Vimizim

Elosulfase alfa is injected into a vein through an IV. You will most likely receive this injection in a clinic or hospital setting.

Elosulfase alfa must be given slowly through an IV infusion, and can take up to 4 hours or longer to complete.

Elosulfase alfa is usually given once per week. Follow your doctor's instructions.

If a child is using this medicine, tell your doctor if the child has any changes in weight. Elosulfase alfa doses are based on body weight.

Your doctor may also prescribe other medications to help prevent an allergic reaction to elosulfase alfa. Take all of your medications as directed.

Your doctor will need to check your progress while you are using elosulfase alfa.

Since this medication is given by a healthcare professional in a medical setting, an overdose is unlikely to occur.

Call your doctor for instructions if you miss an appointment for your elosulfase alfa injection.

• Biomarin Pharmaceutical. Inc.

Serious side effects have been reported with Vimizim. See the “Vimizim Precautions” section.

Common side effects of Vimizim include the following:

• fever
• vomiting
• headache
• nausea
• abdominal pain
• chills
• fatigue

This is not a complete list of Vimizim side effects. Ask your doctor or pharmacist for more information.

Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

• Store Vimizim at room temperature. Once the product is diluted, it must be used immediately.
• Protect from light.

Elosulfase alfa is injected into a vein through an IV. You will most likely receive this injection in a clinic or hospital setting.

Elosulfase alfa must be given slowly through an IV infusion, and can take up to 4 hours or longer to complete.

Elosulfase alfa is usually given once per week. Follow your doctor's instructions.

If a child is using this medicine, tell your doctor if the child has any changes in weight. Elosulfase alfa doses are based on body weight.

Your doctor may also prescribe other medications to help prevent an allergic reaction to elosulfase alfa. Take all of your medications as directed.

Your doctor will need to check your progress while you are using elosulfase alfa.

Biosynthetic (recombinant DNA origin) form of human N-acetylgalactosamine-6-sulfatase (GALNS).1 3 4 5 8

Mucopolysaccharidosis IVA

Replacement therapy in patients with mucopolysaccharidosis IVA (MPS IVA, Morquio A syndrome);1 3 4 5 8 designated an orphan drug by FDA for this use.2

Shown to improve endurance (as indicated by increases in walking distance).1 3 8

Contraindications

• None.1

Warnings/Precautions

Warnings

Hypersensitivity reactions, including life-threatening anaphylaxis, reported.1 3 5 7 (See Boxed Warning.) Manifestations have included cough, erythema, throat tightness, urticaria, flushing, cyanosis, hypotension, rash, dyspnea, chest discomfort, and GI symptoms (e.g., nausea, abdominal pain, retching, vomiting) in conjunction with urticaria.1 Can occur at any time (as early as 30 minutes to as late as several days after the start of infusion) and after any infusion, regardless of course of treatment.1

Closely observe patients during and after administration; ensure that appropriate medical support is readily available.1 Additional monitoring may be required in patients with certain underlying conditions (e.g., acute febrile or respiratory illness).1 (See Acute Respiratory Complications under Cautions.)

To minimize risk of hypersensitivity reactions, premedicate with antihistamines (with or without antipyretics).1 (See General under Dosage and Administration.)

Manage hypersensitivity reactions based on severity.1 If a mild reaction occurs, reduce infusion rate, interrupt infusion, and/or administer additional antihistamines, antipyretics, and/or corticosteroids.1 If a severe reaction occurs, immediately discontinue infusion and initiate appropriate treatment.1 Consider risks and benefits of retreatment following a severe hypersensitivity reaction.1

Other Warnings/Precautions

Patients with acute febrile or respiratory illness may be at increased risk of life-threatening complications from hypersensitivity reactions.1 (See Hypersensitivity Reactions under Cautions.) Carefully consider patient's clinical status prior to infusion; a delay in therapy may be required.1

Sleep apnea is common in patients with MPS IVA; consider evaluating airway patency prior to initiating therapy.1 Patients using supplemental oxygen or continuous positive airway pressure (CPAP) during sleep should have those treatments readily available during elosulfase alfa infusion in the event of an acute reaction or antihistamine-induced episode of extreme drowsiness or sleep.1

Spinal or cervical cord compression, a known serious complication of MPS IVA, reported.1 Monitor for signs and symptoms (e.g., back pain, paralysis of limbs below the level of compression, urinary or fecal incontinence) and provide appropriate treatment if needed.1

Development of antibodies to elosulfase alfa reported in all patients receiving the drug in clinical studies.1 4 5 In addition, neutralizing antibodies that interfere with appropriate cellular uptake of the drug also detected.1 4 5

