Phentermine and Topiramate: Package Insert / Prescribing Info

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 or BMI reduction for pediatric patients aged 12 years and older. If an adult patient has not lost at least 3% of baseline body weight or a pediatric patient has not experienced a reduction of at least 3% of baseline BMI, 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 or BMI reduction for pediatric patients aged 12 years and older. If an adult patient has not lost at least 5% of baseline body weight or a pediatric patient has not experienced a reduction of at least 5% of baseline BMI, 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.
• Monitor the rate of weight loss in pediatric patients. If weight loss exceeds 2 lbs (0.9 kg)/week, consider dosage reduction.

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 (5.9), 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 - 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 - 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 - 15).

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.QSYMIAREMS.comor by telephone at 1-888-998-4887.

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.

In a phentermine and topiramate extended-release capsule clinical trial of pediatric patients aged 12 years and older, 1 (0.6%) of the 167 phentermine and topiramate extended-release capsule-treated patients reported suicidal ideation and behavior which required hospitalization. No placebo-treated patients reported suicidal behavior or ideation.

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.

5.3 Risk of Ophthalmologic 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 12 to 17 years of age. In a 56-week study, average height increased from baseline in both phentermine and topiramate extended-release capsules and placebo-treated patients; however, a lower height velocity of -1.3 to -1.4 cm/year was observed in phentermine and topiramate extended-release capsules-treated compared to placebo-treated 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)] .

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 capsules. 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 capsules treatment. In phentermine and topiramate extended-release capsules 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 capsules 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 are 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 Reactions Due to Inactive Ingredient FD&C Yellow No. 5

This product 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.

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 capsules 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. Data in this section also describe adverse reactions from a 1-year, randomized, double-blind, placebo-controlled multicenter clinical trial that evaluated 223 pediatric patients (12 to 17 years old) with obesity [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 capsule-treated adults and more frequently than in the placebo group are shown in Table 1.

Pediatric Patients Aged 12 Years and Older

Adverse reactions occurring in pediatric patients treated with either phentermine and topiramate extended-release capsules
15 mg/92 mg or phentermine and topiramate extended-release capsules 7.5 mg/46 mg at greater than or equal to 4% and higher than placebo include depression, pyrexia, dizziness, arthralgia, influenza, and ligament sprain.

Adverse reactions reported in greater than or equal to 2% of phentermine and topiramate extended-release capsule-treated pediatric patients and more frequently than in the placebo group from a study in pediatric patients aged 12 years and older are shown in Table 2.

Increase in Heart Rate

In adult and pediatric clinical trials, there was a higher incidence of heart rate elevations observed in phentermine and topiramate extended-release capsule-treated compared to placebo-treated patients. In an 8-week ambulatory blood pressure monitoring (ABPM) study in adults, phentermine and topiramate extended-release capsules increased the 24-hr average heart rate by 3.6 beats per minute (bpm) (95% CI 2.1, 5.2) compared to the placebo group [see Clinical Pharmacology (12.2)] .

In clinical trials, a higher percentage of phentermine and topiramate extended-release capsule-treated adults and pediatric patients aged 12 years and older experienced heart rate increases from baseline of more than 5, 10, 15, and 20 bpm compared to placebo-treated patients. Table 3 and Table 4 provide the numbers and percentages of adult and pediatric patients, respectively, with elevations in heart rate in clinical studies of up to one year.

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). Adverse reactions of paraesthesia were also reported in pediatric patients (see Table 2). Phentermine and topiramate extended-release capsule-treated adult patients discontinued treatment due to these adverse reactions (1% for paraesthesia and 0.6% for dysgeusia); no pediatric patients discontinued treatment due to paraesthesia or dysgeusia.

Mood and Sleep Disorders

The proportion of adult patients in 1-year controlled trials of phentermine and topiramate extended-release capsules reporting one or more adverse reactions related to mood and sleep disorders was 15% and 21% with phentermine and topiramate extended-release capsules 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 capsules 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 capsules 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 capsules 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.

In a pediatric clinical trial, higher proportions of phentermine and topiramate extended-release capsule-treated patients reported one or more adverse reactions related to mood (e.g., depression, anxiety) and sleep disorders (e.g., insomnia) compared to placebo-treated patients (see Table 2).

