1 INDICATIONS AND USAGE

RYPLAZIM® (plasminogen, human-tvmh) is plasma-derived human plasminogen indicated for the treatment of patients with plasminogen deficiency type 1 (hypoplasminogenemia).

2 DOSAGE AND ADMINISTRATION

For intravenous use after reconstitution only.

3 DOSAGE FORMS AND STRENGTHS

RYPLAZIM is available in a single-dose 50 mL vial containing 68.8 mg of plasminogen as a lyophilized powder for reconstitution with 12.5 mL of sterile water for injection (SWFI). After reconstitution, each vial will contain 5.5 mg/mL of plasminogen in a colorless and clear to slightly opalescent solution.

4 CONTRAINDICATIONS

RYPLAZIM is contraindicated in patients with known hypersensitivity to plasminogen or other components of RYPLAZIM [See Hypersensitivity Reactions (5.4)].

5 WARNINGS AND PRECAUTIONS

6 ADVERSE REACTIONS

The most frequent (incidence ≥ 10%) adverse reactions were abdominal pain, bloating, nausea, fatigue, extremity pain, hemorrhage, constipation, dry mouth, headache, dizziness, arthralgia, and back pain.

8 USE IN SPECIFIC POPULATIONS

11 DESCRIPTION

RYPLAZIM is a Glu-plasminogen (> 95% purity) which is the native circulating form of plasminogen in the blood. RYPLAZIM is a sterile, white to off-white, lyophilized preparation of purified, plasma-derived plasminogen (human) to be reconstituted and administered by the intravenous route. Each vial of RYPLAZIM contains 68.8 mg of plasminogen. Following reconstitution with 12.5 mL of sterile water for injection (SWFI), the RYPLAZIM solution contains 5.5 mg/mL plasminogen and the following inactive ingredients: sodium citrate, sodium chloride, glycine, and sucrose. RYPLAZIM contains no preservatives. Biological potency of the plasminogen is determined by a chromogenic assay calibrated with a standard.

All plasma used in the manufacturing of RYPLAZIM is tested using serological assays for hepatitis B virus (HBV) surface antigen and antibodies to human immunodeficiency virus-1/2 (HIV-1/2) and hepatitis C virus (HCV). The plasma is also tested via nucleic acid amplification testing for HBV, HCV, HIV-1, hepatitis A virus (HAV) and human parvovirus B19 virus. Only plasma pools negative for HIV-1, HCV, HBV, and HAV, and containing levels of human parvovirus B19 DNA ≤ 104 IU/mL are used for the manufacture of RYPLAZIM.

The RYPLAZIM manufacturing process encompasses a series of chromatography adsorbents to purify plasminogen and includes multiple steps and controls to ensure that the purified plasminogen is essentially free of known adventitious agents. First, three orthogonal viral removal/inactivation steps are included: affinity chromatography for removal of enveloped and non-enveloped viruses; solvent/detergent treatment for inactivation of enveloped viruses; and 20 nm nanofiltration for removal of both enveloped and non-enveloped viruses. Two independent studies demonstrated effective viral removal/inactivation afforded by these three steps using validated scaled-down models. The overall virus reduction achieved in these studies for enveloped viruses was ≥ 11.8 logs and for non-enveloped viruses was ≥ 9.7 logs (considering both contributing steps), as summarized in Table 2. Second, the plasma used in this process is Human Source Plasma from FDA-approved collection centers; thus, there is minimal risk of contamination that could cause transmissible spongiform encephalopathies. Lastly, the product is tested for microbial and endotoxin levels throughout the process.

12 CLINICAL PHARMACOLOGY

13 NONCLINICAL TOXICOLOGY

14 CLINICAL STUDIES

The efficacy of RYPLAZIM in pediatric and adult patients with plasminogen deficiency type 1 was evaluated in a single-arm, open-label clinical trial (RYPLAZIM Trial 2). A total of 15 patients with plasminogen deficiency type 1 were enrolled. All patients had a baseline plasminogen activity level between <5% and 45% of normal, and biallelic mutations in the plasminogen (PLG) gene. The age range of these patients was 4 to 42 years, including 6 pediatric patients age 4 to 16 years, and 9 adults. Eleven patients were female. All patients were White. All patients received RYPLAZIM at a dose of 6.6 mg/kg administered every 2 to 4 days for 48 weeks to achieve at least an increase of individual trough plasminogen activity by an absolute 10% above baseline and to treat the clinical manifestations of the disease.

