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NUWIQ®
(Antihemophilic Factor, Recombinant) for Intravenous Injection
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.
NUWIQ is a recombinant antihemophilic factor [blood coagulation factor VIII (Factor VIII)] indicated in adults and children with Hemophilia A for:
NUWIQ is not indicated for the treatment of von Willebrand Disease.
For intravenous use after reconstitution.
Required IU = body weight (kg) x desired Factor VIII rise (%) (IU/dL) x 0.5 (IU/kg per IU/dL)
Expected Factor VIII rise (% of normal) = 2 x administered IU / body weight (kg)
A guide for dosing NUWIQ for the on-demand treatment and control of bleeding episodes is provided in Table 1. Selected dosing regimen should maintain plasma Factor VIII activity levels at or above the plasma levels (in % of normal or in IU/dL) outlined in the table.
Table 1: Dosing for Treatment and Control of Bleeding
Episodes
| Type of Bleeding Episodes | Required peak postinfusion Factor VIII activity (% of normal or IU/dL) | Frequency of Dosing (hours) | Duration of Therapy (days) |
| Minor: Superficial muscle or soft tissue and oral bleeds | 20-40 | 12-24 | At least 1 day, until the bleeding episode is resolved, |
| Moderate to Major: Hemorrhage into muscles, into oral cavity, hemarthrosis, known trauma | 30-60 | 12-24 | For 3-4 days or more until bleeding episode is resolved. |
| Life-threatening: Intracranial, intraabdominal, gastrointestinal or intrathoracic bleeds, central nervous system bleeds, bleeding in retropharyngeal spaces or iliopsoas sheath, eyes/retina, fractures or head trauma | 60-100 | 8-24 | Until bleeding risk is resolved. |
A guide for dosing NUWIQ during surgery (perioperative management) is provided in Table 2. Dosing should aim at maintaining a plasma Factor VIII activity level at or above the plasma levels (in % of normal or in IU/dL) outlined in the table.
Table 2: Dosing for Perioperative Management
| Type of Surgery | Required post-infusion Factor VIII activity (% of normal or IU/dL) | Frequency of Doses (hours) | Duration of Therapy (days) |
| Minor including tooth extraction |
30-60 (pre- and post-operative) |
24 | At least 1 day, until healing is achieved. |
| Major Intracranial, intraabdominal, or joint-replacement therapy |
80-100 (pre- and post-operative) |
8-24 | Until adequate wound healing, then continue therapy for at least another 7 days to maintain a Factor VIII activity of 30% to 60% (IU/dL). |
A guide for dosing NUWIQ for routine prophylaxis to reduce the frequency of bleeding is provided in Table 3. Exact dosing should be defined by the patient's clinical status and response.
Table 3: Dosing for Routine Prophylaxis
| Subjects | Dose (IU/kg) | Frequency of infusions |
| Adolescents [12-17 years] and adults | 30 - 40 | Every other day |
| Children [2 to 11 years] | 30 - 50 | Every other day or three times per week |
NUWIQ package contents:
Detach the filled syringe from the vial adapter by turning counter clockwise.
Figure A to H
 |
Do not refrigerate the solution after reconstitution. Use the solution within 3 hours after reconstitution. If solution is not used within this time period, close the filled syringe with the tamper-proof plastic tip, and discard.
For intravenous use after reconstitution only.
NUWIQ is available as a white, sterile, non-pyrogenic, lyophilized powder for reconstitution in single-use vials containing nominally 250, 500, 1000 or 2000 IU Factor VIII potency.
The actual Factor VIII potency is labeled on each NUWIQ vial.
NUWIQ is supplied in packages comprising a single-use vial containing nominally 250, 500, 1000, or 2000 international units (IU) of Factor VIII potency, a pre-filled syringe with 2.5 mL solvent (Water for Injection), a vial adapter, a butterfly needle and two alcohol swabs. The actual amount of NUWIQ in IU is stated on each carton and vial.
