Safety analysis of phentermine; topiramate included 2,318 adult patients and 223 pediatric patients. Cardiovascular adverse reactions reported for adult patients receiving placebo compared to increasing doses of phentermine; topiramate (3.75 mg/23 mg, 7.5 mg/46 mg, and 15 mg/92 mg, respectively) included: chest discomfort (0.4% vs. 2.1%, 0.2%, and 0.9%) and palpitations (0.8% vs. 0.8%, 2.4%, and 1.7%). In addition, phentermine alone has been associated with hypertension and ischemic events, such as chest pain (unspecified) in postmarketing reports. In clinical evaluation, a greater number of patients receiving phentermine; topiramate experienced increased heart rate (sinus tachycardia), with increases from baseline of more than 5, 10, 15, and 20 beats per minute compared to placebo. The clinical significance of a heart rate elevation with treatment is unclear. Periodic measurement of resting heart rate is advised for all patients, especially those at high risk for a cardiovascular event; in addition, monitoring during dose initiation and escalation is recommended for all patients. Instruct patients to inform health care providers of palpitations or feelings of a racing heartbeat while at rest. For patients who experience a sustained increase in resting heart rate during therapy, consider dose reduction or discontinuation. Of note, the effect of phentermine; topiramate on cardiovascular morbidity and mortality has not been established.[51256]

Safety analysis of phentermine; topiramate included 2,318 adult patients and 223 pediatric patients. Adverse reactions reported for patients receiving placebo compared to increasing doses of phentermine; topiramate (3.75 mg/23 mg, 7.5 mg/46 mg, and 15 mg/92 mg, respectively) included: anxiety (2% placebo vs. 3%, 2%, and 3% to 4%), depression (2% vs. 3%, 2% to 3%, and 4%), insomnia (5% vs. 5%, 6%, and 9%), and irritability (1% vs. 2%, 3%, and 4%). Mood and sleep disorder adverse reactions were reported in patients with and without a history of depression. Anticonvulsants, including topiramate, are thought to carry an increased risk of suicidal ideation and behavior. During clinical trials in pediatric patients 12 years and older, 0.6% of phentermine; topiramate treated patients reported suicidal ideation and behavior which required hospitalization versus 0% in placebo-treated patients. Suicidal ideation and behavior has also been reported during postmarketing experience. Patients and caregivers should be informed of the increased risk of suicidal thoughts and behaviors and should be advised to immediately report the emergence or worsening of depression, the emergence of suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior.[51256] When used alone for weight control, CNS reactions reported with phentermine have included overstimulation, restlessness, insomnia, euphoria, dysphoria, and psychosis.[46595]

Safety analysis of phentermine; topiramate included 2,318 adult patients and 223 pediatric patients. Ophthalmic adverse reactions reported for patients receiving placebo compared to increasing doses of phentermine; topiramate (3.75 mg/23 mg, 7.5 mg/46 mg, and 15 mg/92 mg, respectively) included: blurred vision (3.5% vs. 6.3%, 4%, and 5.4%), ocular pain (1.4% vs. 2.1%, 2.2%, and 2.2%), and xerophthalmia (0.8% vs. 0.8%, 1.4%, and 2.5%). Blurred vision was listed among adverse events leading to treatment discontinuation. In addition, topiramate alone has been associated with maculopathy during postmarketing surveillance. Further, topiramate alone has been associated with the onset of acute myopia associated with secondary angle closure glaucoma. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include myopia, mydriasis, anterior chamber shallowing, ocular hyperemia (redness), choroidal detachments, retinal pigment epithelial detachments, macular striae, and increased intraocular pressure (ocular hypertension). This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Visual field defects, independent of elevated intraocular pressure, have been reported in clinical trials and in postmarketing experience in patients receiving topiramate. Patients with preexisting ocular disease should initiate treatment with extreme caution and monitor for symptoms of increased intraocular pressure. Symptoms typically occur within 1 month of initiating topiramate treatment, but may occur at any time during therapy. The primary treatment to reverse symptoms is immediate discontinuation.[51256]

