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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. 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].

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.

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.

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.

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 and CLINICAL STUDIES].

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.

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:

• moderate to severe headache with nausea or vomiting
• moderate to severe headache and a fever
• moderate to severe headache with a stiff neck or stiff back
• fever of 103° F (39.4° C) or higher
• fever and a rash
• confusion
• severe muscle aches with flu-like symptoms, and eyes sensitive to light

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.

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.

Use in specific Populations

Pregnancy

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.

Labor and Delivery

No information is available on the effects of Soliris during labor and delivery.

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.

Pediatric Use

The safety and effectiveness of Soliris therapy in pediatric patients below the age of 18 have not been established.

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.

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