Effect of antibodies on efficacy and safety (e.g., risk of anaphylaxis or other hypersensitivity reaction) not known.1

Specific Populations

Category C.1

No adequate and well-controlled studies in pregnant women; use during pregnancy only if potential benefits justify potential risks to the fetus.1

The Morquio A Registry collects data on pregnant women with MPS IVA who are treated with elosulfase alfa.1 For additional information or to enroll, call 800-983-4587 or contact MARS@bmrn.com.1

Distributed into milk in rats; not known whether distributed into human milk.1 Consider known benefits of breastfeeding, mother's clinical need for the drug, and any potential adverse effects of the disease or drug on the infant.1 Use with caution.1

The Morquio A Registry collects data on nursing women with MPS IVA who are treated with elosulfase alfa.1 For additional information or to enroll, call 800-983-4587 or contact MARS@bmrn.com.1

Safety and efficacy not established in children <5 years of age.1

No experience in patients ≥65 years of age; not known whether geriatric patients respond differently than younger patients.1

Common Adverse Effects

Pyrexia,1 3 vomiting,1 3 headache,1 3 nausea,1 abdominal pain,1 chills,1 fatigue.1

No formal drug interaction studies to date.1

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

In the U.S.

• Vimizim

Available Dosage Forms:

• Solution

Therapeutic Class: Endocrine-Metabolic Agent

Pharmacologic Class: Enzyme

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• It is given as an infusion into a vein over a period of time.

What do I do if I miss a dose?

• Call your doctor to find out what to do.

Vimizim (elosulfase alfa) is indicated for patients with Mucopolysaccharidosis type IVA (MPS IVA; Morquio A syndrome).

Pregnancy

Pregnancy Category C

There is a Morquio A Registry that collects data on pregnant women with MPS IVA who are treated with Vimizim.  Contact MARS@bmrn.com or call 1-800-983-4587 for information and enrollment [see Patient Counseling Information (17)].

Risk Summary

There are no adequate and well-controlled studies with Vimizim in pregnant women.  However, animal reproduction studies have been conducted for elosulfase alfa.  In these studies, no effects on embryo-fetal development were observed in rats given daily administration of elosulfase alfa up to 33 times the human steady-state AUC (area under the curve) at the recommended human weekly dose pre-mating and through the period of organogenesis.  No effects on embryo-fetal development were observed in rabbits given daily administration of elosulfase alfa at doses up to 8 times the human steady-state AUC at the recommended weekly dose during organogenesis, which produced maternal toxicity.  A dose-dependent increase in stillbirths was observed when elosulfase alfa was administered daily in rats during organogenesis through lactation at doses 5 times the human steady-state AUC at the recommended human weekly dose.  An increase in pup mortality was observed at doses producing maternal toxicity.  Vimizim should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Clinical Considerations

Disease-associated maternal and embryo/fetal risk

Pregnancy can adversely affect the health of females affected with MPS IVA and lead to adverse pregnancy outcomes for both mother and fetus.

Animal Data

All reproductive studies with rats included pre-treatment with diphenhydramine to prevent or minimize hypersensitivity reactions.  The effects of elosulfase alfa were evaluated based on comparison to a control group treated with diphenhydramine alone.  Daily intravenous (IV) administration of up to 20 mg/kg elosulfase alfa in rats (33 times the human steady-state AUC at the recommended weekly dose of 2 mg/kg) during a 15-day pre-mating period, mating, and the period of organogenesis, produced no maternal toxicity or effects on embryo-fetal development.  Daily intravenous administration of up to 10 mg/kg in rabbits (8 times the human steady-state AUC at the recommended weekly dose) during the period of organogenesis had no effects on embryo-fetal development.  However, maternal toxicity (gross changes in liver) was observed in rabbits given doses of 1 mg/kg/day and higher (0.1 times the human steady-state AUC at the recommended weekly dose).  Elosulfase alfa produced an increase in the percentage of stillbirths when administered daily to rats at doses of 6 mg/kg IV and higher (5 times the human steady-state AUC at the recommended weekly dose) during the period of organogenesis through lactation.  Daily administration of 20 mg/kg IV (33 times the human steady-state AUC at the recommended weekly dose) produced maternal toxicity and an increase in mortality of offspring during the lactation period.  This study lacked a full evaluation of neurodevelopmental milestones; however, no effects of elosulfase alfa were noted in tests for learning and memory.

