Helixate FS

Antihemophilic factor is a naturally occurring protein in the blood that helps blood to clot. A lack of antihemophilic factor VIII is the cause of hemophilia A.

This medication works by temporarily raising levels of factor VIII in the blood to aid in clotting.

Recombinant antihemophilic factor is used to treat or prevent bleeding episodes in adults and children with hemophilia A. It is also used to control bleeding related to surgery or dentistry in a person with hemophilia, and to prevent joint damage in people age 16 or older with severe hemophilia A and no prior joint damage.

Recombinant antihemophilic factor is not for use in people with von Willebrand disease.

Recombinant antihemophilic factor may also be used for purposes not listed in this medication guide.

In the U.S.

• Advate
• Adynovate
• Afstyla
• Eloctate
• Helixate FS
• Hemofil-M
• Hyate:C
• Koate DVI
• Kogenate FS
• Monarc-M
• Monoclate-P
• Obizur
• Xyntha

Available Dosage Forms:

• Powder for Solution

Therapeutic Class: Antihemophilic Agent

All products:

• If you have an allergy to Helixate FS (antihemophilic factor (recombinant) (helixate FS, kogenate FS, and nuwiq)) or any part of this medicine.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.

Helixate FS and Kogenate FS:

• If you are allergic to hamsters, talk with the doctor.
• If you are allergic to mouse proteins, talk with the doctor.

This medicine may interact with other drugs or health problems.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take Helixate FS with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

Use Helixate FS as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• It is given as a shot into a vein.
• This medicine may be given at home.
• If you will be giving yourself the shot, your doctor or nurse will teach you how to give the shot.
• Follow how to use as you have been told by the doctor or read the package insert.
• Wash your hands before and after use.
• If stored in a refrigerator, let this medicine come to room temperature before mixing. Do not heat Helixate FS.
• This medicine needs to be mixed before use. Follow how to mix as you were told by the doctor.
• Do not shake.
• Most products will be clear and colorless after mixing. Some products may be clear to slightly cloudy and colorless after mixing. Some products may be colorless to a faint yellow after mixing. Be sure you know what the product will look like after mixing.
• Do not use if the solution is cloudy, leaking, or has particles.
• Do not use if solution changes color.
• After mixing, do not refrigerate.
• Use within 3 hours of making.
• Throw away any part of opened vial not used after use.
• Throw away needles in a needle/sharp disposal box. Do not reuse needles or other items. When the box is full, follow all local rules for getting rid of it. Talk with a doctor or pharmacist if you have any questions.

What do I do if I miss a dose?

• Call your doctor to find out what to do.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

All products:

• Irritation where the shot is given.
• Headache.

Nuwiq:

• Back pain.
• Dry mouth.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about Helixate FS, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about Helixate FS (antihemophilic factor (recombinant) (helixate FS, kogenate FS, and nuwiq)). It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using Helixate FS.

Review Date: October 4, 2017

The most serious adverse reactions are systemic hypersensitivity reactions including bronchospastic reactions and/or hypotension and anaphylaxis and the development of high-titer inhibitors necessitating alternative treatments to AHF.

The most common adverse reactions observed in clinical trials (frequency ≥ 4% of patients) are inhibitor formation in previously untreated patients (PUPs) and minimally treated patients (MTPs), skin-related hypersensitivity reactions (e.g., rash, pruritus), infusion site reactions (e.g., inflammation, pain), and central venous access device (CVAD) line-associated infections in patients requiring a CVAD for intravenous administration.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in clinical practice.

Previously Treated Patients (PTPs)

During the clinical studies conducted in PTPs, 451 adverse events (irrespective of the relationship to the study drug) were reported in the course of 24,936 infusions (1.8%). Twenty-four of the 451 adverse events were assessed as related to Helixate FS (0.1%).

Adverse reactions reported by ≥ 4% of the patients are listed in Table 3 below.

Previously Untreated Patients (PUPs) and Minimally Treated Patients (MTPs)

In clinical studies with pediatric PUPs and MTPs, 726 adverse events were reported in the course of 9,389 infusions (7.7%). Twenty-nine of the 726 adverse events were assessed as related to Helixate FS (0.3%).

Adverse reactions reported by ≥ 4% of the patients are listed in Table 4 below.

Minimally Treated Patients (MTPs) in the Joint Outcome Study

In the Joint Outcome Study in MTP pediatric patients treated with routine prophylaxis or episodic enhanced treatment for 5.5 years, 46 of the 65 randomized patients experienced adverse events over the study duration. Adverse events were not assessed for their relationship with Helixate FS.

