Side Effects of Qsymia (phentermine and topiramate extended-release)

Qsymia (phentermine and topiramate extended-release) is a combination of a sympathomimetic agent and an anti-seizure medication used to treat individuals who are overweight or obese, in conjunction with diet and exercise, to lose weight and keep the weight off. Phentermine is used by itself to treat obesity.

The exact mechanism by which phentermine works to promote weight loss is not understood, but it is thought to stimulate the release of chemicals from the hypothalamus, the area of the brain known to have a major role in regulating hunger and food intake. The release of these chemicals is thought to reduce appetite and decrease food intake.

Topiramate has been observed to be effective in causing weight loss. The precise mechanism by which topiramate works to stimulate weight loss is not yet understood.

However, similar to the actions of phentermine, topiramate is also thought to suppress appetite and make a person feel full even after eating less food than usual.

Use and distribution of Qsymia is under strict control by the federal government because it contains phentermine, a medicine that has a high potential for abuse and drug dependence. Qsymia is a schedule IV controlled substance. 

Common side effects of Qsymia include

• sensations of pricking, burning, tingling, or numbness of the skin;
• dizziness,
• blurred vision,
• fatigue,
• indigestion,
• urinary tract infections (UTIs),
• headache,
• nausea,
• back pain,
• taste disturbances,
• constipation, and
• dry mouth.

Serious side effects of Qsymia include

• mood changes,
• insomnia or trouble sleeping,
• problems with concentration or memory,
• speech difficulties,
• increased acid levels in the blood,
• low blood sugar especially in patients with type 2 diabetes mellitus who are also taking medicines to treat their blood sugar,
• seizures,
• kidney stones,
• decreased sweating, and
• fever.

Drug interactions of Qsymia include monoamine oxidase inhibitor (MAOIs), due to the risk of hypertensive crisis, a condition in which blood pressure becomes dangerously high and can cause organ damage or death.

Qsymia can alter blood concentrations of certain birth control medicines.

Taking Qsymia with alcohol or other CNS depressant drugs (such as barbiturates, benzodiazepines or anti-anxiety agents, and sleep medications) increases the risk of

• drowsiness,
• confusion,
• loss of coordination, and
• other central nervous system (CNS) depression symptoms.

Taking Qsymia with certain diuretics (water pills) such as hydrochlorothiazide may cause decreased levels of potassium in the blood (hypokalemia).

Qsymia decreases blood levels of carbamazepine and valproic acid.

Administration of topiramate, a component of Qsymia, with carbonic anhydrase inhibitors may increase levels of acid in the blood, which consequently may increase the risk of kidney stone formation.

Qsymia may cause birth defects and should not be used during pregnancy. Use of topiramate, a component of Qsymia, during pregnancy has been associated with an increased risk of oral clefts.

Females of reproductive age must have a negative pregnancy test before starting Qsymia and monthly thereafter while on Qsymia therapy. Additionally, females of reproductive age should use effective birth control methods during Qsymia therapy.

Qsymia may be excreted into human milk because topiramate, a component of Qsymia, is known to enter breast milk. Due to the potential risk of causing serious side effects in the nursing infant, a decision should be made to either stop breastfeeding or taking Qsymia.

The most common side effects of Qsymia are:

• Paraesthesia (sensations of pricking, burning, tingling, or numbness of the skin)
• Dizziness
• Blurred vision
• Fatigue
• Indigestion
• Urinary tract infections
• Headache
• Nausea
• Back pain
• Taste disturbances
• Insomnia or trouble sleeping
• Constipation
• Dry mouth

Rare, but serious side effects associated with Qsymia therapy include

• mood changes,
• trouble sleeping,
• problems with concentration or memory,
• speech difficulties,
• an increase in acid levels in the blood,
• low blood sugar, especially in patients with type 2 diabetes mellitus who are also taking medicines to treat their blood sugar,
• seizures,
• kidney stones,
• decreased sweating, and
• fever.

