HomeHealth articlesmonoclonal antibodiesHow Does Eculizumab Work in Paroxysmal Nocturnal Hemoglobinuria?

Eculizumab - A Wonder Drug for a Rare Blood Disorder

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Eculizumab is recommended to reduce hemolysis in patients with paroxysmal nocturnal hemoglobinuria (PNH). Read the article to learn more.

Medically reviewed by

Dr. Mubashir Razzaq Khan

Published At May 19, 2023
Reviewed AtMay 24, 2023

Overview:

Eculizumab is used to treat paroxysmal nocturnal hemoglobinuria (PNH), generalized myasthenia gravis, atypical hemolytic uremic syndrome (aHUS), and neuromyelitis optica. Eculizumab is a monoclonal antibody that is directed against the complement protein C5. Binding to this protein inhibits the activation of a complement terminal complex, which helps treat various autoimmune diseases. On March 16, 2007, the FDA (Food and Drug Administration) approved Eculizumab.

It reduces the destruction of red blood cells and the need for blood transfusions in people with PNH, but it does not seem to change the risk of death. Eculizumab was the first medicine licensed for each use, and it was approved based on small trials. It is administered through IV (intravenous) infusion.

Indications:

Eculizumab is indicated for treating paroxysmal nocturnal hemoglobinuria (PNH) to block complement-mediated thrombotic microangiopathy, atypical hemolytic uremic syndrome to reduce the amount of hemolysis and neuromyelitis optica spectrum disease to reduce the amount of hemolysis (NMOSD).

Contraindications:

  • Individuals are allergic to Eculizumab, murine proteins, or other formulation components.

  • Active infection with Neisseria meningitidis and Haemophilus influenza has not been resolved.

Pharmacological Class:

Belongs to the class of monoclonal antibodies.

Route of Administration:

Intravenous.

Composition:

Humanized monoclonal (IgG2/4) antibody Eculizumab is available as 300 mg single-use glass vials containing 30 mL of sterile, preservative-free Eculizumab solution. It is manufactured using recombinant DNA technology.

Storage:

Eculizumab admixed solutions can be stored for 24 hours at two to eight degrees Celsius (36 to 46° Fahrenheit).

Precautions for storage:

  • Refrigerate at two to eight degrees Celsius.

  • Do not freeze.

  • Keep it in the original packaging to prevent exposure to light.

  • Eculizumab's original packaging vials may only be taken from refrigeration for a single 3-day period.

How Does Eculizumab Work?

Eculizumab binds strongly to the complement protein C5, stops it from being cut into C5a and C5b, and prevents the formation of the terminal complement complex C5b-9. As a result, Eculizumab keeps the early parts of complement activation, which are essential for killing microorganisms and getting rid of immune complexes.

What Are the Uses of Eculizumab?

Eculizumab is used to treat paroxysmal nocturnal hemoglobinuria (PNH) to block complement-mediated thrombotic microangiopathy, atypical hemolytic uremic syndrome to reduce the amount of hemolysis, and neuromyelitis optica spectrum disease to reduce the amount of hemolysis (NMOSD).

What Are the Side Effects?

Eculizumab may result in severe adverse effects like

  • Hives (an allergic reaction that manifests as a rash of itchy, red, welt-like lesions on the skin, often with severe swelling)

  • Difficulty in breathing

  • Facial swelling.

  • Fever.

  • Headache.

  • Skin rash.

  • Headache with nausea and vomiting.

  • Body aches.

  • Flu symptoms.

  • Confusion.

  • Increased sensitivity to light.

  • Neck or back stiffness.

  • Painful urination, little or no urination.

  • Swelling of feet or ankles.

  • Fatigue.

  • Shortness of breath.

  • Pale skin.

  • Unusual tiredness.

  • Cold hands and feet.

  • Unusual bleeding.

  • Seizures.

In case of any of the mentioned symptoms, get immediate medical help.

Information for Patients:

What Is Eculizumab and How Is It Used?

Eculizumab is used to treat paroxysmal nocturnal hemoglobinuria, hemolytic uremic syndrome, neuromyelitis optica spectrum disorder, and myasthenia gravis. Eculizumab may be taken alone or in conjunction with other drugs. It belongs to the medication class known as monoclonal antibodies.

