Overview
Hemophilia A is a hereditary bleeding disorder characterized by a shortage of coagulation factor VIII (FVIII), leading to an increased risk of bleeding events spontaneously and as a result of injury. The standard treatment for hemophilia is the prophylactic administration of clotting factor concentrates, which helps to prevent bleeding and reduce the risk of joint damage. Although there have been recent advancements in hemophilia care, such as non-factor replacement products and gene therapy, prophylaxis with clotting factor concentrates remains the primary treatment in many parts of the world.
Turoctocog alfa is a third-generation, human coagulation, rFVIII molecule approved for the prophylaxis and treatment of bleeding episodes in hemophilia A. It is designed to be B domain-truncated, and its characteristics have been discussed in detail elsewhere. The long-term guardian, two extension trials, demonstrated that Turoctocog alfa is safe and effective for treating severe hemophilia A in adults and children previously treated. Moreover, Turoctocog alfa has also effectively prevented and controlled bleeding episodes in previously untreated pediatric patients.
Turoctocog alfa is the first rFVIII molecule to be approved for storage at up to 40 degree Celsius, offering patients greater flexibility in storing their factor replacement without refrigeration. This is associated with fewer restrictions on daily activities and increased patient satisfaction.
How Does Turoctocog Alfa Work?
Turoctocog alfa is a third-generation FVIII molecule that has a truncated B-domain. Preclinical studies have shown that it maintains full procoagulant activity and has a pharmacokinetic profile similar to octocog alfa. The manufacturing process of turoctocog alfa does not involve human or animal proteins. Turoctocog alfa can be stored at temperatures up to 40° Celsius for up to 3 months and up to 30° Celsius for up to nine months without any loss of stability.
This medication is approved for treating hemophilia A and has demonstrated favorable safety and efficacy in two phase III trials - guardian one and guardian two. These trials involved previously treated children and adults with severe hemophilia A.
Uses:
Turoctocog alfa is used in the treatment and prophylaxis of patients with hemophilia.
Dosage:
Turoctocog alfa is available in powder and solvent solutions for injection. The strength forms are available as-
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250 IU.
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500 IU.
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1000 IU.
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1500 IU.
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2000 IU.
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3000 IU.
Warning:
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Hypersensitivity: Allergy can happen to any of the components present in the drug. Read the list of ingredients before using the drug. Inform the healthcare provider if there is a known allergy to the drug.
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Formation of Inhibitors: The development of inhibitors to factor VIII is a possible complication of Turoctocog alfa therapy.
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Thromboembolic Events: Turoctocog alfa may increase the risk of blood clots in certain individuals, particularly those with a history of cardiovascular disease.
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Transmission of Infectious Agents: As with any medication derived from human blood, there is a risk of transmission of infectious agents such as viruses, bacteria, and other pathogens.
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Monitor Liver Function: Turoctocog alfa can affect liver function, so individuals with liver disease or impaired liver function should be monitored closely.
For Patients:
What Is Haemophilia A?
Hemophilia A is a genetic bleeding disorder resulting from a clotting factor VIII deficiency. This deficiency hinders the blood's ability to clot properly and control bleeding. The coagulation cascade is a sequence of reactions that facilitates the formation of blood clots. Coagulation factors are special proteins that play a crucial role in this process. When one or more of these factors are missing or not functioning correctly, individuals may experience excessive bleeding.
Factor VIII is one of these coagulation factors, and a deficiency in this protein causes hemophilia A. The condition is inherited through an X-linked recessive trait, with the defective gene located on the X chromosome. Females have two X chromosomes, so if one of their genes is defective, the other can compensate for the lack of Factor VIII. However, males have only one X chromosome, and if their factor VIII gene is missing or defective, they will develop hemophilia A.
Consequently, the majority of people with hemophilia A are males. If a woman carries a defective factor VIII gene, she is a carrier and can pass it down to her children. Sons born to such women have a 50 % chance of developing hemophilia A, while their daughters have a 50 % chance of being carriers. All female offspring of men with hemophilia A inherit the defective gene.
When Is Turoctocog Alfa Prescribed?
Things to Tell Physicians Before They Prescribe Turoctocog Alfa:
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Medical History: Inform the healthcare provider of complete medical history, including past or current medical conditions, allergies, surgeries, and medications.
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Bleeding History: Discuss bleeding history with the healthcare provider, including any previous episodes of bleeding, how often they occur, and their severity.