The following important adverse reactions are described below and elsewhere in the labeling:

• Fetal Toxicity
• Elevation in Heart Rate
• Suicidal Behavior and Ideation
• Acute Angle Closure Glaucoma
• Mood and Sleep Disorders
• Cognitive Impairment
• Metabolic Acidosis

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 reflects exposure to Qsymia in two, 1-year, randomized, double-blind, placebo-controlled, multicenter clinical trials, and two Phase 2 supportive trials in 2318 adult patients (936 [40.4%] patients with hypertension, 309 [13.3%] patients with type 2 diabetes, 808 [34.9%] patients with BMI greater than 40 kg/m²) exposed for a mean duration of 298 days.

Common Adverse Reactions

Adverse reactions occurring at a rate of greater than or equal to 5% and at a rate at least 1.5 times placebo include

• paraesthesia,
• dizziness,
• dysgeusia,
• insomnia,
• constipation, and
• dry mouth.

Adverse reactions reported in greater than or equal to 2% of Qsymia-treated patients and more frequently than in the placebo group are shown in Table 3.

Table 3. Adverse Reactions Reported in Greater Than or Equal to 2% of Patients and More Frequently than Placebo during 1 Year of Treatment – Overall Study Population

Paraesthesia/Dysgeusia

• Reports of paraesthesia, characterized as tingling in hands, feet, or face, occurred in 4.2%, 13.7%, and 19.9% of patients treated with Qsymia 3.75 mg/23 mg, 7.5 mg/46 mg, and 15 mg/92 mg, respectively, compared to 1.9% of patients treated with placebo.
• Dysgeusia was characterized as a metallic taste, and occurred in 1.3%, 7.4%, and 9.4% of patients treated with Qsymia 3.75 mg/23 mg, 7.5 mg/46 mg, and 15 mg/92 mg, respectively, compared to 1.1% of patients treated with placebo.
• The majority of these events first occurred within the initial 12 weeks of drug therapy; however, in some patients, events were reported later in the course of treatment.
• Only Qsymia-treated patients discontinued treatment due to these events (1% for paraesthesia and 0.6% for dysgeusia).

Mood And Sleep Disorders

• The proportion of patients in 1-year controlled trials of Qsymia reporting one or more adverse reactions related to mood and sleep disorders was 15.8%, 14.5%, and 20.6% with Qsymia 3.75 mg/23 mg, 7.5 mg/46 mg, and 15 mg/92 mg, respectively, compared to 10.3% 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 6.7%, 8.1%, and 11.1% of patients treated with Qsymia 3.75 mg/23 mg, 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 4.6%, 4.8%, and 7.9% of patients treated with Qsymia 3.75 mg/23 mg, 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 5.0%, 3.8%, and 7.6% of patients treated with Qsymia 3.75 mg/23 mg, 7.5 mg/46 mg, and 15 mg/92 mg, respectively, compared to 3.4% of patients treated with placebo.
• The majority of these events first occurred within the initial 12 weeks of drug therapy; however, in some patients, events were reported later in the course of treatments.
• In the Qsymia clinical trials, the overall prevalence of mood and sleep adverse reactions was approximately twice as great in patients with a history of depression compared to patients without a history of depression; however, the proportion of patients on active treatment versus placebo who reported mood and sleep adverse reactions was similar in these two subgroups.
• Occurrence of depression-related events was more frequent in patients with a past history of depression across all treatment groups. However, the placebo-adjusted difference in incidence of these events remained constant between groups regardless of previous depression history.

Cognitive Disorders

• In the 1-year controlled trials of Qsymia, the proportion of patients who experienced one or more cognitive-related adverse reactions was 2.1% for Qsymia 3.75 mg/23 mg, 5.0% for Qsymia 7.5 mg/46 mg, and 7.6% for Qsymia 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 typically began within the first 4 weeks of treatment, had a median duration of approximately 28 days or less, and were reversible upon discontinuation of treatment; however, individual patients did experience events later in treatment, and events of longer duration.

