Fibrogammine

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Fibrogammine uses

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• References
• How supplied/storage and handling
• Patient counseling information
• Patient package insert
• Fibrogammine reviews

1 INDICATIONS AND USAGE

Fibrogammine, Fibrogammine A-Subunit (Recombinant), is indicated for routine prophylaxis for bleeding in patients with congenital factor XIII A-subunit deficiency.

Fibrogammine is not for use in patients with congenital factor XIII B‑subunit deficiency

Fibrogammine, Fibrogammine A-Subunit (Recombinant), is indicated for routine prophylaxis of bleeding in patients with congenital factor XIII A-subunit deficiency. (1)

Fibrogammine is not for use in patients with congenital factor XIII B‑subunit deficiency. (1)

2 DOSAGE AND ADMINISTRATION

For intravenous use only.

For intravenous use only.

Dose:

• 35 international units per kilogram body weight once monthly to achieve a target trough level of FXIII activity at or above 10% using a validated assay.
• Consider dose adjustment if adequate coverage is not achieved with a 35 IU/kg dose. (2.1)
• Once reconstituted, Fibrogammine may be diluted with 0.9% sodium chloride to facilitate measurement of small volumes. (2.2)

Rate: Do not exceed 1-2 mL per minute. (2.3)

2.1 Dose

• Treatment should be initiated under the supervision of a physician experienced in the treatment of rare bleeding disorders.
• The dose for routine prophylaxis for bleeding in patients with congenital factor XIII (FXIII) A-subunit deficiency is 35 international units (IU) per kilogram body weight once monthly to achieve a target trough level of FXIII activity at or above 10% using a validated assay.
• Consider dose adjustment if adequate coverage is not achieved with the recommended 35 IU/kg dose.
• A pharmacokinetic study was conducted in the FXIII congenitally deficient population evaluating five dose cohorts (2, 7, 24, 60 and 89 IU/kg) with blood sampling at 0.5, 1, 4, 8, 24, 48, 72 hours, and 7, 14, and 28 days. Samples were tested for FXIII activity by a chromogenic assay and for FXIII A₂B₂ tetramer levels by an ELISA, as well as for other analytes. It was found that FXIII tetramer levels were proportional to the observed FXIII activity up to the point of replacement of 100% of normal FXIII activity, but there was no increase in FXIII tetramer levels at higher levels of FXIII activity. A dose of 35 IU/kg is sufficient to replace 100% of FXIII activity in this population, and higher doses may not increase the levels of tetrameric Factor XIII.

2.2 Reconstitution

Reconstitute only with sterile water for injection. The product can be reconstituted using the vial adapter included or a needle.

Reconstitute using the following procedures:

• 1. Use aseptic technique.
• 2. Wash hands before starting.
• 3. Bring Fibrogammine (white lyophilized powder) and sterile water for injection (diluent) to room temperature, but not above 25°C (77°F).
• 4. Remove the plastic caps from the two vials.
• 5. Clean the rubber stoppers on the vials with sterile alcohol swabs and allow them to dry before use.
• 6. Remove the protective paper from the vial adapter, but do not unscrew the protective cap. Attach the vial adapter to the diluent vial, without taking the vial adapter out of the protective cap. Once attached, remove the protective cap from the vial adapter by lightly squeezing the protective cap with your thumb and index finger as shown on the figure below.

• 7. Draw back the plunger of the sterile syringe and admit a volume of 3.2 mL air into the syringe.

• 8. Screw the syringe onto the vial adapter on the diluent vial.

• 9. Inject the air from the syringe into the diluent vial until resistance is felt. Then hold the syringe with the diluent vial upside down and withdraw 3.2 mL water into the syringe.

• 10. Remove the empty diluent vial by tipping the syringe with the attached vial adapter.

• 11. Attach the syringe with the vial adapter to the powder vial. Hold the syringe slightly tilted with vial facing downwards. Push the plunger slowly to inject all water (3.2 mL) into the powder vial. Do not inject the diluent directly on the Fibrogammine powder to avoid foaming.

• 12. Gently swirl the vial until all material is dissolved. Do not shake the vial. The reconstituted Fibrogammine is a clear and colorless solution. Use the reconstituted Fibrogammine immediately. If not, store the solution refrigerated or at room temperature not to exceed 25°C (77°F) for up to three hours. Discard after three hours.

