Avlayah Drug Information
Generic name: TIVIDENOFUSP ALFA-EKNM
Hydrolytic Lysosomal Glycosaminoglycan-specific Enzyme [EPC]
Uses of Avlayah
AVLAYAH is indicated for the treatment of neurologic manifestations of Hunter syndrome (Mucopolysaccharidosis type II, MPS II) when initiated in presymptomatic or symptomatic pediatric patients weighing at least 5 kg prior to advanced neurologic impairment. This indication is approved under accelerated approval based on the reduction of cerebrospinal fluid heparan sulfate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
Limitations of Use AVLAYAH is not recommended for use in combination with other enzyme replacement therapies for the treatment of Hunter syndrome.
Dosage & Administration of Avlayah
Important Recommendations Prior to AVLAYAH Treatment Initiation Administer AVLAYAH under the supervision of a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis. Initiate AVLAYAH in a healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment. Consider pretreatment with antihistamines, antipyretics, and/or corticosteroids.
Obtain a baseline hemoglobin value in all patients.
Recommended Dosage
The recommended starting dosage of AVLAYAH for pediatric patients weighing at least 5 kg is 3 mg/kg administered once weekly via intravenous infusion. To reduce the risk of infusion-associated reactions (IARs), follow the dose escalation regimen in Table 1. Administer each dosage level for at least 4 weeks before escalating to the next dosage level.
The recommended maintenance dosage of AVLAYAH for pediatric patients who weigh at least 5 kg is 15 mg/kg administered once weekly via intravenous infusion. Table 1: Recommended AVLAYAH Dosage for Pediatric Patients Weighing ≥5 kg a Dosing Week Dosage Level a Do not escalate the dosage level if the current dosage level is not tolerated.
Dosage and Administration Modifications and Monitoring In the event of a severe hypersensitivity reaction (e.g., anaphylaxis) or a severe IAR, discontinue AVLAYAH and immediately initiate appropriate medical treatment. Consider the risks and benefits of re-administering AVLAYAH following a severe reaction. If the decision is made to re-administer AVLAYAH, re-evaluate pre-treatment medications, slow the infusion rate, and/or reduce the AVLAYAH dose.
Monitor patients closely upon re-administration of AVLAYAH. In the event of a mild to moderate hypersensitivity reaction or a mild to moderate IAR, temporarily hold the infusion and/or reduce the infusion rate by at least 50% from the current rate, then titrate up to the recommended infusion rate as tolerated (see Table 3 ). If the dose has been decreased due to an adverse reaction, evaluate when it is appropriate to increase the dose and follow the recommended dose escalation regimen to achieve the maintenance dosage of 15 mg/kg once weekly.
Preparation Instructions Prepare
AVLAYAH using polypropylene syringes and infusion bags composed of polyvinylchloride (PVC) or polyolefins (PO) such as polyethylene (PE) and polypropylene (PP); infusion sets composed of PVC or PE; and filter membranes composed of polyethersulfone (PES). Use aseptic technique during preparation. Reconstitute and dilute AVLAYAH in the following manner: Reconstitution Instructions 1 Determine the number of AVLAYAH vials to be reconstituted based on the patient's weight in kg and the recommended dosage.
Round the number of vials up to the next whole number. 2 Remove the required number of AVLAYAH vials from the refrigerator and set aside for 15 to 30 minutes to allow vials to reach room temperature 20°C to 25°C (68°F to 77°F). Do not use an external heat source. 3 Reconstitute each vial with 5.2 mL of Sterile Water for Injection by slowly injecting the diluent onto the inside wall of each vial to avoid foaming. Do not inject forcefully or directly onto the lyophilized powder. 4 Gently swirl each vial to completely dissolve the lyophilized powder.
Do not invert or shake the vial. Each reconstituted vial will yield a concentration of 30 mg/mL of tividenofusp alfa-eknm. 5 Visually inspect the reconstituted solution in the vial(s) for particulate matter and discoloration. The solution should be clear to slightly opalescent and colorless to slightly brown/yellow, and free of visible particles.
