Phentermine and Topiramate

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 chronic weight management 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 chronic weight management is not known. Topiramate's effect on chronic weight management 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.

Pharmacodynamics

Typical actions of amphetamines include central nervous system stimulation and elevation of blood pressure. Tachyphylaxis and tolerance have been demonstrated with all drugs of this class in which these phenomena have been looked for.

The effect of Qsymia on the QTc interval was evaluated in a randomized, double-blind, placebo-and active-controlled (400 mg moxifloxacin), and parallel group/crossover thorough QT/QTc study. A total of 54 healthy subjects were administered Qsymia 7.5 mg/46 mg at steady state and then titrated to Qsymia 22.5 mg/138 mg at steady state. Qsymia 22.5 mg/138 mg [a supra-therapeutic dose resulting in a phentermine and topiramate maximum concentration (Cmax) of 4-and 3-times higher than those at Qsymia 7.5 mg/46 mg, respectively] did not affect cardiac repolarization as measured by the change from baseline in QTc.

Pharmacokinetics

Upon oral administration of a single Qsymia 15 mg/92 mg, the resulting mean plasma phentermine maximum concentration (Cmax), time to Cmax (Tmax), area under the concentration curve from time zero to the last time with measureable concentration (AUC0-t), and area under the concentration curve from time zero to infinity (AUC0-∞) are 49.1 ng/mL, 6 hr, 1990 ng•hr/mL, and 2000 ng•hr/mL, respectively. A high fat meal does not affect phentermine pharmacokinetics for Qsymia 15 mg/92 mg. Phentermine pharmacokinetics is approximately dose-proportional from Qsymia 3.75 mg/23 mg to phentermine 15 mg/topiramate 100 mg. Upon dosing phentermine/topiramate 15/100 mg fixed dose combination capsule to steady state, the mean phentermine accumulation ratios for AUC and Cmax are both approximately 2.5.

Upon oral administration of a single Qsymia 15 mg/92 mg, the resulting mean plasma topiramate Cmax, Tmax, AUC0-t, and AUC0-∞, are 1020 ng/mL, 9 hr, 61600 ng•hr/mL, and 68000 ng•hr/mL, respectively. A high fat meal does not affect topiramate pharmacokinetics for Qsymia 15 mg/92 mg. Topiramate pharmacokinetics is approximately dose-proportional from Qsymia 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 Cmax are both approximately 4.0.

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 -41% plasma protein bound over the blood concentration range of 0.5 to 250 μg/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.

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

A single-dose, open-label study was conducted to evaluate the pharmacokinetics of Qsymia 15 mg/92 mg in 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 AUC0-inf was 91%, 45%, and 22% higher in patients with severe, moderate, and mild renal impairment, respectively; phentermine Cmax was 2% to 15% higher. Compared to healthy volunteers, topiramate AUC0-inf was 126%, 85%, and 25% higher for patients with severe, moderate, and mild renal impairment, respectively; topiramate Cmax was 6% to 17% higher. An inverse relationship between phentermine or topiramate Cmax or AUC and creatinine clearance was observed.

Qsymia has not been studied in patients with end-stage renal disease on dialysis [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, and Use In Specific Populations].

A single-dose, open-label study was conducted to evaluate the pharmacokinetics of Qsymia 15 mg/92 mg in healthy volunteers with normal hepatic function compared with patients with mild (Child-Pugh score 5 -6) and moderate (Child-Pugh score 7 -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. Qsymia has not been studied in patients with severe hepatic impairment (Child-Pugh score 10 -15) [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, and Use In Specific Populations].

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.

Table 6: Effect of Phentermine/Topiramate on the Pharmacokinetics of Co-administered Drugs

Table 7: Effect of Co-administered Drugs on the Pharmacokinetics of Phentermine/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 8.

In Table 8, 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.

Table 8: Summary of AED Interactions with 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 Cmax 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.