Components used in the packaging of NUWIQ are not made with natural rubber latex.
| Container NDC | Carton NDC | |
| NUWIQ 250 IU | 68982-140-01 | 68982-139-01 |
| NUWIQ 500 IU | 68982-142-01 | 68982-141-01 |
| NUWIQ 1000 IU | 68982-144-01 | 68982-143-01 |
| NUWIQ 2000 IU | 68982-146-01 | 68982-145-01 |
Manufactured by: Octapharma AB, Elersvägen 40, SE-112 75, Sweden. Distributed by: Octapharma USA, Inc., Waterfront Corporate Center, 121 River Street, Suite 1201, Hoboken, NJ 07030. Revised: Sep 2015.
The following serious adverse reactions are described elsewhere in the labeling:
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 the clinical trials of another drug and may not reflect the rates observed in practice.
In clinical trials using triple therapy with omeprazole, clarithromycin, and amoxicillin, no adverse reactions unique to triple therapy were observed. Adverse reactions observed were limited to those previously reported with omeprazole, clarithromycin, or amoxicillin alone. The most frequent adverse reactions observed in clinical trials using combination therapy with omeprazole, clarithromycin, and amoxicillin (n = 274) were diarrhea (14%), taste perversion (10%), and headache (7%). None of these occurred at a higher frequency than that reported by patients taking antimicrobial agents alone.
The safety data below reflect exposure to omeprazole delayed-release capsules and clarithromycin worldwide in clinical trials for various indications using doses and durations of therapy that may differ from how they are used as a component of Omeclamox®-Pak. For complete information on these reactions, see the full prescribing information for omeprazole delayed-release capsules and clarithromycin.
The most common adverse reactions reported (i.e., with an incidence rate ≥ 2%) in 3096 patients from omeprazole delayed-release capsules-treated patients enrolled in clinical trials included headache (6.9%), abdominal pain (5.2%), nausea (4.0%), diarrhea (3.7%), vomiting (3.2%), and flatulence (2.7%).
Additional adverse reactions that were reported with an incidence rate ≥ 1% included acid regurgitation (1.9%), upper respiratory infection (1.9%), constipation (1.5%), dizziness (1.5%), rash (1.5%), asthenia (1.3%), back pain (1.1%), and cough (1.1%).
The clinical trial safety profile in patients greater than 65 years of age was similar to that in patients 65 years of age or less.
The most frequently reported events in adults were diarrhea (3%), nausea (3%), abnormal taste (3%), dyspepsia (2%), abdominal pain/discomfort (2%), and headache (2%). Most of these events were described as mild or moderate in severity. Of the reported adverse events, only 1% were described as severe. Fewer than 3% of adult patients without mycobacterial infections discontinued therapy because of drug-related side effects.
[See ADVERSE REACTIONS]
Because these reactions are voluntarily reported from a population of uncertain size, it is not always possible to reliably estimate their actual frequency or establish a causal relationship to drug exposure.
Body As a Whole: Hypersensitivity reactions including anaphylaxis, anaphylactic shock, angioedema, bronchospasm, interstitial nephritis, urticaria, (see also Skin below); fever; pain; fatigue; malaise.
Cardiovascular: Chest pain or angina, tachycardia, bradycardia, palpitations, elevated blood pressure, peripheral edema.
Endocrine: Gynecomastia.
Gastrointestinal: Pancreatitis (some fatal), anorexia, irritable colon, fecal discoloration, esophageal candidiasis, mucosal atrophy of the tongue, stomatitis, abdominal swelling, dry mouth. During treatment with omeprazole, gastric fundic gland polyps have been noted rarely. These polyps are benign and appear to be reversible when treatment is discontinued. Gastroduodenal carcinoids have been reported in patients with Zollinger-Ellison syndrome on long-term treatment with omeprazole. This finding is believed to be a manifestation of the underlying condition, which is known to be associated with such tumors.
Hepatic: Liver disease including hepatic failure (some fatal), liver necrosis (some fatal), hepatic encephalopathy hepatocellular disease, cholestatic disease, mixed hepatitis, jaundice, and elevations of liver function tests [ALT, AST, GGT, alkaline phosphatase, and bilirubin].
Metabolic/Nutritional: Hypoglycemia, hyponatremia, weight gain.
Musculoskeletal: Muscle weakness, myalgia, muscle cramps, joint pain, leg pain.
