Lamzede

2.1        Important Recommendations Prior to LAMZEDE Treatment Initiation

For females of reproductive potential, verify that the patient is not pregnant [see Use in Specific Populations ( 8.1,  8.3)].

2.2        Recommended Dosage and Administration

Prior to LAMZEDE administration, consider pre-treating with antihistamines, antipyretics, and/or corticosteroids [see Warnings and Precautions ( 5.1, 5.2)].

The recommended dosage of LAMZEDE is 1 mg/kg (actual body weight) administered once every week as an intravenous infusion.

The total volume of infusion is determined by the patient’s actual body weight and should be administered over a minimum of 60 minutes for patients weighing up to 49 kg. Patients weighing 50 kg and greater should be infused at a maximum infusion rate of 25 mL/hour to control the protein load [see Dosage and Administration ( 2.4)].

If one or more doses are missed, restart the treatment as soon as possible, as long as it is at least 3 days from the next scheduled dose. If it is within 3 days from the next scheduled dose, give only the next dose per schedule.

2.3        Dosage and Administration Modifications Due to Hypersensitivity Reactions and/or Infusion-Associated Reactions

In the event of a severe hypersensitivity reaction (including anaphylaxis) or severe infusion-associated reaction (IAR), immediately discontinue LAMZEDE administration and initiate appropriate medical treatment. For additional recommendations in the event of a severe hypersensitivity reaction or IAR, see Warnings and Precautions ( 5.1, 5.2).

In the event of a mild to moderate hypersensitivity reaction or a mild to moderate IAR, consider temporarily holding the infusion for 15 to 30 minutes, slowing the infusion rate to 25% to 50% of the recommended rate, and initiating appropriate medical treatment [see Warnings and Precautions ( 5.1, 5.2)].

If symptoms:

• Persist despite temporarily holding or slowing the infusion, stop the infusion and monitor the patient. If symptoms continue to persist, discontinue the infusion, and consider re-initiating the infusion within 7 to 14 days at 25% to 50% of the recommended rate with appropriate pretreatment.
  
• Subside following holding or slowing the infusion, resume infusion at 25% to 50% the recommended rate. If tolerated, increase the infusion rate by increments of 25% of the recommended rate until the recommended infusion rate is reached. Closely monitor the patient.

2.4         Reconstitution Instructions

Use aseptic technique during preparation. Reconstitute LAMZEDE in the following manner:

• Determine the number of LAMZEDE vials to be reconstituted based on the patient’s weight in kg and the recommended dose [see Dosage and Administration ( 2.2)]. Round the number of vials up to the next whole number.
  
• Remove vials from the refrigerator and set aside for approximately 30 minutes to allow vials to come to room temperature.
  
• Reconstitute each vial by slowly injecting 5 mL of Sterile Water for Injection, down the inside wall of each vial. Avoid adding the Sterile Water for Injection to the vial forcefully or directly onto the lyophilized powder to minimize foaming.
  
• Allow the reconstituted vials to stand on the table for 5 – 15 minutes. Then gently tilt and roll each vial for 15 – 20 seconds to enhance the dissolution process. Each vial will yield a concentration of 2 mg/mL. Do not invert, swirl, or shake the vials.
  
• Visually inspect the reconstituted solution in the vials for particulate matter and discoloration. The solution should be clear to slightly opalescent. Due to the nature of LAMZEDE, the solution may occasionally contain some proteinaceous particles in the form of thin white strands or translucent fibers which will be removed by the in line filter during infusion. Discard if opaque particles are present or the solution is discolored.
  
• Slowly withdraw the required volume from the vials with caution to avoid foaming in the syringe. If the volume of the solution exceeds one syringe capacity, prepare the required number of syringes in order to replace the syringe quickly during the infusion. Discard unused portion remaining in the vials.

Storage of the Reconstituted Solution

• If the reconstituted LAMZEDE vial is not used immediately, store the vial refrigerated at 2°C to 8°C (36°F to 46°F) for up to 24 hours inclusive of infusion time. Protect from light during refrigeration. Do not freeze.
  
• Reconstituted LAMZEDE vial must be infused within 10 hours after removal from the refrigerator, inclusive of total infusion time. Discard if not used within 10 hours.
  
• Infuse reconstituted solution within 24 hours from the time of preparation, which includes the storage time in the refrigerator, the time at room temperature, and the duration of the infusion.

2.5        Administration Instructions

• Use an infusion set equipped with a pump and a low protein binding, 0.2-micron, in-line filter to administer LAMZEDE. Do not shake the syringe.
  
• The total volume of infusion is determined by the patient’s actual body weight and should be administered over a minimum of 60 minutes for patients weighing up to 49 kg. Patients weighing 50 kg and greater should be infused at a maximum infusion rate of 25 mL/hour to control the protein load.
  
• When the last syringe is empty, replace the dosage syringe with a 20 mL syringe filled with 0.9% Sodium Chloride Injection, and then continue to infuse an additional 10 mL of 0.9% Sodium Chloride Injection through the infusion system to infuse the remaining fraction of LAMZEDE in the line to the patient.

8.1        Pregnancy

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.

8.2        Lactation

Risk Summary

There are no data on the presence of velmanase alfa-tycv or its metabolite 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 LAMZEDE and any potential adverse effects on the breastfed infant from velmanase alfa-tycv or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential

LAMZEDE may cause embryo-fetal harm when administered to a pregnant female [see Use in Specific Populations ( 8.1)].

Pregnancy Testing

For females of reproductive potential, verify that the patient is not pregnant prior to initiating treatment with LAMZEDE.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment and for 14 days after the last dose if LAMZEDE is discontinued.

8.4        Pediatric Use

The safety and effectiveness of LAMZEDE for the treatment of alpha-mannosidosis have been established in pediatric patients.

Use of LAMZEDE for this indication is supported by evidence from an adequate and well-controlled clinical trial in adult and pediatric patients, and from an open label trial in 5 pediatric patients (younger than 6 years of age) [see Clinical Studies ( 14)].

LAMZEDE-treated pediatric patients reported a higher incidence of hypersensitivity reactions compared to LAMZEDE-treated adult patients [see Warnings and Precautions ( 5.1), Adverse Reactions ( 6.1)].

8.5        Geriatric Use

Alpha-mannosidosis is largely a disease of pediatric and young adult patients. Clinical trials of LAMZEDE did not include patients 65 years of age and older.