New FDA Approved: Qsymia – Side Effects

Qsymia (previously known as Qnexa) was approved by the U.S. Food and Drug Administration (FDA) on July 17, 2012. Qsymia was recommended for approval by FDA Endocrinologic and Metabolic Drug Advisory Committee on February 22, 2012 by a vote of 20:2 based on a favorable benefit-risk profile.1,2,3

Approved Indication: Obesity‚Ä® Treatment of obesity, including weight loss and maintenance of weight loss, in patients who are obese (BMI > 30 kg/m2) or overweight (BMI > 27 kg/m2) with co-morbidities such as hypertension, type 2 diabetes, or dyslipidemia.

Qsymia is also in phase 2 clinical development for the treatment of type 2 diabetes and obstructive sleep apnea.

Approved Strengths and Dosage Forms: Four strengths of Qsymia are available:

  • 3.75 mg phentermine/23 mg topiramate XR
  • 7.5 mg phentermine/46 mg topiramate XR
  • 11.25 mg phentermine/69 mg topiramate XR
  • 15 mg phentermine/92 mg topiramate XR

Dose: The recommended dose of Qsymia is 3.75 mg phentermine/23 mg topiramate XR daily for 14 days; then increase to 7.5 mg phentermine/46 mg topiramate XR.

Qsymia is available as an extended-release capsule and a controlled substance Schedule IV drug due to the phentermine component.

Phentermine and topiramate are separately licensed for use in the United States. Both agents are available generically.

Qsymia Warnings And Precautions:

  • Fetal Toxicity: Pregnancy Category X – Negative pregnancy test required before treatment and monthly thereafter in females of reproductive potential; Qsymia is available through a limited program under a Risk Evaluation and Mitigation Strategy (REMS)
  • Increase in Heart Rate: Monitor heart rate in all patients, especially those with cardiac ort cerebrovascular disease.
  • Suicidal Behavior and Ideation: monitor for depression or suicidal thoughts and discontinue if symptoms develop.
  • Acute myopia and secondary angle closure glaucoma: discontinue Qsymia
  • Mood and sleep disorders: consider dose reduction or withdrawal for clinically significant or persistent symptoms.
  • Cognitive impairment: may cause attention or memory disturbances; caution if operating moving vehicle or hazardous machinery when starting treatment.
  • Metabolic acidosis: measure electrolytes before/during treatment.
  • Elevated creatinine: measure creatinine before/during treatment.
  • Use of Antidiabetic Medications: Weight loss may cause hypoglycemia. Measure serum glucose before/during treatment.

Commonly reported side effects include:

  • tingling, paraesthesia
  • dry mouth
  • insomnia
  • dizziness
  • constipation
  • altered taste/dysgeusia

Potentially serious side effects may include:

  • elevated heart rate
  • teratogenicity
  • suicidality risk
  • cognitive dysfunction
  • metabolic acidosis
  • low serum bicarbonate

There were 5 main safety concerns that arose when the original Qsymia NDA was submitted to the FDA and reviewed by the subcommittee in 2010. Subsequently, Vivus completed additional safety studies in the areas of cardiovascular risk assessment and teratogenicity.

Suicidality: A 2008 FDA analysis suggested the antiepileptic drug class (of which topiramate is a member) is associated with an increased risk of suicidality. In the Qsymia one year safety clinical trial, there was one report of suicidality in the active treatment group, and one in the placebo. There were no reported suicidality events in a 2-year safety cohort study. In both studies, there were no reported suicide attempts, suicidal behaviors, or instances of serious suicidal ideation.1,3

Cognitive-related adverse events: Topiramate at doses used for epilepsy and migraine prophylaxis is associated with cognitive related side effects such as confusion, psychomotor slowing, difficulty with concentration and attention, memory impairment, and language difficulties. A similar adverse event profile was demonstrated with Qsymia treatment, ranging in incidence from 2 to 7.8% dependent upon dose. The most common side effect related to cognitive dysfunction was disturbance in attention.1,3

Metabolic Acidosis: Clinical trials with topiramate monotherapy, as well as Qsymia clinical experience, demonstrated that in roughly 30% of patients topiramate can cause metabolic acidosis through inhibition of carbonic anhydrase resulting in levels <21 mEq/L. Consequences of untreated chronic metabolic acidosis may include hyperventilation, fatigue, anorexia, and increased risk for osteomalacia or osteoporosis, but the clinical importance of long-term low bicarbonate levels is unknown in this patient population.

Cardiovascular Risk: Qsymia has demonstrated statistically significant positive effects on blood pressure-lowering in clinical trials. However, in one (n=3879) and two year (n=675) safety cohorts, mean heart rates in the Qsymia groups increased 0.6 to 1.6 beats per minute (bpm). Additionally, 13.5 to 25.8 percent of the Qsymia group had increases in heart rates greater than 20 bpm, compared to 11.9 to 21.6 percent of placebo patients. FDA Advisory Committee members have expressed concern over the increased heart rate side effect noted with Qsymia, and the possibility that this might increase the risk for heart attack or stroke. Vivus has agreed to complete a large, prospective, post-approval clinical trial to assess these risks in an at-risk, obese population.

Teratogenicity Risk: Qsymia is contraindicated for use in women who are pregnant due to an elevated risk for teratogenicity with topiramate. Qsymia has been assigned Pregnancy Risk Category X. In FDA Advisory Committee meetings, the concern with teratogenicity focused on the 2- to 5-fold higher risk for oral clefts. A Risk Evaluation and Mitigation Strategy (REMS) program to address safety issues related to Qsymia will be administered by the manufacturer. Qsymia falls under a restricted distribution program to help prevent its use in pregnancy. Of note, all weight-loss products are being reclassified by the FDA as Pregnancy Category X (no benefit for use in pregnancy and potential risks) according the the Qnexa FDA docket.