Nervous System/Psychiatric: Psychiatric and sleep disturbances including depression, agitation, aggression, hallucinations, confusion, insomnia, nervousness, apathy, somnolence, anxiety, and dream abnormalities; tremors, paresthesia; vertigo.
Respiratory: Epistaxis, pharyngeal pain.
Skin: Severe generalized skin reactions including toxic epidermal necrolysis (some fatal), Stevens-Johnson syndrome, and erythema multiforme; photosensitivity; urticaria; rash; skin inflammation; pruritus; petechiae; purpura; alopecia; dry skin; hyperhidrosis.
Special Senses: Tinnitus, taste perversion.
Ocular: Optic atrophy, anterior ischemic optic neuropathy, optic neuritis, dry eye syndrome, ocular irritation, blurred vision, double vision.
Urogenital: Interstitial nephritis, hematuria, proteinuria, elevated serum creatinine, microscopic pyuria, urinary tract infection, glycosuria, urinary frequency, testicular pain.
Hematologic: Agranulocytosis (some fatal), hemolytic anemia, pancytopenia, neutropenia, anemia, thrombocytopenia, leukopenia, leucocytosis.
Hypersensitivity Reactions: Allergic reactions ranging from urticaria and mild skin eruptions to rare cases of anaphylaxis, Stevens- Johnson syndrome, and toxic epidermal necrolysis have occurred.
Gastrointestinal: Glossitis, stomatitis, oral moniliasis, anorexia, vomiting, pancreatitis, tongue discoloration.
Hematologic: Thrombocytopenia, leukopenia, neutropenia.
Other: There have been reports of tooth discoloration in patients treated with clarithromycin. Tooth discoloration is usually reversible with professional dental cleaning.
Nervous System/Psychiatric: There have been isolated reports of hearing loss, which is usually reversible, occurring chiefly in elderly women. Reports of alterations of the sense of smell, usually in conjunction with taste perversion or taste loss have also been reported.
Transient CNS events including anxiety, behavioral changes, confusional states, convulsions, depersonalization, disorientation, hallucinations, insomnia, manic behavior, nightmares, psychosis, tinnitus, tremor, dizziness and vertigo have been reported during postmarketing surveillance. Events usually resolve with discontinuation of the drug.
Hepatic: Hepatic dysfunction, including increased liver enzymes, and hepatocellular and/or cholestatic hepatitis, with or without jaundice, has been infrequently reported with clarithromycin. This hepatic dysfunction may be severe and is usually reversible. In very rare instances, hepatic failure with fatal outcome has been reported and generally has been associated with serious underlying diseases and/or concomitant medications.
Metabolic: There have been rare reports of hypoglycemia, some of which have occurred in patients taking oral hypoglycemic agents or insulin.
Cardiac: As with other macrolides, clarithromycin has been associated with QT prolongation and ventricular arrhythmias, including ventricular tachycardia and torsades de pointes.
Renal: There have been reports of interstitial nephritis coincident with clarithromycin use.
Gastrointestinal: Nausea, vomiting, diarrhea, and hemorrhagic/Clostridium difficile-associated colitis. Onset of Clostridium difficileassociated diarrhea may occur during or after antibiotic treatment [See WARNINGS AND PRECAUTIONS].
Hypersensitivity Reactions: Serum sickness like reactions, erythematous maculopapular rashes, erythema multiforme, Stevens- Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, hypersensitivity vasculitis and urticaria have been reported. Reactions are more likely to occur in individuals who have previously demonstrated hypersensitivity to penicillins and in those with a history of allergy, asthma, hay fever, or urticaria.
Hepatic: A moderate rise in AST (SGOT) and/or ALT (SGPT) has been noted, but the significance of this finding is unknown. Hepatic dysfunction including cholestatic jaundice, hepatic cholestasis and acute cytolytic hepatitis have been reported.
Renal: Crystalluria has also been reported [See OVERDOSAGE].
Hemic and Lymphatic Systems: Anemia, including hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia and agranulocytosis have been reported during therapy with penicillins. These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena.
Nervous System/Psychiatric: Reversible hyperactivity, agitation, anxiety, insomnia, confusion, behavioral changes, and/or dizziness have been reported rarely.
Miscellaneous: Tooth discoloration (brown, yellow, or gray staining) has been rarely reported. Most reports occurred in pediatric patients. Discoloration was reduced or eliminated with brushing or dental cleaning in most cases.
