Forma Farmacêutica
Capsule
Via de Administração
ORAL
About This Medication
11 DESCRIPTION Phentermine and topiramate extended-release capsules are comprised of immediate-release phentermine hydrochloride, USP (expressed as the weight of the free base) and extended-release topiramate, USP. Phentermine and topiramate extended-release capsules contain phentermine hydrochloride, USP, a sympathomimetic amine anorectic, and topiramate, USP, a sulfamate-substituted monosaccharide. Phentermine Hydrochloride, USP The chemical name of phentermine hydrochloride, USP is α,α-dimethylphenethylamine hydrochloride. The molecular formula is C 10 H 16 ClN and its molecular weight is 185.69 g mol -1 (hydrochloride salt) or 149.2 (free base). Phentermine hydrochloride, USP is a white, odourless, hygroscopic, crystalline powder that is soluble in water and lower alcohols. It is also slightly soluble in chloroform and insoluble in ether. Its structural formula is: Topiramate, USP Topiramate, USP is 2,3:4,5-di-O-isopropylidene-β-D-fructopyranose sulfamate. The molecular formula is C 12 H 21 NO 8 S and its molecular weight is 339.36.Topiramate, USP is a white to off-white powder. It is freely soluble in dichloromethane. Its structural formula is: Phentermine and Topiramate Extended-Release Capsules Phentermine and topiramate extended-release capsules are for oral administration and available in four dosage strengths: • 3.75 mg/23 mg (phentermine 3.75 mg and topiramate USP, 23 mg) (equivalent to 4.665 mg of Phentermine Hydrochloride, USP). • 7.5 mg/46 mg (phentermine 7.5 mg and topiramate USP, 46 mg) (equivalent to 9.33 mg of Phentermine Hydrochloride, USP). • 11.25 mg/69 mg (phentermine 11.25 mg and topiramate USP, 69 mg) (equivalent to 14 mg of Phentermine Hydrochloride, USP). • 15 mg/92 mg (phentermine 15 mg and topiramate USP, 92 mg) (equivalent to 18.66 mg of Phentermine Hydrochloride, USP). Each capsule contains the following inactive ingredients: ethocel, gelatin, hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, talc and titanium dioxide. In addition, the 7.5 mg/46 mg contains FD&C Red No. 40 and FD&C Yellow #6, 11.25 mg/69 mg contains FD&C Yellow #5 and FD&C Blue #1, 15 mg/92 mg contains FD&C Yellow #6 and D&C Red #28. The imprinting ink opacode Black contains shellac, iron oxide black, propylene glycol, FD&C Blue #2, FD&C Red No. 40, D&C Yellow #10, FD&C Blue #1..
Princípios Ativos
| Ingrediente |
Concentração |
| Phentermine Hydrochloride |
- |
| Topiramate |
- |
Indicações e Uso
1 INDICATIONS AND USAGE Phentermine and topiramate extended-release capsules are indicated in combination with a reduced-calorie diet and increased physical activity to reduce excess body weight and maintain weight reduction long term in: Adult patients with obesity Adults with overweight in the presence of at least one weight-related comorbid condition Limitations of Use • The effect of phentermine and topiramate extended-release capsules on cardiovascular morbidity and mortality has not been established. • The safety and effectiveness of phentermine and topiramate extended-release capsules in combination with other products intended for weight loss, including prescription drugs, over-the-counter drugs, and herbal preparations, have not been established. Pediatric use information is approved for Vivus LLC's Qsymia ® (phentermine and topiramate) extended-release capsules. However, due to Vivus LLC's marketing exclusivity rights, this drug product is not labeled with that information. Phentermine and topiramate extended-release capsules are a combination of phentermine, a sympathomimetic amine anorectic, and topiramate indicated in combination with a reduced-calorie diet and increased physical activity to reduce excess body weight and maintain weight reduction long term in: Adult patients with obesity ( 1 ) Adults with overweight in the presence of at least one weight-related comorbid condition Limitations of Use: The effect of phentermine and topiramate extended-release capsules on cardiovascular morbidity and mortality has not been established ( 1 ). The safety and effectiveness of phentermine and topiramate extended-release capsules in combination with other products intended for weight loss, including prescription and over-the-counter drugs, and herbal preparations, have not been established ( 1 ).
Como funciona
12.1 Mechanism of Action Phentermine is a sympathomimetic amine with pharmacologic activity similar to the prototype drugs of this class used in obesity, amphetamine (d- and d/l-amphetamine). Drugs of this class used in obesity are commonly known as "anorectics" or "anorexigenics." The effect of phentermine on weight reduction and long-term maintenance of body weight is likely mediated by release of catecholamines in the hypothalamus, resulting in reduced appetite and decreased food consumption, but other metabolic effects may also be involved. The exact mechanism of action is not known. The precise mechanism of action of topiramate on weight reduction and long-term maintenance of body weight is not known. Topiramate’s effect on weight reduction and long-term maintenance of body weight 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 AOBMPA/kainite excitatory glutamate receptors, or inhibition of carbonic anhydrase.