Pioglitazone

A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of topiramate and pioglitazone when administered alone and concomitantly. A 15% decrease in the area under the concentration-time curve during a dosage interval at steady state (AUCτ,ss) of pioglitazone with no alteration in maximum steady-state plasma drug concentration during a dosage interval (Cmax,ss) was observed. This finding was not statistically significant. In addition, a 13% and 16% decrease in Cmax,ss and AUCτ,ss respectively, of the active hydroxy-metabolite was noted as well as a 60% decrease in Cmax,ss and AUCτ,ss of the active keto-metabolite. The clinical significance of these findings is not known. When topiramate is added to pioglitazone therapy or pioglitazone is added to topiramate therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state.

Glyburide

A drug-drug interaction study conducted in patients with type 2 diabetes evaluated the steady-state pharmacokinetics of glyburide (5 mg/day) alone and concomitantly with topiramate (150 mg/day). There was a 22% decrease in Cmax and a 25% reduction in AUC24 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 Cmax 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 Cmax and 26% for AUC) following topiramate doses up to 600 mg/day. Lithium levels should be monitored when co-administered with high-dose topiramate.

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 Cmax for amitriptyline (25 mg per day) in 18 normal subjects (9 males, 9 females) receiving 200 mg/day of topiramate. Some subjects may experience a large increase in amitriptyline concentration in the presence of topiramate and any adjustments in amitriptyline dose should be made according to the patient's clinical response and not on the basis of plasma levels.

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 Cmax and a 12% increase in AUC12 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 (240 mg Cardizem CD®) 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 AUC12 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.

Reproductive And Developmental Toxicology

Topiramate, a component of Qsymia, causes developmental toxicity, including teratogenicity, in multiple animal species at clinically relevant doses.

When oral doses of 20, 100, or 500 mg/kg were administered to pregnant mice during the period of organogenesis, the incidence of fetal malformations (primarily craniofacial defects) was increased at all doses. The low dose of topiramate in this study (20 mg/kg) is approximately 2 times the MRHD of topiramate in Qsymia 15 mg/92 mg on a mg/m² basis. Fetal body weights and skeletal ossification were reduced at 500 mg/kg in conjunction with decreased maternal body weight gain.

In rat studies (oral doses of 20, 100, and 500 mg/kg or 0.2, 2.5, 30, and 400 mg/kg), the frequency of limb malformations (ectrodactyly, micromelia, and amelia) was increased among the offspring of dams treated with 400 mg/kg (34 times the MRHD of Qsymia based on AUC estimates) or greater during the organogenesis period of pregnancy. Embryotoxicity (reduced fetal body weights, increased incidence of structural variations) was observed at doses as low as 20 mg/kg (2 times the MRHD of Qsymia based on estimated AUC). Clinical signs of maternal toxicity were seen at 400 mg/kg and above, and maternal body weight gain was reduced during treatment with 100 mg/kg or greater.

In rabbit studies (20, 60, and 180 mg/kg or 10, 35, and 120 mg/kg orally during organogenesis), embryo/fetal mortality was increased at 35 mg/kg (2 times the MRHD based on estimated AUC) or greater, and teratogenic effects (primarily rib and vertebral malformations) were observed at 120 mg/kg (6 times the MRHD of Qsymia based on estimated AUC). Evidence of maternal toxicity (decreased body weight gain, clinical signs, and/or mortality) was seen at 35 mg/kg and above.

When female rats were treated during the latter part of gestation and throughout lactation (0.2, 4, 20, and 100 mg/kg or 2, 20, and 200 mg/kg), offspring exhibited decreased viability and delayed physical development at 200 mg/kg (16 times the MRHD of Qsymia based on estimated AUC) and reductions in pre-and/or post-weaning body weight gain at 2 mg/kg (2 times the MRHD of Qsymia based on estimated AUC) and above. Maternal toxicity (decreased body weight gain, clinical signs) was evident at 100 mg/kg or greater.

In a rat embryo/fetal development study with a postnatal component (0.2, 2.5, 30, or 400 mg/kg during organogenesis; noted above), pups exhibited delayed physical development at 400 mg/kg (34 times the MRHD of Qsymia based on estimated AUC) and persistent reductions in body weight gain at 30 mg/kg (2 times the MRHD of Qsymia based on estimated AUC) and higher.

