Nuwiq

NUWIQ, Antihemophilic Factor (Recombinant), is a sterile, non-pyrogenic, lyophilized powder for reconstitution for intravenous injection. The product is supplied in single-use vials containing nominal Factor VIII potencies of 250, 500, 1000 or 2000 IU. When reconstituted with 2.5 mL of solvent (Sterile Water for Injection), the respective nominal concentrations are 100, 200, 400 or 800 IU/mL. The reconstituted product contains the following excipients per mL: 18 mg sodium chloride, 5.4 mg sucrose, 5.4 mg L-arginine hydrochloride, 0.3 mg calcium chloride dihydrate, 1.2 mg poloxamer 188, and 1.2 mg sodium citrate dihydrate. The concentration of each of the excipients is the same for all potencies. NUWIQ contains no preservatives. Each vial of NUWIQ is labeled with the actual Factor VIII potency expressed in IU determined using one-stage clotting assay, using a reference material calibrated against a World Health Organization (WHO) International Standard for Factor VIII concentrates. One IU, as defined by the WHO standard for human Factor VIII concentrates, is approximately equal to the level of Factor VIII activity in 1 mL of fresh pooled, normal, human plasma. The mean specific activity of NUWIQ is 8124 IU/mg total protein.

B-domain deleted recombinant coagulation Factor VIII (BDD-rFVIII) is the active ingredient in NUWIQ. BDD-rFVIII is a recombinant glycoprotein (a heterodimer) with an approximate molecular mass of 170 kDa, comprising the Factor VIII domains A1-A2 (so-called heavy chain of ~90 kDa) and A3-C1-C2 (so-called light chain of ~80 kDa), whereas the B-domain, present in the full-length plasma-derived Factor VIII, has been deleted. The purified protein consists of 1440 amino acids. The amino acid sequence is comparable to the B-domain deleted form of human plasma Factor VIII(90 + 80 kDa).

BDD-rFVIII is produced by recombinant DNA technology in genetically modified human embryonic kidney (HEK) 293F cells with no animal or human derived materials added during the manufacturing process or to the final product. As NUWIQ is produced using a human cell-line, it contains post-translational modifications comparable to human plasma-derived Factor VIII and is devoid of Neu5Gc or α-1,3-Gal epitopes[1] that may be present in products produced in animal cells. Furthermore, BDD-rFVIII is fully sulfated at Tyr1680 [1]. The active substance is concentrated and purified by a series of chromatography steps, which also includes two dedicated viral clearance steps: solvent/detergent (S/D) treatment for virus inactivation and 20 nm nanofiltration for removal of viruses.

Included as part of the PRECAUTIONS section.

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Mechanism Of Action

NUWIQ temporarily replaces the missing clotting Factor VIII that is needed for effective hemostasis.

Pharmacodynamics

Hemophilia A is a bleeding disorder characterized by a deficiency of functional coagulation Factor VIII, resulting in a prolonged plasma clotting time as measured by the activated partial thromboplastin time (aPTT) assay. Treatment with NUWIQ normalizes the aPTT over the effective dosing period.

Pharmacokinetics

The pharmacokinetics (PK) of NUWIQ were evaluated in an open-label, multicenter clinical study of 22 (20 adults and 2 adolescents) previously treated patients (PTPs) with severe Hemophilia A. The PK parameters (Table 4) were based on plasma Factor VIII activity measured by the one-stage clotting assay after a single intravenous infusion of a 50 IU/kg dose.

The PK profile obtained after 6 months of repeated dosing was comparable with the PK profile obtained after the first dose.

Table 4: Pharmacokinetic Parameters of NUWIQ in 22 PTP Adults/Adolecents (Dose: 50 IU/kg)

PK of pediatric patients is presented in Table 5 for the age groups 2 to 5 years and 6 to 12 years. They were based on plasma Factor VIII activity measured by the one-stage clotting assay after a single intravenous infusion of 50 IU/kg dose. Compared to adults and adolescents, IVR and T½ were lower and systemic drug clearance (based on per kg bodyweight) was substantially higher in children 2 to 5 yr of age.