Posologia e Administração
2 DOSAGE AND ADMINISTRATION • Take orally once daily in morning. Avoid administration in evening to prevent insomnia ( 2.2 ). • Recommended starting dosage is 3.75 mg/23 mg (phentermine mg/topiramate mg) daily for 14 days; then increase to 7.5 mg/46 mg daily ( 2.2 ). • Escalate dosage based on weight loss in adults. See the Full Prescribing Information for details regarding discontinuation or dosage escalation. ( 2.2 ). • Gradually discontinue 15 mg/92 mg dosage to prevent possible seizure ( 2.3 ). • Do not exceed 7.5 mg/46 mg dosage for patients with moderate or severe renal impairment or patients with moderate hepatic impairment ( 2.4 , 2.5 ). 2.1 Recommended Testing Prior to and During Treatment with Phentermine and Topiramate Extended-Release Capsules Prior to phentermine and topiramate extended-release capsules initiation and during treatment with phentermine and topiramate extended-release capsules, the following is recommended: Obtain a negative pregnancy test before initiating phentermine and topiramate extended-release capsules in patients who can become pregnant and monthly during phentermine and topiramate extended-release capsules therapy. Phentermine and topiramate extended-release capsules are contraindicated during pregnancy [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.3 )] . Obtain a blood chemistry profile that includes bicarbonate, creatinine, and potassium in all patients, and glucose in patients with type 2 diabetes mellitus on antidiabetic medication prior to initiating phentermine and topiramate extended-release capsules treatment and periodically during treatment [see Warnings and Precautions ( 5.7 , 5.8 , 5.12 )]. 2.2 Recommended Dosage and Administration The recommended dosage, titration, and administration of phentermine and topiramate extended-release capsules are as follows: Take phentermine and topiramate extended-release capsules orally once daily in the morning with or without food. Avoid administration of phentermine and topiramate extended-release capsules in the evening due to the possibility of insomnia. The recommended starting dosage of phentermine and topiramate extended-release capsules is one capsule (containing 3.75 mg of phentermine and 23 mg of topiramate) (3.75 mg/23 mg) taken orally once daily for 14 days; after 14 days increase to the recommended dosage of phentermine and topiramate extended-release capsules 7.5 mg/46 mg orally once daily. After 12 weeks of treatment with phentermine and topiramate extended-release capsules 7.5 mg/46 mg, evaluate weight loss for adults. If an adult patient has not lost at least 3% of baseline body weight, increase the dosage to phentermine and topiramate extended-release capsules 11.25 mg/69 mg orally once daily for 14 days; followed by an increase in the dosage to phentermine and topiramate extended-release capsules 15 mg/92 mg orally once daily. After 12 weeks of treatment with phentermine and topiramate extended-release capsules 15 mg/92 mg, evaluate weight loss for adults. If an adult patient has not lost at least 5% of baseline body weight, discontinue phentermine and topiramate extended-release capsules [see Dosage and Administration ( 2.3 )] , as it is unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment. Pediatric use information is approved for Vivus LLC's Qsymia ® (phentermine and topiramate) extended-release capsules. However, due to Vivus LLC's marketing exclusivity rights, this drug product is not labeled with that information. 2.3 Discontinuation of Phentermine and Topiramate Extended-Release Capsules 15 mg/92 mg Discontinue phentermine and topiramate extended-release capsules 15 mg/92 mg gradually by taking phentermine and topiramate extended-release capsules 15 mg/92 mg orally once daily every other day for at least 1 week prior to stopping treatment altogether, due to the possibility of precipitating a seizure [see Warnings and Precautions ( 5.9 ) and Drug Abuse and Dependence ( 9.3 )]. 2.4 Recommended Dosage in Patients with Renal Impairment The recommended dosage in patients with mild (CrCl greater or equal to 50 and less than 80 mL/min) renal impairment is the same as the recommended dosage for patients with normal renal function [see Warnings and Precautions ( 5.8 ), Use in Specific Populations ( 8.6 ), and Clinical Pharmacology ( 12.3 )] . In patients with severe [creatinine clearance (CrCl) less than 30 mL/min] or moderate (CrCl greater than or equal to 30 and less than 50 mL/min) renal impairment (CrCl calculated using the Cockcroft-Gault equation with actual body weight), the maximum recommended dosage is phentermine and topiramate extended-release capsules 7.5 mg/46 mg once daily. Avoid use of phentermine and topiramate extended-release capsules in patients with end-stage renal disease on dialysis. 2.5 Recommended Dosage in Patients with Hepatic Impairment The recommended dosage of phentermine and topiramate extended-release capsules in patients with mild hepatic impairment (Child-Pugh 5 to 6) is the same as the recommended dosage in patients with normal hepatic function [see Use in Specific Populations ( 8.7 ), and Clinical Pharmacology ( 12.3 )]. In patients with moderate hepatic impairment (Child-Pugh score 7 to 9), the maximum recommended dosage is phentermine and topiramate extended-release capsules 7.5 mg/46 mg orally once daily. Avoid use of phentermine and topiramate extended-release capsules in patients with severe hepatic impairment (Child-Pugh score 10 to 15).
Side Effects Overview
6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Embryo-Fetal Toxicity [see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.1 , 8.6 )] Suicidal Behavior and Ideation [see Warnings and Precautions ( 5.2 )] Risk of Ophthalmologic Adverse Reactions [see Warnings and Precautions ( 5.3 )] Mood and Sleep Disorders [see Warnings and Precautions ( 5.4 )] Cognitive Impairment [see Warnings and Precautions ( 5.5 )] Slowing of Linear Growth [see Warnings and Precautions ( 5.6 )] Metabolic Acidosis [see Warnings and Precautions ( 5.7 )] Decrease in Renal Function [see Warnings and Precautions ( 5.8 )] Risk of Seizures with Abrupt Withdrawal of Phentermine and Topiramate Extended-Release Capsules [see Warnings and Precautions ( 5.9 )] Kidney Stones [see Warnings and Precautions ( 5.10 )] Oligohydrosis and Hyperthermia [see Warnings and Precautions ( 5.11 )] Hypokalemia [see Warnings and Precautions ( 5.12 )] Serious Skin Reactions [see Warnings and Precautions ( 5.13 )] Most common adverse reactions in: • Adults (incidence ≥ 5% and at least 1.5 times placebo) are: paraesthesia, dizziness, dysgeusia, insomnia, constipation, and dry mouth. To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories, Inc. at 1-888-375-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. The data described herein reflect exposure to phentermine and topiramate extended-release in two 1-year, randomized, double-blind, placebo-controlled, multicenter clinical trials and two supportive trials in 2,318 adult patients with overweight or obesity [936 (40%) patients with hypertension, 309 (13%) patients with type 2 