FINTEPLA: Package Insert and Label Information

FINTEPLA- fenfluramine solution
Zogenix, Inc.

WARNING: VALVULAR HEART DISEASE and PULMONARY ARTERIAL HYPERTENSION

There is an association between serotonergic drugs with 5-HT2B receptor agonist activity, including fenfluramine (the active ingredient in FINTEPLA), and valvular heart disease and pulmonary arterial hypertension [see Warnings and Precautions (5.1, 5.2)].

Echocardiogram assessments are required before, during, and after treatment with FINTEPLA. The benefits versus the risks of initiating or continuing FINTEPLA must be considered, based on echocardiogram findings [see Dosage and Administration (2.1, 2.4) and Warnings and Precautions (5.1, 5.2)].

Because of the risks of valvular heart disease and pulmonary arterial hypertension, FINTEPLA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the FINTEPLA REMS [see Warnings and Precautions (5.3)].

1 INDICATIONS AND USAGE

FINTEPLA is indicated for the treatment of seizures associated with Dravet syndrome in patients 2 years of age and older.

2 DOSAGE AND ADMINISTRATION

2.1 Assessments Prior to Initiating FINTEPLA

Prior to starting treatment with FINTEPLA, obtain an echocardiogram assessment to evaluate for valvular heart disease and pulmonary arterial hypertension [see Dosage and Administration (2.4) and Warnings and Precautions (5.1, 5.2)].

2.2 Dosing Information

  • FINTEPLA is to be administered orally and may be taken with or without food.
  • The initial starting and maintenance dosage is 0.1 mg/kg twice daily, which can be increased weekly based on efficacy and tolerability. Table 1 provides the recommended titration schedule, if needed.
  • Patients not on concomitant stiripentol who are tolerating FINTEPLA at 0.1 mg/kg twice daily and require further reduction of seizures may benefit from a dosage increase up to a maximum recommended maintenance dosage of 0.35 mg/kg twice daily (maximum daily dosage of 26 mg).
  • Patients taking concomitant stiripentol and clobazam who are tolerating FINTEPLA at 0.1 mg/kg twice daily and require further reduction of seizures may benefit from a dosage increase up to a maximum recommended maintenance dosage of 0.2 mg/kg twice daily (maximum daily dosage of 17 mg) [see Drug Interactions (7.1)].
Table 1: FINTEPLA Recommended Titration Schedule*
* For patients not on concomitant stiripentol in whom a more rapid titration is warranted, the dose may be increased every 4 days
Without concomitant stiripentol* With concomitant stiripentol and clobazam
Weight-based Dosage Maximum Total Daily Dosage Weight-based Dosage Maximum Total Daily Dosage
Initial Dosage 0.1 mg/kg twice daily 26 mg 0.1 mg/kg twice daily 17 mg
Day 7 0.2 mg/kg twice daily 26 mg 0.15 mg/kg twice daily 17 mg
Day 14 0.35 mg/kg twice daily 26 mg 0.2 mg/kg twice daily 17 mg

2.3 Assessments During and After Administration of FINTEPLA

To evaluate for valvular heart disease and pulmonary arterial hypertension, obtain an echocardiogram assessment every 6 months during treatment with FINTEPLA, and 3 to 6 months after the final dose of FINTEPLA [see Warnings and Precautions (5.1, 5.2)].

2.4 Administration Instructions

A calibrated measuring device (either a 3 mL or 6 mL oral syringe) will be provided by the pharmacy and is recommended to measure and administer the prescribed dose accurately [see How Supplied/Storage and Handling (16.1)]. A household teaspoon or tablespoon is not an adequate measuring device and should not be used.

Discard any unused FINTEPLA oral solution remaining after 3 months of first opening the bottle or the “Discard After” date on the bottle, whichever is sooner.

FINTEPLA is compatible with commercially available gastric and nasogastric feeding tubes.

2.5 Discontinuation of FINTEPLA

When discontinuing FINTEPLA, the dose should be decreased gradually. As with all antiepileptic drugs, abrupt discontinuation should be avoided when possible to minimize the risk of increased seizure frequency and status epilepticus [see Warnings and Precautions (5.7)].

3 DOSAGE FORMS AND STRENGTHS

Oral solution: 2.2 mg/mL fenfluramine as a clear, colorless, cherry flavored liquid.

4 CONTRAINDICATIONS

FINTEPLA is contraindicated in patients with:

  • Hypersensitivity to fenfluramine or any of the excipients in FINTEPLA [see Description (11)]
  • Concomitant use of, or within 14 days of the administration of monoamine oxidase inhibitors because of an increased risk of serotonin syndrome [see Warnings and Precautions (5.8)]

5 WARNINGS AND PRECAUTIONS

5.1 Valvular Heart Disease

Because of the association between serotonergic drugs with 5-HT2B receptor agonist activity, including fenfluramine (the active ingredient in FINTEPLA), and valvular heart disease, cardiac monitoring is required prior to starting treatment, during treatment, and after treatment with FINTEPLA concludes. Cardiac monitoring via echocardiogram can identify evidence of valvular heart disease prior to a patient becoming symptomatic, aiding in early detection of this condition. In clinical trials of up to 3 years in duration, no patient receiving FINTEPLA developed valvular heart disease [see Boxed Warning and Adverse Reactions (6.1)].

Monitoring
Prior to starting treatment, patients must undergo an echocardiogram to evaluate for valvular heart disease.