Cognitive Disorders

In the 1-year controlled trials of phentermine and topiramate extended-release capsules in adults, the proportion of patients who experienced one or more cognitive-related adverse reactions was 5.0% for phentermine and topiramate extended-release capsules 7.5 mg/46 mg and 7.6% for phentermine and topiramate extended-release capsules 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.

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 12 to 17 years of age. In a 56-week study, average height increased from baseline in both phentermine and topiramate extended-release capsules and placebo-treated patients; however, a lower height velocity of -1.3 to -1.4 cm/year was observed in phentermine and topiramate extended-release capsule-treated compared to placebo-treated patients.

Decrease in Bone Mineral Density

Phentermine and topiramate extended-release capsules are associated with less bone mineral acquisition in pediatric patients 12 to 17 years of age. In a substudy (n=66) evaluating bone mineralization via dual-energy X-ray absorptiometry (DEXA), increases in bone mineral density (BMD) at the lumbar spine and total body less head (TBLH) were smaller in pediatric patients treated with phentermine and topiramate extended-release capsules compared to those treated with placebo after 1 year of treatment. Declines in BMD Z-scores of -0.5 or greater from baseline for TBLH were observed in 9% of phentermine and topiramate extended-release capsules 7.5 mg/46 mg-treated patients and 30% of phentermine and topiramate extended-release capsules 15 mg/92 mg-treated patients, compared to 0% of placebo-treated patients. The sample size and study duration were too small to determine if fracture risk is increased. Decreased BMD was not correlated with decreased serum bicarbonate, which commonly occurs with phentermine and topiramate extended-release capsules treatment, or changes in body weight. No patient had a BMD Z-score that went below -2.0 during the trial. Similar findings were observed in a 1 year, active-controlled trial of topiramate in pediatric patients with another condition.

Nephrolithiasis

In the 1-year controlled trials of phentermine and topiramate extended-release capsules in adults, the incidence of nephrolithiasis was 0.2% for phentermine and topiramate extended-release capsules 7.5 mg/46 mg and 1.2% for phentermine and topiramate extended-release capsules 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 capsules 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 capsules 7.5 mg/46 mg and 12.8% for phentermine and topiramate extended-release capsules 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 capsules 7.5 mg/46 mg dose and 0.7% for phentermine and topiramate extended-release capsules 15 mg/92 mg dose, compared to 0.1% for placebo. In a pediatric clinical trial, 60 to 70% phentermine and topiramate extended-release capsule-treated patients had a persistent bicarbonate level below the normal range (<21 mEq/L) compared to 43% of placebo-treated patients.

Serum Potassium

In the 1-year controlled trials of phentermine and topiramate extended-release capsules 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 capsules 7.5 mg/46 mg dose and 4.9% for phentermine and topiramate extended-release capsules 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 capsules 7.5 mg/46 mg dose and 0.7% for phentermine and topiramate extended-release capsules 15 mg/92 mg dose, compared to 0.0% 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 capsules 7.5 mg/46 mg dose and 0.1% receiving phentermine and topiramate extended-release capsules 15 mg/92 mg dose, compared to 0.0% receiving placebo.

Low serum potassium levels (<3.5 mEq/L) were not observed in a 56-week clinical trial of pediatric patients with obesity.

Serum Creatinine

In the 1-year controlled trials of phentermine and topiramate extended-release capsules in adults and pediatric patients, there was an increase in serum creatinine from baseline, peaking between Week 4 to 8 in adults and at Week 16 in pediatric 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 capsules 7.5 mg/46 mg and 8.4% for phentermine and topiramate extended-release capsules 15 mg/92 mg, compared to 2.0% for placebo; 17% of pediatric patients treated with phentermine and topiramate extended-release capsules 7.5 mg/46 mg or phentermine and topiramate extended-release capsules 15 mg/92 mg and 0% of patients treated with placebo had a serum creatinine ≥0.3 mg/dL at any time post-randomization. Increases in serum creatinine of greater than or equal to 50% over baseline occurred in 2.0% of adult subjects receiving phentermine and topiramate extended-release capsules 7.5 mg/46 mg and 2.8% receiving phentermine and topiramate extended-release capsules 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 capsules) and 14% in patients taking topiramate at 50 mg/day (0.6 times the maximum recommended dosage of phentermine and topiramate extended-release capsules), 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.