diabetes mellitus, 808 (35%) patients with BMI greater than 40 kg/m 2 ] exposed for a mean duration of 298 days [see Clinical Studies ( 14 )]. Adults Adverse reactions occurring at greater than or equal to 5% and at least 1.5 times placebo in adults include paraesthesia, dizziness, dysgeusia, insomnia, constipation, and dry mouth. Adverse reactions reported in greater than or equal to 2% of phentermine and topiramate extended-release-treated adults and more frequently than in the placebo group are shown in Table 1. Table 1. Adverse Reactions Reported in ≥2% of Phentermine and Topiramate Extended-Release-Treated Adults with Overweight or Obesity and More Frequently than Placebo in Overall Study Population of 1 Year Duration Adverse Reaction Placebo (N = 1561) % Phentermine and topiramate extended-release 3.75 mg/23 mg (N = 240) % Phentermine and topiramate extended-release 7.5 mg/46 mg (N = 498) % Phentermine and topiramate extended-release 15 mg/92 mg (N = 1,580) % Paraesthesia 2 4 14 20 Dry Mouth 3 7 14 19 Constipation 6 8 15 16 Upper Respiratory Tract Infection 13 16 12 14 Headache 9 10 7 11 Dysgeusia 1 1 7 9 Insomnia 5 5 6 9 Nasopharyngitis 8 13 11 9 Dizziness 3 3 7 9 Sinusitis 6 8 7 8 Nausea 4 6 4 7 Back Pain 5 5 6 7 Fatigue 4 5 4 6 Diarrhea 5 5 6 6 Vision Blurred 4 6 4 5 Bronchitis 4 7 4 5 Urinary Tract Infection 4 3 5 5 Cough 4 3 4 5 Influenza 4 8 5 4 Depression 2 3 3 4 Anxiety 2 3 2 4 Hypoesthesia 1 1 4 4 Irritability 1 2 3 4 Alopecia 1 2 3 4 Disturbance in Attention 1 0 2 4 Pain in Extremity 3 2 3 3 Muscle Spasms 2 3 3 3 Dyspepsia 2 2 2 3 Gastroesophageal Reflux Disease 1 1 3 3 Rash 2 2 2 3 Hypokalemia 0 0 1 3 Dry Eye 1 1 1 3 Gastroenteritis 2 1 2 3 Pharyngolaryngeal Pain 2 3 1 2 Paraesthesia Oral 0 0 1 2 Eye Pain 1 2 2 2 Nasal Congestion 1 2 1 2 Thirst 1 2 2 2 Sinus Congestion 2 3 3 2 Procedural Pain 2 2 2 2 Palpitations 1 1 2 2 Musculoskeletal Pain 1 1 3 2 Decreased Appetite 1 2 2 2 Neck Pain 1 1 2 1 Dysmenorrhea 0 2 0 1 Chest Discomfort 0 2 0 1 Increase in Heart Rate In adult clinical trials, there was a higher incidence of heart rate elevations observed in phentermine and topiramate extended-release-treated compared to placebo-treated patients. In clinical trials, a higher percentage of phentermine and topiramate extended-release-treated adults experienced heart rate increases from baseline of more than 5, 10, 15, and 20 bpm compared to placebo-treated patients. Table 3 provides the numbers and percentages of adult patients with elevations in heart rate in clinical studies of up to one year. Table 3. Number and Percentage of Adults with Overweight or Obesity with an Increase in Heart Rate at a Single Time Point from Baseline Placebo N = 1561 n (%) Phentermine and topiramate extended-release 3.75 mg/23 mg N = 240 n (%) Phentermine and topiramate extended-release 7.5 mg/46 mg N = 498 n (%) Phentermine and topiramate extended-release 15 mg/92 mg N = 1580 n (%) Greater than 5 bpm 1021 (65.4) 168 (70.0) 372 (74.7) 1228 (77.7) Greater than 10 bpm 657 (42.1) 120 (50.0) 251 (50.4) 887 (56.1) Greater than 15 bpm 410 (26.3) 79 (32.9) 165 (33.1) 590 (37.3) Greater than 20 bpm 186 (11.9) 36 (15.0) 67 (13.5) 309 (19.6) Paraesthesia/Dysgeusia In adult clinical trials, reports of paraesthesia, characterized as tingling in hands, feet, or face, and dysgeusia, characterized as a metallic taste, occurred (see Table 1). Phentermine and topiramate extended-release-treated adult patients discontinued treatment due to these adverse reactions (1% for paraesthesia and 0.6% for dysgeusia). Mood and Sleep Disorders The proportion of adult patients in 1-year controlled trials of phentermine and topiramate extended-release reporting one or more adverse reactions related to mood and sleep disorders was 15% and 21% with phentermine and topiramate extended-release 7.5 mg/ 46 mg and 15 mg/92 mg, respectively, compared to 10% with placebo. These events were further categorized into sleep disorders, anxiety, and depression. Reports of sleep disorders were typically characterized as insomnia and occurred in 8.1% and 11% of patients treated with phentermine and topiramate extended-release 7.5 mg/46 mg and 15 mg/92 mg, respectively, compared to 5.8% of patients treated with placebo. Reports of anxiety occurred in 4.8% and 7.9% of patients treated with phentermine and topiramate extended-release 7.5 mg/46 mg and 15 mg/92 mg, respectively, compared to 2.6% of patients treated with placebo. Reports of depression/mood problems occurred in 3.8% and 7.6% of patients treated with phentermine and topiramate extended-release 7.5 mg/46 mg and 15 mg/92 mg, respectively, compared to 3.4% of patients treated with placebo. Mood and sleep disorder adverse reactions occurred in patients with and without a history of depression. Cognitive Disorders In the 1-year controlled trials of phentermine and topiramate extended-release in adults, the proportion of patients who experienced one or more cognitive-related adverse reactions was 5% for phentermine and topiramate extended-release 7.5 mg/46 mg and 7.6% for phentermine and topiramate extended-release 15 mg/92 mg, compared to 1.5% for placebo. These adverse reactions were comprised primarily of reports of problems with attention/concentration, memory, and language (word-finding). These events occurred at any time during treatment with phentermine and topiramate extended-release capsules. Nephrolithiasis In the 1-year controlled trials of phentermine and topiramate extended-release in adults, the incidence of nephrolithiasis was 0.2% for phentermine and topiramate extended-release 7.5 mg/46 mg and 1.2% for phentermine and topiramate extended-release 15 mg/92 mg, compared to 0.3% for placebo. Laboratory Abnormalities Serum Bicarbonate In the 1-year controlled trials of phentermine and topiramate extended-release in adults, the incidence of persistent decreases in serum bicarbonate below the normal range (levels of less than 21 mEq/L at 2 consecutive visits or at the final visit) was 6.4% for phentermine and topiramate extended-release 7.5 mg/46 mg, and 12.8% for phentermine and topiramate extended-release 15 mg/92 mg, compared to 2.1% for placebo. The incidence of persistent, markedly low serum bicarbonate values (levels of less than 17 mEq/L on 2 consecutive visits or at the final visit) was 0.2% for phentermine and topiramate extended-release 7.5 mg/46 mg dose, and 0.7% for phentermine and topiramate extended-release 15 mg/92 mg dose, compared to 0.1% for placebo. Serum Potassium In the 1-year controlled trials of phentermine and topiramate extended-release in adults, the incidence of persistent low serum potassium values (less than 3.5 mEq/L at two consecutive visits or at the final visit) during the trial was 3.6% for phentermine and topiramate extended-release 7.5 mg/46 mg dose and 4.9% for phentermine and topiramate extended-release 15 mg/92 mg, compared to 1.1% for placebo. Of the subjects who experienced persistent low serum potassium, 88% were receiving treatment with a non-potassium sparing diuretic. The incidence of markedly low serum potassium (less than 3 mEq/L, and a reduction from pre‑treatment of greater than 