Berotralstat: Uses, Dosage, Side Effects and Interactions

Berotralstat is a groundbreaking, once-daily oral medication that has transformed the management of hereditary angioedema (HAE). As the first oral long-term prophylactic therapy for HAE, it offers an effective and convenient alternative to previous treatments, which were often injectable or less tolerable. Understanding how berotralstat works, its optimal use, potential side effects, and key drug interactions is essential both for patients and healthcare professionals. This article provides a comprehensive, evidence-based overview, synthesizing the latest research to answer your most important questions about berotralstat.

Uses of Berotralstat

Berotralstat is specifically designed to address the unmet needs of people living with hereditary angioedema (HAE), a rare and potentially life-threatening condition characterized by unpredictable swelling attacks. Unlike traditional therapies that focus on treating acute attacks, berotralstat is used for long-term prevention, helping patients regain control over their lives.

Indication	Patient Group	Benefits	Sources
HAE Prophylaxis	≥12 yrs, C1-INH Def.	Reduces attack frequency	1 3 6 7 8
HAE Type I/II	Adolescents/Adults	Oral, convenient, first-line	3 4 5 8
HAE-nC1-INH, AAE	Selected patients	Reduced attacks (real world)	4 5

Table 1: Main Uses of Berotralstat

What Conditions Does Berotralstat Treat?

Berotralstat is approved for the prevention of hereditary angioedema (HAE) attacks in patients aged 12 years and older with HAE due to C1 inhibitor deficiency (types I and II). It is not intended for treating acute attacks but rather as a daily medication to lower the frequency and severity of swelling episodes 1 3 6 7 8.

While clinical trials focused on HAE with C1 inhibitor deficiency, real-world studies suggest potential benefits in patients with other forms of angioedema, such as acquired C1-inhibitor deficiency (AAE-C1-INH) and HAE with normal C1-INH (HAE-nC1-INH), although these uses are not yet formally approved 4 5.

How Does Berotralstat Work?

Berotralstat is a highly selective oral inhibitor of plasma kallikrein, a key enzyme in the pathway that leads to the excessive production of bradykinin—a peptide responsible for causing the swelling and pain in HAE 1 2 3 8. By blocking this enzyme, berotralstat prevents attacks before they start.

Key advantages include:

• Oral Administration: A once-daily pill, eliminating the need for injections 1 3 5 8.
• Convenience and Adherence: Improved quality of life, as shown by patient-reported outcomes 4 5 8.
• First-line Prophylaxis: Recognized as a first-line option for long-term prevention of HAE attacks 3 8.

Benefits in Real-World Practice

Multiple studies and real-world data confirm that berotralstat substantially reduces the number of angioedema attacks, improves disease control, and enhances quality of life across diverse patient groups 3 4 5 8. The medication is particularly valued for its ease of use, which supports better adherence.

Dosage of Berotralstat

Dosing is an essential consideration for maximizing the effectiveness and safety of berotralstat. The recommended regimen is straightforward, but understanding the rationale and nuances helps ensure optimal results.

Dose	Frequency	Patient Age	Notes/Effectiveness	Sources
150 mg	Once daily	≥12 years	Preferred, most effective	1 3 6 7 8
110 mg	Once daily	≥12 years	Alternative, less used	1 3 6 8
With food	Daily	All	Improves absorption	6

Table 2: Berotralstat Dosage Summary

Standard Dosage Recommendations

• Recommended Dose: 150 mg orally, once daily with food, for patients aged 12 years and older 1 3 6 7 8.
• Alternative Dose: 110 mg once daily may be used in specific cases (e.g., tolerability issues), but 150 mg provides the most favorable benefit-risk profile and is generally preferred 1 3 6 8.

Administration Tips

• Take With Food: Berotralstat should always be taken with food to enhance absorption and minimize gastrointestinal side effects 6.
• Consistency: Take at the same time each day to maintain steady blood levels.

Dose Adjustments

• Renal or Hepatic Impairment: There is limited data on dosage adjustments in patients with severe liver or kidney impairment. Caution is advised, and clinical monitoring is recommended 8.
• Transition from Androgens: When switching from long-term androgen therapy, monitor liver function tests—especially if the transition period is short (<14 days)—as rare elevations in liver enzymes have been observed 9.

Missed Dose

• If a dose is missed, take it as soon as remembered on the same day. Do not double up on doses 6.

Side Effects of Berotralstat

Like all medications, berotralstat can cause side effects. Fortunately, most are mild to moderate, transient, and manageable. Understanding the potential adverse effects helps patients make informed decisions and know when to seek medical attention.