• NOTE:

• For larger dose that requires multiple vials of Fibrogammine, reconstitute each additional vial using the same procedure with a separate syringe.
• For smaller dose that requires less than the full volume in the vial, reconstituted Fibrogammine may be diluted with 0.9% sodium chloride to facilitate measurement of small volumes. Discard remaining product.
• For home administration, any such changes should be communicated by the pharmacist or healthcare provider to the patient or family.

Fibrogammine Vial and Adapter Remoal of the protective paper Attach the vial adapter Draw back the plunger Screw the syringe Inject air from the plunger Remove the empty diluent vial Attach the syringe to the powder vial Gently swirl the vial

2.3 Administration

• Inspect the reconstituted Fibrogammine visually for particulate matter and discoloration prior to administration. Do not use if particulate matter or discoloration is observed.
• Administer at a rate not exceeding 1-2 mL per minute.
• Do not administer with other infusion solutions.
• Do not administer as drip.

3 DOSAGE FORMS AND STRENGTHS

Fibrogammine, Fibrogammine A-Subunit (Recombinant), is available as a white lyophilized powder in single-use vial containing nominally 2500 IU per vial (2000 – 3125 IU) of recombinant Fibrogammine A-subunit. The actual amount of Fibrogammine in IU is stated on each carton and vial.

After reconstitution with the provided Sterile Water for Injection, each vial contains 667-1042 IU/mL recombinant Fibrogammine A-subunit.

• Lyophilized powder in single-use vial containing 2000 - 3125 IU of recombinant Fibrogammine A-subunit.
• After reconstitution with 3.2 mL of sterile water for injection, each vial contains 667-1042 IU/mL of recombinant Fibrogammine A-subunit.

4 CONTRAINDICATIONS

Fibrogammine is contraindicated in patients who have known hypersensitivity to the active substance or to any of the excipients .

Hypersensitivity to the active substance or to any of the excipients. (4)

5 WARNINGS AND PRECAUTIONS

• Discontinue if allergic or hypersensitivity reactions occur.
• Monitor patients for thrombosis. (5.2)
• Analyze for neutralizing antibodies if FXIII activity fails to reach expected levels or if reduced therapeutic effect is observed. (5.3)

5.1 Hypersensitivity Reactions

Fibrogammine may cause allergic reactions. If signs or symptoms of anaphylaxis or hypersensitivity reactions (including urticaria, rash, tightness of the chest, wheezing, hypotension) occur, discontinue immediately and institute appropriate treatment.

5.2 Thromboembolic Risk

Thromboembolic complications may occur. Monitor patients with conditions that predispose to thrombosis for signs and symptoms of thrombosis after administration of Fibrogammine.

5.3 Inhibitors

Inhibitory antibodies may occur with Fibrogammine. Patients with inhibitory antibodies may manifest as an inadequate response to treatment. If expected plasma FXIII activity levels are not attained, or if breakthrough bleeding occurs while receiving prophylaxis, perform an assay that measures FXIII inhibitory antibody concentrations.

6 ADVERSE REACTIONS

The most common adverse reactions reported in clinical trials, were headache, pain in the extremities, injection site pain, and increase in fibrin D dimer levels.

The most common adverse reactions reported in the clinical trials (≥1%) were headache, pain in the extremities, injection site pain, D dimer increase. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc. at 1-844-873-8836 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 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 the clinical trials of another drug and may not reflect the rates observed in practice.

During clinical development, Fibrogammine was administered to 77 subjects with congenital factor XIII A-subunit deficiency (3:2, male: female ratio) for a total of 1990 doses. Fifty subjects (65%) were between the ages of 18 and 77 years (received 1338 doses), 21 subjects (27%) were between the ages of 6 and less than 18 years old (received 560 doses), and 6 subjects (8%) were less than 6 years old (received 92 doses). Subjects were exposed for up to 4.5 years.

Of the 77 subjects, 68 received 1979 monthly doses of 35 IU/kg of Fibrogammine for routine prophylaxis of bleeding. Eleven single doses of Fibrogammine have been administered to nine subjects for pharmacokinetic investigations.

The adverse drug reactions reported included headache, pain in the extremities, pain at the injection site, and increase in fibrin D dimer levels (without evidence of thromboembolic events).

Immunogenicity

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 Fibrogammine with the incidence of antibodies to other products may be misleading.

