Soliris

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

This medication falls into category C. In animal studies, pregnant animals were given this medication and had some babies born with problems. No well-controlled studies have been done in humans. Therefore, this medication may be used if the potential benefits to the mother outweigh the potential risks to the unborn child.

Your doctor will determine the best dose for you.

Paroxysmal Nocturnal Hemoglobinuria (PNH)

The recommended dosage regimen for PNH is:

• 600 mg weekly for the first 4 weeks, followed by
• 900 mg for the fifth dose 1 week later, then
• 900 mg every 2 weeks thereafter.

Soliris should be administered at the recommended dosage regimen time points, or within two days of these time points.

Atypical Hemolytic Uremic Syndrome (aHUS)

The recommended dosage regimen for aHUS is:

For patients 18 years of age and older, Soliris therapy consists of:

• 900 mg weekly for the first 4 weeks, followed by
• 1200 mg for the fifth dose 1 week later, then
• 1200 mg every 2 weeks thereafter.

For patients less than 18 years of age, administer Soliris based upon body weight. Soliris should be administered at the recommended dosage regimen time points, or within two days of these time points.

Keep all of your medical and laboratory appointments. If you miss a scheduled dose, contact your healthcare provider right away.

Contraindications

Active, severe N. meningitidis infection.1

Patients not currently vaccinated against N. meningitidis, unless risk of delaying treatment outweighs risk of developing a meningococcal infection.1

Warnings/Precautions

Warnings

Serious, sometimes life-threatening or fatal meningococcal infections (e.g., sepsis, meningitis) reported.1 6

Do not initiate therapy in patients with unresolved, serious N. meningitidis infections or in those not immunized against N. meningitidis unless risk of delaying therapy outweigh risks of infection.1 (See Contraindications and also see Boxed Warning.)

Unvaccinated patients must receive an appropriate polyvalent meningococcal vaccine series at least 2 weeks prior to first dose of eculizumab and receive revaccination of booster doses thereafter according to current vaccination guidelines.1 5 6 (See Vaccinations under Dosage and Administration.) If urgent treatment with eculizumab is necessary in an unvaccinated patient, administer meningococcal vaccine as soon as possible.1 Vaccination can reduce, but does not eliminate, risk of meningococcal infection; cases of meningococcal septicemia reported in patients treated with eculizumab despite immunization.1 6 10 36

Prophylactic use of antibiotics (e.g., penicillin) also has been employed and is recommended by some clinicians;1 27 29 31 35 however, benefits and risks of antibiotic prophylaxis not established.1

Monitor closely for early manifestations of meningococcal infection during therapy.1 (See Advice to Patients.) Evaluate immediately if infection is suspected; discontinue therapy if serious infection requiring treatment occurs.1

Other Warning and Precautions

Infusion reactions requiring discontinuance of eculizumab not observed during clinical trials, but hypersensitivity or anaphylaxis possible with all therapeutic proteins.1 6

Monitor for infusion-related reactions; if manifestations of cardiovascular instability or respiratory compromise occur, interrupt infusion and initiate appropriate treatment.1

Eculizumab increases susceptibility to infections caused by encapsulated bacteria, particularly meningococcal infections.1 5 10 27 31 35 36 (See Boxed Warning.)

Also increases risk of S. pneumoniae and Hib infections in children; administer appropriate vaccinations.1 (See Vaccinations under Dosage and Administration.)

Use caution in patients with any systemic infection.1

Possible risk of serious hemolysis following discontinuance of therapy in patients with PNH.1 6 10 Monitor patients for ≥8 weeks after discontinuing therapy for manifestations of hemolysis.1

Possible return of thrombotic microangiopathic symptoms following discontinuance of therapy in patients with aHUS; monitor patients for ≥12 weeks after discontinuing therapy for manifestations of thrombotic microangiopathy (e.g., mental status changes, seizures, angina, dyspnea, thrombosis).1 22 28 32 In addition, the occurrence of 2 of the following laboratory changes or a repeat occurrence of any one of the changes may indicate the development of thrombotic microangiopathy: a decrease in platelet count by ≥25% compared with baseline or the peak platelet count during eculizumab treatment; an increase in Scr by ≥25% compared with baseline or the nadir value during eculizumab treatment; or an increase in serum LDH concentration by ≥25% from baseline or the nadir value during eculizumab treatment.1 Consider reinitiation of drug, plasma therapy, and/or supportive measures if manifestations of thrombotic microangiopathy recur after discontinuance of therapy.1

High risk of venous thrombosis (potentially life-threatening or fatal) in patients with PNH.4 8 18 20 Effects of withdrawing anticoagulant therapy in patients receiving eculizumab not established.1 Treatment with eculizumab should not affect concomitant anticoagulant management.1

As with all therapeutic proteins, there is a risk of immunogenicity with eculizumab.1 3 6 Antibodies to eculizumab, including some that were neutralizing, have been detected; no apparent relationship between the development of antibodies and clinical response.1

In patients with PNH, serum LDH concentrations may be used to monitor response to therapy (e.g., hemolysis, PNH erythrocytes).1 10 Following withdrawal of therapy, monitor serum LDH concentrations and other parameters to detect serious hemolysis.1 6 (See Complications Following Treatment Discontinuance under Cautions.)

In patients with aHUS, platelet counts, serum LDH concentrations, and Scr may be used to monitor the effects of eculizumab therapy as well as to monitor for signs of thrombotic microangiopathy.1 (See Complications Following Treatment Discontinuance under Cautions.)