6.2 Postmarketing Experience

The following adverse reactions have been reported during post approval use of phentermine and topiramate extended-release capsules, 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

8.1 Pregnancy

Risk Summary

Phentermine and topiramate extended-release capsules are contraindicated in pregnant patients. The use of phentermine and topiramate extended-release capsules can cause fetal harm, and weight loss offers no clear clinical benefit to a pregnant patient (see Clinical Considerations) . Available data from pregnancy registries and epidemiologic studies indicate an increased risk of major congenital malformations, including but not limited to cleft lip and/or cleft palate (oral clefts), and of being SGA in infants exposed in utero to topiramate (see Data) . When phentermine and topiramate were co-administered to rats at doses of 3.75 and 25 mg/kg, respectively [approximately 2 times the maximum recommended human dose (MRHD) based on area under the curve (AUC)], or at the same dose to rabbits (approximately 0.1 times and 1 time, respectively, the clinical exposures at the MRHD based on AUC), there were no drug-related malformations. However, structural malformations, including craniofacial defects and reduced fetal weights occurred in offspring of multiple species of pregnant animals administered topiramate at clinically relevant doses (see Data) . Advise pregnant women of the potential risk to a fetus.

Clinical Considerations

Disease Associated Maternal and/or Embryo/Fetal Risk

Weight loss during pregnancy may result in fetal harm. Appropriate weight gain based on pre-pregnancy weight is currently recommended for all pregnant patients, including those who are already overweight or obese, due to the obligatory weight gain that occurs in maternal tissues during pregnancy. Maternal obesity increases the risk for congenital malformations, including neural tube defects, cardiac malformations, oral clefts, and limb reduction defects.

Fetal/Neonatal Adverse Reactions

Phentermine and topiramate extended-release capsules can cause metabolic acidosis [see Warnings and Precautions (5.7)] . The effect of topiramate-induced metabolic acidosis has not been studied in pregnancy; however, metabolic acidosis in pregnancy (due to other causes) can cause decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus' ability to tolerate labor.

Data

Human Data

Data evaluating the risk of major congenital malformations, oral clefts, and being SGA with topiramate exposure during pregnancy is available from the North American Antiepileptic Drug (NAAED) Pregnancy Registry and from several larger retrospective epidemiologic studies.

Major Congenital Malformations

The NAAED Pregnancy Registry indicates an increased risk of major congenital malformations, including but not limited to oral clefts in infants exposed to topiramate during the first trimester of pregnancy. Other than oral clefts, no specific pattern of major congenital malformations or grouping of major congenital malformation types were observed. In the NAAED pregnancy registry, when topiramate-exposed infants with only oral clefts were excluded, the prevalence of major congenital malformations (4.1%) was higher than that in infants exposed to a reference antiepileptic drug (AED) (1.8%) or in infants with mothers without epilepsy and without exposure to AEDs (1.1%).

Oral Clefts

In the NAAED Pregnancy Registry, the prevalence of oral clefts among topiramate-exposed infants (1.4%) was higher than the prevalence in infants exposed to a reference AED (0.3%) or the prevalence in infants with mothers without epilepsy and without exposure to AEDs (0.11%). It was also higher than the background prevalence in United States (0.17%) as estimated by the Centers for Disease Control and Prevention (CDC). The relative risk of oral clefts in topiramate-exposed pregnancies in the NAAED Pregnancy Registry was 12.5 (95% Confidence Interval [CI] 5.9-26.37) as compared to the risk in a background population of untreated women. The UK Epilepsy and Pregnancy Register reported a prevalence of oral clefts among infants exposed to topiramate monotherapy (3.2%) that was 16 times higher than the background rate in the UK (0.2%).

Larger retrospective epidemiology studies showed that topiramate monotherapy exposure in pregnancy is associated with an approximately two to five-fold increased risk of oral clefts. The FORTRESS study found an excess risk of 1.5 (95% CI = -1.1 to 4.1) oral cleft cases per 1,000 infants exposed to topiramate during the first trimester.

