FDA

Lamzede

Approved 16 Feb 2023Powder, for injection solution, lyophilized powder

Indications

1 INDICA TIONS AND USAGE LAMZEDE is indicated for the treatment of non-central nervous system manifestations of alpha-mannosidosis in adult and pediatric patients. LAMZEDE is recombinant human lysosomal alpha-mannosidase indicated for the treatment of non-central nervous system manifestations of alpha-mannosidosis in adult and pediatric patients. ( 1 )

Contraindications

None. None. ( 4 )

Warnings and precautions

Infusion -Associ ated Reactions (IARs) : If severe IARs occur, discontinue LAMZEDE and initiate appropriate medical treatment. ( 5.2 ) Embryo - F etal Toxicity : May cause fetal harm. Advise females of reproductive potential to use effective contraception during treatment and for 14 days after the last dose if LAMZEDE is discontinued. ( 5.3 , 8.1 , 8.3 )

5.1Hypersensitivity Reactions Including Anaphylaxis

Hypersensitivity reactions including anaphylaxis have been reported in LAMZEDE-treated patients. In clinical trials, 19 (50%) LAMZEDE-treated patients (5 adult patients and 14 pediatric patients) experienced hypersensitivity reactions, including 2 (5%) patients (1 adult patient and 1 pediatric patient) who experienced anaphylaxis and an additional 3 (8%) pediatric patients who experienced severe hypersensitivity reactions that required medical treatment [see Clinical Studies ( 14 )] .

In the 5 patients who experienced anaphylaxis or severe hypersensitivity requiring medical treatment, 4 (80%) were anti-drug antibody (ADA) positive [see Clinical Pharmacology ( 12.6 ) ] . Anaphylaxis and severe hypersensitivity signs and symptoms included cyanosis, hypotension, emesis, urticaria, erythema, facial swelling, pyrexia, and tremor. Prior to LAMZEDE administration, consider pretreating with antihistamines, antipyretics, and/or corticosteroids.

Appropriate medical support measures, including cardiopulmonary resuscitation equipment, should be readily available during LAMZEDE administration. If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue LAMZEDE immediately and initiate appropriate medical treatment. Consider the risks and benefits of re-administering LAMZEDE following severe hypersensitivity reactions (including anaphylaxis). Patients may be rechallenged using slower infusion rates.

In patients with severe hypersensitivity reaction, desensitization measures to LAMZEDE may be considered. If the decision is made to readminister LAMZEDE, ensure the patient tolerates the infusion. If the patient tolerates the infusion, the rate may be increased to reach the recommended dosage. If a mild or moderate hypersensitivity reaction occurs, consider slowing the infusion rate or temporarily withholding the dose [see Dosage and Administration ( 2.3 )] .

At a glance

Brand name: Lamzede
Active substance: velmanase alfa-tycv
Dosage form: Powder, for injection solution, lyophilized powder
Applicant: Chiesi Farmaceutici SPA
Status: Prescription
FDA approval: 16 Feb 2023
Application: BLA761278-001

Indications

Warnings and precautions

5.1Hypersensitivity Reactions Including Anaphylaxis

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary Based

on findings from animal reproduction studies, LAMZEDE may cause embryo-fetal harm when administered to a pregnant female. In animal reproduction studies, major visceral malformations were observed in rats and rabbits when velmanase alfa-tycv was administered in pregnant rats and rabbits during the period of organogenesis. These malformations were observed in rats at the highest dose level, at exposures that were approximately 7-fold the recommended dose in patients of 1 mg/kg.

Malformations occurred at all dose levels in rabbits with the highest dose exposures approximately 2.5-fold the recommended patient dose of 1 mg/kg ( see Data ) . There are no available data on LAMZEDE use in pregnant females to evaluate a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Advise the pregnant female of the potential risk to the fetus. The decision to continue or discontinue LAMZEDE treatment during pregnancy should consider the female’s need for LAMZEDE, the potential drug-related risks to the fetus, and the potential adverse outcomes from untreated maternal disease.

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, or 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. Data Animal Data In an embryo-fetal development study in the rat, velmanase alfa-tycv was administered during the period of organogenesis from gestation day (GD) 6 to GD 17.

Major malformations and variations were observed at exposures that were approximately 7-fold greater than the recommended dose of 1 mg/kg. Treatment-related major malformations included cleft palate, cleft palatine skull, severely bent pelvic girdle, and duplicated sternebrae. In an embryofetal development study in the rabbit, administration of velmanase alfa-tycv from GDs 6 through 18 was associated with skeletal and/or visceral malformations, which occurred at exposures that were approximately 2.5-fold greater than those observed in patients treated at the 1 mg/kg dose level.

Major malformations observed in rabbits included incomplete intraventricular septum; severely reduced size of one or more lung lobe; unilateral renal agenesis; unilateral ureter; diaphraghmatic hernia involving one or more lobe of the liver; hydrocephaly; single olfactory lobe; cystic dilatation of the cerebellum; malformed cervical, thoracic, caudal, and/or sacral vertebrae; and fused, absent, or vestigial ribs. In the pre- and post-natal development study in rats, velmanase alfa-tycv was administered intravenously every 3 days at 0, 3.3, 10, and 30 mg/kg from GD 6 to lactation day 20.

Velmanase alfa-tycv did not induce effects on maternal reproductive function or on developmental and reproductive parameters of male and female offspring; thus, the maternal and developmental NOAELs were 30 mg/kg. Exposures at this dose, based on the embryo-fetal development study, were estimated to be approximately 10-fold greater than the 1 mg/kg dose of velmanase alfa-tycv.

Adverse reactions

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 (IARs) [see Warnings and Precautions ( 5.2 ) ] Most common adverse reactions (incidence > 20%) are hypersensitivity reactions including anaphylaxis ( 5.1 ), nasopharyngitis, pyrexia, headache, and arthralgia.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Chiesi USA, Inc. at 1-888-661-9260 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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. Adverse Reactions F rom Trial 1 The safety of LAMZEDE was evaluated in Trial 1, which included a total of 15 LAMZEDE-treated patients (8 adult patients aged 18-35 years old and 7 pediatric patients aged 6-17 years old; 9 male, 6 female) with alpha-mannosidosis [see Clinical Studies ( 14 )].

All patients received LAMZEDE 1 mg/kg weekly via intravenous infusion for 52 weeks. A serious adverse reaction of acute renal failure was reported in 1 (7%) LAMZEDE-treated patient (see Description of Selected Adverse Reactions) . Table 1 lists adverse reactions that occurred in at least 2 LAMZEDE-treated patients in Trial 1. Table 1: Adverse Reactions (≥2 patients) in Adult and Pediatric Patients with Alpha-Mannosidosis Treated with LAMZEDE in Trial 1 Adverse Reaction LAMZEDE N=15 n (%) Placebo N=10 n (%) Nasopharyngitis 10 (66) 7 (70) Pyrexia 6 (40) 5 (50) Headache 5 (33) 3 (30) Arthralgia 3 (20) 1 (10) Acute tonsillitis 2 (13) 0 Urinary tract infection 1 2 (13) 1 (10) Eye pruritus 2 (13) 0 Gastroenteritis 2 (13) 0 Hypersensitivity 2 (13) 0 Influenza 2 (13) 0 Syncope 2 (13) 0 Toothache 2 (13) 0 Back pain 2 (13) 1 (10) Ear infection 2 (13) 1 (10) 1 “Urinary tract infection” is composed of similar terms.

Adverse Reactions from Trials 2 and 3 In Trial 2, 5 pediatric patients aged 3 to 5 years old (3 male, 2 female) with alpha-mannosidosis received LAMZEDE weekly for a mean exposure of 121 weeks [see Clinical Studies ( 14 )] . One patient treated with LAMZEDE (20%) presented serious reactions (chills and hyperthermia on the same occasion). The adverse reactions that occurred in at least 2 of 5 patients (and are in addition to the adverse reactions already identified in Trial 1 above) included: cough, otitis media, rhinitis, conjunctivitis, fall, ligament sprain, oropharyngeal pain, swelling face, and upper respiratory tract infection.