Transient non-neutralizing antibodies were seen in one out of 50 healthy subjects after one dose, four out of 77 trial subjects (age < 18 years) with congenital factor XIII A-subunit deficiency after one or two doses (3 discontinued from the trial), and in one subject (age < 18 years) in a post marketing safety study after 3.5 years of treatment. In two subjects, the non-neutralizing antibodies disappeared after continued treatment with Fibrogammine. In all cases, the non-neutralizing antibodies were found to be of no clinical significance. No subjects developed neutralizing antibodies (inhibitors) against Fibrogammine during clinical trials.

7 DRUG INTERACTIONS

Thrombosis may occur if Fibrogammine is administered concomitantly with factor VIIa .

• Do not administer Fibrogammine with recombinant factor VIIa. (7)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no adequate and well-controlled studies using Fibrogammine in pregnant women to determine whether there is a drug-associated risk. Animal reproduction studies have not been conducted with Fibrogammine.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Miscarriage is a known complication of congenital FXIII deficiency. Pooling data from 39 publications, the miscarriage rate was 66% in 63 patients with 192 pregnancies. Miscarriage rate was 91% in the 136 pregnancies without routine prophylaxis with FXIII concentrates and 11% in the 45 pregnancies treated with routine FXIII prophylaxis².

8.2 Lactation

Risk Summary

There is no information regarding the presence of Fibrogammine in human milk, the effect on the breastfed infant, and the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Fibrogammine and any potential adverse effects on the breastfed infant from Fibrogammine or from the underlying maternal condition.

8.4 Pediatric Use

Pediatric subjects in the phase 3 study and the extension study included 6 children in the age range 0-5, 12 children in the age range 6-12, and 9 adolescents in the age range 13-17 who were treated with Fibrogammine for a total of 652 exposures. Adverse reactions were more frequently reported in subjects aged from 6 to less than 18 years old than in adults; a greater number of possible/probably trial drug related events were reported in the subjects below 18 years of age than in those above 18 years (3 subjects with 3 events in 41 enrolled subjects). Three subjects under 18 years experienced non-neutralizing antibodies and were withdrawn from the study. A fourth pediatric subject who had a non-neutralizing antibody remained in the trial. No dose adjustment is required for pediatric age group.

8.5 Geriatric Use

The safety and efficacy of Fibrogammine in the geriatric population have not been established due to an insufficient number of patients.

10 OVERDOSAGE

One subject accidentally received a dose 2.3 times the recommended dose. No clinical signs and symptoms were observed.

11 DESCRIPTION

Fibrogammine, Fibrogammine A-Subunit (Recombinant), is a recombinant human factor XIII-A₂ homodimer composed of two factor XIII (FXIII) A-subunits. The FXIII A-subunit is a 731 amino acid chain with an acetylated N-terminal serine. When FXIII is activated by thrombin, a 37 amino acid peptide is cleaved from the N-terminus of the A‑subunit.

Fibrogammine is manufactured as an intracellular, soluble protein in yeast (Saccharomyces cerevisiae) production strain containing the episomal expression vector, pD16. It is subsequently isolated by homogenization of cells and purification by several chromatography steps, including hydrophobic interaction and ion exchange chromatography. No human or animal derived products are used in the manufacturing process.

Fibrogammine is supplied as a sterile, white lyophilized powder in a single use vial. Table 1 and Table 2 list the vial content of reconstituted Fibrogammine and the diluent, respectively.

Content	Per Vial*	Function
Fibrogammine A-Subunit (Recombinant)	2000 - 3125 IU	Active substance
Sodium Chloride	8.70 mg	Stabilizer
Sucrose	174.0 mg	Stabilizer
Polysorbate 20	0.30 mg	Surfactant
L-Histidine	9.30 mg	Buffer

*Values are given per 3 mL reconstituted Fibrogammine.

Content	Per Vial	Function
Sterile Water for Injection	3.2 mL	Diluent

After reconstitution with 3.2 mL sterile water for injection, each vial contains 667-1042 IU/mL of recombinant Fibrogammine A-subunit. The reconstituted solution has a pH of approximately 8.0. The formulation contains no preservative and must only be administered intravenously.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

FXIII is the terminal enzyme in the blood coagulation cascade. When activated by thrombin at the site of vessel wall injury, FXIII plays an important role in the maintenance of hemostasis through cross-linking of fibrin and other proteins in the fibrin clot.