Safety analysis of phentermine; topiramate included 2,318 adult patients and 223 pediatric patients. Musculoskeletal adverse reactions reported for adult patients receiving placebo compared to increasing doses of phentermine; topiramate (3.75 mg/23 mg, 7.5 mg/46 mg, and 15 mg/92 mg, respectively) included: back pain (5.1% vs. 5.4%, 5.6%, and 6.6%), muscle cramps (2.2% vs. 2.9%, 2.8%, and 2.9%), musculoskeletal pain (1.2% vs. 0.8%, 3%, and 1.6%), neck pain (1.3% vs. 1.3%, 2.2%, and 1.2%), and pain in extremity (2.8% vs. 2.1%, 3%, and 3%). Musculoskeletal chest pain (0% with placebo, 0% with 7.5 mg/46 mg, and 3% with 15 mg/92 mg), arthralgia (0% with placebo, 2% with 7.5 mg/46 mg, and 4% with 15 mg/92 mg), and ligament sprain (0% with placebo, 4% with 7.5 mg/46 mg, and 2% with 15 mg/92 mg) were reported in pediatric patients receiving phentermine; topiramate.[51256]

Safety analysis of phentermine; topiramate included 2,318 adult patients and 223 pediatric patients. Dermatological adverse reactions reported for adult patients receiving placebo compared to increasing doses of phentermine; topiramate (3.75 mg/23 mg, 7.5 mg/46 mg, and 15 mg/92 mg, respectively) included: rash (2.2% vs. 1.7%, 2%, and 2.6%) and alopecia (0.7% vs. 2.1%, 2.6%, and 3.7%). Postmarketing, phentermine alone has been associated with urticaria; topiramate alone has been associated with bullous rash (including erythema multiforme, Stevens-Johnson syndrome [SJS], and toxic epidermal necrolysis [TEN]) and pemphigus. Discontinue phentermine; topiramate at the first sign of a rash unless clearly not drug related. Do not resume use and consider alternative therapy if signs or symptoms suggest SJS or TEN.[51256]

Phentermine; topiramate has been associated with metabolic acidosis due to the carbonic anhydrase inhibitor activity of topiramate. In clinical studies, the incidence of persistent treatment-emergent decreases in serum bicarbonate below the normal range (less than 21 mEq/L at 2 consecutive visits or at the final visit) for patients receiving placebo compared to increasing doses of phentermine; topiramate (7.5 mg/46 mg and 15 mg/92 mg) was 2.1% vs. 6.4%, and 12.8%, respectively; the incidence of persistent, markedly low serum bicarbonate values (less than 17 mEq/L on 2 consecutive visits or at the final visit) was 0.1% vs. 0.2% and 0.7%, respectively. In a pediatric clinical trial, 60% to 70% of phentermine; topiramate treated patients experienced a persistent bicarbonate below the normal range (less than 21 mEq/L) compared to 43% of placebo-treated patients. Generally, decreases in serum bicarbonate occurred early in treatment (4-week visit), however severe decreases and decreases later in treatment occurred. A correction of bicarbonate by week 56 was observed in most subjects. It is therefore prudent to measure baseline and periodic serum bicarbonate, along with other serum chemistries during therapy. If persistent metabolic acidosis develops, reduce the dose or taper to discontinue the dose.[51256]

Safety analysis of phentermine; topiramate included 2,318 adult patients and 223 pediatric patients. Commonly reported gastrointestinal adverse reactions occurring at a rate of 5% or more in adults included dysgeusia, constipation, and xerostomia. Reports of dysgeusia were characterized as a metallic taste. Only phentermine; topiramate-treated patients discontinued treatment due to dysgeusia (0.6%). Adverse reactions reported for patients receiving placebo compared to increasing doses of phentermine; topiramate (3.75 mg/23 mg, 7.5 mg/46 mg, and 15 mg/92 mg, respectively) included: constipation (6.1% vs. 7.9%, 15.1%, and 16.1%), diarrhea (4.9% vs. 5%, 6.4%, and 5.6%), dysgeusia (1.1% vs. 1.3%, 7.4%, and 9.4%), dyspepsia (1.7% vs. 2.1%, 2.2%, and 2.8%), gastroenteritis (2.2% vs. 0.8%, 2.2%, and 2.5%), gastroesophageal reflux (1.3%, vs. 0.8%, 3.2%, and 2.6%), nausea (4.4% vs. 5.8%, 3.6% to 4%, and 4% to 7.2%), oral paresthesias (0.3% vs. 0.4%, 0.6%, and 2.2%), and xerostomia (2.8% vs. 6.7%, 13.5%, and 19.1%). Upper abdominal pain was reported in 3% of pediatric patients receiving phentermine; topiramate 15 mg/92 mg. Postmarketing, topiramate alone has been associated with pancreatitis, hepatic failure (including fatalities), and hepatitis.[51256]