Nursing Mothers

It is not known if Vimizim is present in human milk.  Elosulfase alfa is present in milk from treated rats [see Use in Specific Populations (8.1)].  The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Vimizim and any potential adverse effects on the breastfed child from the drug or from MPS IVA.  Exercise caution when administering Vimizim to a nursing mother. There is a Morquio A Registry that also collects data on breastfeeding women with MPS IVA who are treated with Vimizim.  Contact MARS@bmrn.com or call 1-800-983-4587 for information and enrollment [see Patient Counseling Information (17)]. 

Pediatric Use

Safety and effectiveness of Vimizim have been established in pediatric patients 5 years of age and older.  Use of Vimizim in patients 5 years of age and older is supported by an adequate and well-controlled trial in pediatric and adult patients. Clinical trials with Vimizim were conducted in 176 patients (median age 12 years, range 5 to 57 years old) with the majority of patients in the pediatric age group (53% aged 5 to 11 years, 27% aged 12 to 17 years) [see Clinical Studies (14)].  Safety and effectiveness in pediatric patients below 5 years of age have not been established.

Geriatric Use

Clinical studies of Vimizim did not include any patients aged 65 and over. It is not known whether they respond differently from younger patients.

The safety and efficacy of Vimizim were assessed in a 24-week, randomized, double-blind, placebo-controlled clinical trial of 176 patients with MPS IVA. The age of patients ranged from 5 to 57 years. The majority of the patients (82%) presented with a medical history of musculoskeletal conditions, which includes knee deformity (52%), kyphosis (31%), hip dysplasia (22%), prior spinal fusion surgery (22%) and arthralgia (20%). At baseline, all enrolled patients could walk more than 30 meters (m) but less than 325 m in six minutes. 

Patients received Vimizim 2 mg/kg once per week (n=58), Vimizim 2 mg/kg once every other week (n=59), or placebo (n=59). 

The primary endpoint was the change from baseline in the distance walked in six minutes (six minute walk test, 6-MWT) at Week 24. The other endpoints included changes from baseline in the rate of stair climbing in three minutes (three-minute stair climb test, 3-MSCT) and changes from baseline in urine KS levels at Week 24. The treatment effect in the distance walked in 6 minutes, compared to placebo, was 22.5 m (CI95, 4.0, 40.9; p=0.0174) in patients who received Vimizim 2 mg/kg once per week. There was no difference in the rate of stair climbing between patients who received Vimizim 2 mg/kg once per week and those who received placebo. Patients who received Vimizim 2 mg/kg once every other week performed similarly in the 6-MWT and 3-MSCT as those who received placebo. The reduction in urinary KS levels from baseline, a measure of pharmacodynamic effect, was greater in the Vimizim treatment groups compared to placebo.  The relationship between urinary KS and other measures of clinical response has not been established.

Table 3: Results from Placebo-Controlled Clinical Trial

* One patient in the Vimizim group dropped out after 1 infusion

† Observed Vimizim mean change – Placebo mean change

‡ ANCOVA Model-based Vimizim mean change – Placebo mean change, adjusted for baseline 6MWT categories (less than or equal to 200 meters, greater than 200 meters) and age groups (5-11, 12-18, 19 or older)

§ p-value based on the model-based  difference in means

Extension Trial

Patients who participated in the placebo-controlled trial were eligible to continue treatment in an open-label extension trial. One hundred seventy-three of 176 patients enrolled in the extension trial in which patients received Vimizim 2 mg/kg once per week (n=86) or Vimizim 2 mg/kg once every other week (n=87). In patients who continued to receive Vimizim 2 mg/kg once per week for another 48 weeks (for a total of 72-week exposure), walking ability showed no further improvement beyond the first 24 weeks of treatment in the placebo-controlled trial.   

Some side effects may occur during the Vimizim infusion, or up to several days afterward. Tell your caregiver right away if you feel dizzy, itchy, nauseated, light-headed, or if you have chest pain, tightness in your throat, pale skin, blue lips, diarrhea, or vomiting.

Get emergency medical help if you have any of these signs of an allergic reaction to Vimizim: hives; cough, difficult breathing; feeling like you might pass out; swelling of your face, lips, tongue, or throat.

It may still be possible for you to receive a Vimizim infusion even after you have had a reaction to it. There are other medications that can be given to you before your infusion to help prevent symptoms of a reaction.

Common Vimizim side effects include:

• nausea, vomiting, stomach pain;

• headache;

• fever, chills;

• tired feeling.

Even though it may not be a side effect of Vimizim, increased pressure on the spinal cord is a complication of MPS IVA that may occur while you are using this medicine. Tell your doctor right away if you have any symptoms of spinal cord compression:

• back pain;

• loss of movement in any part of your body; or

• loss of bowel or bladder control.

This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.