ORMALVI

ORMALVI tablets, USP contain dichlorphenamide, an oral carbonic anhydrase inhibitor. Dichlorphenamide, USP a dichlorinated benzenedisulfonamide, is known chemically as 4, 5–dichloro-1,3-benzenedisulfonamide. Its empirical formula is C 6 H 6 Cl 2 N 2 O 4 S 2 and its structural formula is: Dichlorphenamide USP is a white or practically white, crystalline powder with a molecular weight of 305.16. It is very slightly soluble in water but soluble in dilute solutions of alkali carbonate and hydroxide. ORMALVI (dichlorphenamide) tablets, USP are supplied as tablets, for oral administration, each containing 50 mg dichlorphenamide. Inactive ingredients are lactose monohydrate, partially pregelatinized starch and magnesium stearate. FDA approved dissolution test specifications differ from USP. image description

ORMALVI is indicated for the treatment of primary hyperkalemic periodic paralysis, primary hypokalemic periodic paralysis, and related variants. ORMALVI is an oral carbonic anhydrase inhibitor indicated for the treatment of primary hyperkalemic periodic paralysis, primary hypokalemic periodic paralysis, and related variants ( 1 )

• Initiate dosing at 50 mg by mouth once or twice daily ( 2.1 ) • Titrate up or down dose based on individual response ( 2.1 ) • The minimum recommended dosage is 50 mg daily, and the maximum recommended dosage is 200 mg daily ( 2.1 ) • Evaluate response to ORMALVI after 2 months of treatment ( 2.2 ) 2.1 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. 2.2 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. 2.3 Monitoring to Assess Safety Baseline and periodic measurements of serum potassium and sodium bicarbonate during ORMALVI treatment is recommended [see Warnings and Precautions ( 5.3 , 5.4 )] .

ORMALVI is contraindicated in the following circumstances: Hypersensitivity to dichlorphenamide or other sulfonamides [see Warnings and Precautions ( 5.1 )] Concomitant use of ORMALVI and high dose aspirin [see Warnings and Precautions ( 5.2 ) and Drug Interactions ( 7.1 )] Severe pulmonary disease, limiting compensation to metabolic acidosis caused by ORMALVI [see Warnings and Precautions ( 5.4 )] Hepatic insufficiency: ORMALVI may aggravate hepatic encephalopathy. Hepatic insufficiency ( 4 ) Severe pulmonary obstruction ( 4 ) Hypersensitivity to dichlorphenamide or other sulfonamides ( 4 ) Concomitant use with high dose aspirin ( 4 )

The following serious adverse reactions are described elsewhere in labeling: Hypersensitivity and Other Life-Threatening Reactions [see Warnings and Precautions ( 5.1 )] Hypokalemia [see Warnings and Precautions ( 5.3 )] Metabolic Acidosis [see Warnings and Precautions ( 5.4 )] Falls [ see Warnings and Precautions ( 5.5 )] Most common adverse reactions (incidence at least 10% and greater than placebo) include paresthesias, cognitive disorder, dysgeusia, and confusional state ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Cycle Pharmaceuticals Ltd at 1-857-437-3969 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 1 Adverse Reaction Dichlorphenamide N = 36 (%) Placebo N = 29 (%) Nervous system disorders Paresthesia 44 14 Cognitive disorder 1 14 7 Dysgeusia 14 0 Confusional state 11 0 Headache 8 7 Hypoesthesia 8 0 Lethargy 8 0 Dizziness 6 0 Gastrointestinal disorders Diarrhea 6 3 Nausea 6 0 General disorders and administration site conditions Fatigue 8 0 Malaise 6 0 Investigations Weight decreased 6 0 Musculoskeletal and connective tissue disorders Muscle spasms 8 0 Arthralgia 6 3 Muscle twitching 6 0 Respiratory Dyspnea 6 0 Pharyngolaryngeal pain 6 0 Skin Rash 8 0 Pruritus 6 0 1 Cognitive disorder combined cases with the preferred terms of cognitive disorder, disturbance in attention, and mental impairment. 6.2 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. The following are adverse reactions which have been reported during postapproval use of dichlorphenamide and were serious or are not reported in the previous section of labeling [see Clinical Trials Experience ( 6.1 ) ] : amnesia, cardiac failure, condition aggravated, convulsion, hallucination, nephrolithiasis, pancytopenia, psychotic disorder, renal tubular necrosis, stupor, syncope, tremor.

Aspirin: anorexia, tachypnea, lethargy, and coma have been reported with concomitant use of dichlorphenamide and high-dose aspirin. The concomitant use of ORMALVI and high-dose aspirin is contraindicated. ORMALVI should be used with caution in patients receiving lower doses of aspirin ( 4 , 5.2 , 7.1 ) 7.1 Aspirin and Other Salicylates Carbonic anhydrase inhibitors, including ORMALVI, can cause metabolic acidosis [see Warning and Precautions ( 5.2 , 5.4 )] , 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 [see Contraindications ( 4 ) and Warnings and Precautions ( 5.2 )]. 7.2 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 [see Clinical Pharmacology ( 12.3 )]. 7.3 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) [see Warnings and Precautions ( 5.3 )]. 7.4 Drugs that Cause Metabolic Acidosis Coadministration of ORMALVI and other drugs that can cause metabolic acidosis may increase the severity of the acidosis [see Warnings and Precautions ( 5.4 )]. 7.5 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 [see Clinical Pharmacology ( 12.3 )] . Therefore, signs of dichlorphenamide toxicity should be monitored when administered with OAT1 or OAT3 inhibitors.