Laboratory Abnormalities

Serum Bicarbonate

• In the 1-year controlled trials of Qsymia, the incidence of persistent treatment-emergent 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 8.8% for Qsymia 3.75 mg/23 mg, 6.4% for Qsymia 7.5 mg/46 mg, and 12.8% for Qsymia 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 1.3% for Qsymia 3.75 mg/23 mg, 0.2% for Qsymia 7.5 mg/46 mg dose, and 0.7% for Qsymia 15 mg/92 mg dose, compared to 0.1% for placebo.
• Generally, decreases in serum bicarbonate levels were mild (average 1-3 mEq/L) and occurred early in treatment (4-week visit), however severe decreases and decreases later in treatment occurred.

Serum Potassium

• In the 1-year controlled trials of Qsymia, 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 0.4% for Qsymia 3.75 mg/23 mg, 3.6% for Qsymia 7.5 mg/46 mg dose, and 4.9% for Qsymia 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 0.0% for Qsymia 3.75 mg/23 mg, 0.2% for Qsymia 7.5 mg/46 mg dose, and 0.7% for Qsymia 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 0.0% of subjects receiving Qsymia 3.75 mg/23 mg, 0.2% receiving Qsymia 7.5 mg/46 mg dose, and 0.1% receiving Qsymia 15 mg/92 mg dose, compared to 0.0% receiving placebo.
• Hypokalemia was reported by 0.4% of subjects treated with Qsymia 3.75 mg/23 mg, 1.4% of subjects treated with Qsymia 7.5 mg/46 mg, and 2.5% of subjects treated with Qsymia 15 mg/92 mg compared to 0.4% of subjects treated with placebo.
• “Blood potassium decreased” was reported by 0.4% of subjects treated with Qsymia 3.75 mg/23 mg, 0.4% of subjects treated with Qsymia 7.5 mg/46 mg, 1.0% of subjects treated with Qsymia 15 mg/92 mg, and 0.0% of subjects treated with placebo.

Serum Creatinine

• In the 1-year controlled trials of Qsymia, there was a dose-related increase from baseline, peaking between Week 4 to 8, which 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 was 2.1% for Qsymia 3.75 mg/23 mg, 7.2% for Qsymia 7.5 mg/46 mg, and 8.4% for Qsymia 15 mg/92 mg, compared to 2.0% for placebo.
• Increases in serum creatinine of greater than or equal to 50% over baseline occurred in 0.8% of subjects receiving Qsymia 3.75 mg/23 mg, 2.0% receiving Qsymia 7.5 mg/46 mg, and 2.8% receiving Qsymia 15 mg/92 mg, compared to 0.6% receiving placebo.

Nephrolithiasis

• In the 1-year controlled trials of Qsymia, the incidence of nephrolithiasis was 0.4% for Qsymia 3.75 mg/23 mg, 0.2% for Qsymia 7.5 mg/46 mg, and 1.2% for Qsymia 15 mg/92 mg, compared to 0.3% for placebo.

Drug Discontinuation Due To Adverse Reactions

• In the 1-year placebo-controlled clinical studies, 11.6% of Qsymia 3.75 mg/23 mg, 11.6% of Qsymia 7.5 mg/46 mg, 17.4% of Qsymia 15 mg/92 mg, and 8.4% of placebo-treated patients discontinued treatment due to reported adverse reactions.
• The most common adverse reactions that led to discontinuation of treatment are shown in Table 4.

Table 4. Adverse Reactions Greater Than or Equal To 1% Leading to Treatment Discontinuation (1-Year Clinical Trials)

Postmarketing Experience

• The following adverse reactions have been reported during post approval use of phentermine and topiramate, the components of Qsymia.
• 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.

Qsymia

Psychiatric Disorders

Suicidal ideation, Suicidal behavior

Ophthalmic disorders

Acute angle closure glaucoma
Increased intraocular pressure

Phentermine

Allergic adverse reactions

Urticaria

Cardiovascular adverse reactions

Elevation of blood pressure, Ischemic events

Central nervous system adverse reactions

Euphoria, Psychosis, Tremor

Reproductive adverse reactions

Changes in libido, Impotence

Topiramate

Dermatologic disorders

Bullous skin reactions (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), Pemphigus

Gastrointestinal disorders

Pancreatitis

Hepatic disorders

Hepatic failure (including fatalities), Hepatitis

Metabolic disorders

Hyperammonemia
Hypothermia

Ophthalmic disorders

Maculopathy

Monoamine Oxidase Inhibitors

• Use of phentermine is contraindicated during or within 14 days following the administration of monoamine oxidase inhibitors because of the risk of hypertensive crisis.