Efficacy was established on the basis of overall rate of clinical success at 48 weeks. Overall rate of clinical success is defined as 50% of patients with visible or other measurable non-visible lesions achieving at least 50% improvement in lesion number/size, or functionality impact from baseline. Spirometry was the only test of organ function used and one patient had abnormal spirometry at baseline. This patient had a history of ligneous airway disease with a severe obstructive ventilatory defect (FEV1: 46.7% of predicted normal) at baseline prior to treatment that corrected to normal (FEV1: 89.3% of predicted normal) after 12 weeks of treatment. All patients with any lesion at baseline had at least 50% improvement in the number/size of their lesions.

16 HOW SUPPLIED/STORAGE AND HANDLING

RYPLAZIM is supplied in a single-dose vial [NDC 70573-099-01] containing 68.8 mg of plasminogen (human) (5.5 mg/mL after reconstitution with 12.5 mL of SWFI), one vial per carton [NDC 70573-099-02]. The treating physician will provide reconstitution and administration supplies. RYPLAZIM contains no preservatives.

17 PATIENT COUNSELING INFORMATION

• Advise patients and/or caregiver to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
• Counsel patients and/or caregiver to discontinue RYPLAZIM and immediately contact their physicians if signs or symptoms of a possible hypersensitivity reaction occur, such as hives, generalized urticaria, angioedema, chest tightness, wheezing, tachycardia, and hypotension [see Contraindications (4)], Warnings and Precautions (5.4)].
• Inform patients that bleeding from active mucosal disease-related lesions and worsening of active bleeding not related to those lesions during RYPLAZIM therapy may occur. Depending on the lesion sites, this may manifest as gastrointestinal bleeding, hemoptysis, epistaxis, vaginal bleeding, or hematuria. Prior to initiation of treatment with RYPLAZIM, lesions or wounds suspected as the source of recent bleeding events should be confirmed to have healed. RYPLAZIM may prolong or worsen bleeding in patients with bleeding diatheses and/or taking anticoagulants or antiplatelet drugs. If a patient develops serious bleeding, seek emergency care and discontinue RYPLAZIM immediately [see Warnings and Precautions (5.1)].
• Inform patients that tissue sloughing at mucosal sites may occur at initiation of RYPLAZIM therapy as lesions resolve. Patients with respiratory lesion are at risk for respiratory compromise and initial treatment with RYPLAZIM should be performed in a clinical setting with close monitoring. Patients with lesions in gastrointestinal and genitourinary systems may experience tissue sloughing that may cause pain, mucosal bleeding, or passage of tissue referable to those organ systems. Patients should report persistent abdominal, flank or pelvic pain to their physicians if not resolved. [see Warnings and Precautions (5.2)].
• Inform patients and/or caregiver that RYPLAZIM is made from human plasma and may contain infectious agents that can cause disease (eg, viruses, the variant Creutzfeldt-Jakob disease [vCJD] agent and, theoretically the CJD agent). Explain that the risk that RYPLAZIM may transmit an infectious agent has been reduced by screening the plasma donors, by testing donated plasma for certain virus infections, and by inactivating or removing certain viruses during manufacturing. Counsel patients and/or caregiver to report any symptoms that concern them. [see Warnings and Precautions (5.3)].
• Advise patients and/or caregivers that antibodies may develop during treatment that make RYPLAZIM less effective [see Warnings and Precautions (5.5)].
• Advise female patients who are pregnant or may become pregnant that the potential effects of RYPLAZIM on pregnancy and breastfeeding are unknown. They should notify their physicians if they become or intend to become pregnant, or if they plan to breastfeed. [see Use in Special Populations (8.1) and (8.2)].
• Self-administration: ensure patient/caregiver has received detailed instructions and training and has shown the ability to safely and independently administer RYPLAZIM.