Safety analysis of phentermine; topiramate included 2,318 adult patients and 223 pediatric patients. Commonly reported nervous system adverse reactions occurring at a rate of 5% or more in adults included paraesthesia and dizziness. Reports of paresthesia were characterized as tingling in hands, feet, or face. Only phentermine; topiramate-treated patients discontinued treatment due to paresthesias (1%). Headache and dizziness were also listed among events leading to discontinuation. Adverse reactions reported for patients receiving placebo compared to increasing doses of phentermine; topiramate (3.75 mg/23 mg, 7.5 mg/46 mg, and 15 mg/92 mg, respectively) included: disturbance in attention (0.6% vs. 0.4%, 2%, and 3.5%), dizziness (3.4% vs. 2.9%, 2% to 7.2%, and 4% to 8.6%), headache (9.3% vs. 10.4%, 7%, and 10.6%), hypoesthesia (1.2% vs. 0.8%, 3.6%, and 3.7%), and paraesthesia (1.9% vs. 4.2%, 2% to 13.7%, and 3% to 19.9%). Impaired cognition was reported in 5% and 7.6% of patients receiving phentermine; topiramate 7.5 mg/46 mg and 15 mg /92 mg, respectively, compared to 1.5% of patients receiving placebo and was comprised primarily of reports of problems with attention/concentration, memory impairment, and language (word finding). These events occurred at any time during treatment. Postmarketing, phentermine alone has been associated with tremor.[51256]

Safety analysis of phentermine; topiramate included 2,318 adult patients and 223 pediatric patients. Respiratory related adverse reactions reported for patients receiving placebo compared to increasing doses of phentermine; topiramate (3.75 mg/23 mg, 7.5 mg/46 mg, and 15 mg/92 mg, respectively) included: bronchitis (4.2% vs. 6.7%, 4.4%, and 5.4%), cough (3.5% vs. 3.3%, 3.8%, and 4.8%), influenza (4.4% vs. 7.5%, 4% to 4.6%, and 2% to 4.4%), nasal congestion (1.4% vs. 1.7%, 1.2%, and 2%), naso-pharyngitis (8% vs. 12.5%, 10.6%, and 9.4%), pharyngolaryngeal pain (2% vs. 2.5%, 1.2%, and 2.3%), sinus congestion (2% vs. 2.5%, 2.6%, and 2%), sinusitis (6.3% vs. 7.5%, 6.8%, and 7.8%), and upper respiratory tract infection (12.8% vs. 15.8%, 12.2%, and 13.5%). Fever (2% with placebo, 2% with 7.5 mg/46 mg, and 4% with 15 mg/92 mg) and ear infection (0% with placebo, 2% with 7.5 mg/46 mg, and 3% with 15 mg/92 mg) were reported in pediatric patients receiving phentermine; topiramate.[51256]

Safety analysis of phentermine; topiramate included 2,318 adult patients and 223 pediatric patients. Genitourinary adverse reactions reported for adult patients receiving placebo compared to increasing doses of phentermine; topiramate (3.75 mg/23 mg, 7.5 mg/46 mg, and 15 mg/92 mg, respectively) included: dysmenorrhea (0.2% vs. 2.1%, 0.4%, and 0.8%) and urinary tract infection (3.6% vs. 3.3%, 5.2%, and 5.2%). Nephrolithiasis was reported in 0.2% and 1.2% of patients receiving phentermine; topiramate 7.5 mg/46 mg and 15 mg/92 mg, respectively, compared to 0.3% of patients receiving placebo. An increase in urinary calcium and marked decrease in urinary citrate, which is associated with an increased risk of nephrolithiasis and/or nephrocalcinosis, has been reported in pediatric patients treated with topiramate. Postmarketing, phentermine alone has been associated with impotence (erectile dysfunction), and changes in libido (libido increase and libido decrease).[51256]

