Emicizumab

Usage

• Emicizumab is prescribed for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and children (including newborns) with hemophilia A (congenital factor VIII deficiency), with or without factor VIII inhibitors.
• Pharmacological classification: Bispecific monoclonal antibody, antihemophilic agent.
• Mechanism of Action: Emicizumab is a bispecific antibody that mimics the cofactor function of activated factor VIII (FVIIIa). It bridges activated factor IX (FIXa) and factor X (FX), facilitating the activation of FX to FXa, a critical step in the coagulation cascade, thus restoring the function of missing or deficient activated FVIII needed for effective hemostasis.

Alternate Names

• INN: emicizumab
• Brand Name: Hemlibra

How It Works

• Pharmacodynamics: Emicizumab restores the function of missing activated factor VIII by bridging FIXa and FX. This promotes thrombin generation and clot formation.
• Pharmacokinetics:
  • Administered subcutaneously.
  • Absorption: Bioavailability is approximately 80%.
  • Metabolism: Emicizumab, like other IgG antibodies, is primarily catabolized through intracellular proteolysis.
  • Elimination: The half-life is approximately 4 to 5 weeks and can persist for months. The primary elimination route is unknown.
• Mode of Action: Emicizumab is a bispecific, humanized monoclonal antibody that binds to both activated factor IX and factor X. It facilitates the activation of factor X by factor IXa, bypassing the need for factor VIIIa.
• Receptor Binding: Emicizumab binds to activated factor IX and factor X.
• Enzyme Inhibition: Not applicable.
• Neurotransmitter Modulation: Not applicable.
• Elimination pathways: Primarily catabolized through intracellular proteolysis, like other IgG antibodies, with the exact elimination pathway remaining unknown.

Dosage

Standard Dosage

Adults and Children:

• Loading dose: 3 mg/kg subcutaneously once weekly for the first 4 weeks.
• Maintenance dose:
  • 1.5 mg/kg subcutaneously once weekly, OR
  • 3 mg/kg subcutaneously every two weeks, OR
  • 6 mg/kg subcutaneously every four weeks.
• The maintenance dose is chosen based on physician/patient preference and adherence considerations.

Special Cases:

• Elderly Patients: No dose adjustment is recommended.
• Patients with Renal Impairment: No dose adjustment is recommended for mild to moderate impairment. Emicizumab’s use in patients with severe renal impairment hasn’t been studied.
• Patients with Hepatic Dysfunction: No dose adjustment is recommended for mild to moderate impairment. Emicizumab’s use in patients with severe hepatic impairment hasn’t been studied.
• Patients with Comorbid Conditions: No specific dosage adjustments are indicated based on comorbid conditions. Individualized assessments are necessary, especially for patients with a thrombotic history.

Clinical Use Cases

• The primary clinical use of emicizumab is for routine prophylaxis of bleeding in hemophilia A. Its use in other acute scenarios below is not established.
• Intubation, Surgical Procedures, Mechanical Ventilation, Intensive Care Unit (ICU) Use, Emergency Situations: Bypassing agents (e.g., aPCC, rFVIIa) are typically used based on established protocols. If bypassing agents are necessary for patients on emicizumab, careful consideration of potential thrombotic complications is warranted.

Dosage Adjustments

• No specific dosage adjustments are recommended based on renal or hepatic function, metabolic disorders, or genetic polymorphisms.
• In case of breakthrough bleeding while on emicizumab prophylaxis, factor VIII or bypassing agents may be used.

Side Effects

Common Side Effects

• Injection site reactions (redness, pain, swelling, itching)
• Headache
• Joint pain

Rare but Serious Side Effects

• Thrombotic microangiopathy (TMA), particularly when given concomitantly with activated prothrombin complex concentrate (aPCC) for 24 hours or more at high doses (>100 U/kg/24 hours).
• Thromboembolic events (blood clots) - similar risk as seen with bypassing agents

Long-Term Effects

• Development of anti-emicizumab antibodies (including neutralizing antibodies), which may lead to a loss of efficacy.

Adverse Drug Reactions (ADR)

• Thrombotic microangiopathy with concurrent high-dose aPCC use requires immediate discontinuation of aPCC and suspension of emicizumab.

Contraindications

• Known hypersensitivity to emicizumab or any of its components.

