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AVLAYAH is a brand name for Tividenofusp Alfa. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: 1 INDICATIONS AND USAGE 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…
Verbatim from this product's FDA label. Tap a section to expand.
2 DOSAGE AND ADMINISTRATION Administration of AVLAYAH should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis. 1) Obtain a baseline hemoglobin value in all patients.
1 ) Recommended AVLAYAH maintenance dosage for pediatric patients who weigh at least 5 kg is 15 mg/kg administered once weekly as an intravenous infusion over approximately 4 hours. 6 ) Initiate AVLAYAH treatment with a dose escalation regimen.
2 ) See the full prescribing information for dosage and administration modifications and monitoring. 3 ) See the full prescribing information for preparation and administration instructions. 1) ] . 1) ]. 2) ] . 3) ] . 2 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.
2) ] . 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.
3) ] . , 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.
2) ] . 2) ]. 2) ]. 4 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. 2) ] . 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. 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.
4) ] Most common adverse reactions (incidence ≥20%) were IAR, upper respiratory tract infection, ear infection, pyrexia, anemia, cough, vomiting, diarrhea, rash, COVID-19, rhinorrhea, nasal congestion, fall, headache, skin abrasion, and urticaria.
gov/medwatch. 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.
The safety of AVLAYAH was evaluated in male pediatric patients with Hunter syndrome in Trial 1 [see Clinical Studies (14) ] . 2 to 2 times the approved recommended maintenance dose) weekly, and the majority of patients received 15 mg/kg intravenously weekly after Week 24.
The median (minimum, maximum) duration of exposure was 117 (19, 219) 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 [66%] patients). Other frequently reported adverse reactions leading to dose interruption were COVID-19 (18 [38%] patients), pyrexia (16 [34%]), upper respiratory tract infection (16 [34%]), nasal congestion (6 [13%]), and vomiting (6 [13%]).
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.
5 WARNINGS AND PRECAUTIONS Infusion-Associated Reactions (IARs) : If a severe IAR occurs, discontinue AVLAYAH and initiate appropriate medical treatment. 2 ) Anemia : Obtain baseline hemoglobin levels in all patients and monitor 3 months after initiation, and as clinically indicated.
Administer appropriate supportive measures for anemia based on clinical judgment. 3 ) Membranous Nephropathy: Monitor serum creatinine and urinary protein to creatinine ratio. If membranous nephropathy is suspected, conduct diagnostic evaluation and initiate appropriate treatment.
1 Hypersensitivity Reactions Including Anaphylaxis Life-threatening hypersensitivity reactions, including anaphylaxis, have been reported in patients treated with enzyme replacement therapies (ERTs), including AVLAYAH [see Adverse Reactions (6) ] .
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). , antihistamines, antipyretics, and/or corticosteroids), slow the infusion rate, and/or reduce the AVLAYAH dose.
4 CONTRAINDICATIONS None. None ( 4 )
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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. 6) ] 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. 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. 9% Sodium Chloride Injection. Avoid introducing air into the infusion bag. 5) Gently invert the infusion bag to mix the solution. Do not shake. 6 mg/mL and 15 mg/mL.
5 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. 6 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.
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.
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. 7) ] . 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. 7 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.
6) ] .
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.
Table 4:
Adverse Reactions That Occurred in >15% in AVLAYAH-treated Pediatric Patients With Hunter Syndrome (Trial 1) 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%) Description of Selected Adverse Reactions Infusion-Associated Reaction Three (6%) AVLAYAH-treated patients experienced severe IARs.
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. 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.
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 ).
3) ] . 2) ]. 1) ] . 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. Prior to AVLAYAH administration, consider pre-treatment with antihistamines, antipyretics, and/or corticosteroids to reduce the risk of IARs.
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. If a severe IAR occurs, discontinue AVLAYAH and immediately initiate appropriate medical treatment.
Consider the risks and benefits of re-administering AVLAYAH following a severe IAR. 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.
If a mild or moderate IAR 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. 2) ] . 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. 1) ] . 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. 1) ] . 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.