Clinical Studies

The effect of Qsymia on weight loss in conjunction with reduced caloric intake and increased physical activity was studied in 2 randomized, double-blind, placebo-controlled studies in obese patients (Study 1) and in obese and overweight patients with two or more significant co-morbidities (Study 2). Both studies had a 4-week titration period, followed by 52 weeks of treatment. There were 2 co-primary efficacy outcomes measured after 1 year of treatment (Week 56): 1) the percent weight loss from baseline; and 2) treatment response defined as achieving at least 5% weight loss from baseline.

In Study 1, obese patients (BMI greater than or equal to 35 kg/m²) were randomized to receive 1 year of treatment with placebo (N=514), Qsymia 3.75 mg/23 mg (N=241), or Qsymia 15 mg/92 mg (N=512) in a 2:1:2 ratio. Patients ranged in age from 18-71 years old (mean age 43) and 83% were female. Approximately 80% were Caucasian, 18% were African American, and 15% were Hispanic/Latino. At the beginning of the study the average weight and BMI of patients was 116 kg and 42 kg/m², respectively. Patients with type 2 diabetes were excluded from participating in Study 1. During the study, a well-balanced, reduced-calorie diet to result in an approximate 500 kcal/day decrease in caloric intake was recommended to all patients and patients were offered nutritional and lifestyle modification counseling.

In Study 2, overweight and obese patients were randomized to receive 1 year of treatment with placebo (N=994), Qsymia 7.5 mg/46 mg (N=498), or Qsymia 15 mg/92 mg (N=995) in a 2:1:2 ratio. Eligible patients had to have a BMI greater than or equal to 27 kg/m² and less than or equal to 45 kg/m² (no lower limit on BMI for patients with type 2 diabetes) and two or more of the following obesity-related co-morbid conditions:

• Elevated blood pressure (greater than or equal to 140/90 mmHg, or greater than or equal to 130/85 mmHg for diabetics) or requirement for greater than or equal to 2 antihypertensive medications;
• Triglycerides greater than 200-400 mg/dL or were receiving treatment with 2 or more lipid-lowering agents;
• Elevated fasting blood glucose (greater than 100 mg/dL) or diabetes; and/or
• Waist circumference greater than or equal to 102 cm for men or greater than or equal to 88 cm for women.

Patients ranged in age from 19-71 years old (mean age 51) and 70% were female. Approximately 86% were Caucasian, 12% were African American, and 13% were Hispanic/Latino. The average weight and BMI of patients at the start of the study was 103 kg and 36.6 kg/m², respectively. Approximately half (53%) of patients had hypertension at the start of the study. There were 388 (16%) patients with type 2 diabetes at the start of the study. During the study, a well-balanced, reduced-calorie diet to result in an approximate 500 kcal/day decrease in caloric intake was recommended to all patients and patients were offered nutritional and lifestyle modification counseling.

A substantial percentage of randomized patients withdrew from each study prior to week 56, 40% in Study 1, and 31% in Study 2.

Table 9 provides the results for the weight loss at 1 year in Studies 1 and 2. After 1 year of treatment with Qsymia, all dose levels resulted in statistically significant weight loss compared to placebo (Table 9, Figures 1 and 2). A statistically significant greater proportion of the patients randomized to Qsymia than placebo achieved 5% and 10% weight loss.

Table 9: Weight Loss at One Year in Study 1 and 2

Figure 1: Study 1 Percent Weight Change and  Figure 2: Study 2 Percent Weight Change

The changes in cardiovascular, metabolic, and anthropometric risk factors associated with obesity from Study 1 and 2 are presented in Table 10 and 11. One year of therapy with Qsymia resulted in relative improvement over placebo in several risk factors associated with obesity with the exception of heart rate [see WARNINGS AND PRECAUTIONS].