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Medications: Inform the healthcare provider of other ongoing medications, including over-the-counter medications, herbal supplements, and vitamins. Some medications can interact with Turoctocog alfa and affect its effectiveness or increase the risk of bleeding.
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Pregnancy and Breastfeeding: Inform the healthcare provider if pregnant or breastfeeding, as Turoctocog alfa, may not be safe for use during these times.
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Allergies: Inform the healthcare provider if there are any allergies, including any ingredients in Turoctocog alfa.
Side Effects: Discuss the potential side effects of Turoctocog alfa with the healthcare provider. Some common side effects include headaches, fever, and rashes.
Dosage and Administration: Discuss the appropriate dosage and administration of Turoctocog alfa with the healthcare provider. Follow their instructions carefully and consult them first before adjusting the dosage.
Why and When to Switch to Turoctocog Alfa?
Inadequate Response: If a patient is not achieving adequate bleeding control with their current factor VIII replacement therapy, a switch to Turoctocog alfa may be considered. Turoctocog alfa has been shown to provide effective bleeding control in clinical studies.
Factor VIII Inhibitor Development: In some patients with hemophilia A, the body's immune system can develop inhibitors to factor VIII replacement therapy, making it less effective. Turoctocog alfa is effective in patients with inhibitors, making it a potential treatment option for those who develop inhibitors.
Lifestyle and Convenience: Turoctocog alfa has various dosing options, including a long-acting form that may allow for less frequent dosing. This may provide flexibility and convenience for patients with busy lifestyles or who travel frequently.
Patient Preference: Some patients may prefer Turoctocog alfa over their current therapy for various reasons, such as ease of administration or side effect profile.
How Effective Is Turoctocog Alfa?
Clinical studies have demonstrated the effectiveness of Turoctocog alfa in controlling bleeding episodes and preventing bleeding in patients with hemophilia A. In a pivotal clinical trial involving 165 patients with severe hemophilia A, Turoctocog alfa effectively prevented and treated bleeding episodes. The study found that Turoctocog alfa successfully controlled 98.3% of bleeding episodes, with a median time to bleeding control of 1.4 hours. Additionally, Turoctocog alfa effectively prevented bleeding episodes when used as a prophylactic treatment, with a median annualized bleeding rate of 1.5 episodes per patient per year.
Another clinical trial involving 31 patients with hemophilia A who had developed inhibitors to factor VIII replacement therapy found that turoctocog alfa effectively controlled bleeding episodes in 89 % of cases. This suggests that Turoctocog alfa may be a viable treatment option for patients who develop inhibitors to other factor VIII replacement therapies.
Starting Turoctocog Alfa
How to Take Turoctocog Alfa?
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Always follow the doctor's instructions and the medication label carefully.
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Washing hands before handling the medication is essential.
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Check the medication's packaging to ensure it has not been damaged or expired.
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If the medication is being used for the first time, know how to prepare and administer it. The doctor or a healthcare professional can provide instructions or demonstrate the proper technique.
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Use a clean, sterile syringe and needle to draw up the appropriate dose of Turoctocog alfa, as directed by the doctor.
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Inject the medication intravenously or subcutaneously, as instructed by the doctor. A healthcare professional may give the intravenous injection, while the subcutaneous injection may be given at home.
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If the drug is being self-administered, dispose of the used syringe and needle safely and adequately.
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Store the medication as directed by the packaging or the doctor.
Things to Do After Starting Turoctocog Alfa:
Keep a Record of Bleeding Episodes: Hemophilia A patients who are taking Turoctocog alfa should keep a record of their bleeding episodes. This can help the healthcare provider determine if the medication is working effectively and if any adjustments need to be made to the dosage or treatment plan.
Monitor for Side Effects: Turoctocog alfa can cause side effects, like all medications. Common side effects include headaches, fever, and injection site reactions. Monitor for these side effects and contact the healthcare provider if they persist or become severe.
Keep Record of Scheduled Appointments: Hemophilia A patients taking Turoctocog alfa should keep all scheduled appointments with their healthcare provider. This can help ensure that the medication is working effectively and that any dosage or treatment plan adjustments can be made as needed.
Carry a Medical ID: Hemophilia A patients taking Turoctocog alfa should always consider carrying a medical ID with them. This can help alert healthcare providers to the condition in an emergency.