In plasma, FXIII circulates as a heterotetramer [A₂B₂] composed of two FXIII A-subunits and two FXIII B-subunits held together by strong non-covalent interactions. The FXIII A is the catalytic subunit and FXIII B-subunit acts as carrier molecule for the FXIII A-subunit in circulation, and is present in excess in plasma. When FXIII A-subunit is bound to FXIII B-subunit [A₂B₂] the half-life of the FXIII A-subunit [A₂] is prolonged. FXIII is a pro-enzyme, which is activated by thrombin in the presence of Ca²⁺. The enzymatic activity resides with the FXIII A-subunit. Upon activation, the FXIII A‑subunit dissociates from the FXIII B-subunit and thereby exposes the active site of the FXIII A-subunit. The active transglutaminase cross-links fibrin and other proteins resulting in increased mechanical strength and resistance to fibrinolysis of the fibrin clot and contributes to enhance platelet and clot adhesion to injured tissue.

Fibrogammine A-Subunit (Recombinant) is a protransglutaminase (rFXIII [rA₂] homodimer) and binds to free human FXIII B-subunit resulting in a heterotetramer [rA₂B₂] with a similar half-life to [A₂B₂]. rFXIII has been shown to be activated by thrombin in the presence of Ca²⁺. Activated rFXIII has been shown in dose-dependent manner to increase mechanical strength of fibrin clots, retard fibrinolysis, and rFXIII has been shown to enhance platelet adhesion to the site of injury. After combining with available plasma B-subunits, Fibrogammine A-subunit (Recombinant) has been shown to have the same pharmacodynamic properties in plasma as endogenous FXIII.

12.2 Pharmacodynamics

A qualitative assay of clot solubility is widely used as an indicator of FXIII deficiency; when performed correctly the test is positive only when the FXIII activity in the sample is close to zero. The results of standard coagulation tests are normal as it is the quality of the clot that is affected. In addition, at present there are no markers that can quantitatively assess the in vivo pharmacodynamics of FXIII.

12.3 Pharmacokinetics

Steady State in Subjects with Congenital Factor XIII Deficiency

In 23 subjects with congenital FXIII A-subunit deficiency on prophylaxis, the pharmacokinetics of rFXIII were evaluated over a dosing interval of 28 days during steady state.

The pharmacokinetic parameters based on steady state baseline adjusted FXIII activity (Berichrom assay) values are shown in Table 3.

• Table 3 Pharmacokinetic parameters based on steady state baseline adjusted FXIII activity

Parameters	Mean (SD)
Css, max (IU/mL)	0.71 (0.17)
Css, min (IU/mL)	0.05 (0.05)
AUC(0-inf) (IU*h/mL)	128.3 (40.5)
Clearance (mL/h/kg)	0.33 (0.11)
Half-life (days)	5.1 (2.6)
Vss (mL/kg)	65.9 (26.9)
MRT (days)	7.9 (3.4)

At steady state, the pharmacokinetics of rFXIII are comparable with the single dose pharmacokinetics of rFXIII.

Pediatric (Ages 1 to < 6 Years Old)

In a pharmacokinetic trial six children with congenital FXIII A-subunit deficiency on prophylaxis treatment were administered a single intravenous dose of 35 IU/kg. The pharmacokinetic parameters based on baseline adjusted FXIII activity (Berichrom assay) values are shown in Table 4. No dose adjustment is needed for pediatric patients as there is no influence of age on the pharmacokinetics of Fibrogammine.

• Table 4 The pharmacokinetic parameters based on baseline adjusted FXIII activity

Parameters	Mean (SD)
Cmax (IU/mL)	0.48 (0.14)
AUC(0-inf) (IU*h/mL)	107.8 (32.2)
Clearance (mL/h/kg)	0.41 (0.20)
Half-life (days)	7.1 (1.9)
Vss (mL/kg)	61.2 (41.0)
MRT (days)	7.5 (4.8)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals to evaluate the carcinogenic potential of Fibrogammine, or studies to determine the effects of Fibrogammine on genotoxicity or fertility have not been performed. An assessment of the carcinogenic potential of Fibrogammine was completed and suggests minimal carcinogenic risk from product use.

13.2 Animal Toxicology and/or Pharmacology

Exaggerated pharmacologic effects, including general thrombosis, ischemic necrosis and mortality were observed in nonclinical studies with Fibrogammine and non-proteolytically activated recombinant FXIII at a dose of 1670 IU/kg, i.e., 48 times the recommended human dose of 35 IU/kg.