Changes in laboratory values with possible clinical significance were as follows: Hepatic – elevated SGPT (ALT) less than 1%, SGOT (AST) less than 1%, GGT less than 1%, alkaline phosphatase less than 1%, LDH less than 1%, total bilirubin less than 1%; Hematologic – decreased WBC less than 1%, elevated prothrombin time 1%; Renal – elevated BUN 4%, elevated serum creatinine less than 1%. GGT, alkaline phosphatase, and prothrombin time data are from adult studies only.
Omeprazole is a substrate and an inhibitor of CYP2C19 in vivo, a substrate of CYP3A4 in vivo, and an inhibitor of CYP2C19 in vitro. Therefore, omeprazole may affect the metabolism and plasma concentrations of drugs that are metabolized by these CYP enzymes. Although in healthy subjects no interaction with theophylline or propranolol was reported, there have been reports of an interaction with other drugs metabolized via the CYP enzyme system (e.g., cyclosporine, disulfiram, benzodiazepines). Carefully monitor patients taking these drugs to determine if dosage adjustments of these drugs are necessary when taken concomitantly with omeprazole.
Clarithromycin is a substrate and inhibitor of CYP3A enzymes. Coadministration of clarithromycin with drugs metabolized by CYP3A may be associated with elevations in drug concentrations that could increase the therapeutic and adverse effects of the concomitant drug. There have been reports of CYP3A-based interactions of erythromycin and/or clarithromycin with cyclosporine, tacrolimus, alfentanil, rifabutin, methylprednisolone, cilostazol, and bromocriptine. In addition, there have been reports of interactions of erythromycin or clarithromycin with drugs not thought to be metabolized by CYP3A, including: hexobarbital, phenytoin, and valproate.
Concurrent use of colchicine and Omeclamox®-Pak may increase plasma colchicine concentrations. Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). The clarithromycin component of Omeclamox®-Pak is known to inhibit CYP3A and Pgp. When clarithromycin and colchicine are administered together, inhibition of Pgp and/or CYP3A by clarithromycin may lead to increased plasma exposure to colchicine. Monitor patients for clinical symptoms of colchicine toxicity [See WARNINGS AND PRECAUTIONS].
Ergotamine/dihydroergotamine plasma concentrations may increase when administered concomitantly with Omeclamox®-Pak. Post-marketing reports indicate that coadministration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system. Concomitant administration of clarithromycin with ergotamine or dihydroergotamine is contraindicated [See CONTRAINDICATIONS].
The coadministration of pimozide and Omeclamox®-Pak may increase the pimozide plasma concentrations due to an interaction with the clarithromycin component of Omeclamox®-Pak. Post-marketing reports indicate that coadministration of clarithromycin with pimozide has been associated with cardiac arrhythmias (QT prolongation, ventricular tachycardia, ventricular fibrillation, and torsades de pointes). Two sudden deaths have been reported when clarithromycin was added to ongoing pimozide therapy. Pimozide is metabolized partly by CYP3A4. When clarithromycin and pimozide are administered together, inhibition of CYP3A4 by clarithromycin may lead to increased plasma exposure to pimozide. Omeclamox®-Pak is contraindicated in patients receiving pimozide [See CONTRAINDICATIONS].
Concurrent use of antiarrhythmic drugs and Omeclamox®-Pak may potentiate the antiarrhythmic effects due to an interaction with the clarithromycin component of Omeclamox®-Pak. There have been post-marketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have also been reported in post-marketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Monitor electrocardiograms for QTc prolongation during coadministration of Omeclamox®-Pak with antiarrhythmic drugs. Serum concentrations of antiarrhythmics, including digoxin, should also be monitored.
The simultaneous administration of anticoagulants and Omeclamox®-Pak may alter the anticoagulant effects of warfarin and other oral anticoagulants due to an interaction with the omeprazole and clarithromycin components of Omeclamox®-Pak. Monitor prothrombin time and INR in patients receiving Omeclamox®-Pak and oral anticoagulants simultaneously.
There have been reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Spontaneous reports in the post-marketing period suggest that concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants.