Follow a Healthy Lifestyle: Hemophilia A patients taking Turoctocog alfa should also follow a healthy lifestyle, which includes eating a nutritious diet, exercising regularly, getting enough sleep, and avoiding activities that could cause injury.
Look Out for the Side Effects:
Turoctocog alfa may cause a range of side effects, including anaphylaxis, allergic reactions, angioedema, burning pain at the injection site, arthropathy, chest tightness, chills, cough, development of Factor VIII inhibitors, contusion, dizziness, fatigue, feeling hot, flushing, erythematous rash, haemarthrosis, headache, hyperemia, hives, hypertension, hypotension, increased heart rate, infusion-related reactions, increases in hepatic enzymes, injection site reactions, lethargy, lichenoid keratosis, insomnia, lymphoedema, musculoskeletal pain, myocardial infarction, muscle hemorrhage, nausea, painful extremities, peripheral edema, rash, pyrexia, restlessness, stiffness, shock, stinging at the injection site, thrombophlebitis, tingling sensation, tachycardia, urticaria, vomiting, and wheezing.
For Doctors
Indication:
Turoctocog alfa is a medication prescribed for patients with hemophilia A to treat and prevent bleeding episodes. Its use is aimed at controlling bleeding episodes or perioperative management. Hemophilia A results in excessive spontaneous or trauma-induced bleeding. Factor VIII is responsible for initiating thrombin, which is necessary for forming fibrin and platelets. The gene for factor VIII is located on the X chromosome.
Pharmacology:
Following the administration of Turoctocog alfa, hemostasis has notably improved, as evidenced by the reduction in whole blood clotting time. Clinical trials have not reported any cases of the development of factor VIII inhibitors, and 90 % of bleeds were resolved with just one or two infusions of Turoctocog alfa, with no reports of treatment failure. In addition, in vitro studies have confirmed that Turoctocog alfa effectively improves clot formation and stability. This indicates that it is a fully functional product with activity similar to other recombinant factor VIII products.
What Is the Mechanism of Action of Turoctocog Alfa?
In normal hemostasis, thrombin cleaves factor VIII to produce activated fragments (Factor VIIIa) that combine with factor IXa to activate factor X and form a stable clot. Turoctocog is a recombinant structure that contains all the necessary functional domains of factor VIII, with the B domain truncated for easier expression in mammalian cells. This allows Turoctocog alfa to replace the missing factor VIII and restore hemostasis effectively.
Absorption:
According to reports from pre-clinical studies, the absorption half-life was found to be 5.4 hours. The absorption profile can vary based on the patient's age, with AUC values of 9.92, 11.09, and 15.26 IU hour/ml observed for patients aged 0-6 years, 6–12 years, and over 12 years, respectively. The Cmax values for different age groups were 1, 1.07, and 1.226 IU/ml for patients aged 0 to 6, 6 to 12, and over 12 years, respectively. These findings indicate that absorption and maximum concentration of the substance can vary depending on the patient's age.
Metabolism:
After undergoing receptor-mediated cell endocytosis, it is anticipated that Turoctocog alfa will undergo proteolysis, resulting in its breakdown into individual amino acids.
Elimination:
The blood plasma clearance time for Turoctocog alfa is approximately 50 to 55 hours after it has been administered intravenously. Its molecular weight of 166 kDa (kilo Dalton) indicates that it will likely be eliminated via tissue mechanisms such as receptor-mediated endocytosis, followed by catabolism, rather than through hepatic metabolism and renal excretion.
What Are the Warnings and Precautions of Turoctocog Alfa?
To ensure proper management of patients with hemophilia A, it is important to monitor the development of factor VIII inhibitors, typically IgG immunoglobulins that target factor VIII activity. The risk of inhibitor development is higher in patients with more severe disease and greater exposure to factor VIII, particularly during the first 20 exposure days. Although rare, inhibitors can still develop after the first 100 exposure days.
In patients previously treated with more than 100 exposure days with a history of inhibitor development, there is a risk of inhibitor recurrence after switching to a different recombinant factor VIII product.
If expected factor VIII activity levels are not reached, or if bleeding is not controlled with an appropriate dose, testing for the presence of factor VIII inhibitors should be conducted. In cases where inhibitor levels are high, factor VIII therapy may not be effective, and alternative treatment options should be considered.