In a monkey cardiovascular safety pharmacology model evaluating the combination of excessive doses of Fibrogammine (585 IU/kg, 17 times the expected human dose) in combination with rFVIIa (1000 mcg/kg, 11 times the expected human dose), one of the twelve monkeys died 4 hours after treatment due to thrombosis. Procoagulant risk factors, including 6 indwelling catheters per monkey and the induction of anesthesia, may have complicated the study results. It is unclear whether the mortality was related to the overdose of one or both products, or a specific interaction between them. Nonclinical and clinical studies with the combination of Fibrogammine and rFVIIa at recommended human doses have not been performed.

14 CLINICAL STUDIES

To establish the efficacy of Fibrogammine for the prevention of bleeding in patients with congenital FXIII A-subunit deficiency, a multi-center, open-label, non-controlled trial was conducted for 52 weeks in forty-one (41) subjects ≥ 6 years. All subjects received monthly doses of Fibrogammine at 35 IU/kg. Bleeding episodes that required treatment with a FXIII-containing product were observed to evaluate the efficacy of monthly replacement therapy with Fibrogammine on prevention of bleeding episodes.

Subjects with congenital FXIII A-subunit deficiency confirmed by genotyping were included. Subjects who before entering the trial had received regular replacement therapy were to have initiated regular replacement therapy at least 6 months prior to screening and were to have a documented history of at least one treatment-requiring bleeding episode before initiation of regular replacement therapy or a documented family history of FXIII congenital deficiency. Subjects who before entering the trial had only received on-demand treatment were to have a documented history of at least two treatment-requiring bleeding episodes within 12 months of the screening visit. Severe bleeders as defined by a documented history of ≥2 treatment requiring bleedings per year during regular FXIII replacement therapy were excluded.

During the prophylaxis treatment period with Fibrogammine (434 subject months), five bleeding episodes treated with FXIII-containing products were observed in four subjects. All five were associated with trauma. When calculated for all 41 subjects, this translated into a mean annual rate of bleeding episodes that required treatment of 0.14 [95% CI:0.058- 0.332] per subject year, which was statistically significantly lower than the historic bleeding rate of 1.68 per subject year for on-demand treatment. The age-adjusted rate of bleeding episodes that required treatment during the Fibrogammine treatment period was 0.05 [95% CI: 0.0094 - 0.2501] per subject year with a model-based estimate corresponding to the mean age of 26.4 years. The mean annual bleeding rate in subjects below 18 years of age was higher compared to that in adults (0.362 versus 0.040 bleeds/subject/year). Table 5 below lists the estimated bleeding rates by age.

• Table 5 Estimated Bleeding Rates by Age

Group	N	Estimated Bleeding Rate (bleeds/subject/year)	95% CI	Historical Control Group Estimated Bleeding Rate (bleeds/subject/year)
All	41	0.138	[0.058; 0.332]	1.68
< 18 years	15	0.362	[0.136; 0.963]	2.00
≥ 18 years	26	0.040	[0.006; 0.283]	1.59

Thirty-four (34) of the 41 subjects and an additional 21 new subjects were enrolled in an ongoing second trial. During a total treatment period of 107.5 subject years (mean of 1.95 years per subject), 5 subjects experienced 6 bleeds that required treatment with a FXIII-containing product. The mean annual rate of bleeding episodes that required treatment was determined to be 0.056 per subject year. The age-adjusted rate of bleeding episodes that required treatment during the Fibrogammine treatment period was 0.022 per subject year [95% CI:0.0045; 0.1023] with a model-based estimate corresponding to a mean age of 29.5 years. The annual mean bleeding rate in subjects below age 18 was higher compared to that in adults (0.127 versus 0.026 bleeds/subject/year) with some overlap of the respective 95% confidence intervals. Table 6 lists the estimated bleeding rates by age.

• Table 6 Estimated Bleeding Rates by Age

Group	N	Estimated Bleeding Rate (bleeds/subject/year)	95% CI
All	55	0.056	[0.025; 0.124]
< 18 years	16	0.127	[0.048; 0.339]
≥ 18 years	39	0.026	[0.007; 0.105]

15 REFERENCES

• Inbal, A., et.al.:Recombinant factor XIII: a safe and novel treatment for congenital factor XIII deficiency, Blood. 2012;119(22): 5111-5117
• Sharief, LAT., Kadir RA.:Congenital factor XIII deficiency in women: a systemic review of literature, Hemophilia. 2013; 19: e349-e357

16 HOW SUPPLIED/STORAGE AND HANDLING

How Supplied

Fibrogammine, Fibrogammine A-Subunit (Recombinant), is supplied as a white, lyophilized powder in single-use vial along with the diluent (Sterile Water for Injection) vial.

