Dosing & Uses
See pediatric dosing
Dosage Forms & Strengths
suspension for IV infusion
- 1.33 x 1013 vector genomes (vg)/mL
Duchenne Muscular Dystrophy
Indicated for Duchenne muscular dystrophy (DMD) in ambulatory pediatric patients aged 4-5 years with a confirmed mutation in the DMD gene
1.33 x 1014 vector genomes (vg)/kg of body weight (or 10 mL/kg)
Calculate dose
- Dose (in mL) = patient body weight (in kg) x 10
- The multiplication factor 10 represents the per kilogram dose (1.33 x 1014 vg/kg) divided by the amount of vector genome copies per mL of the suspension (1.33 x 1013 vg/mL)
- Number of vials needed = dose (in mL) divided by 10 (round to nearest number of vials)
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Example: Calculation of volume for 19.6 kg patient
- 19.6 kg x 10 = 196 mL
- Number of vials needed = 196 divided by 10, rounded to nearest number of vials = 20 vials
Pre- and post-infusion corticosteroid dosing
- Not to exceed prednisone (or prednisone equivalent) total daily dose (TDD) of 60 mg/day
- Deflazacort is not recommended for use as a peri-infusion corticosteroid
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Baseline corticosteroid use daily or intermittent
- Start 1 day before infusion
- 1 mg/kg/day (and continue baseline dose)
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Baseline high-dose corticosteroids 2 days/wk
- Start 1 day before infusion
- 1 mg/kg/day on days without high-dose corticosteroid treatment (and continue baseline dose)
-
Not on corticosteroids
- Start 1 week before infusion
- 1.5 mg/kg day
Recommended corticosteroid regimen dose modification for liver function abnormalities following infusion
- GGT ≥150 U/L and/or other clinically significant liver function abnormalities (eg, total bilirubin >2 x ULN) following infusion; for GGT or bilirubin elevations that do not respond to these oral corticosteroid increases, IV bolus corticosteroids may be considered; deflazacort is not recommended for use as a peri-infusion corticosteroid
- Not to exceed prednisone (or prednisone equivalent) TDD of 120 mg/day
- Peri-infusion baseline + 1 mg/kg/day: Increase to 2 mg/kg/day (and continue baseline dose)
- Peri-infusion baseline + 1 mg/kg/day (on days without high-dose corticosteroid): Increase to 2 mg/kg/day on days without high-dose corticosteroids
- Peri-infusion 1.5 mg/kg/day: Increase to 2.5 mg/kg/day
Dosage Modifications
Hepatic impairment
- Safety and efficacy in patients with hepatic impairment or elevated GGT not studied
- Postpone administration in patients with acute liver disease until resolved or controlled
- Carefully consider use in patients with preexisting liver impairment or chronic hepatic viral infection; these patients may be at increased risk of acute serious liver injury
Dosing Considerations
Patient selection
- Select patients for treatment with anti-AAVrh74 total binding antibody titers <1:400
- An FDA-authorized test for detection of AAVrh74 total binding antibodies is not currently available; current available tests may vary in accuracy and design
Monitoring
- In view of the increased risk of serious systemic immune response, postpone administration in patients with infections until completely resolved
- Before administration, perform liver enzyme testing, then monitor liver function (clinical exam, GGT, and total bilirubin) weekly x 3 months following infusion
- Measure baseline anti-AAVrh74 antibody titers using a total binding antibody enzyme-linked immunosorbent assay (ELISA); not recommended if titer ≥1:400
- Obtain platelet count
- Monitor troponin-I before infusion and weekly for first month following infusion
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Contraindicated (0)
Serious - Use Alternative (0)
Monitor Closely (18)
- diphtheria & tetanus toxoids
delandistrogene moxeparvovec, diphtheria & tetanus toxoids. Other (see comment). Use Caution/Monitor. Comment: Consider patient vaccination status before initiating corticosteroid regimen required before delandistrogene moxeparvovec administration. If possible, ensure patients are current with all immunizations according to immunization guidelines. Complete vaccinations at least 4 weeks before starting corticosteroid regimen. High-dose or long-term corticosteroids may decrease immungenicity of vaccines.