0.5 mEq/L) at any time during the trial was 0.2% for phentermine and topiramate extended-release 7.5 mg/46 mg dose and 0.7% for phentermine and topiramate extended-release 15 mg/92 mg dose, compared to 0% for placebo. Persistent markedly low serum potassium (less than 3 mEq/L, and a reduction from pre-treatment of greater than 0.5 mEq/L at two consecutive visits or at the final visit) occurred in 0.2% receiving phentermine and topiramate extended-release 7.5 mg/46 mg dose and 0.1% receiving phentermine and topiramate extended-release 15 mg/92 mg dose, compared to 0% receiving placebo. Serum Creatinine In the 1-year controlled trials of phentermine and topiramate extended-release in adults there was an increase in serum creatinine from baseline, peaking between Week 4 to 8 in adult patients. Serum creatinine values declined but remained elevated over baseline over 1 year of treatment. The incidence of increases in serum creatinine of greater than or equal to 0.3 mg/dL at any time during treatment in adults was 7.2% for phentermine and topiramate extended-release 7.5 mg/46 mg and 8.4% for phentermine and topiramate extended-release 15 mg/92 mg, compared to 2% for placebo. Increases in serum creatinine of greater than or equal to 50% over baseline occurred in 2% of adult subjects receiving phentermine and topiramate extended-release 7.5 mg/46 mg and 2.8% receiving phentermine and topiramate extended-release 15 mg/92 mg, compared to 0.6% receiving placebo. Serum Ammonia Hyperammonemia with or without encephalopathy has been reported with topiramate. The risk for hyperammonemia with topiramate appears dose related and has been reported more frequently when concomitantly used with valproic acid [see Drug Interactions ( 7 )] . The incidence of hyperammonemia in pediatric patients 12 to 17 years of age in clinical trials of another condition was 26% in patients taking topiramate at 100 mg/day (1.1 times the maximum recommended dosage of phentermine and topiramate extended-release) and 14% in patients taking topiramate at 50 mg/day (0.6 times the maximum recommended dosage of phentermine and topiramate extended-release), compared to 9% in patients taking placebo. There was also an increased incidence of markedly increased hyperammonemia (defined as 50% above the upper limit of normal reference range) at the 100 mg dose. Pediatric use information is approved for Vivus LLC's Qsymia ® (phentermine and topiramate) extended-release capsules. However, due to Vivus LLC's marketing exclusivity rights, this drug product is not labeled with that information. 6.2 Postmarketing Experience The following adverse reactions have been reported during post approval use of phentermine and topiramate extended-release,phentermine, and topiramate. Because these reactions are reported voluntarily from a population of uncertain size it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Phentermine and Topiramate Extended-Release Capsules Psychiatric: suicidal ideation, suicidal behavior Ophthalmic: acute angle closure glaucoma, increased intraocular pressure Phentermine Allergic Reactions : urticaria Cardiovascular: elevation of blood pressure, ischemic events Central Nervous System : euphoria, psychosis, tremor Reproductive: changes in libido, impotence Topiramate Dermatologic : bullous skin reactions (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), pemphigus Gastrointestinal : pancreatitis Hepatic : hepatic failure (including fatalities), hepatitis Metabolic : hyperammonemia with or without encephalopathy has been reported with concomitant valproic acid [see Drug Interactions ( 7 ) ], hypothermia Ophthalmic: maculopathy
Advertências e Precauções
5 WARNINGS AND PRECAUTIONS • Embryo-Fetal Toxicity: Can cause fetal harm. Inpatients who can become pregnant, a negative pregnancy test is recommended before initiating phentermine and topiramate extended-release capsules and monthly during therapy; advise use of effective contraception. Phentermine and topiramate extended-release capsules are available through a limited program under a Risk Evaluation and Mitigation Strategy (REMS) ( 5.1 ). • Suicidal Behavior and Ideation : Monitor for depression or suicidal thoughts. Discontinue phentermine and topiramate extended-release capsules if symptoms develop (5.2). • Risk of Ophthalmologic Adverse Reactions : Acute myopia and secondary angle closure glaucoma have been reported. Immediately discontinue phentermine and topiramate extended-release capsules if symptoms develop. Consider phentermine and topiramate extended-release capsules discontinuation if visual field defects occur. (5.3). • Mood and Sleep Disorders : Consider dosage reduction or discontinuation for clinically significant or persistent mood or sleep disorder symptoms (5.4). • Cognitive Impairment: May cause disturbances in attention or memory, or speech/language problems. Caution patients about operating automobiles or hazardous machinery when starting treatment (5.5). • Slowing of Linear Growth : Consider dosage reduction or discontinuation if pediatric patients are not growing or gaining height as expected (5.6). • Metabolic Acidosis: Measure electrolytes before and during treatment. If persistent metabolic acidosis develops, reduce dosage or discontinue phentermine and topiramate extended-release capsules (5.7). • Decrease in Renal Function: Measure creatinine before and during treatment. For persistent creatinine elevations, reduce dosage or discontinue phentermine and topiramate extended-release capsules (5.8). • Serious Skin Reactions : Phentermine and topiramate extended-release capsules should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related (5.13). 5.1 Embryo-Fetal Toxicity Phentermine and topiramate extended-release capsules can cause fetal harm. Data from pregnancy registries and epidemiologic studies indicate that a fetus exposed to topiramate in the first trimester of pregnancy has an increased risk of major congenital malformations, including but not limited to cleft lip and/or cleft palate (oral clefts), and of being small for gestational age (SGA). When multiple species of pregnant animals received topiramate at clinically relevant doses, structural malformations, including craniofacial defects, and reduced fetal weights occurred in offspring. A negative pregnancy test is recommended before initiating phentermine and topiramate extended-release capsules treatment in patients who can become pregnant and monthly during phentermine and topiramate extended-release capsules therapy. Advise patients who can become pregnant of the potential risk to a fetus and to use effective contraception during phentermine and topiramate extended-release capsules therapy [see Use in Specific Populations ( 8.1 , 8.3 )] . Phentermine and Topiramate Extended-Release Capsules Risk Evaluation and Mitigation Strategy (REMS) Because of the teratogenic risk associated with phentermine and topiramate extended-release capsules therapy, phentermine and topiramate extended-release capsules are available through a limited program under the REMS. Under the phentermine and topiramate extended-release capsules REMS, only certified pharmacies may distribute phentermine and topiramate extended-release capsules. Further information is available at www.PhenTopREMS.com or by telephone at 1‐800‐269‐6816. 