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FULL PRESCRIBING INFORMATION
WARNING: SERIOUS MENINGOCOCCAL INFECTIONS
Soliris increases the risk of meningococcal infections. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early (5.1).
1 INDICATIONS AND USAGE
Soliris is indicated for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis.
2 DOSAGE AND ADMINISTRATION
Patients must be administered a meningococcal vaccine at least two weeks prior to initiation of Soliris therapy and revaccinated according to current medical guidelines for vaccine use [see Warnings and Precautions (5.1)].
2.1 Recommended Dosage Regimen
Soliris therapy consists of:
Soliris should be administered at the recommended dosage regimen time points, or within two days of these time points. [see Warnings and Precautions (5.5)].
2.2 Preparation for Administration
Soliris must be diluted to a final admixture concentration of 5 mg/mL using the following steps:
The final admixed Soliris 5 mg/mL infusion volume is 120 mL for 600 mg doses or 180 mL for 900 mg doses. Gently invert the infusion bag containing the diluted Soliris solution to ensure thorough mixing of the product and diluent. Discard any unused portion left in a vial, as the product contains no preservatives.
Prior to administration, the admixture should be allowed to adjust to room temperature [18°-25° C, 64-77° F]. The admixture must not be heated in a microwave or with any heat source other than ambient air temperature. The Soliris admixture should be inspected visually for particulate matter and discoloration prior to administration.
Do Not Administer As An Intravenous Push Or Bolus Injection
The Soliris admixture should be administered by intravenous infusion over 35 minutes via gravity feed, a syringe-type pump, or an infusion pump. Admixed solutions of Soliris are stable for 24 hours at 2-8° C (36-46° F) and at room temperature.
If an adverse reaction occurs during the administration of Soliris, the infusion may be slowed or stopped at the discretion of the physician. If the infusion is slowed, the total infusion time should not exceed two hours. Monitor the patient for at least one hour following completion of the infusion for signs or symptoms of an infusion reaction.
3 DOSAGE FORMS AND STRENGTHS
Soliris is supplied as 300 mg single-use vials each containing 30 mL of 10 mg/mL sterile, preservative-free eculizumab solution.
Do not initiate Soliris therapy in patients:
5 WARNINGS AND PRECAUTIONS
5.1 Serious Meningococcal Infections
The use of Soliris increases a patient's susceptibility to serious meningococcal infections (septicemia and/or meningitis). All patients without a history of prior meningococcal vaccination must receive the meningococcal vaccine at least 2 weeks prior to receiving the first dose of Soliris and revaccinated according to current medical guidelines for vaccine use. Quadravalent, conjugated meningococcal vaccines are strongly recommended. Vaccination may not prevent meningococcal infections.
All patients must be monitored for early signs and symptoms of meningococcal infections and evaluated immediately if an infection is suspected. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early. Physicians should strongly consider discontinuation of Soliris during the treatment of serious meningococcal infections.
In clinical studies, 2 out of 196 PNH patients developed serious meningococcal infections while receiving treatment with Soliris; both had been vaccinated [see Adverse Reactions (6.1)]. In clinical studies among non-PNH patients, meningococcal meningitis occurred in one patient, who was unvaccinated [see Adverse Reactions (6.1)].
5.2 Other Infections
Soliris blocks terminal complement; therefore patients may have increased susceptibility to infections, especially with encapsulated bacteria. Use caution when administering Soliris to patients with any systemic infection.
5.3 Monitoring After Soliris Discontinuation
Since Soliris therapy increases the number of PNH cells [in study 1, the proportion of PNH RBCs increased among Soliris-treated patients by a median of 28% from baseline (range from -25% to 69%)], patients who discontinue treatment with Soliris may be at increased risk for serious hemolysis. Serious hemolysis is identified by serum LDH levels greater than the pre-treatment level, along with any of the following: greater than 25% absolute decrease in PNH clone size (in the absence of dilution due to transfusion) in one week or less; a hemoglobin level of <5 gm/dL or a decrease of >4 gm/dL in one week or less; angina; change in mental status; a 50% increase in serum creatinine level; or thrombosis. Monitor any patient who discontinues Soliris for at least 8 weeks to detect serious hemolysis and other reactions.