- diphtheria & tetanus toxoids/ acellular pertussis vaccine
delandistrogene moxeparvovec, diphtheria & tetanus toxoids/ acellular pertussis vaccine. Other (see comment). Use Caution/Monitor. Comment: Consider patient vaccination status before initiating corticosteroid regimen required before delandistrogene moxeparvovec administration. If possible, ensure patients are current with all immunizations according to immunization guidelines. Complete vaccinations at least 4 weeks before starting corticosteroid regimen. High-dose or long-term corticosteroids may decrease immungenicity of vaccines.
- diphtheria & tetanus toxoids/acellular pertussis/poliovirus, inactivated vaccine
delandistrogene moxeparvovec, diphtheria & tetanus toxoids/acellular pertussis/poliovirus, inactivated vaccine. Other (see comment). Use Caution/Monitor. Comment: Consider patient vaccination status before initiating corticosteroid regimen required before delandistrogene moxeparvovec administration. If possible, ensure patients are current with all immunizations according to immunization guidelines. Complete vaccinations at least 4 weeks before starting corticosteroid regimen. High-dose or long-term corticosteroids may decrease immungenicity of vaccines.
- haemophilus influenzae type b vaccine
delandistrogene moxeparvovec, haemophilus influenzae type b vaccine. Other (see comment). Use Caution/Monitor. Comment: Consider patient vaccination status before initiating corticosteroid regimen required before delandistrogene moxeparvovec administration. If possible, ensure patients are current with all immunizations according to immunization guidelines. Complete vaccinations at least 4 weeks before starting corticosteroid regimen. High-dose or long-term corticosteroids may decrease immungenicity of vaccines.
- hepatitis b vaccine
delandistrogene moxeparvovec, hepatitis b vaccine. Other (see comment). Use Caution/Monitor. Comment: Consider patient vaccination status before initiating corticosteroid regimen required before delandistrogene moxeparvovec administration. If possible, ensure patients are current with all immunizations according to immunization guidelines. Complete vaccinations at least 4 weeks before starting corticosteroid regimen. High-dose or long-term corticosteroids may decrease immungenicity of vaccines.
- influenza virus vaccine quadrivalent
delandistrogene moxeparvovec, influenza virus vaccine quadrivalent. Other (see comment). Use Caution/Monitor. Comment: Consider patient vaccination status before initiating corticosteroid regimen required before delandistrogene moxeparvovec administration. If possible, ensure patients are current with all immunizations according to immunization guidelines. Complete vaccinations at least 4 weeks before starting corticosteroid regimen. High-dose or long-term corticosteroids may decrease immungenicity of vaccines.
- influenza virus vaccine quadrivalent, cell-cultured
delandistrogene moxeparvovec, influenza virus vaccine quadrivalent, cell-cultured. Other (see comment). Use Caution/Monitor. Comment: Consider patient vaccination status before initiating corticosteroid regimen required before delandistrogene moxeparvovec administration. If possible, ensure patients are current with all immunizations according to immunization guidelines. Complete vaccinations at least 4 weeks before starting corticosteroid regimen. High-dose or long-term corticosteroids may decrease immungenicity of vaccines.
- measles mumps and rubella vaccine, live
delandistrogene moxeparvovec, measles mumps and rubella vaccine, live. Other (see comment). Use Caution/Monitor. Comment: Consider patient vaccination status before initiating corticosteroid regimen required before delandistrogene moxeparvovec administration. If possible, ensure patients are current with all immunizations according to immunization guidelines. Complete vaccinations at least 4 weeks before starting corticosteroid regimen. High-dose or long-term corticosteroids may decrease immungenicity of vaccines.
- meningococcal A C Y and W polysaccharide tetanus toxoid conjugate vaccine
delandistrogene moxeparvovec, meningococcal A C Y and W polysaccharide tetanus toxoid conjugate vaccine. Other (see comment). Use Caution/Monitor. Comment: Consider patient vaccination status before initiating corticosteroid regimen required before delandistrogene moxeparvovec administration. If possible, ensure patients are current with all immunizations according to immunization guidelines. Complete vaccinations at least 4 weeks before starting corticosteroid regimen. High-dose or long-term corticosteroids may decrease immungenicity of vaccines.