What Is Paroxysmal Nocturnal Hemoglobinuria (PNH)?

PNH, also known as paroxysmal nocturnal hemoglobinuria, is an extremely rare condition in which the red blood cells in the body break down prematurely. It is a condition that develops in the hematopoietic stem cells over time. Hematopoietic stem cells are produced in the bone marrow, the sponge-like center of the body's long bones. These cells eventually mature into red blood cells as they divide and multiply. People with PNH have faulty hematopoietic stem cells, which in turn cause them to create blood cells with abnormalities. These abnormal red blood cells, a symptom of PNH, are especially vulnerable to premature destruction at the hands of a specific component of a person's immune system known as the complement system. The breakdown of red blood cells, known as hemolysis, caused by complement can occasionally result in hemoglobin in the individual's urine, known as hemoglobinuria.

Hemoglobin is the oxygen-containing, iron-rich pigment that gives blood its characteristic red color. As a result, individuals who suffer from hemoglobinuria may have urine that is a dark tint or even blood-colored urine. People with PNH are more likely to experience hemolysis than the general population. The individuals also have an increased risk of developing clots in their blood which can be potentially fatal (thromboses). Those affected also suffer from an underlying malfunction of their bone marrow to varying degrees. Extreme malfunction in the bone marrow leads to decreased numbers of all three types of blood cells, known as pancytopenia. The particular signs and symptoms of PNH can vary considerably from one individual to the next, and people affected by the illness typically do not display all of the symptoms linked with it.

What Are the Precautions That Should Be Followed?

  • The doctor monitors the progress at frequent intervals to ensure that this medication is effective. Blood and urine testing may be advised to detect adverse effects.

  • Eculizumab may raise the risk of severe infections, such as meningococcal disease. Inform the physician if having any infections.

  • Notify the doctor immediately if one experiences headaches, nausea, vomiting, fever, stiff neck or back, rash, disorientation, muscle aches, or light sensitivity in the eyes.

  • Individuals must ensure that they receive a meningococcal vaccine at least two weeks before receiving this medication. If the individuals are to use this medication immediately, they may also be prescribed antibiotics for two weeks to avoid infections. If the individual has previously had the meningococcal vaccine, the doctor will determine if you require a second dose.

  • Patients diagnosed with PNH should be aware that discontinuing this medication may result in the destruction or breakdown of red blood cells (hemolysis). After the individuals have stopped using this medication, the physician will need to follow up for a minimum of eight weeks carefully.

  • Ensure to attend every scheduled appointment.

  • Eculizumab has the potential to cause infusion-related events, including anaphylaxis, which may pose a threat to a patient's life and requires prompt medical attention. After taking this medication, if one experiences any adverse effects like fever, chills or shaking, dizziness, chest pain, difficulty breathing, itching or rash, lightheadedness, fainting, or swelling of the face, tongue, or throat. The individual should immediately inform the physician.

How to Take Eculizumab?

  • Use Eculizumab according to the instructions on the label or as prescribed by the doctor. Do not exceed the specified dosage or duration.

  • The physician will conduct tests to ensure that Eculizumab is appropriate for the individual.

  • Eculizumab is not administered each day. Carefully adhere to the doctor's dosage directions. The dose schedule may differ between children, adolescents, and adults.

  • A healthcare professional injects Eculizumab into a vein. Infusions can take 35 minutes for adults and up to four hours for children.

  • In children and adolescents, the dosage is based on weight. The child's dosage may need to be adjusted if they gain or lose weight.

  • After each infusion, the patient must be thoroughly monitored for at least one hour to ensure no adverse reaction.

  • The individuals receiving this medication may be more susceptible to infections, potentially severe or fatal ones. So, this will require regular medical checks.

  • The patients will receive a card that describes the signs of meningococcal disease. Read this material to become aware of the symptoms to watch for. Carry the card at all times while using Eculizumab and for at least three months following the final dosage.

  • Do not discontinue Eculizumab without first consulting the doctor. If medication is interrupted, the red blood cell count might change drastically.

What Other Medications Might React Negatively With Eculizumab?

  • In some instances, it is alright to combine two different medications. This is not the case for all medications, however. In certain circumstances, the physician may adjust the dosage or recommend other preventative measures that may be required. One should inform the doctor if one is taking other prescribed or available medications without a prescription (over-the-counter or OTC).

