ADAMTS13, Recombinant-krhn (Monograph)

Brand name: Adzynma
Drug class: Enzymes

Introduction

Recombinant form of endogenous “A disintegrin and metalloproteinase with thrombospondin motifs 13” (rADAMTS13) enzyme.

Uses for ADAMTS13, Recombinant-krhn

Congenital Thrombotic Thrombocytopenic Purpura

Prophylactic or on-demand enzyme replacement therapy (ERT) in adult and pediatric patients with congenital thrombotic thrombocytopenic purpura (TTP).

Designated an orphan drug by FDA for treatment of TTP including congenital, acquired idiopathic, and secondary forms.

Current standard of therapy for patients with congenital TTP includes prophylactic or on-demand infusions of fresh-frozen plasma, plasma treated with a solvent-detergent process, or ADAMTS13-containing plasma-derived factor VIII-von Willebrand factor concentrates.

International Society on Thrombosis and Haemostasis (ISTH) guideline for management of TTP recommends ADAMTS13, recombinant-krhn over plasma infusion to prevent acute episodes in patients with congenital TTP who are in remission. The use of ADAMTS13, recombinant-krhn for on-demand treatment of congenital TTP is not addressed in the guideline.

ADAMTS13, Recombinant-krhn Dosage and Administration

Administration

IV Administration

Administer as an IV infusion. Supplied in single-dose vials as lyophilized powder containing 500 or 1500 International Units (IU) that must be reconstituted prior to administration.

Do not administer in same tubing or container at same time with other medicinal products for infusion.

Reconstitution

Reconstitute lyophilized powder with BAXJECT II Hi-Flow device and diluent vial provided by manufacturer.

Allow drug vial and diluent to reach room temperature before use.

After drug is reconstituted, swirl the connected vials gently and continuously until powder is completely dissolved; do not shake.

Inspect reconstituted solution for particulate matter and discoloration prior to administration. Solution should be clear and colorless. Do not use if particulate matter or discoloration is observed.

Consult manufacturer's labeling for additional details on reconstitution and administration.

Rate of Administration

Administer IV infusion at rate of 2–4 mL/minute. Syringe pump may be used to control rate of administration.

Dosage

Dosage of ADAMTS13, recombinant-krhn is expressed in IU. Actual potency is printed on label of each vial and carton.

Dosing of ADAMTS13, recombinant-krhn is based on body weight.

Pediatric Patients

Prophylaxis of Congenital TTP

IV

40 IU/kg once every other week by IV infusion. Dosing frequency may be adjusted to 40 IU/kg once weekly based on prior prophylactic dosing regimen or clinical response.

On-Demand Treatment of Congenital TTP

IV

40 IU/kg on day 1, 20 IU/kg on day 2, then 15 IU/kg once daily until 2 days after acute event is resolved.

Adults

Prophylaxis of Congenital TTP

IV

40 IU/kg once every other week by IV infusion. Dosing frequency may be adjusted to 40 IU/kg once weekly based on prior prophylactic dosing regimen or clinical response.

On-Demand Treatment of Congenital TTP

IV

40 IU/kg on day 1, 20 IU/kg on day 2, then 15 IU/kg once daily until 2 days after acute event is resolved.

Special Populations

Hepatic Impairment

No dosage adjustment required.

Renal Impairment

No dosage adjustment required.

Geriatric Patients

No dosage adjustment required.

Cautions for ADAMTS13, Recombinant-krhn

Contraindications

Life threatening hypersensitivity reactions to ADAMTS13, recombinant-krhn or its components.

Warnings/Precautions

Hypersensitivity

Risk of allergic-type hypersensitivity including anaphylactic reactions.

Inform patients of early signs of hypersensitivity (e.g., tachycardia, tightness of chest, wheezing and/or acute respiratory distress, hypotension, generalized urticaria, pruritus, rhinoconjunctivitis, angioedema, lethargy, nausea, vomiting, paresthesia, restlessness). If signs and symptoms of severe allergic reactions occur, immediately discontinue drug and provide appropriate supportive care.

Immunogenicity

Low-titer anti-drug antibodies detected, with no observable clinical impact on safety or efficacy, and no increase in antibody titers over time. No neutralizing antibodies detected.

Due to low occurrence of anti-drug antibodies, effects on pharmacokinetics, pharmacodynamics, safety, and/or efficacy unknown. There are no data on immunogenicity in previously untreated patients.

Specific Populations

Pregnancy

Insufficient data on use in pregnancy.

Four patients in clinical studies exposed during pregnancy; 1 patient experienced a miscarriage that was unrelated to ADAMTS13, recombinant-krhn, 2 patients delivered healthy babies with no safety concerns, and 1 patient delivered at week 29 with no adverse events.

Decision to use during pregnancy should balance potential benefits with risks.

Lactation

Unknown whether ADAMTS13, recombinant-krhn is distributed in human milk, or if drug has any effects on breastfed infant or on milk production. Consider developmental and health benefits of breastfeeding along with mother’s clinical need for ADAMTS13, recombinant-krhn and any potential adverse effects to breastfed child.

Pediatric Use

Safety and efficacy established in pediatric patients; clinical trials included pediatric patients ≥2 years of age. Based on pharmacokinetic analysis, no dosage adjustment required; recommended body weight-based dosing regimen in pediatric patients is the same as that in adults.

Geriatric Use

Clinical studies did not include patients ≥65 years of age to determine whether they respond differently from younger patients.

Hepatic Impairment

Hepatic impairment not expected to affect drug pharmacokinetics.

Renal Impairment

Renal impairment not expected to affect drug pharmacokinetics.

Common Adverse Effects

Most common adverse reactions (>5%): headache, diarrhea, migraine, abdominal pain, nausea, upper respiratory tract infection, dizziness, vomiting.

Drug Interactions

No formal drug interaction studies to date.

ADAMTS13, Recombinant-krhn Pharmacokinetics

Absorption

Activity

Activity of drug appears to reach a maximum 1 hour post-infusion or earlier.

Elimination

Half-life

Mean half-life in adults: 47.8 hours.

Stability

Storage

Parenteral

Powder for Injection

Store in refrigerator at 2–8ºC for up to 36 months from date of manufacture until expiration date stated on vial label and carton; within this period, may be stored at room temperature (≤30ºC) for up to 6 months. Do not return to refrigerator after storage at room temperature.

Do not freeze; store in original box and protect from extreme exposure to light.

Reconstituted solution: Keep at room temperature (≤30ºC) for up to 3 hours.

Actions

Recombinant form of the ADAMTS13 enzyme; replaces deficient endogenous ADAMTS13 in patients with congenital TTP.
ADAMTS13 is a plasma zinc metalloprotease that regulates activity of von Willebrand factor (vWF) by cleaving large and ultra-large vWF multimers to smaller units and thereby reducing platelet binding proteins of vWF and its propensity to form microthrombi.

Advice to Patients

Advise patients to read the FDA-approved patient labeling.
Advise patients about early signs of hypersensitivity reactions, including tachycardia, tightness of the chest, wheezing and/or acute respiratory distress, hypotension, generalized urticaria, pruritus, rhinoconjunctivitis, angioedema, lethargy, nausea, vomiting, paresthesia, and restlessness. Advise patients to discontinue use of the product if these symptoms occur and seek immediate treatment with appropriate supportive care.
Advise patients to consult with their physician or healthcare provider prior to traveling. While traveling, advise patients to bring an adequate supply of ADAMTS13, recombinant-krhn based on their current regimen.
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Advise patients to inform their clinician if they are or plan to become pregnant or plan to breastfeed.
Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

ADAMTS13, recombinant-krhn is available through specialty pharmacies/distributors. Contact the manufacturer or consult the ADAMTS13, recombinant-krhn website ([Web]) for more information.

ADAMTS13, Recombinant-krhn
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection, for IV infusion	Nominally 500 international units (IU)	Adzynma (available as lyophilized powder in single-dose vials)	Takeda Pharmaceuticals America
		Nominally 1500 international units (IU)	Adzynma (available as lyophilized powder in single-dose vials)	Takeda Pharmaceuticals America