Manufactured by:
Prometic Bioproduction, Inc
531 Blvd. des Prairies, Building 15
Laval, Quebec, Canada, H7V1B7

Manufactured for:
Prometic Biotherapeutics, Inc
Parker Plaza, 400 Kelby Street, Suite 1104
Fort Lee, New Jersey 07024
U.S. License number 2065

PATIENT INFORMATION

RYPLAZIM®
plasminogen, human-tvmh

The following summarizes important information that you should read carefully before using RYPLAZIM (pronounced ri plaz' im). This does not replace talking with your healthcare provider, and it does not include all of the important information about RYPLAZIM. If you have any questions after reading this information, then ask your healthcare provider.

What is RYPLAZIM?

RYPLAZIM is a medicine containing human plasminogen and is used to increase the blood levels of plasminogen in people with plasminogen deficiency type 1 (hypoplasminogenemia). It is injected into a vein.

Who should not use RYPLAZIM?

Do not take RYPLAZIM if you have had a severe reaction to RYPLAZIM or another product containing plasminogen.

What should I tell my healthcare provider before using RYPLAZIM?

Before taking RYPLAZIM, tell your healthcare provider if you:

• Have had other medical problems, particularly bleeding problems.
• Use any medicine, including prescription and over-the-counter drugs, supplements, and herbal remedies.
• Have had reactions to any medications.
• Are pregnant or planning to become pregnant. It is not known whether RYPLAZIM may affect your pregnancy or an unborn baby.
• Are breastfeeding or are planning to breastfeed. It is not known whether RYPLAZIM affects milk production, passes into breast milk and may affect a baby.

How do I take RYPLAZIM?

• RYPLAZIM is given directly into the bloodstream.
• You may receive RYPLAZIM at a healthcare facility, or you may receive it at home from a nurse, caregiver or by injecting it yourself. If your healthcare provider believes you would be able to inject RYPLAZIM yourself or with the help of others at home, then you will receive detailed instructions and training on preparation and infusion (see Instructions for Use at the end of this document).
• Your healthcare provider will tell you how often to take RYPLAZIM and how much RYPLAZIM to use each time.
• Your healthcare provider may order periodic blood tests to check your plasminogen level.

What are the possible or reasonably likely side effects of RYPLAZIM?

• Common side effects of RYPLAZIM are:
  • abdominal pain
  • bloating
  • nausea
  • fatigue
  • extremity pain
  • hemorrhage
  • constipation
  • dry mouth
  • headache
  • dizziness
  • joint pain
  • back pain
• You may have an allergic reaction while taking RYPLAZIM. Stop treatment and contact your healthcare provider immediately if you develop trouble breathing, wheezing, chest tightness, light headedness, dizziness, swelling in the face or throat, itching, a rash, or hives.
• Your body may make antibodies against RYPLAZIM that may stop RYPLAZIM from working properly. Your healthcare provider will monitor you periodically for lesions which may be due to a low plasminogen level. If you develop new lesions or a recurrence of a previous lesion, then your healthcare provider will obtain blood to test for plasminogen activity level.
• RYPLAZIM may worsen or prolong ongoing bleeding. In addition, if you have abnormal tissue growths because of your low plasminogen level, then you may have bleeding as these growths heal in response to treatment with RYPLAZIM.
  • If you vomit blood, have blood from your rectum or black tarry stools or any bleeding that is heavy or does not resolve after 30 minutes of direct pressure seek emergency care and discontinue further use of RYPLAZIM.
• As your lesions heal then they will fall off, known as tissue sloughing, this is in response to treatment with RYPLAZIM. This is also normal response and is not a side effect. Specific examples:
  • If you have tissue growths in your airway or lungs you may cough up small amounts of tissue and you may cough up a small amount of blood or blood clots.
  • If you have tissue growths in your genitourinary system then you may pass tissue or blood clots in your urine or from your penis or vagina.
  • If you have tissue growths in your gastrointestinal system you may have some tissue or blood clots in your stool or you may vomit blood or blood clots.
  • If you have eye lesions you may have oozing of blood from the lesions in your eye.
  • Notify your healthcare provider if you develop breathing difficulty, wheezing, cough, changes in speech, or pain in the back, abdomen, groin, or pelvic area, because these could be symptoms of tissue from resolving lesions that are obstructing the lungs, the kidneys, the bladder, the uterus and/or vagina, or the intestines.
• Other side effects are possible. Speak with your healthcare provider about any side effects that do not go away or bother you.

