1020 ng/ml, 9 hr, and 61,600—68,000 ng•h/ml, respectively. A high fat meal does not affect exposure. Topiramate exhibits approximately dose-proportional pharmacokinetics throughout the recommended dosing range. Upon dosing to steady state, the mean topiramate accumulation ratios for AUC and Cmax are both approximately 4.