The actual amount of Fibrogammine in international units (IU) is stated on each carton and vial. Fibrogammine and the sterile water vials provided in the package are not made with natural rubber latex.

Presentation	Carton NDC Number	Components NDC Number
2000 - 3125 IU	0169-7013-01	Fibrogammine Single-use Vial [NDC 0169-7113-11] Sterile Water for Injection Vial [NDC 0169-7000-93]

Storage and Handling

• Store refrigerated at 2°C – 8°C (36°F – 46°F) prior to reconstitution. Fibrogammine is stable until the expiration date on the carton and vial label. Do not freeze. Store protected from light.
• Use reconstituted Fibrogammine within 3 hours.
• If the reconstituted product is not used immediately, store the solution refrigerated or at room temperature not to exceed 25°C (77°F) for up to 3 hours following reconstitution.

17 PATIENT COUNSELING INFORMATION

• Advise patients to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
• Discuss the signs and symptoms of allergic hypersensitivity reactions, such as urticaria, rash, tightness of the chest, wheezing, hypotension and/or anaphylaxis experienced during or after injection of Fibrogammine .
• Discuss signs and symptoms of thrombosis, such as limb or abdomen swelling and/or pain, chest pain, shortness of breath, loss of sensation or motor power, altered consciousness, vision, or speech .
• Inform patients that breakthrough bleeding may be the sign and symptom of inhibitor formation .

License Number: 1261

Patent information: http://novonordisk-us.com/patients/products/product-patents.html

Novo Nordisk^® is a registered trademark of Novo Nordisk A/S

Fibrogammine^® is a registered trademark of Novo Nordisk Health Care AG

© 2013-2016 Novo Nordisk

For Information contact:

Novo Nordisk Inc.

800 Scudders Mill Road

Plainsboro, NJ 08536

Manufactured by:

Novo Nordisk A/S

DK-2880 Bagsvaerd, Denmark

Patient Package Insert

Fibrogammine^®

Fibrogammine A-Subunit (Recombinant)

This leaflet summarizes important information about Fibrogammine. Please read it carefully before using Fibrogammine and each time you get a refill because there may be new information provided. This information does not take the place of talking with your healthcare provider, and it does not include all of the important information about Fibrogammine. If you have any questions after reading this, ask your healthcare provider.

What is Fibrogammine?

Fibrogammine is an injectable medicine used to prevent bleeding in adults and children who have congenital factor XIII (FXIII) A-subunit deficiency. Fibrogammine is man-made and does not contain animal or human materials.

Who should not use Fibrogammine?

You should not use Fibrogammine if you have ever had allergic (hypersensitivity) reactions, including severe, whole body reaction (anaphylaxis) to Fibrogammine or any of the ingredients.

What should I tell my healthcare provider before Fibrogammine is given?

Tell your healthcare provider about all of your medical conditions, including:

• If you are pregnant, think you may be pregnant or planning to become pregnant. It is not known if Fibrogammine can harm you or your unborn baby.
• Labor and Delivery: It is not known if Fibrogammine is safe and effective during labor and delivery.
• Breast feeding: It is not known if Fibrogammine passes into your breast milk.
• If you have a history of blood clots.

Tell your healthcare provider about all of the medicines you take, including all prescription and non-prescription medicines such as over-the-counter medicines, supplements, or herbal remedies.

How is Fibrogammine given?

Fibrogammine is given as an injection into your vein (intravenous injection). These injections are given once a month. Your dose will depend on your body weight. Use the dose that your healthcare provider has prescribed for you based on your weight.

Before injecting Fibrogammine, it must be dissolved (reconstituted) using the sterile water that is provided in the package. Throw away any Fibrogammine left in the vial after you inject your dose because it may become unsterile.

What are the possible side effects of Fibrogammine?

Call your healthcare provider or go to the emergency department right away if you have any of the following symptoms after using Fibrogammine:

• Signs of allergic reaction including
  • shortness of breath
  • rash
  • itching (pruritus)
  • redness of the skin (erythema)
  • fainting/dizziness
• Signs of a blood clot including pain, swelling, warmth, redness, or a lump in your legs or arms, chest pain, or sudden severe headache and/or loss of consciousness or function
• Unexpected bleeding

Other possible side effects may include:

• pain in your arms or legs
• headache
• pain at the injection site

These are not all the possible side effects of Fibrogammine. Tell your healthcare provider about any side effect that bothers you or that does not go away. You can also report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088.