- meningococcal C and Y/haemophilus influenza type B vaccine
delandistrogene moxeparvovec, meningococcal C and Y/haemophilus influenza type B vaccine. Other (see comment). Use Caution/Monitor. Comment: Consider patient vaccination status before initiating corticosteroid regimen required before delandistrogene moxeparvovec administration. If possible, ensure patients are current with all immunizations according to immunization guidelines. Complete vaccinations at least 4 weeks before starting corticosteroid regimen. High-dose or long-term corticosteroids may decrease immungenicity of vaccines.
- pneumococcal vaccine 13-valent
delandistrogene moxeparvovec, pneumococcal vaccine 13-valent. Other (see comment). Use Caution/Monitor. Comment: Consider patient vaccination status before initiating corticosteroid regimen required before delandistrogene moxeparvovec administration. If possible, ensure patients are current with all immunizations according to immunization guidelines. Complete vaccinations at least 4 weeks before starting corticosteroid regimen. High-dose or long-term corticosteroids may decrease immungenicity of vaccines.
- pneumococcal vaccine 15-valent
delandistrogene moxeparvovec, pneumococcal vaccine 15-valent. Other (see comment). Use Caution/Monitor. Comment: Consider patient vaccination status before initiating corticosteroid regimen required before delandistrogene moxeparvovec administration. If possible, ensure patients are current with all immunizations according to immunization guidelines. Complete vaccinations at least 4 weeks before starting corticosteroid regimen. High-dose or long-term corticosteroids may decrease immungenicity of vaccines.
- pneumococcal vaccine 20-valent
delandistrogene moxeparvovec, pneumococcal vaccine 20-valent. Other (see comment). Use Caution/Monitor. Comment: Consider patient vaccination status before initiating corticosteroid regimen required before delandistrogene moxeparvovec administration. If possible, ensure patients are current with all immunizations according to immunization guidelines. Complete vaccinations at least 4 weeks before starting corticosteroid regimen. High-dose or long-term corticosteroids may decrease immungenicity of vaccines.
- poliovirus vaccine inactivated
delandistrogene moxeparvovec, poliovirus vaccine inactivated. Other (see comment). Use Caution/Monitor. Comment: Consider patient vaccination status before initiating corticosteroid regimen required before delandistrogene moxeparvovec administration. If possible, ensure patients are current with all immunizations according to immunization guidelines. Complete vaccinations at least 4 weeks before starting corticosteroid regimen. High-dose or long-term corticosteroids may decrease immungenicity of vaccines.
- rotavirus oral vaccine, live
delandistrogene moxeparvovec, rotavirus oral vaccine, live. Other (see comment). Use Caution/Monitor. Comment: Consider patient vaccination status before initiating corticosteroid regimen required before delandistrogene moxeparvovec administration. If possible, ensure patients are current with all immunizations according to immunization guidelines. Complete vaccinations at least 4 weeks before starting corticosteroid regimen. High-dose or long-term corticosteroids may decrease immungenicity of vaccines.
- tetanus & reduced diphtheria toxoids/ acellular pertussis vaccine
delandistrogene moxeparvovec, tetanus & reduced diphtheria toxoids/ acellular pertussis vaccine. Other (see comment). Use Caution/Monitor. Comment: Consider patient vaccination status before initiating corticosteroid regimen required before delandistrogene moxeparvovec administration. If possible, ensure patients are current with all immunizations according to immunization guidelines. Complete vaccinations at least 4 weeks before starting corticosteroid regimen. High-dose or long-term corticosteroids may decrease immungenicity of vaccines.
- varicella virus vaccine live
delandistrogene moxeparvovec, varicella virus vaccine live. Other (see comment). Use Caution/Monitor. Comment: Consider patient vaccination status before initiating corticosteroid regimen required before delandistrogene moxeparvovec administration. If possible, ensure patients are current with all immunizations according to immunization guidelines. Complete vaccinations at least 4 weeks before starting corticosteroid regimen. High-dose or long-term corticosteroids may decrease immungenicity of vaccines.