Small for Gestational Age

Data from the NAAED Pregnancy Registry and population-based birth registry cohort indicate that exposure to topiramate in utero is associated with an increased risk of SGA newborns (birth weight <10 th percentile). In the NAAED Pregnancy Registry, 19.7% of topiramate-exposed newborns were SGA compared to 7.9% of newborns exposed to a reference AED and 5.4% of newborns of mothers without epilepsy and without AED exposure. In the medical Birth Registry of Norway, a population-based pregnancy registry, 25% of newborns in the topiramate monotherapy exposure group were SGA compared to 9% in the comparison group unexposed to AEDs. The long-term consequences of the SGA findings are not known.

Animal Data

Phentermine/Topiramate

Embryo-fetal development studies have been conducted in rats and rabbits with combination phentermine and topiramate treatment. Phentermine and topiramate co-administered to rats during the period of organogenesis (gestation day (GD) 6 through 17) caused reduced fetal body weights but did not cause fetal malformations at the maximum dose of 3.75 mg/kg phentermine and 25 mg/kg topiramate [approximately 2 times the maximum recommended human dose (MRHD) based on area under the curve (AUC) estimates for each active ingredient]. In a similar study in rabbits in which the same doses were administered from GD 6 through 18, no effects on embryo-fetal development were observed at approximately 0.1 times (phentermine) and 1 time (topiramate) clinical exposures at the MRHD based on AUC. Significantly lower maternal body weight gain was recorded at these doses in rats and rabbits.

A pre- and post-natal development study was conducted in rats with combination phentermine and topiramate treatment. There were no adverse maternal or offspring effects in rats treated throughout organogenesis and lactation with 1.5 mg/kg/day phentermine and 10 mg/kg/day topiramate (approximately 2- and 3-times clinical exposures at the MRHD, respectively, based on AUC). Treatment with higher doses of 11.25 mg/kg/day phentermine and 75 mg/kg/day topiramate (approximately 5 and 6 times maximum clinical doses based on AUC, respectively) caused reduced maternal body weight gain and offspring toxicity. Offspring effects included lower pup survival after birth, increased limb and tail malformations, reduced pup body weight and delayed growth, development, and sexual maturation without affecting learning, memory, or fertility and reproduction. The limb and tail malformations were consistent with results of animal studies conducted with topiramate alone.

Phentermine

Animal reproduction studies have not been conducted with phentermine. Limited data from studies conducted with the phentermine/topiramate combination indicate that phentermine alone was not teratogenic but resulted in lower body weight and reduced survival of offspring in rats at 5-fold the MRHD of phentermine and topiramate extended-release capsules, based on AUC.

Topiramate

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

Developmental toxicity, including teratogenicity, occurred at clinically relevant doses in multiple animal species in which topiramate was administered during the period of organogenesis (GD 6 – 15 in rodents, GD 6 – 18 in rabbits. In these studies, fetal malformations (primarily craniofacial defects such as cleft palate), limb malformations (ectrodactyly, micromelia, and amelia), rib/vertebral column anomalies, and/or reduced fetal weights were observed at dosages ≥ 20 mg/kg in mice (approximately 2 times the MRHD of topiramate in phentermine and topiramate extended-release capsules 15 mg/92 mg on a mg/m 2 basis), 20 mg/kg in rats (2 times the MRHD of phentermine and topiramate extended-release capsules based on estimated AUC), and 35 mg/kg in rabbits (2 times the MRHD based on estimated AUC). When rats were administered topiramate from GD 15 through lactation day 20, reductions in pre- and/or post-weaning weights occurred at dosages ≥ 2 mg/kg (2 times the MRHD of phentermine and topiramate extended-release capsules based on estimated AUC).

8.2 Lactation

Risk Summary

Topiramate and phentermine are present in human milk. There are no data on the effects of topiramate and phentermine on milk production. Diarrhea and somnolence have been reported in breastfed infants with maternal use of topiramate. There are no data on the effects of phentermine in breastfed infants. Because of the potential for serious adverse reactions, including changes in sleep, irritability, hypertension, vomiting, tremor, and weight loss in breastfed infants with maternal use of phentermine, advise patients that breastfeeding is not recommended during phentermine and topiramate extended-release capsules therapy.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Pregnancy testing is recommended in patients who can become pregnant before initiating phentermine and topiramate extended-release capsules and monthly during phentermine and topiramate extended-release capsules therapy [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)] .