Trial 3 is an integrated analysis that pooled the cumulative databases from LAMZEDE phase 1, 2, and 3 trials in patients with alpha-mannosodosis. A total of 33 patients (20 male, 13 female) aged 6 to 35 years old (14 adults, 19 pediatric) received LAMZEDE weekly for a mean exposure of 89 weeks in adult patients and 155 weeks in pediatric patients. One patient was withdrawn from the trial due to repeated IARs and successfully reintroduced after 89 weeks of pause.

The adverse reactions that occurred in at least 10% of patients (and are in addition to the adverse reactions already identified in Trial 1 and 2 above) included abdominal pain upper, contusion, excoriation, post-lumbar puncture syndrome, wound, weight increased, erythema, rash, and tooth extraction. Description of S elected A dverse R eactions Acute R enal F ailure One patient out of 38 (3%) experienced one episode of acute renal failure.

This patient paused LAMZEDE treatment for 4 weeks and acute renal failure resolved within 12 weeks of diagnosis. This patient is noted to have received the concomitant medication of ibuprofen. Immunoglobulin A V asculitis One episode of immunoglobulin A vasculitis (IgAV), reported as Henoch Schonlein Purpura , occurred in one patient out of 38 (3%) who developed high anti-drug antibody (ADA) levels. Seizure One patient out of 38 (3%), with no prior history of seizures experienced more than one episode of seizures.

A relationship between the occurrence of seizures in this patient and exposure to LAMZEDE cannot be excluded. Pediatric Patients Hypersensitivity reactions overall were reported in 36% of adult patients and 58% of pediatric patients. Immunogenicity: Anti - D rug Antibody-Associated Adverse Reactions Infusion-associated reactions (including anaphylaxis and severe hypersensitivity reactions) occurred in a higher incidence in LAMZEDE-treated patients who developed anti-velmanase alfa-tycv antibodies (anti-drug antibodies, ADA) compared to patients who were ADA-negative (80% versus 20%) [see Clinical Pharmacology ( 12.6 ) ] .

In Trial 1 following treatment with LAMZEDE for up to 52 weeks, 1 out of 5 ADA-positive patients developed severe hypersensitivity and this patient developed the highest ADA level among all the ADA-positive patients in the trial. In Trial 2 following treatment with LAMZEDE for up to 174 weeks, 2 out of 4 ADA-positive pediatric patients experienced IARs. In Trial 3, 3 out of 33 patients (9.1%) reported IARs; two of these patients were ADA positive (one of these two patients is described in Trial 1); one patient was ADA negative. 6. 2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of velmanase alfa outside of the United States.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac disorders: aortic valve incompetence, palpitations, tachycardia Ear and labyrinth disorders: deafness Eye disorders: lacrimation increased Gastrointestinal disorders: odynophagia General disorders and administration site conditions: asthenia, fatigue Infections and infestations: endocarditis, staphylococcal infection, bacterial disease carrier, furuncle Metabolism and nutrition disorders: decreased appetite Musculoskeletal and connective tissue disorders: joint swelling, joint warmth Nervous system disorders: ataxia, nervous system disorder, somnolence Psychiatric disorders : psychotic disorder, agitation, encopresis, nervousness Respiratory, thoracic and mediastinal disorders: pharyngeal edema, wheezing Skin, subcutaneous tissue disorders: angioedema Vascular disorders: vascular fragility, hypotension

Lamzede

Indications

Contraindications

Warnings and precautions

5.1Hypersensitivity Reactions Including Anaphylaxis

At a glance

Two medicines in one question?

Lamzede

Indications

Contraindications

Warnings and precautions

5.1Hypersensitivity Reactions Including Anaphylaxis

At a glance

Two medicines in one question?

5.2Infusion-Associated Reactions

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary Based

Adverse reactions

6.1Clinical Trials Experience

Composition

Official product information