  • Because there could be interactions, some medications should not be taken at or close to mealtimes or when consuming specific foods. There could be problems if combined with certain medicines with alcohol or tobacco. The use of the medication with food, alcohol, or tobacco should be discussed with the healthcare provider.

Can One Take Eculizumab During Pregnancy or Breastfeeding?

Follow the doctor's instructions on the use of this medication during pregnancy. During pregnancy, it is crucial to manage the blood disease to prevent adverse consequences on the mother and the baby. Also, ask the doctor if breastfeeding is safe while using this medication.

For Doctors

Pharmacologic Class of Drug:

Monoclonal antibodies.

Formulation:

It is formulated as 300 mg single-use vials containing 30 mL of sterile, non-preserved Eculizumab solution at 10 mg/mL.

Active Ingredient:

Eculizumab.

Excipients:

Monobasic sodium phosphate monohydrate, 13.8 mg.

Dibasic sodium phosphate heptahydrate, 53.4 mg.

Sodium chloride, 263.1 mg.

Polysorbate 80 (vegetable origin), 6.6 mg.

Water for injections.

Route of Administration:

Intravenous. (Do not administer intravenously as a push or bolus injection).

Shelf Life:

  • 30 months.

  • After dilution, the drug should be administered immediately. However, chemical and physical stability for 24 hours at two degrees Celsius to eight degrees Celsius has been demonstrated.

Preclinical Safety and Animal Studies:

  • In vitro, studies examined Eculizumab's specificity for C5 in human serum. Eculizumab's cross-reactivity was tested on 38 human tissues. This investigation found C5 expression in smooth muscle, striated muscle, and renal proximal tubular epithelium, consistent with previous studies. No cross-reactivity was found.

  • Lack of pharmacologic efficacy in non-human species prevents animal reproduction research using Eculizumab.

  • A 26-week toxicity trial in mice with a murine C5 surrogate antibody did not impact any toxicity measures. Female and male mice prevented hemolytic activity during the investigation.

  • No noticeable treatment-related effects or harmful consequences were detected in reproductive toxicology investigations in mice with a surrogate terminal complement inhibitory antibody. These investigations assessed fertility. However, the exposure did not increase neonatal death or fetal loss.

  • Eculizumab's genotoxicity and carcinogenicity have not been evaluated in animals.

Animal Studies on Interference with Reproduction:

Based on body weight, animal reproduction tests were undertaken in mice using doses of a murine anti-C5 antibody that were two to four times (low dose) and four to eight times (high dose) the recommended human dose of Eculizumab. When animals were exposed to the antibody from before mating through early gestation, there was no reduction in fertility or reproductive performance, early embryogenesis, developmental toxicity, and prenatal and postnatal development.

Among 230 infants born to mothers exposed to the higher antibody dose, two instances of retinal dysplasia and one instance of umbilical hernia were detected (approximately four times the maximum recommended human Soliris dose, based on body weight comparison). When maternal exposure to the antibody occurred, it resulted in retinal dysplasia and one case of umbilical hernia among 230 offspring born to mothers exposed to the higher antibody dose; however, there was no increase in fetal loss or neonatal mortality. When maternal antibody exposure occurred between implantation and weaning, a more significant proportion of male offspring was moribund or died (1 out of 25 controls, 2 out of 25 low dose group, 5/25 high dose group). However, the offspring that survived had normal development and reproductive function.

Therapeutic Indications:

Eculizumab is approved for the treatment of the following conditions in adults and children:

  • Paroxysmal nocturnal hemoglobinuria (PNH).

  • Regardless of prior transfusion history, patients with hemolysis and clinical symptoms indicative of high disease activity demonstrate therapeutic benefit.

  • Hemolytic uremic syndrome atypical (aHUS).

Eculizumab is authorized for the treatment of the following conditions in adults:

  • Refractory generalized myasthenia gravis (gMG) in anti-acetylcholine receptor (AChR) antibody-positive individuals.

  • Neuromyelitis optica spectrum disorder (NMOSD) in anti-aquaporin-4.

  • Antibody-positive individuals with relapsing illness.

Contraindications:

Do not initiate therapy with Eculizumab in patients:

  • With unresolved Neisseria meningitidis infection.