Table 10: Least-Squares (LS) Mean† Change from Baseline and Treatment Difference from Placebo in Risk Factors Following One Year of Treatment in Study 1 (Obesity)

Table 11: Least-Squares (LS) Mean† Change from Baseline and Treatment Difference from Placebo in Risk Factors Following One Year of Treatment in Study 2 (Overweight and Obese with Comorbidities)

Among the 388 subjects with type 2 diabetes treated in study 2, reductions in HbA1c from baseline (6.8%) were 0.1% for placebo compared to 0.4% and 0.4% with Qsymia 7.5 mg/46 mg and Qsymia 15 mg/92 mg, respectively [see WARNINGS AND PRECAUTIONS].

QSYMIA®
(Kyoo sim ee' uh)
(phentermine and topiramate) Extended Release Capsules

Read this Medication Guide before you start taking Qsymia and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. If you have any questions about Qsymia, talk to your healthcare provider or pharmacist.

What is the most important information I should know about Qsymia?

(For other side effects, also see “What are the possible side effects of Qsymia?”)

Qsymia can cause serious side effects, including:

• Birth defects (cleft lip/cleft palate). If you take Qsymia during pregnancy, your baby has a higher risk for birth defects called cleft lip and cleft palate. These defects can begin early in pregnancy, even before you know you are pregnant.

Women who are pregnant must not take Qsymia.

Women who can become pregnant should:

1. Have a negative pregnancy test before taking Qsymia and every month while taking Qsymia.
2. Use effective birth control (contraception) consistently while taking Qsymia. Talk to your healthcare provider about how to prevent pregnancy.

If you become pregnant while taking Qsymia, stop taking Qsymia immediately, and tell your healthcare provider right away. Healthcare providers and patients should report all cases of pregnancy to:

• FDA MedWatch at 1-800-FDA-1088, and
• The Qsymia Pregnancy Surveillance Program at 1-888-998-4887
• Increases in heart rate. Qsymia can increase your heart rate at rest. Your healthcare provider should check your heart rate while you take Qsymia. Tell your healthcare provider if you experience, while at rest, a racing or pounding feeling in your chest lasting several minutes when taking Qsymia.
• Suicidal thoughts or actions. Topiramate, an ingredient in Qsymia, may cause you to have suicidal thoughts or actions.

Call your healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:

• thoughts about suicide or dying
• attempts to commit suicide
• new or worse depression
• new or worse anxiety
• feeling agitated or restless
• panic attacks
• trouble sleeping (insomnia)
• new or worse irritability
• acting aggressive, being angry, or violent
• acting on dangerous impulses
• an extreme increase in activity and talking (mania) o other unusual changes in behavior or mood
• Serious eye problems which include:
  • any sudden decrease in vision, with or without eye pain and redness,
  • a blockage of fluid in the eye causing increased pressure in the eye (secondary angle closure glaucoma).

These problems can lead to permanent vision loss if not treated. Tell your healthcare provider right away if you have any new eye symptoms.

What is Qsymia?

Qsymia is a prescription medicine that contains phentermine and topiramate extended-release that may help some obese adults or some overweight adults who also have weight-related medical problems lose weight and keep the weight off.

Qsymia should be used with a reduced calorie diet and increased physical activity.

It is not known if Qsymia changes your risk of heart problems or stroke or of death due to heart problems or stroke.

It is not known if Qsymia is safe and effective when taken with other prescription, over-the-counter, or herbal weight loss products.

It is not known if Qsymia is safe and effective in children under 18 years old.

Qsymia is a federally controlled substance (CIV) because it contains phentermine and can be abused or lead to drug dependence. Keep Qsymia in a safe place, to protect it from theft. Never give your Qsymia to anyone else, because it may cause death or harm them. Selling or giving away this medicine is against the law.

Who should not take Qsymia?

Do not take Qsymia if you:

• are pregnant, planning to become pregnant, or become pregnant during Qsymia treatment.
• have glaucoma
• have thyroid problems (hyperthyroidism)
• are taking certain medicines called monoamine oxidase inhibitors (MAOIs) or have taken MAOIs in the past 14 days.
• are allergic to topiramate, sympathomimetic amines such as phentermine, or any of the ingredients in Qsymia. See the end of this Medication Guide for a complete list of ingredients in Qsymia.