Contraception

Females

Phentermine and topiramate extended-release capsules can cause fetal harm when administered to a pregnant patient [see Use in Specific Populations (8.1)] . Advise patients who can become pregnant to use effective contraception during therapy with phentermine and topiramate extended-release capsules.

For patients taking combined oral contraceptives (COCs), use of phentermine and topiramate extended-release capsules may cause irregular bleeding [see Drug Interactions (7)] . Advise patients not to discontinue taking their COC and to contact their health care provider.

8.4 Pediatric Use

The safety and effectiveness of phentermine and topiramate extended-release capsules as an adjunct to a reduced-calorie diet and increased physical activity for weight reduction and long-term maintenance of body weight have been established in pediatric patients aged 12 years and older with obesity. Use of phentermine and topiramate extended-release capsules for this indication is supported by a 56-week, double-blind, placebo-controlled study in 223 pediatric patients aged 12 years and above, a pharmacokinetic study in pediatric patients, and studies in adults with obesity [see Clinical Pharmacology (12.3) and Clinical Studies (14)] .

In a pediatric clinical trial, there was one episode of serious suicidal ideation in a phentermine and topiramate extended-release capsule-treated patient requiring hospitalization and pharmacologic treatment [see Warnings and Precautions (5.2)] more patients treated with phentermine and topiramate extended-release capsules versus placebo reported adverse reactions related to mood (e.g., depression, anxiety) and sleep disorders (e.g., insomnia) [see Warnings and Precautions (5.4)] . Increases in bone mineral density and linear growth were attenuated in phentermine and topiramate extended-release capsules- versus placebo-treated patients [see Warnings and Precautions (5.6)] . Serious adverse reactions seen in pediatric patients using topiramate include acute angle glaucoma, oligohidrosis and hyperthermia, metabolic acidosis, cognitive and neuropsychiatric reactions, hyperammonemia and encephalopathy, and kidney stones.

The safety and effectiveness of phentermine and topiramate extended-release capsules in pediatric patients below the age of 12 years have not been established.

8.5 Geriatric Use

In the phentermine and topiramate extended-release capsules clinical trials, a total of 254 (7%) of the patients were 65 to 69 years of age; no patients 70 years of age or older were enrolled.

Clinical studies of phentermine and topiramate extended-release capsules did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6 Renal Impairment

Compared to healthy volunteers with normal renal function, patients with moderate and severe renal impairment as estimated by the Cockcroft-Gault equation had higher exposures to phentermine and topiramate.

The recommended dosage of phentermine and topiramate extended-release capsules in patients with mild renal impairment (CrCl greater or equal to 50 and less than 80 mL/min) is the same as the recommended dosage for patients with normal renal function.

In patients with moderate (CrCl greater than or equal to 30 to less than 50 mL/min) and severe (CrCl less than 30 mL/min) renal impairment, the maximum recommended dosage is phentermine and topiramate extended-release capsules 7.5 mg/46 mg once daily.

Phentermine and topiramate extended-release capsules have not been studied in patients with end-stage renal disease on dialysis. Avoid phentermine and topiramate extended-release capsules in this patient population [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)] .

8.7 Hepatic Impairment

In patients with mild (Child-Pugh 5 - 6) and moderate (Child-Pugh 7 - 9) hepatic impairment, exposure to phentermine was higher compared to healthy volunteers with normal hepatic function. Exposure to topiramate was similar among patients with mild and moderate hepatic impairment and healthy volunteers.

The recommended dosage of phentermine and topiramate extended-release capsules in patients with mild hepatic impairment (Child-Pugh 5 - 6) is the same as the recommended dosage in patients with normal hepatic function.

In patients with moderate hepatic impairment, the maximum recommended dosage is phentermine and topiramate extended-release capsules 7.5 mg/46 mg once daily.

Phentermine and topiramate extended-release capsules have not been studied in patients with severe hepatic impairment (Child-Pugh score 10 - 15). Avoid phentermine and topiramate extended-release capsules in this patient population [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)] .

9.1 Controlled Substance

Phentermine and topiramate extended-release capsules contain phentermine, a Schedule IV controlled substance, and topiramate, which is not a controlled substance.