Concurrent use of antiretroviral agents and Omeclamox®-Pak may alter the antiretroviral effects due to interactions with the omeprazole or clarithromycin components of Omeclamox®-Pak. Omeprazole has been reported to interact with some antiretroviral drugs such as atazanavir, nelfinavir, and saquinavir.
Concomitant use of atazanavir or nelfinavir with omeprazole is not recommended unless the benefits of taking atazanavir or nelfinavir with Omeclamox®-Pak outweigh the risks. Coadministration of atazanavir or nelfinavir with proton pump inhibitors is expected to substantially decrease atazanavir or nelfinavir plasma concentrations and thereby reduce the therapeutic effect of either of these drugs [See CLINICAL PHARMACOLOGY].
Coadministration of saquinavir with omeprazole may increase the serum concentrations of saquinavir. Dose reduction of saquinavir should be considered when coadministered with Omeclamox®-Pak [See CLINICAL PHARMACOLOGY].
Concomitant administration of Omeclamox®-Pak and cilostazol may increase systemic exposure of cilostazol due to an interaction with the omeprazole component of Omeclamox®-Pak. Therefore, a dose reduction of cilostazol by 50% should be considered when concomitantly administered with Omeclamox®-Pak [See CLINICAL PHARMACOLOGY].
Concomitant administration of Omeclamox®-Pak and tacrolimus may increase the serum concentrations of tacrolimus due to an interaction with the omeprazole component of Omeclamox®-Pak. Frequent monitoring of whole blood trough concentrations of tacrolimus is recommended when concomitantly administered with Omeclamox®-Pak.
Omeclamox®-Pak use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations due to an interaction with the clarithromycin component of Omeclamox®-Pak. Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range [See CLINICAL PHARMACOLOGY].
The simultaneous administration of carbamazepine and Omeclamox®-Pak may alter the effect of carbamazepine due to an interaction with the clarithromycin component of Omeclamox®-Pak. Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine should be considered when administered concomitantly with Omeclamox®-Pak.
The systemic exposure of sildenafil may increase when it is administered concomitantly with Omeclamox®-Pak due to an interaction with the clarithromycin component of Omeclamox®-Pak; consider a reduction in sildenafil dosage (see sildenafil full prescribing information).
Concurrent use of HMG-CoA reductase inhibitors (statins) and Omeclamox®-Pak may alter the effect of HMG-CoA due to an interaction with the clarithromycin component of Omeclamox®-Pak. As with other macrolides, clarithromycin has been reported to increase concentrations of statins (e.g., lovastatin and simvastatin). Rare reports of rhabdomyolysis have been reported in patients taking these drugs concomitantly.
The effect of triazolobenziodidiazepines/related benzodiazepines may be altered when administered concomitantly with Omeclamox®- Pak due to an interaction with the clarithromycin component. There have been postmarketing reports of drug interactions and CNS effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam.
Probenecid decreases the renal tubular secretion of amoxicillin. Concurrent use of Omeclamox®-Pak and probenecid may result in increased and prolonged blood concentrations of the amoxicillin component of Omeclamox®-Pak.
Due to its effects on gastric acid secretion, omeprazole can reduce the absorption of drugs where gastric pH is an important determinant of their bioavailability. As with other drugs that decrease the intragastric acidity, the absorption of drugs such as ketoconazole, atazanavir, iron salts, erlotinib, and mycophenolate mofetil can decrease, while the absorption of drugs such as digoxin can increase during treatment with omeprazole.
Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (30% in two subjects). Coadministration of digoxin with omeprazole is expected to increase the systemic exposure of digoxin. Therefore, patients may need to be monitored when digoxin is taken concomitantly with omeprazole.
Coadministration of omeprazole in healthy subjects and in transplant patients receiving mycophenolate mofetil has been reported to reduce the exposure to mycophenolic acid (MPA), the active moiety, possibly due to a decrease in MPA solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving proton pump inhibitors (PPIs) and mycophenolate mofetil. Use omeprazole with caution in transplant patients receiving mycophenolate mofetil [See CLINICAL PHARMACOLOGY].
High urine concentrations of ampicillin may result in false-positive reactions when testing for the presence of glucose in urine using Clinitest,® Benedict's Solution or Fehling's Solution. Since this effect may also occur with amoxicillin, it is recommended that glucose tests based on enzymatic glucose oxidase reactions (such as Clinistix®) be used.