What should I tell my healthcare provider before taking Qsymia?

Tell your healthcare provider if you:

• are pregnant or planning to become pregnant
• have had a heart attack or stroke
• have or have had an abnormal heart rhythm
• have or have had depression, mood problems, or suicidal thoughts or behavior
• have eye problems, especially glaucoma
• have a history of metabolic acidosis (too much acid in the blood) or a condition that puts you at higher risk for metabolic acidosis such as
  • chronic diarrhea, surgery, a diet high in fat and low in carbohydrates (ketogenic diet), weak, brittle, or soft bones (osteomalacia, osteoporosis, osteopenia), or decreased bone density
• have kidney problems, have kidney stones, or are getting kidney dialysis
• have liver problems
• have seizures or convulsions (epilepsy)
• are breastfeeding. It is not known if Qsymia passes into your breast milk. You and your healthcare provider should decide if you will take Qsymia or breastfeed. You should not do both.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Qsymia taken with other medicines may affect how each medicine works and may cause side effects.

Especially tell your healthcare provider if you take:

• Birth control pills. Tell your healthcare provider if your menstrual bleeding changes while you are taking birth control pills and Qsymia.
• Water pills (diuretics) such as hydrochlorothiazide (HCTZ)
• Any medicines that impair or decrease your thinking, concentration, or muscle coordination
• Carbonic anhydrase inhibitors [such as ZONEGRAN® (zonisamide), DIAMOX® (acetazolamide) or NEPTAZANE® (methazolamide)]
• Seizure medicines such as Valproic acid (DEPAKENE® or DEPAKOTE®)

Ask your healthcare provider or pharmacist for a list of these medicines, if you are not sure.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist each time you get a new medicine. Do not start a new medicine without talking to your healthcare provider.

How should I take Qsymia?

• Your healthcare provider should start you on a diet and exercise program when you start taking Qsymia. Stay on this program while you are taking Qsymia.
• Do not change your dose without talking to your healthcare provider.
• Qsymia can be taken with or without food.
• If you miss a dose of Qsymia, wait until the next morning to take your usual dose of Qsymia.
• Do not double your dose.
• To start treatment with Qsymia
  • Take one Qsymia 3.75 mg/23 mg capsule (Figure A) once each morning for the first 14 days
  • After taking Qsymia 3.75 mg/23 mg capsule for 14 days, then take one Qsymia 7.5 mg/46 mg capsule (Figure B) once each morning
• After taking Qsymia for 12 weeks
  • Your healthcare provider should either (1) tell you to stop taking Qsymia or (2) increase your dose of Qsymia if you do not lose a certain amount of weight within the first 12 weeks of treatment at the recommended dose.
• If your healthcare provider increases the dose of Qsymia
  • Take one Qsymia 11.25 mg/69 mg capsule (Figure C) once each morning for 14 days
  • After taking 14 days of Qsymia 11.25 mg/69 mg capsule, then take one Qsymia 15 mg/92 mg capsule (Figure D) once each morning
• Stopping Qsymia treatment

Your healthcare provider should tell you to stop taking Qsymia if you have not lost a certain amount of weight after an additional 12 weeks of treatment on the higher dose.

Do not stop taking Qsymia without talking to your healthcare provider. Stopping Qsymia suddenly can cause serious problems, such as seizures. Your healthcare provider will tell you how to stop taking Qsymia slowly.

Figure A,B,C and D

If you take too much Qsymia, call your healthcare provider or go to the nearest emergency room right away.

What should I avoid while taking Qsymia?

• Do not get pregnant while taking Qsymia. See “What is the most important information I should know about Qsymia.”
• Do not drink alcohol while taking Qsymia.Qsymia and alcohol can affect each other causing side effects such as sleepiness or dizziness.
• Do not drive a car or operate heavy machinery, or do other dangerous activities until you know how Qsymia affects you. Qsymia can slow your thinking and motor skills, and may affect vision.

