Gepirone ER (Exxua): Uses, Dose, MOA, Side Effects, FDA Approval

Gepirone ER (Exxua) got FDA approval on 22 September 2023 for the treatment of patients with major depression [Ref].

Gepirone is the first oral 5 HT-1A receptor agonist. It is similar to Buspirone which is also one of the safe drugs used to treat generalized anxiety disorder.

The major advantage of Gepirone ER (Exxua) over other conventional antidepressants is that it does not cause sexual dysfunction. In fact, it enhances sexual function [Ref].

Gepirone ER (Exxua) Indications:

The FDA has approved Gepirone ER for treating patients with major depression.

Gepirone ER (Exxua) Dose:

The recommended starting dose is 18.2 mg orally once daily with food.

The dose may be increased in increments on day 4, day 7, and day 14 to 36.3 mg, 54.5 mg, and 72.6 mg respectively.

The maximum recommended dose is 72.6 mg orally once daily with food.

In older patients, the recommended dose is 18.2 mg which may be increased to the maximum of 36.3 mg after one week if it is well tolerated.

Dose Modification in Special Situations:

 Exxua dose needs to be adjusted in patients with renal or hepatic impairment and in patients on drugs that inhibit the enzyme CYP3A4.

Exxua Dose in Renal Impairment:

The renal dose of Exxua needs adjustment only if the CrCl is 50 ml/minute or less. In patients with kidney impairment, the starting dose is 18.2 mg orally once a day for 7 days.

The dose may then be increased after 7 days to 36.3 mg once daily.

It is advisable not to exceed 36.3 mg in patients with kidney disease.

Exxua Dose in Hepatic Impairment:

Exxua dose in patients with mild hepatic impairment, Child Class A, is similar to normal individuals.

In patients with Child Class B, the starting dose is 18.2 mg orally once a day for 7 days.

The dose may then be increased after 7 days to 36.3 mg once daily.

In patients with severe hepatic impairment, Child Class C, Exxua use is not recommended.

Exxua Dose in Patients on Concomitant CYP3A4 Inhibitors:

The dose of Exxua is reduced to half (50%) in patients who are on concomitant moderate CYP3A4 inhibitors.

In those who are taking strong CYP3A4 inhibitors, the concomitant use of Exxua is not recommended.

Use in Pregnancy and Breastfeeding Women:

Because of limited data regarding its use in pregnant and breastfeeding women, it is best to avoid Exxua in these patients.

How To Switch From Gepirone to MAO Inhibitors or Vice Versa:

Gepirone and MAO inhibitors are not recommended to be taken together. Combining both may result in serotonin syndrome which can be life-threatening.

Giving a gap of at least 14 days between the two drugs is recommended. If Exxua treatment is planned, MAO inhibitors should be stopped and after 14 days, treatment with Exxua can be safely initiated.

Gepirone ER Side Effects and Contraindications:

Gepirone is contraindicated in the following situations:

• A person who is allergic to the drug
• Patients with severe (Child Class C) hepatic impairment
• Those on strong CYP3A4 inhibitors
• Concomitant use with MAO inhibitors
• Patients with congenital or acquired prolonged QT interval.

• Suicidal thoughts:

Suicidal ideations are common in people who are depressed. Also, people on antidepressants are likely to have more frequent suicidal thoughts than the general population.

Like SSRIs, Exxua use has also been associated with suicidal thoughts and ideas. However, they are common in individuals who are younger than 24 years of age.

Older individuals have a relatively reduced incidence of suicides and suicidal thoughts and ideas.

Caregivers and family members must be cautious and notify any unusual behavior.

• QT prolongation:

QT interval prolongation has been observed with Exxua. The manufacturer recommends avoiding treatment with Exxua if the baseline QTc is 450 msec or more.

In addition, treatment should also be avoided in patients with severe hepatic impairment and those on concomitant strong CYP3A4 inhibitors.

Other patients who should be cautious include:

• Patients with electrolyte imbalances such as hypokalemia, hypomagnesemia, and hypocalcemia.
• Those with a recent myocardial infarction or heart failure.
• Patients with bradyarrhythmias
• Those with angina, uncontrolled hypertension, uncontrolled hypothyroidism, AV block, and aortic stenosis

ECG is recommended before treatment initiation and when dose escalation is required.

• Serotonin Syndrome:

Serotonin syndrome is a life-threatening condition. It can occur in patients who are on drugs that increase the serotonin levels.

Patients are more at risk of serotonin syndrome if they are on more than one SSRI. Serotonin syndrome is also common when Exxua is combined with a tricyclic antidepressant (TCA).

Patients may develop high-grade fever, hypertonia, rigidity, altered mental status, and dysautonomia manifesting as rapid changes in blood pressure and heart rate.

If serotonin syndrome, treatment should be stopped immediately.

• Mania and Hypomania:

Mania or hypomania may develop in patients on Exxua. It is more common in patients with a personal or a family history of bipolar disorder.

• Other side effects:

The most frequent side effects reported in clinical trials were:

• Dizziness
• Nausea
• Headache
• Sleepiness
• Tiredness
• Insomnia, and 
• Diarrhea

These side effects were present in 10% or more of the patients taking Exxua.

Less common side effects which affected 5% to 10% of the individuals taking Exxua are:

• Respiratory tract infection
• Dry mouth
• Vomiting
• Abdominal pain
• Increased satiety
• Dyspepsia

Rare side effects reported in less than 5% of the patients included:

• Constipation
• Nasal symptoms
• Paraesthesia
• excessive sweating
• Weight gain
• Agitation and Jitteriness
• Palpitations and increased heart rate
• Abnormal thinking
• Breast tenderness, and
• Abnormal sleep

Gepirone MOA (Mechanism of Action):

Gepirone acts on the serotonin receptors both on the presynaptic and post-synaptic membranes.

It is very similar in its mechanism of action to Buspirone. However, Gepirone (Exxua) is much more specific compared to Buspirone.

In addition, it binds with great affinity with the presynaptic membranes and has a partial agonistic activity on the post-synaptic receptors.

Unlike Buspirone, it has little dopaminergic effects as it does not bind as effectively to D2 receptors as Buspirone.

• Bioavailability:

14 to 17%

• Steady-state plasma concentration:

It takes 2 to 4 days to reach a steady state concentration in the plasma after taking it daily.

• Protein-binding:

72%

• Excretion:

81% in urine and 13% in feces