Safety analysis of phentermine; topiramate included 2,318 adult patients and 223 pediatric patients. General adverse reactions reported for patients receiving placebo compared to increasing doses of phentermine; topiramate (3.75 mg/23 mg, 7.5 mg/46 mg, and 15 mg/92 mg, respectively) included: decreased appetite (0.6% vs. 2.1%, 1.8%, and 1.5%), fatigue (4.3% vs. 5%, 4.4%, and 3% to 5.9%), procedural pain (1.7% vs. 2.1%, 2.4%, and 1.9%), and thirst (0.7% vs. 2.1%, 1.8%, and 2%). In clinical studies, increased serum creatinine was observed with peak increases after 4 to 8 weeks of treatment in adults and 16 weeks in pediatric patients. On average, serum creatinine gradually declined but remained elevated over baseline creatinine values. The incidence of increases in serum creatinine of 0.3 mg/dL or more for adult patients receiving phentermine; topiramate was 7.2% (7.5 mg/46 mg) and 8.4% (15 mg/92 mg) compared to 2%, placebo. The incidence of increases in serum creatinine of 0.3 mg/dL or more for pediatric patients treated with phentermine; topiramate 7.5 mg/46 mg or 15 mg/92 mg was 17% vs. 0%, placebo. Increases of serum creatinine of 50% or more over baseline occurred in 2% (7.5 mg/46 mg) and 2.8% (15 mg/92 mg) of adult patients receiving phentermine; topiramate compared to 0.6% receiving placebo. Measurement of serum creatinine prior to starting therapy and during treatment is recommended. If persistent elevations in creatinine occur, reduce the dose or discontinue. Topiramate alone has been associated with hyperammonemia and hypothermia; the risk for hyperammonemia appears dose related. In adolescent migraine prophylaxis trials, the incidence of hyperammonemia was 9% for placebo, 14% for topiramate 50 mg/day, and 26% for 100 mg/day. The incidence of markedly increased hyperammonemia (i.e., ammonia values at least 50% higher than the upper limit of normal) was greatest at the 100 mg dose.[51256]

Phentermine; topiramate has been associated with hypokalemia. In clinical studies, the incidence of persistent low serum potassium values (less than 3.5 mEq/L at 2 consecutive visits or at the final visit) for patients receiving placebo compared to increasing doses of phentermine; topiramate (7.5 mg/46 mg and 15 mg/92 mg) was 1.1% vs. 3.6% and 4.9%, respectively; 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% vs. 0.2% and 0.7%, respectively; persistent markedly low serum potassium (less than 3 mEq/L, and a reduction from pre-treatment of greater than 0.5 mEq/L at 2 consecutive visits or at the final visit) occurred in 0% vs. 0.2% and 0.1%. Of the subjects who experienced persistent low serum potassium, 88% were receiving treatment with a non-potassium-sparing diuretic. Hypokalemia was not observed in a 56-week clinical trial of pediatric patients with obesity.[51256]

Physiological dependence and psychological dependence may occur in patients treated with phentermine; topiramate. For topiramate, abrupt discontinuation has been associated with seizures in patients without a history of seizures or epilepsy. For phentermine, abrupt cessation after prolonged high dosage administration results in extreme fatigue and mental depression; changes are also noted on a sleep electroencephalogram. Gradually taper phentermine; topiramate, particularly at a dose of 15 mg/92 mg once daily, to reduce the possibility of precipitating a seizure. In situations where rapid withdrawal is required, appropriate medical monitoring is recommended.[51256] Evidence-based data from the literature are relatively limited, and some experts suggest that long-term phentermine pharmacotherapy for obesity does not induce abuse or psychological dependence (addiction), drug craving, and that abrupt treatment cessation within the normal prescription dose range does not induce amphetamine-like withdrawal.[57587]

Phentermine; topiramate is associated with growth inhibition in obese pediatric patients 12 to 17 years. A lower height velocity of -1.3 to -1.4 cm/year was observed in patients receiving phentermine; topiramate in clinical trials. Additionally, phentermine; topiramate is associated with less bone mineral acquisition. 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; topiramate 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 patients receiving phentermine; topiramate 7.5 mg/46mg and 30% of patients receiving 15 mg/92 mg compared to 0% of placebo-treated patients. No patient had a BMD Z-score that went below -2 during the trial.[51256]