9.2 Abuse

Phentermine has a known potential for abuse. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects.

Phentermine is related chemically and pharmacologically to amphetamines. Amphetamines and other stimulant drugs have been extensively abused. Abuse of amphetamines and related drugs (e.g., phentermine) may be associated with impaired control over drug use and severe social dysfunction. There are reports of patients who have increased the dosage of these drugs to many times higher than recommended. Assess the risk of abuse prior to prescribing phentermine and topiramate extended-release capsules as part of a weight reduction and long-term maintenance of body weight program.

9.3 Dependence

Physical dependence may occur in patients treated with phentermine and topiramate extended-release capsules. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.

The following adverse reactions have been associated with the abrupt discontinuation of the individual components of phentermine and topiramate extended-release capsules:

• For topiramate, abrupt discontinuation has been associated with seizures in patients without a history of seizures or epilepsy [see Warnings and Precautions (5.9)] .
• For phentermine, abrupt discontinuation following prolonged high dosage administration results in extreme fatigue and mental depression; changes are also noted on a sleep electroencephalogram.

Thus, in situations where rapid withdrawal of phentermine and topiramate extended-release capsules are required, appropriate medical 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)] .

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 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 drugs in this class.

Cardiac Electrophysiology

The effect of phentermine and topiramate extended-release capsules 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 phentermine and topiramate extended-release capsules 7.5 mg/46 mg at steady state and then titrated to phentermine and topiramate extended-release capsules 22.5 mg/138 mg at steady state. Phentermine and topiramate extended-release capsules 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 phentermine and topiramate extended-release capsules 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 males and females received phentermine and topiramate extended-release capsules 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 phentermine and topiramate extended-release capsules treatment and returned to baseline within 4 weeks after discontinuing phentermine and topiramate extended-release capsules [see Warnings and Precautions (5.8)]

Ambulatory Blood Pressure Monitoring

The effect of phentermine and topiramate extended-release capsules on blood pressure as measured by 24-hr ABPM was evaluated in a randomized, double-blind, 3-arm (phentermine and topiramate extended-release capsules, placebo, and active phentermine comparator) study of adults with obesity or overweight and at least one weight-related comorbidity. The study had a treatment duration of 8 weeks, and the primary endpoint was the change from baseline to Week 8 in mean systolic blood pressure (SBP) as measured by 24-hr ABPM.

Phentermine and topiramate extended-release capsules 15 mg/92 mg did not demonstrate a pressor effect (see Table 6). At Week 8, placebo-adjusted mean (95% CI) treatment differences by 24-hr ABPM for phentermine and topiramate extended-release capsules 15 mg/92 mg were SBP -3.2 mmHg (-5.5, -0.9), DBP +1.2 mmHg (-0.2, +2.6), and heart rate (HR) +3.6 bpm (+2.1, +5.2). Placebo-adjusted mean weight loss was -3.9% (-4.9%, -3.0%) for phentermine and topiramate extended-release capsules 15 mg/92 mg and -3.8% (-4.7%, -2.9%) for phentermine 30 mg at Week 8.

12.3 Pharmacokinetics

Absorption

Phentermine

Upon oral administration of a single phentermine and topiramate extended-release capsules 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, 1990 ng⋅hr/mL, and 2000 ng⋅hr/mL, respectively. A high fat meal does not affect phentermine pharmacokinetics for phentermine and topiramate extended-release capsules 15 mg/92 mg. Phentermine pharmacokinetics are approximately dose-proportional from phentermine and topiramate extended-release capsules 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 maxare both approximately 2.5.

Topiramate

Upon oral administration of a single phentermine and topiramate extended-release capsules 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 phentermine and topiramate extended-release capsules 15 mg/92 mg. Topiramate pharmacokinetics are approximately dose-proportional from phentermine and topiramate extended-release capsules 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 maxare 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.