Side Effect	Frequency	Severity	Sources
Abdominal pain	Common	Mild-Moderate	1 3 5 7 8
Diarrhea	Common	Mild-Moderate	1 3 5 7 8
Nausea/Vomiting	Common	Mild-Moderate	1 5 7 8
Headache	Occasional	Mild	8
Respiratory infections	Occasional	Mild-Moderate	3 7 8
Arthralgia/Back pain	Less common	Mild	1 3
Liver enzyme increase	Rare	May be serious	9
Discontinuation (AEs)	~8%	Usually GI-related	8

Table 3: Common and Notable Side Effects

Most Frequently Reported Side Effects

The most commonly reported adverse effects in clinical trials and real-world studies include:

• Gastrointestinal symptoms: Abdominal pain, diarrhea, nausea, and vomiting are the most frequent side effects, often occurring early in treatment and usually resolving with continued use 1 3 5 7 8.
• Headache and upper respiratory infections: These are also seen but tend to be mild 3 7 8.

Severity and Duration

• Most side effects are mild to moderate and transient.
• Serious adverse events related to the drug are rare 1 3 5 7 8.
• Approximately 8% of patients discontinued berotralstat due to adverse events, most commonly gastrointestinal symptoms 8.

Rare and Serious Adverse Effects

• Liver Enzyme Elevation: Rare increases in alanine aminotransferase (ALT) have been observed, especially in patients transitioning quickly from androgen therapy. These were reversible and no cases led to lasting harm 9.
• Serious Drug-Related Events: Very rare, but include potential for severe liver-related side effects, particularly in the context of recent androgen use 9.

Patient Experience and Quality of Life

• Most patients report high satisfaction with treatment, as the side effects are generally well tolerated and outweighed by the benefits of fewer HAE attacks and improved quality of life 5 8.
• Real-world data confirms these findings, with the majority of patients either experiencing no side effects or only mild, transient symptoms 5.

Interactions of Berotralstat

Drug interactions are an important consideration, especially for patients on multiple medications. While berotralstat is generally safe, attention to certain interactions and special populations is warranted.

Interaction	Effect	Recommendation	Sources
Androgens	↑ Liver risk	Monitor, allow washout	9
Liver metabolism	CYP enzymes involved	Caution with inducers	8 9
Other HAE meds	Data limited	Avoid unless necessary	6 8

Table 4: Notable Drug Interactions

Interactions with Androgen Therapy

• Transition Caution: Patients switching from long-term androgen therapy to berotralstat should have liver function monitored, particularly if the washout period is less than 14 days. Rare but significant elevations in liver enzymes have occurred in this group 9.
• Recommendation: Allow for a washout period, if possible, and monitor liver enzymes during the transition 9.

Interactions via Liver Metabolism

• CYP Enzyme Involvement: Berotralstat is metabolized in the liver primarily by CYP2D6 and CYP3A4 enzymes 8.
  • Strong CYP3A4 Inducers: Drugs like rifampin may reduce berotralstat effectiveness.
  • Strong CYP2D6 or CYP3A4 Inhibitors: These may increase berotralstat levels and risk of side effects.
• Recommendation: Caution is advised when using berotralstat with strong inducers or inhibitors of these enzymes 8 9.

Concomitant HAE Medications

• Acute Attack Treatments: Berotralstat is not for acute attacks; other therapies such as C1-inhibitor infusions or icatibant may be used as rescue medications if needed 6.
• Combining Prophylaxis: There is limited data on using berotralstat with other long-term HAE prophylactic agents; this is generally not recommended unless specifically advised by a specialist 6 8.

Other Considerations

• Renal and Hepatic Impairment: As berotralstat is metabolized in the liver, caution is warranted in patients with hepatic impairment. Data in severe cases are limited 8.
• Food Interactions: Should be taken with food to optimize absorption and minimize gastrointestinal side effects 6.

Conclusion

Berotralstat represents a significant advance in the long-term management of hereditary angioedema, offering an effective, convenient, oral prophylactic option. Here’s what you need to remember:

• Primary Use: Prevention of HAE attacks in patients ≥12 years old with C1-INH deficiency 1 3 6 7 8.
• Dosing: 150 mg once daily with food is preferred; 110 mg is an alternative for specific patients 1 3 6 8.
• Side Effects: Most are mild and transient, particularly gastrointestinal symptoms; serious adverse events are rare 1 3 5 7 8.
• Interactions: Monitor liver function when transitioning from androgens; caution with CYP450 inducers/inhibitors 8 9.
• Patient Benefit: Substantial reduction in HAE attacks, improved quality of life, and high treatment satisfaction 3 4 5 8.

By understanding how to use berotralstat safely and effectively, patients and clinicians can work together to manage hereditary angioedema and enhance everyday life.