Immunogenicity

In clinical studies with 73 PTPs (defined as having more than 100 exposure days), one patient had a pre-existing inhibitor. In the other 72 patients, followed over 4 years, no de-novo inhibitors were observed.

In clinical studies with pediatric PUPs and MTPs, inhibitor development was observed in 9 out of 60 patients (15%), 6 were high titer1(>5 BU) and 3 were low-titer inhibitors. Inhibitors were detected at a median number of 7 exposure days (range 2 to 16 exposure days).

In the Joint Outcome Study with Helixate FS,5 de-novo inhibitor development was observed in 8 of 64 patients with negative baseline values (12.5%), 2 patients developed high titer1 (>5 BU) and were withdrawn from the study. Six patients developed low-titer inhibitors. Inhibitors were detected at a median number of 44 exposure days (range 5 to 151 exposure days).

Post-Marketing Experience

The following adverse reactions have been identified during post approval use of Helixate FS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Among patients treated with Helixate FS, cases of serious allergic/hypersensitivity reactions (which may include facial swelling, flushing, hives, blood pressure decrease, nausea, rash, restlessness, shortness of breath, tachycardia, tightness of the chest, tingling, urticaria, vomiting) have been reported, particularly in very young patients or patients who have previously reacted to other factor VIII concentrates.

The following table represents the post-marketing adverse reactions as MedDRA Preferred Terms.

Helixate FS Antihemophilic Factor (Recombinant) is a coagulation factor VIII produced by recombinant DNA technology. It is produced by Baby Hamster Kidney (BHK) cells into which the human factor VIII gene has been introduced.8 The cell culture medium contains Human Plasma Protein Solution (HPPS) and recombinant insulin, but does not contain any proteins derived from animal sources. Helixate FS is a purified glycoprotein consisting of multiple peptides including an 80 kD and various extensions of the 90 kD subunit. It has the same biological activity as factor VIII derived from human plasma. No human or animal proteins, such as albumin, are added during the purification and formulation processes of Helixate FS.

The purification process includes a solvent/detergent virus inactivation step in addition to the use of the purification methods of ion exchange chromatography, monoclonal antibody immunoaffinity chromatography, along with other chromatographic steps designed to purify recombinant factor VIII and remove contaminating substances.

Additionally, the manufacturing process was investigated for its capacity to decrease the infectivity of an experimental agent of transmissible spongiform encephalopathy (TSE), considered as a model for the vCJD and CJD agents.9-21 Several of the individual production and raw material preparation steps in the Helixate FS manufacturing process have been shown to decrease TSE infectivity of that experimental model agent. TSE reduction steps include the Fraction II+III separation step for HPPS (6.0 log10) and an anion exchange chromatography step (3.6 log10).

Helixate FS is formulated with the following as stabilizers (see Table 7) in the final container and is then lyophilized. The final product is a sterile, nonpyrogenic, preservative-free, powder preparation for intravenous (IV) injection. Intravenous administration of sucrose contained in Helixate FS will not affect blood glucose levels.

The following inactive ingredients/excipients are also contained in the final product:

Each vial of Helixate FS contains the labeled amount of recombinant factor VIII in international units (IU). One IU, as defined by the World Health Organization standard for blood coagulation factor VIII, human, is approximately equal to the level of factor VIII activity found in 1 mL of fresh pooled human plasma.

Preclinical studies evaluating Helixate FS in hemophilia A with mice, rats, rabbits, and dogs demonstrated safe and effective restoration of hemostasis. Doses several fold higher than the recommended clinical dose (related to body weight) did not demonstrate any acute or subacute toxic effect for Helixate FS in laboratory animals.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies have been conducted with Helixate FS to assess its mutagenic or carcinogenic potential and impairment of fertility. Helixate FS has been shown to be comparable to the predecessor product with respect to its biochemical and physiochemical properties, as well as its non-clinical in vivo pharmacology and toxicology. By inference, the predecessor product and Helixate FS would be expected to have equivalent mutagenic and carcinogenic potential.

The predecessor product did not demonstrate reverse mutation or chromosomal aberrations at doses substantially greater than the maximum expected clinical dose. In vivo evaluation with the predecessor product in animals using doses ranging between 10 and 40 times the expected clinical maximum also indicated that the predecessor product did not possess a mutagenic potential. Long-term investigations of carcinogenic potential in animals have not been performed due to the immune response to heterologous proteins in all non-human mammalian species.