Discard the reconstituted AVLAYAH solution if it is discolored, cloudy, or contains visible particulates. Dilution Instructions Dilute the reconstituted AVLAYAH solution with 0.9% Sodium Chloride Injection to a final concentration between 0.6 mg/mL and 15 mg/mL in an infusion bag as follows: 1 Determine the appropriate volume of the infusion bag based on patient weight (see Table 2 ) and determine the volume of reconstituted AVLAYAH solution required for the calculated dose. 2 Prepare the infusion bag: a. Remove any airspace within the infusion bag. b.
Withdraw a volume of 0.9% Sodium Chloride Injection from the infusion bag equivalent to the volume of AVLAYAH to be added. 3 Slowly withdraw the required volume of reconstituted solution from the AVLAYAH vial(s). Discard unused portion after each use; do not administer more than one dose from the vial. 4 Slowly inject AVLAYAH into the infusion bag of 0.9% Sodium Chloride Injection. Avoid introducing air into the infusion bag. 5 Gently invert the infusion bag to mix the solution.
Do not shake. Table 2: Recommended Total Infusion Volumes for AVLAYAH Based on Patient Weight and Dose
Storage Instructions for the Reconstituted and Diluted Solutions Reconstituted Solution Do not shake. Do not freeze. If the reconstituted AVLAYAH vials are not diluted immediately, store at controlled room temperature between 20°C to 25°C (68°F to 77°F) for up to 4 hours.
Diluted Solution If the diluted AVLAYAH solution is not used immediately, store refrigerated at 2°C to 8°C (36°F to 46°F) for up to 24 hours. After removal of the diluted solution from the refrigerator: Completely infuse within 10 hours. Do not store back into the refrigerator.
Discard the diluted solution if refrigerated more than 24 hours or if the diluted solution cannot be completely infused within 10 hours after removal from the refrigerator. Do not shake. Do not freeze.
Administration Instructions 1 Administer
AVLAYAH without delay as an intravenous infusion using only infusion sets composed of PVC or PE and filter membranes composed of PES. 2 If the diluted solution was refrigerated, allow solution to equilibrate to room temperature prior to infusion. 3 Use a dedicated infusion line equipped with a sterile, non-pyrogenic, low protein-binding, 0.2 micron, in-line filter to administer AVLAYAH. 4 Infuse AVLAYAH over approximately 4 hours per the recommended infusion rates in Table 3. Increase the initial infusion rate to the subsequent infusion rate every hour based on patient tolerance. Total infusion time should not exceed 8 hours. 5 In the absence of hypersensitivity reactions and IARs, AVLAYAH infusion rate can be gradually increased to complete the infusion in a minimum infusion duration of 3 hours based on patient tolerance.
Table 3: AVLAYAH Infusion Rate Based on 6 At the end of the infusion, flush the infusion line with 0.9% Sodium Chloride Injection using the final infusion rate that was used to administer AVLAYAH. 7 Do not infuse AVLAYAH in the same intravenous infusion line with other products. Home Infusion If a patient reaches and tolerates the maintenance AVLAYAH dosage, the patient may receive home infusion under the supervision of a healthcare provider. The decision to have patients move to home infusion should be made after evaluation and recommendation by a healthcare provider.
In case of a missed dose or an IAR, contact a healthcare provider.
Missed Dose If an AVLAYAH dose is missed, skip the missed dose. Do not double a dose to compensate for a missed dose. Restart AVLAYAH treatment as soon as possible, maintaining the one-week interval between infusions thereafter.
