Primary Periodic Paralysis (PPP) Information

Primary Periodic Paralysis PPP is a genetic condition that can be progressive and debilitating1,2

A group of rare channelopathies manifesting as recurrent attacks of muscle weakness or temporary paralysis often precipitated by triggers

  • This condition includes a spectrum of chronic, autosomal-dominant neuromuscular disorders caused by mutations in the skeletal muscle sodium, calcium, and potassium channel genes3
  • Muscle weakness or temporary paralysis is caused by depolarization of the muscle sarcolemma, which in turn causes sodium channel inactivation and reduced fiber excitability3
  • Primary Periodic Paralysis PPP is very rare, with only ~4,000 to 5,000 diagnosed individuals in the US4
Read a white paper about PPP morbidity and consequences.

Educational segment on Primary Periodic Paralysis

Strongbridge Biopharma sponsored an educational segment about Primary Periodic Paralysis on The Balancing Act, “Behind the Mystery: Rare and Genetic Diseases.” The segment features Linda Feld, Vice President of Periodic Paralysis Association (PPA), and Steve Cannon, MD, PhD, neurologist and professor of physiology at UCLA. A broad range of topics related to Primary Periodic Paralysis are addressed within the segment, including symptoms, triggers, misdiagnosis, and genetic testing.

There are several subtypes of Primary Periodic Paralysis PPP with varying prevalence3

Hyperkalemic (~1 in 200,000)3,5

Common symptoms include attacks of weakness in the limbs and elevated serum levels of potassium as the potassium shifts from the muscle to the extracellular space. Sometimes serum potassium levels can remain normal.

Hypokalemic (~1 in 100,000)3,6

Typically manifests as flaccid muscle weakness that can last for at least several hours. Serum levels of potassium usually decrease as the potassium shifts from the extracellular space to skeletal muscle.

Paramyotonia congenita (PMC) (<1 in 100,000)1,7

Patients may present with sustained muscle tensing that prevents muscles from relaxing. PMC can present with elevated or normal serum potassium levels.

Andersen-Tawil syndrome (ATS) (1 in 1 million)3*

Serum potassium levels can be low, high, or normal. Other characteristics include abnormal skeletal features and cardiac abnormalities such as ventricular arrhythmias, prolonged QT interval, and prominent U waves.

*Patients with ATS were not included in clinical trials for KEVEYIS.

PPP triggers can vary from patient to patient, and from one type of PPP to another1,3

Although there are many different PPP triggers, some of the common ones include:
  • Certain foods or beverages that are high in salt, carbohydrates, or potassium
  • Stress or fatigue
  • Exposure to cold temperatures or cold air
  • Periods of inactivity
  • Resting after exercise

There are more possible triggers of PPP attacks.3

Work with your patients to determine their individual triggers.

Stefanie, living with PPP, discusses her triggers in adolescence

Signs and symptoms are often nonspecific, and may have varying clinical presentations among patients1,2

Attacks can vary considerably between patients

Attacks can range in severity. In a study* of patients with hyperkalemic periodic paralysis surveyed about their disease1:

  • 43.3% said the majority of their attacks were mild (defined as “some limitations on mobility, others would notice I am in an attack”)1
  • 15.6% said their attacks were either severe (defined as “can speak, cannot move at all, can call for help”) or very severe (defined as “cannot speak, cannot call for help”)1

Attacks also often range in frequency2†:

  • In this survey, the frequency of attacks was 59% weekly, 28% daily, and no attacks in 11%
  • As patients age, the frequency of attacks may either increase or decrease; however, in about two-thirds of patients in one study, there was no change in frequency2
  • *Based on a survey of 137 adults (>18 years of age) with a diagnosis of hyperkalemic PPP and a genetic diagnosis. Percentages are based on the total number of respondents who answered a given question.1
  • Based on a survey of 66 self-selected patients over the age of 40 years with a clinical diagnosis of PPP who sought support via the internet.2

PPP can have a significant impact on patients’ everyday lives1

Symptoms can persist after attacks have subsided: Patients have reported experiencing lingering symptoms, including weakness, extreme fatigue, muscle pain, and clumsiness.1‡

The burden of PPP attacks is not only physical: Living with PPP can be stressful, and since stress can trigger attacks, it may compound the problem. Furthermore, the fear of unpredictable future attacks can cause social anxiety in patients.1

Over time, uncontrolled PPP may lead to persistent muscle weakness: In addition to attacks, persistent muscle weakness—constant weakness that can occur independently of attacks and becomes more likely in the fifth and sixth decades of life—may develop as muscle atrophies.2,9

  • These symptoms need to be considered within the overall treatment plan. No treatment for Primary Periodic Paralysis PPP is indicated to address all of these symptoms.
To learn more about PPP and its impact on patients’ lives, review the PPP white paper series.