What are the possible side effects of Qsymia?

• See “What is the most important information I should know about Qsymia?” at the beginning of this Medication Guide
• Mood changes and trouble sleeping. Qsymia may cause depression or mood problems, and trouble sleeping. Tell your healthcare provider if symptoms occur.
• Concentration, memory, and speech difficulties. Qsymia may affect how you think and cause confusion, problems with concentration, attention, memory, or speech. Tell your healthcare provider if symptoms occur.
• Increases of acid in bloodstream (metabolic acidosis). If left untreated, metabolic acidosis can cause brittle or soft bones (osteoporosis, osteomalacia, osteopenia), kidney stones, can slow the rate of growth in children, and may possibly harm your baby if you are pregnant. Metabolic acidosis can happen with or without symptoms. Sometimes people with metabolic acidosis will:
  • feel tired
  • not feel hungry (loss of appetite)
  • feel changes in heartbeat
  • have trouble thinking clearly

Your healthcare provider should do a blood test to measure the level of acid in your blood before and during your treatment with Qsymia.

• Low blood sugar (hypoglycemia) in people with type 2 diabetes mellitus who also take medicines used to treat type 2 diabetes mellitus. Weight loss can cause low blood sugar in people with type 2 diabetes mellitus who also take medicines used to treat type 2 diabetes mellitus (such as insulin or sulfonylureas). You should check your blood sugar before you start taking Qsymia and while you take Qsymia.
• Possible seizures if you stop taking Qsymia too fast. Seizures may happen in people who may or may not have had seizures in the past if you stop Qsymia too fast. Your healthcare provider will tell you how to stop taking Qsymia slowly.
• Kidney stones. Drinking plenty of fluids when taking Qsymia to help decrease your chances of getting kidney stones. If you get severe side or back pain, and/or blood in your urine, call your healthcare provider
• Decreased sweating and increased body temperature (fever). People should be watched for signs of decreased sweating and fever, especially in hot temperatures. Some people may need to be hospitalized for this condition.

Common side effects of Qsymia include:

• numbness or tingling in the hands, arms, feet, or face (paraesthesia)
• dizziness
• change in the way foods taste or loss of taste (dysgeusia)
• trouble sleeping (insomnia)
• constipation
• dry mouth

Tell your healthcare provider if you have any side effect that bothers you or does not go away.

These are not all of the possible side effects of Qsymia. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to VIVUS at 1-888-998-4887 or FDA at 1-800-FDA-1088.

How should I store Qsymia?

• Store Qsymia at room temperature between 59°F to 77°F (15°C to 25°C).

Keep Qsymia and all medicines out of the reach of children.

General Information about Qsymia

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Qsymia for a condition for which it was not prescribed. Do not give Qsymia to other people, even if they have the same symptoms you have. It may harm them.

This Medication Guide summarizes important information about Qsymia. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Qsymia that is written for healthcare professionals.

For more information, go to www.QsymiaREMS.com or call 1-888-998-4887.

What are the ingredients in Qsymia?

Active Ingredient: phentermine hydrochloride and topiramate extended-release

Inactive Ingredients: methylcellulose, sucrose, starch, microcrystalline cellulose, ethylcellulose, povidone, gelatin, talc, titanium dioxide, FD&C Blue #1, FD&C Red #3, FD&C Yellow #5 and #6, and pharmaceutical black and white inks.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Phentermine and topiramate combination is used together with a reduced-calorie diet and proper exercise to help you lose weight. It is also used in overweight people who may also have diabetes, high blood pressure, high cholesterol, or heart disease.

phentermine and topiramate is available only under a special restricted distribution program called Qsymia™ REMS program.

It is very important that your doctor check your progress at regular visits, to make sure that phentermine and topiramate is working properly. Blood and urine tests may be needed to check for unwanted effects.

Using phentermine and topiramate while you are pregnant can harm your unborn baby. Use an effective form of birth control to keep from getting pregnant. If you think you have become pregnant while using phentermine and topiramate, tell your doctor right away.

You must have a negative pregnancy test before you will be allowed to take phentermine and topiramate. You will also be required to have a pregnancy test every month during your treatment. If you miss a period while you are using phentermine and topiramate, tell your doctor right away.

Do not use phentermine and topiramate if you have used an MAO inhibitor (MAOI) such as Eldepryl®, Marplan®, Nardil®, or Parnate® within the past 14 days. Using these medicines together may cause serious unwanted effects.

phentermine and topiramate may be habit-forming. If you think phentermine and topiramate is not working properly after you have taken it for a few weeks, do not increase the dose. Instead, check with your doctor.

phentermine and topiramate may increase your heart rate. Check with your doctor right away if you have a racing heartbeat while at rest after taking phentermine and topiramate.

phentermine and topiramate may cause some people to be agitated, irritable, or display other abnormal behaviors. It may also cause some people to have suicidal thoughts and tendencies or to become more depressed. If you or your caregiver notice any of these side effects, tell your doctor right away.

Check with your doctor immediately if you have a decrease in vision, blurred vision, or pain around the eyes during and after treatment with phentermine and topiramate. Your doctor may want you to have your eyes checked by an eye doctor.

phentermine and topiramate may cause some people to become dizzy, drowsy, or have trouble in thinking or speaking. Make sure you know how you react to phentermine and topiramate before you drive, use machines, or do anything else that could be dangerous if you are not alert, well-coordinated, or able to think or see well.

phentermine and topiramate may cause nausea, muscle tremors, fast breathing, problems eating, fast heartbeat, restlessness, and abdominal or stomach pain. Tell your doctor right away if you have any of these symptoms. This may be a sign that you may be having a metabolic acidosis (too much acid in the blood).

For diabetic patients: phentermine and topiramate may affect blood sugar levels. If you notice a change in the results of your blood or urine sugar tests or if you have any questions, check with your doctor.

For patients with high blood pressure: phentermine and topiramate may increase risk of lowering your blood pressure. If you feel dizzy, faint, or lightheaded after taking phentermine and topiramate, check with your doctor.

phentermine and topiramate will add to the effects of alcohol and other CNS depressants (medicines that make you drowsy or less alert). Some examples of CNS depressants are antihistamines or medicine for hay fever, other allergies, or colds, prescription pain medicines, or sleep medicines. Check with your doctor before taking any of the above while you are using phentermine and topiramate.

Do not suddenly stop taking phentermine and topiramate without first checking with your doctor. Stopping the medicine suddenly may cause your seizures to return or to occur more often. Your doctor may want you to gradually reduce the amount you are using before stopping completely.

Check with your doctor right away if you have sudden back pain, abdominal or stomach pain, pain while urinating, or bloody or dark urine. These may be symptoms of kidney stones.

phentermine and topiramate may make you sweat less, causing your body temperature to increase. Use extra care not to become overheated during exercise or hot weather while you are taking phentermine and topiramate. Overheating may result in heat stroke. Also, hot baths or saunas may make you dizzy or faint while you are taking phentermine and topiramate.

phentermine and topiramate may cause your body temperature to go down especially when taking valproic acid, which is a medicine to control seizures. You may have tiredness, weakness, confusion, and abnormal heartbeat and breathing. Tell your doctor right away if you feel any of these side effects.

Birth control pills (containing estrogen) may not work properly if you take them while you are taking phentermine and topiramate. Unplanned pregnancies may occur. You should use a different or additional means of birth control while you are using phentermine and topiramate. If you have any questions about this, check with your doctor or pharmacist.

Check with your doctor right away if you are having unusual drowsiness, dullness, tiredness, weakness, or feelings of sluggishness, mental depression or anxiety, nightmares or unusually vivid dreams, or vomiting. These may be symptoms of a serious condition called hyperammonemic encephalopathy.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements (including any weight loss products).

