Ormalvi

Description for 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 C₆H₆Cl₂N₂O₄S₂ 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.

Uses for Ormalvi

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

Dosage for Ormalvi

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 [see WARNINGS AND PRECAUTIONS].

HOW SUPPLIED

Dosage Forms And Strengths

White to off-white, round shaped, flat faced beveled edged tablet, scored on one side, engraved with ‘ZD’ above the score and ‘50’ below the score, the other side is plain.

Storage And Handling

Each ORMALVI (dichlorphenamide) tablet USP, 50 mg is white to off-white, round shaped, flat faced beveled edged tablet, scored on one side, engraved with ‘ZD’ above the score and ‘50’ below the score, the other side is plain.

ORMALVI (dichlorphenamide) tablets are supplied as follows:

Bottles of 100 NDC 70709-085-10

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].

Manufactured by: ZENARA PHARMA PVT. LTD., Hyderabad-500051, INDIA. Manufactured for: CYCLE PHARMACEUTICALS LT,DThe Broers Building, 21 JJ Thomson Ave, Cambridge, CB3 0FA, United Kingdom, AW000307. Revised: Feb 2024

Side Effects for Ormalvi

The following serious adverse reactions are described elsewhere in labeling:

• Hypersensitivity and Other Life-Threatening Reactions [see WARNINGS AND PRECAUTIONS]
• Hypokalemia [see WARNINGS AND PRECAUTIONS]
• Metabolic Acidosis [see WARNINGS AND PRECAUTIONS]
• Falls [see WARNINGS AND PRECAUTIONS]

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 ORMALVI, with rates greater than placebo, were paresthesia, cognitive disorder, dysgeusia, and confusional state. The mean dose of ORMALVI 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 ORMALVI and more commonly than in patients treated with placebo in Study 1.

Table 1: Adverse Reactions in Patients Treated with ORMALVI with Incidence 5% and more common than in Patients Treated with Placebo in Study 1

	Adverse Reaction	ORMALVI N = 36 (%)	Placebo N = 29 (%)
Nervous system disorders	Paresthesia	44	14
	Cognitive disorder1	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
1Cognitive disorder combined cases with the preferred terms of cognitive disorder, disturbance in attention, and mental impairment.

Postmarketing Experience

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]: amnesia, cardiac failure, condition aggravated, convulsion, hallucination, nephrolithiasis, pancytopenia, psychotic disorder, renal tubular necrosis, stupor, syncope, tremor.

Drug Interactions for Ormalvi

Aspirin And Other Salicylates

Carbonic anhydrase inhibitors, including ORMALVI, can cause metabolic acidosis [see WARNINGS AND PRECAUTIONS], 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 lowdose aspirin should be carefully monitored [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].

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].

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].

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].

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]. Therefore, signs of dichlorphenamide toxicity should be monitored when administered with OAT1 or OAT3 inhibitors.

Warnings for Ormalvi

Included as part of the PRECAUTIONS section.

Precautions for Ormalvi

Hypersensitivity And Other Life-threatening Reactions

Fatalities associated with the administration of sulfonamides have occurred because of adverse reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. Pulmonary involvement can occur in isolation or as part of a systemic reaction.

ORMALVI should be discontinued at the first appearance of skin rash or any sign of immune-mediated or other life-threatening adverse reaction.

Concomitant Use Of Aspirin Or Other Salicylates

Carbonic anhydrase inhibitors, including ORMALVI, can cause metabolic acidosis [see WARNINGS AND PRECAUTIONS], 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, the concomitant use of ORMALVI and high-dose aspirin is contraindicated. Patients with concomitant use of ORMALVI and low-dose aspirin should be carefully monitored.

Hypokalemia

ORMALVI increases potassium excretion and can cause hypokalemia. The risk of hypokalemia is greater when ORMALVI is used in patients with conditions associated with hypokalemia (e.g., adrenocortical excess, renal tubular acidosis type 1 and 2), and in patients receiving other drugs that may cause hypokalemia [see DRUG INTERACTIONS].

Baseline and periodic measurements of serum potassium during ORMALVI treatment is recommended.

If hypokalemia develops or persists, consideration should be given to reducing the dose or discontinuing ORMALVI and correction of potassium levels.

Metabolic Acidosis

ORMALVI can cause hyperchloremic non-anion gap metabolic acidosis. Concomitant use of ORMALVI with other drugs that cause metabolic acidosis may increase the severity of acidosis. Concomitant use of ORMALVI in compensated patients with respiratory acidosis, such as in advanced lung diseases, may lead to respiratory decompensation.

Baseline and periodic measurements of serum bicarbonate during ORMALVI treatment are recommended.