5.2 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including topiramate, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Pooled analyses of 199 placebo-controlled clinical studies (monotherapy and adjunctive therapy, median treatment duration 12 weeks) of 11 different AEDs across several indications showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI 1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. The estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in AED-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about AED effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as 1 week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age in the clinical trials analyzed. Monitor all patients for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Discontinue phentermine and topiramate extended-release capsules in patients who experience suicidal thoughts or behaviors [see Warnings and Precautions ( 5.9 )]. Avoid phentermine and topiramate extended-release capsules in patients with a history of suicidal attempts or active suicidal ideation. Pediatric use information is approved for Vivus LLC's Qsymia ® (phentermine and topiramate) extended-release capsules. However, due to Vivus LLC's marketing exclusivity rights, this drug product is not labeled with that information. 5.3 Risk of Ophthalmological Adverse Reactions Acute Myopia and Secondary Angle Closure Glaucoma A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients treated with topiramate. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include myopia, mydriasis, anterior chamber shallowing, ocular hyperemia (redness), choroidal detachments, retinal pigment epithelial detachments, macular striae, and increased intraocular pressure. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms typically occur within 1 month of initiating treatment with topiramate but may occur at any time during therapy. In contrast to primary narrow angle glaucoma, which is rare under 40 years of age, secondary angle closure glaucoma associated with topiramate has been reported in pediatric patients as well as adults. The primary treatment to reverse symptoms is discontinuation of phentermine and topiramate extended-release capsules as rapidly as possible in consultation with the treating physician. Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent loss of vision. Visual Field Defects Visual field defects (independent of elevated intraocular pressure) have been reported in clinical trials and in postmarketing experience in patients receiving topiramate. In clinical trials, most of these events were reversible after topiramate discontinuation. If visual problems occur at any time during treatment, consider discontinuing phentermine and topiramate extended-release capsules. 5.4 Mood and Sleep Disorders Phentermine and topiramate extended-release capsules can cause mood disorders, including depression and anxiety, as well as insomnia. Patients with a history of depression may be at increased risk of recurrent depression or other mood disorders while taking phentermine and topiramate extended-release capsules [see Adverse Reactions ( 6.1 )] . Consider dosage reduction or discontinuation of phentermine and topiramate extended-release capsules if clinically significant or persistent symptoms occur. Discontinue phentermine and topiramate extended-release capsules if patients have symptoms of suicidal ideation or behavior [see Warnings and Precautions ( 5.2 )]. 5.5 Cognitive Impairment Phentermine and topiramate extended-release capsules can cause cognitive dysfunction (e.g., impairment of concentration/attention, difficulty with memory, and speech or language problems, particularly word-finding difficulties). Rapid titration or high initial doses of phentermine and topiramate extended-release capsules may be associated with higher rates of cognitive events such as attention, memory, and language/word-finding difficulties [see Adverse Reactions ( 6.1 )] . The concomitant use of alcohol or central nervous system (CNS) depressant drugs with phentermine and topiramate extended-release capsules may potentiate CNS depression or other centrally mediated effects of these agents, such as dizziness, cognitive adverse reactions, drowsiness, light-headedness, impaired coordination, and somnolence. Caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain phentermine and topiramate extended-release capsules therapy does not affect them adversely. Caution patients against excessive alcohol intake while receiving phentermine and topiramate extended-release capsules. If cognitive dysfunction persists, consider dosage reduction or discontinuation of phentermine and topiramate extended-release capsules [see Warnings and Precautions ( 5.9 )]. 5.6 Slowing of Linear Growth Phentermine and topiramate extended-release capsules are associated with a reduction in height velocity (centimeters of height gained per year) in obese pediatric patients. Monitor height velocity in pediatric patients treated with phentermine and topiramate extended-release capsules. Consider dosage reduction or discontinuation of phentermine and topiramate extended-release capsules if pediatric patients are not growing or gaining height as expected [see Warnings and Precautions ( 5.9 )]. Pediatric use information is approved for Vivus LLC's Qsymia ® (phentermine and topiramate) extended-release capsules. However, due to Vivus LLC's marketing exclusivity rights, this drug product is not labeled with that information. 5.7 Metabolic Acidosis Hyperchloremic, non-anion gap, metabolic acidosis (decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis) has been reported in patients treated with phentermine and topiramate extended-release capsules [see Adverse Reactions ( 6.1 )]. Manifestations of acute or chronic metabolic acidosis may include hyperventilation, nonspecific symptoms such as fatigue and anorexia, or more severe sequelae including cardiac arrhythmias or stupor. Chronic, untreated metabolic acidosis may increase the risk for nephrolithiasis or nephrocalcinosis and may also result in osteomalacia (referred to as rickets in pediatric patients) and/or osteoporosis with an increased risk for fractures. Chronic metabolic acidosis in pediatric patients may also reduce growth rates, which may decrease the maximal height achieved. Conditions or therapies that predispose to acidosis (i.e., renal disease, severe respiratory disorders, status epilepticus, diarrhea, surgery, or ketogenic diet) may be additive to the bicarbonate lowering effects of phentermine and topiramate extended-release. Concomitant use of phentermine and topiramate extended-release capsules and a carbonic anhydrase inhibitor may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation [see Warnings and Precautions ( 5.10 )] . Avoid use of phentermine and topiramate extended-release capsules with other carbonic anhydrase inhibitors. If concomitant use of phentermine and topiramate extended-release capsules with another carbonic anhydrase inhibitor is unavoidable, the patient should be monitored for the appearance or worsening of metabolic acidosis. Measure electrolytes including serum bicarbonate prior to starting phentermine and topiramate extended-release capsules and during phentermine and topiramate extended-release treatment. In phentermine and topiramate extended-release clinical trials, the peak reduction in serum bicarbonate typically occurred within 4 weeks of titration to the assigned dose, and in most patients, there was a correction of bicarbonate by week 56, without any dosage reduction. However, if persistent metabolic acidosis develops while taking phentermine and topiramate extended-release capsules, reduce the dosage or discontinue phentermine and topiramate extended-release capsules [see Warnings and Precautions ( 5.9 )]. 