If serious hemolysis occurs after Soliris discontinuation, consider the following procedures/treatments: blood transfusion (packed RBCs), or exchange transfusion if the PNH RBCs are >50% of the total RBCs by flow cytometry; anticoagulation; corticosteroids; or reinstitution of Soliris.
In clinical studies, 16 of 196 PNH patients discontinued treatment with Soliris. Patients were followed for evidence of worsening hemolysis and no serious hemolysis was observed.
5.4 Thrombosis Prevention and Management
The effect of withdrawal of anticoagulant therapy during Soliris treatment has not been established. Therefore, treatment with Soliris should not alter anticoagulant management.
5.5 Laboratory Monitoring
Serum LDH levels increase during hemolysis and may assist in monitoring Soliris effects, including the response to discontinuation of therapy. In clinical studies, six patients achieved a reduction in serum LDH levels only after a decrease in the Soliris dosing interval from 14 to 12 days. All other patients achieved a reduction in serum LDH levels with the 14 day dosing interval [see Clinical Pharmacology (12.2) and Clinical Studies (14)].
5.6 Infusion Reactions
As with all protein products, administration of Soliris may result in infusion reactions, including anaphylaxis or other hypersensitivity reactions. In clinical trials, no PNH patients experienced an infusion reaction which required discontinuation of Soliris. Soliris administration should be interrupted in all patients experiencing severe infusion reactions and appropriate medical therapy administered.
6 ADVERSE REACTIONS
6.1 Clinical Trial Experience
Meningococcal infections are the most important adverse reactions experienced by patients receiving Soliris therapy. In PNH clinical studies, two patients experienced meningococcal sepsis. Both patients had previously received a meningococcal vaccine. In clinical studies among patients without PNH, meningococcal meningitis occurred in an unvaccinated patient [see Warnings and Precautions (5.1)].
The data described below reflect exposure to Soliris in 196 adult patients with PNH, age 18-85, of whom 55% were female. All had signs or symptoms of intravascular hemolysis. Soliris was studied in a placebo-controlled clinical study (in which 43 patients received Soliris and 44, placebo); a single arm clinical study and a long term extension study. 182 patients were exposed for greater than one year. All patients received the recommended Soliris dose regimen.
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. Table 1 summarizes the adverse reactions that occurred at a numerically higher rate in the Soliris group than the placebo group and at a rate of 5% or more among patients treated with Soliris.
In the placebo-controlled clinical study, serious adverse reactions occurred among 4 (9%) patients receiving Soliris and 9 (21%) patients receiving placebo. The serious reactions included infections and progression of PNH. No deaths occurred in the study and no patients receiving Soliris experienced a thrombotic event; one thrombotic event occurred in a patient receiving placebo.
Among 193 patients with PNH treated with Soliris in the single arm, clinical study or the follow-up study, the adverse reactions were similar to those reported in the placebo-controlled clinical study. Serious adverse reactions occurred among 16% of the patients in these studies. The most common serious adverse reactions were: viral infection (2%), headache (2%), anemia (2%), and pyrexia (2%).
As with all proteins there is a potential for immunogenicity. Low titers of antibodies to Soliris were detected in 3/196 (2%) of all PNH patients treated with Soliris. No apparent correlation of antibody development to clinical response was observed. The immunogenicity data reflect the percentage of patients whose test results were considered positive for antibodies to Soliris in an enzyme linked immunosorbent assay (ELISA) and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in the assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies to Soliris with the incidence of antibodies to other products may be misleading.
8 USE IN SPECIFIC POPULATIONS
Pregnancy Category C:
PNH is a serious illness. Pregnant women with PNH and their fetuses have high rates of morbidity and mortality during pregnancy and the postpartum period. There are no adequate and well-controlled studies of Soliris in pregnant women. Soliris, a recombinant IgG molecule (humanized anti-C5 antibody), is expected to cross the placenta. Animal studies using a mouse analogue of the Soliris molecule (murine anti-C5 antibody) showed increased rates of developmental abnormalities and an increased rate of dead and moribund offspring at doses 2-8 times the human dose. Soliris should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Animal reproduction studies were conducted in mice using doses of a murine anti-C5 antibody that approximated 2-4 times (low dose) and 4-8 times (high dose) the recommended human Soliris dose, based on a body weight comparison. When animal exposure to the antibody occurred in the time period from before mating until early gestation, no decrease in fertility or reproductive performance was observed. When maternal exposure to the antibody occurred during organogenesis, two cases of retinal dysplasia and one case of umbilical hernia were observed among 230 offspring born to mothers exposed to the higher antibody dose; however, the exposure did not increase fetal loss or neonatal death. When maternal exposure to the antibody occurred in the time period from implantation through weaning, a higher number of male offspring became moribund or died (1/25 controls, 2/25 low dose group, 5/25 high dose group). Surviving offspring had normal development and reproductive performance.