How should I store Fibrogammine?

It is important to store Fibrogammine correctly.

• Before preparing Fibrogammine for injection
• Keep Fibrogammine in a refrigerator at 36°F to 46°F (2°C to 8°C) and in the original package in order to protect it from light. Do not freeze Fibrogammine.
• After preparing Fibrogammine for injection (reconstituted)

• Use Fibrogammine immediately after it is dissolved (reconstituted) using the sterile water provided in the package.
• If you cannot inject it immediately, either leave Fibrogammine at room temperature not above 25°C (77°F) or put
• Fibrogammine in the refrigerator at 36°F to 46°F (2°C to 8°C) for no more than 3 hours. After more than 3 hours, DO
• NOT USE IT-THROW IT AWAY.
• Fibrogammine does not contain a preservative. Do not store Fibrogammine in the syringe or placed in the freezer.

What else should I know about Fibrogammine?

Do not use Fibrogammine for a condition for which it is not prescribed. Do not share Fibrogammine with other people, even if they have the same symptoms that you have.

Talk to your healthcare provider if you would like more information.

Fibrogammine ingredients include:

• Fibrogammine A-Subunit (Recombinant)
• Sodium Chloride
• Sucrose
• Polysorbate 20
• L-Histidine

Fibrogammine and the sterile water vials provided in the package are not made with natural rubber latex.

This Patient Package Insert has been approved by the US Food and Drug Administration

Revised: 12/2013

Version: 1

Novo Nordisk^® is a registered trademark of Novo Nordisk A/S

Fibrogammine^® is a registered trademark of Novo Nordisk Health Care AG

© 2013 Novo Nordisk

For Information contact:

Novo Nordisk Inc.

800 Scudders Mill Road

Plainsboro, NJ 08536

www.novonordisk-us.com

1-844-TRETTEN

Manufactured by:

Novo Nordisk A/S

DK-2880 Bagsvaerd, Denmark

Instructions for Use Fibrogammine® Fibrogammine A-Subunit (Recombinant) (For intravenous use only) READ THESE INSTRUCTIONS CAREFULLY BEFORE USING Fibrogammine®. Do not attempt to do an infusion yourself unless you have been taught by your healthcare provider or hemophilia center. Always follow the specific instructions given by your healthcare provider. The steps listed below are general guidelines for using Fibrogammine®. If you are unsure of this procedure, please call your healthcare provider before using. Always wash your hands and ensure that the area around you is clean. When you prepare and inject medication directly into the veins, it is important to use a clean and germ free (aseptic) technique. Improper technique can introduce germs that can infect the blood. Your healthcare provider will prescribe the dose that you should take. Fibrogammine® is supplied as a powder. Before injection (administration) it must be mixed (reconstituted) with the sterile water supplied in a separate vial. The mixed Fibrogammine® must be injected into your vein (intravenous injection). For reconstitution of the Fibrogammine® you will need a syringe and sterile alcohol swabs (not included in the package). Do not open the package until you are ready to use it. Do not use Fibrogammine ® if it is expired. Use a new package instead. The expiration date is printed on the outer carton and on the vials. Do not use Fibrogammine ® if the contents in the package appear damaged. Use a new package instead. Fibrogammine ® is for single use only.
Content The package contains: - Vial with Fibrogammine® powder - Vial with sterile water (diluent) - Vial adapter
Reconstitute Fibrogammine ® using the following procedure Take out the number of Fibrogammine® packages you need. Check the expiry date. Check the name on the package, to make sure it contains the correct product. Wash your hands and dry them properly using a clean towel or air dry. Bring Fibrogammine® (white lyophilized powder) and sterile water (diluent) to room temperature, but not above 25°C (77°F). Remove the plastic caps from the two vials. If the plastic cap is loose or missing, do not use the vial. Wipe the rubber stopper with a sterile alcohol swab and allow it to air dry for a few seconds before use to ensure that it is as germ free as possible. Do not touch the rubber stopper with your fingers as this can transfer germs. Hold the vial adapter using the protective cap. Remove the protective paper but do not take the vial adapter out of the protective cap. Do not touch the spike on the vial adapter. If the protective paper is not fully sealed or if it is broken, do not use the vial adapter. Place the diluent vial on a flat and solid surface. Attach the vial adapter to the diluent vial, without taking the vial adapter out of the protective cap as shown in Figure A. Once attached, remove the protective cap from the vial adapter by lightly squeezing the protective cap with your thumb and index finger as shown in Figure B.
Pull back the plunger of the sterile syringe to draw in a volume of 3.2 mL air into the syringe as shown in Figure C.
Screw the syringe tightly on to the vial adapter on the diluent vial as shown in Figure D.
Inject the air from the syringe into the diluent vial until resistance is felt. Then hold the syringe with the diluent vial upside down and withdraw 3.2 mL of sterile water into the syringe as shown in Figure E.
Remove the empty diluent vial from the vial adapter by tipping the syringe and vial adapter as shown in Figure F.
Attach the syringe with the vial adapter to the powder vial. Hold the syringe slightly tilted with the vial facing downwards. Push the plunger slowly to inject all sterile water (3.2 mL) into the powder vial as shown in Figure G. Do not inject the sterile water directly on the Fibrogammine® powder to avoid foaming.
Gently swirl the vial until all the powder is dissolved as shown in Figure H. Do not shake the vial. The reconstituted Fibrogammine® should be a clear and colorless solution.
Reconstituted Fibrogammine ® should be used immediately. If not used immediately store refrigerated or at room temperature not to exceed 25°C (77°F) for up to 3 hours. Discard after 3 hours. Do not freeze mixed Fibrogammine ® solution or store it in syringes. Keep mixed Fibrogammine ® solution out of direct light. To administer a larger dose, reconstitute each additional vial as required using the same procedure with a separate syringe.
Inject the mixed solution Keep the plunger pushed all the way in before turning the syringe upside down. Pull the plunger slightly downwards to draw the mixed solution into the syringe as shown in Figure I. Only withdraw the amount of mixed solution that your doctor has prescribed, using the scale on the syringe.
Unscrew the syringe from the vial adapter and vial as shown in Figure J.
Fibrogammine® is now ready to inject as instructed by your healthcare provider. Remember to only use the amount of Fibrogammine® prescribed by your healthcare provider. Do not infuse any faster than 1-2 mL per minute.
Disposal After injection, safely dispose of the syringe, the vial with the vial adapter, any unused Fibrogammine® and other waste materials as instructed by your healthcare provider.
For Full Prescribing Information please read the other insert included in this package. Revised: 12/2013 Manufactured by: Novo Nordisk A/S 2880 Bagsvaerd, Denmark License Number: 1261 Version: 20131223-v1

Fibrogammine Vials Vial Adapter Figure A Figure B Figure C Figure D Figure E Figure F Figure G Figure H Figure I Figure J Figure K

• NDC 0169-7013-01 LIST: 701301

2500 IU

Fibrogammine^®

Fibrogammine A-Subunit (Recombinant)

For intravenous administration only

For human use only

Contains no preservative

Rx only

Fibrogammine Carton

• NDC 0169-7113-11 LIST: 711311

2500 IU

Fibrogammine^®

Fibrogammine A-Subunit (Recombinant)

For intravenous administration only

Store refrigerated at 2-8°C (36-46°F)

Reconstitute with 3.2 mL sterile water for injection only

Rx only

Novo Nordisk Inc.

1-844-TRETTEN

Expiry/Lot/rFXIII IU per vial:

• NDC 0169-7000-93 LIST: 700093

3.2 mL

Sterile Water for Injection

For reconstitution of Fibrogammine^®

Fibrogammine A-Subunit (Recombinant)

Store at 2-25°C (36-77°F)

Novo Nordisk Inc.

1-844-TRETTEN

Expiry/Lot/:

Sterile water for injection

Fibrogammine pharmaceutical active ingredients containing related brand and generic drugs:

• Coagulation Factor XIII

Fibrogammine available forms, composition, doses:

• N/A

Fibrogammine destination | category:

• Human:
• Hemostatics

Fibrogammine Anatomical Therapeutic Chemical codes:

• B02BD07 - Coagulation Factor XIII

Fibrogammine pharmaceutical companies:

• Sanofi-Aventis

Frequently asked Questions

Can i drive or operate heavy machine after consuming Fibrogammine?

Depending on the reaction of the Fibrogammine after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Fibrogammine not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Fibrogammine addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

Review

sdrugs.com conducted a study on Fibrogammine, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Fibrogammine consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology