ADAMTS13, Recombinant-krhn (Monograph)

Brand name: Adzynma
Drug class: Enzymes

Introduction

ADAMTS13, recombinant-krhn is a human recombinant form of the endogenous “A disintegrin and metalloproteinase with thrombospondin motifs 13” (rADAMTS13) enzyme.

Uses for ADAMTS13, Recombinant-krhn

ADAMTS13, recombinant-krhn has the following uses:

ADAMTS13, recombinant-krhn is indicated for prophylactic or on demand enzyme replacement therapy (ERT) in adult and pediatric patients with congenital thrombotic thrombocytopenic purpura (cTTP).

ADAMTS13, Recombinant-krhn Dosage and Administration

General

ADAMTS13, recombinant-krhn is available in the following dosage form(s) and strength(s):

Lyophilized powder in single-dose vials containing nominally 500 or 1500 international units (IU).

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

For IV use after reconstitution only.

Each vial is labeled with the actual rADAMTS13 activity, measured in terms of its potency in International Units (IU). Calculate administration dose and volume based on the patient's body weight using the actual potency (and not the nominal potency) as printed on vial.

The recommended body-weight based dosing regimen in pediatric patients is the same as that in adults.

See Full Prescribing Information for specific instructions on preparation and administration.

Prophylactic Therapy in Adults and Pediatric Patients

• Administer 40 IU/kg body weight once every other week by IV infusion at a rate of 2 to 4 mL per minute.

• The prophylaxis dosing frequency may be adjusted to 40 IU/kg body weight once weekly based on prior prophylactic dosing regimen or clinical response.

On-Demand Therapy in Adults and Pediatric Patients

The following is a guide for dosing of ADAMTS13, recombinant-krhn for on-demand therapy. Administer the following doses by IV infusion at a rate of 2 to 4 mL per minute:

• 40 IU/kg body weight on treatment day 1.

• 20 IU/kg body weight on treatment day 2.

• 15 IU/kg body weight on treatment day 3 and beyond until two days after the acute event is resolved.

Cautions for ADAMTS13, Recombinant-krhn

Contraindications

Do not use in patients who have manifested life threatening hypersensitivity reactions to ADAMTS13, recombinant-krhn or its components.

Warnings/Precautions

Hypersensitivity

Allergic-type hypersensitivity including anaphylactic reactions may occur with ADAMTS13, recombinant-krhn. Patients should be informed of the early signs of hypersensitivity including but not limited to tachycardia, tightness of the chest, wheezing and/or acute respiratory distress, hypotension, generalized urticaria, pruritus, rhinoconjunctivitis, angioedema, lethargy, nausea, vomiting, paresthesia, and restlessness. If signs and symptoms of severe allergic reactions occur, immediately discontinue administration of ADAMTS13, recombinant-krhn and provide appropriate supportive care.

Immunogenicity

There is a potential for immunogenicity with ADAMTS13, recombinant-krhn. Patients may develop neutralizing antibodies to ADAMTS13, which could potentially result in a decreased or lack of response to ADAMTS13. Neutralizing antibodies were not reported in the congenital thrombotic thrombocytopenic purpura (cTTP) clinical trials. All subjects had been previously exposed to ADAMTS13 through plasma-based products. There are no data on immunogenicity with ADAMTS13, recombinant-krhn in previously untreated patients (subjects naïve to plasma-based products).

Patients may develop antibodies to host cell proteins which could potentially result in adverse reactions. There are no data on immunogenicity to host cell proteins in previously untreated patients (subjects naïve to plasma-based products).

Specific Populations

Pregnancy

The safety of ADAMTS13, recombinant-krhn for use during pregnancy has not been established in controlled clinical trials. Limited data with use during pregnancy are insufficient to inform a drug-associated risk of adverse developmental outcomes. In determining whether ADAMTS13, recombinant-krhn should be used in pregnancy, healthcare providers should balance the potential benefits with the potential risks.

The background rate of major birth defects and miscarriage in the indicated population is unknown. In the U.S. general population, the estimated background rate of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

There have been four cTTP patients exposed to ADAMTS13, recombinant-krhn during pregnancy.

Two patients in a long-term extension study were found to be pregnant early in the first trimester while receiving prophylaxis with ADAMTS13, recombinant-krhn. Both patients were discontinued from the study to comply with the protocol requirements. The first patient had no further exposure to ADAMTS13, recombinant-krhn and had a first trimester miscarriage approximately two months after study discontinuation. The investigator assessed the event was unrelated to ADAMTS13, recombinant-krhn. The second patient resumed treatment with ADAMTS13, recombinant-krhn under a compassionate use program and delivered a healthy full-term baby with no safety concerns reported by the investigator.

Two additional cTTP patients were treated with ADAMTS13, recombinant-krhn in a compassionate use program during pregnancy. The first patient, in the third trimester of her second pregnancy, experienced a stroke and thrombocytopenia that was refractory to daily plasmapheresis. At 33 weeks of gestation, ADAMTS13, recombinant-krhn treatment was started once weekly. ADAMTS13 activity levels normalized, thrombocytopenia resolved, and a healthy baby was delivered at 37 weeks with no safety concerns reported by the treating physician due to ADAMTS13, recombinant-krhn. The second patient had an exacerbation of her cTTP during her second trimester of pregnancy despite prior daily plasma exchange. Her pregnancy was considered to be at risk, with inadequate response to plasma-based therapies. ADAMTS13, recombinant-krhn was started once weekly and induced clinical remission. The baby was delivered by a cesarean section at week 29 and the treating physician reported no adverse events due to ADAMTS13, recombinant-krhn.

Whether ADAMTS13, recombinant-krhn should be used in pregnancy is solely up to the medical judgment of the healthcare provider.

Lactation

There is no information regarding the presence of ADAMTS13, recombinant-krhn in human milk, its effects on milk production or the breastfed infant. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ADAMTS13, recombinant-krhn and any potential adverse effects to the breastfed child.

Pediatric Use

The safety and effectiveness of ADAMTS13, recombinant-krhn has been established in pediatric patients. Clinical trials included patients 2 years of age and older. Based on data from population pharmacokinetic (PK) analysis, no additional dose adjustments beyond body weight are required for this age group. The recommended body-weight based dosing regimen in pediatric patients is the same as that in adults.

Geriatric Use

Clinical studies of ADAMTS13, recombinant-krhn did not include patients 65 years of age and older to determine whether they respond differently from younger patients. Based on the results from population pharmacokinetics analysis, no dose adjustment is required for elderly patients.

Common Adverse Effects

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

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Please see product labeling for drug interaction information.

Actions

Mechanism of Action

ADAMTS13, recombinant-krhn is a recombinant form of the endogenous ADAMTS13. ADAMTS13 is a plasma zinc metalloprotease that regulates the activity of von Willebrand factor (VWF) by cleaving large and ultra-large VWF multimers to smaller units and thereby reducing the platelet binding properties 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 emergency treatment with appropriate supportive care.

• Advise patients to consult with their physicians or healthcare provider prior to traveling. While traveling, advise patients to bring an adequate supply of ADAMTS13, recombinant-krhn based on their current regimen of treatment.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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.

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