Qsymia (Page 6 of 9)

11 DESCRIPTION

Qsymia capsule is a combination oral product comprised of immediate-release phentermine hydrochloride (expressed as the weight of the free base) and extended-release topiramate. Qsymia contains phentermine hydrochloride, a sympathomimetic amine anorectic, and topiramate, a sulfamate-substituted monosaccharide related to fructose antiepileptic drug.

Phentermine Hydrochloride

The chemical name of phentermine hydrochloride is α,α-dimethylphenethylamine hydrochloride. The molecular formula is C 10 H 15 N • HCl and its molecular weight is 185.7 (hydrochloride salt) or 149.2 (free base). Phentermine hydrochloride is a white, odorless, hygroscopic, crystalline powder that is soluble in water, methanol, and ethanol. Its structural formula is:

Chemical StructureChemical Structure

Topiramate

Topiramate 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 339.4. Topiramate is a white to off-white crystalline powder with a bitter taste. It is freely soluble in methanol and acetone, sparingly soluble in pH 9 to pH 12 aqueous solutions and slightly soluble in pH 1 to pH 8 aqueous solutions. Its structural formula is:

Chemical StructureChemical Structure

Qsymia

Qsymia is available in four dosage strengths:

  • Qsymia 3.75 mg/23 mg (phentermine 3.75 mg and topiramate 23 mg extended-release) capsules;
  • Qsymia 7.5 mg/46 mg (phentermine 7.5 mg and topiramate 46 mg extended-release) capsules;
  • Qsymia 11.25 mg/69 mg (phentermine 11.25 mg and topiramate 69 mg extended-release) capsules;
  • Qsymia 15 mg/92 mg (phentermine 15 mg and topiramate 92 mg extended-release) capsules.

Each capsule contains the following 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.

12 CLINICAL PHARMACOLOGY

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 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.

12.2 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.

Cardiac Electrophysiology

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 (C max ) 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.

Glomerular Filtration Rate (GFR)

Healthy obese men and women received Qsymia daily for 4 weeks (3.75 mg/23 mg on Days 1 to 3, 7.5 mg/46 mg on Days 4 to 6, 11.25 mg/69 mg on Days 7 to 9, and 15 mg/92 mg on Days 10 to 28). The glomerular filtration rate (GFR) of these participants was assessed via iohexol clearance. On average, GFR decreased during Qsymia treatment and returned to baseline within 4 weeks after discontinuing Qsymia [See Warnings and Precautions (5.8)]

12.3 Pharmacokinetics

Phentermine

Upon oral administration of a single Qsymia 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 measureable concentration (AUC 0-t ), and area under the concentration curve from time zero to infinity (AUC 0- ) 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 C max are both approximately 2.5.

Topiramate

Upon oral administration of a single Qsymia 15 mg/92 mg, the resulting mean plasma topiramate C max , T max , AUC 0-t , and AUC 0- , 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 C max are both approximately 4.0.

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 — 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.

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

Renal Impairment

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 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.

Qsymia has not been studied in patients with end-stage renal disease on dialysis [see Dosage and Administration (2.2), Warnings and Precautions (5.13), and Use in Specific Populations (8.6)] .

Hepatic Impairment

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 (2.3), Warnings and Precautions (5.14), and Use in Specific Populations (8.7)] .

Drug Interactions

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 5. 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
*
A single study examined the effect of multiple-dose Qsymia 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 men and 10 women (mean BMI of 27.1 kg/m 2 and range of 22.2 – 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 – 5, 6 – 10, 11 – 28, 29, 30 – 34, and 35 – 39, respectively.
*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%

Effect of Other Drugs on Phentermine/Topiramate

Table 6. 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
*
The same single study examined the effect of multiple-dose 500 mg metformin twice daily, a single-dose 2 g 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 men and 10 women (mean BMI of 27.1 kg/m 2 and range of 22.2 – 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 – 5, 6 – 10, 11 – 28, 29, 30 – 34, and 35 – 39, respectively.
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 g QD 15 mg/92 mg dose QD for 11 days phentermine topiramate ↓ 0.3% ↑ 0.7% ↑ 4% ↑ 3%

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 7.

In Table 7, 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 7. Summary of AED Interactions with Topiramate
AED Co-administered AED Concentration Topiramate Concentration
NC = Less than 10% change in plasma concentration; NE = Not Evaluated; TPM = topiramate
*
Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
Is not administered but is an active metabolite of carbamazepine.
Phenytoin NC or 25% increase * 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxide 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

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.

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. The clinical significance of these findings is not known.

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 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. 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 C max 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 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 (240 mg Cardizem CD ®) 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 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.

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