  • Who are not immunized against Neisseria meningitidis (unless they receive prophylactic treatment with suitable antibiotics for two weeks after immunization) or have not been vaccinated against Neisseria meningitidis.

Dose and Schedule:

For the treatment of PNH, Eculizumab is provided as a weekly dose of 600 mg via intravenous infusion for 35 minutes from week one to week four, followed by an infusion of 900 mg at week five, then 900 mg every 14 days indefinitely.

Usage of Drugs in Specific Populations:

Pediatric Use:

  • The safety and effectiveness of treating PNH in children under 18 are unknown.

  • Twenty-five pediatric patients participated in three clinical studies evaluating Eculizumab for aHUS (ages two months to 17 years). Eculizumab appears safe and effective in treating aHUS in children and adults.

  • Administer Neisseria meningitidis, Streptococcus pneumonia, and Hib immunizations per ACIP guidelines.

Geriatric Use:

Eculizumab was given to 16 older adults (15 with PNH and 1 with aHUS). Although no age-related differences were detected in these investigations, the number of 65-plus individuals is insufficient to determine the response compared to younger individuals.

Pregnancy:

There are no suitable studies that have been carefully monitored and have been conducted on pregnant women. However, it is anticipated that the recombinant IgG molecule known as Eculizumab (humanized anti-C5 antibody) will pass through the placenta. Studies conducted on animals with a mouse equivalent of the Eculizumab molecule (murine anti-C5 antibody) revealed an increased risk of developmental defects and an increased risk of death and dying offspring at two to eight times higher doses than the human dose. Therefore, during pregnancy, Eculizumab should only be taken if there is a possibility that the potential benefits will outweigh any possible risks to the developing baby.

Breastfeeding Mothers:

Eculizumab milk excretion is unknown. Eculizumab should be in human milk since IgG is eliminated. Published data demonstrate that human milk antibodies do not penetrate neonatal and newborn circulation. Therefore, Eculizumab should not be given to nursing mothers. Eculizumab's unknown hazards to infants should be considered against the benefits of breastfeeding.

Mechanism of Action:

Eculizumab binds to C5 with high affinity, preventing its cleavage to C5a and C5b and the formation of C5b-9. Eculizumab retains early complement components required for opsonizing bacteria and clearing immune complexes.

In PNH patients, Eculizumab blocks uncontrolled terminal complement activation and complement-mediated intravascular hemolysis. In most PNH patients, 35 micrograms/mL of Eculizumab is enough to suppress complement-mediated intravascular hemolysis. It also reduces complement-mediated hemolysis in PNH.

Eculizumab blocks complement-mediated thrombotic microangiopathy in aHUS patients. Eculizumab reduced terminal complement activity in all patients when used as directed. In all aHUS patients, Eculizumab serum values of 50-100 microgram/mL suppressed the terminal complement activation.

In patients with refractory gMG, uncontrolled terminal complement activation leads to failure of neuromuscular transmission by causing membrane attack complex (MAC) dependent lysis and C5a-dependent inflammation at the neuromuscular junction (NMJ). Persistent administration of Eculizumab resulted in immediate, complete, and sustained inhibition of terminal complement activity. Patients with NMOSD have uncontrolled terminal complement activation caused by autoantibodies directed against AQP4. This activation leads to the formation of the MAC and C5a-dependent inflammation, which in turn leads to astrocyte necrosis and increased permeability of the blood-brain barrier, as well as the death of the surrounding oligodendrocytes and neurons. For example, suppose the individual administers Eculizumab regularly. In that case, it inhibits terminal complement activity that is immediate, complete, and long-lasting (Eculizumab serum concentrations of less than 116 micrograms per milliliter).

Pharmacodynamics:

Eculizumab lowered blood LDH levels from 2200 ± 1034 U/L (mean standard deviation) at baseline to 700 ±388 U/L (mean standard deviation) by week one and maintained this effect through the end of the research at week 26 (327 ±442 U/L). In a clinical investigation with a single arm, Eculizumab maintained this efficacy for 52 weeks.

Pharmacokinetics:

Special studies evaluating the pharmacokinetics in patient populations distinguished by gender, race, age (pediatric or geriatric), or renal or hepatic impairment have not been done. The aHUS clinical investigations covered pediatric and adolescent patients (less than 18 years of age) and individuals with renal impairment. Studies revealed that age, gender, race, and renal function do not affect the pharmacokinetics of Eculizumab.

Route of Elimination:

Monoclonal antibodies do not pass out of the body through the urine; only a trace amount is passed through the bile. Instead, most monoclonal antibodies are broken down into constituent amino acids in the lysosomes.

Warnings:

  • There have been life-threatening and fatal meningococcal infections in patients treated with Eculizumab.

  • Meningococcal disease can swiftly turn deadly or life-threatening without prompt diagnosis and treatment.

  • Adhere to the most recent recommendations of the ACIP (Advisory Committee on Immunization Practices) for meningococcal vaccination in patients with complement deficiency.

  • Eculizumab is given as a dose unless the risk of getting a meningococcal infection is greater than the risk of delaying Eculizumab therapy.

  • Keep an eye on patients for any early symptoms that could indicate a meningococcal infection, and initiate an evaluation right once an infection is suspected.

  • Eculizumab can only be obtained through participation in a limited program that is part of a risk assessment and mitigation strategy (REMS). Prescribers are required to register for the program to comply with the Soliris REMS.

Supply and Storage:

  • Supplied as a concentrated solution for intravenous infusion is a sterile, clear, colorless, preservative-free solution.

  • Keep the vials in the original carton and keep them in the refrigerator at a temperature between two degrees Celsius to eight degrees Celsius. Do not continue to use the product after the expiration date that is indicated on the carton.

Preparation and Administration:

Eculizumab admixture should be delivered intravenously through gravity feed and an infusion pump over 25 to 45 minutes in adults and one to four hours in pediatric patients. The diluted solution of Eculizumab does not require protection from light prior to delivery to the patient. If an adverse event occurs during the delivery of Eculizumab, the physician may choose to slow or stop the infusion. If the infusion is delayed, the total infusion time cannot exceed two hours for adults and four hours for children. Observe the patient for at least one hour after the completion of the infusion for any signs or symptoms of an infusion response.

If the occurrence of an adverse event occurs during the administration of Eculizumab, the physician may choose to slow or stop the infusion. If the infusion is slowed, the total infusion time cannot exceed two hours for adults and four hours for children. Observe the patient for at least one hour after the conclusion of the infusion for any signs or symptoms of an infusion response.

The administration route of Eculizumab is the same for all age groups, including children.

Eculizumab may be administered to patients 65 years of age and older. Although experience with Eculizumab in these populations is minimal, there is no evidence to suggest that any particular precautions are required when treating older patients. Do not administer intravenously as a push or bolus injection.

Renal impairment:

Patients with renal impairment do not require a dosage change.

Hepatic impairment:

The safety and efficacy of Eculizumab in patients with hepatic impairment have not been evaluated.

Special Precautions for Administration and Disposal:

  • Before administration, check for particle debris and discoloration. Gently combine the product and diluent in the infusion bag.

  • Before administering, let the diluted solution warm to room temperature in ambient air.

  • Infuse the recommended dose only.

  • The product includes no preservatives. Therefore, discard any unused amount.

  • Reconstitution and dilution must follow appropriate practices, including asepsis.

  • Add sodium chloride 9 mg/ml (0.9 percent) solution for injection, sodium chloride 4.5 mg/ml (0.45 percent) solution for injection, or 5 percent dextrose in water to the infusion bag to dilute to 5 mg/ml. 60 ml for 300 mg dosages, 120 ml for 600 mg doses, 180 ml for 900 mg, and 240 ml for 1,200 mg doses.

  • Any unused medicine or garbage should be disposed of properly.

Education Information:

All physicians who plan to prescribe Eculizumab must familiarize themselves with the prescribing guide. In addition, patients must be informed of the benefits and dangers of Eculizumab therapy and given a patient information leaflet and a patient safety card. Patients should be advised to seek medical attention promptly if they develop fever, headache, stiff neck, or photosensitivity, as these symptoms may indicate meningococcal infection.

Conclusion:

Eculizumab is a significant advancement in the treatment of PNH. Although clinical experience is limited, long-term studies in individuals with PNH have demonstrated the safety and efficacy of Eculizumab, with few severe side effects.

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Dr. Mubashir Razzaq Khan
Dr. Mubashir Razzaq Khan

Hematology

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eculizumabmonoclonal antibodies
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