8.2 Labor and Delivery
No information is available on the effects of Soliris during labor and delivery.
8.3 Nursing Mothers
It is not known whether Soliris is secreted into human milk. IgG is excreted in human milk, so it is expected that Soliris will be present in human milk. However, published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Caution should be exercised when Soliris is administered to a nursing woman. The unknown risks to the infant from gastrointestinal or limited systemic exposure to Soliris should be weighed against the known benefits of breastfeeding.
8.4 Pediatric Use
The safety and effectiveness of Soliris therapy in pediatric patients below the age of 18 have not been established.
8.5 Geriatric Use
In PNH studies, 15 patients 65 years of age or older were treated with Soliris. Although there were no apparent age-related differences observed in these studies, the number of patients aged 65 and over is not sufficient to determine whether they respond differently from younger patients.
Soliris is a formulation of eculizumab which is a recombinant humanized monoclonal IgG2/4κ antibody produced by murine myeloma cell culture and purified by standard bioprocess technology. Eculizumab contains human constant regions from human IgG2 sequences and human IgG4 sequences and murine complementarity-determining regions grafted onto the human framework light- and heavy-chain variable regions. Eculizumab is composed of two 448 amino acid heavy chains and two 214 amino acid light chains and has a molecular weight of approximately 148 kDa.
Soliris is a sterile, clear, colorless, preservative-free 10 mg/mL solution for intravenous infusion and is supplied in 30-mL single-use vials. The product is formulated at pH 7 and each vial contains 300 mg of eculizumab, 13.8 mg sodium phosphate monobasic, 53.4 mg sodium phosphate dibasic, 263.1 mg sodium chloride, 6.6 mg polysorbate 80 (vegetable origin) and Water for Injection, USP.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Eculizumab, the active ingredient in Soliris, is a monoclonal antibody that specifically binds to the complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a and C5b and preventing the generation of the terminal complement complex C5b-9. Soliris inhibits terminal complement mediated intravascular hemolysis in PNH patients.
A genetic mutation in PNH patients leads to the generation of populations of abnormal RBCs (known as PNH cells) that are deficient in terminal complement inhibitors, rendering PNH RBCs sensitive to persistent terminal complement-mediated destruction. The destruction and loss of these PNH cells (intravascular hemolysis) results in low RBC counts (anemia), and also fatigue, difficulty in functioning, pain, dark urine, shortness of breath, and blood clots.
In the placebo-controlled clinical study, Soliris when administered as recommended reduced hemolysis as shown by the reduction of serum LDH levels from 2200 ± 1034 U/L (mean ± SD) at baseline to 700 ± 388 U/L by week one and maintained the effect through the end of the study at week 26 (327 ± 433 U/L). In the single arm clinical study, Soliris maintained this effect through 52 weeks [see Clinical Studies (14)].
A population PK analysis with a standard 1-compartmental model was conducted on the multiple dose PK data from 40 PNH patients receiving the recommended Soliris regimen [see Dosage and Administration (2.1)]. In this model, the clearance of Soliris for a typical PNH patient weighing 70 kg was 22 mL/hr and the volume of distribution was 7.7 L. The half-life was 272 ± 82 hrs (mean ± SD). The mean observed peak and trough serum concentrations of Soliris by week 26 were 194 ± 76 mcg/mL and 97 ± 60 mcg/mL, respectively.
Studies have not been conducted to evaluate the PK of Soliris in special patient populations identified by gender, race, age (pediatric or geriatric), or the presence of renal or hepatic impairment.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term animal studies have not been conducted to evaluate the carcinogenic and genotoxic potential of Soliris. Effects of Soliris upon fertility have not been studied in animals. Intravenous injections of male and female mice with a murine anti-C5 antibody at up to 4-8 times the equivalent of the clinical dose of Soliris had no adverse effects on mating or fertility.