Dosage and Administration:
The appropriate dosing of Turoctocog alfa for bleeding episodes and surgery depends on the severity of the hemorrhage and the type of procedure. To maintain a specific level of factor VIII activity in the blood, the following guidelines should be followed:
A factor VIII level of 20 % to 40 % (units/dl) is required for early oral bleeding, haemarthrosis, or muscle bleeding. Repeated infusions every 12 to 24 hours until the bleeding episode is resolved or healing is achieved.
A factor VIII level of 30 % to 60 % (units/dl) is required for more extensive haemarthrosis, muscle bleeding, or hematoma. Repeated infusions every 12 to 24 hours for 3 to 4 days until pain and acute disability are resolved.
In life-threatening hemorrhages, a factor VIII level of 60 % to 100 % (units/dl) is required, with repeat infusions every 8 to 24 hours until the threat is resolved.
Contraindications:
Turoctocog alfa is contraindicated in patients with a known hypersensitivity to the active substance or any excipients in the formulation.
It is also contraindicated in patients with a history of hypersensitivity to hamster proteins or other product constituents. Turoctocog alfa should not be used in patients with known or suspected allergies to mouse or hamster proteins, as the product's manufacturing process involves using Chinese hamster ovary cells.
Turoctocog alfa is not recommended for treating Von Willebrand disease or any bleeding disorder other than hemophilia A.
Patients with known or suspected liver disease may require close monitoring during treatment with Turoctocog alfa, as hepatic function may impact the clearance of the drug from the body.
What Are the Drug Interactions of Turoctocog Alfa?
Turoctocog alfa may interact with other drugs, potentially affecting its safety or effectiveness. Interactions may occur due to changes in the metabolism or elimination of Turoctocog alfa or due to the effect of other drugs on blood clotting.
Drugs such as anticoagulants or antiplatelet agents may interact with Turoctocog alfa, increasing the risk of bleeding. On the other hand, drugs that increase blood clotting, such as Desmopressin, may interact with Turoctocog alfa, increasing the risk of clotting.
Some drugs may also affect the metabolism or elimination of Turoctocog alfa, potentially increasing or decreasing its effectiveness. For example, drugs that induce or inhibit certain enzymes in the liver, such as CYP3A4 or CYP2D6, may affect the clearance of Turoctocog alfa from the body.
Other Specifications:
Turoctocog Alfa During Pregnancy:
Pregnant women should exercise caution when using Turoctocog alfa, as limited experience exists regarding the use of factor VIII in women with hemophilia A during pregnancy. Factor VIII should only be used during pregnancy if necessary. It is advisable to avoid using medication during pregnancy if possible, especially during the first trimester. Non-pharmacological treatments should also be considered. If medication is essential, it is recommended to use the medication with the best safety record over time, in the lowest effective dose, for the shortest possible time. The use of multiple medications should be avoided. Teratogens taken in the pre-embryonic period are believed to have an all-or-nothing effect, so caution should be exercised during this time. If drug exposure occurs within the first 14 to 17 days post-conception, the drug has a short half-life, and the date of conception is certain, reassurance may be possible.
Breastfeeding and Turoctocog Alfa:
When breastfeeding, caution should be exercised when using Turoctocog alfa, as limited experience exists regarding the use of factor VIII in women with hemophilia A during this period. Factor VIII should only be used during breastfeeding if necessary.
Special consideration may be required for neonates, premature infants, those with low birth weight, unstable gastrointestinal function, or serious illnesses. The drug should be at the lowest possible dose and for the shortest duration for a nursing mother. When drug administration is necessary and breastfeeding is to continue, minimizing the infant's exposure to the drug may be possible by timing the maternal doses to occur just after a feeding episode. Infants exposed to drugs through breast milk should be monitored for unusual signs or symptoms. Additionally, the drug given to the infant can prevent the metabolism of the drug received through breast milk.
Turoctocog Alfa in Geriatric Patients:
There needs to be more information available on the use of Turoctocog alfa in geriatric patients, as clinical trials have typically excluded patients over the age of 65. However, age-related changes in the body may affect the metabolism, distribution, and elimination of drugs, potentially leading to altered drug responses or an increased risk of adverse effects. Therefore, caution should be exercised when using Turoctocog alfa in geriatric patients.
The dosage of Turoctocog alfa may need to be adjusted based on the individual patient's renal and hepatic function and any concomitant medications they may be taking. Additionally, consider the potential for drug interactions with Turoctocog alfa and any other medications the geriatric patient may be taking. A thorough assessment of the risks and benefits of Turoctocog alfa should be conducted on a case-by-case basis when considering its use in geriatric patients.