Specific Populations

Category C.1

Not known whether eculizumab is distributed into human milk.1 (See Extent under Pharmacokinetics.) Caution if used in nursing women.1

Safety and efficacy for the treatment of PNH not established in children <18 years of age.1

Safety and efficacy for the treatment of aHUS has been established in children ≥2 months of age.1 Response and safety in these pediatric patients were similar to those in adults.1

Ensure that pediatric patients receive appropriate vaccinations for the prevention of N. meningitidis, S. pneumoniae, and Hib infections.1 (See Serious Meningococcal Infections and also see Other Infections under Cautions.)

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients.1

Common Adverse Effects

Patients with PNH: Headache,1 3 4 21 nasopharyngitis,1 3 4 back pain,1 3 21 nausea,1 3 4 21 fatigue,1 cough,1 1 herpes simplex infections,1 sinusitis,1 respiratory tract infection,1 constipation,1 myalgia,1 pain in extremity,1 influenza-like illness.1

Patients with aHUS: Hypertension, upper respiratory tract infection,1 diarrhea,1 headache,1 anemia,1 vomiting,1 nausea,1 urinary tract infection,1 leukopenia,1 insomnia,1 cough,1 pharyngolaryngeal pain,1 abdominal pain,1 fatigue,1 peripheral edema,1 pyrexia,1 vertigo,1 extremity pain.1

• Importance of patients fully understanding risks and benefits of therapy prior to initiation.1 21

• Risk of serious meningococcal infections and other systemic infections (e.g., S. pneumoniae, Hib infections).1 21

  Importance of immunization against meningococcal infections at least 2 weeks prior to initiation of therapy and revaccination or booster doses according to current guidelines while on therapy.1 6 21 Advise patients that vaccination may not prevent infection; importance of informing clinician immediately if manifestations of meningococcal infection (headache with nausea, vomiting, fever, stiff neck or back; temperature ≥39.4°C; fever with rash; confusion; severe muscle aches with flu-like symptoms; light sensitivity) develop.1 21

  Advise parents/caregivers of children with aHUS that their child should be vaccinated against S. pneumoniae and Hib infections prior to initiation of therapy.1

• Importance of informing patients with PNH that discontinuance of therapy may cause sudden hemolysis; importance of monitoring for hemolysis for at least 8 weeks following treatment discontinuance.1 21

  Importance of informing patients with aHUS that discontinuance of therapy may result in a worsening of disease symptoms or problems related to thrombotic microangiopathy.1

• Importance of patients carrying a patient safety card (describing symptoms requiring immediate medical attention) at all times during treatment and for 3 months following discontinuance of therapy because the risk of meningococcal infection may persist for weeks after the last dose is given.1 21

• Importance of women informing their clinicians if they are or plan to become pregnant or plan to breast-feed.1 21

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.1 21

• Importance of informing patients of other important precautionary information.1 21 (See Cautions.)

In the U.S.

• Soliris

Available Dosage Forms:

• Solution

Therapeutic Class: Blood Modifier Agent

Pharmacologic Class: Monoclonal Antibody

• It is used to treat a blood disease called paroxysmal nocturnal hemoglobinuria (PNH).
• It is used to treat a blood and kidney disease called atypical hemolytic uremic syndrome (aHUS).

• Tell all of your health care providers that you take this medicine (Soliris). This includes your doctors, nurses, pharmacists, and dentists.
• You may have more chance of getting an infection. Wash hands often. Stay away from people with infections, colds, or flu.
• Make sure you are up to date with all your vaccines before treatment with this medicine.
• Vaccines lower the risk of infections; they do not get rid of the risk of infections. Talk with the doctor.
• Have patient safety card with you at all times and for 3 months after drug is stopped.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• Some patients have very bad side effects during the infusion. Tell your doctor if you have any bad effects during the infusion.
• Some health problems may happen after this medicine (Soliris) is stopped. You will need to be watched closely for several weeks after you stop this medicine. Follow up with your doctor as you have been told. After stopping this medicine (Soliris), call your doctor right away if you have a change in how much urine is passed; dark urine; swelling, warmth, or pain in the leg or arm; chest pain or pressure; coughing up blood; trouble breathing; weakness on 1 side of the body, trouble speaking or thinking, change in balance, or change in eyesight; change in thinking clearly and with logic; any bruising or bleeding that is not normal; or seizures.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this medicine while you are pregnant.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

Soliris, a complement inhibitor, 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-dose 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.

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 and complement-mediated thrombotic microangiopathy (TMA) in patients with aHUS.

A genetic mutation in patients with PNH 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 aHUS, impairment in the regulation of complement activity leads to uncontrolled terminal complement activation, resulting in platelet activation, endothelial cell damage and thrombotic microangiopathy.

Pharmacodynamics

In the PNH 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)].

Pharmacokinetics

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.

A second population PK analysis with a standard 1 compartmental model was conducted on the multiple dose PK data from 57 aHUS patients receiving the recommended Soliris regimen in studies 1, 2 and 3. In this model, the clearance of Soliris for a typical aHUS patient weighing 70 kg was 14.6 mL/hr and the volume of distribution was 6.14 L. The elimination half-life was 291 h (approximately 12.1 days).

The clearance and half-life of eculizumab were also evaluated during plasma exchange interventions. Plasma exchange increased the clearance of eculizumab to 3660 mL/hr and reduced the half-life to 1.26 hours. Supplemental dosing is recommended when Soliris is administered to aHUS patients receiving plasma infusion or exchange [see Dosage and Administration (2.2)].

Dedicated studies have not been conducted to evaluate the PK of Soliris in special patient populations identified by gender, race, age (geriatric), or the presence of renal or hepatic impairment. Pediatric and adolescent patients (less than 18 years of age) and patients with renal impairment were included in the aHUS clinical studies [see Clinical Studies (14)]. Population PK analysis showed age, gender, race, and renal function do not influence the PK of eculizumab.

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

Other drugs may interact with eculizumab, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell your doctor about all your current medicines and any medicine you start or stop using.