IVR analysis after 3 and 6 months of prophylactic treatment yielded comparable results with the IVR after the first dose.

As in the adult population, similar PK values were obtained using the chromogenic and the one-stage assay.The values in Table 5 reflect those obtained using the one-stage assay.

Table 5: Pharmacokinetic Parameters of NUWIQ in 26 PTP Children Age 2 to 5 Years and 6 to 12 Years (Dose: 50 IU/kg)

Clinical Studies

The efficacy of NUWIQ was evaluated in three multi-center, open-label, prospective clinical trials in PTPs with severe Hemophilia A. For routine prophylaxis, the efficacy of NUWIQ was evaluated in two multi-center studies, one in adult patients (n = 32) and one in pediatric patients (n = 59). For the treatment of bleeding episodes, efficacy was evaluated in one multi-center study in adolescents (n = 2) and adults (n = 20) who were treated on-demand only, and also in patients who experienced breakthrough bleeding episodes in the two prophylaxis studies. Across all studies, subjects undergoing surgical procedures were evaluated for hemostatic efficacy during perioperative management.

A total of 1124 bleeding episodes in 69 subjects (35 adults, 2 adolescents, and 32 children) were treated with NUWIQ. Response to each treatment was assessed by the patients using an ordinal scale of excellent (abrupt pain relief and/or unequivocal improvement in objective signs of bleeding within approximately 8 hours after a single infusion), good (definite pain relief and/or improvement in signs of bleeding within approximately 8–12 hours after an infusion requiring up to 2 infusions for complete resolution), moderate (probable or slight beneficial effect within approximately 12 hours after the first infusion requiring more than two infusions for complete resolution), or none (no improvement within 12 hours, or worsening of symptoms, requiring more than 2 infusions for complete resolution).

The majority of treated bleeding episodes (n = 986) was from the study where patients only received on-demand treatment. 642 (65%) bleeding episodes occurred spontaneously, 341 (35%) were traumatic, and 3 (0.3%) bleeding episodes were due to other causes. The mean dose per injection used to treat a bleeding episode was 32 IU/kg. Hemostatic efficacy in response to NUWIQ treatment was rated as excellent or good in 94% and as moderate in 6% of the bleeds.

In case of breakthrough bleeding episodes, the mean dose per injection used to treat a bleeding episode was 33.3 IU/kg in adults (n=15 with 30 bleeding episodes) and 45 IU/kg in pediatric patients (n=32 with 108 bleeding episodes). The median number of injections to treat a bleeding episode was 1. Hemostatic efficacy was excellent or good in 100% of bleeds in adults and 82% of bleeds in pediatric patients.

Across all studies, the efficacy of NUWIQ as surgical prophylaxis was assessed in a total of 33 surgical procedures in 19 patients; 20 procedures in 7 patients were classed as minor and 13 procedures in 12 patients were classed as major. NUWIQ pre-operative dosing ranged from 35 IU/kg to 50 IU/kg per infusion. The total number of infusions administered ranged from 1 to 5 for minor and 4 to 35 for major surgeries; one surgery required an injection of NUWIQ during surgery.

The efficacy of surgical prophylaxis was rated for each case by a surgeon and a hematologist, taking into account both the intra- and postoperative assessment. Hemostasis efficacy was rated at the end of the surgery by the surgeon and postoperatively by the surgeon and hematologist using ordinal scales as follows:

Excellent: Intra-operative: intra-operative blood loss lower than or equal to the average expected blood loss for the type of procedure performed in a patient with normal hemostasis;. Postoperative: No postoperative bleeding or oozing that was not due to complications of surgery. All postoperative bleeding (due to complications of surgery) was controlled with NUWIQ as anticipated for the type of procedure.

Good: Intra-operative: intra-operative blood loss was higher than average expected blood loss but lower than or equal to the maximal expected blood loss for the type of procedure in a patient with normal hemostasis; Postoperative: No postoperative bleeding or oozing that was not due to complications of surgery. Control of postoperative bleeding due to complications of surgery required increased dosing with NUWIQ or additional infusions, not originally anticipated for the type of procedure.