If metabolic acidosis develops or persists, consideration should be given to reducing the dose or discontinuing ORMALVI [see DRUG INTERACTIONS].

Falls

ORMALVI increases the risk of falls. The risk of falls is greater in the elderly and with higher doses of ORMALVI. Consider dose reduction or discontinuation of ORMALVI in patients who experience falls while treated with ORMALVI.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Studies to assess the carcinogenic potential of dichlorphenamide have not been conducted.

Mutagenesis

Studies to assess the genotoxicity of dichlorphenamide have not been conducted.

Impairment Of Fertility

Studies to assess the effects of dichlorphenamide on fertility have not been conducted.

Use In Specific Populations

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 2% to 4%, and 15% to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

ORMALVI treatment can cause metabolic acidosis [see WARNINGS AND PRECAUTIONS]. 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 ) basis. A no-effect dose for adverse effects on embryofetal development has not been established.

Lactation

Risk Summary

There are no data on the presence of dichlorphenamide in human milk, the effects on the breastfed infant, or the effects on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ORMALVI and any potential adverse effects on the breastfed infant from ORMALVI or from the underlying maternal condition.

Pediatric Use

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

Geriatric Use

The risk of falls and of metabolic acidosis are greater in elderly patients [see WARNINGS AND PRECAUTIONS].

Overdose Information for Ormalvi

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.

Contraindications for Ormalvi

ORMALVI is contraindicated in the following circumstances:

• Hypersensitivity to dichlorphenamide or other sulfonamides [see WARNINGS AND PRECAUTIONS]
• Concomitant use of ORMALVI and high dose aspirin [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS]
• Severe pulmonary disease, limiting compensation to metabolic acidosis caused by ORMALVI [see WARNINGS AND PRECAUTIONS]
• Hepatic insufficiency: ORMALVI may aggravate hepatic encephalopathy.

Clinical Pharmacology for Ormalvi

Mechanism Of Action

Dichlorphenamide is a carbonic anhydrase inhibitor. However, the precise mechanism by which dichlorphenamide exerts its therapeutic effects in patients with primary periodic paralysis is unknown.

Pharmacodynamics

ORMALVI can cause metabolic acidosis, which can increase the risk of salicylate toxicity with coadministration [see WARNINGS AND PRECAUTIONS]. ORMALVI-induced metabolic acidosis can also increase in severity with coadministration of other drugs that cause metabolic acidosis [see WARNINGS AND PRECAUTIONS].

Pharmacokinetics

After single-dose administration in healthy subjects in fasted state, dichlorphenamide Cmax and AUC increased in a dose-proportional manner within the range of 25 mg to 400 mg (2 times the maximum recommended dose). The steady-state is expected to be achieved within 10 days of twice-daily dosing.

Absorption

The median time to reach maximum concentration (Tmax) of dichlorphenamide was about 1.5 to 3 hours postdose after both single and multiple dose administrations.

Distribution

The plasma protein binding of dichlorphenamide is approximately 88%.

Elimination

Following a single-dose administration, mean terminal half-life was in the range of 32 to 66 hours.

Metabolism

Dichlorphenamide is not a substrate for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 isoforms when tested in vitro.

Drug Interaction Studies

In vitro Assessment Of Drug Interactions

Drug-Metabolizing Enzyme Inhibition

Dichlorphenamide is not an inhibitor for CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4 enzymes when tested in vitro.

Drug-Metabolizing Enzyme Induction

Dichlorphenamide is not an inducer for CYP1A2, 2B6, or 3A4 enzymes when tested in vitro.

In vitro Assessment Of Transporter-Drug Interactions

Dichlorphenamide is neither a substrate nor inhibitor for p-gp, BCRP, OATP1B1, OATP1B3, OAT2, OAT4, OCT1, OCT2, MATE1, or MATE2-K when tested in vitro.

Dichlorphenamide is not an inhibitor of OAT3, but is an inhibitor of OAT1 based on in vitro studies [see DRUG INTERACTIONS].

Dichlorphenamide is a substrate for transporters OAT1 and OAT3 based on in vitro studies [see DRUG INTERACTIONS].

In Vivo Drug Interactions

The use of dichlorphenamide in combination with high-dose aspirin is contraindicated as it may lead to salicylate toxicity. The mechanism(s) of this interaction is not known.

Specific Populations

Geriatrics

The pharmacokinetics of dichlorphenamide in the elderly has not been determined.

Clinical Studies

The efficacy of ORMALVI was evaluated in two clinical studies, Study 1 and Study 2.