Echocardiograms should be repeated every 6 months, and once 3-6 months post-treatment with FINTEPLA.

If valvular heart disease is observed on an echocardiogram, the prescriber must consider the benefits versus the risks of initiating or continuing treatment with FINTEPLA.

FINTEPLA is available only through a restricted program under a REMS [see Warnings and Precautions (5.3)].

5.2 Pulmonary Arterial Hypertension

Because of the association between serotonergic drugs with 5-HT2B receptor agonist activity, including fenfluramine (the active ingredient in FINTEPLA), and pulmonary arterial hypertension, cardiac monitoring is required prior to starting treatment, during treatment, and after treatment with FINTEPLA concludes. Cardiac monitoring via echocardiogram can identify evidence of pulmonary arterial hypertension prior to a patient becoming symptomatic, aiding in early detection of this condition. In clinical trials of up to 3 years in duration, no patient receiving FINTEPLA developed pulmonary arterial hypertension [see Boxed Warning and Adverse Reactions (6.1)].

MonitoringPrior to starting treatment, patients must undergo an echocardiogram to evaluate for pulmonary arterial hypertension.

Echocardiograms should be repeated every 6 months, and once 3-6 months post-treatment with FINTEPLA.

If pulmonary arterial hypertension is observed on an echocardiogram, the prescriber must consider the benefits versus the risks of initiating or continuing treatment with FINTEPLA.

FINTEPLA is available only through a restricted program under a REMS [see Warnings and Precautions (5.3)].

5.3 FINTEPLA REMS Program

FINTEPLA is available only through a restricted distribution program called the FINTEPLA REMS program because of the risk of valvular heart disease and pulmonary arterial hypertension [see Warnings and Precautions (5.1, 5.2)].

Notable requirements of the FINTEPLA REMS Program include:

  • Prescribers must be certified by enrolling in the FINTEPLA REMS program.
  • Prescribers must counsel patients receiving FINTEPLA about the risk of valvular heart disease and pulmonary arterial hypertension, how to recognize signs and symptoms of valvular heart disease and pulmonary arterial hypertension, the need for baseline (pretreatment) and periodic cardiac monitoring via echocardiogram during FINTEPLA treatment, and cardiac monitoring after FINTEPLA treatment.
  • Patients must enroll in the REMS program and comply with ongoing monitoring requirements [see Warnings and Precautions (5.1, 5.2)].
  • The pharmacy must be certified by enrolling in the REMS program and must only dispense to patients who are authorized to receive FINTEPLA.
  • Wholesalers and distributers must only distribute to certified pharmacies.

Further information is available at www.FinteplaREMS.com or by telephone at 1-877-964-3649.

5.4 Decreased Appetite and Decreased Weight

FINTEPLA can cause decreases in appetite and weight. In Study 1 and Study 2 combined, approximately 37% of patients treated with FINTEPLA reported, as an adverse reaction, decreased appetite and approximately 9% reported decreased weight, as compared to 8% and 1%, respectively, of patients on placebo [see Adverse Reactions (6.1)]. By the end of the controlled studies, 19% of patients treated with FINTEPLA had a measured decrease in weight of 7% or greater from their baseline weight, compared to 2% of patients on placebo. This measured decrease in weight appeared to be dose-related, with 26% of patients on FINTEPLA 0.7 mg/kg/day, 19% of patients on FINTEPLA 0.4 mg/kg/day in combination with stiripentol, and 13% of patients taking FINTEPLA 0.2 mg/kg/day experiencing at least a 7% decrease in weight from baseline. Most patients resumed the expected measured increases in weight by the end of the open-label extension study. Given the frequency of these adverse reactions, the growth of pediatric patients treated with FINTEPLA should be carefully monitored. Weight should be monitored regularly during treatment with FINTEPLA and dose modifications should be considered if a decrease in weight is observed.

5.5 Somnolence, Sedation, and Lethargy

FINTEPLA can cause somnolence, sedation, and lethargy. In Study 1 and Study 2 combined, the incidence of somnolence, sedation, and lethargy was 25% in patients treated with FINTEPLA, compared with 11% of patients on placebo. In general, these effects may diminish with continued treatment [see Adverse Reactions (6.1)].

Other central nervous system (CNS) depressants, including alcohol, could potentiate these effects of FINTEPLA. Prescribers should monitor patients for somnolence and sedation and should advise patients not to drive or operate machinery until they have gained sufficient experience on FINTEPLA to gauge whether it adversely affects their ability to drive or operate machinery.

5.6 Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs) increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with an AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs that did not include FINTEPLA showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as 1 week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs.

Table 2: Risk of Suicidal Thoughts or Behaviors by Indication for Antiepileptic Drugs in the Pooled Analysis
Indication Placebo Patients with Events Per 1000 Patients Drug Patients with Events Per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/ Incidence in in Placebo Patients Risk Difference: Additional Drug Patients with Events per 1000 Patients
Epilepsy 1.0 3.4 3.5 2.4
Psychiatric 5.7 8.5 1.5 2.9
Other 1.0 1.8 1.9 0.9
Total 2.4 4.3 1.8 1.9

The relative risk for suicidal thoughts or behavior was higher in clinical trials in patients with epilepsy than in clinical trials in patients with psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing FINTEPLA or any other AED must balance the risk of suicidal thoughts or behaviors with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

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