You may report side effects to +1(855)-353-7466 and US_Medicalinfo@kedrion.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

How do I store RYPLAZIM?

• Store RYPLAZIM vials in the refrigerator or at room temperature (36°F to 77°F, [2°C to 25°C]). Do not freeze.
• Store the other supplies at room temperature (68°F to 77°F [20°C to 25°C]).
• After the RYPLAZIM vials are opened and mixed with Sterile Water for Injection (SWFI), they must be used within 3 hours.
• Keep the RYPLAZIM vials in the original package before using.
• Do not use RYPLAZIM or SWFI after the expiration date on the vials.

Do not use RYPLAZIM for a condition other than that prescribed by your healthcare provider.

Do not share RYPLAZIM with other people, even if they have the same symptoms that you have.

RYPLAZIM® plasminogen, human-tvmh
Instructions for Use

For intravenous use after reconstitution only

Do not attempt an intravenous infusion on yourself unless you or your caregiver has been trained by a healthcare provider. Always follow the specific instructions that your healthcare provider has given you. The steps listed below are general guidelines for using RYPLAZIM. If you are unsure about any of the steps, contact your healthcare provider before using.

A.

Gathering Supplies

1. Your healthcare provider should tell you how many vials of RYPLAZIM to use based on your weight. If you store RYPLAZIM in the refrigerator, then let the vials sit at room temperature for at least 15 minutes before you use them.
2. Check the expiration date on the vial labels and carton. Do not use RYPLAZIM or Sterile Water for Injection, USP vials after the expiration date.
3. Make sure you work on a clean, flat surface.
4. Gather the following supplies and any other materials that you will need, as instructed by your healthcare provider:
   • Required number of vials of RYPLAZIM
   • One 20-mL syringe per vial of RYPLAZIM for mixing the drug
   • 18- to 22-gauge needles for reconstitution and administration
   • Sterile Water for Injection, USP (SWFI) (10 mL, 20 mL or 50 mL)
   • One syringe disc filter per infusion of RYPLAZIM required (Baxter Supor® 5-micron Syringe Filter or equivalent)
   • One (or more) administration syringe(s) (20mL, 30mL or 60 mL)
   • Alcohol wipes
   • Antiseptic surface wipes
   • Medical tape
   • Butterfly needle or sterile infusion set
   • 10 mL normal saline
   • Sterile gauze pad
   • Bandage

B.

Preparing RYPLAZIM

1. Always work on a clean surface and wash your hands before performing the procedure.
2. Once the RYPLAZIM has been prepared, use it at room temperature within 3 hours. Do not refrigerate after preparation.
3. Remove the caps from the RYPLAZIM vials and the Sterile Water for Injection, USP (SWFI) vials to expose the central portion of the rubber stoppers.
4. Clean the surface of the rubber stoppers with alcohol wipes and allow to dry. Do not blow on them. Do not touch the rubber stoppers with your hand after cleaning them.
5. Using a syringe with an 18- to 22-gauge needle, draw 12.5 mL of SWFI. Ensure that all air bubbles have been removed.
   Note: Depending on the SWFI vial sizes used, more than one SWFI vial(s) may be required.
   • If using a 10-mL vial of SWFI, you will need two 10-mL vials of SWFI for each vial of RYPLAZIM. Draw 9.0 mL of SWFI from the first SWFI vial with the 20-mL syringe. Discard the first needle, attach a new 18- to 22-gauge sterile needle and draw 3.5 mL from the second 10-mL vial of SWFI to equal to 12.5 mL.
   • Repeat the above process for every vial of RYPLAZIM that will need to be reconstituted.
   • If using a 20-mL or 50-mL vial of SWFI, only one vial of SWFI per vial of RYPLAZIM will be needed for reconstitution.
   • Do not use the remaining SWFI in the vial with a different RYPLAZIM vial.
6. Gently and slowly add the 12.5 mL of SWFI down the side of the RYPLAZIM vial to prevent foaming. This should resemble a stream down the side of the vial. (Fig. A). Discard used syringe and needle(s).
   