14 CLINICAL STUDIES
The safety and efficacy of Soliris in PNH patients with hemolysis were assessed in a randomized, double-blind, placebo-controlled 26 week study (Study 1); PNH patients were also treated with Soliris in a single arm 52 week study (Study 2); and in a long term extension study. Patients received meningococcal vaccination prior to receipt of Soliris. In all studies, the dose of Soliris was 600 mg study drug every 7 ± 2 days for 4 weeks, followed by 900 mg 7 ± 2 days later, then 900 mg every 14 ± 2 days for the study duration. Soliris was administered as an intravenous infusion over 25 - 45 minutes.
PNH patients with at least four transfusions in the prior 12 months, flow cytometric confirmation of at least 10% PNH cells and platelet counts of at least 100,000/microliter were randomized to either Soliris (n = 43) or placebo (n = 44). Prior to randomization, all patients underwent an initial observation period to confirm the need for RBC transfusion and to identify the hemoglobin concentration (the "set-point") which would define each patient’s hemoglobin stabilization and transfusion outcomes. The hemoglobin set-point was less than or equal to 9 g/dL in patients with symptoms and was less than or equal to 7 g/dL in patients without symptoms. Endpoints related to hemolysis included the numbers of patients achieving hemoglobin stabilization, the number of RBC units transfused, fatigue, and health-related quality of life. To achieve a designation of hemoglobin stabilization, a patient had to maintain a hemoglobin concentration above the hemoglobin set-point and avoid any RBC transfusion for the entire 26 week period. Hemolysis was monitored mainly by the measurement of serum LDH levels, and the proportion of PNH RBCs was monitored by flow cytometry. Patients receiving anticoagulants and systemic corticosteroids at baseline continued these medications.
Major baseline characteristics were balanced (see Table 2).
Patients treated with Soliris had significantly reduced (p< 0.001) hemolysis resulting in improvements in anemia as indicated by increased hemoglobin stabilization and reduced need for RBC transfusions compared to placebo treated patients (see Table 3). These effects were seen among patients within each of the three pre-study RBC transfusion strata (4 - 14 units; 15 - 25 units; > 25 units). After 3 weeks of Soliris treatment, patients reported less fatigue and improved health-related quality of life. Because of the study sample size and duration, the effects of Soliris on thrombotic events could not be determined.
Study 2 and Extension Study:
PNH patients with at least one transfusion in the prior 24 months and at least 30,000 platelets/microliter received Soliris over a 52-week period. Concomitant medications included anti-thrombotic agents in 63% of the patients and systemic corticosteroids in 40% of the patients. Overall, 96 of the 97 enrolled patients completed the study (one patient died following a thrombotic event). A reduction in intravascular hemolysis as measured by serum LDH levels was sustained for the treatment period and resulted in a reduced need for RBC transfusion and less fatigue. 187 Soliris-treated PNH patients were enrolled in a long term extension study. All patients sustained a reduction in intravascular hemolysis over a total Soliris exposure time ranging from 10 to 54 months. There were fewer thrombotic events with Soliris treatment than during the same period of time prior to treatment. However, the majority of patients received concomitant anticoagulants; the effects of anticoagulant withdrawal during Soliris therapy was not studied [see Warnings and Precautions (5.4)].
16 HOW SUPPLIED/STORAGE AND HANDLING
Soliris (eculizumab) is supplied as 300 mg single-use vials containing 30 mL of 10 mg/mL sterile, preservative-free Soliris solution per vial.
Soliris vials must be stored in the original carton until time of use under refrigerated conditions at 2-8º C (36-46º F) and protected from light. Do not use beyond the expiration date stamped on the carton. Refer to Dosage and Administration (2) for information on the stability and storage of diluted solutions of Soliris.
DO NOT FREEZE. DO NOT SHAKE.
NDC 25682-001-01 Single unit 300 mg carton: Contains one (1) 30 mL vial of Soliris (10 mg/mL).
17 PATIENT COUNSELING INFORMATION
See Medication Guide.