Oral Contraceptives

• Co-administration of multiple-dose Qsymia 15 mg/92 mg once daily with a single dose of oral contraceptive containing 35 µg ethinyl estradiol (estrogen component) and 1 mg norethindrone (progestin component), in obese otherwise healthy volunteers, decreased the exposure of ethinyl estradiol by 16% and increased the exposure of norethindrone by 22%.
• Although this study did not specifically address the impact of the interaction on contraceptive efficacy, an increased risk of pregnancy is not anticipated.
• The primary determinant of contraceptive efficacy is the progestin component of the combination oral contraceptive, so higher exposure to the progestin would not be expected to be deleterious.
• However, irregular bleeding (spotting) may occur more frequently due to both the increased exposure to the progestin and lower exposure to the estrogen, which tends to stabilize the endometrium.
• Patients should be informed not to discontinue their combination oral contraceptive if spotting occurs, but to notify their healthcare provider if the spotting is troubling to them.

CNS Depressants Including Alcohol

• Specific drug interaction studies of Qsymia and alcohol or other CNS depressant drugs have not been performed.
• The concomitant use of alcohol or CNS depressant drugs (e.g., barbiturates, benzodiazepines, and sleep medications) with phentermine or topiramate may potentiate CNS depression such as dizziness or cognitive adverse reactions, or other centrally mediated effects of these agents.
• Therefore, if Qsymia is used with alcohol or other CNS depressants, the patient should be counseled regarding possible increased risk of CNS depression or side effects.

Non-Potassium Sparing Diuretics

• Concurrent use of Qsymia with non-potassium sparing diuretics may potentiate the potassium-wasting action of these diuretics.
• Concomitant administration of hydrochlorothiazide alone with topiramate alone has been shown to increase the Cmax and AUC of topiramate by 27% and 29%, respectively.
• When prescribing Qsymia in the presence of non-potassium-sparing medicinal products, patients should be monitored for hypokalemia.

Antiepileptic Drugs

• Concomitant administration of phenytoin or carbamazepine with topiramate in patients with epilepsy, decreased plasma concentrations of topiramate by 48% and 40%, respectively, when compared to topiramate given alone.
• Concomitant administration of valproic acid and topiramate has been associated with hyperammonemia with and without encephalopathy. Concomitant administration of topiramate with valproic acid in patients has also been associated with hypothermia (with and without hyperammonemia).
• It may be prudent to examine blood ammonia in patients in whom the onset of hypothermia or encephalopathy has been reported.

Carbonic Anhydrase Inhibitors

• Concomitant use of topiramate, a component of Qsymia, with any other carbonic anhydrase inhibitor (e.g., zonisamide, acetazolamide, or dichlorphenamide) may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation.
• Avoid the use of Qsymia with other drugs that inhibit carbonic anhydrase.

Drug Abuse And Dependence

Controlled Substance

• Qsymia is controlled in Schedule IV of the Controlled Substances Act because it contains phentermine a Schedule IV drug.
• Any material, compound, mixture, or preparation that contains any quantity of phentermine is controlled as a Schedule IV drug.
• Topiramate is not controlled in the Controlled Substances Act.

Abuse

• Phentermine, a component of Qsymia, has a known potential for abuse.
• Phentermine, a component of Qsymia, is related chemically and pharmacologically to the amphetamines.
• Amphetamines and other stimulant drugs have been extensively abused and the possibility of abuse of phentermine should be kept in mind when evaluating the desirability of including Qsymia as part of a weight reduction program.
• 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 many times more than recommended.

Dependence

• Qsymia has not been systematically studied for its potential to produce physical dependence.
• Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use.
• Physical dependence manifests by drug-class-specific withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug.
• Limited information on the potential for physical dependence for the individual components of Qsymia is available.
• For topiramate, abrupt discontinuation has been associated with seizures in patients without a history of seizures or epilepsy.
• For phentermine, abrupt cessation 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 Qsymia is required, appropriate medical monitoring is recommended.