AVLAYAH Powder for solution for injection Ref.[116748] Active ingredients: Tividenofusp alfa

5.1 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). 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 [see Dosage and Administration (2.3)].

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 [see Dosage and Administration (2.2)].

5.2 Infusion-Associated Reactions

Infusion-associated reactions (IARs) have been reported in patients treated with AVLAYAH [see Adverse Reactions (6.1)]. 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.

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 [see Dosage and Administration (2.2)].

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.

5.3 Anemia

Anemia has been reported in patients treated with AVLAYAH [see Adverse Reactions (6.1)].

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.

5.4 Membranous Nephropathy

A case of steroid-refractory membranous nephropathy with immune complex deposits in the kidney was reported in an AVLAYAH-treated patient [see Adverse Reactions (6.1)]. 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.

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Hypersensitivity Reactions Including Anaphylaxis [see Warnings and Precautions (5.1)]
• Infusion-Associated Reactions [see Warnings and Precautions (5.2)]
• Anemia [see Warnings and Precautions (5.3)]
• Membranous Nephropathy [see Warnings and Precautions (5.4)]

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)]. A total of 47 male patients (age range: 3 months to 13 years) received intravenous AVLAYAH at 3 mg/kg to 30 mg/kg (0.2 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.

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):

^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.

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. 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.

The observed incidence of anti-drug antibodies (ADAs) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADAs in the studies described below with the incidence of ADAs in other studies, including those of AVLAYAH or of other tividenofusp alfa products.

In Trial 1 [see Clinical Studies (14)], anti-tividenofusp alfa-eknm antibodies (referred to as ADAs) were detected in 100% (47/47) of AVLAYAH-treated patients with Hunter syndrome following 19 to 219 weeks of treatment. In Trial 1, neutralizing antibodies (NAbs) that inhibit enzyme activity of tividenofusp alfa-eknm were detected in 87% (41/47) of AVLAYAH-treated patients with Hunter syndrome. NAbs that inhibit cellular uptake of tividenofusp alfa-eknm were not characterized in this trial.

Among the 10 enzyme replacement therapy (ERT)-experienced and 13 ERT-naïve patients with Hunter syndrome who were ADA negative at baseline, all of the patients became ADA positive following AVLAYAH treatment.

ADA responses in both ERT-experienced and ERT-naïve patients with Hunter syndrome were more frequently directed against the IDS component of tividenofusp alfa-eknm than the Fc component. ADA titers peaked at approximately Week 13, remained elevated through Week 24, and declined thereafter in the majority of patients.

Antibodies against other IDS ERTs are expected to be cross-reactive to tividenofusp alfa-eknm.

Prevalence for ADAs and NAbs that inhibited enzyme activity in AVLAYAH-treated pediatric patients with Hunter syndrome are summarized in Table 6.

Table 6. ADA and NAb Prevalence at Baseline and Post-AVLAYAH Treatment in Pediatric Patients With Hunter Syndrome:

Abbreviations: ADA = anti-drug antibody (anti-tividenofusp alfa-eknm antibody); ERT = enzyme replacement therapy; NAb = neutralizing antibody.
Data are presented as n/N (%). Prevalence reflects ADA detected at baseline or post-baseline.
^a ERT-experienced was defined as patients who had ≥4 months of ERT treatment at any time prior to AVLAYAH treatment initiation.
^b ERT-naïve was defined as patients who had <4 months of continuous ERT treatment at any time prior to AVLAYAH treatment initiation.

Anti-Drug Antibody Effects on Pharmacokinetics, Pharmacodynamics, Safety, and Efficacy

Development of ADAs was associated with reduced serum tividenofusp alfa-eknm concentrations. AVLAYAH-treated patients who developed higher ADA titers had greater reductions in serum tividenofusp alfa-eknm concentrations. The observed ADA-associated pharmacokinetic changes did not result in significant effects on the reduction in CSF HS or urine HS at the recommended dosage [see Dosage and Administration (2.2)].

The effect of ADAs on the safety of AVLAYAH in patients with Hunter syndrome has not been fully characterized.

The effect of ADAs on the effectiveness of AVLAYAH in the treatment of Hunter syndrome is unknown.

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 2% to 4% and 15% to 20%, respectively.

Risk Summary

There are no data on the presence of tividenofusp alfa-eknm in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for AVLAYAH and any potential adverse effects on the breastfed infant from AVLAYAH or from the underlying maternal condition.

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 [see Indications and Usage (1)]. The safety and effectiveness of AVLAYAH have not been established in pediatric patients weighing less than 5 kg.

Clinical trials of AVLAYAH in patients with Hunter syndrome did not include patients 65 years of age or older.