- varicella zoster immune globulin, human
delandistrogene moxeparvovec, varicella zoster immune globulin, human. Other (see comment). Use Caution/Monitor. Comment: Consider patient vaccination status before initiating corticosteroid regimen required before delandistrogene moxeparvovec administration. If possible, ensure patients are current with all immunizations according to immunization guidelines. Complete vaccinations at least 4 weeks before starting corticosteroid regimen. High-dose or long-term corticosteroids may decrease immungenicity of vaccines.
Minor (0)
Adverse Effects
>10%
Vomiting (61-65%)
Nausea (35-40%)
Liver function test vaules increased (25-37%)
Pyrexia (20-24%)
Thrombocytopenia (12%)
Warnings
Contraindications
Patients with any deletion in exon 8 and/or exon 9 in DMD gene
Cautions
Acute serious liver injury
- Acute serious liver injury observed; administration may result in elevated liver enzymes (eg, GGT, ALT) and total bilirubin, typically seen within 8 weeks; if suspected, consultation with a specialist is recommended
- Patients with preexisting liver impairment, chronic hepatic condition, or acute liver disease (eg, acute hepatic viral infection) may be at higher risk of acute serious liver injury
- Postpone administration in patients with acute liver disease until resolved or controlled
- Patients with hepatic impairment, acute liver disease, chronic hepatic condition, or elevated GGT have not been studied in clinical trials
- In clinical studies, liver function test increases (including increases in GGT, GLDH, ALT, AST, or total bilirubin) were commonly reported, typically within 8 weeks following infusion; majority of cases were asymptomatic
- Cases observed resolved spontaneously or with systemic corticosteroids and resolved without clinical sequelae within 2 months; no cases of liver failure were reported
- Before administration, perform liver enzyme testing, then monitor liver function (clinical exam, GGT, and total bilirubin) weekly x 3 months following infusion
- Continue monitoring if clinically indicated, until results are unremarkable
- Systemic corticosteroid treatment recommended for patients before and after infusion; adjust corticosteroid regimen when indicated
Immune-mediated myositis
- Immune-mediated myositis observed ~1 month following infusion in patients with deletion mutations involving exon 8 and/or exon 9 in the DMD gene
- Symptoms of severe muscle weakness, including dysphagia, dyspnea, and hypophonia, were observed
- In a life-threatening case of immune-mediated myositis, symptoms resolved during hospitalization following additional immunomodulatory treatment; muscle strength gradually improved, but did not return to baseline level
- Immune reactions may be due to a T-cell based response from lack of self-tolerance to a specific region encoded by the transgene corresponding to exons 1-17 of the DMD gene
- Limited data are available regarding delandistrogene moxeparvovec treatment in patients with mutations in the DMD gene in exons 1-17 and/or exons 59-71; patients with deletions in these regions may be at risk for a severe immune-mediated myositis reaction
- Contraindicated in patients with any deletion in exon 8 and/or exon 9 in DMD gene due to increased risk for a severe immune-mediated myositis
- Advise caregivers to contact a physician immediately if child experiences any unexplained increased muscle pain, tenderness, or weakness, including dysphagia, dyspnea or hypophonia as these may be symptoms of myositis
- Consider additional immunomodulatory treatment (immunosuppressants [eg, calcineurin-inhibitor] in addition to corticosteroids) based on patient’s clinical presentation and medical history if these symptoms occur
Myocarditis
- Acute serious myocarditis and troponin-I elevations observed following infusion
- Monitor troponin-I before infusion and weekly for first month following infusion
- Continue monitoring if clinically indicated; more frequent monitoring may be warranted in the presence of cardiac symptoms (eg, chest pain, shortness of breath)
- Advise caregivers to contact a physician immediately if child experiences cardiac symptoms
Pre-existing immunity against AAVhr74
- In AAV-vector based gene therapies, preexisting anti-AAV antibodies may impede transgene expression at desired therapeutic levels
- Following treatment all subjects developed anti-AAVrh74 antibodies
- Perform baseline testing for presence of anti-AAVrh74 total binding antibodies before administration
- Not recommended in patients with elevated anti-AAVrh74 total binding antibody titers (≥1:400)