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 capsules 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-infwas 91%, 45%, and 22% higher in patients with severe, moderate, and mild renal impairment, respectively; phentermine C maxwas 2% to 15% higher. Compared to healthy volunteers, topiramate AUC 0-infwas 126%, 85%, and 25% higher for patients with severe, moderate, and mild renal impairment, respectively; topiramate C maxwas 6% to 17% higher. An inverse relationship between phentermine or topiramate C maxor 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 capsules 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. Phentermine and topiramate extended-release capsules have not been studied in patients with severe hepatic impairment (Child-Pugh score 10 - 15) [see Dosage and Administration (2.5) and Use in Specific Populations (8.7)] .

Pediatric Patients 12 to 17 years old

A randomized, double-blind, placebo-controlled study was conducted to evaluate the population pharmacokinetics of phentermine and topiramate extended-release capsules using data from 37 pediatric patients (12 to 17 years of age) with obesity. Phentermine and topiramate extended-release capsules dosages of 3.75 mg/23 mg, 7.5 mg/46 mg, and 15 mg/92 mg were studied. Phentermine and topiramate extended-release capsules exposure in the pediatric patients appeared comparable to that in adults.

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 7describes the effect of phentermine/topiramate on the pharmacokinetics of co-administered drugs.

Effect of Other Drugs on Phentermine/Topiramate

Table 8describes the effect of other drugs on the pharmacokinetics of phentermine/topiramate.

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 [seeDrug Interactions (7)].

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 maxincreased 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 [seeDrug Interactions (7)andWarnings 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,ssand AUC τ,ssrespectively, of the active hydroxy-metabolite was noted as well as a 60% decrease in C max,ssand AUC τ,ssof the active keto-metabolite [seeDrug 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 maxand a 25% reduction in AUC 24for 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 maxwas 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 maxand 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 maxfor amitriptyline (25 mg per day) in 18 normal subjects (9 males, 9 females) receiving 200 mg/day of topiramate [seeDrug 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 maxand a 12% increase in AUC 12of 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 maxand a 25% decrease in diltiazem AUC, a 27% decrease in C maxand 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 maxand a 19% increase in AUC 12of 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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Phentermine/Topiramate

No animal studies have been conducted with the combination of phentermine/topiramate to evaluate carcinogenesis, mutagenesis, or impairment of fertility. The following data are based on findings in studies performed individually with phentermine or topiramate, phentermine and topiramate extended-release capsules' two active ingredients.

Phentermine

Phentermine was not mutagenic or clastogenic with or without metabolic activation in the Ames bacterial mutagenicity assay, a chromosomal aberration test in Chinese hamster lung (CHL-K1) cells, or an in vivo micronucleus assay.

Rats were administered oral doses of 3, 10, and 30 mg/kg/day phentermine for 2 years. There was no evidence of carcinogenicity at the highest dose of phentermine (30 mg/kg) which is approximately 11 to 15 times the maximum recommended clinical dose of phentermine and topiramate extended-release capsules 15 mg/92 mg based on AUC exposure.

No animal studies have been conducted with phentermine to determine the potential for impairment of fertility.

Topiramate

Topiramate did not demonstrate genotoxic potential when tested in a battery of in vitro and in vivo assays. Topiramate was not mutagenic in the Ames test or the in vitro mouse lymphoma assay; it did not increase unscheduled DNA synthesis in rat hepatocytes in vitro; and it did not increase chromosomal aberrations in human lymphocytes in vitro or in rat bone marrow in vivo.

An increase in urinary bladder tumors was observed in mice given topiramate (20, 75, and 300 mg/kg) in the diet for 21 months. The elevated bladder tumor incidence, which was statistically significant in males and females receiving 300 mg/kg, was primarily due to the increased occurrence of a smooth muscle tumor considered histomorphologically unique to mice. Plasma exposures in mice receiving 300 mg/kg were approximately 2 to 4 times steady-state exposures measured in patients receiving topiramate monotherapy at the MRHD of phentermine and topiramate extended-release capsules 15 mg/92 mg. The relevance of this finding to human carcinogenic risk is uncertain. No evidence of carcinogenicity was seen in rats following oral administration of topiramate for 2 years at doses up to 120 mg/kg (approximately 4 to 10 times the MRHD of phentermine and topiramate extended-release capsules based on AUC estimates).

No adverse effects on male or female fertility were observed in rats at doses up to 100 mg/kg (approximately 4 to 8 times male and female MRHD exposures of phentermine and topiramate extended-release capsules based on AUC).