Class

• Norepinephrine and dopamine reuptake inhibitor (phentermine) combined with a voltage-sensitive sodium channel modulator (topiramate); weight management medication

PHENTERMINE–TOPIRAMATE commonly prescribed for

(Bold for FDA approved)

How PHENTERMINE–TOPIRAMATE works

• Phentermine increases dopamine and norepinephrine by blocking both the dopamine and the norepinephrine transporters. In the hypothalamus, these 2 neurotransmitters activate POMC neurons, causing the release of POMC. POMC is then broken down into alpha-melanocytestimulating hormone, which binds to melanocortin 4 receptors to suppress appetite. However, stimulation of POMC neurons also activates an endogenous opioid-mediated negative feedback loop, which mitigates the appetite-suppressing effects.

• Theoretically, through modulation of voltage-sensitive sodium channels, topiramate may reduce glutamatergic stimulation and increase GABAergic inhibition in the appetite-stimulating pathway, resulting in net inhibition of this pathway. Such an action would synergize with simultaneous activation of the appetite- suppressing pathway by phentermine. This results in more robust and long-lasting appetite suppression than with either drug alone.

How long until PHENTERMINE–TOPIRAMATE works

• At least 3% weight loss is generally achieved after 14 weeks; at least 5% weight loss is generally achieved after an additional 12 weeks on maximum daily dose

Notable Side Effects

• Constipation, dry mouth

• Paresthesia, dizziness, dysgeusia, insomnia

• Visual field defects

• Cognitive impairment (may be more likely with rapid titration or high initial doses)

Life Threatening Side Effects

• Hypoglycemia

• Increased heart rate

• Metabolic acidosis

• Kidney stones

• Secondary angle-closure glaucoma

• Rare severe dermatologic reactions (purpura, Stevens–Johnson syndrome)

• Oligohidrosis and hyperthermia (more common in children)

• Sudden unexplained deaths have occurred in epilepsy (unknown if related to topiramate use)

• Rare activation of suicidal ideation and behavior (suicidality)

• Effect on cardiovascular morbidity and mortality has not been established

weight gain

unusual

sedation

unusual

What to do about PHENTERMINE–TOPIRAMATE side effects

• Wait

• Avoid dosing in evening due to the possibility of insomnia

• In a few weeks, switch to another agent

usual dosage range

• 7.5 mg/46 mg once daily in the morning

Dosage Forms

• Capsule (phentermine mg/topiramate mg extended-release) 3.75 mg/23 mg, 7.5 mg/46 mg, 11.25 mg/69 mg, 15 mg/92 mg

long term use

• Has been evaluated in controlled studies up to 1 year

habit forming

• Phentermine is a Schedule IV drug

• Topiramate is not controlled in the Controlled Substances Act

Renal Impairment

• Maximum dose is 7.5 mg/46 mg per day in patients with moderate to severe impairment

• Not studied or recommended for use in patients with end-stage renal disease

Hepatic Impairment

• Maximum dose is 7.5 mg/46 mg per day in patients with moderate impairment

• Not recommended for use in patients with severe impairment

Cardiac Impairment

• Not systematically evaluated in patients with cardiac impairment

• Not recommended for patients with recent or unstable cardiac or cerebrovascular disease

Elderly

• Some patients may tolerate lower doses better

Children and Adolescents

• Safety and efficacy have not been established in children under the age of 12

Pregnancy

• Contraindicated

• There is an increased risk of cleft lip/palate with topiramate

Breast Feeding

• Some drug is found in mother’s breast milk

• Recommended to discontinue drug or formula feed