Because of the risk of hypertensive crisis due to the interaction between monoamine oxidase inhibitors (MAOIs) and sympathomimetic amines such as phentermine, the use of phentermine; topiramate is contraindicated during or within 14 days of MAOI therapy.[51256]

Phentermine; topiramate products are federally controlled substances because they contain phentermine and can be abused or lead to drug dependence. Patients should be advised to keep this product in a safe place, to protect it from theft and to never give the drug product to anyone else, because it may cause death or harm them. Selling or giving away this medicine is against the law. It is advisable to use phentermine-containing agents with caution in patients with a known history of substance abuse. Phentermine is related chemically and pharmacologically to amphetamines. The possibility of abuse of phentermine should be kept in mind when evaluating the desirability of including a drug as part of a weight reduction program. However, the abuse and dependence potential of phentermine; topiramate has not been systematically evaluated. As with most controlled substances, the least amount reasonable should be prescribed or dispensed at one time to limit the potential for overuse or drug diversion.[51256] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, other weight loss medications should be considered first in patients with a substance abuse disorder. There are insufficient data on the use of phentermine; topiramate in patients with obesity and alcoholism; however, topiramate might exert therapeutic benefits in patients with alcohol use disorder.[62881]

Phentermine; topiramate can cause an increase in resting heart rate. In clinical evaluation, a higher number of patients receiving phentermine; topiramate experienced heart rate increases from baseline of more than 5, 10, 15, and 20 beats per minute compared to placebo. The clinical significance of a heart rate elevation with treatment is unclear, but may be of concern primarily for those with cardiac disease or cerebrovascular disease (e.g., patients with a history of sinus tachycardia, acute myocardial infarction or stroke in the previous 6 months, life-threatening cardiac arrhythmias, or congestive heart failure). Periodic measurement of resting heart rate is advised for all patients, especially those at high risk for a cardiovascular event; in addition, monitoring during treatment initiation and dose escalation is recommended for all patients. Clinicians should instruct their patients to inform health care providers of palpitations or feelings of a racing heartbeat while at rest. For patients who experience a sustained increase in resting heart rate during therapy, dose reduction or discontinuation should be considered. Of note, the effect of phentermine; topiramate on cardiovascular morbidity and mortality has not been established.[51256] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, phentermine; topiramate is a preferred weight loss medication in obese patients with existing hypertension, with careful monitoring of heart rate. Phentermine; topiramate is not a preferred weight loss medication in patients with an established atherosclerotic coronary artery disease or a history or risk of cardiac arrhythmias, but is reasonable to use with caution if weight loss goals are met, with careful monitoring of blood pressure and heart rate. Heart rhythm should also be monitored in those with a history or risk of arrhythmias. The AACE/ACE Obesity Guidelines state that data are insufficient regarding the benefits of the use of phentermine; topiramate in obese patients with heart failure and the use of this product in this population should be avoided.[62881]

Phentermine; topiramate is contraindicated in patients with glaucoma. A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in pediatric patients and adults 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. The primary treatment to reverse symptoms is immediate discontinuation of phentermine; topiramate 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.[51256] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, other weight loss medications (i.e., orlistat, lorcaserin, and liraglutide) are preferred treatment options for patients with glaucoma; the use of phentermine; topiramate is contraindicated.[62881]

Phentermine; topiramate is contraindicated in patients with hyperthyroidism since sympathomimetics like phentermine can exacerbate these conditions. This product should also be used with caution in patients with thyroid disease.[51256]

Phentermine; topiramate 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; topiramate. For clinically significant or persistent symptoms consider dose reduction or withdrawal of this obesity treatment. Avoid phentermine; topiramate use in patients with a history of suicidal attempts or active suicidal ideation. Antiepileptic drugs (AEDs), including topiramate, a component of phentermine; topiramate, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Monitor patients for the emergence or worsening of depression, suicidal thoughts or behavior, and any unusual changes in mood or behavior during treatment. Discontinue phentermine; topiramate in patients who experience suicidal thoughts or behavioral changes.[51256] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, phentermine; topiramate may be considered in obese patients with depression, using low initial and maintenance doses; avoid maximum dosing. The maximum daily dose should also be avoided if possible in patients with a comorbid anxiety disorder. All patients undergoing weight loss therapy should be monitored for mood disorders, depression, and suicidal ideation. Evidence assessing safety and efficacy of weight loss medications in patients with a psychotic disorder (e.g., schizophrenia) is insufficient, and the AACE/ACE Obesity Guidelines recommend avoidance of phentermine; topiramate in these patients. The AACE/ACE Obesity Guidelines recommend that patients receiving an antipsychotic be treated with structured lifestyle modifications to promote weight loss and weight gain prevention; metformin may be beneficial for modest weight loss and metabolic improvements in patients receiving an antipsychotic.[62881]

