Lamzede^® (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Chiesi Farmaceutici, S.p.A. (Italy)

Manufactured By

Patheon Italia, S.P.A. (Italy)

ATC Code

A16AB15 (Velmanase alfa)

Active Substance

Velmanase alfa (Rec.INN registered by WHO)

Dosage Form

Lamzede®

Lyophilisate for preparation of solution for infusion 10 mg

Dosage Form, Packaging, and Composition

Lyophilisate for preparation of solution for infusion

10 mg – vials – cardboard packs – Prescription only
10 mg – vials (10 pcs.) – cardboard packs – Prescription only
10 mg – vials (5 pcs.) – cardboard packs – Prescription only

Clinical-Pharmacological Group

Enzyme preparation

Pharmacotherapeutic Group

Other agents for the treatment of gastrointestinal diseases and metabolic disorders; enzymes

Pharmacological Action

Alpha-mannosidosis is a rare autosomal recessive hereditary disease from the group of lysosomal storage diseases associated with impaired breakdown of mannose-rich oligosaccharides due to reduced activity of the lysosomal enzyme alpha-mannosidase.

Velmanase alfa is a recombinant form of human alpha-mannosidase. The amino acid sequence of the monomeric protein is identical to that of the natural human enzyme alpha-mannosidase.

Velmanase alfa is intended to replenish or replace natural alpha-mannosidase, an enzyme that catalyzes the sequential breakdown in lysosomes of hybrid and complex oligosaccharides with a high mannose content, reducing the amount of accumulated mannose-rich oligosaccharides in cells.

Pharmacokinetics

It is administered intravenously as an infusion. At steady state after weekly infusion administration of velmanase alfa at a dose of 1 mg/kg body weight, the mean C_max in plasma was about 8 µg/ml and was reached 1.8 hours after the start of administration, which corresponds to the average infusion duration time. As expected for a protein of this size, the V_d at steady state was low – 0.27 L/kg, indicating that its distribution is limited to the blood plasma. The clearance of velmanase alfa from blood plasma (on average 6.7 ml/h/kg body weight) is consistent with rapid cellular uptake of velmanase alfa by mannose receptors. The metabolic conversion pathway of velmanase alfa is assumed to be similar to that of other natural proteins, which are broken down into small peptides and eventually into amino acids. After the end of the infusion, the concentration of velmanase alfa in blood plasma decreased biphasically with a mean terminal T_1/2 of about 30 hours.

Indications

For enzyme replacement therapy (ERT) in the treatment of non-neurological symptoms in children, adolescents and adults with mild to moderate alpha-mannosidosis.

ICD codes

Dosage Regimen

Administer intravenously as an infusion at a dose of 1 mg/kg body weight once every week.

Calculate the exact dose based on the patient’s current body weight prior to each administration.

Reconstitute the lyophilisate with Water for Injections; gently swirl the vial to dissolve; do not shake.

Dilute the reconstituted solution in 0.9% Sodium Chloride intravenous infusion solution; use a low-protein-binding infusion set with an in-line filter.

Initiate the infusion at a rate of 1 ml/kg/hour for the first 15 minutes.

If tolerated, increase the infusion rate to 2 ml/kg/hour for the next 15 minutes.

If no infusion-associated reactions occur, further increase to a maximum rate of 3 ml/kg/hour for the remainder of the infusion.

The total infusion duration is typically 1.5 to 3.5 hours, depending on the patient’s body weight and tolerance.

Monitor the patient closely for signs of infusion-associated reactions during the administration and for at least one hour after completion.

For mild to moderate infusion reactions, temporarily slow or interrupt the infusion and administer antihistamines, antipyretics, or corticosteroids as needed.

In case of severe hypersensitivity or anaphylaxis, discontinue the infusion immediately and initiate appropriate emergency treatment.

Consider premedication with antihistamines and/or corticosteroids for patients who have experienced previous infusion reactions.

No dose adjustment is required for pediatric or geriatric patients, or for patients with hepatic or renal impairment.

Adverse Reactions

Metabolism and nutrition disorders common – increased appetite.

Psychiatric disorders common – psychotic behavior, sleep initiation disorder.