Drug Interactions

• Activated Prothrombin Complex Concentrate (aPCC): Concurrent use, particularly high-dose aPCC (> 100 U/kg/24 hours) for extended periods (≥ 24 hours), increases the risk of thrombotic complications (TMA and thromboembolic events). Discontinue aPCC at least 24 hours before starting emicizumab and avoid concurrent use.
• Recombinant Factor VIIa (rFVIIa) and Factor VIII: Potential for hypercoagulability with coadministration exists based on preclinical studies.
• Anti-fibrinolytics: Thrombotic events may occur when used with aPCC or rFVIIa in patients receiving emicizumab.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: No FDA category assigned. No human or animal reproductive studies. Emicizumab should only be used during pregnancy if the potential benefit outweighs the potential risk to the fetus. Contraception is recommended during treatment and for at least 6 months following discontinuation.
• Breastfeeding: Excretion in human milk is unknown. Potential risks to infants are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for emicizumab and any potential adverse effects on the breastfed child.

Drug Profile Summary

• Mechanism of Action: Bispecific monoclonal antibody mimicking FVIIIa cofactor function, bridging FIXa and FX.
• Side Effects: Injection site reactions, headache, joint pain; rare but serious - TMA (with aPCC) and thromboembolic events.
• Contraindications: Hypersensitivity to emicizumab.
• Drug Interactions: aPCC (increased thrombotic risk), rFVIIa and FVIII (potential hypercoagulability), anti-fibrinolytics (thrombotic events).
• Pregnancy & Breastfeeding: No data from reproductive studies. Use with caution if benefit outweighs risk. Contraception recommended.
• Dosage: Loading dose: 3 mg/kg SC weekly x 4 weeks. Maintenance dose: 1.5 mg/kg SC weekly OR 3 mg/kg SC every 2 weeks OR 6 mg/kg SC every 4 weeks.
• Monitoring Parameters: Monitor for bleeding episodes, signs of thrombotic complications (especially with aPCC use), and development of anti-drug antibodies.

Popular Combinations (It is crucial to note that combining emicizumab with other agents, especially those affecting coagulation, requires careful evaluation and individualized risk assessment due to potential interactions.)

• In some cases, factor VIII or bypassing agents (aPCC, rFVIIa) might be used to manage breakthrough bleeding despite emicizumab prophylaxis, but not as a standard combination.

Precautions

• General Precautions: Screen for hypersensitivity. Evaluate the potential for thrombotic complications, especially with aPCC coadministration.
• Specific Populations:
  • Pregnant Women: Limited safety data. Use only if benefit outweighs risk. Contraception recommended.
  • Breastfeeding Mothers: Unknown effects on infants. Weigh the benefits of breastfeeding against potential risks.
  • Children & Elderly: No specific precautions besides individual weight-based dosing adjustments.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Emicizumab?

A: Adults and children: Loading dose - 3 mg/kg SC once weekly for 4 weeks. Maintenance dose (choose one): 1.5 mg/kg SC weekly OR 3 mg/kg SC every 2 weeks OR 6 mg/kg SC every 4 weeks.

Q2: How does Emicizumab differ from factor VIII replacement therapy?

A: Emicizumab is a bispecific antibody, not a factor VIII replacement. It mimics FVIIIa function by bridging FIXa and FX, whereas factor VIII replacement directly replaces deficient FVIII. Emicizumab is administered subcutaneously, offering easier administration.

Q3: What are the most common side effects of Emicizumab?

A: Injection site reactions, headache, and joint pain are the most common adverse effects.

Q4: Can Emicizumab be used in patients with factor VIII inhibitors?

A: Yes, emicizumab is indicated for hemophilia A patients with and without factor VIII inhibitors.

Q5: What is the major drug interaction concern with Emicizumab?

A: Concomitant use of high-dose activated prothrombin complex concentrate (aPCC) for extended durations significantly increases the risk of thrombotic microangiopathy (TMA) and other thromboembolic events.

Q6: Is dose adjustment needed for patients with renal or hepatic impairment?

A: No dose adjustments are currently recommended for mild to moderate renal or hepatic impairment. Emicizumab has not been studied in patients with severe renal or hepatic impairment.

Q7: Can Emicizumab be used during pregnancy or breastfeeding?

A: Data on use during pregnancy and breastfeeding are limited. Emicizumab should only be used if the potential benefit outweighs the potential risks to the fetus or infant.

Q8: What should be done if a patient misses a dose of Emicizumab?

A: The missed dose should be administered as soon as possible, up to a day before the next scheduled dose. The subsequent dose should be given on the usual scheduled day. Do not double the dose.

Q9: How is Emicizumab administered?

A: Emicizumab is administered via subcutaneous injection. Patients can self-administer after appropriate training.

Q10: How long does Emicizumab stay in the body?

A: Emicizumab has a long half-life of approximately 4 to 5 weeks and can persist in the circulation for several months.