Ormalvi Drug Information

ORMALVI is indicated for the treatment of primary hyperkalemic periodic paralysis, primary hypokalemic periodic paralysis, and related variants.

Dosage Information

Initiate dosing at 50 mg by mouth once or twice daily. The dosage may be increased or decreased based on individual response, at weekly intervals (or sooner in case of adverse reaction). The minimum recommended total daily dosage is 50 mg, and the maximum recommended total daily dosage is 200 mg.

Monitoring to Assess Effectiveness

Primary hyperkalemic periodic paralysis, primary hypokalemic periodic paralysis, and related variants are a heterogeneous group of conditions, for which the response to ORMALVI may vary. Therefore, prescribers should evaluate the patient's response to ORMALVI after 2 months of treatment to decide whether ORMALVI should be continued.

Monitoring to Assess Safety Baseline and periodic measurements of serum potassium and sodium bicarbonate during ORMALVI treatment is recommended.

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 trials of another drug and may not reflect the rates observed in practice. In a 9-week randomized controlled trial in adults with hyperkalemic or hypokalemic periodic paralysis (Study 1), the most common adverse reactions in patients treated with dichlorphenamide, with rates greater than placebo, were paresthesia, cognitive disorder, dysgeusia, and confusional state. The mean dose of dichlorphenamide was 94 mg/day in patients with hypokalemic periodic paralysis and 82 mg/day in patients with hyperkalemic periodic paralysis.

Table 1 lists the incidence of adverse reactions that occurred in 5% of patients treated with dichlorphenamide and more commonly than in patients treated with placebo in Study 1. Table 1: Adverse Reactions in Patients Treated with Dichlorphenamide with Incidence 5% and more common than in Patients Treated with Placebo in Study Cognitive disorder combined cases with the preferred terms of cognitive disorder, disturbance in attention, and mental impairment.

Postmarketing Experience

Adverse reactions have been identified during postapproval use of dichlorphenamide. 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.

Aspirin and Other Salicylates

Carbonic anhydrase inhibitors, including ORMALVI, can cause metabolic acidosis, which can increase the risk of salicylate toxicity. Anorexia, tachypnea, lethargy, and coma have been reported with concomitant use of dichlorphenamide and high-dose aspirin. Therefore, concomitant use of ORMALVI and high-dose aspirin is contraindicated.

Patients with concomitant use of ORMALVI and low-dose aspirin should be carefully monitored.

Drugs that are Substrates of Organic Anion Transporter1 (OAT1) In vitro, dichlorphenamide is an inhibitor of OAT1 transporters. The concomitant administration of ORMALVI may increase the plasma exposures of OAT1 substrates. Use of ORMALVI with drugs that are sensitive to OAT1 inhibition (e.g., methotrexate, famotidine, oseltamivir) is not recommended.

Drugs that Cause Hypokalemia

The risk of hypokalemia is greater with coadministration of ORMALVI and other drugs that can cause hypokalemia (e.g., loop diuretics, thiazide diuretics, laxatives, antifungals, penicillins, and theophylline).

Drugs that Cause Metabolic Acidosis Coadministration of ORMALVI and other drugs that can cause metabolic acidosis may increase the severity of the acidosis.

Drugs that are Inhibitors of OAT1 or OAT3 An in vitro transporter study indicated that dichlorphenamide is a substrate of human transporters OAT1 and OAT3. Therefore, signs of dichlorphenamide toxicity should be monitored when administered with OAT1 or OAT3 inhibitors.

Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of ORMALVI in pregnant women. A no-effect dose has not been established. Dichlorphenamide was teratogenic when administered orally to pregnant rats.

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Clinical Considerations Fetal/Neonatal adverse reactions ORMALVI treatment can cause metabolic acidosis.

The effect of dichlorphenamide-induced metabolic acidosis has not been studied in pregnancy; however, metabolic acidosis in pregnancy (due to other causes) can cause decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus’ ability to tolerate labor. Pregnant patients should be monitored for metabolic acidosis and treated as in the nonpregnant state. Newborns of mothers treated with ORMALVI should be monitored for metabolic acidosis because of possible occurrence of transient metabolic acidosis following birth.

Labor or Delivery Although the effect of ORMALVI on labor and delivery in humans has not been established, the development of dichlorphenamide-induced metabolic acidosis in the mother and/or in the fetus might affect the fetus’ ability to tolerate labor. Data Animal Data Teratogenic effects (fetal limb reduction defects) were reported following oral administration of dichlorphenamide to pregnant rats during organogenesis at 350 mg/kg, or 17 times the maximum recommended human dose (200 mg/day) on a body surface area (mg/m 2 ) basis.

Pediatric Use Safety and effectiveness of ORMALVI in pediatric patients have not been established.

• ORMALVI is contraindicated in the following circumstances: Hypersensitivity to dichlorphenamide or other sulfonamides Concomitant use of ORMALVI and high dose aspirin Severe pulmonary disease, limiting compensation to metabolic acidosis caused by ORMALVI Hepatic insufficiency: ORMALVI may aggravate hepatic encephalopathy. Hepatic insufficiency Severe pulmonary obstruction Hypersensitivity to dichlorphenamide or other sulfonamides Concomitant use with high dose aspirin

Symptoms of overdosage or toxicity may include drowsiness, anorexia, nausea, vomiting, dizziness, ataxia, tremor, and tinnitus. In the event of overdosage, induce emesis or perform gastric lavage. The electrolyte disturbances most likely to be encountered from overdosage are hypokalemia and hyperchloremic metabolic acidosis.