Moderate: Intra-operative: Intra-operative blood loss was higher than maximal expected blood loss for the type of procedure performed in a patient with normal hemostasis, but hemostasis was controlled. Postoperative: Some postoperative bleeding and oozing that was not due to complications of surgery; control of postoperative bleeding required increased dosing with NUWIQ or additional infusions, not originally anticipated for the type of procedure.

None: Intra-operative: Hemostasis was uncontrolled necessitating a change in clotting factor replacement regimen. Postoperative: Extensive uncontrolled postoperative bleeding and oozing. Control of postoperative bleeding required use of an alternate FVIII concentrate.

Efficacy for major surgeries was rated as excellent in 9 (69%) cases and as good in 3 (23%) cases. In 1 (8%) case, efficacy was rated as moderate. The efficacy of all minor surgeries was rated as excellent.

In the study evaluating the efficacy and safety of NUWIQ for routine prophylaxis in 32 adult subjects (29 White, 3 Asian), the product was given every other day with a dose of 30-40 IU/kg for at least 6 months. In another study evaluating the safety, immunogenicity and hemostatic efficacy in 59 pediatric subjects aged 2 to 12 years (all White, 29 were 2 to 5 years old, and 30 between 6 and 12 years), subjects received NUWIQ prophylactically every other day or 3 times per week for at least 6 months. Clinical outcomes are summarized in Table 6.

Table 6: Clinical Outcomes in Adult and Pediatric Subjects

REFERENCES

1. Kannicht C, Ramström M, Kohla G, Tiemeyer M, Casademunt E, Walter O, Sandberg H. Characterisation of the post-translational modifications of a novel, human cell line-derived recombinant human factor VIII. Thromb Res. 2013;131:78-88

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.

Recombinant antihemophilic factor 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.

Follow all directions on your medicine label and package. Tell each of your healthcare providers about all your medical conditions, allergies, and all medicines you use.

You should not use this medicine if you have ever had a severe allergic reaction to antihemophilic factor, or if you are allergic to mouse, hamster, or beef proteins.

Before using recombinant antihemophilic factor, your specific blood clotting disorder must be diagnosed as factor VIII deficiency. Recombinant antihemophilic factor will not treat von Willebrand disease.

It is not known whether recombinant antihemophilic factor will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medicine.

It is not known whether recombinant antihemophilic factor passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

Get emergency medical help if you have signs of an allergic reaction: hives; difficulty breathing; feeling light-headed, fainting; swelling of your face, lips, tongue, or throat.

Stop using recombinant antihemophilic factor and call your doctor at once if you have:

• chest pain;
• easy bruising, increased bleeding episodes; or
• bleeding from a wound or where the medicine was injected.

Common side effects may include:

• nausea, vomiting, diarrhea;
• headache;
• joint pain;
• sore throat, cough, stuffy nose;
• weakness, feeling tired;
• fever; or
• pain, swelling, itching, or irritation where the injection was given.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Follow all directions on your prescription label. Do not use this medicine in larger or smaller amounts or for longer than recommended. Always check the strength of the medicine on the label to be sure you are using the correct potency.

Recombinant antihemophilic factor is injected into a vein through an IV. You may be shown how to use an IV at home. Do not give yourself this medicine if you do not understand how to use the injection and properly dispose of needles, IV tubing, and other items used.

Recombinant antihemophilic factor is usually given every 8 to 24 hours for 1 to 4 days, depending on the reason you are using the medicine.

Read all patient information, medication guides, and instruction sheets provided to you. Ask your doctor or pharmacist if you have any questions.

Always wash your hands before preparing and giving your injection.

Recombinant antihemophilic factor must be mixed with a liquid (diluent) before injecting it. If you are using the injections at home, be sure you understand how to properly mix and store the medicine.

After mixing the medicine and diluent, keep the mixture at room temperature and use it within 3 hours. Do not put mixed medicine into a refrigerator.

Prepare your dose in a syringe only when you are ready to give yourself an injection. Each vial is for one use only. After measuring your dose, throw the vial away, even if there is medicine left in it.

Do not use recombinant antihemophilic factor if it has changed colors or has particles in it. Call your pharmacist for new medication.

Use a disposable needle and syringe only once. Follow any state or local laws about throwing away used needles and syringes. Use a puncture-proof "sharps" disposal container (ask your pharmacist where to get one and how to throw it away). Keep this container out of the reach of children and pets.

While using recombinant antihemophilic factor, you may need frequent blood tests.

Your body may develop antibodies to antihemophilic factor, making it less effective. Call your doctor if this medicine seems to be less effective in controlling your bleeding.

Store the medicine and the diluent in their original container in the refrigerator. Do not allow them to freeze. Take the medicine out of the refrigerator and allow it to reach room temperature before injecting your dose.

You may also store the medication and diluent at room temperature until the expiration date on the label. Some brands of this medicine can be stored at room temperature for only a certain number of months, or until the expiration date (whichever comes first). Follow the storage directions on the medicine label.

If you store this medicine at room temperature, do not return it to the refrigerator.

Do not store this medicine in bright light. Throw away any leftover medicine and diluent if the expiration date has passed.

Wear a medical alert tag or carry an ID card stating that you have hemophilia. Any doctor, dentist, or emergency medical care provider who treats you should know that you have a bleeding or blood-clotting disorder.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Since recombinant antihemophilic factor is used when needed, you may not be on a dosing schedule. If you are on a schedule, use the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not use extra medicine to make up the missed dose.

The most common adverse reactions ( > 0.5% of subjects) reported in clinical trials were paresthesia, headache, injection site inflammation, injection site pain, non-neutralizing anti-Factor VIII antibody formation, back pain, vertigo, and dry mouth.

Clinical Trial 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 the rate in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety profile of NUWIQwas evaluated in five prospective, open-label clinical studies in previously treated patients (PTPs - exposed to a Factor VIII containing product for ≥ 150 exposure days (EDs) in the case of adolescents and adults or ≥ 50 EDs in the case of subjects below 12 years of age) with severe Hemophilia A (Factor VIII ≤ 1%). Subjects who had a history of detectable Factor VIII inhibitor, severe liver or kidney disease, were not immune competent (CD4+ count < 200/μL), or scheduled to receive immunomodulating drugs, were excluded.

Across all clinical studies, 135 patients were stratified, among them, 74 were adults, 3 adolescents between 12 and 17 years old, and 58 pediatric patients between 2 and 11 years old. A total of 127 (94.1%) subjects were treated for at least 180 days. Collectively, patients received between 24,005 and 996,550 IU (555 to 8629 IU/kg) from14 to 319 infusions over 14 to 299 exposure days, over a period of 33 to 563 days. An exposure day was defined as any day on which at least one infusion was started.

With a total of 16,134 infusions over 15,950 EDs, reported adverse reactions included paresthesia, headache, injection site inflammation, injection site pain, back pain, vertigo, and dry mouth. Each of these adverse reactions occurred once in the study population of 135, and thus each had a rate of 0.7%. Non-neutralizing anti-

Factor VIII antibodies (without inhibitory activity as measured by the modified Bethesda assay) were reported in four patients, giving a rate of 3%. Three of four subjects had pre-existing non-neutralizing antibodies prior to exposure with NUWIQ. The binding antibodies were transient in two of these three subjects. In one subject who was tested negative at screening, the non-neutralizing antibody was measured once at study end.

All clinical trial subjects (N = 135) were monitored for neutralizing antibodies (inhibitors) to Factor VIII by the modified Bethesda assay using blood samples obtained prior to the first infusion of NUWIQ, at defined intervals (at ED 10 to 15, at 3 months, and every further 3 months) during the studies and at the completion visit. No subject developed neutralizing antibodies to Factor VIII. Four subjects (3%) developed a non-neutralizing antibody without any inhibitory activity.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to NUWIQ with the incidence of antibodies to other products may be misleading.

Read the entire FDA prescribing information for Nuwiq (Antihemophilic Factor Recombinant Intravenous Infusion)