Resume dosing at the last administered dosage following the recommended infusion rate.
| Dosing Week | Dosage Level |
|---|---|
| a Do not escalate the dosage level if the current dosage level is not tolerated [see Dosage and Administration (2.3) ]. | |
| Week 1 to Week 4 | 3 mg/kg once weekly |
| Week 5 to Week 8 | 7.5 mg/kg once weekly |
| Week 9 and beyond | 15 mg/kg once weekly (maintenance dosage) |
| Patient Weight Range | AVLAYAH Dose | ||
|---|---|---|---|
| 3 mg/kg | 7.5 mg/kg | 15 mg/kg | |
| Recommended Total Infusion Volumes a | |||
| a Ensure the final concentration of the diluted AVLAYAH solution is between 0.6 mg/mL and 15 mg/mL. | |||
| 5 kg to less than 10 kg | 25 mL | 25 mL or 50 mL | 25 mL or 50 mL |
| 10 kg to less than 20 kg | 25 mL or 50 mL | 25 mL, 50 mL, or 100 mL | 25 mL, 50 mL, or 100 mL |
| 20 kg to less than 25 kg | 25 mL, 50 mL, or 100 mL | 25 mL, 50 mL, or 100 mL | 25 mL, 50 mL, or 100 mL |
| 25 kg to less than 50 kg | 25 mL, 50 mL, or 100 mL | 25 mL, 50 mL, or 100 mL | 50 mL or 100 mL |
| 50 kg to less than 60 kg | 50 mL or 100 mL | 50 mL or 100 mL | 100 mL |
| 60 kg to less than 100 kg | 50 mL, 100 mL, or 250 mL | 50 mL, 100 mL, or 250 mL | 100 mL or 250 mL |
| 100 kg or greater | 100 mL or 250 mL | 100 mL or 250 mL | 250 mL |
| Total Infusion Volume | Infusion Duration | ||
|---|---|---|---|
| First hour | Second hour | Third hour to completion | |
| Infusion Rate (mL/hour) | |||
| 25 mL | 2.5 mL/hour | 5 mL/hour | 10 mL/hour |
| 50 mL | 5 mL/hour | 10 mL/hour | 20 mL/hour |
| 100 mL | 10 mL/hour | 20 mL/hour | 40 mL/hour |
| 250 mL | 25 mL/hour | 50 mL/hour | 100 mL/hour |
Side Effects of Avlayah
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. The safety of AVLAYAH was evaluated in male pediatric patients with Hunter syndrome in Trial 1. The median (minimum, maximum) duration of exposure was 117 weeks.
In Trial 1, the most common adverse reactions (≥20%) reported in AVLAYAH-treated patients were infusion-associated reaction (IAR), upper respiratory tract infection, ear infection, pyrexia, anemia, cough, vomiting, diarrhea, rash, COVID-19, rhinorrhea, nasal congestion, fall, headache, skin abrasion, and urticaria. Dose interruptions of AVLAYAH due to an adverse reaction occurred in 91% of patients. The most frequently reported adverse reaction leading to dose interruption was IAR (31 patients).
Other frequently reported adverse reactions leading to dose interruption were COVID-19 (18 patients), pyrexia, upper respiratory tract infection, nasal congestion, and vomiting. Dose interruption included skipped infusions due to an adverse reaction as well as temporary infusion pauses with subsequent completion during the same visit. Dose reductions of AVLAYAH due to adverse reactions occurred in 57% of patients; the majority of these reactions were IARs.
In Trial 1, one (2%) AVLAYAH-treated patient experienced anaphylaxis, which occurred in the first month of treatment. Table 4 summarizes adverse reactions that occurred in >15% of AVLAYAH-treated pediatric patients with Hunter syndrome. One patient permanently discontinued treatment due to an IAR.
Anemia Two (4%) AVLAYAH-treated patients experienced severe anemia (defined as hemoglobin <8 g/dL) prior to Week 24. One (2%) AVLAYAH-treated patient, aged 0.5 years, experienced moderate anemia (hemoglobin 9.2 g/dL), which was considered serious due to the patient's age. Membranous Nephropathy A case of biopsy-confirmed, steroid-refractory membranous nephropathy with immune complex deposits in the kidney was reported in an AVLAYAH-treated patient.
| Adverse Reaction | Any Severity N (%) (N = 47) |
|---|---|
| a Infusion-associated reaction includes infusion-related reaction. | |
| b Ear infection includes ear infection, otitis media, otitis media acute, otitis externa. | |
| c Anemia includes anemia, iron deficiency anemia, and decreased hemoglobin. | |
| Infusion-associated reaction a | 41 (87%) |
| Upper respiratory tract infection | 28 (60%) |
| Ear infection b | 26 (55%) |
| Pyrexia | 26 (55%) |
| Anemia c | 24 (51%) |
| Cough | 22 (47%) |
| Vomiting | 20 (43%) |
| Diarrhea | 19 (40%) |
| Rash | 19 (40%) |
| COVID-19 | 18 (38%) |
| Rhinorrhea | 18 (38%) |
| Nasal congestion | 17 (36%) |
| Fall | 11 (23%) |
| Headache | 11 (23%) |
| Skin abrasion | 11 (23%) |
| Urticaria | 10 (21%) |
| Constipation | 8 (17%) |
| Contusion | 8 (17%) |
| Gastroenteritis | 8 (17%) |
| Infusion site extravasation | 8 (17%) |
| Insomnia | 8 (17%) |
| Neutropenia | 8 (17%) |
Warnings & Cautions for Avlayah
Hypersensitivity Reactions Including Anaphylaxis
Life-threatening hypersensitivity reactions, including anaphylaxis, have been reported in patients treated with enzyme replacement therapies (ERTs), including AVLAYAH. Symptoms of anaphylaxis that have occurred with AVLAYAH have included tachycardia, hypotension, wheezing, vomiting, hives, and lip and tongue swelling. Anaphylaxis has occurred during the early course of ERT and after extended duration of therapy.
Administer AVLAYAH under the supervision of a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis. Initiate AVLAYAH in a healthcare setting with appropriate medical monitoring and support measures including access to cardiopulmonary resuscitation equipment. Prior to AVLAYAH administration, consider pre-treatment with antihistamines, antipyretics, and/or corticosteroids.
If a severe hypersensitivity reaction (including anaphylaxis) occurs, discontinue AVLAYAH and immediately initiate appropriate medical treatment, including use of epinephrine. Consider the risks and benefits of re-administering AVLAYAH following a severe hypersensitivity reaction (including anaphylaxis). If the decision is made to re-administer AVLAYAH, re-evaluate pre-treatment medications (e.g., antihistamines, antipyretics, and/or corticosteroids), slow the infusion rate, and/or reduce the AVLAYAH dose.
Monitor patients closely upon re-administration of AVLAYAH. Inform patients of the symptoms of life-threatening hypersensitivity reactions, including anaphylaxis, and to seek immediate medical care should symptoms occur. If a mild or moderate hypersensitivity reaction occurs, temporarily hold the infusion and/or reduce the infusion rate by at least 50% from the current rate, then titrate up to the recommended infusion rate as tolerated (see Table 3 ).
Re-evaluate the pre-treatment medication regimen. If the dose has been decreased due to an adverse reaction, evaluate when it is appropriate to increase the dose and follow the recommended dose escalation regimen to achieve the maintenance dosage of 15 mg/kg once weekly.
Infusion-Associated Reactions
Infusion-associated reactions (IARs) have been reported in patients treated with AVLAYAH. IARs are defined as adverse reactions occurring during or within 24 hours of the infusion. Symptoms of IARs observed with AVLAYAH can include (but are not limited to) chills, angioedema, hypotension, tachycardia, urticaria, vomiting, wheezing, pyrexia, flushing, erythema, rash, cough, diarrhea, abdominal pain, retching, headache, irritability, and papules.
IARs have been reported more frequently in ERT-naïve patients compared to ERT-experienced patients. Cases of infusion-associated reactions occurring 2 hours or more after completion of the infusion have occurred with AVLAYAH. IARs may still occur in patients after receiving pre-treatment.