5.8 Decrease in Renal Function Phentermine and topiramate extended-release capsules can cause an increase in serum creatinine that reflects a decrease in renal function (glomerular filtration rate). In clinical trials, peak increases in serum creatinine were observed after 4 to 8 weeks of treatment. On average, serum creatinine gradually declined but remained elevated over baseline creatinine values. The changes in serum creatinine (and measured GFR) with short-term (4-weeks) phentermine and topiramate extended-release treatment appear reversible with treatment discontinuation, but the effect of chronic treatment on renal function is not known. Measure serum creatinine prior to starting phentermine and topiramate extended-release capsules and during phentermine and topiramate extended-release capsules treatment. If persistent elevations in creatinine occur, reduce the dosage or discontinue phentermine and topiramate extended-release capsules [see Warnings and Precautions ( 5.9 ), Adverse Reactions ( 6.1 ), and Clinical Pharmacology ( 12.2 )]. 5.9 Risk of Seizures with Abrupt Withdrawal of Phentermine and Topiramate Extended-Release Capsules Abrupt withdrawal of topiramate has been associated with seizures in individuals without a history of seizures or epilepsy. In situations where immediate termination of phentermine and topiramate extended-release capsules is medically required, appropriate monitoring is recommended. Patients discontinuing phentermine and topiramate extended-release capsules 15 mg/92 mg should be gradually tapered to reduce the possibility of precipitating a seizure [see Dosage and Administration ( 2.3 ) and Drug Abuse and Dependence ( 9.3 )] 5.10 Kidney Stones Phentermine and topiramate extended-release capsules have been associated with kidney stone formation [see Adverse Reactions ( 6.1 )] . Topiramate inhibits carbonic anhydrase activity and promotes kidney stone formation by reducing urinary citrate excretion and increasing urine pH. Patients on a ketogenic diet may be at increased risk for kidney stone formation. An increase in urinary calcium and a marked decrease in urinary citrate was observed in topiramate-treated pediatric patients in a one-year, active-controlled study. Increased ratio of urinary calcium/citrate increases the risk of kidney stones and/or nephrocalcinosis. Avoid the use of phentermine and topiramate extended-release capsules with other drugs that inhibit carbonic anhydrase [see Drug Interactions ( 7 )] . Advise patients to increase fluid intake (to increase urinary output), which may decrease the concentration of substances involved in kidney stone formation. 5.11 Oligohidrosis and Hyperthermia Oligohidrosis (decreased sweating), infrequently resulting in hospitalization, has been reported in association with the use of topiramate. 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. The majority of the reports associated with topiramate have been in pediatric patients. Advise all patients and caregivers to monitor for decreased sweating and increased body temperature during physical activity, especially in hot weather. Patients on concomitant medications that predispose them to heat-related disorders may be at increased risk. 5.12 Hypokalemia Phentermine and topiramate extended-release capsules can increase the risk of hypokalemia through its inhibition of carbonic anhydrase activity. In addition, when phentermine and topiramate extended-release capsules are used in conjunction with non-potassium sparing diuretics this may further potentiate potassium-wasting. Measure potassium before and during treatment with phentermine and topiramate extended-release capsules [see Adverse Reactions ( 6.1 ), Drug Interactions ( 7 ), and Clinical Pharmacology ( 12.3 )]. 5.13 Serious Skin Reactions Serious skin reactions (Stevens-Johnson Syndrome [SJS] and Toxic Epidermal Necrolysis [TEN]) have been reported in patients receiving topiramate. Phentermine and topiramate extended-release capsules should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. Inform patients about the signs of serious skin reactions. 5.14 Allergic Reaction s Due to Inactive Ingredient FD&C Yellow No. 5 Phentermine and topiramate extended-release capsules, 11.25 mg/69 mg contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.
Contraindicações
4 CONTRAINDICATIONS Phentermine and topiramate extended-release capsules are contraindicated in patients: • Who are pregnant [see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.1 )] • With glaucoma [see Warnings and Precautions ( 5.3 )] • Wjith hyperthyroidism • Taking or within 14 days of stopping a monoamine oxidase inhibitors [see Drug Interactions ( 7 )] • With known hypersensitivity to phentermine, topiramate or any of the excipients in phentermine and topiramate extended-release capsules, or idiosyncrasy to the sympathomimetic amine [see Adverse Reactions ( 6.2 )]. • Pregnancy ( 4 ) • Glaucoma ( 4 ) • Hyperthyroidism ( 4 ) • Taking or within 14 days of stopping monoamine oxidase inhibitors ( 4 ) • Known hypersensitivity to any component of phentermine and topiramate extended-release capsules or idiosyncrasy to sympathomimetic amines ( 4 )
Farmacocinética
12.3 Pharmacokinetics Absorption Phentermine Upon oral administration of a single phentermine and topiramate extended-release capsule 15 mg/92 mg, the resulting mean plasma phentermine maximum concentration (C max ), time to C max (T max ), area under the concentration curve from time zero to the last time with measurable concentration (AUC 0-t ), and area under the concentration curve from time zero to infinity (AUC 0‑∞ ) are 49.1 ng/mL, 6 hr, 1,990 ng⋅hr/mL, and 2,000 ng⋅hr/mL, respectively. A high fat meal does not affect phentermine pharmacokinetics for phentermine and topiramate extended-release 15 mg/92 mg. Phentermine pharmacokinetics are approximately dose-proportional from phentermine and topiramate extended-release 3.75 mg/23 mg to phentermine 15 mg/topiramate 100 mg. Upon dosing phentermine 15 mg/topiramate 100 mg fixed dose combination capsule to steady state, the mean phentermine accumulation ratios for AUC and C max are both approximately 2.5. Topiramate Upon oral administration of a single phentermine and topiramate extended-release capsule 15 mg/92 mg, the resulting mean plasma topiramate C max , T max , AUC 0-t , and AUC 0-∞ , are 1,020 ng/mL, 9 hr, 61,600 ng⋅hr/mL, and 68,000 ng⋅hr/mL, respectively. A high fat meal does not affect topiramate pharmacokinetics for phentermine and topiramate extended-release 15 mg/92 mg. Topiramate pharmacokinetics are approximately dose-proportional from phentermine and topiramate extended-release 3.75 mg/23 mg to phentermine 15 mg/topiramate 100 mg. Upon dosing phentermine 15 mg/topiramate 100 mg fixed dose combination capsule to steady state, the mean topiramate accumulation ratios for AUC and C max are both approximately 4. Distribution Phentermine Phentermine is 17.5% plasma protein bound. The estimated phentermine apparent volume of distribution (Vd/F) is 348 L via population pharmacokinetic analysis. Topiramate Topiramate is 15 to 41% plasma protein bound over the blood concentration range of 0.5 to 250 mcg/mL. The fraction bound decreased as blood topiramate increased. The estimated topiramate Vc/F (volume of the central compartment), and Vp/F (volume of the peripheral compartment) are 50.8 L, and 13.1 L, respectively, via population pharmacokinetic analysis. Elimination Metabolism and Excretion Phentermine Phentermine has two metabolic pathways, namely p-hydroxylation on the aromatic ring and N-oxidation on the aliphatic side chain. Cytochrome P450 (CYP) 3A4 primarily metabolizes phentermine but does not show extensive metabolism. Monoamine oxidase (MAO)-A and MAO-B do not metabolize phentermine. Seventy to 80% of a dose exists as unchanged phentermine in urine when administered alone. The mean phentermine terminal half-life is about 20 hours. The estimated phentermine oral clearance (CL/F) is 8.79 L/h via population pharmacokinetic analysis. Topiramate Topiramate does not show extensive metabolism. Six topiramate metabolites (via hydroxylation, hydrolysis, and glucuronidation) exist, none of which constitutes more than 5% of an administered dose. About 70% of a dose exists as unchanged topiramate in urine when administered alone. The mean topiramate terminal half-life is about 65 hours. The estimated topiramate CL/F is 1.17 L/h via population pharmacokinetic analysis. Specific Populations Patients with Renal Impairment A single-dose, open-label study was conducted to evaluate the pharmacokinetics of phentermine and topiramate extended-release 15 mg/92 mg in adult patients with varying degrees of chronic renal impairment compared to healthy volunteers with normal renal function. The study included patients with renal impairment classified on the basis of creatinine clearance as mild (greater or equal to 50 and less than 80 mL/min), moderate (greater than or equal to 30 and less than 50 mL/min), and severe (less than 30 mL/min). Creatinine clearance was estimated from serum creatinine based on the Cockcroft-Gault equation. Compared to healthy volunteers, phentermine AUC 0-inf was 91%, 45%, and 22% higher in patients with severe, moderate, and mild renal impairment, respectively; phentermine C max was 2% to 15% higher. Compared to healthy volunteers, topiramate AUC 0-inf was 126%, 85%, and 25% higher for patients with severe, moderate, and mild renal impairment, respectively; topiramate C max was 6% to 17% higher. An inverse relationship between phentermine or topiramate C max or AUC and creatinine clearance was observed. Phentermine and topiramate extended-release capsules have not been studied in patients with end-stage renal disease on dialysis [see Dosage and Administration ( 2.4 ), and Use in Specific Populations ( 8.6 )]. Patients with Hepatic Impairment A single-dose, open-label study was conducted to evaluate the pharmacokinetics of phentermine and topiramate extended-release 15 mg/92 mg in healthy volunteers with normal hepatic function compared with patients with mild (Child-Pugh score 5 to 6) and moderate (Child-Pugh score 7 to 9) hepatic impairment. In patients with mild and moderate hepatic impairment, phentermine AUC was 37% and 60% higher compared to healthy volunteers. Pharmacokinetics of topiramate was not affected in patients with mild and moderate hepatic impairment when compared with healthy volunteers. Phentermine and topiramate extended-release capsules have not been studied in patients with severe hepatic impairment (Child-Pugh score 10 to 15) [see Dosage and Administration ( 2.5 ), and Use in Specific Populations ( 8.7 )]. Drug Interaction Studies In Vitro Assessment of Drug Interactions Phentermine Phentermine is not an inhibitor of CYP isozymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4, and is not an inhibitor of monoamine oxidases. Phentermine is not an inducer of CYP1A2, CYP2B6, and CYP3A4. Phentermine is not a P-glycoprotein substrate. Topiramate Topiramate is not an inhibitor of CYP isozymes CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4/5. However, topiramate is a mild inhibitor of CYP2C19. Topiramate is a mild inducer of CYP3A4. Topiramate is not a P-glycoprotein substrate. Effects of Phentermine/Topiramate on Other Drugs Table 7 describes the effect of phentermine/topiramate on the pharmacokinetics of co‑administered drugs. Table 7. Effect of Phentermine/Topiramate on the Pharmacokinetics of Co-administered Drugs Phentermine/Topiramate Co-administered Drug and Dosing Regimen Drug and Dose (mg) Change in AUC Change in C max * 15 mg/92 mg dose QD for 16 days Metformin 500 mg BID for 5 days ↑ 23% ↑ 16% * 15 mg/92 mg dose QD for 21 days Sitagliptin 100 mg QD for 5 days ↓ 3% ↓ 9% **15 mg/92 mg dose QD for 15 days Oral contraceptive single dose norethindrone 1 mg ethinyl estradiol 35 mcg ↑ 16% ↓ 16% ↑ 22% ↓ 8% * A single study examined the effect of multiple-dose phentermine and topiramate extended-release 15 mg/92 mg once daily on the pharmacokinetics of multiple-dose 500 mg metformin twice daily and multiple-dose 100 mg sitagliptin once daily in 10 males and 10 females (mean BMI of 27.1 kg/m 2 and range of 22.2 to 32.7 kg/m 2 ). The study participants received metformin, sitagliptin, phentermine/topiramate only, phentermine/topiramate plus probenecid, phentermine/topiramate plus metformin, and phentermine/topiramate plus sitagliptin on Days 1 to 5, 6 to 10, 11 to 28, 29, 30 to 34, and 35 to 39, respectively. The significance of these interaction is unknown. ** See Drug Interactions ( 7 ) Effect of Other Drugs on Phentermine/Topiramate Table 8 describes the effect of other drugs on the pharmacokinetics of phentermine/topiramate. Table 8. Effect of Co-administered Drugs on the Pharmacokinetics of Phentermine/Topiramate Co-administered Drug and Dosing Regimen Phentermine/Topiramate Dose (mg) Change in AUC Change in C max Topiramate 92 mg single dose 15 mg phentermine single dose ↑ 42% ↑ 13% Phentermine 15 mg single dose 92 mg topiramate single dose ↑ 6% ↑ 2% * Metformin 500 mg BID for 5 days 15 mg/92 mg dose QD for 16 days phentermine topiramate ↑ 5% ↓ 5% ↑ 7% ↓ 4% * Sitagliptin 100 mg QD for 5 days 15 mg/92 mg dose QD for 21 days phentermine topiramate ↑ 9% ↓ 2% ↑ 10% ↓ 2% * Probenecid 2 grams QD 15 mg/92 mg dose QD for 11 days phentermine topiramate ↓ 0.3% ↑ 0.7% ↑ 4% ↑ 3% * The same single study examined the effect of multiple-dose 500 mg metformin twice daily, a single-dose 2 grams probenecid, and multiple-dose 100 mg sitagliptin once daily on the pharmacokinetics of multiple-dose phentermine/topiramate 15 mg/92 mg once daily in 10 males and 10 females (mean BMI of 27.1 kg/m 2 and range of 22.2 to 32.7 kg/m 2 ). The study participants received metformin, sitagliptin, phentermine/topiramate only, phentermine/topiramate plus probenecid, phentermine/topiramate plus metformin, and phentermine/topiramate plus sitagliptin on Days 1 to 5, 6 to 10, 11 to 28, 29, 30 to 34, and 35 to 39, respectively. Effects of Topiramate Alone on Other Drugs and Effects of Other Drugs on Topiramate Antiepileptic Drugs Potential interactions between topiramate and standard antiepileptic (AED) drugs were assessed in controlled clinical pharmacokinetic studies in patients with epilepsy. The effects of these interactions on mean plasma AUCs are summarized in Table 9. In Table 9, the second column (AED concentration) describes what happens to the concentration of the AED listed in the first column when topiramate is added. The third column (topiramate concentration) describes how the co-administration of a drug listed in the first column modifies the concentration of topiramate in experimental settings when topiramate was given alone [see Drug Interactions ( 7 )] . Table 9. Summary of AED Interactions with Topiramate AED Co-administered AED Concentration Topiramate Concentration Phenytoin NC or 25% increase a 48% decrease Carbamazepine (CBZ) NC 40% decrease CBZ epoxide b NC NE Valproic acid 11% decrease 14% decrease Phenobarbital NC NE Primidone NC NE Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease a Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. b Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration; NE = Not Evaluated; TPM = topiramate . Digoxin In a single-dose study, serum digoxin AUC was decreased by 12% with concomitant topiramate administration. The clinical relevance of this observation has not been established. Hydrochlorothiazide A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of hydrochlorothiazide (HCTZ) (25 mg q24h) and topiramate (96 mg q12h) when administered alone and concomitantly. The results of this study indicate that topiramate C max increased by 27% and AUC increased by 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not significantly influenced by the concomitant administration of topiramate. Clinical laboratory results indicated decreases in serum potassium after topiramate or HCTZ administration, which were greater when HCTZ and topiramate were administered in combination [see Drug Interactions ( 7 ) and Warnings and Precautions ( 5.12 )]. Pioglitazone A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of topiramate (96 mg twice daily) and pioglitazone (30 mg daily) when administered alone and concomitantly for 7 days. A 15% decrease in the area under the concentration-time curve during a dosage interval at steady state (AUC τ,ss ) of pioglitazone with no alteration in maximum steady-state plasma drug concentration during a dosage interval (C max , ss ) was observed. This finding was not statistically significant. In addition, a 13% and 16% decrease in C max , ss and AUC τ,ss respectively, of the active hydroxy-metabolite was noted as well as a 60% decrease in C max , ss and AUC τ,ss of the active keto-metabolite [see Drug Interactions ( 7 )]. Glyburide A drug-drug interaction study conducted in patients with type 2 diabetes mellitus evaluated the steady-state pharmacokinetics of glyburide (5 mg/day) alone and concomitantly with topiramate (150 mg/day). There was a 22% decrease in C max and a 25% reduction in AUC 24 for glyburide during topiramate administration. Systemic exposure (AUC) of the active metabolites, 4-trans-hydroxyglyburide (M1), and 3-cis-hydroxyglyburide (M2), was reduced by 13% and 15%, and C max was reduced by 18% and 25%, respectively. The steady-state pharmacokinetics of topiramate were unaffected by concomitant administration of glyburide. Lithium 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 C max and 26% for AUC) following topiramate doses up to 600 mg/day. Haloperidol The pharmacokinetics of a single dose of haloperidol (5 mg) were not affected following multiple dosing of topiramate (100 mg every 12 hours) in 13 healthy adults (6 males, 7 females). Amitriptyline There was a 12% increase in AUC and C max for amitriptyline (25 mg per day) in 18 normal subjects (9 males, 9 females) receiving 200 mg/day of topiramate [see Drug Interactions ( 7 )]. Sumatriptan Multiple dosing of topiramate (100 mg every 12 hrs) in 24 healthy volunteers (14 males, 10 females) did not affect the pharmacokinetics of single-dose sumatriptan either orally (100 mg) or subcutaneously (6 mg). Risperidone When administered concomitantly with topiramate at escalating doses of 100, 250, and 400 mg/day, there was a reduction in risperidone systemic exposure (16% and 33% for steady-state AUC at the 250 and 400 mg/day doses of topiramate). No alterations of 9-hydroxyrisperidone levels were observed. Co-administration of topiramate 400 mg/day with risperidone resulted in a 14% increase in C max and a 12% increase in AUC 12 of topiramate. There were no clinically significant changes in the systemic exposure of risperidone plus 9-hydroxyrisperidone or of topiramate; therefore, this interaction is not likely to be of clinical significance. Propranolol Multiple dosing of topiramate (200 mg/day) in 34 healthy volunteers (17 males, 17 females) did not affect the pharmacokinetics of propranolol following daily 160 mg doses. Propranolol doses of 160 mg/day in 39 volunteers (27 males, 12 females) had no effect on the exposure to topiramate, at a dose of 200 mg/day of topiramate. Dihydroergotamine Multiple dosing of topiramate (200 mg/day) in 24 healthy volunteers (12 males, 12 females) did not affect the pharmacokinetics of a 1 mg subcutaneous dose of dihydroergotamine. Similarly, a 1 mg subcutaneous dose of dihydroergotamine did not affect the pharmacokinetics of a 200 mg/day dose of topiramate in the same study. Diltiazem Co-administration of diltiazem hydrochloride extended-release with topiramate (150 mg/day) resulted in a 10% decrease in C max and a 25% decrease in diltiazem AUC, a 27% decrease in C max and an 18% decrease in des-acetyl diltiazem AUC, and no effect on N-desmethyl diltiazem. Co-administration of topiramate with diltiazem hydrochloride extended-release resulted in a 16% increase in C max and a 19% increase in AUC 12 of topiramate. Venlafaxine Multiple dosing of topiramate (150 mg/day) in healthy volunteers did not affect the pharmacokinetics of venlafaxine or O-desmethyl venlafaxine. Multiple dosing of venlafaxine (150 mg extended release) did not affect the pharmacokinetics of topiramate. Pediatric use information is approved for Vivus LLC's Qsymia ® (phentermine and topiramate) extended-release capsules. However, due to Vivus LLC's marketing exclusivity rights, this drug product is not labeled with that information.