Nervous system disorders common – confusion, loss of consciousness, syncope, tremor, dizziness, headache.

Eye disorders common – eye irritation, eyelid edema, eye hyperemia.

Cardiac disorders common – bradycardia, cyanosis.

Respiratory, thoracic and mediastinal disorders common – epistaxis.

Gastrointestinal disorders very common – diarrhea; common – abdominal pain, upper abdominal pain, nausea, vomiting, reflux gastritis.

Skin and subcutaneous tissue disorders : common – urticaria, hyperhidrosis.

Musculoskeletal and connective tissue disorders common – arthralgia, back pain, joint stiffness, myalgia, limb pain.

Renal and urinary disorders common – acute renal failure.

General disorders and administration site conditions very common – pyrexia; common – chills, feeling hot, fatigue, malaise.

Administration site conditions common – infusion site pain.

Investigations very common – increased body weight.

Injury, poisoning and procedural complications common – post-procedural headache.

Contraindications

Hypersensitivity to velmanase alfa.

Use in Pregnancy and Lactation

Since therapy with velmanase alfa is aimed at normalizing alpha-mannosidase activity in patients with alpha-mannosidosis, this agent should be used during pregnancy only when absolutely necessary.

It is not known whether Velmanase alfa or its metabolites are excreted in human breast milk. However, absorption of velmanase alfa contained in milk by a breastfed infant is considered minimal, and therefore no adverse consequences for the infant are expected. Velmanase alfa can be used during breastfeeding.

Use in Hepatic Impairment

No dose adjustment is required in patients with hepatic impairment.

Use in Renal Impairment

No dose adjustment is required in patients with renal impairment.

Pediatric Use

The dosage regimen for children does not differ from the dosage regimen for adults.

Geriatric Use

There are no available data on the use of the drug in elderly patients.

Special Precautions

The effectiveness of treatment with velmanase alfa should be periodically assessed and if no beneficial effect is observed, discontinuation should be considered.

Due to the fact that target organ damage progresses over time in alpha-mannosidosis, it becomes increasingly difficult to achieve regression of lesions or demonstrate positive dynamics with ERT. Like other ERT drugs, Velmanase alfa does not cross the blood-brain barrier. The treating physician should consider that the administration of velmanase alfa cannot affect irreversible changes, such as skeletal deformities, multiple dysostoses, neurological symptoms and cognitive impairment.

When administering velmanase alfa, facilities for providing emergency medical care in emergency situations must be available. If serious allergic or anaphylactic reactions occur, immediate discontinuation of velmanase alfa administration and implementation of measures in accordance with current medical standards for emergency medical care are recommended.

Infusion reactions observed during the administration of velmanase alfa were characterized by rapid onset of symptoms and were mild to moderate in intensity.

The management of infusion reactions is determined by the severity of the reaction and includes reducing the infusion rate and using medications such as antihistamines, antipyretics and/or corticosteroids, and/or discontinuing velmanase alfa and resuming its administration with an increased infusion duration. Premedication with antihistamines and/or corticosteroids may prevent the development of infusion reactions in cases where symptomatic therapy was previously required during drug administration.

If symptoms such as angioedema (swelling of the tongue and throat), upper airway obstruction, or arterial hypotension develop during or immediately after the infusion, an anaphylactic or anaphylactoid reaction should be suspected. In such a case, treatment with antihistamines and/or corticosteroids may be recommended. In the most severe cases, it is necessary to follow current medical standards for emergency medical care. After the infusion, patients should remain under medical supervision for the development of infusion reactions for one hour or for a longer period as decided by the treating physician.

Antibody formation observed during therapy with velmanase alfa may play a role in the development of infusion reactions. To further assess the relationship with antibody formation in cases of severe infusion reactions or lack/loss of therapeutic effect, patients may be tested for the presence of antibodies to velmanase alfa. If the patient’s condition worsens during ERT, discontinuation of this treatment should be considered. There is a potential for immunogenicity.

Effect on ability to drive and use machines

Has no or negligible influence on the ability to drive and use machines.

Storage Conditions

Store at 2°C (36°F) to 8°C (46°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.