Following administration of ampicillin to pregnant women, a transient decrease in plasma concentration of total conjugated estradiol, estriol-glucuronide, conjugated estrone, and estradiol has been noted. This effect may also occur with amoxicillin.
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.
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.
No information provided.
Included as part of the PRECAUTIONS section.
Hypersensitivity reactions, including anaphylaxis, are possible with NUWIQ. Early signs of hypersensitivity reactions that can progress to anaphylaxis may include angioedema, chest tightness, dyspnea, wheezing, urticaria, or pruritus. Immediately discontinue administration and initiate appropriate treatment if hypersensitivity reactions occur.
The formation of neutralizing antibodies (inhibitors) to Factor VIII can occur following the administration of NUWIQ. Monitor all patients for the development of Factor VIII inhibitors by appropriate clinical observations and laboratory tests. If the plasma Factor VIII level fails to increase as expected, or if bleeding is not controlled after NUWIQ administration, suspect the presence of an inhibitor (neutralizing antibody) [see Monitoring And Laboratory Tests].
Long-term studies in animals to evaluate the carcinogenic potential of Nuwiq or studies to determine the effects of Nuwiq on genotoxicity or fertility have not been performed.
There are no data with NUWIQ use in pregnant women to inform a drug-associated risk. Animal reproduction studies have not been conducted with NUWIQ. It is not known whether NUWIQ can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. NUWIQ should be given to a pregnant woman only if clearly needed. In the U.S. general population, the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
There is no information regarding the presence of NUWIQ in human milk, the effect on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for NUWIQ and any potential adverse effects on the breastfed infant from NUWIQ or from the underlying maternal condition.
Safety and efficacy studies were performed in 59 previously treated pediatric patients (58 patients 2 to 11 years old) who received at least one dose of NUWIQ for routine prophylaxis. Efficacy in routine prophylaxis and on-demand treatment of bleeding episodes is comparable between children and adults [see Clinical Studies]. The children received a total of 5746 infusions. Of these infusions, 5316 (93%) were for prophylaxis, 216 (4%) for the treatment of bleeding episodes, 41 (0.7%) for peri-operative management and 173 (3%) for pharmacokinetic (PK) and recovery assessments. For two adverse events (mild back pain, mild headache) in two (3%) subjects, causality was rated as possibly related to NUWIQ administration. The pediatric pharmacokinetic data of NUWIQ were obtained in 29 children between 2 and 5 years of age and 30 children between 6 and ≤ 12 years of age. Half-life (T½) and incremental in vivo recovery (IVR) are lower in children than in adults and systemic drug clearance is substantially higher in the pediatric age group 2 to 5 yrs compared to adults [see CLINICAL PHARMACOLOGY]. Higher doses and/or a more frequent dosing schedule for prophylactic treatment should be considered in pediatric patients aged 2 to 5 yrs.
Clinical studies of NUWIQ did not include sufficient numbers of subjects age 65 and over to provide conclusive evidence as to whether or not they respond differently than younger subjects.
No information provided.
NUWIQ is contraindicated in patients who have manifested life-threatening hypersensitivity reactions, including anaphylaxis, to the product or its components.
NUWIQ temporarily replaces the missing clotting Factor VIII that is needed for effective hemostasis.
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.