Drug interaction overview
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Vaccinations
- Complete vaccinations at least 4 weeks before initiating pretreatment corticosteroid regimen
Pregnancy & Lactation
Pregnancy
Not intended for use in pregnant females
Lactation
Not intended for use in lactating females
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
DMD is caused by a mutation in DMD gene resulting in lack of functional dystrophin protein
Delandistrogene moxeparvovec carries a transgene encoding a micro-dystrophin protein consisting of selected domains of dystrophin expressed in normal muscle cells
Absorption
Peak plasma time: 5.3 hr (serum); 6.7 hr (saliva); 6.4 hr (urine); 13.5 days (feces)
Distribution
Undergoes distribution via systemic circulation and is distributed into target muscle tissues; eliminated in the urine and feces
Metabolism
Capsid proteins are broken down through proteasomal degradation following AAV entry into target cells
Elimination
Half-life (vector genome)
- Serum: ~12 hr
- Urine: 40 hr
- Feces: 55 hr
- Saliva: 60 hr
Clearance
- Majority of drug expected to be cleared from the serum by 1-week post-dose
- Median times to achieve complete elimination, defined as first below limit of detection (BLOD) sample followed by 2 consecutive BLOD samples, were 49.8 days, 123 days, and 162 days post dose for saliva, urine, and feces, respectively
Administration
IV Preparation
General precautions
- Prepare using aseptic technique
- Verify required dose based on the patient’s body weight
- Confirm that kit contains sufficient number of vials to prepare infusion
- Visually inspect for particulate matter and discoloration before administration
- Delandistrogene moxeparvovec may contain white to off-white particles
Thaw before use
- Thaw in refrigerator: Vials stable for up to 14 days at 2-8ºC (36-46ºF) when stored in upright position
- Frozen vials will thaw in ~2 hr when placed at room temperature (up to 25ºC [77ºF]) when removed from original packaging
- Sealed thawed vials are stable up to 24 hr at room temperature (up to 25ºC [77ºF]) when stored in upright position
When thawed
- Inspect vials to ensure no ice crystals are present before preparation
- When thawed, swirl gently
- Do not shake
- Do not refreeze
- Do not place back in refrigerator
Visually inspect each vial
- Visually inspect; delandistrogene moxeparvovec is a clear, colorless liquid that may have some opalescence
- May contain white to off-white particles
- Do not use if suspension is cloudy or discolored
Draw up dose
- Remove plastic flip-off cap from vials and disinfect rubber stoppers with sterilizing agent (eg, alcohol wipes)
- Withdraw 10 mL from each vial provided in the customized kit (refer to prescribing information)
- Do not use filter needles during this process
- Multiple syringes will be required to withdraw required volume
- Remove air from syringes, and cap the syringes
- Maintain syringes at room temperature before and during administration
IV Administration
Administer as single-dose IV infusion through a peripheral venous catheter
Consider application of topical anesthetic to infusion site before administration of IV insertion
Recommend inserting a back-up catheter
Flush IV access line before delandistrogene moxeparvovec infusion at same infusion rate
Administer via IV infusion using a syringe infusion pump with an in-line 0.2-micron filter over a duration of ~1-2 hr, or longer at discretion of care team
Infusion
- Infuse at rate <10 mL/kg/hr
- Do NOT administer IV push
- Do NOT infuse in same IV access line with any other product
- Use within 4 hr after drawing into syringe; discard if infusion has not started within the 4-hr timeframe
- Flush IV access line with 0.9% NaCl when infusion completed
- Discard unused drug; dispose of needle and syringe
Monitoring post-infusion
- Assess liver function (clinical exam, GGT, and total bilirubin) weekly for the first 3 months; continue monitoring if clinically indicated, until results are unremarkable (normal clinical exam, GGT and total bilirubin levels returning to near baseline levels)
- Obtain platelet counts weekly for the first 2 weeks
- Continue monitoring if clinically indicated
- Measure troponin-I weekly for first month; continue monitoring if clinically indicated
Storage
Shipped and delivered at ≤ −60ºC (−76ºF)
May be refrigerated in upright position at 2-8ºC (36-46ºF) for up to 14 days
Do not refreeze
Do not shake
Do not place back in refrigerator once brought to room temperature
Follow local guidelines on handling of biological waste
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