Study 1

Study 1 was a 9-week, double-blind, placebo-controlled multi-center study. Study 1 consisted of two substudies: a substudy in patients with hypokalemic periodic paralysis (n=44), and a substudy in patients with hyperkalemic periodic paralysis (n=21). The primary efficacy endpoint in both substudies was the average number of self-reported attacks of muscle weakness per week over the final 8 weeks of the trial. Withdrawal from the study for acute severe worsening (increase in attack frequency or severity) was also assessed as an endpoint.

In Study 1, the dose of ORMALVI was 50 mg b.i.d. for treatment-naïve patients. Patients already on dichlorphenamide prior to the study continued on the same dose while on ORMALVI during the study. In patients taking acetazolamide prior to the study, the dose of ORMALVI was set at 20% of the acetazolamide dose. Dose reduction for tolerability was permitted.

Hypokalemic Periodic Paralysis Substudy Of Study 1

In the hypokalemic periodic paralysis substudy, median age of patients was 45 years and 73% of patients were male. Patients treated with ORMALVI (n=24) had 2.2 fewer attacks per week than patients (n=20) treated with placebo (p=0.02). None of the patients randomized to ORMALVI reached the endpoint of withdrawal from the study for acute worsening, vs. five patients randomized to placebo. The mean dose of ORMALVI at Week 9 was 94 mg/day.

Hyperkalemic Periodic Paralysis Substudy Of Study 1

In the Hyperkalemic Periodic Paralysis substudy, median age of patients was 43 years and 43% of patients were male. During the double-blind treatment period, patients treated with ORMALVI (n=12) had 3.9 fewer attacks per week than patients (n=9) treated with placebo (p=0.08). None of the patients randomized to ORMALVI reached the endpoint of withdrawal from the study for acute worsening, vs. two patients randomized to placebo. The mean dose of ORMALVI at Week 9 was 82 mg/day.

Study 2

Study 2 was a 35-week, double-blind, placebo-controlled, multi-center, two-period crossover study. Study 2 also consisted of two substudies: a substudy in patients with hypokalemic periodic paralysis (n=42), and a substudy in patients with hyperkalemic periodic paralysis (n=31), including patients with Paramyotonia Congenita. The primary endpoint in the hypokalemic periodic paralysis substudy was the incidence of acute intolerable worsening (based on attack frequency or severity) necessitating withdrawal. The primary endpoint in the hyperkalemic periodic paralysis substudy was the average number of self-reported attacks of muscle weakness per week. Dosing was determined similarly to Study 1.

Hypokalemic Periodic Paralysis Substudy Of Study 2

The hypokalemic periodic paralysis substudy included patients with a mean age of 38 years; 79% of patients were male. Acute intolerable worsening was observed in 2 patients on ORMALVI vs. 11 patients on placebo (p=0.02). The mean dose of ORMALVI at the end of the study was 96 mg/day.

Hyperkalemic Periodic Paralysis Substudy Of Study 2

The hyperkalemic periodic paralysis substudy included patients with a mean age of 37 years; and 79% of patients were male. Patients treated had 2.3 fewer attacks per week on ORMALVI than on placebo (p=0.006). The mean dose of ORMALVI at the end of the study was 73 mg/day.

Patient Information for Ormalvi

Worsening Of Symptoms

Advise patients to notify their physician if they experience acute worsening of symptoms of periodic paralysis.

Hypersensitivity And Other Life-threatening Reactions

Inform patients that hypersensitivity and immune mediated reactions can occur with ORMALVI, and could be fatal. Advise patients to discontinue ORMALVI and notify their healthcare provider immediately if they develop a rash or signs and symptoms of anaphylaxis or other life-threatening reactions [see WARNINGS AND PRECAUTIONS].

Drug Interactions

Instruct patients to notify their healthcare provider of all of the drugs and over-thecounter medications that they take and to not take aspirin or other salicylates without first discussing with their healthcare provider [see DRUG INTERACTIONS].

Metabolic Acidosis

Instruct patients to contact their healthcare provider immediately if they develop possible manifestations of metabolic acidosis (e.g., fast breathing, fatigue/tiredness, loss of appetite, or irregular heart beat or palpitations) [see WARNINGS AND PRECAUTIONS].

Falls

Inform patients that ORMALVI can increase their risk of falls [see WARNINGS AND PRECAUTIONS].

Cognitive Impairment

Advise patients to notify their healthcare provider if they experience symptoms of cognitive impairment including confusion and memory lapse [see ADVERSE REACTIONS].

Driving And Operating Machinery

ORMALVI may cause drowsiness/fatigue in some patients [see ADVERSE REACTIONS]. Caution patients on the potential for impaired ability to drive and operate machinery.