Phentermine; topiramate 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 may be associated with higher rates of cognitive events such as attention, memory, and language/word-finding difficulties. Since this treatment has the potential to impair cognitive function, patients should be cautioned about driving or operating machinery or performing other tasks that require mental alertness until they are aware of how therapy will affect their mental and motor performance. If cognitive impairment persists, consider dose reduction; consider a withdrawal of therapy for symptoms that are moderate to severe, bothersome, or those which fail to resolve with dose reduction.[51256] Alcohol may aggravate these effects, so advise patients to avoid ethanol ingestion while taking phentermine; topiramate. Coadministration with other CNS depressants 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.[51256]

Use phentermine; topiramate with caution in any patients with renal disease. Phentermine; topiramate can cause an increase in serum creatinine that reflects a decrease in renal function as noted by a decrease in glomerular filtration rate (GFR). On average, the serum creatinine gradually declines but remains elevated over baseline values. After discontinuation of short-term treatment with phentermine; topiramate, the changes in serum creatinine and GFR appear reversible although the effect of chronic treatment on renal function or renal disease is not known. Therefore, measurement of serum creatinine prior to starting therapy and during treatment is recommended. If persistent elevations in creatinine occur, reduce the dose or discontinue. Both phentermine and topiramate are cleared by renal excretion and exposure to phentermine; topiramate is increased in patients with moderate (CrCl 30 to less than 50 mL/minute) and severe (CrCl less than 30 mL/minute) renal impairment; therefore, a lower maximum daily dose is recommended in these populations. The use of this product has not been studied in patients with renal failure on dialysis; avoid use in this patient population.[51256] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, phentermine; topiramate can be used with appropriate caution in obese patients with mild renal impairment (i.e., CrCl 50 to 79 mL/minute). A dose of 7.5 mg/46 mg per day should not be exceeded in patients with moderate renal impairment (i.e., CrCl 30 to 49 mL/minute). Accumulation of phentermine; topiramate occurs in severe renal impairment (i.e., CrCl less than 30 mL/min) and use of the drug should be avoided in this population. Phentermine; topiramate should not be used in patients with end-stage renal failure.[62881]

Phentermine; topiramate should be used with caution in patients with a history of kidney stones (nephrolithiasis). Topiramate is a carbonic anhydrase inhibitor and promotes kidney stone formation by reducing urinary citrate excretion and by increasing urinary pH. During clinical trials of topiramate for epilepsy, 1.3% to 1.5% of topiramate-treated patients developed kidney stones; this incidence is about 2 to 4 times that expected in a similar, untreated population and was higher in men.[31428] The concomitant use of topiramate with other carbonic anhydrase inhibitors or in patients on a ketogenic diet may create a physiological environment that increases the risk of kidney stone formation, and should, therefore, be avoided. Patients who are receiving phentermine; topiramate, especially those who have a history of kidney stones, should be instructed to maintain adequate fluid intake to reduce the formation of nephrolithiasis.[51256] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, phentermine; topiramate should be avoided in patients with recent nephrolithiasis as calcium phosphate stone formation is possible. Caution should be exercised when using phentermine; topiramate in patients with a history of nephrolithiasis.[62881]

Use phentermine; topiramate with caution in patients with hepatic disease. Exposure to phentermine was higher in patients with mild or moderate (Child-Pugh Class A and B) hepatic impairment. A 7.5 mg/46 mg daily dose should not be exceeded in patients with moderate hepatic impairment. Phentermine; topiramate has not been studied in patients with severe hepatic disease (Child-Pugh Class C); avoid use in this patient population.[51256] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, all weight loss medications should be used cautiously in patients with hepatic impairment and should be avoided in severe liver impairment (i.e., Child-Pugh score greater than 9). In patients with moderate hepatic impairment, the AACE/ACE guidelines recommend that the dose of phentermine; topiramate not exceed 7.5 mg/46 mg per day. Close monitoring for cholelithiasis is recommended in any obese patients undergoing weight loss therapy, regardless of modality, due to a proven association between these conditions.[62881]