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 Parameters | Mean ± SD |
| AUC (hIU/mL) | 18.0 ± 5.6 |
| AUCnorm (hIU/mL/(IU/kg)) | 0.4 ± 0.1 |
| Cmaxnorm (IU/mL/(IU/kg)) | 0.022 ± 0.003 |
| T½ (h) | 17.1 ± 11.2* |
| IVR (%/IU/kg) | 2.1 ± 0.3 |
| MRT (h) | 22.5 ± 14.2 |
| CL (mL/h/kg) | 3.0 ± 1.0 |
| Vss (mL/kg) | 59.8 ± 19.8 |
| AUC = Area under the curve (Factor VIII:C); AUCnorm = AUC
divided by the dose; Cmaxnorm = Maximal plasma concentration divided by the
dose; CL = Clearance;Factor VIII:C = Factor VIII coagulation activity; IVR =
Incremental in vivo recovery; MRT = Mean residence time; PK = Pharmacokinetics;
SD = Standard deviation; T½ = Terminal half-life; Vss = Volume of
distribution at steady state; *Median, lower/upper quartile: 13.7, 12.0/17.5 |
|
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)
| PK Parameters | 2 to 5 years (N = 13) Mean ± SD |
6 to ≤ 12 years (N = 13) Mean ± SD |
| AUC (h•U/mL) | 10.1 ± 4.6 | 11.8 ± 2.7 |
| AUCnorm (h•U/mL/(IU/kg)) | 0.2 ± 0.1 | 0.3 ± 0.1 |
| Cmaxnorm (IU/mL/(IU/kg)) | 0.016 ± 0.002 | 0.017 ± 0.004 |
| T½ (h) | 11.9 ± 5.4* | 13.1 ± 2.6# |
| IVR (%/IU/kg) | 1.6 ± 0.2 | 1.6 ± 0.4 |
| MRT (h) | 15.1 ± 7.4 | 16.5 ± 2.9 |
| CL (mL/h/kg) | 5.4 ± 2.3 | 4.1 ± 0.9 |
| Vss (mL/kg) | 68.3 ± 10.4 | 66.1 ± 16.0 |
| AUC = Area under the curve (Factor VIII:C); AUCnorm = AUC divided by the dose; Cmaxnorm = Maximal plasma concentration divided by the dose; CL = Clearance;Factor VIII:C = Factor VIIIcoagulation activity; IVR = Incremental in vivo recovery; MRT = Mean residence time; PK = Pharmacokinetics; SD = Standard deviation; T½ = Terminal half-life; Vss = Volume of distribution at steady state; *Median, lower/upper quartile: 10.1, 9.4/13.7; #Median, lower/upper quartile: 12.8, 11.2/15.9 | ||
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
| Adults (N=32) |
Children (N=59) |
|
| Mean dose (± standard deviation) | 32.8 ± 2.8 IU/kg | 38.9 ± 7.2 IU/kg |
| Subjects with 0 bleeding episodes | 16 (50.0%) | 20 (33.9%) |
| Subjects with 1 bleeding episode | 11 (34.4%) | 14 (23.7%) |
| Subjects with 2 bleeding episodes | - | 3 (5.1%) |
| Subjects with > 3 bleeding episodes | - | 22 (37.3%) |
| Subjects with > 5 bleeding episodes | 5 (15.6%) | |
| Annualized bleeding rate (per subject) - spontaneous bleeds | 1.16 ± 2.57 (median 0, range 0-8.6) | 1.50 ± 3.32 (median 0, range 0-13.8) |
| Annualized bleeding rate (per subject) for all types of bleeds | 2.28 ± 3.73 (median 0.9, range 014.7) | 4.12 ± 5.22 (median 1.90, range 020.7) |
| Reduction in annualized bleeding rate compared to on-demand treatment in a different study* | 96% | 93% |
| Severity of bleeds (% of bleeds) in the adults were major
16 (36.4%), minor – 28 (63.6%), life threatening 0. Severity of bleeds in the
children were moderate or major 64 (42.6%), minor 61 (56.5%), unknown 1 (0.9%),
life threatening 0. * Based on a negative binomial model. |
||
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
NUWIQ/nu' veek / Antihemophilic Factor
(Recombinant) Intravenous Infusion
Please read this Patient Information carefully before using NUWIQ and each time you get a refill, as there may be new information. This Patient Information does not take the place of talking with your healthcare provider about your medical condition or your treatment.
What is NUWIQ?
NUWIQ is an injectable medicine that is used to help treat and control bleeding in adults and children with Hemophilia A (congenital clotting Factor VIII deficiency). NUWIQ can reduce the number of bleeding episodes in children and adults when used regularly (prophylaxis). Usually, Hemophilia A treatment is life-long.
Your healthcare provider may also give you NUWIQ when you have surgery.
NUWIQ is NOT used to treat von Willebrand disease.
Who should not use NUWIQ?
You should not use NUWIQ if you had an allergic reaction to it in the past.
Tell your healthcare provider if you are (or are planning to become) pregnant and/or breastfeeding because NUWIQ may not be right for you.