   

   Fig. A   

7. Gently swirl the RYPLAZIM vial in slow rotation to ensure it is fully dissolved. Do not shake the vial. The RYPLAZIM should fully dissolve within 10 minutes. Discard if the product is not fully dissolved after 10 minutes. (Fig B)
   
   

   Fig. B         

8. After the RYPLAZIM is dissolved in the SWFI, inspect the solution. It should be colorless and clear to slightly pearly. Discard if discoloration or particulate matter is observed.
9. Repeat Preparation Steps 3 to 8 above for each vial of RYPLAZIM needed.
10. Select an administration syringe of appropriate volume based on the dose required. Depending on the syringe size used, more than one vial of mixed RYPLAZIM can be drawn into one administration syringe.
    NOTE: A 30-mL syringe cannot hold more than 2 vials of reconstituted RYPLAZIM and a 60-mL syringe cannot hold more than 4 vials of reconstituted RYPLAZIM.
11. Using the selected administration syringe(s) with an 18- to 22-gauge needle, slowly draw the RYPLAZIM from each reconstituted vial to administer the required dose of RYPLAZIM. Do not mix RYPLAZIM with other medications.
12. After drawing the RYPLAZIM from the last vial, push the plunger down to remove any air bubbles. Dispose of the needle in an appropriate container.

Infusing RYPLAZIM

1. One filter is needed per infusion.
2. Only administer RYPLAZIM by infusing it into a vein through a syringe disc filter.
3. Inspect the solution in the syringe. Do not use if you see discoloration or particulate matter.
4. Administer RYPLAZIM by a separate infusion line. Do not administer RYPLAZIM with other medications.
5. Draw 10 mL of normal saline into a different syringe. Push the plunger down to remove any air bubbles.
6. Attach a syringe disc filter to the pre-filled syringe of normal saline (from previous step) and the infusion tubing with butterfly needle. (Fig. C)
   
   

   Fig. C   

7. Inject the normal saline through the syringe disc filter and butterfly needle tubing to remove any air bubbles.
8. Remove the normal saline syringe. The syringe disc filter must remain attached to the tubing, as it is required for administration of the RYPLAZIM. Discard the normal saline syringe.
9. Attach the administration syringe containing RYPLAZIM to the syringe disc filter that is connected to the butterfly needle tubing.
10. Choose a peripheral vein (e.g., antecubital or dorsum of hand). Clean the injection site with a sterile alcohol wipe and allow to dry. Do not blow on it.
11. Insert the butterfly infusion set needle in the chosen peripheral vein, as taught by your healthcare provider, and tape in place.
12. Infuse the amount of RYPLAZIM you need as instructed by your healthcare provider. Deliver the total dose slowly over 10-30 minutes (approximately 5 mL/min). Using a timer (e.g., watch or clock), push the plunger of the syringe approximately 1 mL every 12 seconds. (Fig. D)
    
    

    Fig. D   

13. Discard any open vials, unused solution, and administration equipment following administration.

Manufactured by:
Prometic Bioproduction Inc
531 Blvd. des Prairies,
Laval, Quebec, Canada, H7V1B7

Manufactured for:
Prometic Biotherapeutics, Inc
Parker Plaza, 400 Kelby Street, Suite 1104
Fort Lee, New Jersey 07024
U.S. License number 2065

PRINCIPAL DISPLAY PANEL - 68.8 mg Vial Label

NDC 70573-099-01

68.8 mg/vial

plasminogen, human-tvmh
Ryplazim®

For Intravenous Use Only

Sterile, Preservative-Free

Single-Dose Vial

Discard Unused Portion

US LIC. NO.: 2065
Rx Only

PRINCIPAL DISPLAY PANEL - 68.8 mg Vial Carton

68.8 mg/vial

plasminogen, human-tvmh
Ryplazim®

For Intravenous Use Only

Sterile, Preservative-Free

Single-Dose Vial

Discard Unused Portion

US LIC NO.: 2065
Rx Only