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Chest discomfort
• convulsions
• decreased urine
• fast, irregular, pounding, or racing heartbeat or pulse
• loss of appetite
• mood changes
• muscle pain or cramps
• nausea or vomiting
• numbness or tingling in the hands, feet, or lips
• shortness of breath
• unusual tiredness or weakness

• Blood in the urine
• pain in the groin or genitals
• sharp back pain just below the ribs

• Blistering, peeling, or loosening of the skin
• blisters on the mouth, trunk, scalp, or other areas
• blurred or decreased vision
• chest pain
• chills or shivering
• clumsiness
• continuing nausea or vomiting
• cough or sore throat
• dark urine
• diarrhea or light-colored stools
• dizziness
• headache
• increase in the frequency of seizures
• irregular heartbeat
• itching
• joint or muscle pain
• loss of appetite
• low body temperature
• muscle aches or weakness
• pain in the shoulders, arms, jaw, or neck
• red skin lesions, often with a purple center
• red, irritated eyes
• shakiness in the legs, arms, hands, or feet
• sores, ulcers, or white spots in the mouth or on the lips
• sweating
• swelling of the face
• tiredness and weakness
• trouble thinking, speaking, or walking
• upper right abdominal or stomach pain
• weak or feeble pulse
• weight gain
• yellow eyes or skin

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Back pain
• change in taste
• difficulty having a bowel movement (stool)
• ear congestion
• fear or nervousness
• loss of taste
• loss of voice
• memory problems
• pain or tenderness around the eyes and cheekbones
• sneezing
• stuffy or runny nose
• trouble sleeping

• Belching
• cramps
• decreased appetite
• dry eyes
• eye pain
• hair loss
• heartburn or indigestion
• heavy bleeding
• irritability
• rash
• stomach discomfort, upset, or pain

• Bloating
• false or unusual sense of well-being
• feeling that others are watching you or controlling your behavior
• feeling that others can hear your thoughts
• feeling, seeing, or hearing things that are not there
• hives or welts
• change in sexual ability, desire, drive, or performance
• severe mood or mental changes
• unusual behavior

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• This medicine comes with an extra patient fact sheet called a Medication Guide. Read it with care. Read it again each time phentermine and topiramate is refilled. If you have any questions about this medicine, please talk with the doctor, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take phentermine and topiramate or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to phentermine and topiramate. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

• Qsymia

Phentermine: A sympathomimetic amine with pharmacologic properties similar to amphetamines. The mechanism of action in reducing appetite appears to be secondary to CNS effects, including stimulation of the hypothalamus to release norepinephrine.

Topiramate: Effect on weight management may be due to its effects on appetite suppression and satiety enhancement and based on a combination of potential mechanisms: blocks neuronal voltage-dependent sodium channels, enhances GABA(A) activity, antagonizes AMPA/kainite glutamate receptors, and weakly inhibits carbonic anhydrase.

Weight management: Adjunct to a reduced-calorie diet and increased physical activity, in patients with either an initial body mass index (BMI) of ≥30 kg/m2 or an initial BMI of ≥27 kg/m2 and at least one weight-related comorbid condition (eg, hypertension, dyslipidemia, type 2 diabetes)

Administer in the morning without regard to meals; avoid late evening administration (potential for insomnia).

Store at 15°C to 25°C (59°F to 77°F).

Use of this combination product is contraindicated in pregnant women. Based on human data, topiramate may cause fetal harm if used during pregnancy. An increased risk of adverse maternal and fetal outcomes is associated with obesity; however, medications for weight loss therapy are not recommended at conception or during pregnancy (ACOG 156 2015).

Females of reproductive potential should have a negative pregnancy test prior to and monthly during therapy. Effective contraception should be used during treatment. If irregular bleeding or spotting occurs while using hormonal contraceptives during therapy, patients should be instructed to continue the contraceptive (contraceptive failure is not expected) and notify their health care provider if symptoms become troubling. Refer to individual monographs for additional information.

Health care providers are encouraged to enroll women exposed to Qsymia during pregnancy in the Qsymia Pregnancy Surveillance Program (888-998-4887).