What should I tell my healthcare provider before using NUWIQ?
Talk to your healthcare provider about any medical conditions that you have or have had, including if you have been told that you have inhibitors to Factor VIII, because NUWIQ may not work for you.
Tell your healthcare provider about all of the prescription and non-prescription medicines you take, including over-the-counter medicines, dietary supplements, and/or herbal medicines.
How should I use NUWIQ?
You get NUWIQ as an infusion into your vein. NUWIQ is sold as a powder in a vial. The powder is mixed with sterile water supplied in a prefilled syringe. See instructions for reconstitution and injection of NUWIQ.
Your healthcare provider will instruct you on how to do reconstitutions and infusions on your own or with the help of a family member. Your healthcare provider may watch you give yourself the first dose of NUWIQ .
You must carefully follow your healthcare provider's instructions regarding the dose and schedule for infusing NUWIQ so that your treatment will work optimally for you.
NUWIQ comes in different dosage strengths. The actual number of international units (IU) of Factor VIII in the vial will be printed on the label and box. Always check the actual number of IU of Factor VIII printed on the label to make sure you are using the strength prescribed by your healthcare provider.
Contact your healthcare provider right away if bleeding is not controlled after using NUWIQ .
Talk to your healthcare provider before travelling. Plan to bring enough NUWIQ for your treatment during this time.
Do not stop using NUWIQ without consulting with your healthcare provider.
What are the possible side-effects of NUWIQ?
Allergic reactions may occur with NUWIQ. Stop the injection immediately and call your healthcare provider or emergency department right away if you have any of the following symptoms: dizziness, loss of consciousness, difficulty breathing, wheezing, chest tightness, swelling of lips and tongue, rash, or hives.
Your body can also make antibodies (known as inhibitors) against Factor VIII, which may stop NUWIQ from working properly. Your healthcare provider may test your blood to check for inhibitors at regular intervals.
Side-effects that have been reported with NUWIQ include: injection site inflammation, injection site pain, prickling or tingling sensation, headache, back pain, dizziness, and dry mouth.
These are not all the possible side effects of NUWIQ. Talk to your healthcare provider about any side-effect that bothers you or that does not go away.
How should I store NUWIQ?
Keep NUWIQ in its original box to protect it from exposure to light. Do not freeze NUWIQ .
You can store NUWIQ in the refrigerator for up to 24 months at 2-8°C (36-46°F). NUWIQ can be kept at room temperature [up to 25°C (77°F)] for a single period not exceeding 3 months (note on the carton the date when the product was removed from the refrigerator). After storage at room temperature, the product must be used or discarded, and it must not be put back into the refrigerator.
Do not use NUWIQ after the expiration date printed on the vial.
Do not use NUWIQ if the reconstituted solution is cloudy, contains particles, and/or is not colorless.
NUWIQ should be used as soon as possible after reconstitution. Protect reconstituted NUWIQ from light and temperatures above 25°C (77°F). Discard any product not used within three hours.
Dispose of all materials, including any unused NUWIQ , in an appropriate container.
What else should I know about NUWIQ?
Do not use NUWIQ for a medical condition for which it was not prescribed. Do not share NUWIQ with other people, even if they have the same diagnosis and symptoms that you have.
Recredits at Octapharma available to patients
For more product information on NUWIQ, please visit www.NUWIQ.com.
For more information on patient assistance programs that are available to you, please contact the Octapharma Patient Support Center at 1-800-554-4440.
For more information on additional Octapharma patient recredits, please visit www.NUWIQ.com.
Instructions for Use
NUWIQ/nu' veek / Antihemophilic Factor
(Recombinant)
Read these instructions carefully before using NUWIQ for the first time. You should ensure that you have the appropriate training from your healthcare provider or hemophilia treatment center before attempting a self-infusion of NUWIQ. Always follow the prescribed dose and specific instructions given by your healthcare provider. The general guidelines for mixing and infusing NUWIQ are listed below. If you are unsure of any of these steps, please contact your healthcare provider before using NUWIQ.
Instruction for Mixing NUWIQ
Figure A to H
 |
Instructions for Injecting NUWIQ
For intravenous use after reconstitution only.