Onset of IARs was most common during the first 8 weeks of treatment with a median time to onset of approximately 2 weeks for the first IAR; IARs declined in frequency with continued use of AVLAYAH. IARs may still occur despite extended duration of AVLAYAH treatment. Appropriate medical monitoring and support measures, including cardiopulmonary resuscitation equipment, should be readily available during AVLAYAH administration.
Patients with Hunter syndrome may have compromised cardiac and respiratory function which may predispose them to a higher risk of severe complications from IARs. Closely monitor patients with compromised cardiac and respiratory function following AVLAYAH administration.
Anemia Anemia has been reported in patients treated with AVLAYAH. The incidence of anemia after initiation of AVLAYAH was higher in patients with pre-existing anemia compared to those without pre-existing anemia. Reductions in hemoglobin levels were generally observed by Week 13, though the occurrence was observed up to one year in some patients.
Overall, the incidence and severity of anemia decreased over time, with the majority of patients recovering by Week 24. Anemia did not result in treatment discontinuation; management may include supplementation with iron. Obtain hemoglobin levels prior to initiating AVLAYAH, at 3 months after initiation, and periodically thereafter as clinically indicated.
Administer appropriate supportive measures for anemia based on clinical judgment.
Membranous Nephropathy
A case of steroid-refractory membranous nephropathy with immune complex deposits in the kidney was reported in an AVLAYAH-treated patient. Monitor serum creatinine and urinary protein to creatinine ratio. If membranous nephropathy is suspected, conduct diagnostic evaluation and initiate appropriate treatment.
Consider risks and benefits of continuing AVLAYAH in patients who develop membranous nephropathy.
Pregnancy Safety for Avlayah
Pregnancy Risk Summary There are no available data on the use of AVLAYAH during pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Animal studies to evaluate the potential for embryofetal developmental toxicity and pre- and postnatal developmental toxicity of tividenofusp alfa-eknm have not been conducted. The background risk of major birth defects and miscarriage for the indicated population is unknown.
All pregnancies have a background risk of birth defects, loss, and other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively.
Pediatric Use of Avlayah
Pediatric Use The safety and effectiveness of AVLAYAH have been established under accelerated approval for the treatment of neurologic manifestations of Hunter syndrome (Mucopolysaccharidosis type II, MPS II) when initiated in presymptomatic or symptomatic pediatric patients weighing at least 5 kg prior to advanced neurologic impairment and the information on this use is discussed throughout the labeling. The safety and effectiveness of AVLAYAH have not been established in pediatric patients weighing less than 5 kg.
Clinical Studies of Avlayah
Patients who received 30 mg/kg weekly dosage (2 times the approved recommended maintenance dosage) did not show additional reductions from baseline in cerebrospinal fluid (CSF) or urine heparan sulfate (HS) concentration compared to patients who received 15 mg/kg weekly. The most common AVLAYAH dosage (57% of the patients) in Trial 1 was 15 mg/kg administered once weekly. Of the 47 patients, 15 patients were enzyme replacement therapy (ERT)-naïve, and 32 patients were ERT-experienced, 2 of whom had a history of prior treatment for Hunter syndrome with hematopoietic stem cell transplantation (HSCT), and 2 of whom had a history of prior treatment for Hunter syndrome with gene therapy.
The median duration of previous ERT treatment was 26 months (range: 1 to 134 months). In Trial 1, treatment with AVLAYAH resulted in a significant reduction of CSF HS. For the 44 patients who had measurements at Week 24, the CSF HS mean percent reduction from baseline was the minimum and maximum percent change in CSF HS from baseline were 72% and 98%, respectively.
At baseline, 0% (0 of 47) of patients had CSF HS levels below the upper limit of normal (ULN). At Week of AVLAYAH-treated patients had CSF HS levels below the ULN.
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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