Phentermine; topiramate has been associated with metabolic acidosis. Topiramate is a carbonic anhydrase inhibitor that can promote metabolic acidosis and also hypokalemia. Conditions that may predispose patients to acidosis [i.e., renal disease, diarrhea, ketogenic diet, severe pulmonary disease (chronic obstructive pulmonary disease (COPD), emphysema, status asthmaticus), surgery, status epilepticus or administration with other bicarbonate-lowering drugs] may have an additive risk for this complication. Metabolic acidosis may manifest as fatigue and anorexia, or more severely, cardiac arrhythmias or stupor. Chronic, untreated metabolic acidosis may increase the risk for nephrolithiasis or nephrocalcinosis and may also result in osteomalacia (rickets) and/or osteoporosis with an increased fracture risk. In pediatric patients, chronic metabolic acidosis may also reduce growth rates. Measurement of baseline and periodic serum bicarbonate and potassium, along with other serum chemistries, is recommended during therapy. In clinical trials, the peak reduction in serum bicarbonate occurred by week 4, and in most subjects there was a correction of bicarbonate by week 56, without any change to study drug. However, if persistent metabolic acidosis develops, reduce the dose or taper to discontinue the dose. Hypokalemia risk may be aggravated by the use of diuretic therapy.[51256]

Weight loss may increase the risk of hypoglycemia in patients with type 2 diabetes mellitus treated with insulin and insulin secretagogues (e.g., sulfonylureas). Phentermine; topiramate has not been studied in combination with insulin. Blood glucose monitoring is warranted in patients with type 2 diabetes before starting and during phentermine; topiramate treatment. Dosage adjustments of anti-diabetic medications should be considered. If a patient develops hypoglycemia during treatment, adjust the anti-diabetic drug regimen accordingly.[51256] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, weight loss medications such as phentermine; topiramate should be considered as an adjunct to lifestyle therapy in all patients with type 2 diabetes as needed for weight loss sufficient to improve glycemic control, lipids, and blood pressure. During controlled trial evaluation of phentermine; topiramate as an adjunct to lifestyle therapy versus lifestyle therapy alone for diabetes prevention, a more significant weight loss and more profound reductions in incident diabetes occurred with medication plus lifestyle therapy than lifestyle therapy alone.[62881]

Topiramate has been associated with oligohidrosis and hyperthermia, infrequently resulting in hospitalization; most reports have been in pediatric patients. Decreased sweating and an elevation in body temperature above normal characterized these cases. Some of the cases have been reported with topiramate after exposure to elevated environmental temperatures. Therefore, patients taking phentermine; topiramate should be instructed to limit exposure to ambient temperature increase (i.e., elevated environmental temperature) or other temperature extremes that might aggravate temperature regulation. Proper hydration to help prevent oligohidrosis and hyperthermia is suggested before and during strenuous exercise or exposure to warm temperatures. Use caution when prescribing with other drugs that predispose patients to heat-related disorders, such as anticholinergic medications and other carbonic anhydrase inhibitors.[51256]

Similar to other weight loss products,  phentermine; topiramate use is not likely to be appropriate in patients with eating disorders such as anorexia nervosa or bulimia nervosa. The AACE/ACE) Obesity Clinical Practice Guidelines state that there are insufficient data on the use of phentermine; topiramate in overweight or obese patients with binge eating disorder (BED); however, there is a possible benefit in BED based on studies with topiramate, and approved medications containing topiramate may be considered along with non-medication interventions (i.e., behavioral/lifestyle program, psychotherapy). The AACE/ACE Obesity Guidelines state that there are limited data available on the benefits of the use of phentermine; topiramate in patients following bariatric surgery.[62881]

Abrupt discontinuation of phentermine; topiramate, particularly at a dose of 15 mg/92 mg once daily, should be avoided since the withdrawal of topiramate has been associated with seizures, even in individuals without a history of seizures or epilepsy. If immediate discontinuation is medically necessary in any patient, careful monitoring and symptom management is warranted. Patients discontinuing higher-dose therapy due to a lack of efficacy should follow recommended tapering (e.g., every other day dosing for 1 week) to avoid precipitating a seizure.[51256]