Prior to treatment, patients should fully understand the risks and benefits of Soliris, in particular the risk of meningococcal infection. Ensure that patients receive the Medication Guide.
Patients should be informed that they are required to receive a meningococcal vaccination at least 2 weeks prior to receiving the first dose of Soliris, if they have not previously been vaccinated. They are required to be revaccinated according to current medical guidelines for meningococcal vaccine use while on Soliris therapy. Patients should also be informed that vaccination may not prevent meningococcal infection. Patients should be educated about any of the signs and symptoms of meningococcal infection, and strongly advised to seek immediate medical attention if these signs or symptoms occur. These signs and symptoms are as follows:
Patients should be informed that they would be provided with the Patient Safety Card that they should carry with them at all times. This card describes symptoms which, if experienced, should prompt the patient to immediately seek medical evaluation.
Patients should be informed that there is a potential for serious hemolysis when Soliris is discontinued and that they will be monitored by their healthcare professional for at least 8 weeks following Soliris discontinuation.
Alexion Pharmaceuticals, Inc.
US License Number 1743
This product, or its use, may be covered by one or more US patents, including U.S. Patent No. 6,355,245 in addition to others including patents pending.
Read the Medication Guide before you start Soliris and before each dose (infusion). This Medication Guide does not take the place of talking with your doctor about your condition or your treatment. Talk to your doctor if you have any questions about your treatment with Soliris.
What Is The Most Important Information I Should Know About Soliris?
Soliris is a medicine that affects your immune system. Soliris can lower the ability of your immune system to fight infections.
• Soliris increases your chance of getting serious and life-threatening meningococcal infections.
Call your doctor or get emergency medical care right away if you have any of these symptoms.
You will receive a Patient Safety Card that lists these symptoms and what to do if you have them. Carry it with you at all times. You will need to show the card to any healthcare provider that treats you.
What Is Soliris?
Soliris is a medicine called a monoclonal antibody. Soliris is used for the treatment of patients with a disease that affects red blood cells called Paroxysmal Nocturnal Hemoglobinuria (PNH).
Soliris works by blocking part of your immune system. This can help your PNH symptoms but it can also increase your chance for infection. It is important that you:
Who Should Not Receive Soliris?
Do not receive Soliris if you:
Tell your doctor if you:
How Do I Receive Soliris?
What If I Miss a Dose or Stop Soliris Treatment?
What Are The Possible Side Effects With Soliris?
Serious side effects with Soliris include:
Common side effects with Soliris include:
Call your doctor if you have any of these side effects. These are not all the side effects with Soliris. Ask your doctor for more information.
General Information About Soliris
Medicines are sometimes prescribed for conditions other than those listed in a Medication Guide. If you have any concerns about Soliris, ask your doctor. Your doctor or pharmacist can give you information about Soliris that was written for health care professionals.
Soliris contains eculizumab in a solution of water, polysorbate, sodium phosphate and sodium chloride.
Manufactured by Alexion Pharmaceuticals, Inc., 352 Knotter Drive, Cheshire, CT 06410 USA.
Revised: June 2009
This Medication Guide has been approved by the U.S. Food and Drug Administration
PRINCIPAL DISPLAY PANEL - container label
300 mg/30 mL
30 mL Single-Use Vial
CONTAINS NO PRESERVATIVES.
Concentrated Solution for Intravenous Infusion Only.
Protect from Light. Do Not Freeze.
STORE REFRIGERATED, 2-8ºC (36-46ºF).
PRINCIPAL DISPLAY PANEL - CARTON LABEL
30 mL Single-Use Vial
300 mg/30 mL
Each mL contains:10 mg eculizumab, 8.77 mg sodium chloride, 1.78 mg sodium phosphate dibasic, 0.46 mg sodium phosphate monobasic, 0.22 mg polysorbate 80 and water for injection, q.s.
No U.S. Standard of Potency.
Each patient is requiredto receive the enclosedPrescribing Information.
See package insert for dosage, dilution, and administration instructions.
Must be dilutedprior to use.
Discard any unused portion.
Store in Carton Until Use.
Store refrigerated, 2-8°C (36-46°F).
Do Not Freeze.
Do Not Shake.
Revised: 06/2009 Alexion Pharmaceuticals
Reproduced with permission of U.S. National Library of Medicine
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