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Indication

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

Important Safety Information

Contraindications
  • Hypersensitivity to dichlorphenamide or other sulfonamides
  • Concomitant use of KEVEYIS and high-dose aspirin
  • Severe pulmonary disease, limiting compensation to metabolic acidosis caused by KEVEYIS
  • Hepatic insufficiency: KEVEYIS may aggravate hepatic encephalopathy
Warnings and Precautions

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.
  • Discontinue KEVEYIS 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 anhydrous inhibitors, including KEVEYIS, 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.
  • Concomitant use of KEVEYIS and high-dose aspirin is contraindicated. Use with caution and carefully monitor in patients receiving low-dose aspirin.

Hypokalemia

  • KEVEYIS increases potassium excretion and can cause hypokalemia.
  • The risk of hypokalemia is greater when KEVEYIS 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 (e.g., loop diuretics, thiazide diuretics, laxatives, antifungals, penicillin, and theophylline).
  • Baseline and periodic measurements of serum potassium are recommended.
  • If hypokalemia develops or persists, consider reducing the dose or discontinuing KEVEYIS and correction of potassium levels.

Metabolic Acidosis

  • KEVEYIS can cause hyperchloremic non-anion gap metabolic acidosis.
  • Concomitant use of KEVEYIS with other drugs that cause metabolic acidosis may increase the severity of acidosis.
  • Concomitant use of KEVEYIS 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 KEVEYIS treatment are recommended.
  • If metabolic acidosis develops or persists, consider reducing the dose or discontinuing KEVEYIS.

Falls

  • KEVEYIS increases the risk of falls; risk is greater in the elderly and with higher doses.
  • Consider dose reduction or discontinuation of KEVEYIS in patients who experience falls while treated with KEVEYIS.
Pregnancy and Lactation

Use during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is not known in humans whether dichlorphenamide is excreted in human milk; exercise caution when administered to a nursing woman.

Adverse Reactions

The most common adverse reactions seen in clinical trials (incidence ≥ 10% and greater than placebo) include paresthesias, cognitive disorder, dysgeusia, and confusional state.

References

  1. Charles G, Zheng C, Lehmann-Horn F, Jurkat-Rott K, Levitt J. Characterization of hyperkalemic periodic paralysis: a survey of genetically diagnosed individuals. J Neurol. 2013;260:2606-2613.
  2. Cavel-Greant D, Lehmann-Horn F, Jurkat-Rott K. The impact of permanent muscle weakness on quality of life in periodic paralysis: a survey of 66 patients. Acta Myol. 2012;31:126–133.
  3. Statland JM, Fontaine B, Hanna MG, et al. Review of the diagnosis and treatment of periodic paralysis. Muscle Nerve. 2018;57:522-530.
  4. Data on file. Feasterville-Trevose, PA: Strongbridge Biopharma; 2017.
  5. Cannon SC. Channelopathies of skeletal muscle excitability. Compr Physiol. 2015;5:761–790.
  6. Cheng C-J, Kuo E, Huang C-L. Extracellular potassium homeostasis: insights from hypokalemic periodic paralysis. Semin Nephrol. 2013;33:237-247.
  7. National Institutes of Health. Paramyotonia congenita. Available at: https://ghr.nlm.nih.gov/condition/paramyotonia-congenita. Accessed March 19, 2020.
  8. Weber F, Jurkat-Rott K, Lehmann-Horn F. Hyperkalemic Periodic Paralysis. GeneReviews®. NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health. 2016.
  9. Jurkat-Rott K, Weber M-A, Fauler M, et al. K+-dependent paradoxical membrane depolarization and Na+ overload, major and reversible contributors to weakness by ion chanel leaks. Proc Natl Acad Sci. 2009;106:4036-4041.