Clinical studies of phentermine; topiramate did not include sufficient numbers of elderly subjects to determine whether they respond differently from younger subjects. In those studied, no age-related differences were observed. Nevertheless, use caution when selecting a dose for a geriatric patient, given their propensity to have concurrent disease states that may influence drug tolerability, usually starting at the low end of the dosing range.[51256] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, there are limited data on the use of phentermine; topiramate for weight reduction in the elderly and extra caution is advisable in this population. Elderly patients selected for weight loss therapy should have structured lifestyle interventions including reduced calorie meal plans and exercise, clear health-related goals including blood pressure reduction, diabetes prevention in high risk patients with pre-diabetes, and improvements in osteoarthritis, mobility, and physical functioning. Overweight or obese elderly patients being considered for a weight loss medication should be evaluated for osteopenia and sarcopenia.[62881]

Phentermine; topiramate is contraindicated during pregnancy because weight loss during pregnancy may result in fetal harm. Data from pregnancy registries and epidemiology studies indicate increased fetal risk with the use of topiramate; a risk in oral clefts (cleft lip with or without cleft palate) and a risk of being small for gestational age has been associated with in utero exposure. When multiple species of pregnant animals received topiramate at clinically relevant doses, structural malformations, including craniofacial defects, and reduced fetal weights occurred in offspring. In the North American Antiepileptic Drug (NAAED) Pregnancy Registry, topiramate-exposed infants had higher rates of major congenital malformations (4.1%) compared to infants exposed to a reference antiepileptic drug (AED) (1.8%) or in infants with mothers without epilepsy and without exposure to AEDs (1.1%). The presence of oral clefts was also higher in infants exposed to topiramate (1.4%) than infants exposed to a reference AED (0.3%) or those with mothers without epilepsy and without exposure to AEDs (0.11%). Topiramate-exposed newborns were also noted to be small for gestational age (defined as less than 10th percentile for body weight) when compared to newborns on a reference AED or born to mothers without epilepsy and without AED exposure (19.7% exposed to topiramate; 7.9% exposed to reference AED; 5.4% without exposure). The Qsymia Pregnancy Surveillance Program is a maternal-fetal outcomes program which monitors pregnancies that occur during therapy; providers and patients are encouraged to report pregnancies to the program by calling 1-888-998-4887. The effect of phentermine; topiramate on labor and obstetric delivery in humans is unknown. However, metabolic acidosis has been reported in patients treated with phentermine; topiramate and metabolic acidosis in pregnancy can cause decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the ability of the fetus to tolerate labor.[51256] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, phentermine; topiramate must not be used during pregnancy; discontinue the drug if pregnancy occurs.[62881]

Due to the reproductive risk, pregnancy testing is needed in patients who may become pregnant before starting phentermine; topiramate therapy and after that, monthly pregnancy testing is necessary during treatment to identify early pregnancy. There are risks to the fetus associated with early in utero exposure to topiramate. Contraception requirements also exist; individuals of reproductive potential should use adequate and effective contraception during therapy. Topiramate can reduce the efficacy of combination oral contraceptives and is associated with an increased risk of breakthrough bleeding; have patients report any change in their bleeding patterns. However, contraceptive efficacy can be decreased even in the absence of breakthrough bleeding. If phentermine; topiramate is inadvertently used during pregnancy, or if a patient becomes pregnant while on therapy, discontinue treatment immediately and inform the patient of the potential hazard to the fetus.[51256] [62881]

Both 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. Due to 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, breast-feeding is not recommended during phentermine; topiramate therapy.[51256] During lactation, first line weight loss strategies include a healthy diet and exercise, if appropriate. Sufficient calories and nutrition are important for proper lactation. The American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines recommend against the use of phentermine; topiramate if an individual is breast-feeding.[62881]

Periodically monitor for growth inhibition during phentermine; topiramate therapy in children and adolescents. Phentermine; topiramate is associated with a reduction in height velocity in obese pediatric patients 12 to 17 years. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted.[51256]

Phentermine; topiramate contains tartrazine dye; use with caution in patients with tartrazine dye hypersensitivity. 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.[51256]