Previously Treated Patients (PTPs)

A total of 73 patients with severe (≤ 2% FVIII) hemophilia A, ages 12–59, who had been previously treated with other recombinant or with plasma-derived AHF products, were treated up to 54-months in open label studies with Helixate FS in Europe and North America. A total of 5,684 bleeding episodes were treated during the studies. Patients could be treated on demand or on prophylaxis. Regularly scheduled prophylaxis treatment represented 76% of all infusions (treatment regimens of 2-3 infusions per week) (see Table 11).

A total of 31 patients received Helixate FS for 43 surgical procedures during the PTP studies. There were both minor and major surgery types, 27 and 16 respectively. The surgeon or treating physician assigned a rating to the hemostatic outcome according to 4 categories; "excellent", "good", "moderate", or "none". Hemostasis was rated as satisfactory ("excellent" or "good") in all cases (see Table 13).

Previously Untreated and Minimally Treated Patients (PUPs and MTPs)

Helixate FS has been used in the treatment of bleeding episodes in previously untreated pediatric patients (PUPs) and minimally treated patients (MTPs) with severe (< 2% FVIII) hemophilia A. There were 37 PUPs and 24 MTPs (defined as having equal to or less than 4 exposure days) treated with a total of 9,419 infusions of Helixate FS for a follow up duration up to 3.1 years. A total of 1,047 bleeding episodes were treated.

A total of 29 surgical procedures were performed in 23 patients during the PUPs and MTPs study. There were both minor and major surgery types, 23 and 6 respectively. The surgeon or treating physician assigned a rating to the hemostatic outcome according to 4 categories; "excellent", "good", "moderate", or "none". Hemostasis was rated as satisfactory ("excellent" or "good") in all cases (see Table 13).

Pediatric Prophylaxis and Joint Damage Risk Reduction

A total of 65 boys less than 30 months of age with severe hemophilia A (FVIII level ≤ 2 IU/dL) and with ≤ 2 bleeds into each index joint and normal baseline joint imaging, were observed for up to 5.5 years in a multicenter, open-label, prospective, randomized, controlled clinical study.5 Patients received either 25 IU/kg every other day (primary prophylaxis; n=32) or at least 3 doses totaling a minimum of 80 IU/kg at the time of a bleeding episode (enhanced episodic; n=33). Joint damage was evaluated by magnetic resonance imaging (MRI) or radiography, as well as the frequency of bleeding episodes. Joint damage detected by MRI or radiography in the ankles, knees, and elbows (i.e. index joints) was statistically significantly lower (p=0.002) for subjects receiving prophylactic therapy (7%) than for subjects receiving episodic therapy (42%). This corresponds to a 6.29-fold relative risk of joint damage for subjects treated with enhanced episodic therapy compared to prophylaxis. The mean rate of index joint hemorrhages for subjects on episodic therapy was 4.89 bleeds per year, versus 0.63 bleeds per year observed in the prophylaxis arm. Three of 33 (9.1%) subjects in the episodic arm experienced recurrent life threatening bleeds (intracranial, gastrointestinal) compared to no subjects in the prophylaxis arm. On a per joint basis, joints in the regular prophylaxis arm were 8-fold more likely to remain damage-free than those in the episodic arm. Joint damage was most frequently observed in ankle joints and was detected at higher rates by MRI than by radiography. Ankles were also the index joint that demonstrated the highest frequency of bleeding events in this study (left ankle, mean 2.7 hemorrhages; right ankle, mean 2.6 hemorrhages).

As shown in Table 14 below, the incidence of joint damage was statistically significantly lower in the prophylactic group as compared to the episodic treatment group when assessed by MRI, or either MRI or radiography, using predefined criteria (described below) for establishing joint damage. However, there was no statistically significant difference between the two groups when joint damage was assessed by radiography alone.

To evaluate joint damage, MRIs were scored using a scale developed by Nuss et al.22, and X-rays were scored using the method of Pettersson et al.23 Both scales have been validated in various clinical trials and are routinely used for joint damage evaluation in hemophiliacs. Joint damage was defined as bone and/or cartilage damage including subchondral cysts, erosions and cartilage loss with narrowing of joint space. This corresponded to a total MRI score of ≥ 7 or an X-ray score of ≥ 1 in any of the following categories: subchondral cysts, erosions of joint surfaces or narrowing of joint spaces. Images were read separately by two independent radiologists centrally. Any discrepant reading was read by an independent third radiologist who was not aware of the initial reading results. The concordant reading of two out of three readers was used for analysis purposes.

As shown in Table 15 below, the assessment of endpoints in all randomized subjects assuming that those without complete baseline and endpoint data are treatment failures (intention-to-treat analysis). The incidence of joint damage was statistically significantly lower in the prophylactic group as compared to the episodic treatment group, with similar p-values, when assessed by MRI, or either MRI or radiography.